MD19 • Physicians and Physician Assistants 2019

Table of Contents

MD19 • Physicians and Physician Assistants 2019

How to Receive Credit

NetCE 10 Hour Course #98400 • Dizziness and Vertigo

98400 • Dizziness and Vertigo

1. INTRODUCTION

2. ANATOMY AND PHYSIOLOGY

3. EPIDEMIOLOGY

4. PERIPHERAL CAUSES OF DIZZINESS AND VERTIGO

5. CENTRAL CAUSES OF DIZZINESS AND VERTIGO

6. SYSTEMIC ETIOLOGIES

7. VESTIBULAR IMPAIRMENT, ANXIETY, AND PERCEPTION

8. POST-TRAUMA OR TOXIC EXPOSURE

9. ADVERSE DRUG EFFECTS

10. DIAGNOSIS: THE "TIMING AND TRIGGERS" WORKUP

11. CLINICAL MANAGEMENT

12. DIZZINESS AND FALLS PREVENTION IN OLDER PATIENTS

13. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

14. CONCLUSION

15. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #40942 • Acute Coronary Syndrome

40942 • Acute Coronary Syndrome

1. INTRODUCTION

2. OVERVIEW OF ACUTE CORONARY SYNDROME

3. DIAGNOSIS AND RISK STRATIFICATION

4. TREATMENT OF UA/NSTEMI

5. TREATMENT OF STEMI

6. DISCHARGE PLANNING AND SECONDARY PREVENTION

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 6 Hour Course #96441 • Suicide Assessment and Prevention

96441 • Suicide Assessment and Prevention

1. INTRODUCTION

2. EPIDEMIOLOGY OF SUICIDE

3. PATHOPHYSIOLOGY OF SUICIDAL BEHAVIOR

4. SUICIDE AND SPECIAL POPULATIONS

5. RISK AND PROTECTIVE FACTORS FOR SUICIDE

6. IMMINENT SUICIDE

7. SUICIDE ATTEMPTS

8. SCREENING AND ASSESSMENT OF SUICIDE RISK

9. MANAGEMENT OF SUICIDAL PATIENTS

10. SUICIDE PREVENTION

11. SUICIDE SURVIVORS: TREATMENT AND RESOURCES

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

MD19 • Physicians and Physician Assistants 2019

Mark Rose, BS, MA, LP

Lori L. Alexander, MTPW, ELS, MWC

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

MD19 • Physicians and Physician Assistants 2019

Expiration Date: 06/30/2021

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

98400 • Dizziness and Vertigo

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2018 NetCE, All rights reserved.

Dizziness is a nonspecific term used by patients to describe symptoms related to vestibular dysfunction, presyncope, disequilibrium, psychiatric disorders, and other etiologies. A primary complaint of dizziness accounts for 5.6 million clinic visits annually in the United States. Accurate diagnosis and effective treatment of dizziness is very important. Dizziness and vertigo in the elderly elevates risks for falls, the leading cause of disability and death from injury in this population. However, considerable practice variations exist in the management of dizziness and vertigo. This variance between guideline recommendations and clinical practice suggests an important role for educational intervention.

Table of Contents

98400 • Dizziness and Vertigo

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. ANATOMY AND PHYSIOLOGY

3. EPIDEMIOLOGY

4. PERIPHERAL CAUSES OF DIZZINESS AND VERTIGO

BENIGN PAROXYSMAL POSITIONAL VERTIGO

VIRAL OR BACTERIAL INFECTIOUS CAUSES

MÉNIÈRE DISEASE

BILATERAL VESTIBULOPATHY

VESTIBULAR PAROXYSMIA

5. CENTRAL CAUSES OF DIZZINESS AND VERTIGO

VESTIBULAR MIGRAINE

CEREBROVASCULAR ETIOLOGIES

STRUCTURAL ABNORMALITIES AND LESIONS

DEMYELINATING AND NEURODEGENERATIVE DISORDERS

PERSISTENT POSTURAL PERCEPTUAL DIZZINESS

MAL DE DÉBARQUEMENT SYNDROME

6. SYSTEMIC ETIOLOGIES

ORTHOSTATIC HYPOTENSION

DIABETES

CIGARETTE SMOKING

7. VESTIBULAR IMPAIRMENT, ANXIETY, AND PERCEPTION

SHARED CLINICAL FEATURES

ANXIETY, BALANCE, AND VESTIBULAR INTERACTIONS

DISRUPTED MULTISENSORY INTEGRATION

COGNITIVE FUNCTION

8. POST-TRAUMA OR TOXIC EXPOSURE

POST-CONCUSSIVE AND CERVICOGENIC VERTIGO

EXPOSURE TO TOXINS

9. ADVERSE DRUG EFFECTS

SIDE EFFECTS

OTOTOXIC DRUGS

10. DIAGNOSIS: THE "TIMING AND TRIGGERS" WORKUP

TRIAGE

TIMING

TRIGGERS

TARGETED EXAMS

ACUTE VESTIBULAR SYNDROME

EPISODIC VESTIBULAR SYNDROME

CHRONIC VESTIBULAR SYNDROME

11. CLINICAL MANAGEMENT

COMMON PHARMACOTHERAPIES

VESTIBULAR REHABILITATION

ANXIETY AND DIZZINESS

SPONTANEOUS ACUTE VESTIBULAR SYNDROMES

TRIGGERED EPISODIC VESTIBULAR SYNDROMES

SPONTANEOUS EPISODIC VESTIBULAR SYNDROMES

CHRONIC VESTIBULAR SYNDROMES

12. DIZZINESS AND FALLS PREVENTION IN OLDER PATIENTS

RISK FACTORS FOR FALLS IN THE ELDERLY

ASSESSMENT OF FALLS RISK

13. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

14. CONCLUSION

15. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

98400 • Dizziness and Vertigo

Education Category. Infection Control / Internal Medicine

Release Date. 10/01/2018

Expiration Date. 09/30/2021

Course Overview

Dizziness is a nonspecific term used by patients to describe symptoms related to vestibular dysfunction, presyncope, disequilibrium, psychiatric disorders, and other etiologies. A primary complaint of dizziness accounts for 5.6 million clinic visits annually in the United States. Accurate diagnosis and effective treatment of dizziness is very important. Dizziness and vertigo in the elderly elevates risks for falls, the leading cause of disability and death from injury in this population. However, considerable practice variations exist in the management of dizziness and vertigo. This variance between guideline recommendations and clinical practice suggests an important role for educational intervention.

Audience

This course is designed for physicians and nurses involved in the diagnosis, treatment, and care of patients with dizziness and/or vertigo.

Course Objective

The purpose of this course is to provide clinicians with the information necessary to appropriately diagnose and treat causes of dizziness and vertigo and improve patients' quality of life.

Learning Objectives

Upon completion of this course, you should be able to:

1. Identify models used to describe vertigo and dizziness.

2. Outline anatomy and physiology of structures involved in vestibular disorders.

3. List peripheral etiologies of vertigo.

4. Describe the clinical presentations of central etiologies of vertigo.

5. Discuss the causes and underlying pathophysiology of other dizziness/vertigo etiologies (e.g., trauma).

6. Devise a best practice, cost-effective diagnostic workup for patients presenting with dizziness and/or vertigo.

7. Apply diagnostic reasoning and appropriate clinical evaluation and management strategies to the differential diagnosis of dizziness and vertigo.

8. Compare and contrast pharmacotherapy agents that may be used to manage vertigo and dizziness.

9. Analyze the role of vestibular rehabilitation in the clinical management of dizziness/vertigo.

10. Describe other approaches to the management of specific dizziness etiologies.

11. Outline preventive approaches and safety considerations for patients with dizziness/vertigo.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Advances in knowledge of pathophysiology and newer imaging techniques have led to a paradigm shift in the classification system and diagnostic algorithm for managing dizziness and vertigo. With this newly identified connectivity between vestibular, balance, and anxiety disorders comes an enhanced ability to identify the stroke mimics of benign dizziness or vertigo. These and other breakthroughs are transforming the clinical care of patients with dizziness and vertigo complaints, connecting clinical syndromes previously considered unrelated, and expanding the range of effective treatment options for patients.

The modern paradigm for the clinical management of dizziness and vertigo was introduced by Drachman and Hart in a seminal 1972 publication [1]. Based on patient response to the question "What do you mean by 'dizzy?'," dizziness was classified into one of four types that best reflected the subjective descriptions of the symptoms [2,3]:

- Vertigo: Dizziness experienced as a definite sensation of movement or rotation in space

- Presyncope: A sensation of impending faint or loss of consciousness

- Disequilibrium: A sense of unsteadiness or loss of balance without head sensations

- Lightheadedness: Cannot be classed as vertigo, syncope, or disequilibrium

The Drachman-Hart model also suggested that vertigo had a vestibular cause, presyncope a cardiovascular cause, disequilibrium a neurologic cause, and nonspecific dizziness (lightheadedness) a psychiatric or metabolic cause [4]. In accordance with this framework, the character of symptoms reported by the patient determined the type (pathophysiology) of disorder and guided subsequent clinical evaluation, differential diagnosis, testing, and treatment [3].

By current standards, the Drachman-Hart model was based on weak evidence and developed in the absence of modern diagnostic imaging. In reality, patients often have difficulty describing their symptoms and may give conflicting accounts at different times. In one study, an estimated 62% of patients presenting to the emergency department (ED) with past-week dizziness selected more than one type of dizziness on a multi-response questionnaire, and 52% chose a different type when retested six minutes later [5,6]. As such, the character and quality of symptoms alone does not reliably predict the cause of dizziness or serve as a dependable guide to management.

Primary care providers see at least 50% of patients who seek medical attention for dizziness or vertigo. The differential diagnosis is large, and each common etiology accounts for 5% to 10% of cases [7]. The central task for providers is to distinguish benign from serious or life-threatening causes of dizziness and vertigo, such as posterior circulation stroke. Misdiagnoses are common and diagnostic testing can be costly, especially if too much reliance is placed on this outdated diagnostic paradigm [8].

These factors can make the medical care of patients with dizziness/vertigo seem daunting. However, a new diagnostic paradigm has replaced the standard symptom-based approach with an algorithm that streamlines the differential diagnosis, increases diagnostic accuracy for benign and dangerous causes alike, and reduces the use of expensive and unhelpful brain imaging [3,9].

A "timing and triggers" approach to patient history guides the diagnostic workup. The onset (timing), precipitating factors/events (triggers), evolution, associated symptoms and signs, and the context of dizziness episodes can be used to classify cases as triggered or spontaneous forms of episodic, acute, or chronic vestibular syndromes. Placement within one of six vestibular syndromes informs the differential diagnosis, targeted physical exams, and testing. Targeted exams are a range of procedures that assess for peripheral or central causes of dizziness/vertigo without using less accurate, expensive brain imaging [8].

2. ANATOMY AND PHYSIOLOGY

The labyrinth in each inner ear houses the systems that serve the functions of hearing (auditory) and balance (vestibular). The auditory system involves the cochlea, which transmits sound signals to the brainstem via the cochlear branch of the 8th cranial nerve. The vestibular system is comprised of the vestibular end-organs in the labyrinth, the vestibular nuclei in the brainstem and cerebellum, and the vestibular branch of the 8th nerve, which relays labyrinthine input to the vestibular nuclei. The 8th cranial nerve is also called the vestibulo-cochlear nerve [10,11,12].

Within each labyrinth are five vestibular end-organs (three semicircular canals and two otolith organs) that help maintain spatial orientation, postural control, and egocentric perception. Changes in angular and linear head acceleration, movement, and orientation to gravity are detected and signaled via the 8th nerve to brainstem and cerebellar circuits, through thalamic and spinal vestibular projections, and finally to the cerebral cortex [13,14,15].

This vestibular input, along with visual input from the eyes and proprioceptive input from peripheral sensory nerves (via the spinal cord), is relayed to the cerebral cortex, which integrates the sensory inputs and adjusts outgoing motor responses to maintain balance, posture, and gaze stabilization of retinal images (via the vestibulo-ocular reflex) [11,14,16].

Vertigo, dizziness, spatial disorientation, and disequilibrium can result from: asymmetrical vestibular inputs; vestibular hypofunction causing sensory mismatch in brain integration of sensory inputs; pathologies that affect any peripheral (e.g., inner ear, 8th cranial nerve) or central (e.g., vestibular nuclei and brainstem or cerebellar connections) vestibular system component; or a host of systemic, drug-effect, psychiatric, and physical trauma-related factors [14,16,17]. Around 80% of dizziness or vertigo cases are peripheral and 20% are central in origin [11,18].

3. EPIDEMIOLOGY

Dizziness is a general, umbrella term that encompasses symptoms of impaired spatial perception. Vertigo is often consolidated into the umbrella term dizziness due to highly variable descriptions of the experience. Dizziness/vertigo is the second most common complaint in the ambulatory setting and constitutes 25% of neurology outpatient referrals, 13% of ED neurology consultations, and more than 3 million ED visits annually [9,19]. The primary complaint of dizziness accounts for 5.6 million clinic visits annually in the United States. Vertigo is roughly two-thirds more common in women than men. Prevalence increases with age but varies depending on the etiology [20].

Benign paroxysmal positional vertigo (BPPV) is the most frequent vestibular disorder and the most common cause of peripheral vertigo, with a lifetime prevalence of 10% [21]. In the general population, the one-year prevalence rate is about 5% for vertigo, 1.6% for BPPV, and <1% for vestibular migraine [20]. An estimated 17% to 42% of vertigo cases are diagnosed as BPPV [22].

Peripheral causes of vertigo are usually, but not always, benign, while central vertigo often indicates a more serious pathology [18]. The negative impact of vertigo should not be underestimated; around 80% of patients report interruption in daily activities, including employment, from symptoms and the need for medical attention [20].

Dizziness, vertigo, and associated symptoms do not always fall easily into either a peripheral or central syndrome or disorder. Patients can have a dominant group of symptoms more closely tied to peripheral or central origin, while others will show a mix of both groups [23].

In the following discussion of pathophysiology, the diagnostic entities associated with dizziness or vertigo are mainly organized by peripheral or central origin and by shared etiologies or clinical features in a few instances. Throughout this course, "benign" is a pathologic and not a clinical descriptor; "benign" vestibular conditions can be intensely distressing for the patient.

4. PERIPHERAL CAUSES OF DIZZINESS AND VERTIGO

BENIGN PAROXYSMAL POSITIONAL VERTIGO

As indicated by the name, BPPV describes benign (not life-threatening or malignant) paroxysmal (comes in sudden, brief spells) positional (triggered by certain head positions or movements) vertigo [24]. It is characterized by rotational vertigo induced by head position changes, especially when extending or turning the neck, lying down, or rolling over in bed [21].

Epidemiology

As noted, BPPV is the most frequent vestibular disorder and the most common cause of peripheral vertigo, with a lifetime prevalence of 10% [21]. Women are more often affected than men, with a female-to-male ratio of 1.5–2.2 to 1 [22,25,26].

The most frequent age of onset is between the fifth and seventh decades of life. BPPV has an overall prevalence of 3.4% in persons older than 60 years of age and is present in 40% of geriatric patients seen for dizziness [27]. The incidence increases with age due to age-related degeneration of otolithic membrane [9]. The adverse impact on health and quality of life is more severe in older individuals, and BPPV is an important health concern in the elderly because it contributes to falls and associated morbidity and mortality [15,22].

With a 27% to 50% rate of spontaneous resolution, BPPV can be self-limiting or may persist to become a chronic recurrent disorder [15,22]. An estimated 85% of patients experience interrupted daily activities/lost days at work, 68% reduce their workload, 4% change their job, and 6% quit their job from the disruptive impact of BPPV [28].

The direct and indirect costs of BPPV are significant. Delayed diagnosis and treatment is frequent. It costs an average $2,000 to arrive at the correct diagnosis, and costs related to BPPV diagnosis alone approach $2 billion annually [22].

Only 10% to 20% of patients with BPPV seen by a physician receive recommended repositioning therapy. Before specialist referral, more than 65% of patients receive potentially unnecessary diagnostic testing or treatment, including magnetic resonance imaging (MRI) (70%), computed tomography (CT) (45%), electrocardiogram (41%), and medication therapy (53%). Delayed diagnosis and treatment of BPPV has cost and quality-of-life implications for patients and their caregivers [22,28].

Across disciplines, the practice variations in BPPV management are considerable, and medication treatment of BPPV varies substantially among primary care providers and across specialties [22].

Pathophysiology

The vestibular system includes three semicircular canals (or simply "canals") and two otolith organs (the saccule and utricle). The canals (posterior, lateral, and anterior) are positioned at right angles to each other to detect angular accelerations of the head. The canals are organized as functional pairs (left and right ear) in the same spatial plane; any rotation in that plane excites one pair member and inhibits the other [29,30]. The canals are filled with endolymph fluid and lined with sensitive hair cells to act like a gyroscope. Motion from head rotation induces endolymph movement in the canal oriented in the spatial plane, which stimulates hair cells, activates the ampulla (the motion sensor) and cupula, and sends sensory output to the brain via the vestibular nerve [15,29].

The saccule and utricle contain sensory epithelium and function to detect linear or translational acceleration forces (e.g., gravity, accelerating or braking a car) [15]. Hair cells in the saccule and utricle are embedded in a matrix of calcium carbonate crystals (otoliths). Deflection of otoliths by gravity stimulates or inhibits neuronal output from the attached hair cells [11].

Otoliths that dislodge and migrate into a canal are called otoconia. Endolymph fluid is usually non-reactive to gravity, but otoconia moves with gravity, causing inappropriate endolymph motion and hair cell stimulation and false signaling of head motion to the brain [24].

The brain receives and integrates peripheral sensory inputs. A false vestibular input conflicts with inputs from ocular, proprioceptive, and the unaffected vestibular systems. This causes a sensory mismatch in the brain integration, perceived as a spinning sensation (vertigo) normally lasting less than 60 seconds after cessation of head movement and inappropriate endolymph motion [24,31].

BPPV is subtyped by afflicted canal and mechanism. Posterior canal BPPV (85% to 95%) is the most common. Lateral canal BPPV (5% to 15%) is less common, likely because it self-resolves sooner. Anterior canal BPPV (<1%) is uncommon due to the orientation. Rare variants include multi-canal and bilateral multi-canal BPPV [15,22].

Otoconia contact abnormally stimulates the cupula, triggering vertigo and nystagmus. BPPV is subtyped as [21,32]:

- Canalolithiaisis: Head movements cause free-floating otoconia to stimulate the cupula

- Cupulolithiasis: Otoconia attach to the cupula, rendering it hypersensitive to linear acceleration and gravity

Canalolithiasis is much more common because the otoconia particulate mass required to exceed the symptomatic threshold is much lower than in cupulolithiasis (0.087 ug vs. 0.69 ug) [21,33].

Recurrence and Cardiovascular Risk Factors

Cardiovascular comorbidities are significantly associated with, and potentially important risk factors for, recurrent BPPV. In a nationwide study of 2,682 patients with BPPV (mean age: 59.3 years; 61% female), the prevalence of high blood pressure (55.8%), hypercholesterolemia (38.6%), diabetes (17.7%), and family history of cardiovascular disease (49.4%) were significantly higher than the national averages. A high percentage of patients had hearing loss (42.9%), tinnitus (41.2%), or both (26.8%). The presence of hypertension, dyslipidemia, and pre-existing cardiovascular comorbidities were significantly related to recurrent BPPV episodes, and the presence of diabetes or thyroid/autoimmune disease was also relevant [34].

VIRAL OR BACTERIAL INFECTIOUS CAUSES

Vestibular Neuritis

Vestibular neuritis, the second most common cause of vertigo (after BPPV), is a viral or post-viral inflammatory disorder affecting the vestibular portion of the 8th cranial nerve. It most commonly affects persons 30 to 50 years of age, and men and women are equally affected. New cases are more common in the spring and early summer [10,35]. Histopathologic nerve studies of these patients are consistent with a viral inflammatory etiology [15].

Vestibular neuritis is characterized by the sudden, acute onset of severe vertigo, nausea, vomiting, and gait instability without hearing loss, typically preceded by an upper respiratory tract infection [36]. The course and treatment of vestibular neuritis and viral labyrinthitis are similar; in both, the severity of acute vestibular symptoms can raise concerns of a central etiology, and the severity of vertigo, nausea, and vomiting reflects the severity of vestibular asymmetry [7,15,35].

Viral Labyrinthitis

Labyrinthitis is an inflammatory disorder affecting both the vestibular and cochlear components of the 8th cranial nerve, caused by local or systemic viral or bacterial infection resulting in acute loss of vestibular and hearing function [10]. Viral labyrinthitis, the most common form of labyrinthitis, often results from varicella zoster, influenza, or herpes simplex-1 infection [36]. Sudden sensorineural hearing loss in the affected ear is due to pan-labyrinthine inflammation affecting the cochlea. The estimated prevalence of sudden sensorineural hearing loss is 1 case in 10,000 persons; up to 40% of these patients have prominent vertigo or disequilibrium symptoms, and up to 15% of patients presenting with positional vertigo have viral labyrinthitis [36].

The acute onset of sudden sensorineural hearing loss with severe vertigo, nausea, and vomiting can leave patients bedridden until the symptoms subside. Upper respiratory tract infection precedes the onset of vestibulo-cochlear symptoms in up to 50%. Vertigo usually resolves after several days to weeks, due to spontaneous partial recovery of vestibular function and central compensation of residual unilateral vestibular deficits. Unsteadiness and positional vertigo can persist for months, and return of hearing usually coincides with return of vestibular function [35,36].

Herpes zoster oticus (Ramsay-Hunt syndrome) is labyrinthitis due to reactivation of a latent varicella zoster virus infection. Inflammation of the vestibulo-cochlear nerve causes vertigo and symptoms of deep, burning, auricular pain followed by eruption of a vesicular rash in the external auditory canal and concha. Symptoms usually improve after several weeks, but permanent hearing loss is common [15,20].

Bacterial Labyrinthitis

Viral labyrinthitis should be differentiated from the more dangerous disorder of bacterial labyrinthitis, which occurs through direct bacterial invasion (suppurative labyrinthitis) or passage of bacterial toxins and other inflammatory mediators into the inner ear (serous labyrinthitis) [36,37]. The bacteria that cause labyrinthitis are the same bacteria responsible for meningitis and otitis; potential bacterial causes include Streptococcus pneumoniae, Neisseria meningitidis, Streptococcus species, Staphylococcus species, Escherichia coli, and Mycobacterium tuberculosis [36].

Profound hearing loss, severe vertigo, ataxia, and nausea and vomiting are common symptoms of bacterial labyrinthitis. Suppurative labyrinthitis almost always results in permanent, profound unilateral hearing loss (or bilateral loss with meningitis). Serous labyrinthitis results in unilateral, high-frequency hearing loss in the affected ear. Regardless of etiology, bacterial labyrinthitis accounts for 35% of all adult-onset cases of hearing loss [36].

MÉNIÈRE DISEASE

Ménière disease is a clinical syndrome of cochlear and vestibular symptoms with a prevalence of 34 to 190 per 100,000 population, an age of onset ranging from the third to seventh decades of life, and a slight female predominance. The odds of Ménière disease are greater among older subjects, persons of European descent, and severely obese persons. Common comorbid conditions in Ménière disease include arthritis, psoriasis, gastroesophageal reflux disease, irritable bowel syndrome, and migraine [15,38].

The clinical features of Ménière disease are characterized by sudden, fluctuating, unilateral low-frequency sensorineural hearing loss with tinnitus and aural fullness and by spontaneous attacks of vertigo with nausea and vomiting, usually lasting hours [15]. Cochlear symptoms can occur between vertigo episodes. Vertigo is often more frequent in the first years of Ménière disease, but the clinical course is variable, with cochlear and vestibular symptoms taking years to develop in some patients. Bilateral sudden sensorineural hearing loss, migraine, BPPV, or systemic autoimmune disease develops in a subgroup of patients [38].

Evidence Based Practice Recommendation

The Bárány Society recommends that familial Ménière disease should be considered if at least one other relative (first- or second-degree) fulfills all the criteria of definite or probable Ménière disease.

http://www.jvr-web.org/images/55807-Lopez-Escamez.pdf

Last Accessed: September 18, 2018

Level of Evidence: Expert Opinion/Consensus Statement

Ménière disease is idiopathic but is also associated with endolymphatic hydrops, a process whereby accumulation of excess pressure within the inner ear endolymphatic system causes fluctuating hearing loss, episodic vertigo, tinnitus, and aural fullness (i.e., pressure and uncomfortable fullness in the ears) [39]. An interaction of genetics and environmental factors is thought to determine the onset of Ménière disease. While associated with the accumulation of endolymph in the cochlear duct and vestibular organs, endolymphatic hydrops per se does not fully account for the frequency of vertigo attacks, progression of hearing loss, and other clinical features of Ménière disease [38].

BILATERAL VESTIBULOPATHY

Bilateral vestibulopathy (also called bilateral vestibular loss) has both central and peripheral processes. The cardinal symptoms of bilateral vestibulopathy reflect the pathophysiology, including motion-dependent postural vertigo with unsteady gait and stance that worsens in darkness and on uneven ground (vestibulo-spinal impairment), and oscillopsia with blurred vision when walking or moving the head (vestibulo-ocular reflex impairment). Patients with bilateral vestibulopathy are typically symptom-free when sitting or lying [40,41].

The prevalence of bilateral vestibulopathy in the U.S. adult population is 28 per 100,000. The age distribution ranges from youth to old age, depending on etiology, and the mean age at diagnosis is 50 to 60 years. About 60% of patients develop bilateral vestibulopathy slowly and progressively; depending on etiology, 40% of patients have a clinical course marked by episodes of dizziness leading incrementally to bilateral loss of vestibular function [41,42].

Bilateral vestibulopathy involves atrophy of the hippocampus, with associated impairments in spatial memory and navigation. It is the most frequent cause of motion-dependent postural vertigo in older patients. The three most frequently identified causes of bilateral vestibulopathy are ototoxic aminoglycosides, bilateral Ménière disease, and meningitis, but most cases are idiopathic [40,41].

A connection between bilateral vestibulopathy and degenerative cerebellar diseases has been established. A syndrome comprised of bilateral vestibulopathy, sensory axonal polyneuropathy, cerebellar ataxia, and oculomotor disturbances accounts for around 30% of cases previously considered idiopathic [40,43]. Bilateral vestibulopathy can be severely debilitating but is partially reversible with vestibular rehabilitation. It is important for clinicians not to overlook this condition when assessing patients with complaints of dizziness/vertigo [44].

VESTIBULAR PAROXYSMIA

Vestibular paroxysmia is characterized by recurrent spontaneous vertigo attacks that are brief (several seconds up to one minute), and frequent (up to 30 per day) [45]. In one study, vestibular paroxysmia accounted for 3.7% of 17,718 consecutive outpatients in a multidisciplinary vertigo and balance disorders center. Men are affected twice as often as women, and the bimodal age of onset peaks in early childhood and again between 40 and 70 years of age [46].

Vestibular paroxysmia symptoms are triggered by neurovascular compression involving the anterior inferior cerebellar artery and the 8th cranial nerve. More than 95% of cases show vessel-nerve contact at the exit point of the 8th nerve from the brainstem, but the finding is nonspecific because it may be seen in healthy, asymptomatic adults as well [47].

5. CENTRAL CAUSES OF DIZZINESS AND VERTIGO

The vestibular nuclei and its connections to cerebellar, brainstem, spinal cord, and higher cortical structures comprise the central vestibular system. Dizziness, vertigo, ataxia, or disequilibrium can result from pathologies involving central vestibular structures, the most common of which are migraine-related vestibulopathy, brainstem strokes, head trauma, multiple sclerosis, and cerebellar degeneration [48].

Vertigo, vestibular dysfunction, and anxiety disorders are now recognized as co-factors, and the inter-relationship is substantial. Dizziness and vertigo are associated with diverse systemic disorders, trauma, and toxic exposures. Etiologies in psychiatric and systemic disorders are complex and diffuse.

Central abnormalities cause about 20% of dizziness complaints, and patients may present with disequilibrium or ataxia rather than vertigo. Dizziness/vertigo may be the sole presenting symptom of an impending cerebrovascular event origination in the brainstem or cerebellum [7]. In these presentations, distinguishing benign from potentially or imminently dangerous cerebrovascular causes has been the focus of extensive research effort.

VESTIBULAR MIGRAINE

Vestibular migraine is the most common central cause of recurrent spontaneous attacks of vertigo. "Vestibular migraine" is the preferred name for this disorder, because patients may experience a range of vestibular symptoms not limited to vertigo (e.g., dizziness, nausea, vomiting) [19,49].

Vestibular migraine accounts for 7% of patients seen in dizziness clinics and 9% of patients seen in headache clinics, but it remains underdiagnosed [49]. It is three times more common in women and occurs most often between 20 and 50 years of age. A family history of migraine is a risk factor, and vestibular migraine may involve a genetic susceptibility to enhanced excitability during sensory information processing, which induces interactions of vestibular and pain pathways [7,49].

Pain and vestibular sensory inputs converge in brainstem structures that modulate pain sensitivity and anxiety responses to pain and vestibular signaling. Vestibular stimulation activates some higher cortical regions involved in pain perception. Vestibular and pain pathways also overlap at brainstem and thalamic levels. This may explain, in part, the frequent clinical overlap of migraine (including vestibular migraine), balance, and anxiety disorders [49,50].

Vestibular migraine is a clinical diagnosis in which central and peripheral mechanisms arise from genetic and environment interactions. Mechanistic interactions cause excessive sensitivity to pain perception (e.g., headache, allodynia), hearing (e.g., phonophobia), vestibular stimulation (e.g., vertigo, motion sickness, visual vertigo), vision (e.g., photophobia), and sense of smell (e.g., osmophobia) [49,50,51].

Vestibular migraine is diagnosed primarily by patient history and exclusion of alternative causes; neurologic exams performed between episodes generally show normal findings [49]. The migraine may occur with episodic vertigo, chronic motion sensitivity, or other vestibular symptoms. Vertigo and motion sickness, with or without headache, is the common presentation, and some patients report mild, transient auditory symptoms of tinnitus, muffled hearing, or ear pressure [15,19].

CEREBROVASCULAR ETIOLOGIES

Patients with potentially serious or life-threatening stroke may present with vestibular symptoms without other focal neurologic signs. This acute presentation is linked to stroke involving one of several branches that supply the brainstem, cerebellum, or inner ear. Early differentiation is an area of intense research focus. Early recognition of isolated vertigo as a stroke sign allows specific intervention and secondary prevention. Misdiagnosis of stroke-related vertigo as a peripheral cause may result in significant morbidity or mortality, and overdiagnosis of stroke as peripheral vertigo leads to expensive and unnecessary workups, medication, and hospital admissions [52,53].

Vertebrobasilar Artery Territory (Posterior Circulation) Infarcts or Strokes

Around 20% of all ischemic events occur in the vertebrobasilar artery territory, with dizziness/vertigo the sole presentation in up to 33% of patients. Inferior cerebellar and small brainstem infarctions are an increasingly recognized cause of isolated vertigo, and transient isolated vertigo is a common manifestation of vertebrobasilar artery ischemia. Vertebrobasilar artery transient ischemic attacks (TIAs) typically last eight minutes on average [52,54]. Several syndromes are associated with TIAs, ischemia, or infarcts in vertebrobasilar artery territories (e.g., the brainstem, cerebellum) [48].

Numerous arteries extend from the posterior inferior cerebellar artery to supply the medial, lateral, and dorsal aspects of the medulla. Vertigo is more frequent in posterior inferior cerebellar artery strokes, and these are the most common cerebellar infarcts [55]. Dizziness/vertigo is one of the most common symptoms of cerebellar ischemic stroke. A large prospective study showed 11% of patients with cerebellar infarction had isolated vertigo, of whom 96% had an infarct in the medial branch of the posterior inferior cerebellar artery [56].

Medial Medullary Infarcts

Medial medullary infarctions usually cause a vertiginous labyrinthian syndrome that mimics peripheral vestibulopathy. Severe vertigo and nystagmus are prominent, and some patients describe feeling as if being pulled to the ipsilateral side by a magnet [53].

Lateral Medullary Infarcts

The vestibular nuclei are more vulnerable to ischemia than other structures in the posterior fossa, and ischemia of the lateral medulla (including the vestibular nuclei) may be a common mechanism of isolated vascular vertigo [52]. Wallenberg syndrome describes a lateral medullary infarction that presents with a range of focal neurologic signs.

Vestibulo-cerebellar symptoms/signs are almost always present, because lateral medullary infarcts involve the vestibular nuclei and their connections. The symptoms/signs include dizziness or disequilibrium; acute vertigo, nausea, or vomiting; ipsilateral facial pain, numbness, and ataxia (falling to the side of the infarct); and decreased contralateral pain and thermal sensitivity. The nystagmus has horizontal and rotational components [48,53,54].

Dorsal Medullary Infarcts

Less prevalent than medial or lateral medullary infarction, dorsal medullary infarcts typically cause dizziness/vertigo, imbalance, and ocular motor abnormalities. This is because the dorsal medulla also contains the vestibular nuclei and other structures that relay and process vestibular and ocular motor signals [57].

Anterior Inferior Cerebellar Artery Distribution

The anterior inferior cerebellar artery supplies the lateral pons and branches off to form the internal auditory artery, which irrigates the cochlea and vestibular labyrinth. The labyrinth is especially vulnerable to ischemia, because the internal auditory artery is an end-artery with minimal collaterals. Isolated acute audio-vestibular loss may herald an impending anterior inferior cerebellar artery territory infarction. Auditory artery occlusion causes loss of auditory and vestibular function [48,52].

Pontine syndrome is a partial pontine ischemia produced by anterior inferior cerebellar artery occlusion, characterized by vertigo, tinnitus, and hearing loss [48,54].

STRUCTURAL ABNORMALITIES AND LESIONS

Malformations or lesions that affect the vestibular system can cause dizziness or vertigo, as can any process that leads to acute vestibular asymmetry. The brain may adapt to this asymmetry over time to prevent or diminish vertigo, but imbalance may persist when vestibulo-cerebellar pathways are impacted. For example, sudden-onset vertigo is more likely with stroke, but less likely with a slow-growing acoustic neuroma (a vestibular tumor) because central adaptation to the asymmetry is gradual and imperceptible [15].

Superior Canal Dehiscence Syndrome

Superior canal dehiscence syndrome is caused by an abnormal opening (dehiscence) in the thin bony roof of the superior semicircular canal. This is thought to be related to congenital thinning of the temporal bone and occurs in 0.1% of the population. Development of the bony opening renders the membranous labyrinth unusually susceptible to changes in sound and pressure. In addition to dizziness and sensitivity to loud noises, patients with superior canal dehiscence syndrome experience autophony, whereby one's voice, breathing, or bodily sounds are excessively audible [58]. The dizziness/vertigo induced by sound and pressure stimuli can be associated with auditory symptoms of conductive or mixed hearing loss [59].

Chiari Malformation

A Chiari malformation is defined as descent of the cerebellar tonsils ≥5 mm past the foramen magnum [19]. This occurs when the lower part of the cerebellum does not fully migrate rostrally during fetal development. Compression of the cerebellum from this condition may lead to occipital headaches, vertigo, nystagmus, and ataxia in early childhood or later in life [15]. Patients also commonly describe occipital and neck pain provoked by physical activity or maneuvers that increase intracranial pressure [19].

Symptomatic Chiari malformations should be referred for neurosurgical evaluation and considered for posterior fossa decompression. Asymptomatic Chiari malformations can be discovered incidentally during MRI for dizziness from a different etiology. Asymptomatic patients should be spared the risks of surgery [19].

Acoustic Neuroma (Vestibular Schwannoma or Schwann Cell Tumors)

Acoustic neuromas are tumors of the vestibular portion of the 8th cranial nerve, diagnosed in roughly 3,000 cases annually. Acoustic neuromas can expand and compress surrounding structures along the brainstem, potentially leading to sensorineural hearing loss and vertiginous symptoms [20,60].

DEMYELINATING AND NEURODEGENERATIVE DISORDERS

Multiple Sclerosis

Multiple sclerosis (MS), an idiopathic demyelinating disorder of the central nervous system (CNS), is considered an autoimmune disease most likely caused by an autoantigen to a myelin protein [48]. MS has an annual incidence of 10 to 80 cases per 100,000 individuals in the United States and affects twice as many women than men [60].

CNS demyelinization usually occurs in the white matter, where plaque formation disrupts signal conduction and leads to symptoms [48]. Demyelinating plaques that develop in central vestibular pathways may cause recurrent episodes of vestibular symptoms, especially during illness and with heat exposure (Uhthoff phenomenon). The plaques may be visible on MRI [19,20].

Vertigo is the presenting symptom at onset in 5% of MS cases, and more than 50% of patients present with vertigo at some point in the disease course. MS can mimic an 8th cranial nerve lesion when plaque develops in the entry of the nerve root in the brainstem to produce vertigo and horizontal nystagmus [48].

MS may present with dizziness, vertigo, or imbalance, especially with brainstem or cerebellum lesions that affect the vestibular system; these lesions may also result in nystagmus, ataxia, slurred speech, and diplopia. Despite the increased risk of CNS vertigo in patients with MS, non-MS (peripheral and central) causes (e.g., BPPV, vestibular migraine) can co-occur [15].

Parkinson Disease and Parkinson-Plus Syndromes

Dizziness may be a manifestation of many neurodegenerative disorders. At presentation, patients with Parkinson disease may describe the shuffling or festinating gait as being "dizzy" or "off balance." Medications such as levodopa or dopamine agonists (e.g., pramipexole, ropinirole) may cause orthostatic hypotension, and hence presyncopal dizziness [19].

The Parkinson-plus syndromes (e.g., multiple system atrophy, dementia with Lewy bodies) often cause many symptoms that are construed as "dizziness." Multiple system atrophy causes dysautonomia (causing orthostatic presyncope or syncope), vertigo, nystagmus (causing oscillopsia), and/or cerebellar findings (leading to gait ataxia). Progressive supranuclear palsy often presents with falls and complaints of imbalance; loss of downgaze often causes imbalance when descending stairs [19].

Cerebellar Vertigo Syndromes

Neurodegenerative and hereditary diseases of the cerebellum often lead to postural vertigo, gait disorders with ataxia, and cerebellar oculomotor disorders such as saccadic dysmetria, gaze saccades, gaze nystagmus, and downbeat nystagmus [61].

Episodic ataxia type 2 is a rare but important disorder to identify because the random attacks of vertigo, ataxic gait, and slurred speech lasting minutes to days often respond dramatically to acetazolamide. The onset of recurrent episodes may occur in childhood or early adulthood, but the condition is often undiagnosed into late adulthood. This disorder is due to a voltage-sensitive calcium channel mutation [15].

PERSISTENT POSTURAL PERCEPTUAL DIZZINESS

Persistent postural perceptual dizziness (PPPD) develops when a precipitating condition (typically an acute vestibular event, vestibular migraine, panic attacks, or anxiety with prominent dizziness) occurs in individuals with a maladaptive behavioral response to the acute symptoms [62]. In this way, PPPD is a new diagnostic entity that bridges previous knowledge gaps by connecting persistent non-vertiginous dizziness, perceptual hypersensitivity, and chronic anxiety [15,62].

PPPD may be a highly prevalent cause of chronic non-vertiginous dizziness. The population and primary care prevalence is not yet known, but the female-to-male ratio is 5:1. PPPD symptoms are often worsened by sleep deprivation and stress but not by head motion to the degree seen with most vestibular disorders [15,62].

The central etiology relates to behavioral factors, neurotransmitter function, and other probable CNS mechanisms [15]. Brain imaging of patients with PPPD shows reduced connectivity in multisensory vestibular processing and spatial cognition, with increased connectivity between visual and emotional processing. Dizziness burden, anxiety, and depression correlate with connectivity in clinically relevant brain regions [63]. PPPD may linger following minor head injury and become entwined with other symptoms of post-concussive syndrome [15].

MAL DE DÉBARQUEMENT SYNDROME

A transient experience of ''sea legs'' after returning to land from riding on a boat is not uncommon, but in mal de débarquement syndrome it persists for weeks, months, or years. Mal de débarquement syndrome is an uncommon vestibular disorder in which a sense of rocking first appears soon after disembarking and is most common in women. Travel by aircraft or automobile can also trigger the persistent unsteadiness. Symptoms typically abate during passive motion (e.g., a boat or car ride) but resume when motion ceases. The cause is unknown, but it may be a disorder of the vestibular velocity storage mechanism with a limited adaptive ability [15,62].

6. SYSTEMIC ETIOLOGIES

Dizziness and vertigo are associated with systemic diseases or conditions as symptoms, comorbidities, risk factors, or shared pathophysiologic pathways. These most commonly involve hemodynamic (orthostatic hypotension), metabolic (diabetes), cigarette smoking, and cardiovascular origins.

ORTHOSTATIC HYPOTENSION

Orthostatic hypotension is typically defined by a sustained decline in blood pressure of at least 20 mm Hg systolic or 10 mm Hg diastolic within three minutes of standing, with symptoms of lightheadedness or presyncope on arising. Vertigo is a common and under-appreciated symptom [8].

Orthostatic hypotension is common in older people and a frequent complication of (excessive) hypertensive medication. Such patients experience postural dizziness without documented syncope based on transient reductions in cerebral blood flow. Orthostatic hypotension may occur 5 to 30 minutes after remaining asymptomatic in the upright position, or when orthostatic vital signs have been normal. It may be missed as a cause of periodic syncope or presyncopal dizziness [15].

DIABETES

Vestibular dysfunction is a complication of type 2 diabetes, with reported rates 70% higher compared with age-matched controls. Both central and peripheral vestibular dysfunction are observed in type 1 and type 2 diabetes. Hypertension mediates 42% of the association between type 2 diabetes and BPPV, suggesting that hypertension provides the mediating pathway for diabetes' impact on the vestibular system [177].

CIGARETTE SMOKING

In one study, the association between peripheral vestibular disorders and smoking was examined in patients (mean age: 65.3 years) treated for hypertension, dyslipidemia, or diabetes in primary care and followed over one year for new peripheral vestibular disorder events [64]. Compared with never-smokers, the risk of new-onset peripheral vestibular disorder was 2.22 times greater for ever-smokers and 2.70 for all ever-smokers with ≥30 pack-years. Compared with male never-smokers, the risk of new onset peripheral vestibular disorder was 4.41 greater for male ever-smokers with ≥30 pack-years. There were too few female heavy smokers to compare against female never-smokers [64].

7. VESTIBULAR IMPAIRMENT, ANXIETY, AND PERCEPTION

Clinically relevant vestibular system interactions with traumatic stress, depressive disorders, and other psychiatric disorders have been described. However, vestibular-anxiety interactions are the most extensively studied and compelling and will be the focus of this section.

Anxiety disorders account for 8% to 10% of cases with vestibular symptoms as primary complaints [65]. In patients presenting with dizziness concerns, the rates of panic disorder are 5 to 15 times greater than the general population. Patients with panic disorder frequently experience significant dizziness and often demonstrate vestibular dysfunction [66].

The high co-occurrence of vertigo and anxiety has been described since antiquity [51]. By the late 1800s, dizziness and vertigo, anxiety, autonomic arousal, appraisal of spatial orientation, and threat assessment were appreciated as core contributors to agoraphobia; otologic disease was found to precipitate agoraphobia in patients with anxiety. As otology, neurology, and psychiatry matured into separate specialties in the early 20th century, agoraphobia became a psychiatric disorder and lost its spatial and motion context [62,67].

While traditional medical teaching describes a narrow range of vestibular system functions (e.g., gaze stability, balance) and dysfunctions (e.g., dizziness, unsteadiness, vertigo), vestibular involvement in brain processes beyond balance, spatial orientation, and gait is established. The inter-relationship of anxiety and balance disorders is being rediscovered more than a century later [68,69,70].

Increasingly demonstrated is the extent of multi-directional connectivity and interaction between threat/anxiety, vestibular, visual, and somatosensory systems, and how this helps explain the shared pathophysiology, clinical features, and prevalent comorbidity [71]. As such, it is important to assess for, and treat when present, anxiety disorders, cognitive impairment, and perceptual disturbances in patients with dizziness/vertigo complaints [50,68,69]. The suggestion is made that dichotomous thinking (structural disease vs. "emotional issues") should be discarded in order to effectively assess vestibular, psychiatric, and perceptual dysfunction. Each of these domains should be addressed simultaneously for favorable treatment outcomes [72].

SHARED CLINICAL FEATURES

Patients with vestibular or balance disorders often have anxiety symptoms. Likewise, patients with anxiety disorders often show vestibulo-ocular and/or peripheral vestibular dysfunction [73]. Vestibular and balance abnormalities are especially common in panic disorder with agoraphobia [70].

Chronic anxiety and anxiety disorders may be causes or complications of vestibular symptoms or disorders. These psychiatric disorders affect 30% to 50% of patients who seek specialist care for vestibular symptoms, and they adversely affect the treatment outcomes of patients with vestibular disease, especially when unrecognized [62,71]. Vestibular function is linked to emotional states through complex bidirectional interactions; vertigo worsens emotional symptoms, and emotional states can amplify perceptions of vertigo or disequilibrium [69].

ANXIETY, BALANCE, AND VESTIBULAR INTERACTIONS

Anxiety can impair ocular motor reflexes and gaze control, which may contribute to visual and visual-vestibular syndromes. Anxious states can amplify a normative gaze bias toward potentially threatening stimuli in the visual field, which, in patients with social anxiety disorder, may drive hypervigilance-avoidance gaze patterns. The impairing effect of anxiety on gaze control reduces gaze stability on visual targets, which may underlie dizziness and visual symptoms in PPPD [73,74].

Exposure to heights reflexively increases body sway in normal subjects by reducing visual feedback to body sway (in the absence of motion). Body sway is more pronounced in subjects with height phobia, and anxiety-related gaze diversion may increase gait instability in patients with fear of falling [74,75].

Space-motion discomfort describes symptoms of uneasiness over spatial orientation and hyperawareness of motion stimuli. In affected individuals, space-motion discomfort is triggered by movement in visually rich environments and exposure to moving or patterned objects while stationary. It is especially prevalent in patients with panic disorder and agoraphobia; persons with panic symptoms often become destabilized under conflicting sensory conditions. Visual vertigo and other situation-specific interactions between balance and anxiety may be part of a broader space-motion discomfort profile [62,73,76].

DISRUPTED MULTISENSORY INTEGRATION

The vestibular system maintains equilibrium through vestibular spinal reflexes, stabilizes visualization through the vestibular-ocular reflex, and contributes to spatial orientation [77]. Accurate perception of gravity and maintenance of spatial orientation, balance, and gait rely on brain integration of visual, vestibular, proprioceptive, and somatosensory signals and cognitive processes [78].

The brain normally resolves mismatched sensory information by updating and realigning the internal spatial representation of the body with the surrounding space. Impairment of one sensory signal is compensated by reweighting of intact sensory inputs [62,77]. Unsuccessful reweighting impairs multisensory integration, leading to incongruity between visual and vestibular information and visual-vestibular sensory mismatch. This can elicit an erroneous cortical representation of the body within the surrounding space, producing spatial disorientation, anxiety, dizziness, balance problems, and increased risk of falls [62,77,78,79].

Visual Dependence

Visual dependence is an over-reliance on visual information to maintain spatial orientation, which compensates for vestibular dysfunction that impairs multisensory integration. Space-motion discomfort, a prominent feature resulting from the visual-vestibular conflict, may cause symptoms of imbalance, discomfort, anxiety, or phobic avoidance in situations where moving, complex, or conflicting visual environments trigger intense dizziness/vertigo symptoms [70,79].

Depersonalization and Derealization

Depersonalization and derealization are perceptual abnormalities, described primarily from the psychiatric perspective for more than a century. Depersonalization (feeling detached, numb from one's emotions, experiences), derealization (objects, people, and surroundings experienced as unreal, distant, artificial, lifeless), and intact reality testing are symptoms of depersonalization/derealization disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [80,81]. The DSM-5 also lists derealization and depersonalization as potential panic attack symptoms in the diagnostic criteria for panic disorder [81].

Trauma history and anxiety disorders are prevalent co-factors and antecedents of depersonalization/derealization. Phencyclidine or cannabis use can trigger acute symptoms [82]. Derealization symptoms are particularly distressing, if not profoundly intolerable; an anxious or panic response can amplify depersonalization/derealization symptoms, creating a vicious cycle [80].

Patients diagnosed with depersonalization/derealization disorder have high rates of past-year inpatient hospitalization (25.6%) and ongoing outpatient psychotherapy (40.4%). Depersonalization/derealization disorder has been described as highly chronic, severely underdiagnosed, and often refractory to pharmacotherapy and psychotherapy [83].

The psychiatric perspective is important, but inadequate by failing to consider recent evidence implicating vestibular dysfunction, impaired multisensory integration, and sensory mismatch in depersonalization/derealization [84,85]. Vestibular inputs provide a frame of reference within which spatial information from other senses is interpreted. Depersonalization/derealization associated with vestibular dysfunction is a consequence of a sensory mismatch between disordered vestibular input and other sensory signals of orientation, creating a misleading frame of reference and impaired bodily representation in the cortex. This leads to a perception of disembodiment and other "unreal" perceptions [84,85,86].

Stimulation of semicircular canals or otoliths can provoke depersonalization/derealization symptoms in healthy volunteers without a history of depersonalization/derealization [86]. However, depersonalization/derealization symptoms in vestibular patients with anxiety are more frequent, more severe, and qualitatively distinct from symptoms in patients without anxiety. Anxiety is essential to the appearance and intensity of depersonalization/derealization symptoms in vestibular patients [87].

Out-of-Body Experiences

Out-of-body experiences are states in which the individual experiences the center of awareness as located outside his or her physical body, with the sensation of seeing the environment from this elevated vantage point. Persistent vestibular dysfunction disrupts the integration of visual, somatosensory, and vestibular signals. Perceptual incoherence, a byproduct of the resultant visual-vestibular mismatch, can produce an out-of-body experience, with anxiety a significant co-factor in out-of-body experience etiology. In non-dizzy persons, out-of-body experience is associated with depersonalization or derealization symptoms [88].

COGNITIVE FUNCTION

Vestibular input activates a broad neural network in the cortex for visuospatial processing and memory. Vestibular function is strongly linked to visuospatial ability—how the mind organizes and understands two- and three-dimensional space. Impaired vestibular input can fundamentally change one's mental representation of, and awareness of one's position in, three-dimensional space [69].

Vestibular dysfunction is also implicated in impaired attention, cognitive processing ability, memory, and executive function [69]. This is especially relevant in the elderly, for whom cognitive impairment from vestibular dysfunction is broader and more diffuse. It should be considered in any older patient with dizziness or vertigo [89].

8. POST-TRAUMA OR TOXIC EXPOSURE

POST-CONCUSSIVE AND CERVICOGENIC VERTIGO

Patients with post-concussive syndrome or cervicogenic dizziness following a whiplash can experience chronic dizziness with headache, insomnia, cognitive symptoms, or mood lability [62].

Post-Concussion Syndrome

In the United States, there are approximately 3.8 million sports-related concussions annually in adolescents and adults. Concussion, the mildest form of traumatic brain injury (TBI), is a transient functional disorder caused by direct trauma, rapid acceleration-deceleration of the head, or blast forces. Post-concussion syndrome persists beyond three months in up to 20% of affected individuals [90].

Headache and dizziness are common symptoms. Other symptoms include light and sound sensitivity, nausea, tinnitus, cognitive dysfunction (mental fog), problems with visual focus, sleep changes, depression, anxiety, and irritability. Dizziness may be due to the direct CNS effects of the trauma (e.g., axonal injury, other microstructural damage), vestibular migraine, or neuropsychiatric disorders (e.g., anxiety, depression, post-traumatic stress disorder). Post-concussion BPPV is not uncommon. A detailed history and examination are crucial when assessing dizziness in these patients, because treatment should address the underlying etiology [91,92].

Mild TBI

Balance disorders, migraine, and anxiety are also components of mild TBI that appear following exposure to blunt-force or blast trauma, along with symptoms of headache, nausea, vomiting, dizziness/balance problems, fatigue, sleep disturbances, and difficulty with memory or concentration [90,92]. Dizziness and headache are reported in more than 70% of cases presenting acutely or chronically post-exposure; vertigo emerges sub-acutely. Other significant sequelae are hearing loss, emergent and delayed post-traumatic balance disorders, and chronic migrainous disorders without radiologic evidence of damage, often accompanied by tinnitus and sensitivity to light or sound [50].

Patients with chronic (at least six months) post-traumatic head injury vestibular symptoms (e.g., imbalance, dizziness) show high rates of multiple peripheral and central vestibular disorders. Despite expert neuro-otologic management, 20% of patients have persistent vestibular symptoms at two years. Treatment-resistant vestibular symptoms in these patients may result from brain trauma-induced impairment of brain plasticity-mediated repair mechanisms [93].

Cervicogenic Vertigo

Cervicogenic dizziness is characterized by imbalance, unsteadiness, disorientation, neck pain, limited cervical range of motion, and headache. It is closely related to changes in cervical spine position or cervical joint movement. Common etiologies are post-whiplash injury and inflammatory, degenerative, or mechanical cervical spine dysfunction. The cause of imbalance, unsteadiness, and disorientation symptoms is suggested to involve pain, faulty cervical proprioceptive inputs, and disrupted signaling from upper cervical proprioceptor to vestibular nuclei [94].

Cervicogenic dizziness is diagnosed after mimics are ruled out, including central and peripheral vestibular disorders, vestibular migraine, labyrinthine concussion, cervical arterial dysfunction, and whiplash-associated disorder [94].

EXPOSURE TO TOXINS

Lead or mercury exposure can be ototoxic and may cause vertigo through temporary or permanent damage to the inner ear or auditory nerve [95].

9. ADVERSE DRUG EFFECTS

Dizziness or vertigo can occur as a direct side effect of medication that resolves after discontinuation without cochleo-vestibular damage, or it may develop (and persist) secondary to cochleo-vestibular damage (ototoxicity).

SIDE EFFECTS

The list of drugs that may cause vertigo or dizziness is extensive and diverse. Medications consistently associated with dizziness include the antihypertensive drugs amlodipine and hydrochlorothiazide; the antibiotics ciprofloxacin, amoxicillin, and clavulanic acid; pantoprazole (a proton pump inhibitor); aripiprazole (an atypical antipsychotic); and atazanavir (a protease inhibitor). Selective serotonin reuptake inhibitors (SSRIs) such as paroxetine and sertraline can induce vertigo or dizziness as side effects or with abrupt cessation; mirtazapine may cause dizziness side effects [95].

Antiepileptic drugs in particular are linked to adverse effects on auditory or vestibular systems that may be reversible or irreversible. Even at therapeutic dose ranges, long-term treatment with oxcarbazepine, carbamazepine, lamotrigine, phenytoin, valproate, gabapentin, or vigabatrin may result in auditory, central, and/or peripheral vestibular dysfunction [96].

OTOTOXIC DRUGS

Ototoxic drugs can damage cochleo-vestibular structures, which may result in hearing loss, tinnitus, dizziness, or disequilibrium [97]. Cochlear damage can present acutely as tinnitus. Early hearing loss, which patients may not recognize, manifests in the highest frequencies (>4,000 Hz). With progression, the lower frequencies are affected, and patients may become profoundly deaf if the drug is continued. Stopping the drug early, before extensive damage, may prevent further loss. Partial recovery of auditory thresholds is possible, but the loss is usually permanent [97,98].

Vestibular toxicity typically includes imbalance and visual symptoms. As with bilateral vestibulopathy, imbalance is worse in the dark or situations in which footing is uncertain; oscillopsia occurs when the head is moving. Patients do not present with nystagmus or vertigo complaints, because vestibulotoxicity is bilateral [97].

Ototoxicity is linked to more than 100 drug classes. The best-known and most ototoxic are aminoglycosides, amiodarone, macrolides, vancomycin, loop diuretics, antineoplastic agents, salicylates, and antiseptics.

Aminoglycosides

Aminoglycosides are the most vestibulotoxic of all ototoxic drugs. The introduction of streptomycin in 1944 for treatment of tuberculosis brought ototoxicity to clinical attention, as a substantial number of treated patients developed irreversible cochleo-vestibular dysfunction [97,98].

The aminoglycosides remain widely used and differ in cochleo-vestibular toxicity. Kanamycin, amikacin, neomycin, and dihydrostreptomycin are preferentially cochleotoxic. Gentamicin affects both cochlear and vestibular systems but is primarily vestibulotoxic, as are streptomycin, tobramycin, and netilmicin [97,98].

The onset or progression of hearing loss can occur long after cessation of treatment, because aminoglycosides are cleared more slowly from inner ear fluids than from serum. Patients should be monitored for vestibulotoxic effects up to six months after discontinuation [97,98].

Amiodarone

Amiodarone is a widely used antiarrhythmic drug. Reports of amiodarone-induced vertigo and gait instability followed its introduction in the 1980s, and the drug was first implicated in bilateral vestibulopathy causality in 2017. The prevalence of bilateral vestibulopathy is as high as 81 per 100,000. Most cases are idiopathic, and amiodarone may account for a substantial proportion of bilateral vestibulopathy with unexplained causation [99].

Macrolides

Erythromycin has been sporadically linked to reversible ototoxicity in patients with ototoxic risk factors. Azithromycin and clarithromycin have also been suggested as possibly ototoxic [97].

Vancomycin

Vancomycin is a glycopeptide antibiotic introduced in the 1950s and commonly used for efficacy in methicillin-resistant staphylococcal infections. Ototoxicity is reported in patients with other risk factors, but vancomycin monotherapy at therapeutic doses has not shown ototoxicity [97].

Loop Diuretics

Loop diuretics are used for treating congestive heart failure, renal failure, cirrhosis, and hypertension. The most effective and widely used (i.e., ethacrynic acid, furosemide, and bumetanide) can cause ototoxicity [97].

Antineoplastic Agents

Antineoplastic agents most associated with ototoxicity are the platinum-based compounds cisplatin and (to a lesser extent) carboplatin. Ototoxicity and nephrotoxicity are dose-proportional with both compounds [97].

Salicylates

Salicylate (aspirin) can produce tinnitus and a generally reversible flat sensorineural hearing loss at low doses, especially in elderly patients [97].

Antiseptics

Some antiseptics used for surgical preparation are ototoxic. Povidone-iodine is safe for middle ear surgeries. However, chlorhexidine is toxic if it reaches the inner ear and should not be used, and VoSol and Gentian violet also show ototoxicity [100].

10. DIAGNOSIS: THE "TIMING AND TRIGGERS" WORKUP

As mentioned, the prevailing clinical model in dizziness and vertigo is being replaced by the "timing and triggers" approach to streamline the differential diagnosis, increase diagnostic accuracy, and reduce unnecessary imaging tests and misdiagnosis.

Publications have brought into focus the misdiagnosis of patients with stroke who present with isolated dizziness. The "timing and triggers" approach is shown to reduce this highly concerning problem largely resulting from [8]:

- Over-reliance on the symptom quality approach

- Lack of familiarity with key physical exam findings

- Overweighting traditional stroke risk factors for patient screening (e.g., age, vascular risk factors) and not considering stroke in younger patients

- Over-reliance on CT

The "timing and triggers" approach departs from the Drachman-Hart model by de-emphasizing patient descriptions of symptom quality, dropping presyncope and lightheadedness as dizziness and vertigo classes, and limiting use of the vague term "lightheadedness" [2,7]. The term "dizziness" is used as a generic descriptor for disturbed balance or spatial orientation, vertigo, lightheaded, spinning, rocking, and others.

Accurate diagnosis is an essential precondition for effective treatment of dizziness and vertigo, best ensured by defining the rapidity of onset, the context, associated symptoms, intermittent or persistent nature of dizziness, and triggers of intermittent symptoms during patient history-taking. This is called the "timing and triggers" diagnostic workup. The workup is structured using the algorithm Triage-TiTrATE-Test [8,37,101]:

- Triage: Identify dangerous causes by noting the presence of prominent associated symptoms, abnormal vital signs, altered mental status, or ancillary test results.

- Timing: In the history of presenting illness, classify the pattern of dizziness attacks as episodic, acute, or chronic in duration.

- Triggers: In the history and review of systems, seek an underlying pathophysiologic mechanism by searching for obvious triggers or exposures.

- Targeted exam: Differentiate benign from dangerous causes within a timing-trigger category by using specific exam findings, emphasizing a targeted eye movement exam.

- Test: Choose the best laboratory or imaging test when clinically relevant uncertainty remains about a dangerous cause that has not been ruled out.

The timing and triggers history of the TiTrATE algorithm divides patients into six vestibular syndrome categories [8,37]:

- Acute vestibular syndrome (AVS)

- Postexposure (traumatic/toxic) (t-AVS)

- Spontaneous (s-AVS)

- Episodic vestibular syndrome (EVS)

- Triggered (t-EVS)

- Spontaneous (s-EVS)

- Chronic vestibular syndrome (CVS)

- Context-specific (t-CVS)

- Spontaneous (s-CVS)

In this context, "vestibular" refers to vestibular symptoms and not etiology. Vestibular symptoms include vertigo, dizziness, nausea, vomiting, and nystagmus [49].

The large differential diagnosis of potential dizziness etiologies is daunting to many clinicians. Triage-TiTrATE-Test greatly streamlines this process such that every forward step eliminates potential etiologies, substantially narrows the range, and by the final step, an accurate diagnosis is already evident or confirmed by referral for specialized testing [8]. This differential diagnosis process has been referred to as a funnel approach [37].

TRIAGE

Some patients with a primary symptom of dizziness have obvious associated symptoms (e.g., gastrointestinal bleeding) or context (e.g., new antihypertensive medications, anticonvulsant toxicity), abnormal vital signs, altered mental status, and/or ancillary test results that usually point to a likely diagnosis. These potential medication, toxicity, metabolic, cardiac, or psychiatric etiologies of dizziness are examined and patients are treated or referred for further evaluation as needed [10,37].

Other dizziness, medical, and major neurologic etiologies lack prominent associated features, but can be ruled out by assessing [20]:

- Neurologic history

- Recent viral or bacterial infection

- Patient medication list

- Social history for alcohol and substance use

- Psychiatric history

Important associated symptoms to note include headache, hearing loss, tinnitus, nausea and vomiting, impaired vision, focal weakness, and difficulty walking. The severity of impairment should be assessed by asking about impact on work, driving, and recreational and social functioning [11].

Review of systems should seek symptoms of causative disorders, including upper respiratory infection symptoms (inner ear disorders); chest pain and palpitations (cardiovascular disease); dyspnea (pulmonary disease); dark stools (anemia from GI blood loss); and weight change and heat or cold intolerance (thyroid disease) [11]. Past medical history should note recent head trauma (usually obvious by history), migraine, diabetes, heart or lung disease, and regular or daily drug and alcohol use. Identify all current medications, including recent changes in drugs, dosages, or both [11].

After major medical and other etiologies are ruled out, patients with dizziness or vertigo, with or without associated headache, otologic, autonomic, or balance symptoms, should receive a timing and triggers evaluation [37].

TIMING

Timing refers to the onset, duration, and evolution of the dizziness attacks. Narrow the differential diagnosis by classifying the pattern of dizziness attacks as episodic, acute, or chronic in duration by defining the following [102]:

- Onset of dizziness attacks: Sudden or gradual and ill-defined

- Duration of dizziness attacks (minimal and maximal): Seconds to minutes, several minutes to hours, or several hours to days

- Evolution of dizziness attacks:

- Episodic dizziness lasting seconds to minutes, several minutes to hours, or several hours to days

- Acute with symptoms lasting days to weeks

- Persisting symptoms more than three months (chronic)

TRIGGERS

Almost all patients with vertigo feel worse with head movements. The critical distinction is whether head movements trigger (symptoms appear only when provoked by movements) or exacerbate (movements worsen pre-movement vertigo) symptoms [8,20].

Head movement usually exacerbates dizziness/vertigo of any vestibular cause (benign or dangerous, central or peripheral), but the worsened dizziness is often conflated with a triggered peripheral cause, potentially missing a serious or life-threatening central etiology [6,8,37].

Explicitly assess for the following symptom-triggering circumstances and note whether symptoms are triggered, exacerbated, or improved [15,102]:

- Rolling over in bed, looking up, changing head position relative to gravity

- Turning the head to the side

- Any head movement

- When standing up or walking

- When supine or recumbent

- Vibration or loud sounds

- Seeing objects in motion

Assessment of triggers establishes the distinctions between positional (change of head orientation with respect to gravity), head motion-induced (head motion regardless of direction), and orthostatic position changes. Obligate triggers are specific triggers that consistently cause dizziness [8].

TARGETED EXAMS

Eye Movement Assessments

At this point in the workup, the patient is placed into one of six vestibular syndromes after some possible etiologies were ruled out during the patient history. The differential diagnosis does not extend beyond possible etiologies within the vestibular syndrome, which substantially narrows the range.

The next task is to differentiate dangerous central mimics from benign causes in acute and episodic vestibular syndromes and to diagnose BPPV by identifying the affected canal. This involves the use of targeted examinations, also called "bedside examinations," which emphasize the assessment of eye movements to detect and localize the underlying pathology of dizziness. The accuracy of eye movement assessment is superior to CT or MRI imaging in differentiating serious CNS from benign causation. Healthcare costs are also reduced by eliminating (in many but not all cases) expensive but unhelpful brain imaging.

Nystagmus is a repetitive, involuntary movement of the eyes, and nystagmus assessment is a core component of the diagnostic workup. Whether spontaneous or triggered, the characteristics of nystagmus help to localize the pathology and suggest a diagnosis. The nystagmus is tested first, because some disorders are diagnosed solely by the nystagmus characteristics [10,20,48,103].

The vestibulo-ocular reflex keeps vision focused on a target during head movement. When looking to one side, the labyrinth on that side signals the head-turn, and the eyes automatically move in the opposite direction to maintain fixed gaze. The vestibulo-ocular reflex maintains gaze for continued reading while turning the head alternately to each side [103,104]. Vestibulo-ocular reflex assessment is used in the diagnosis of vestibular disorders, because vestibular dysfunction causes inappropriate activation of the vestibulo-ocular reflex that manifests in nystagmus [16].

With vestibular disturbance, when the head is rapidly turned toward the affected side, the eyes move with the head and visual fixed gaze is broken, followed by a refixation ("catch-up") saccade back to the original visual target [104]. This is nystagmus.

In peripheral or central vestibular disorders, understanding the simple "rules" of nystagmus allows rapid, confident diagnoses. With peripheral causes of nystagmus, the fast-phase direction is away from the affected side (of canal/vestibular nerve), and this direction remains constant, regardless of gaze direction. The pattern is primarily horizontal with a torsional component—never purely torsional or vertical. In central nystagmus, the fast-phase varies with the direction with gaze (i.e., right-beating on rightward gaze, then left-beating on leftward gaze). The pattern is any direction, but primarily torsional or vertical.

HINTS is an acronym for three ocular motor tests—the head impulse test (HIT), gaze testing for nystagmus, and alternate cover test for skew deviation—that are combined to differentiate central from peripheral causes of dizziness. Nystagmus is a key observed response. Normal visual fixation can suppress mild nystagmus, but Frenzel lenses worn by the patient block visual fixation and magnify examiner view of eye movements [8,10,20]. When conducting the HIT, have the patient fixate his/her gaze on a midline target (e.g., the examiner's nose), then rapidly rotate his/her head 20 degrees to the right or left, bring head back to midline, then rotate to the other side. The presence of a corrective saccade is ''positive'' for abnormal vestibulo-ocular reflex, which generally indicates a peripheral vestibular process. Gaze that remains locked on the midline target is normal. A normal HIT in patients with AVS is highly suspicious for stroke, but HIT is only useful in patients with AVS and nystagmus. In patients with dizziness (with urosepsis or dehydration) without nystagmus, a normal HIT is a misleading false-positive for stroke.

Gaze testing for nystagmus consists of having the patient look straight ahead (''neutral'' or ''primary'' gaze) and observing for eye movements. Patients whose eyes drift leftward and snap back horizontally to the right have right-beating horizontal nystagmus. Next, look for ''gaze-evoked'' nystagmus by having the patient look to the right and then to the left, each for several seconds; observe for nystagmus and direction of its fast-beating component. Two patterns suggest stroke or other central cause:

- Dominantly vertical or torsional nystagmus in any gaze position

- Dominantly horizontal nystagmus that changes direction in different gaze positions, termed bilateral or gaze-evoked nystagmus

However, the most common pattern in patients with AVS and stroke is direction-fixed horizontal nystagmus, an acute vestibular neuritis mimic that requires further testing.

Skew deviation is a vertical misalignment of the eyes due to imbalance in gravity-sensing vestibular pathways. Alternate eye cover testing checks for ability to maintain vertical alignment of the eyes. Have the patient gaze directly on a midline target (e.g., the examiner's nose), then cover one eye, and the other, alternating back and forth every one to two seconds.

Skew is shown by slight upward vertical correction on one side, and downward on the other side, appearing the moment the eye is uncovered. Horizontal movements are irrelevant; no vertical misalignment equals no skew. This test is very specific for central etiologies.

The timing-and-trigger syndrome should be identified before targeting the exam, because the same clinical feature can predict a benign condition in one syndrome and a dangerous condition in another syndrome [6,37].

ACUTE VESTIBULAR SYNDROME

AVS is defined by acute-onset, persistent dizziness lasting days to weeks, sometimes with lingering sequelae. The temporal evolution at onset and progression during the first week is more important diagnostically than total illness duration. Many patients have an early peak in symptom severity, rapid symptom improvement over the first week, and gradual recovery over weeks to months. Unusual cases resolve in less than 48 to 72 hours [37].

Triggered AVS

For diagnostic purposes, AVS is classified into acquired (postexposure/triggered) and spontaneous forms. Triggers in t-AVS refer to behavior or exposures that precipitate dizziness. Patients with AVS typically experience worsening of dizziness (exacerbation) with head movement. This feature can be confusing or misleading, as for example when triggered dizziness in a patient with vestibular neuritis or stroke is misdiagnosed as BPPV [8].

Triggered AVS results from trauma or toxic exposure and is typically diagnosed largely based on exposure history, which is usually obvious. The most common causes are blunt head injury or ingestion of prescribed or illicit drugs affecting the brainstem, cerebellum, or peripheral vestibular apparatus. Carbon monoxide exposure and acute toxicity is a rare but important consideration [37].

Most patients experience a single, acute attack resolving gradually over days to weeks following the exposure. Depending on the nature of trauma or toxin, other symptoms (e.g., headache, altered mental status) may predominate. Rotatory vertigo, spontaneous nystagmus (when looking straight ahead), and head-motion intolerance may be absent or unimpressive if the pathologic effects are bilateral and relatively symmetric (as with most toxins) [37].

Head Injury

Blunt head trauma, blast injuries, whiplash, or barotrauma may lead to direct vestibular nerve injury, labyrinthine concussion, or mechanical disruption of inner ear membranes to result in an AVS presentation. Basal skull fracture and traumatic vertebral artery dissection should always be considered. TBI may cause post-concussion syndrome, typically with a combination of dizziness, headache, fatigue, and minor cognitive impairment, with dizziness the most common symptom in the first two post-injury weeks [37].

Drug Side Effects/Toxicity

Anticonvulsant side effects or toxicity are a frequent cause of dizziness and vertigo seen in the ED. As mentioned, aminoglycoside toxicity is an established cause of acute bilateral vestibular failure. Gentamicin can cause profound, permanent loss of vestibular function with relatively spared hearing; toxicity may occur after just a single antibiotic dose. Patients usually show gait unsteadiness and oscillopsia (bouncing vision) while walking [37].

Spontaneous AVS

Spontaneous AVS is defined as acute onset of persistent dizziness and vertigo associated with nausea or vomiting, gait instability, nystagmus, or head motion intolerance. A focused physical exam is often diagnostic, because patients are usually symptomatic at presentation [8]. Prototype causes include vestibular neuritis and labyrinthitis [10]. Possible dangerous causes include posterior circulation stroke of the cerebellum or brainstem (the most frequent), bacterial labyrinthitis, and labyrinthine stroke (much less frequent) [8,37].

Peripheral causes of s-AVS are more common, but central causes are not infrequent and can be fatal if missed, especially with vertebro-basilar ischemia [19]. This would not be as concerning if patients with posterior circulation TIA or stroke presented with classical focal neurologic signs along with the vestibular symptoms of AVS, as the diagnosis would be straightforward [57,105]. However, this is often not the case.

The 1975 National Institutes of Health (NIH) recommendation that isolated dizziness or vertigo not be considered a TIA persists as a standard teaching [106]. This has contributed to missed diagnoses of TIA and stroke, because many patients with posterior circulation TIA or stroke present with isolated dizziness or vertigo without focal neurologic signs [37,105,107]. Patients with s-AVS presenting to the ED with dizziness are at high risk (25%) for stroke. Of nearly 800,000 annual strokes in the United States, 18% are strokes in the posterior fossa (within the brainstem or cerebellum) and up to 70% present with dizziness [8,19].

An estimated 45,000 to 75,000 patients with stroke are misdiagnosed annually. Roughly 28% to 59% of cerebellar strokes are misdiagnosed in the ED, and isolated dizziness is a risk factor for this misdiagnosis. Posterior circulation strokes are missed more than twice as often as anterior circulation strokes, and cerebellar strokes are four times more likely to be misdiagnosed than stroke misdiagnosis overall. These misdiagnosed patients suffer higher mortality and disability at follow-up [10,108,109,110].

CT is widely used but ineffective to rule out ischemic stroke in s-AVS; MRI with diffusion-weighted imaging (MRI-DWI) is markedly superior. However, within the first 48 hours of symptom onset, MRI-DWI is falsely negative in 12% to 18% of patients with AVS and 53% of patients with small brainstem strokes. Posterior circulation strokes are five times more likely to be falsely negative than anterior circulation strokes. Indiscriminate CT angiography also has very low utility (1.3%) [8,52,111].

In the first 48 hours, physical examination outperforms MRI. If the initial physical examination suggests stroke, a negative MRI result should not be interpreted as excluding stroke. Delayed MRI (three to seven days post-onset) may be required to confirm the presence of a new infarct [8]. Posterior circulation stroke should be differentiated from benign peripheral vestibular disorder (Table 1) [8,10,19]. Nearly all patients with AVS due to a peripheral cause exhibit nystagmus, which may be inhibited if benzodiazepines/other vestibular suppressants are taken before the exam. When possible, assess for nystagmus before medications to manage symptoms are administered [8,10].

Table 1: TESTING TO DIFFERENTIATE POSTERIOR CIRCULATION STROKE FROM BENIGN PERIPHERAL VESTIBULAR DISORDER

HINTS is performed in sequence. Test nystagmus first; HINTS is validated only in patients with nystagmus, and gaze testing is non-intrusive (i.e., head movement unnecessary).

- Gaze testing: Is there a central pattern of nystagmus?

- Alternate cover test: Is skew deviation present?

- HIT: Is the head impulse test result negative?

Patients with s-AVS and worrisome nystagmus, skew deviation, or bilateral normal HIT have a presumed stroke and should be admitted to a hospital. If all three tests seem reassuring, perform a targeted neurologic exam to determine if there are any CNS signs. This involves testing for:

- 4D symptoms:

- Diplopia (double vision)

- Dysphagia (difficulty swallowing)

- Dysarthria (difficulty with speech)

- Dysmetria (lack of coordination)

- The cranial nerves for hearing

- Anisocoria (unequal pupil size)

- Facial loss of pain or temperature sensation

- Cerebellar function for limb ataxia.

The next step is gait testing to determine if the patient can walk unassisted.

If the answer to any of these questions is yes, the cause is presumed central and treated as stroke. If the answer to all questions is no, the cause is presumed peripheral. All answers must be no in order to exclude stroke because none is sufficiently sensitive individually.

Source: [8,10,19]

EPISODIC VESTIBULAR SYNDROME

Whether intermittent dizziness is triggered or spontaneous, the duration of dizziness episodes (seconds, minutes, hours) is more important than total illness duration. EVS excludes relapsing and remitting symptoms lasting weeks at a time [37].

Triggered EVS

Triggered EVS is characterized by brief episodes of dizziness lasting seconds to minutes (depending on etiology), precipitated by an obligate trigger. Common triggers are changes in head position or body posture, as when rising from a seated or lying position, tipping the head back to wash one's hair, or rolling over in bed. Uncommon triggers include loud sounds and the Valsalva maneuver. Patients with nausea or vomiting may overestimate the episode duration, but this can usually be clarified by careful history-taking [8].

As mentioned, clinicians should distinguish triggers from exacerbating features [37]. Prototype t-EVS causes are BPPV and orthostatic hypotension; less commonly, it is caused by superior canal dehiscence syndrome [8]. Possible dangerous causes include central paroxysmal positional vertigo and serious causes of orthostatic hypotension, such as internal bleeding. Patients with panic or anxiety disorders may also complain of episodic vertigo, lightheadedness, or dizziness during panic attacks that are triggered or spontaneous. Studies show a high prevalence of vestibular dysfunction for these patients [112].

Episodic positional symptoms are common to all causes of t-EVS, differentiated by targeted history and exams. BPPV is identified by maneuvers that reproduce dizziness combined with an observed pattern of nystagmus. Orthostatic hypotension is diagnosed by observing a significant fall in blood pressure upon sitting and standing. Dangerous t-EVS mimics are identified by careful attention to the corresponding signs and symptoms that differentiate these benign conditions from potentially more serious disorders [37]. Positional triggers, such as rolling over in bed or reclining, are common in BPPV but should not occur in orthostatic hypotension [8]. Unlike head position changes in BPPV, the vertigo and oscillopsia attacks in superior canal dehiscence syndrome are triggered by pressure-related changes of the external auditory canals (e.g., loud sounds, Valsalva maneuver) [22].

The nystagmus characteristics of BPPV and central paroxysmal positional vertigo are distinct. Atypical nystagmus (downbeat or horizontal) is suggestive of central paroxysmal positional vertigo, and pure vertical (up- or downbeating) nystagmus should be considered of central origin until proven otherwise [8,23]. Central mimics of BPPV less often involve strokes and more often involve posterior fossa neoplasm, hemorrhage, or demyelination recognized by association with other abnormalities [104,113].

Central paroxysmal positional vertigo also includes common, benign causes, such as alcohol or sedative intoxication. Such patients are more apt to complain of continuous, persistent dizziness exacerbated (not triggered) by position change, often readily diagnosed based on context and other signs of intoxication [8,37].

In general, BPPV is not associated with vertiginous episodes provoked simply by head and body movements in general, but by sudden positional changes relative to gravity. Moreover, unprovoked (spontaneous) episodes while immobile or the constant sensation of unsteadiness also suggest a diagnosis other than BPPV [22].

BPPV

Within any (semicircular) canal, BPPV is caused by abnormal stimulation of the cupula by otoconia that are free-floating (canalolithiasis) or have attached to the cupula (cupulolithiasis) [114]. With head motion in the plane of the affected canal, cupula stimulation produces error signaling that triggers eye movement patterns (nystagmus) specific to the afflicted canal [22]. BPPV should be differentiated from other causes of imbalance, dizziness, and vertigo. Patients should also be assessed for factors that modify management, including impaired mobility or balance, CNS disorders, lack of home support, and increased risk for falling. In patients meeting BPPV diagnostic criteria, it is not necessary to obtain radiography or order vestibular testing in the absence of signs/symptoms inconsistent with BPPV [22].

Provoked nystagmus is used clinically to diagnose BPPV by positioning the head to spatially align the plane of the affected canal with gravity. Gravity challenge moves otolithic debris in the canal, inducing excitation and resultant nystagmus. This identifies the afflicted canal, determines the canal-specific therapy, and distinguishes BPPV from central causes of vertigo [15,24,40,114].

Head movement tests are canal-specific. Because posterior canal BPPV is the most common type, the Dix-Hallpike maneuver is used first. For this maneuver, the patient is moved quickly from sitting upright with head turned 45° in the direction of involved ear, to supine position with head still turned 45° and neck extended 20° off the end of the exam table with the affected ear down [21,22].

Before initiating physical maneuvers that involve head rotation, the neck should be evaluated to determine if the procedure should be modified or avoided. The Dix-Hallpike maneuver should be performed with caution or avoided in patients with a current or past neck or back injury, surgery, or painful condition [24,114].

A diagnosis of BPPV affecting the posterior canal (pc-BPPV) is confirmed by vertigo with torsional (rotatory), upbeating (toward the forehead) nystagmus, with onset 5 to 20 seconds after completion of the Dix-Hallpike maneuver (latency) and duration less than 60 seconds. Provoked nystagmus that lasts longer than 60 seconds with no or brief latency identifies cupulolithiasis [21,22]. If the initial maneuver is negative, it should be repeated with the opposite ear down.

Before performing the Dix-Hallpike maneuver, the patient should be advised that sudden, intense vertigo or nausea is possible but should subside within 60 seconds. The sequential steps and expected results of the maneuver should be explained, orienting the patient to the supine position and location of the head and providing reassurance that the head and body will be supported and guided safely and securely through the maneuver [21,22].

Evidence Based Practice Recommendation

According to the American Academy of Otolaryngology, if the patient has a history compatible with BPPV and the Dix-Hallpike test exhibits horizontal or no nystagmus, the clinician should perform, or refer to a clinician who can perform, a supine roll test to assess for lateral semicircular canal BPPV.

http://journals.sagepub.com/doi/pdf/10.1177/0194599816689667

Last Accessed: September 18, 2018

Strength of Recommendation: Recommendation (Benefits exceed the harms, but the quality of evidence is not as high)

There are two types of BPPV affecting the lateral canal (lc-BPPV)—geotropic or apogeotropic—with two types of direction-changing positional nystagmus [22,40]. When BPPV is suspected and the Dix-Hallpike maneuver is negative, the supine roll test should be used to assess for lc-BPPV. The supine roll test provokes a linear, horizontal nystagmus in patients with lc-BPPV. In cases of lc-BPPV caused by canalolithiasis, the nystagmus beats to the ear under the head (i.e., higher intensity on the affected side). If the condition results from cupulolithiasis, the nystagmus beats to the upward ear (i.e., higher intensity on the non-affected side).

The Dix-Hallpike maneuver also provokes vertigo and nystagmus in BPPV affecting the anterior canal (ac-BPPV), which shows downbeating nystagmus, sometimes with a torsional component, toward the affected ear. Downbeating positional nystagmus may reflect brainstem or cerebellar lesion, which should be ruled out [21,40]. BPPV can also mimic orthostatic hypotension by producing dizziness on arising and often goes undiagnosed in the elderly.

Serious Causes of Orthostatic Hypotension

As noted, vertigo is a common but under-appreciated symptom in orthostatic hypotension. Older patients taking antihypertensives can show incidental orthostatic hypotension. Orthostatic dizziness and hypotension are not always related; orthostatic dizziness without systemic orthostatic hypotension may indicate hemodynamic TIA or intracranial hypotension [8].

Serious causes of orthostatic hypotension include fluid loss from bleeding, vomiting, diarrhea, and excessive urination/sweating. Occult internal bleeding is the primary dangerous concern [2]. Concomitant chest, back, abdominal, or pelvic pain suggests an intrathoracic or intra-abdominal emergency [37]. Myocardial infarction, occult sepsis, adrenal insufficiency, or diabetic ketoacidosis may present with severe orthostatic hypotension without other overt signs [8].

Spontaneous EVS

s-EVS is marked by recurrent, spontaneous episodes of dizziness that range in duration from seconds to days, with most lasting minutes to hours. Spells sometimes occur up to several times per day, but they are usually less frequent and can be separated by months or even years, depending on etiology [8].

Unlike t-EVS, dizziness episodes in s-EVS cannot be provoked and diagnostic evaluation relies almost entirely on patient history [37]. Vestibular migraine is the most common cause of s-EVS, with a population prevalence of roughly 1% [37]. The classical Ménière disease symptom triad of episodic vertigo, unilateral tinnitus and aural fullness, and reversible sensorineural hearing loss is initially present in only 25% of patients. Patients with suspected Ménière disease should generally be referred to an otolaryngologist, but care should be taken to avoid missing TIA mimics with audio-vestibular symptoms [37].

Reflex (vasovagal) syncope is also a common cause. In reflex syncope, episodes of near-syncope without loss of consciousness substantially outnumber true syncope. Patients usually have prodromal symptoms for 3 to 30 minutes, most commonly dizziness (70% to 75% of cases) that can manifest in vertigo. Diagnosis is based on clinical history, exclusion of dangerous mimics (especially cardiac arrhythmia), and confirmation (if needed) by formal head-up tilt table testing [8,37].

s-EVS has been reported in panic attacks; episodes begin rapidly, usually peak within 10 minutes, and are accompanied by additional autonomic, cognitive, and perceptual symptoms. Panic attacks can be precipitated by situational stress, such as airplane travel, but often occur spontaneously [115]. Panic attack mimics include ictal panic attacks from temporal lobe epilepsy that usually last seconds with altered mental status, hypoglycemia, cardiac arrhythmias, and basilar TIA, which can produce dizziness and neurologic and autonomic features [8].

Another cause of s-EVS is vestibular paroxysmia, a condition that should be considered when the patient reports 10 or more spontaneous vertigo attacks per day lasting less than one minute (sometimes mere seconds). These attacks respond to a carbamazepine or oxcarbazepine trial [45].

The most common dangerous causes of s-EVS are vertebrobasilar TIA and cardiac arrhythmias. Less commonly, episodes have been observed with other cerebrovascular (e.g., subarachnoid hemorrhage), cardiorespiratory (e.g., unstable angina, pulmonary embolus), and endocrine (e.g., hypoglycemia) disorders. Carbon monoxide exposure is a rare serious cause [37].

Vestibular symptoms associated with s-EVS cannot be reproduced by bedside examination, and patients may be asymptomatic by the time they present to outpatient care. The history is used to distinguish vestibular migraine from TIA or other causes. Diagnosis of benign s-EVS causes can be clear-cut in typical cases, but as mentioned, classical features of vestibular migraine, vasovagal syncope, Ménière disease, or panic attacks are often absent [37].

Isolated attacks of spontaneous dizziness are the most common symptom of an imminent posterior circulation TIA and are frequent in the days to weeks preceding posterior circulation stroke [8,37]. TIA presenting with isolated dizziness is easily missed; 90% of patients who seek medical attention for transient dizziness that preceded vertebrobasilar stroke are initially misdiagnosed [107]. Dizziness is the most common presenting symptom of basilar artery occlusion and vertebral artery dissection. Prompt diagnosis is critical; 5% of patients with TIA suffer a stroke within 48 hours, but the risk is much greater with posterior circulation TIA. Prompt treatment lowers stroke risk after TIA by 80% [8,116,117].

The clinical presentation of vestibular migraine is highly variable. The duration of attacks ranges from seconds to days. Nystagmus (peripheral or central), headache, and nausea, vomiting, photophobia, phonophobia or visual auras can be present or absent during an attack. Hearing loss or tinnitus can occur, mimicking Ménière disease [8].

Vestibular migraine is diagnosed by clinical findings of recurrent migraine headache episodes: five or more episodes characterized by moderate-to-severe vestibular symptoms; ≥50% of episodes have pulsating, impairing headache; photo- or phonophobia; and/or visual aura [49].

The prevalence of migraine syndrome is high in patients with Ménière disease, and when such patients present with attacks of s-EVS, the diagnostic attribution may seem difficult. The presence of low frequency hearing loss favors the diagnosis of Ménière disease [19,49].

Cardiac arrhythmia should be suspected when syncope or exertion is the precipitating factor for the onset of dizziness. Clinical features may increase or decrease the odds of a dangerous cardiac cause, but cardiac specialist testing is often required for diagnostic confirmation [8,37].

CHRONIC VESTIBULAR SYNDROME

Triggered CVS

Central compensatory mechanisms can ameliorate vestibular symptoms over time, but to an unpredictable extent, and lasting vestibular compensation does not develop or incompletely develops. Thus, some vestibular syndromes become chronic, with persistent dizziness or unsteadiness lasting months to years, with oscillopsia, nystagmus, and/or gait disturbance. CVS develops from poorly compensated unilateral or bilateral vestibulopathy or cerebellar degeneration [118]. Other etiologies include PPPD, autoimmune or neoplastic disease, central vestibular syndromes with downbeat or upbeat nystagmus, and dizziness due to isolated causes [119]. In t-CVS, dizziness or vertigo is provoked by head movement (as in uncompensated vestibular loss), medication side effects, and/or anxiety, depression, or other psychiatric conditions [118].

Bilateral vestibulopathy is a CVS characterized by unsteadiness when walking or standing that worsens in darkness, on uneven ground, or during head motion. Patients may describe head or body movement-induced blurred vision or oscillopsia. Symptoms usually remit when sitting or lying down. Bilateral vestibulo-ocular reflex function is significantly impaired or absent in bilateral vestibulopathy and is assessed using the HIT, video-HIT, or other tests [41].

As discussed, PPPD is a newly defined CVS that unifies key features of chronic subjective dizziness, phobic postural vertigo, and related disorders. Patients with PPPD often develop gait disorder, anxiety, avoidance behaviors, and severe disability [120].

Evidence Based Practice Recommendation

According to the Bárány Society, the differential diagnosis of PPPD includes chronic sequelae of acute precipitants, recurrent attacks of episodic precipitants, ongoing manifestations of chronic precipitants, other chronic vestibular syndromes, medical or psychiatric disorders that produce persistent unsteadiness or dizziness, and adverse effects of regularly consumed prescription or non-prescription medications.

https://content.iospress.com/articles/journal-of-vestibular-research/ves622

Last Accessed: September 18, 2018

Level of Evidence: Expert Opinion/Consensus Statement

A PPPD diagnosis requires dizziness, unsteadiness, or non-spinning vertigo present on most days for at least three months, exacerbated by posture, movement, and/or moving/complex visual stimuli. Symptoms are precipitated by any condition that causes vertigo, unsteadiness, dizziness, or problems with balance and cause significant distress or impairment [62].

In addition to timing and triggers, the diagnostic approach should also capture the dynamic features of patient history to uncover the nuances of psychologic distress, maladaptive coping, and differential diagnosis. Patients who fulfill diagnostic criteria for PPPD after a TBI or whiplash should receive the diagnosis. The presence of other injury sequelae determines additional diagnoses [62].

Spontaneous Chronic Vestibular Syndrome

s-CVS conditions include chronic dizziness or vertigo associated with nystagmus, blurred vision, or impaired visual acuity from oscillopsia, originating from cerebellar or brainstem degeneration or atrophy [121]. Other central etiologies of s-CVS include cervical vertigo and Chiari malformations [118]. Several cerebellar syndromes due to neurodegenerative and hereditary diseases can lead to ataxia and postural instability associated with cerebellar oculomotor disorders (e.g., downbeat nystagmus, gaze-evoked nystagmus) [121].

Episodic ataxia type 2, the most frequent inherited cerebellar ataxia syndrome, is characterized by recurrent attacks of dizziness and ataxia lasting several hours, often elicited by physical activity, alcohol consumption, or stress. More than 90% of patients with episodic ataxia type 2 have oculomotor disorders such as downbeat nystagmus [118].

The vertigo symptoms are usually associated with degenerative cervical spine disease and may resemble BPPV due to proprioceptive abnormalities related to cervical spine dysfunction. However, cervical vertigo may be triggered by rotating the head relative to the body while upright, as opposed to the vertigo triggered by changes in head position relative to gravity in BPPV [22,122].

11. CLINICAL MANAGEMENT

Returning to the funnel analogy, a range of possible dizziness and vertigo etiologies (e.g., orthostatic hypotension, vasovagal syncope, head injury, medication side effects/toxicity, posterior circulation TIA/stroke, central paroxysmal positional vertigo, and cardiac arrhythmias) would be excluded or diagnosed. Certain patients would be treated, and others referred to specialists or admitted to an ED. This would include all etiologies categorized as t-AVS.

After vestibular disorders have been differentiated and diagnosed, treatment selection can be divided into approaches that focus on symptom control, those specific to the underlying vestibular etiology, and those aimed at promoting recovery [123]. Therapeutic approaches broadly used across vestibular etiologies are discussed first, followed by treatments specific to acute, episodic, and chronic vestibular syndromes.

COMMON PHARMACOTHERAPIES

Most pharmacotherapies for dizziness or vertigo related to peripheral or central vestibular, cerebellar, or oculomotor disorders fall into one of seven groups, or the 7 As [61]:

- Antiemetics

- Anti-inflammatory

- Anti-Ménière

- Anti-migraine

- Antidepressants

- Anticonvulsants

- Aminopyridines

Patients with severe nausea or vomiting greatly prefer non-oral administration [123]. As such, vestibular suppressants are usually administered in non-oral routes initially for rapid symptom control, followed by oral medications.

Vestibular Suppressant Medications

As discussed, dizziness, vertigo, disequilibrium, and associated symptoms can arise from diverse central or peripheral disturbances of vestibular function. By suppressing vestibular sensory input, vestibular suppressant medications can reduce conflicting sensory input, control undesirable perceptions, and diminish patient distress [13].

Many distressing vestibular-related symptoms are mediated by the vomiting center in the medulla. The vomiting center is activated through neurotransmitter release involving vestibular and CNS (histamine, acetylcholine), visceral (gut) (dopamine, serotonin), and chemoreceptor trigger zone (dopamine, serotonin) pathways [124]. These pathways are therapeutic targets of most vestibular suppressants, which are effectively used for symptomatic control in nearly all AVS or EVS subtypes, regardless of underlying etiology. These medications are variously effective for controlling dizziness, vertigo, motion sickness, associated symptoms (e.g., nausea, vomiting, diarrhea), and patient distress or anxiety during episodes, which can be severe [22,178].

Drug classes and agents commonly used as vestibular suppressants include antihistamines, benzodiazepines, scopolamine, dopamine antagonists, and ondansetron (Table 2). Antihistamines (e.g., meclizine, diphenhydramine, dimenhydrinate) block the release of histamine and acetylcholine and are especially beneficial in vestibular-mediated nausea, vomiting, and motion sickness. Side effects include sedation, confusion, dry mouth, and urinary retention. Meclizine is preferred because it has minimal anticholinergic effects, causes less sedation, and is effective in the treatment of vertigo due to labyrinth dysfunction. It is also the drug of choice in pregnancy [123].

Table 2: VESTIBULAR SUPPRESSANT MEDICATIONS

Medication

Dosage and Route

Antihistamine Agents

Diphenhydramine

50 mg PO twice daily

10–50 mg IM or IV

Meclizine

25–50 mg PO three to four times per day

Promethazine

12.5–50 mg PO every four to six hours

50 mg RS four times per day

10–50 mg IM or IV

Benzodiazepines

Lorazepam

0.5–2 mg PO two to three times per day

Diazepam

2–5 mg PO three to four times per day

Clonazepam

0.25–1 mg PO two to three times per day

Antiemetic Agents

Metoclopramide

10–20 mg PO every four to six hours

10–20 mg IM or IV

Prochlorperazine

10–20 mg PO every four to six hours

25 mg RS every six hours

5–10 mg IM or IV

Domperidone

10–20 mg PO every six to eight hours

Ondansetron

8 mg PO every 6 to 12 hours

4 mg SL, IM, or IV

Anti-Motion Sickness

Scopolamine

1 TD patch (1.5 mg) every three days

IM = intramuscular; IV = intravenous; PO = oral; RS = rectal suppository; SL = sublingual; TD = transdermal.

Source: [15,22,119,123,125]

Benzodiazepines (e.g., diazepam, clonazepam, lorazepam) potentiate the inhibitory effects of the gamma-amino butyric acid system to produce anxiolytic, sedative, muscle-relaxant, and anticonvulsant effects. Benzodiazepines can be highly effective in vertigo unresponsive to antihistamines and for calming intensely distressed patients, but they are sedating and mainly used when antihistamines are inadequate [123].

Scopolamine is a belladonna alkaloid that blocks CNS neurotransmission of acetylcholine and is one of the most effective agents for preventing motion sickness. Scopolamine is also effective for vestibular-mediated nausea/vomiting and is better tolerated as a transdermal patch than when taken orally. Common side effects are sedation, constipation, dry mouth, and urinary retention [114,124].

Dopamine antagonists (e.g., metoclopramide, domperidone, promethazine, prochlorperazine) block dopamine stimulation in the intestines and chemoreceptor trigger zone, limiting emetic input to the medullary vomiting center. Promethazine and prochlorperazine also inhibit central muscarinic and histamine receptors, which contributes to their antiemetic and sedative properties [124].

Ondansetron inhibits serotonin-5HT3 receptors in the small bowel, vagal nerve, and chemoreceptor trigger zone, suppressing serotonergic activation of the vomiting center to alleviate nausea and vomiting. Adverse effects are uncommon but can include headache, constipation, diarrhea, and fatigue [124].

Extrapyramidal symptoms, including irreversible tardive dyskinesia (an involuntary movement disorder), are a potential risk with all central dopamine antagonists. Extended use (duration of 12 or more weeks) increases the risk of tardive dyskinesia [126]. However, dopamine antagonists are considered safe for use as acute therapy and are usually reserved for patients with severe vomiting [123].

In peripheral vestibular disorders, all vestibular suppressants can interfere with central compensation, and their use is recommended to not exceed three days [15,22,125]. The goal is for patients to rapidly receive specialist care, but patients may not get an immediate appointment and remain highly symptomatic. In this context, vestibular suppressants should continue for symptom control until optimized treatment is initiated by a specialist [119].

Vestibular suppressants can cause drowsiness and interfere with driving. In particular, the use of benzodiazepines is a significant risk factor for falls; this risk increases with polypharmacy, common in the elderly [15,22]. Antihistamines carry added risks of impaired cognitive functioning, gastrointestinal motility, and vision in elderly patients [22]. Some patients can develop psychologic dependence to benzodiazepines and have difficulty discontinuing the medication [119].

Betahistine

First approved for use in Europe in the 1970s, betahistine has been prescribed to more than 100 million patients with vestibular disorders and is the first-line treatment of Ménière disease in Germany. Betahistine is not approved by the U.S. Food and Drug Administration, but it may be obtained through compounding pharmacies in the United States with a prescription [15,127]. It reduces vestibular symptoms but seems to differ from vestibular suppressants by promoting vestibular compensation. Histamine regulates sensory coding in the peripheral vestibular system. Betahistine (dihydrochloride or dimesylate), a structural analogue of histamine, is a potent histamine H3 receptor antagonist and a weak histamine H1 receptor agonist [15]. Betahistine reduces the frequency and severity of vertigo, nausea, and vomiting in diverse unilateral vestibular etiologies. Central and peripheral histamine receptor activity is a presumed mechanism [127,128,129].

Betahistine dose-dependently increases vestibulo-cochlear blood flow, increases central and vestibular system histamine turnover, decreases peripheral vestibular system input, and reduces histamine-induced excitation in vestibular cells through local H3 receptor blockade. These mechanisms are thought to improve vestibular compensation, reduce functional asymmetry of vestibular organs, and improve labyrinth microcirculation by rebalancing the production and resorption of endolymphatic fluid [127,128,129]. In this course, all discussions of betahistine refer to betahistine dihydrochloride, unless otherwise stated.

Antidepressant Drugs

Monoamines are the neurochemicals serotonin, norepinephrine, and dopamine. Dysregulated monoamine neurotransmission is implicated in anxiety disorders and depression. A bi-directional relationship between impaired monoamine neurotransmission and vestibular signaling dysfunction is suggested, with asymmetric vestibular system release of serotonin, norepinephrine, or dopamine linked to vestibular migraine and other dizziness/vertigo etiologies [51,61,119].

Antidepressant drugs include SSRIs (e.g., fluoxetine, escitalopram), serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine), and tricyclic antidepressants (e.g., nortriptyline, imipramine, amitriptyline). They modulate serotonin, norepinephrine, and dopamine neural pathways (with varying specificities) and are first-line treatments for anxiety disorders and depression. These agents are increasingly recommended for use in some vestibular-related disorders [51,119,130].

Aminopyridines

Aminopyridines are potassium-channel blockers, established as pharmacotherapy for cerebellar diseases that include downbeat nystagmus, upbeat nystagmus, central positional nystagmus, episodic ataxia type 2, and gait disorders in cerebellar ataxia [61].

Aminopyridines used in these disorders are 3,4-diaminopyridine (3,4-DAP) and 4-aminopyridine (4-AP). 4-AP crosses the blood-brain barrier more easily and is superior to 3,4-DAP in some cases. Both drugs are well-tolerated and without major side effects apart from nausea, transient paresthesia, or headache [121].

QT Interval Prolongation

Some vestibular disorder pharmacotherapies may interact with other medications to risk QT interval prolongation [119]. A prolonged QT interval is a symptom of disordered myocardial repolarization that increases the risk of potentially life-threatening ventricular tachycardia (i.e., torsades de pointes) [131]. A complete list of medications that prolong the QT interval is available at https://www.crediblemeds.org.

VESTIBULAR REHABILITATION

Vestibular rehabilitation, another therapeutic modality broadly used across dizziness and vertigo etiologies, is a specific physical therapy for patients with peripheral or central vestibular disorders. Vestibular rehabilitation reduces symptoms and improves functioning by promoting CNS compensation through exercise-based strategies [132,133].

Evidence Based Practice Recommendation

The American Physical Therapy Association concludes that clinicians may prescribe a home exercise program of gaze stability exercises consisting of a minimum of three times per day for a total of at least 12 minutes per day for patients with acute/subacute vestibular hypofunction and at least 20 minutes per day for patients with chronic vestibular hypofunction.

https://www.asha.org/articlesummary.aspx?id=

Last Accessed: September 18, 2018

Strength of Recommendation: D (Expert opinion from the clinical experience of the guideline development team)

Following an acute peripheral vestibular event, clinical recovery occurs in advance of improved peripheral vestibular function. This suggests that most of the early recovery and a substantial portion of total recovery derives from central compensation (long-term changes in neuronal responses to head movements) that is multisensory and is the primary target of vestibular rehabilitation. Early rehabilitation (during a critical period of adaptation and compensation) may be more effective than late intervention. As such, vestibular rehabilitation should begin shortly after symptom onset [132,134].

Patients typically receive supervised therapy one to two times per week and are taught daily home exercises. The average duration of therapy is 6 to 12 weeks for patients with peripheral vestibular disorder and longer for patients with central vestibular disorder or mobility-impairing comorbidities [44,133].

General Components

Vestibular rehabilitation uses several approaches to reduce symptoms and impairment and to promote function in patients with dizziness, postural instability, and gaze instability. Visual-vestibular interaction (adaptation) exercises strengthen the vestibulo-ocular reflex and gaze stability to promote central compensation for reduced vestibular input, improving gaze instability, balance, and dizziness [44,132].

Strategic substitution exercises promote the use of sensory stimuli and spatial cues from vision and proprioception to substitute for loss of vestibular inputs. Cervico-ocular reflex input is strengthened to reduce spatial uncertainty, and alternative spatial cues can improve balance and walking [44,132].

Balance and gait training under challenging sensory and dynamic conditions facilitates visual and somatosensory cues to offset vestibular hypofunction. Equipment to augment training includes gaming technology, optokinetic drums, and virtual reality [44].

Habituation exercises reduce visual motion sensitivity (e.g., visual vertigo, space and motion discomfort) through systematic exposure to noxious stimuli evoking mild, temporary symptoms. Approaches include optokinetic stimuli and virtual reality for immersion in repetitive moving and visually challenging environments [44,132].

Vestibular rehabilitation can help counteract the negative effects of deconditioning, common in vestibular patients, to avoid symptom provocation [44]. Psychologic deconditioning can progress to PPPD (phobic postural vertigo) to become the greatest obstacle to recovery. After a vestibular event, elderly patients can develop fear of falling, avoidance behavior, and indefinite mobility limitation without vestibular rehabilitation [74].

Based on strong evidence and a preponderance of benefit over harm, patients with acute, subacute, or chronic unilateral or bilateral vestibular hypofunction should be offered vestibular rehabilitation [44]. Without head movements, saccadic or smooth-pursuit exercises should not be used alone as gaze stability exercises.

Acute Peripheral Vertigo

For cases of acute peripheral vertigo, vestibular rehabilitation begins with the patient focusing on an object with a blank background, then moving the head slowly (to avoid severe nausea) to the right and left, and then up/down. This is done two to three times per day for several minutes, and the patient is encouraged to increase the speed as tolerated [132].

Chronic Peripheral Vestibular Hypofunction

The vestibular rehabilitation approach for chronic peripheral vestibular hypofunction is more aggressive, with increasingly more difficult tasks while keeping symptoms manageable. Tasks include eye and head movements while standing, walking forward, walking backward, and standing or walking on compliant or uneven surfaces [132].

Bilateral Vestibular Loss

Central adaptation is much less likely with bilateral vestibular loss than in unilateral loss, but vestibular rehabilitation can promote strategic substitution through strengthening saccadic eye movements and optimizing the efficacy of neck stretch receptors. Vestibulo-ocular exercises are initiated when residual vestibular function is a possibility. Improved balance and gait speed help offset the bilateral loss [135]. Education on fall prevention is critical, because these patients have an especially high fall risk, compounded by darkness and uneven surfaces [132].

Central Vertigo

Recovery of vestibular function in patients with central vertigo is limited because pathologic involvement of central vestibular structures restricts compensation, and improvement takes longer than with peripheral vestibular dysfunction [133]. For these patients, vestibular rehabilitation emphasizes gait and balance activities, along with eye and head movements. Adaptive methods to perform activities of daily function are often taught. If nausea is limiting, antiemetic medications used in conjunction with vestibular rehabilitation may improve participation and final outcomes [132].

ANXIETY AND DIZZINESS

The demonstrable interconnectivity between threat/anxiety, vestibular, visual, and somatosensory systems, and the interactions between anxiety disorders and vestibular morbidity point to the importance of a multimodality treatment approach for patients with anxiety and dizziness [71].

Studies have followed patients with dizziness over time and made several important findings [62,71]. A highly anxious response to the acute dizziness/vertigo of new-onset vestibular neuritis or BPPV predicts continued dizziness 3, 6, and 12 months later. This initial psychologic response has a far greater impact on long-term outcomes than measurable vestibular dysfunction at baseline or follow-up. Patients with emerging symptoms of PPPD who receive cognitive-behavioral therapy within eight weeks of onset have marked reductions in dizziness and avoidance of provocative situations six months later. A highly anxious response to a precipitating event may be the pivotal initiating pathophysiologic process in PPPD (the leading cause of long-term vestibular disability), and early symptom-specific interventions might counter this effect.

Patients with poor recovery from acute vestibular neuritis have higher rates of visual dependence, autonomic arousal, anxiety, and fear of vestibular symptoms [136,137]. Poor recovery is also unrelated to vestibular function, but significantly related to acute visual dependence and failure of sensory integration mechanisms to down-regulate visual contribution to central compensation processes. These data highlight the importance of [136,137]:

- Early identification of abnormal visual dependence and concurrent anxiety

- Early treatment to improve long-term outcomes by reducing visual dependence with sensory re-weighting strategies

- Combining pharmacotherapy and cognitive therapies to reduce anxiety and autonomic arousal

In vestibular patients, successful treatment outcomes require the simultaneous assessment of vestibular, psychiatric (anxiety), and functional (phobic vertigo) disorders. Only when identified can they be addressed by systematically applied treatment that incorporates patient education, vestibular rehabilitation, cognitive-behavioral therapies, and medications to control morbidity and increase the potential for sustained remission [72].

SPONTANEOUS ACUTE VESTIBULAR SYNDROMES

Acute Unilateral Vestibulopathy/Vestibular Neuritis

This acute, spontaneous, peripheral vestibular disorder is characterized by the rapid onset of severe vertigo with nausea, vomiting, and gait instability. The symptoms can be severe and disabling in the short term; patients may need to be hospitalized for intravenous fluids and medications [125,138]. Panic disorder has been found to develop in 10% of patients followed for two years after the initial acute vestibular neuritis episode [139].

Vertigo, nausea, and vomiting can be treated with a combination of vestibular suppressants, not exceeding seven days to avoid disrupting CNS adaptation and compensation [15,125]. The vestibular nerve is selectively vulnerable to inflammation-related swelling and entrapment by its pathway in a narrow, bony canal [35]. Oral corticosteroids may help reduce the severity of vestibular neuritis if initiated in the first few days. The recommended agents are [15,119]:

- Methylprednisolone initiated at 100 mg/day and then reduced by 20 mg every fourth day, OR

- Prednisone 60 mg/day for one week

When acute symptoms subside, patients should begin vestibular rehabilitation to promote CNS adaptation and sensory re-weighting [15,125].

Labyrinthitis

A presumed viral acute labyrinthitis is reasonable to treat with corticosteroid therapy, such as a 10-day course of prednisone with 60 mg/daily on days 1 through 5, reduced to 10 mg/daily on days 6 through 9, and 5 mg on day 10. Some evidence suggests corticosteroid therapy may hasten recovery but does not change the long-term prognosis [138]. Patients with bacterial labyrinthitis should be referred to an ENT specialist.

Herpes Zoster Oticus

Patients with herpes zoster oticus should be treated with corticosteroids and a high-dose oral antiviral (acyclovir, famciclovir, or valacyclovir) when reactivation of latent varicella zoster virus is suspected. Carefully look for painful vesicles on the external ear and within the back of the external ear canal. Even in the absence of visible vesicles, treatment with an antiviral agent is probably prudent with significant localized ear pain and normal tympanic membrane [15].

TRIGGERED EPISODIC VESTIBULAR SYNDROMES

Benign Paroxysmal Positional Vertigo

Canalith repositioning procedures (CRPs) are the first-line therapy option and the most effective treatment for BPPV for patients with prolonged symptoms and/or frequent recurrences. Vestibular suppressants are generally avoided, though a brief course of an antihistamine (e.g., meclazine) may be indicated for initial symptom control. This may be all that is needed for patients with mild, self-limited symptoms and infrequent recurrences. Rarely, BPPV can be refractory to CRPs and require surgical occlusion of the affected semicircular canal [15].

Outcome assessment within one month of initial observation or treatment is necessary to document symptom resolution or persistence. Patients with persistent symptoms should be evaluated for treatment failure. Referral to a specialist is recommended to identify unresolved BPPV and/or an underlying peripheral or central vestibular disorder.

In general, CRPs move the patient through a sequence of head position changes that use gravity to move otolith debris (including the pathologic trigger) out of the affected canal and back into the vestibule [22]. CRPs used in canalolithiasis or cupulolithiasis appear similar [22]. These procedures should only be performed after the affected canal is identified by diagnostic positioning techniques. Patients should be informed that dizziness, vertigo, or a sense of falling can develop during a CRP. Patients who had severe nausea or vomiting with the Dix-Hallpike should receive antiemetics 30 to 60 minutes before the procedure [22,119].

Posterior Canal BPPV

Evidence Based Practice Recommendation

The American Academy of Otolaryngology recommends clinicians should treat, or refer to a clinician who can treat, patients with posterior canal BPPV with a canalith repositioning procedure.

http://journals.sagepub.com/doi/pdf/10.1177/0194599816689667

Last Accessed: September 18, 2018

Strength of Recommendation: Strong recommendation (Benefits of the recommended approach clearly exceed the harms and that the quality of the supporting evidence is high)

CRP is strongly recommended as initial therapy for pc-BPPV [22]. The Epley maneuver is the preferred CRP for pc-BPPV and has more than 20 years of evidential support. Meta-analyses have found that, compared with sham or control groups, the Epley led to significantly greater rates of complete vertigo resolution and conversion from a positive to a negative Dix-Hallpike. After 12 months, the Epley was superior to sham maneuver in conversion to negative Dix-Hallpike and perceived disability [22,140].

The Semont maneuver uses inertial and gravitational forces to move patients briskly down into a side-lying position and then through a rapid 180° arc. In this manner, the Semont repositions free-floating debris from the posterior canal into the vestibule or breaks off canalith from adherence to the cupula [119].

The Semont and Epley maneuvers are comparably effective in pc-BPPV [22]. With speed of rotation critical for a successful Semont, and adequate neck extension and flexibility required for a successful Epley, patient features such as obesity and neck mobility can guide CRP selection [21]. The Semont is a suggested alternative to the Epley for patients with back problems [119].

Lateral Canal BPPV

Compared with apogeotropic lc-BPPV, the geotropic form is the best-researched and most clinically responsive form. The most frequently used repositioning approaches in lc-BPPV are [21,22,40]:

- Gradual rotations around the longitudinal axis of the body toward the nonaffected ear

- Lying for 12 hours overnight on the nonaffected ear (for geotropic) or on the affected ear (for apogeotropic)

- The Gufoni maneuver, which moves the patient from sitting to lying sideways with the head turned downward, holding, and repeating

The Gufoni maneuver can effectively treat canalolithiasis or cupulolithiasis lc-BPPV and has the advantage of eliminating the need to determine the involved form [40,141]. An alternative is to first convert cupulolithiasis of the lateral canal to canalolithiasis by shaking the head after bending it 90° forward into the vertical plane [40].

Anterior Canal BPPV

The Gufoni maneuver or a reverse Epley maneuver has demonstrated symptom resolution in more than 75% of patients with ac-BPPV [142].

Vestibular Suppressant Treatment

Routine use of vestibular suppressants is not recommended in BPPV, as they may interfere with central compensation and obscure Dix-Hallpike findings. None are as effective as CRPs and cannot be used as CRP substitutes [15,22].

In some patients, acute/short-term pharmacotherapy can be indicated. Anxiety and BPPV often co-occur; anxiety levels of patients with panic disorder and agoraphobia diagnosed with BPPV remained significantly elevated 14 days after CRP [143]. Thus, benzodiazepines have a role in patients with significant anxiety or who are too anxious to proceed with CRP [15,22].

Dimenhydrinate, scopolamine, or diazepam may be required in severely symptomatic patients before CRP, patients who become severely symptomatic after CRP, or those who refuse CRP. Patients exceptionally prone to motion sickness should receive meclizine [15,22,114]. CRP plus betahistine more effectively reduced vertigo symptoms than CRP alone [144]. If prescribed, clinicians should educate patients that vestibular suppressants can increase risks of cognitive impairment, falls, drug interactions, and machinery or driving accidents [22].

BPPV and CNS Disorders

Aside from migraine, BPPV in patients with pre-existing central neurologic disorders is rarely addressed in the literature. In one study of 93 patients with BPPV, 31.2% had a central neurologic disorder, with cerebrovascular disease and migraine the most common. The efficacy of repositioning therapy was excellent for BPPV with or without a pre-existing central neurologic disorder [145].

Post-CRP Residual Dizziness

Residual dizziness following successful repositioning is common in patients with BPPV, described as continuous or intermittent imbalance, lightheadedness, or unsteadiness without positional vertigo. The duration of vertigo before CRP is linked to residual dizziness and incomplete central adaptation. Residual dizziness is significantly associated with anxiety disorders, and subjects with high anxiety show more durable and disabling dizziness even after the resolution of acute vertigo in absence of otolithic or vestibular dysfunction [128,146].

Anxiety is highly prevalent in elderly patients with BPPV, and the adverse impact of residual dizziness on psychologic, social, and daily functioning can be severe. Early recognition and treatment of BPPV and comorbid anxiety is recommended to decrease the incidence of residual dizziness [128].

Refractory BPPV

If BPPV remains refractory despite a correct diagnosis and competently performed repositioning maneuvers, surgery may be indicated. The two surgical options are partial neurectomy of the vestibular nerve (singular nerve) or occlusion of the affected (mainly posterior) semicircular canal. Of the two, posterior canal occlusion is favored based on symptom reduction and complications [147].

Superior Canal Dehiscence Syndrome

In superior canal dehiscence syndrome, sound- or pressure-induced dizziness with auditory symptoms of autophony, hyperacusis, or tinnitus results from a bony dehiscence of the superior semicircular canal. Surgical repair of the canal is the recommended treatment [119].

SPONTANEOUS EPISODIC VESTIBULAR SYNDROMES

For patients with vestibular migraine or Ménière disease, vertigo attacks are unpredictable and difficult to control or avoid. The unpredictable, distressing experience may elevate patient anxiety over the next attack sufficiently to induce a secondary panic-like disorder, substantially adding to the psychologic burden [51].

Migraine and anxiety disorders share common genetic and environmental risk factors, and an interaction between migraine and anxiety is established. Auditory center, limbic system, and vestibular system interconnections may account for high rates of anxiety in patients with persistent tinnitus, fluctuating hearing loss, and vertigo symptoms in vestibular migraine or Ménière disease [51,148].

Ménière Disease and Endolymphatic Hydrops

The episodic vertigo, hearing loss, and tinnitus in Ménière disease is associated with endolymphatic hydrops in the labyrinthine system of the affected ear [125]. Ménière disease should be viewed and managed as a chronic condition, and treatment is tiered by disease stage and severity [149]. Acute symptomatic relief does not address the underlying pathophysiology, and the clinical goal is to minimize recurrent vertigo attacks and hearing symptoms to prevent new or additional damage to vestibular structures [150].

First Tier

Patients with Ménière disease are vulnerable to dietary and environmental factors that can impact hearing and balance. Triggers for Ménière disease may include high salt intake, caffeine, alcohol, nicotine, stress, monosodium glutamate, and allergies. Patients who identify and avoid triggers may greatly reduce their Ménière disease symptoms [150]. Therefore, lifestyle modification is the cornerstone of first-tier treatment.

Caffeine and nicotine are vasoconstrictors that may reduce microvascular flow in the labyrinthine system. Alcohol also causes fluid and electrolyte shifts that can stress a fragile ear. Smoking cessation and limiting daily intake to one caffeinated or alcoholic beverage are typically recommended [150].

When dietary and environmental changes fail to control the episodes, combinations of diuretic and as-needed vestibular suppressant/antiemetic agents are effective to control vertigo episodes in many patients, but do not protect hearing loss. Off-label use of sublingual lorazepam (0.5–1 mg up to four times per day) is anecdotally effective in achieving relief from acute vertigo attacks [150].

Betahistine is a conservative treatment option widely used in Europe for Ménière disease. It is believed to decrease symptoms by improving microcirculation in the inner ear and re-balancing endolymph production with resorption [151]. In one study, patients with mixed vestibular etiologies including Ménière disease received betahistine 48 mg/day. The decrease in average vertigo attacks per month from baseline to 60 days on betahistine persisted unchanged at 60 days off betahistine, which may suggest durable vestibular compensation [129]. As mentioned, demonstrating a treatment effect separate from spontaneous remission is difficult in Ménière disease and other s-EVS disorders.

Based on clinical experience with long-term treatment in patients with Ménière disease, long-term, high-dose betahistine is the recommended therapy, initiated at 48 mg three times per day [40,61]. If symptom alleviation is insufficient after three months, the dose can be increased up to 480 mg/day [119,152]. As noted, betahistine can be obtained at compounding pharmacies in the United States with a prescription [15].

Second Tier

Intratympanic injection (ITI) of corticosteroids is suggested for patients with Ménière disease-related disabling vertigo attacks despite conservative treatments, as the complication rates are low and side effects minimal. ITI of 0.4–1.0 mL high-dose dexamethasone solution (12 mg/mL) can improve vertigo symptoms and patient functioning, which may remain durable over 6 to 24 months [119]. However, patients may require repeated injections to maintain efficacy that can wane over time, and intratympanic gentamicin may be more effective [150].

Third Tier

Intratympanic gentamicin, a vestibulotoxic antibiotic, is a favored approach for Ménière disease refractory to less invasive options. Gentamicin induces unilateral vestibular loss to facilitate central compensation, reduce Ménière disease symptoms, and improve overall function [97,153]. Meta-analyses of published clinical trials found 92.7% of patients achieved complete or substantial vertigo control and 74.7% achieved complete vertigo control with intratympanic gentamicin [98,154].

ITI of gentamicin is ototoxic in some patients and has mainly been reserved for patients with Ménière disease and pre-existing hearing loss. To offset this limitation, a newer technique injects a minimal dose of gentamicin (0.5–0.75 mL of a 40 mg/mL solution) into the middle ear. A single injection provided good vertigo control over four years in 76% of patients; 15% to 20% required a second injection [150].

ITI gentamicin (2.0 mL of 40.0 mg/mL solution; up to two injections) was superior to ITI dexamethasone (4 mg/mL, three injections over seven days) in achieving complete vertigo control (81.0% vs. 43%) and complete or substantial vertigo control (93.5% vs. 61%). Significant hearing loss (>10 dB) developed in 13% of patients taking gentamicin [150,155].

Intractable Bilateral Ménière Disease

Ménière disease may become bilateral in 15% to 20% of patients, usually within the first several years of onset. Bilateral involvement limits some vestibular ablation options, because treating both ears can result in bilateral vestibular loss [15]. Treating one side may not relieve vertigo, and interventional treatment can cause permanent hearing loss in a patient already at risk of hearing loss in both ears [125].

Options for intractable Ménière disease include endolymphatic mastoid shunt procedures, vestibular neurectomy, or labyrinthectomy, the latter used only in patients already deaf in the affected ear. Ablative surgical procedures are mainly reserved for ITI gentamicin failure. Because the development of Ménière disease is multifactorial, no single approach to therapy is expected to become the standard for all patients [147].

Vestibular Migraine

Treatment efficacy for vestibular migraine is not well-studied, partially because the disorder was only defined in 2013 [156]. Established treatments for migraine and/or vertigo are primarily recommended as abortive or prophylactic therapies for migraine symptoms in vestibular migraine. These medications may improve both headache and vertigo symptoms but can be hit or miss, and patients may need several different trials to find an individualized therapy [156,157].

Symptomatic Treatment of Acute Episodes

Acute attacks of vestibular migraine are treated with vestibular suppressants that include benzodiazepines (e.g., clonazepam, lorazepam), antiemetics (e.g., promethazine), antihistamines (e.g., meclizine, dimenhydrinate), and anticholinergic agents (e.g., scopolamine) [157]. Patients with excessive nausea or vomiting may prefer non-oral (e.g., IV, nasal spray, suppositories, subcutaneous injections) routes [158].

Abortive Treatment

Acute migraine treatment with triptans may offer benefit for patients with vestibular migraine. Sumatriptan was particularly efficacious in improving vertigo; rizatriptan helped prevent motion sickness symptoms. Zolmitriptan probably has little benefit in vestibular migraine [157].

Prophylactic Treatment

Treatment with migraine prophylactic medication may be needed when symptoms are frequent or severe and interfere with quality of life [15]. The indications for prophylactic therapy in vestibular migraine mirror those in migraine, which consider the frequency, duration, and disabling nature of attacks [119]. If caffeine and other triggers play a role in inciting episodes, they should be avoided when possible, as avoidance may enhance the efficacy of prophylactic therapy in vestibular migraine [49,157].

Medications evaluated for prophylactic efficacy in vestibular migraine include antiepileptic drugs (e.g., topiramate, valproate/valproic acid, lamotrigine), beta-adrenergic blockers (e.g., propranolol, metoprolol sustained-release, bisoprolol), calcium channel blockers (e.g., flunarizine, verapamil extended-release, cinnarizine), and antidepressants (e.g., venlafaxine, nortriptyline, imipramine, amitriptyline). Prophylactic recommendations have been based on available evidence, attack frequency, and clinical profile (Table 3).

Table 3: PROPHYLACTIC PHARMACOTHERAPY FOR VESTIBULAR MIGRAINE

Characteristic

Recommended Agent(s)

By Available Evidence

High-quality evidence of efficacy

Topiramate 25–100 mg/day

Valproate 300–900 mg/day

Metoprolol sustained-release 50–200 mg/day

Moderate-quality evidence of efficacy

Propranolol 40–240 mg/day

Flunarizine 5–10 mg/day

Low-to-moderate-quality evidence of efficacy

Amitriptyline 50–100 mg/day

Verapamil extended-release 120–360 mg/day

Cinnarizine 37.5–75 mg/day

Lowest-quality evidence of efficacy

Acetazolamide 250–750 mg/day

By Attack Frequency

Three or more attacks per month or long-lasting/disabling attacks

First-line: Propranolol 80–240 mg/day, metoprolol 50–200 mg/day, or bisoprolol 5–10 mg/day

Second-line: Flunarizine 5–10 mg/day

Third-line: Topiramate 25–100 mg/day or valproic acid 500–600 mg/day

Fifteen migraine attacks or more than eight migraine headaches per month for longer than three months

First-line: Topiramate 25–100 mg/day

Second-line: A trial of onabotulinum toxin type A (155 MU) is reasonable but unlikely to improve vestibular symptoms

By Clinical Profile

Prominent nausea and/or headaches and less prominent or minimal anxiety

Verapamil 120–240 mg/day (well-tolerated medication with good efficacy)

Alternative: Topiramate 50–200 mg/day (often effective)

Prominent vertigo or dizziness, less frequent migraine headache

Lamotrigine 25–100 mg/day to reduce the frequency of vertigo episodes; less effective in reducing headache frequency

Severe vestibular migraine

Combination of two or three migraine prophylactic medications from different drug classes

Consider zonisamide or acetazolamide

Source: [15,15,119,158,159,160,161]

Vestibular Migraine and Anxiety

Patients with vestibular migraine are more anxious than patients with non-vestibular migraine [162]. Anxiety is so prevalent in vestibular migraine, migraine, and vestibular disorders that a new disorder—migraine-anxiety-related dizziness—was proposed to define the association [49].

The recommended pharmacotherapy for vestibular patients with prominent anxiety, panic attacks, or depression and less prominent nausea is [15]:

- Venlafaxine 75 mg/day, OR

- A tricyclic antidepressant (e.g., nortriptyline, imipramine, amitriptyline) 50–75 mg/day

The established efficacy of venlafaxine in anxiety disorder treatment suggests a potential advantage over other vestibular migraine prophylaxis. One study evaluated patients with vestibular migraine randomized to venlafaxine (37.5 mg/day), flunarizine (10 mg/day), or valproic acid (1,000 mg/day) for three months [163]. Significant decreases in precipitating physical factors and functional consequences of vestibular migraine were noted with all three medications. Improvements in emotional consequences of vestibular migraine (with venlafaxine only), vertigo attack severity (with venlafaxine and flunarizine but not valproic acid), and vertigo attack frequency (with venlafaxine and valproic acid but not flunarizine) were also noted. This suggests venlafaxine more effectively reduced emotional distress and anticipatory anxiety related to vestibular migraine attacks, as well as attack frequency and severity [163].

Other Treatment Options

Betahistine plus flunarizine leads to greater improvements in vertigo frequency and severity than betahistine alone. Decreases in headache frequency and severity are comparable [164].

Vestibular rehabilitation is effective, with improved symptoms and disability in patients with vestibular migraine as add-on treatment to medical therapy or as stand-alone treatment [49,157].

Vestibular Paroxysmia

With vestibular paroxysmia, the characteristic brevity (seconds up to a few minutes, very seldom many hours) and frequently of recurring vertigo attacks makes the differential diagnosis generally straightforward [46]. The frequent vertigo attacks respond to carbamazepine (200–800 mg/day) or oxcarbazepine (300–900 mg/day), even in the lower dose range. Both drugs are recommended to start with a low dose, slowly progressing to higher doses as necessary [119].

Second-Line Therapies for Carbamazepine/Oxcarbazepine Intolerance

Alternative drug options include phenytoin, gabapentin, valproate, lamotrigine, topiramate, and baclofen or other non-antiepileptic drugs used in trigeminal neuralgia [46]. Treatment should start with low doses. Options include [119]:

- Phenytoin 100 mg once daily, increased up to three times per day

- Gabapentin 300 mg once daily, increased to three times daily over four to seven days and further increased with insufficient symptom relief (up to a maximum 1,800 mg)

- Valproate dosing proportional to body weight (start with 10 mg per kg body weight, increasing the dose every three days up to 20 mg/kg)

Antiepileptic medications can themselves elicit dizziness and should be prescribed cautiously, ideally by specialists who can differentiate possible side effects from dizziness or vertigo sensations per se [119].

Refractory Vestibular Paroxysmia

Surgical microvascular decompression of the 8th cranial nerve is used for medically intractable cases or in rare cases with non-vascular compression of the 8th nerve by a tumor or cyst [46].

CHRONIC VESTIBULAR SYNDROMES

Context-Specific (Triggered) CVS

Most t-CVS syndromes have been defined too recently for consistently effective therapies to surface. There is some evidence for the treatment of bilateral vestibulopathy, PPPD, depersonalization and derealization disorder, and mal de débarquement syndrome.

Bilateral Vestibulopathy

The primary cause of bilateral vestibulopathy is aminoglycoside ototoxicity, typically gentamicin or streptomycin. In these cases, the ototoxic medication should be stopped or switched to a non-ototoxic drug. Other underlying causes of bilateral vestibulopathy include autoimmune processes, local or systemic infectious/inflammatory processes, bacterial or viral meningitis, bilateral Ménière disease, head trauma, neoplasms, or malformations. The cause should be identified and resolved or symptomatically managed [119].

Vestibular rehabilitation improves dynamic visual acuity, diminishes oscillopsia, and lessens asymmetry of vestibulo-ocular function by promoting adaptation and substitution using vision and proprioceptive cues to stabilize gait and mobility [165]. Vestibular rehabilitation is strongly recommended for patients with bilateral vestibulopathy [15,119].

Persistent Postural Perceptual Dizziness

Cognitive-behavioral therapy, possibly combined with an SNRI such as venlafaxine or duloxetine, is strongly recommended for patients with PPPD. Patients should be encouraged to not stop taking the antidepressant too early; four to five weeks is required to assess effectiveness [15,119]. Vestibular rehabilitation can help address phobic avoidance behavior.

Depersonalization and Derealization Disorder

Patients with depersonalization and derealization disorder have benefited from SSRIs, benzodiazepines, lamotrigine, opioid antagonists, and CNS stimulants, probably from targeting other mental disorders commonly associated with or precipitated by the disorder [80].

Mal de Débarquement Syndrome

There is no established treatment for mal de débarquement syndrome, but an uncontrolled trial suggests that inducement of re-adaptation of the vestibulo-ocular reflex may result in improvement. In this approach, patients are exposed periodically to a rocking that mimics the pace and direction of their perceived sway while in a full-field optokinetic stimulus [15,166].

Spontaneous CVS

Central Vestibular and Cerebellar Syndromes

The American Academy of Neurology has made the following treatment recommendations for cerebellar syndromes associated with nystagmus, vertigo, and ataxia [167]:

- Episodic ataxia type 2: 4-AP 15 mg/day

- Spinocerebellar ataxia or ataxia of mixed etiology: Riluzole

- Spinocerebellar ataxia type 3: Valproic acid 1,200 mg/day

- Spinocerebellar degeneration: Thyrotropin-releasing hormone over 14 days

- Degenerative ataxias: Inpatient rehabilitation (four weeks) to improve ataxia and function, transcranial magnetic stimulation to improve cerebellar motor signs

In episodic ataxia type 2, other treatment recommendations include [15,119]:

- Acetazolamide 375–1,500 mg/day

- Dalfampridine sustained-release 10 mg PO once or twice per day

Cervicogenic Vertigo

With cervical vertigo, treatment options include manual therapy, muscle relaxant or anti-inflammatory medication, and tailored vestibular rehabilitation. With significant nerve compression that cannot be treated conservatively, interventional approaches remain a therapeutic option [119].

Post-Traumatic Vertigo

In patients with post-traumatic vertigo, the primary diagnosis should be treated. With BPPV present, CRP plus vestibular rehabilitation is the recommended approach. For patients with brainstem or labyrinthine concussion, use vestibular rehabilitation. Vestibular suppressants may be added in cases of labyrinthine concussion [22].

12. DIZZINESS AND FALLS PREVENTION IN OLDER PATIENTS

Dizziness and imbalance in older adults deserves specific attention. Among older adults (i.e., age older than 65 years), falls are the leading cause of disability, institutionalization, and premature mortality from injury and the fifth leading cause of death. Fear of falling, also called post-fall anxiety syndrome, is a well-recognized syndrome in older adults [168,169,170]. In 2015, the estimated cost of fall-related injuries in older adults in the United States was $50 billion [171].

As such, vestibular dysfunction is critical to identify in older adults. Dizziness is highly prevalent (up to 38%) in older patients, and symptomatic dizziness or vertigo substantially increases the risk for falls [172,173].

During 2001–2004, an estimated 35.4% of adult Americans had vestibular dysfunction requiring medical attention. The prevalence of balance impairment and vestibular dysfunction increases with age—the rate is 75% among persons older than 70 years and 85% among persons 80 years of age or older. Persons with vestibular disorders have an eight-fold increase in risk of falling and resultant morbidity/mortality. Uncompensated vestibular hypofunction results in postural instability, visual blurring with head movement, and subjective complaints of dizziness and/or imbalance [44].

RISK FACTORS FOR FALLS IN THE ELDERLY

Falls typically result when age-related and environmental (e.g., unfamiliar surroundings, unsafe walking surface) risk factors intersect. Gait and balance impairment are the most consistent risk factors, followed by medications (e.g., benzodiazepines, antidepressants) and polypharmacy [174]. Older patients may have multiple risk factors, including vestibular dysfunction, cerebrovascular disease, cervical spine disorders, physical deconditioning, and postural hypotension. Visual impairment is common and promotes multisensory deficit [173,175].

Postural control and balance rely on sensory input from proprioceptive and vestibular systems. Age-related changes in these systems impair postural control and increase the risk of falls; they include loss of proprioceptive sensitivity in the lower extremities and loss of labyrinthine hair cells, vestibular ganglion cells, and nerve fibers in the vestibular system [174]. Compounding the loss of proprioceptive and vestibular function are age-related changes in the CNS, including neuronal loss and neurotransmitter depletion, causing further impairments in postural control [174].

ASSESSMENT OF FALLS RISK

A targeted history and physical exam can identify patients at risk for falling. All older patients, especially patients with a dizziness/vertigo diagnosis, should be asked at least once yearly about falls [174]. Questions for initial screening of falls risk include [22]:

- Have you had a fall in the past year? How many times? Were you injured?

- Do you feel unsteady when standing or walking?

- Do you worry about falling?

With positive response, the clinician can perform a more detailed assessment or refer the patient to a specialist [22]. Treatment should be directed at the most readily modifiable fall risk factor(s) [173].

Clinicians should counsel patients and their families on the risk of falls with any balance, dizziness, or vestibular disorder, especially the frail elderly, who are more susceptible to serious injury from falling. Counseling should occur during the initial diagnosis and can include assessment of home safety, activity restrictions, and the need for home supervision until symptoms resolve. Healthcare providers should also ask about dizziness while driving, which may require intervention to prevent patient and public injury or fatality [22,173,176].

13. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient education is such an important aspect of the care of patients with dizziness/vertigo, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient or caregiver understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. In any case in which information regarding diagnostic procedures, treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered.

14. CONCLUSION

Knowledge advances are transforming the clinical care of patients with dizziness and vertigo. A paradigm-changing classification system and diagnostic algorithm for dizziness and vertigo affords greater diagnostic ease and accuracy for clinicians. An expanded understanding of the vestibular system highlights the relationship of anxiety to vestibular dysfunction. The differentiation of potentially dangerous cerebrovascular mimics of benign vertigo and dizziness enhances early detection and rapid intervention. The important contribution of vestibular dysfunction to risk for falls in the elderly has been clarified, as falls are a leading cause of disability and death from injury in this population. Despite the demonstrated efficacy of repositioning therapy for the management of BPPV and the ease with which this can be used in the primary care setting, patients with BPPV frequently experience delayed diagnosis, unnecessary testing, and non-recommended treatment. Thus, continuing education has an important role in helping to ensure that clinicians and their patients benefit from current concepts, tools of evaluation, and strategies for managing dizziness and vertigo.

15. RESOURCES

Vestibular Disorders Association (VeDA)

https://vestibular.org

Fall Prevention Center of Excellence

http://stopfalls.org

David E. Newman-Toker, MD, PhD

Johns Hopkins Medicine

HINTS Video

https://collections.lib.utah.edu/details?id=177180

Dix-Hallpike Maneuver Video

https://collections.lib.utah.edu/details?id=177177

Supine Head Roll Video

https://collections.lib.utah.edu/details?id=177185

Works Cited

1. Drachman DA, Hart CW. An approach to the dizzy patient. Neurology. 1972;22(4):323-334.

2. Goh LG. Dizziness update: a new approach and treatment based on timing and triggers. Arch Gen Intern Med. 2018;2(2):17-22.

3. Edlow JA. Diagnosing dizziness: we are teaching the wrong paradigm! Acad Emerg Med. 2013;20(10):1064-1066.

4. Ammar H, Govindu R, Fouda R, Zohdy W, Supsupine E. Dizziness in a community hospital: central neurological causes, clinical predictors, and diagnostic yield and cost of neuroimaging studies. J Community Hosp Intern Med Perspect. 2017;7(2):73-78.

5. Newman-Toker DE, Cannon LM, Stofferahn ME, Rothman RE, Hsieh YH, Zee DS. Imprecision in patient reports of dizziness symptom quality: a cross-sectional study conducted in an acute care setting. Mayo Clin Proc. 2007;82(11):1329-1340.

6. Stanton VA, Hsieh YH, Camargo CA Jr, et al. Overreliance on symptom quality in diagnosing dizziness: results of a multicenter survey of emergency physicians. Mayo Clin Proc. 2007;82(11):1319-1328.

7. Muncie HL, Sirmans SM, James E. Dizziness: approach to evaluation and management. Am Fam Physician. 2017;95(3):154-162.

8. Edlow JA, Gurley KL, Newman-Toker DE. A new diagnostic approach to the adult patient with acute dizziness. J Emerg Med. 2018;54(4):469-483.

9. Palmeri R. Benign Paroxysmal Positional Vertigo (BPPV). Available at http://knowledge.statpearls.com/chapter/0/38044. Last accessed September 12, 2018.

10. Edlow JA. Diagnosing patients with acute-onset persistent dizziness. Ann Emerg Med. 2018;71(5):625-631.

11. Tucci DL. Dizziness and Vertigo. Available at https://www.merckmanuals.com/professional/ear,-nose,-and-throat-disorders/approach-to-the-patient-with-ear-problems/dizziness-and-vertigo. Last accessed September 12, 2018.

12. Rughani AI. Brain Anatomy. Available at https://emedicine.medscape.com/article/1898830-overview. Last accessed September 12, 2018.

13. Lee C, Jones TA. Neuropharmacological targets for drug action in vestibular sensory pathways. J Audiol Otol. 2017;21(3):125-132.

14. Cronin T, Arshad Q, Seemungal BM. Vestibular deficits in neurodegenerative disorders: balance, dizziness, and spatial disorientation. Front Neurol. 2017;8:538.

15. Fife TD. Dizziness in the outpatient care setting. Continuum (Minneap Minn). 2017;23(2):359-395.

16. Merfeld DM, Priesol A, Lee D, Lewis RF. Potential solutions to several vestibular challenges facing clinicians. J Vestib Res. 2010;20(1):71-77.

17. Shupert CL. Vestibular Neuritis and Labyrinthitis. Available at https://vestibular.org/labyrinthitis-and-vestibular-neuritis. Last accessed September 12, 2018.

18. Baumgartner B. Peripheral Vertigo. Available at https://www.statpearls.com/kb/viewarticle/27021. Last accessed September 12, 2018.

19. Beh SC. Top 5 CNS Causes of Dizziness. Available at http://www.neurologytimes.com/headache-and-migraine/top-5-cns-causes-dizziness. Last accessed September 12, 2018.

20. Stanton M. Vertigo. Available at http://knowledge.statpearls.com/chapter/0/31130. Last accessed September 12, 2018.

21. Pérez-Vázquez P, Franco-Gutiérrez V. Treatment of benign paroxysmal positional vertigo: a clinical review. J Otol. 2017;12(4):165-173.

22. Bhattacharyya N, Gubbels SP, Schwartz SR, et al. Clinical practice guideline: benign paroxysmal positional vertigo (update). Otolaryngol Head Neck Surg. 2017;156(3 Suppl):S1-S47.

23. Shepard NT. Signs and Symptoms of Central Vestibular Disorders. Available at https://www.asha.org/Articles/Signs-and-Symptoms-of-Central-Vestibular-Disorders. Last accessed September 12, 2018.

24. Woodhouse S. Benign Paroxysmal Positional Vertigo (BPPV). Available at https://vestibular.org/understanding-vestibular-disorders/types-vestibular-disorders/benign-paroxysmal-positional-vertigo. Last accessed September 12, 2018.

25. Kollén L, Frändin K, Möller M, Fagevik Olsén M, Möller C. Benign paroxysmal positional vertigo is a common cause of dizziness and unsteadiness in a large population of 75-year-olds. Aging Clin Exp Res. 2012;24(4):317-323.

26. Kerrigan MA, Costigan MF, Blatt KJ, Mathiason MA, Domroese ME. Prevalence of benign paroxysmal positional vertigo in the young adult population. Phys Med Rehab. 2013;5(9):778-785.

27. Ekvall Hansson E, Månsson NO, Håkansson A. Benign paroxysmal positional vertigo among elderly patients in primary health care. Gerontology. 2005;51(6):386-389.

28. von Brevern M, Radtke A, Lezius F, et al. Epidemiology of benign paroxysmal positional vertigo: a population based study. J Neurol Neurosurg Psychiatry. 2007;78(7):710-715.

29. Shaia WT. Dizziness Evaluation: Overview, Technique, Pathology and Treatment. Available at https://emedicine.medscape.com/article/1831429-overview. Last accessed September 12, 2018.

30. Talmud JD. Dix Hallpike Maneuver. Available at http://knowledge.statpearls.com/chapter/0/20632. Last accessed September 12, 2018.

31. D'Silva LJ, Whitney SL, Santos M, Dai H, Kluding PM. The impact of diabetes on mobility, balance, and recovery after repositioning maneuvers in individuals with benign paroxysmal positional vertigo. J Diabetes Complications. 2017;31(6):976-982.

32. von Brevern M, Bertholon P, Brandt T, et al. Benign paroxysmal positional vertigo: diagnostic criteria. J Vestib Res. 2015;25(3-4):105-117.

33. House MG, Honrubia V. Theoretical models for the mechanisms of benign paroxysmal positional vertigo. Audiol Neurootol. 2003;8(2):91-99.

34. Messina A, Casani AP, Manfrin M, Guidetti G. Italian survey on benign paroxysmal positional vertigo. Acta Otorhinolaryngol Ital. 2017;37(4):328-335.

35. Jeong SH, Kim HJ, Kim JS. Vestibular neuritis. Semin Neurol. 2013;33(3):185-194.

36. Boston ME. Labyrinthitis. Available at https://emedicine.medscape.com/article/856215-overview. Last accessed September 12, 2018.

37. Newman-Toker DE, Edlow JA. TiTrATE: a novel, evidence-based approach to diagnosing acute dizziness and vertigo. Neurol Clin. 2015;33(3):577-599.

38. Lopez-Escamez JA, Carey J, Chung WH, et al. Diagnostic criteria for Ménière's disease. J Vestib Res. 2015;25(1):1-7.

39. Li JC. Meniere Disease (Idiopathic Endolymphatic Hydrops). Available at https://emedicine.medscape.com/article/1159069-overview. Last accessed September 12, 2018.

40. Strupp M, Dieterich M, Brandt T. The treatment and natural course of peripheral and central vertigo. Dtsch Arztebl Int. 2013;110(29-30):505-515.

41. Strupp M, Kim JS, Murofushi T, et al. Bilateral vestibulopathy: diagnostic criteria consensus document of the Classification Committee of the Bárány Society. J Vestib Res. 2017;27(4):177-189.

42. Ward BK, Agrawal Y, Hoffman HJ, Carey JP, Della Santina CC. Prevalence and impact of bilateral vestibular hypofunction: results from the 2008 US National Health Interview Survey. JAMA Otolaryngol Head Neck Surg. 2013;139(8):803-810.

43. Lucieer F, Vonk P, Guinand N, Stokroos R, Kingma H, van de Berg R. Bilateral vestibular hypofunction: insights in etiologies, clinical subtypes, and diagnostics. Front Neurol. 2016;7:26.

44. Hall CD, Herdman SJ, Whitney SL, et al. Vestibular rehabilitation for peripheral vestibular hypofunction: an evidence-based clinical practice guideline. J Neurol Phys Ther. 2016;40(2):124-155.

45. Strupp M, Lopez-Escamez JA, Kim JS, et al. Vestibular paroxysmia: diagnostic criteria. J Vestib Res. 2016;26(5-6):409-415.

46. Brandt T, Strupp M, Dieterich M. Vestibular paroxysmia: a treatable neurovascular cross-compression syndrome. J Neurol. 2016;263(Suppl 1):S90-S96.

47. Strupp M, von Stuckrad-Barre S, Brandt T, Tonn JC. Teaching neuroimages: compression of the eighth cranial nerve causes vestibular paroxysmia. Neurology. 2013;80(7):e77.

48. Antunes MB. CNS Causes of Vertigo. Available at https://emedicine.medscape.com/article/884048-overview. Last accessed September 12, 2018.

49. Dieterich M, Obermann M, Celebisoy N. Vestibular migraine: the most frequent entity of episodic vertigo. J Neurol. 2016;263(Suppl 1):S82-S89.

50. Balaban CD, Jacob RG, Furman JM. Neurologic bases for comorbidity of balance disorders, anxiety disorders and migraine: neurotherapeutic implications. Expert Rev Neurother. 2011;11(3):379-394.

51. Yuan Q, Yu L, Shi D, Ke X, Zhang H. Anxiety and depression among patients with different types of vestibular peripheral vertigo. Medicine (Baltimore). 2015;94(5):e453.

52. Lee H. Isolated vascular vertigo. J Stroke. 2014;16(3):124-130.

53. Caplan LR. Posterior Circulation Cerebrovascular Syndromes. Available at https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes. Last accessed September 12, 2018.

54. Lang ES. Vertebrobasilar Atherothrombotic Disease. Available at https://emedicine.medscape.com/article/794678-overview. Last accessed September 12, 2018.

55. Pirau L. Vertebrobasilar Insufficiency. Available at http://knowledge.statpearls.com/chapter/0/31123. Last accessed September 12, 2018.

56. Lee H, Sohn SI, Cho YW, et al. Cerebellar infarction presenting isolated vertigo: frequency and vascular topographical patterns. Neurology. 2006;67(7):1178-1183.

57. Lee SU, Park SH, Park JJ, et al. Dorsal medullary infarction: a distinct syndrome of isolated central vestibulopathy. Stroke. 2015;46(11):3081-3087.

58. Zhou G, Gopen Q, Poe DS. Clinical and diagnostic characterization of canal dehiscence syndrome: a great otologic mimicker.Otol Neurotol. 2007;28(7):920-926.

59. Bertholon P, Karkas A. Otologic disorders causing dizziness, including surgery for vestibular disorders. Handb Clin Neurol. 2016;137:279-293.

60. Foris LA. Central Vertigo. Available at http://knowledge.statpearls.com/chapter/0/19151. Last accessed September 12, 2018.

61. Strupp M, Kremmyda O, Brandt T. Pharmacotherapy of vestibular disorders and nystagmus. Semin Neurol. 2013;33(3):286-296.

62. Staab JP, Eckhardt-Henn A, Horii A, et al. Diagnostic criteria for persistent postural-perceptual dizziness (PPPD): consensus document of the committee for the Classification of Vestibular Disorders of the Bárány Society. J Vestib Res. 2017;27(4):191-208.

63. Lee JO, Lee ES, Kim JS, et al. Altered brain function in persistent postural perceptual dizziness: a study on resting state functional connectivity. Hum Brain Mapp. 2018;39(8):3340-3353.

64. Wada M, Takeshima T, Nakamura Y, et al. Association between smoking and the peripheral vestibular disorder: a retrospective cohort study. Scientific Reports. 2017;7:16889.

65. Wei W, Sayyid ZN, Ma X, Wang T, Dong Y. Presence of anxiety and depression symptoms affects the first time treatment efficacy and recurrence of benign paroxysmal positional vertigo. Front Neurology. 2018;9:178.

66. Simon NM, Pollack MH, Tuby KS, Stern TA. Dizziness and panic disorder: a review of the association between vestibular dysfunction and anxiety. Ann Clin Psychiatry. 1998;10(2):75-80.

67. Balaban CD, Jacob RG. Background and history of the interface between anxiety and vertigo. J Anxiety Disord. 2001;15(1-2):27-51.

68. Balaban CD, Thayer JF. Neurological bases for balance-anxiety links. J Anxiety Disord. 2001;15(1-2):53-79.

69. Bigelow RT, Agrawal Y. Vestibular involvement in cognition: visuospatial ability, attention, executive function, and memory.J Vestib Res. 2015;25(2):73-89.

70. Coelho CM, Silva J, Pereira AF, et al. Visual-vestibular and postural analysis of motion sickness, panic, and acrophobia. Acta Neuropsychologica. 2017;15(1):21-33.

71. Staab JP. Functional and psychiatric vestibular disorders. Handb Clin Neurol. 2016;137:341-351.

72. Dieterich M, Staab JP, Brandt T. Functional (psychogenic) dizziness. Handb Clin Neurol. 2016;139:447-468.

73. Jacob RG, Redfern MS, Furman JM. Space and motion discomfort and abnormal balance control in patients with anxiety disorders. J Neurol Neurosurg Psychiatry. 2009;80(1):74-78.

74. Staab JP, Rohe DE, Eggers SD, Shepard NT. Anxious, introverted personality traits in patients with chronic subjective dizziness.J Psychosom Res. 2014;76(1):80-83.

75. Brandt T, Grill E, Strupp M, Huppert D. Susceptibility to fear of heights in bilateral vestibulopathy and other disorders of vertigo and balance. Front Neurol. 2018;9:406.

76. Furman JM, Jacob RG. A clinical taxonomy of dizziness and anxiety in the otoneurological setting. J Anxiety Disord. 2001;15(1-2):9-26.

77. Viaud-Delmon I, Venault P, Chapouthier G. Behavioral models for anxiety and multisensory integration in animals and humans. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(6):1391-1399.

78. Medendorp WP, Alberts BBGT, Verhagen WIM, Koppen M, Selen LPJ. Psychophysical evaluation of sensory reweighting in bilateral vestibulopathy. Front Neurol. 2018;9:377.

79. Maire R, Mallinson A, Ceyte H, et al. Discussion about visual dependence in balance control: European Society for Clinical Evaluation of Balance Disorders. J Int Adv Otol. 2017;13(3):404-406.

80. Spiegel D. Depersonalization/Derealization Disorder. Available at https://www.merckmanuals.com/professional/psychiatric-disorders/dissociative-disorders/depersonalization-derealization-disorder. Last accessed September 12, 2018.

81. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013.

82. Spiegel D, Loewenstein RJ, Lewis-Fernandez R, et al. Dissociative disorders in DSM-5. Depress Anxiety. 2011;28(9):824-852.

83. Michal M, Adler J, Wiltink J, et al. A case series of 223 patients with depersonalization-derealization syndrome. BMC Psychiatry. 2016;16:203.

84. Jáuregui RK. Vestibular function and depersonalization/derealization symptoms. Multisens Res. 2015;28(5-6):637-651.

85. Schulz A, Köster S, Beutel ME, et al. Altered patterns of heartbeat-evoked potentials in depersonalization/derealization disorder: neurophysiological evidence for impaired cortical representation of bodily signals. Psychosom Med. 2015;77(5):506-516.

86. Aranda-Moreno C, Jáuregui-Renaud K. Derealization during utricular stimulation. J Vestib Res. 2016;26(5-6):425-431.

87. Kolev OI, Georgieva-Zhostova SO, Berthoz A. Anxiety changes depersonalization and derealization symptoms in vestibular patients. Behavioural Neurology. 2014;847054.

88. Lopez C, Elzière M. Out-of-body experience in vestibular disorders: a prospective study of 210 patients with dizziness. Cortex. 2018;104:193-206.

89. Smith PF. The vestibular system and cognition. Curr Opin Neurol. 2017;30(1):84-89.

90. Bramley H, Hong J, Zacko C, Royer C, Silvis M. Mild traumatic brain injury and post-concussion syndrome: treatment and related sequela for persistent symptomatic disease. Sports Meds Arthrosc. 2016;24(3):123-129.

91. Mullally WJ. Concussion. Am J Med. 2017;130(8):885-892.

92. Fife TD, Kalra D. Persistent vertigo and dizziness after mild traumatic brain injury. Ann Acad NY Sci. 2015;1343:97-105.

93. Arshad Q, Roberts RE, Ahmad H, et al. Patients with chronic dizziness following traumatic head injury typically have multiple diagnoses involving combined peripheral and central vestibular dysfunction. Clin Neurol Neurosurg. 2017;155:17-19.

94. Reiley AS, Vickory FM, Funderburg SE, Cesario RA, Clendaniel RA. How to diagnose cervicogenic dizziness. Arch Physiother. 2017;7:12.

95. Chimirri S, Aiello R, Mazzitello C, et al. Vertigo/dizziness as a drugs' adverse reaction. J Pharmacol Pharmacother. 2013;4(Suppl 1):S104-S109.

96. Hamed SA. The auditory and vestibular toxicities induced by antiepileptic drugs. Expert Opin Drug Saf. 2017;16(11):1281-1294.

97. Mudd PA. Ototoxicity. Available at https://emedicine.medscape.com/article/857679-overview. Last accessed September 12, 2018.

98. Selimoglu E. Aminoglycoside-induced ototoxicity. Curr Pharm Des. 2007;13(1):119-126.

99. Gürkov R. Amiodarone: a newly discovered association with bilateral vestibulopathy. Front Neurol. 2018;9:119.

100. Lai P, Coulson C, Pothier DD, Rutka J. Chlorhexidine ototoxicity in ear surgery, part 1: review of the literature. J Otolaryngol Head Neck Surg. 2011;40(6):437-440.

101. Gold DR. Dizziness and Vertigo Update. Available at http://upandrunningnetworks.com/files/C137_2.pdf. Last accessed September 12, 2018.

102. Strupp ML. How to take the patient history. Presented at: The 3rd Congress of the European Academy of Neurology; Amsterdam, The Netherlands: June 24–27, 2017.

103. Bardorf CM. Acquired Nystagmus. Available at https://emedicine.medscape.com/article/1199177-overview. Last accessed September 12, 2018.

104. Nelson JA, Viire E. The clinical differentiation of cerebellar infarction from common vertigo syndromes. West J Emerg Med. 2009;10(4):273-277.

105. Saber TAS, Kattah JC, Mantokoudis G, et al. Small strokes causing severe vertigo: frequency of false-negative MRIs and nonlacunar mechanisms. Neurology. 2014;83(2):169-173.

106. National Institutes of Health. A classification and outline of cerebrovascular diseases. II. Stroke. 1975;6(5):564-616.

107. Paul NL, Simoni M, Rothwell PM, Oxford Vascular Study. Transient isolated brainstem symptoms preceding posterior circulation stroke: a population-based study. Lancet Neurol. 2013;12(1):65-71.

108. Calic Z, Cappelen-Smith C, Anderson CS, Xuan W, Cordato DJ. Cerebellar infarction and factors associated with delayed presentation and misdiagnosis. Cerebrovasc Dis. 2016;42(5-6):476-484.

109. Arch AE, Weisman DC, Coca S, Nystrom KV, Wira CR 3rd, Schindler JL. Missed ischemic stroke diagnosis in the emergency department by emergency medicine and neurology services. Stroke. 2016;47(3):668-673.

110. Richoz B, Hugli O, Dami F, Carron PN, Faouzi M, Michel P. Acute stroke chameleons in a university hospital: risk factors, circumstances, and outcomes. Neurology. 2015;85(6):505-511.

111. Cutfield NJ, Seemungal BM, Millington H, Bronstein AM. Diagnosis of acute vertigo in the emergency department. Emerg Med J. 2011;28(6):538-539.

112. Jacob RG, Furman JM, Durrant JD, Turner SM. Panic, agoraphobia, and vestibular dysfunction. Am J Psychiatry. 1996;153(4):503-512.

113. Soto-Varela A, Rossi-Izquierdo M, Sanchez-Sellero I, Santos-Perez S. Revised criteria for suspicion of non-benign positional vertigo. QJM. 2013;106(4):317-321.

114. Lee SH, Kim JS. Benign paroxysmal positional vertigo. J Clin Neurol. 2010;6(2):51-63.

115. Katon WJ. Clinical practice: panic disorder. N Engl J Med. 2006;354(22):2360-2367.

116. Shah KH, Kleckner K, Edlow JA. Short-term prognosis of stroke among patients diagnosed in the emergency department with a transient ischemic attack. Ann Emerg Med. 2008;51(3):316-323.

117. Blum CA, Kasner SE. Transient ischemic attacks presenting with dizziness or vertigo. Neurol Clin. 2015;33(3):629-642.

118. Spiegel R, Kirsch M, Rosin C, et al. Dizziness in the emergency department: an update on diagnosis. Swiss Med Wkly. 2017;147:w14565.

119. Spiegel R, Rust H, Baumann T, et al. Treatment of dizziness: an interdisciplinary update. Swiss Med Wkly. 2017;147:w14566.

120. Popkirov S, Staab JP, Stone J. Persistent postural-perceptual dizziness (PPPD): a common, characteristic and treatable cause of chronic dizziness. Pract Neurol. 2018;18(1):5-13.

121. Kalla R, Teufel J, Feil K, Muth C, Strupp M. Update on the pharmacotherapy of cerebellar and central vestibular disorders.J Neurol. 2016;263(Suppl 1):S24-S29.

122. Bracher ES, Almeida CI, Almeida RR, Duprat AC, Bracher CB. A combined approach for the treatment of cervical vertigo.J Manipulative Physiol Ther. 2000;23(2):96-100.

123. Furman JM, Barton JJS. Evaluation of the Patient with Vertigo. Available at https://www.uptodate.com/contents/evaluation-of-the-patient-with-vertigo. Last accessed September 12, 2018.

124. Flake ZA, Linn BS, Hornecker JR. Practical selection of antiemetics in the ambulatory setting. Am Fam Physician. 2015;91(5):293-296.

125. Wipperman J. Dizziness and vertigo. Prim Care. 2014;41(1):115-131.

126. Cornett EM, Novitch M, Kaye AD, Kata V, Kaye AM. Medication-induced tardive dyskinesia: a review and update. Ochsner J. 2017;17(2):162-174.

127. Adrion C, Fischer CS, Wagner J, et al. Efficacy and safety of betahistine treatment in patients with Ménière disease: primary results of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial). BMJ. 2016;352:h6816.

128. Giommetti G, Lapenna R, Panichi R, et al. Residual dizziness after successful repositioning maneuver for idiopathic benign paroxysmal positional vertigo: a review. Audiol Res. 2017;7(1):178.

129. Parfenov VA, Golyk VA, Matsnev EI, et al. Effectiveness of betahistine (48 mg/day) in patients with vestibular vertigo during routine practice: the VIRTUOSO study. PLoS One. 2017;12(3):e0174114.

130. Perna G, Caldirola D. Management of treatment-resistant panic disorder. Curr Treat Options Psych. 2017;4(4):371-386.

131. Berul CI. Acquired Long QT Syndrome: Definitions, Causes, and Pathophysiology. Available at https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-causes-and-pathophysiology. Last accessed September 12, 2018.

132. Furman JM, Barton JJS. Treatment of Vertigo. Available at https://www.uptodate.com/contents/treatment-of-vertigo. Last accessed September 12, 2018.

133. Farrell L. Peripheral versus Central Vestibular Disorders. Available at http://www.neuropt.org/docs/vsig-physician-fact-sheets/peripheral-vs-central-vestibular-disorders.pdf?sfvrsn=e8c34543_2. Last accessed September 12, 2018.

134. Helmchen C, Klinkenstein JC, Krüger A, Gliemroth J, Mohr C, Sander T. Structural brain changes following peripheral vestibulo-cochlear lesion may indicate multisensory compensation. J Neurol Neurosurg Psychiatry. 2011;82(3):309-316.

135. Zingler VC, Weintz E, Jahn K, et al. Follow-up of vestibular function in bilateral vestibulopathy. J Neurol Neurosurg Psychiatry. 2008;79(3):284-288.

136. Cousins S, Cutfield NJ, Kaski D, et al. Visual dependency and dizziness after vestibular neuritis. PLoS One. 2014;9(9):e105426.

137. Cousins S, Kaski D, Cutfield N, et al. Predictors of clinical recovery from vestibular neuritis: a prospective study. Ann Clin Translational Neurol. 2017;4(5):340-346.

138. Furman JM. Vestibular Neuritis and Labyrinthitis. Available at https://www.uptodate.com/contents/vestibular-neuritis-and-labyrinthitis. Last accessed September 12, 2018.

139. Godemann F, Schuller J, Uhlemann H, et al. Psychodynamic vulnerability factors in the development of panic disorders: a prospective trial in patients after vestibular neuritis. Psychopathology. 2009;42(2):99-107.

140. Hilton MP, Pinder DK. The Epley (canalith repositioning) manoeuvre for benign paroxysmal positional vertigo. Cochrane Database Syst Rev. 2014;12:CD003162.

141. Gufoni M, Mastrosimone L, Di Nasso F. Repositioning maneuver in benign paroxysmal vertigo of horizontal semicircular canal. Acta Otorhinolaryngol Ital. 1998;18(6):363-367.

142. Anagnostou E, Kouzi I, Spengos K. Diagnosis and treatment of anterior-canal benign paroxysmal positional vertigo: a systematic review. J Clin Neurol. 2015;11(3):262-267.

143. Kahraman SS, Arli C, Copoglu US, Kokacya MH, Colak S. The evaluation of anxiety and panic agoraphobia scores in patients with benign paroxysmal positional vertigo on initial presentation and at the follow-up visit. Acta Otolaryngol. 2017;137(5):485-489.

144. Guneri EA, Kustutan O. The effects of betahistine in addition to Epley maneuver in posterior canal benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg. 2012;146(1):104-108.

145. Chen CC, Cho HS, Lee HH, Hu CJ. Efficacy of repositioning therapy in patients with benign paroxysmal positional vertigo and preexisting central neurologic disorders. Front Neurol. 2018;9:486.

146. Jung HJ, Koo JW, Kim CS, Kim JS, Song JJ. Anxiolytics reduce residual dizziness after successful canalith repositioning maneuvers in benign paroxysmal positional vertigo. Acta Otolaryngol. 2012;132(3):277-284.

147. Volkenstein S, Dazert S. Recent surgical options for vestibular vertigo. GMS Curr Top Otorhinolaryngol Head Neck Surg. 2017;16:1.

148. Krog NH, Engdahl B, Tambs K. The association between tinnitus and mental health in a general population sample: results from the HUNT Study. J Psychoso Res. 2010;69(3):289-298.

149. Nauta JJ. Meta-analysis of clinical studies with betahistine in Ménière's disease and vestibular vertigo. Eur Arch Otorhinolaryngol. 2014;271(5):887-897.

150. Moskowitz HS, Dinces EA. Meniere Disease. Available at https://www.uptodate.com/contents/meniere-disease. Last accessed September 12, 2018.

151. Møller MN, Kirkeby S, Vikeså J, Nielsen FC, Caye-Thomasen P. Expression of histamine receptors in the human endolymphatic sac: the molecular rationale for betahistine use in Ménière's disease. Eur Arch Otorhinolaryngol. 2016;273(7):1705-1710.

152. Lezius F, Adrion C, Mansmann U, Jahn K, Strupp M. High-dosage betahistine dihydrochloride between 288 and 480 mg/day in patients with severe Ménière's disease: a case series. Eur Arch Otorhinolaryngol. 2011;268(8):1237-1240.

153. Rybak LP, Whitworth CA. Ototoxicity: therapeutic opportunities. Drug Discov Today. 2005;10(19):1313-1321.

154. Cohen-Kerem R, Kisilevsky V, Einarson TR, Kozer E, Koren G, Rutka JA. Intratympanic gentamicin for Menière's disease: a meta-analysis. Laryngoscope. 2004;114(12):2085-2091.

155. Casani AP, Piaggi P, Cerchiai N, Seccia V, Franceschini SS, Dallan I. Intratympanic treatment of intractable unilateral Ménière disease: gentamicin or dexamethasone? A randomized controlled trial. Otolaryngol Head Neck Surg. 2012;146(3):430-437.

156. Iliades C. Carving Out an Identity for Vestibular Migraine. Available at http://www.neurologyadvisor.com/migraine-and-headache/vestibular-migraine-diagnosis-and-treatment/article/394575. Last accessed September 12, 2018.

157. Robertson CE. Vestibular Migraine. Available at https://www.uptodate.com/contents/vestibular-migraine. Last accessed September 12, 2018.

158. Obermann M, Strupp M. Current treatment options in vestibular migraine. Front Neurol. 2014;5:257.

159. Bisdorff AR. Management of vestibular migraine. Ther Adv Neurol Disord. 2011;4(3):183-191.

160. Lempert T. Vestibular migraine. Semin Neurol. 2013;33(3):212-218.

161. Taghdiri F, Togha M, Razeghi Jahromi S, Refaeian F. Cinnarizine for the prophylaxis of migraine associated vertigo: a retrospective study. SpringerPlus. 2014;3:231.

162. Kutay Ö, Akdal G, Keskinoğlu P, Balcı BD, Alkın T. Vestibular migraine patients are more anxious than migraine patients without vestibular symptoms. J Neurol. 2017;264(Suppl 1):37-41.

163. Liu F, Ma T, Che X, Wang Q, Yu S. The efficacy of venlafaxine, flunarizine, and valproic acid in the prophylaxis of vestibular migraine. Front Neurol. 2017;8:524.

164. Lepcha A, Amalanathan S, Augustine AM, Tyagi AK, Balraj A. Flunarizine in the prophylaxis of migrainous vertigo: a randomized controlled trial. Eur Arch Otorhinolaryngol. 2014;271(11):2931-2936.

165. Porciuncula F, Johnson CC, Glickman LB. The effect of vestibular rehabilitation on adults with bilateral vestibular hypofunction: a systematic review. J Vestib Res. 2012;22(5-6):283-298.

166. Dai M, Cohen, B, Smouha E, Cho C. Readaptation of the vestibulo-ocular reflex relieves the mal de debarquement syndrome.Front Neurol. 2014;5:124.

167. Zesiewicz TA, Wilmot G, Kuo SH, et al. Comprehensive systematic review summary: treatment of cerebellar motor dysfunction and ataxia: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(10):464-471.

168. Austin N, Devine A, Dick I, Prince R, Bruce D. Fear of falling in older women: a longitudinal study of incidence, persistence, and predictors. J Am Geriatr Soc. 2007;55(10):1598-1603.

169. Deshpande N, Metter EJ, Lauretani F, Bandinelli S, Guralnik J, Ferrucci L. Activity restriction induced by fear of falling and objective and subjective measures of physical function: a prospective cohort study. J Am Geriatr Soc. 2008;56(4):615-620.

170. Visschedijk J, Achterberg W, Van Balen R, Hertogh C. Fear of falling after hip fracture: a systematic review of measurement instruments, prevalence, interventions, and related factors. J Am Geriatr Soc. 2010;58(9):1739-1748.

171. Florence CS, Bergen G, Atherly A, Burns E, Stevens J, Drake C. Medical costs of fatal and nonfatal falls in older adults. J Am Geriatr Soc. 2018;66(4):693-698.

172. Jumani K, Powell J. Benign paroxysmal positional vertigo: management and its impact on falls. Ann Otol Rhinol Laryngol. 2017;126(8):602-605.

173. Branch WT, Barton JJS. Approach to the Patient with Dizziness. Available at https://www.uptodate.com/contents/approach-to-the-patient-with-dizziness. Last accessed September 12, 2018.

174. Kiel DP. Falls in Older Persons: Risk Factors and Patient Evaluation. Available at https://www.uptodate.com/contents/falls-in-older-persons-risk-factors-and-patient-evaluation. Last accessed September 12, 2018.

175. Maarsingh OR, Dros J, Schellevis FG, et al. Causes of persistent dizziness in elderly patients in primary care. Ann Fam Med. 2010;8(3):196-205.

176. Rubenstein LZ. Falls in older people: epidemiology, risk factors and strategies for prevention. Age Ageing. 2006;35(suppl 2):ii37-ii41.

177. D'Silva LJ, Staecker H, Lin J, et al. Retrospective data suggests that the higher prevalence of benign paroxysmal positional vertigo in individuals with type 2 diabetes is mediated by hypertension. J Vestib Res. 2016;25(5-6):233-239.

178. Hain TC, Yacovino D. Pharmacologic treatment of persons with dizziness. Neurol Clin. 2005;23(3):831-853.

Evidence-Based Practice Recommendations Citations

1. Lopez-Escamez JA, Carey J, Chung WH, et al. Diagnostic criteria for Menière's disease. J Vestib Res. 2015;25(1):1-7. Available at http://www.jvr-web.org/images/55807-Lopez-Escamez.pdf. Last accessed September 18, 2018.

2. Bhattacharyya N, Gubbels SP, Schwartz SR, et al. Clinical practice guideline: benign paroxysmal positional vertigo (update). Otolaryngol Head Neck Surg. 2017;156(3 suppl):S1-S47. Available at http://journals.sagepub.com/doi/pdf/10.1177/0194599816689667. Last accessed September 18, 2018.

3. Staab JP, Eckhardt-Henn A, Horii A, et al. Diagnostic criteria for persistent postural-perceptual dizziness (PPPD): sonsensus document of the committee for the Classification of Vestibular Disorders of the Bárány Society. J Vestib Res. 2017;27(4):191-208. Available at https://content.iospress.com/articles/journal-of-vestibular-research/ves622. Last accessed September 18, 2018.

4. Hall CD, Herdman SJ, Whitney SL, et al. Vestibular rehabilitation for peripheral vestibular hypofunction: an evidence-based clinical practice guideline: from the American Physical Therapy Association Neurology Section. J Neurol Phys Ther. 2016;40(2):124-155. Summary available at https://www.asha.org/articlesummary.aspx?id=8589969232. Last accessed September 18, 2018.

40942 • Acute Coronary Syndrome

Lori L. Alexander, MTPW, ELS, MWC

www.netce.com

Copyright © 2018 NetCE, All rights reserved.

Acute coronary syndrome (ACS) is a spectrum of life-threatening disorders that includes unstable angina (UA), non-ST-segment elevation MI (NSTEMI), and ST-segment elevation MI (STEMI). Mortality rates have declined considerably over the past decade as therapeutic options have expanded and evidence-based guidelines have been developed for the diagnosis and treatment of NSTEMI and STEMI. The course begins by providing a context for ACS through a discussion of the epidemiology of coronary heart disease (CHD) and ACS, a description of the pathophysiology of ACS, and the primary prevention of CHD, which helps to lower the prevalence of ACS. The course then focuses on the diagnosis of UA/NSTEMI and STEMI and risk stratification in the emergency department setting. Although many of the same classes of drugs are used to treat UA/NSTEMI and STEMI, the therapeutic approaches vary considerably. The treatment of ACS is a complex issue because of the wide scope of cardiac disease related to ACS and the extensive treatment decisions involved. As such, the content is limited to an overview of the diagnosis, treatment, and secondary prevention in an uncomplicated course of ACS.

Table of Contents

40942 • Acute Coronary Syndrome

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. OVERVIEW OF ACUTE CORONARY SYNDROME

DEFINITION OF TERMS

PREVALENCE AND MORTALITY OF NSTEMI AND STEMI

PATHOPHYSIOLOGY OF ACS

RISK FACTORS FOR CHD

3. DIAGNOSIS AND RISK STRATIFICATION

HISTORY AND PHYSICAL EXAMINATION

DIAGNOSTIC EVALUATION

ECG

COMPREHENSIVE RISK SCORE AND PROGNOSIS

FINAL DIAGNOSIS

4. TREATMENT OF UA/NSTEMI

GENERAL CARE

ANALGESIC AND ANTI-ISCHEMIC THERAPY

ANTIPLATELET THERAPY

ANTICOAGULANT THERAPY

CHOICE OF TREATMENT STRATEGY: EARLY INVASIVE VS. ISCHEMIA-GUIDED STRATEGY

5. TREATMENT OF STEMI

TIMING

PCI

FIBRINOLYTIC THERAPY

NO REPERFUSION THERAPY

CABG

NONINVASIVE TESTING

GENERAL CARE AND ADJUVANT THERAPIES

6. DISCHARGE PLANNING AND SECONDARY PREVENTION

CARDIAC REHABILITATION

SECONDARY PREVENTION STRATEGIES

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

40942 • Acute Coronary Syndrome

Education Category. Medical / Surgical

Release Date. 07/01/2018

Expiration Date. 06/30/2021

Course Overview

Acute coronary syndrome (ACS) is a spectrum of life-threatening disorders that includes unstable angina (UA), non-ST-segment elevation MI (NSTEMI), and ST-segment elevation MI (STEMI). Mortality rates have declined considerably over the past decade as therapeutic options have expanded and evidence-based guidelines have been developed for the diagnosis and treatment of NSTEMI and STEMI. The course begins by providing a context for ACS through a discussion of the epidemiology of coronary heart disease (CHD) and ACS, a description of the pathophysiology of ACS, and the primary prevention of CHD, which helps to lower the prevalence of ACS. The course then focuses on the diagnosis of UA/NSTEMI and STEMI and risk stratification in the emergency department setting. Although many of the same classes of drugs are used to treat UA/NSTEMI and STEMI, the therapeutic approaches vary considerably. The treatment of ACS is a complex issue because of the wide scope of cardiac disease related to ACS and the extensive treatment decisions involved. As such, the content is limited to an overview of the diagnosis, treatment, and secondary prevention in an uncomplicated course of ACS.

Audience

This course is designed for physicians, physician assistants, and nurse practitioners to enhance their knowledge of the diagnosis, assessment, management, and secondary prevention of acute coronary syndrome.

Course Objective

The pace at which acute coronary syndrome guidelines are updated make it challenging for clinicians to remain current with the recommendations that lead to improved outcomes for this substantial patient population. The purpose of this course is to reduce the widening gap between care according to guidelines and actual care delivered by providing healthcare professionals with knowledge necessary to implement the most appropriate approach to diagnosis and treatment.

Learning Objectives

Upon completion of this course, you should be able to:

1. Discuss the prevalence and definition of coronary heart disease (CHD) and acute coronary syndrome (ACS).

2. Explain the pathophysiology of ACS, including the role of plaque formation and rupture.

3. Devise a strategy for screening and evaluation of asymptomatic individuals for ACS.

4. Describe the various clinical presentations of ACS and the differential diagnosis of chest pain, including considerations for non-English-proficient patients.

5. More effectively utilize ECG and cardiac biomarkers in the diagnosis of ST-segment elevation myocardial infarction (STEMI) and unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI).

6. Discuss the factors involved in risk stratification of individuals with suspected ACS.

7. Assess the consistency of your and your team's adherence to guidelines for the acute treatment of UA/NSTEMI.

8. Select the optimal anti-ischemic, antiplatelet, and anticoagulant agents for the treatment of UA/NSTEMI.

9. Distinguish between the clinical indications for an ischemia-guided or invasive strategy for patients with UA/NSTEMI.

10. Discuss the issue of timing in selecting reperfusion therapy for patients with STEMI.

11. Describe the role of percutaneous coronary intervention (PCI) for STEMI.

12. Identify contraindications and cautions for fibrinolysis in the treatment of STEMI.

13. List other reperfusion therapies used in the treatment of STEMI, and identify the appropriate therapy for individual patients.

14. Outline appropriate secondary prevention measures for patients with ACS.

15. Discuss the relationship between guideline adherence in practice and patient outcomes

Faculty

Lori L. Alexander, MTPW, ELS, MWC, is President of Editorial Rx, Inc., which provides medical writing and editing services on a wide variety of clinical topics and in a range of media. A medical writer and editor for more than 30 years, Ms. Alexander has written for both professional and lay audiences, with a focus on continuing education materials, medical meeting coverage, and educational resources for patients. She is the Editor Emeritus of the American Medical Writers Association (AMWA) Journal, the peer-review journal representing the largest association of medical communicators in the United States. Ms. Alexander earned a Master’s degree in technical and professional writing, with a concentration in medical writing, at Northeastern University, Boston. She has also earned certification as a life sciences editor and as a medical writer.

Faculty Disclosure

Contributing faculty, Lori L. Alexander, MTPW, ELS, MWC, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

John V. Jurica, MD, MPH

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Coronary heart disease (CHD), which encompasses angina pectoris (stable angina), coronary insufficiency (unstable angina or UA), and myocardial infarction (MI) affects an estimated 16.5 million Americans 20 years of age and older [1]. CHD is the leading cause of death in the United States, accounting for 43.8% of all deaths [1]. As a chronic disease, CHD has a significant impact on quality of life, negatively affecting physical, psychologic, and social well-being. CHD also carries a tremendous economic burden: an estimated direct and indirect cost of $204.4 billion. This figure is expected to grow to nearly $400 billion by 2035 [1].

Atherosclerosis, the underlying condition of CHD, is progressive, with periods of stable and nonstable disease. Periods of instability can cause the occurrence of acute coronary syndrome (ACS), a spectrum of life-threatening disorders that includes UA, non-ST-segment elevation MI (NSTEMI), and ST-segment elevation MI (STEMI). In 2014, there were 633,000 hospitalizations associated with a principal diagnosis of ACS [1]. As with CHD, the financial cost associated with ACS is high; the mean cost for the first ACS admission is an estimated $71,336 [1].

Advances in the understanding of the pathophysiology of ACS have led to the identification of UA/NSTEMI and STEMI as distinct clinical entities, with differences in prevalence, etiology, clinical features, treatment, and outcomes [2,3,4]. In addition, the development and evaluation of pharmacologic therapies and reperfusion procedures in a multitude of large-scale trials have resulted in a redefinition of the diagnosis and treatment of acute MI. The results of these trials have formed the evidence base for clinical practice guidelines developed by the American College of Cardiology (ACC) and the American Heart Association (AHA), in conjunction with other specialty organizations [2,3,5,6]. Despite the widespread dissemination of these guidelines and documentation of better outcomes and decreased risk for subsequent events with guideline-driven treatment, adherence to many aspects of guideline-directed treatment could be improved [7,8,9,10]. Variations in practice have resulted in reports of disparities in assessment, treatment, and outcomes across subgroups according to age, gender, race/ethnicity, risk level, type of MI, and practice setting [7,11,12,13,14,15,16,17,18]. Highlighting the different needs of different populations of patients and the disparities in care, as well as emphasizing the appropriate use of treatment guidelines, can help to reduce the gap between evidence-based care and actual care delivered.

The novel therapies for ACS developed over the past few years have reduced its associated morbidity and mortality [1]. However, treatment strategies can be complex, leaving many clinicians unsure of the most appropriate approach to diagnosis and treatment. Optimizing patient outcomes in ACS depends on several factors, including:

- Timely access to care

- Appropriate use of diagnostic tools, including cardiac biomarkers

- Systematic and accurate risk stratification

- Knowledge of the risks and benefits of treatment options (e.g., pharmacologic therapies, revascularization procedures)

- Appropriate follow-up care

- Adherence to secondary prevention measures

Primary care clinicians, emergency healthcare professionals, and cardiologists should understand these factors, especially as they relate to care in their specific settings, and should become familiar with evidence-based strategies for assessment, diagnosis, treatment, and prevention. Primary care clinicians are in a unique position to identify patients who may be at risk for CHD (and thus the potential for ACS) and to educate these patients regarding the benefits of lowering their risk profile through changes in health behaviors, such as smoking cessation, diet, exercise, and compliance with medications. However, adherence to guideline-recommended prevention strategies has been a challenge, in part because of frequently changing guidelines and gender disparities [19,20,21,22]. Primary care providers also play a crucial role in the care of patients after ACS, managing secondary prevention strategies.

Several registries have been developed to collect data on the use of guideline-directed treatment and patient outcomes. These initiatives include Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation? (CRUSADE) and the Acute Coronary Treatment and Intervention Outcome Network (ACTION)-Get With the Guidelines (GWTG) [23,24]. Data from these initiatives have shown that adherence to guidelines enhances outcomes [7,25,26].

Data related to CHD and ACS are taken from several sources, and differences in the source populations (e.g., age, gender, health status), and the dates of study should be considered when interpreting the findings (Table 1). Data from community surveillance programs enable the calculation of the prevalence and incidence of CHD, angina, and MI among identified populations. Individuals in these programs are asymptomatic and usually do not have CHD at the beginning of the study. Several registries have been established to collect information from multiple institutions on individuals with ACS, and these registries, along with data from quality improvement initiatives and large-scale, multi-institutional clinical trials, have served to provide demographic profiles of individuals with CHD and ACS, temporal patterns in treatment practices, and overall adherence to evidence-based guidelines. When reviewing data from registries, it is important to consider several factors, including differences in the composition of the populations (according to age, gender, and race/ethnicity), the type of ACS (UA, NSTEMI, or STEMI), variations in treatment according to the timeframe of the study (because of advances in treatment options), and better outcomes in quality improvement initiatives and clinical trials than in registries (because of level of care). Lastly, the National Hospital Care Survey provides information on discharge diagnoses, as well as national patterns of healthcare delivery in hospital-based settings and ambulatory surgery centers. Although information on discharge diagnoses can help provide a better understanding of the prevalence of the different components of ACS, because the survey is event-driven (rather than person-driven), the number of hospitalizations does not necessarily correlate to the number of individuals.

Table 1: SOURCES OF DATA ON CORONARY ARTERY DISEASE AND ACUTE CORONARY SYNDROME (ACS)

Data Source

Years

Population

Purpose

Community Surveillance Programs

Framingham Heart Study

(http://www.framinghamheartstudy.org)

1948 to present

5,209 men and women (original cohort)

5,124 adult children (and spouses) of original participants (1971)

4,095 grandchildren of original cohort (2002)

Age at entry: 30 to 62 years (original cohort)

Identify common factors or characteristics contributing to cardiovascular disease by following its development over a long period of time

Atherosclerosis Risk in Communities

(https://www2.cscc.unc.edu/aric)

1987–1989 to present

15,792 men and women in four U.S. communities

Age at entry: 45 to 64 years

Investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care, and disease by race, gender, location, and date

Cardiovascular Health Study

(http://www.chs-nhlbi.org)

1989 through 1999

5,201 men and women (687 black men and women added in 1992–1993)

Age at entry: 65 years or older

Observe risk factors for cardiovascular disease in individuals 65 years of age or older

Data Registries

National Registry of Myocardial Infarction (NRMI) 1-4

1990–2006

2.2 million men and women with acute myocardial infarction (MI)

Tracked the characteristics, treatment, and outcomes for patients with acute MI (largest observational registry of ACS)

National Cardiovascular Data Registries (NCDR)

(https://cvquality.acc.org/NCDR-Home)

1997

2,400 hospitals

2,000 outpatient providers

Provides data on evidence-based cardiovascular care, patient outcomes, and healthcare costs

Global Registry of Acute Coronary Events (GRACE)

1999

102,341 men and women with ACS at 247 hospitals in 30 countries

Ongoing international registry

Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry and Get With the Guidelines (GWTG)

2007 to present

More than 2,500 hospitals and more than 3 million patients

A national surveillance system to assess patients with STEMI and NSTEMI to provide data on patient outcomes and adherence to evidence-based guidelines

Source: [27,28,29]

This course begins by providing a context for ACS through a discussion of the epidemiology of CHD and ACS and the pathophysiology of ACS, as well as the primary prevention of CHD, which helps to lower the prevalence of ACS. The diagnostic evaluation of patients suspected of having ACS and risk stratification in the emergency department setting are presented in detail. Although many of the same classes of drugs are used to treat UA/NSTEMI and STEMI, the therapeutic approaches vary considerably. The treatment of ACS is a complex issue because of the wide scope of related cardiac disease and the extensive treatment decisions involved. As such, this course is limited to provide an overview of an uncomplicated course of ACS. Clinicians are encouraged to consult the evidence-based guidelines related to the diagnosis, treatment, and secondary prevention of ACS.

2. OVERVIEW OF ACUTE CORONARY SYNDROME

Since the early 1990s, an enhanced understanding of the pathogenesis of CHD has helped to create a framework for defining ischemic heart disease. The AHA/ACC define ACS as "a spectrum of conditions compatible with acute myocardial ischemia and/or infarction that are usually due to an abrupt reduction in coronary blood flow" [3]. The concept of ACS is helpful, as the initial clinical presentations of UA, NSTEMI, and STEMI often appear similar. However, UA/NSTEMI and STEMI differ in many ways, including their prevalence, severity, pathophysiology, clinical presentation, treatment, and prognosis.

DEFINITION OF TERMS

In patients with CHD, transient imbalances can occur in the supply and demand of oxygen to the myocardium. This ischemia can manifest as precordial chest discomfort, or angina pectoris. Angina is considered stable when it is precipitated by stress or exertion and rapidly resolves with rest or the use of nitrates. Angina is considered unstable when it occurs suddenly (without a precipitating factor); it may occur at rest and may increase in frequency or severity. With both stable angina and UA, ischemia is fully reversible, with no evidence of myocardial necrosis as indicated by elevated levels of serum cardiac biomarkers (e.g., cardiac troponin) [3]. UA may or may not be associated with signs of ischemic changes on electrocardiography (ECG), such as ST-segment depression or new T-wave inversion [3].

UA is closely related to NSTEMI, and the two entities are often indistinguishable from each other, especially during the initial evaluation of a patient [3]. Recognizing the continuum of UA and NSTEMI, the authors of the 2014 AHA/ACC guideline for the management of the conditions created the term NSTE-ACS (non-ST-elevation acute coronary syndromes) to replace "UA/NSTEMI" [3]. Unlike UA, NSTEMI is associated with myocardial necrosis and resultant release of cardiac biomarkers. In addition, the ECG usually shows ST-segment depression, transient ST-elevation, and/or prominent T-wave inversions, but these findings are not required for a diagnosis of NSTEMI [3]. In contrast, STEMI is associated with myocardial damage, with both elevated serum cardiac biomarker levels and persistent ST-segment elevation on ECG [2].

An MI was once defined according to symptoms, ECG abnormalities, and serum cardiac enzyme levels. The advent of more sensitive and specific cardiac biomarkers and imaging studies has led to an ability to detect smaller amounts of myocardial necrosis and, in turn, a need for a more precise definition of MI. The European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), the AHA, and the World Heart Federation jointly developed a consensus document establishing a universal definition of MI, which was most recently updated in 2012 [30]. According to the definition, MI may be diagnosed with the detection of rise and/or fall of cardiac biomarker levels (preferably cardiac troponin) with at least one value above the 99th percentile of the upper reference limit, together with evidence of myocardial ischemia with at least one of the following [30]:

- Symptoms of ischemia

- New or presumed new significant ST-segment T wave changes or new left bundle branch block

- Development of pathologic Q waves in the ECG

- Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

- Identification of an intracoronary thrombus by angiography or autopsy

The consensus document also classifies MI into six categories based on when or how the infarction occurs. Type 1 MI is defined as a "spontaneous [MI] related to atherosclerotic plaque rupture, ulceration, assuring, erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries, leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis" [30]. Other types are defined as occurring in conjunction with percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or stent thrombosis; secondary to increased oxygen demand or decreased supply (e.g., coronary artery spasm, arrhythmias); or sudden cardiac death [30].

PREVALENCE AND MORTALITY OF NSTEMI AND STEMI

The overall prevalence of CHD among adults is 6.3%, with a higher prevalence among men compared with women (7.4% vs. 5.3%) [1]. The prevalence increases with age, with the highest rates found among people 80 years and older (Figure 1) [1]. Women tend to be older than men at the time of a first cardiac event [14,31,32].

Figure 1: PREVALENCE OF MYOCARDIAL INFARCTION BY AGE AND SEX

Source : Reprinted with permission from Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2016 update. A report from the American Heart Association. Circulation. 2016;133(4):e39-e316.

The prevalence of CHD, MI, and angina vary considerably according to gender and race/ethnicity. For CHD, the rate is highest for white men (7.7%) and lowest for white women (5.3%); similarly, the prevalence of MI is highest for white men (4.0%) and lowest for Hispanic and black women (2.1% and 2.2%, respectively) (Table 2) [1]. The prevalence of angina is highest for black women (5.0%) and lowest for white women (2.9%) [1].

Table 2: PREVALENCE OF CORONARY HEART DISEASE (CHD), MYOCARDIAL INFARCTION (MI), AND ANGINA AMONG ADULTS 20 YEARS AND OLDER ACCORDING TO RACE/ETHNICITY

Condition

Men

Women

White

Black

Hispanic

White

Black

Hispanic

CHD

7.7%

7.1%

5.9%

5.3%

5.7%

6.1%

MI

4.0%

3.3

2.9%

2.4%

2.2%

2.1%

Angina

3.7%

3.5%

2.7%

3.3%

3.3%

3.8%

Source: [1]

ACS is also more prevalent among men; 785,000 of the more than 1.3 million unique hospitalizations for ACS (as a primary or secondary discharge diagnosis) occurred among men, compared with 554,000 among women [1]. Of all of these unique hospitalizations, 957,000 were for MI alone, 682,000 were for UA alone [1]. Data on the population characteristics of patients with MI in the ACTION Registry-GWTG provide insight on racial/ethnic variations in MI. Among 119,967 patients, approximately 86% were white, 12% were black, and 2% were Asian; 0.6% and 0.2% were American Indian/Alaskan or Hawaiian/Pacific Islander, respectively [33]. In addition, approximately 5% were of Hispanic or Latino ethnicity [33].

The incidence of STEMI has decreased since 2003, while the incidence of NSTEMI has increased [2]. STEMI continues to be less prevalent than NSTEMI, accounting for 29% to 39% of MIs documented in various registries [33]. However, STEMI is more common than NSTEMI among younger patients, with a rate of nearly 32% among patients younger than 55 years and of 30% among patients 55 to 64 years old [33]. STEMI is also more common among some racial/ethnic groups; for example, STEMI accounted for a slightly higher proportion of the MIs among white, Asian, and Hispanic/Latino individuals (Table 3) [33].

Table 3: PREVALENCE OF NON-ST-ELEVATION MYOCARDIAL INFARCTION (NSTEMI) AND ST-ELEVATION MYOCARDIAL INFARCTION (STEMI) ACCORDING TO RACE/ETHNICITY

Type of MI

White

Black

Asian

AI/AN

Hawaiian/PI

Hispanic or Latino Ethnicity

NSTEMI (73,176)

84.7%

12.4%

1.7%

0.5%

0.2%

4.8%

STEMI (46,791)

86.8%

10.0%

1.9%

0.6%

0.2%

5.1%

AI = American Indian, AN = Alaskan Native, PI = Pacific Islander.

Source: [33]

As noted, CHD-related mortality rates continue to decrease. CHD deaths are projected to decrease by 30% between 2010 and 2020 [1]. Heart disease is still the overall leading cause of death in the United States and represents a similar proportion of all deaths for men and women (24.5% vs 23.4%) [1]. CHD-related mortality increases with age, with CHD accounting for 20.8% of all deaths among people 45 to 64 years of age, 25.5% of all deaths among people 65 years of age and older, and 29.2% of all deaths among people 85 years of age and older [34].

With regard to race, CHD is the leading cause of death among all racial/ethnic populations (Table 4) [34]. Heart disease is the leading cause of death among non-Hispanic white and black populations, but the second leading cause of death in the Hispanic populations.

Table 4: CORONARY HEART DISEASE (CHD) AS A PERCENTAGE OF ALL DEATHS ACCORDING TO RACE AND ETHNICITY

Racial/Ethnic Population

CHD as Percentage of All Deaths

Race

White

23.4%

Black

23.7%

Asian/Pacific Islander

21.6%

American Indian/Alaska Native

23.7%

Ethnicity

Non-Hispanic white

23.7%

Non-Hispanic black

23.7%

Hispanic

20.1%

Source: [34]

Improved adherence to evidence-based guidelines has been associated with decreased mortality rates after ACS events. Rates of short-term morbidity mortality are higher for STEMI than for NSTEMI. Review of data in the National Cardiovascular Data Registry ACTION Registry-GTWG showed in-hospital mortality rates of approximately 5% to 7% for STEMI and rates of approximately 3% to 5% for NSTEMI [33,35]. The rate of in-hospital cardiogenic shock has also been higher among patients with STEMI (4.5% vs 1.8%), whereas the rates of in-hospital reinfarction, heart failure, and stroke have been similar (0.9% vs 0.6%, 5.3% vs 5.5%, and 0.5% vs 0.6%, respectively) [33]. At one year, however, the risk of mortality is similar for STEMI and NSTEMI [36].

PATHOPHYSIOLOGY OF ACS

ACS is most commonly caused by rupture of the fibrous cap of an atheromatous plaque (especially in men), which leads to exposure of highly thrombogenic, necrotic core material rich in red cells [37]. Plaque erosion is another primary cause of ACS [37]. The mechanisms underlying plaque erosion are not as well understood as those for plaque rupture, but inflammation plays a central role in both [37,38,39].

Other causes of ACS include dynamic obstruction (coronary artery spasm or vasoconstriction), spontaneous coronary dissection, infection, hypercoagulability states, or progressive mechanical obstruction. However, these causes are rare [40].

Plaque Formation

The gradual process of atherosclerosis usually causes no symptoms over the course of many years, with most plaques causing no symptoms [37]. However, the condition renders vessels susceptible to the formation of plaque through damage to the vascular endothelium. This damage is brought about by the primary risk factors for atherosclerosis, including high plasma levels of low-density lipoprotein (LDL), low plasma levels of high-density lipoprotein (HDL), cigarette smoking, hypertension, diabetes mellitus, male sex, and family history [37]. The process of plaque formation begins when monocytes infiltrate a damaged endothelial wall by binding to endothelial adhesion molecules. The monocytes then undergo differentiation and become macrophages. Macrophages become foam cells by digesting LDL that has also penetrated the arterial wall, helping to create a lipid-filled plaque. Macrophages produce inflammatory cell mediators, such as tumor necrosis factor alpha (TNF-α), interleukins, and metalloproteinases, which can lead to the infiltration of a high number of inflammatory cells at the site of the plaque.

A system for classifying the severity of atherosclerotic plaques (lesions) was developed in the 1990s, with lesions categorized into several types according to their histologic composition and structure [41,42,43,44]. A simpler classification, based on morphologic characteristics, was later introduced [45]. According to this system, lesions are defined in seven categories: intimal xanthoma (so-called fatty streak), intimal thickening, pathologic intimal thickening, fibrous cap atheroma, thin-cap fibroatheroma (TCFA), calcified nodule, and fibrocalcific plaque [45]. Pathologic intimal thickening or a thick-cap fibroatheroma is usually involved in plaque erosion [39]. Erosion is often the cause of thrombosis in young patients, particularly women younger than 50 years of age [31,39]. The least often cause of thrombosis is a calcified nodule, which is usually found in older patients with substantially calcified and tortious arteries [39].

Plaque Rupture

The stability of plaque is a crucial factor in the potential for rupture. Plaque that is at high risk of rupture is referred to as vulnerable plaque [46]. Vulnerable plaque has the following hallmark characteristics [37,47]:

- Large lipid core (more than 40% of the total lesion area)

- Thin, fibrous cap (usually less than 65 micrometers)

- High infiltration of macrophages

- Few smooth muscle cells

- Expansive remodeling preserving the lumen

- Neovascularization from the vasa vasorum

- Adventitial/perivascular inflammation

- Spotty calcification

Because of its high lipid content, vulnerable plaque is associated with the progressive development of ischemic disease [37]. The high level of macrophage infiltration reflects the important role of inflammation plaque rupture as well as initiation. Plaque rupture generally begins where the cap is thinnest and has the highest infiltration of macrophages, which release lytic enzymes and toxic metabolites that act to degrade the cap, leading to rupture [37]. Plaque rupture triggers the formation of a thrombus when thrombogenic elements of the lipid core are exposed to circulating blood; rupture and thrombosis may occur at the same time, but a temporary increase in stress (emotional or physical) may be the trigger for a cardiac event [37]. However, a life-threatening luminal thrombus develops only occasionally; it is theorized that other factors are involved, such as thrombogenicity of the exposed plaque material, local flow disturbances, and systemic thrombotic propensity [37]. The presence of plaque material interspersed in a thrombus indicates that severe thrombosis developed immediately after plaque rupture; more often, however, the thrombus develops over several days before an ACS event [37]. In one study, the thrombus was days or weeks old in 49% of patients with STEMI [48]. Researchers have used a variety of imaging techniques to determine the distribution of TCFAs, and the lesions are most often found in the proximal third of the major coronary arteries, although the left circumflex and right coronary arteries were affected evenly throughout their length in one study [49,50,51]. The findings of another study suggest that TCFAs causing ACS events are also more likely to be found in proximal locations and that the left main coronary artery was less commonly affected [52].

Why some plaque ruptures cause an ACS event and most do not is unclear. Plaque rupture in nonculprit lesions has been found in approximately 14% of patients with ACS, and among these lesions, plaque burden was significantly greater in lesions with plaque rupture than in lesions without plaque rupture [53]. Plaque rupture in combination with large plaque burden and luminal narrowing appears to lead to ACS [4]. Lipid-rich plaque and intracoronary thrombus have been found significantly less often in patients with asymptomatic CHD compared with patients with NSTEMI [54].

It was once thought that the degree of occlusion caused by a thrombus differentiated STEMI from NSTEMI, with complete and sustained occlusion resulting in STEMI, and incomplete or transient occlusion resulting in NSTEMI [55]. However, research is challenging this theory; for example, studies have shown that the degree of stenosis in some cases of acute MI is not severe enough to limit blood flow [55]. Other studies have demonstrated that ACS is often associated with plaque with little or no calcification and positive vessel remodeling (outward expansion of the artery wall) and that plaque rupture, TCFAs, and red thrombus are significantly more common with STEMI than with NSTEMI [56,57].

RISK FACTORS FOR CHD

Some risk factors for CHD were established many years ago, and researchers continue to seek to identify other risk factors that add predictive value to traditional risk factors.

Traditional Risk Factors

The Framingham Heart Study identified the first risk factors, and these factors were integrated into a risk-assessment tool, the Framingham Risk Score [58]. The factors in the Framingham Risk Score include age, total cholesterol level, HDL level, systolic blood pressure, treatment for hypertension, and cigarette smoking, and the score is used to determine the 10-year risk of so-called hard CHD (defined as MI or coronary-related death) among asymptomatic adults. The Framingham risk score is one of several scores that involve several traditional risk factors for assessing risk; other scores recommended include the Systematic Coronary Risk Evaluation (SCORE), PROCAM (men) and Reynolds (separate scores for men and women) [59]. The use of one of these risk calculators is a class IB recommendation from the American College of Cardiology Foundation and American Heart Association [59]. It is important to consider the populations on which these risk scores are based. For example, the Framingham Risk Score was developed on the basis of risk factors identified in the Framingham Heart Study, which involved a primarily white, middle-aged population. When the risk score has been evaluated in other populations, it has been found to underestimate the risk of CHD among older (mean age: 73.5 years) black and white individuals, especially women [60]. ACC/AHA guidelines published in 2013 recommend that race- and sex-specific Pooled Cohort Equations be used to predict 10-year risk of a first hard atherosclerotic cardiovascular disease event in non-Hispanic black and non-Hispanic white individuals (class IB) [61]. These equations were developed on the basis of data on participants from several large racially and geographically diverse studies [61]. The guidelines also note that the sex-specific pooled cohort equations for non-Hispanic white individuals may be considered to estimate risk for people other than black and non-Hispanic white individuals (class IB) [61].

Primary care clinicians are also encouraged to routinely evaluate the presence of individual CHD risk factors, and the U.S. Preventive Services Task Force (USPSTF) has recommended routine screening for hypertension and dyslipidemia as well as counseling and pharmacologic interventions for smoking cessation [62,63,64].

Nontraditional Risk Factors

Many nontraditional risk factors have been evaluated for their usefulness in enhancing the estimation of CHD risk, and the ACC/AHA has issued evidence-based recommendations according to individual risk (Table 5) [59,61]. The nontraditional risk factors that have been evaluated most often are inflammatory markers, lipid-related markers, other biochemical markers, testing for subclinical atherosclerosis, electrocardiography (ECG), and imaging studies.

Table 5: EVIDENCE-BASED RECOMMENDATIONS FOR USE OF NONTRADITIONAL RISK FACTORS TO EVALUATE CHD RISK IN ASYMPTOMATIC ADULTS

Nontraditional Risk Factor

Recommendation (Class, Level of Evidence)

Family history of CHD

Recommended for all asymptomatic women (IB)

May be considered if risk-based treatment decision is uncertain after quantitative risk assessment (IIbB)a

Family history of atherothrombotic CHD

Recommended for all asymptomatic adults (IB)

Genomic testing

Not recommended (IIIB)

Lipoprotein and apolipoprotein assessments

Not recommended (IIIC)

Natriuretic peptides

Not recommended (IIIB)

C-reactive protein

May be considered if a risk-based treatment decision is uncertain (after quantitative risk assessment IIbB)a

Not recommended for asymptomatic adults at high risk (IIIB)

May be reasonable for asymptomatic men (50 years of age or younger) or women (60 years of age or younger) who are at intermediate risk (IIbB)

Hemoglobin A1C

May be reasonable for risk assessment in asymptomatic adults who do not have diabetes (IIbB)

May be considered for asymptomatic adults with diabetes (IIbB)

Testing for microalbuminuria

Utility is uncertaina

Reasonable for asymptomatic adults with hypertension or diabetes (IIaB)

Might be reasonable for asymptomatic adults at intermediate risk who do not have hypertension or diabetes (IIbB)

Lipoprotein-associated phospholipase A2

Might be reasonable for asymptomatic adults at intermediate risk (IIbB)

Resting electrocardiography (ECG)

Reasonable for asymptomatic adults with hypertension or diabetes (IIaC)

May be considered for asymptomatic adults who do not have hypertension or diabetes (IIbC)

Transthoracic echocardiography (to detect left ventricular hypertrophy)

May be considered for asymptomatic adults who have hypertension (IIbB)

Not recommended for asymptomatic adults who do not have hypertension (IIIC)

Measurement of carotid intima-media thickness

Not recommended (IIIB)a

Reasonable for asymptomatic adults at intermediate risk (IIaB)b

Brachial/peripheral flow-mediated dilation

Not recommended (IIIB)

Measurement of arterial stiffness

Not recommended outside of research settings (IIIC)

Measurement of ankle-brachial index

May be considered if a risk-based treatment decision is uncertain after quantitative risk assessment (IIbB)a

Reasonable for asymptomatic adults at intermediate risk (IIaB)

Exercise ECG

May be considered for asymptomatic adults at intermediate risk (IIbB)c

Stress echocardiography

Not indicated for asymptomatic adults at low or intermediate risk (IIIC)

Stress myocardial perfusion imaging

Not indicated for asymptomatic adults at low or intermediate risk (IIIC)

May be considered for assessment of advanced cardiovascular risk in asymptomatic adults who have diabetes or asymptomatic adults with a strong family history of CHD or when previous risk assessment suggests high risk of CHD (IIbC)

Coronary artery calcium scoring

May be considered if a risk-based treatment decision is uncertain after quantitative risk assessment(IIbB)a

Not recommended for persons at low risk (10-year risk <6%) (IIIB)

Reasonable for asymptomatic adults at intermediate risk (10-year risk of 10% to 20%) (IIaB)

Reasonable for asymptomatic adults (40 years and older) who have diabetes (IIaB)

May be reasonable for persons at low to intermediate risk (10-year risk of 6% to 10%) (IIbB)

Coronary computed tomography angiography

Not recommended for asymptomatic adults (IIIC)

Magnetic resonance imaging of plaque

Not recommended for asymptomatic adults (IIIC)

aRecommended in the 2014 guideline.

bPublished recommendations on required equipment, technical approach, and operator training and experience for performance of the test must be carefully followed to achieve high-quality results.

cMay also be considered for sedentary adults who plan to start a vigorous exercise program.

Source: [59,61]

Inflammatory Markers

The recognition of the important role of inflammation in the development of CHD has led to increased research on the value of inflammatory markers in predicting risk. C-reactive protein (CRP) is the marker that has been most rigorously studied. The USPSTF found moderate, consistent evidence that adding a CRP level to a risk algorithm improves risk stratification for individuals at intermediate risk, and the 2010 ACCF/AHA guideline subsequently noted that measuring the CRP level may be reasonable for asymptomatic men (50 years of age or younger) or women (60 years of age or younger) who are at intermediate risk for cardiovascular disease [59,65]. The ACCF/AHA guideline does not recommend a CRP level for asymptomatic adults at high risk [59]. One study suggested improved 10-year risk prediction when a CRP or fibrinogen level was added to a traditional risk score [66]. A later ACCF/AHA guideline notes that a high-sensitivity CRP may be considered when a risk-based treatment decision is uncertain after quantitative risk assessment [61].

The USPSTF found no evidence that homocysteine levels or leukocyte counts were useful in further stratifying risk among individuals at intermediate risk [67].

Lipid-Related Markers

The 2010 ACCF/AHA guideline for assessment of cardiovascular risk does not recommend assessment of lipoprotein or apolipoprotein levels [59]. Measurement of a lipoprotein-associated phospholipase A2 level "might be reasonable" for asymptomatic adults at intermediate risk [59]. In a study published after the ACCF/AHA guideline, the prediction of CHD improved slightly when information on apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass was added to risk scores that included total cholesterol and HDL levels [68]. However, the 2013 ACCF/AHA guideline notes that the contribution of apolipoprotein B is uncertain [61].

Other Biochemical Markers

According to the 2010 ACCF/AHA guideline, natriuretic peptide levels are not recommended for the evaluation of risk among asymptomatic adults [59]. A hemoglobin A1C "may be reasonable" for assessing risk in asymptomatic adults without diabetes and "may be considered" for asymptomatic adults with diabetes [59]. This guideline also notes that testing for microalbuminuria is reasonable for asymptomatic adults with hypertension or diabetes and "might be reasonable" for asymptomatic adults with hypertension or diabetes who are at intermediate risk [59]. However, in its 2013 guideline, the ACCF/AHA expert panel notes that the contribution of albuminuria is uncertain [61].

Testing for Subclinical Atherosclerosis

Historically, screening for atherosclerosis has been done through measurement of lipid levels as surrogate markers. Now, coronary artery calcium scoring has become a strong risk predictor, improving risk classification of asymptomatic adults when the score combined with traditional risk factors [69,70]. The 2010 ACCF/AHA guideline notes that calcium scoring is reasonable for asymptomatic adults at intermediate risk (10-year risk of 10% to 20%), and for asymptomatic adults (40 years and older) who have diabetes and "may be reasonable" for individuals at low-to-intermediate risk (10-year risk of 6% to 10%) [59]. The test is not recommended for persons at low risk (10-year risk of less than 6%). Similarly, 2010 appropriate use criteria state that determination of a coronary calcium score with noncontrast CT is appropriate for individuals with a family history of premature CHD and for asymptomatic individuals with no known CHD who are at intermediate risk [71]. Subsequent systematic reviews have confirmed that coronary artery calcium scoring has additional predictive value (in combination with traditional risk factors), primarily for asymptomatic individuals at intermediate risk [72,73]. The 2013 ACCF/AHA guideline notes that a CAC score may be considered if a risk-based treatment decision is uncertain after quantitative risk assessment [61].

The clinical utility of other tests for identifying subclinical disease is not as clear. In 2009, the USPSTF found no evidence that measurement of carotid intima-media thickness or ankle-brachial index were useful in further stratifying risk among individuals at intermediate risk [67]. However, the 2010 ACCF/AHA guideline notes that measurement of carotid intima-media thickness and ankle-brachial index is reasonable for asymptomatic adults at intermediate risk; however, the 2013 ACCFR/AHA guideline does not recommend routine measurement of carotid intima-media thickness and states that ankle-brachial index may be considered if a risk-based treatment decision is uncertain after quantitative risk assessment [59,61]. The 2010 ACCF/AHA guideline does not recommend measurement of flow-mediated dilation or arterial stiffness as part of risk assessment [59]. Still more recently, systematic reviews have shown that measurement of flow-mediated dilation and carotid intima-media thickness had additional predictive value (in combination with traditional risk factors), primarily for asymptomatic individuals at intermediate risk [72,73]. Magnetic resonance imaging of plaque is not recommended [59].

ECG

The ACC/AHA, ACP, and USPSTF have all recommended against routine screening with resting ECG and exercise treadmill test for asymptomatic individuals at low risk [59,74,75,76]. The 2010 ACCF/AHA guideline notes that exercise ECG "may be considered" for asymptomatic adults at intermediate risk, but the USPSTF notes that there is insufficient evidence to assess the balance of benefits and harms of such screening among asymptomatic adults at intermediate or high risk [59,76].

Imaging Studies

The 2010 ACCF/AHA guideline and the ACP screening guideline note that stress echocardiography is not indicated for asymptomatic adults at low or intermediate risk [59,75]. Transthoracic echocardiography (to detect left ventricular hypertrophy) is not recommended for asymptomatic adults but "may be considered" for asymptomatic adults with hypertension. Coronary CT angiography is not recommended for asymptomatic adults. Stress myocardial perfusion imaging is not indicated for asymptomatic adults at low or intermediate risk but "may be considered" for assessment of advanced cardiovascular risk in asymptomatic adults with diabetes or with a strong family history of CHD [59,75].

Primary Prevention Interventions Based on Risk Assessment

Primary prevention interventions should be implemented when a patient has one or more risk factors. Recent guideline updates have created shifts away from established goals and thresholds for interventions, especially with regard to hypertension and dyslipidemia.

The 2017 Guideline for High Blood Pressure in Adults sets goals for systolic and diastolic blood pressure and provides evidence-based recommendations on treatment approaches [77]. This guideline replaces the report from the Eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC8). One study showed that fewer adults in the United States would need antihypertension treatment according to the JNC8 recommendations, compared with the JNC7 recommendations, while another study indicated that more cardiology patients with hypertension would be treated [78,79]. The 2017 Guideline for High Blood Pressure in Adults consolidates the recommendations for most major organizations, including the American Society of Hypertension [80]. The authors of a meta-analysis found that, although antihypertension treatment provides similar benefit for individuals at all levels of baseline risk of CHD, the absolute risk reductions are progressively greater as baseline risk increases [81,82].

With regard to the treatment of cholesterol levels, ACC/AHA guidelines published in 2013 differ greatly from the National Cholesterol Education Program (NCEP) guideline in 2001, with a substantially greater number of people eligible for treatment with cholesterol-lowering drugs, especially within the population of individuals at moderate risk of CHD [22,83,84,85]. The new guideline matches statin assignment to total plaque burden better than the NCEP guideline, according to a study in which plaque burden was determined by CT angiography [86]. A clinician-patient risk discussion is recommended to ensure that patients understand the benefits of risk-reduction interventions, potential adverse effects, drug-drug interactions, and patient preferences [87]. This approach also has the potential to enhance patient adherence to medication.

Increased emphasis has been placed on better management of lifestyle habits as primary prevention of CHD. Lifestyle risk factors such as obesity, poor diet, and physical inactivity have a great influence on traditional risk factors such as blood pressure and cholesterol levels, as well as on novel risk factors, such as inflammation and endothelial function [88]. Lifestyle management is a key component of the new guidelines for the treatment of cholesterol levels and hypertension, and several other guidelines have addressed issues related to lifestyle behaviors, such as obesity, diet, and physical activity. The ACC/AHA/TOS (The Obesity Society) developed a guideline on the management of overweight and obesity, and some members of the Expert Panel authored a separate review on the evidence statements related to cardiovascular risk [89,90]. The AHA/ACC also published a guideline on lifestyle management to reduce cardiovascular risk in 2013 [91]. In its guideline of cardiac screening, the ACP notes that strategies to improvement lifestyle behaviors should be emphasized [75]. The USPSTF recommends counseling to promote a healthful diet and physical activity to prevent cardiovascular disease, and the AHA focuses on changing lifestyle behaviors in its guide for improving cardiovascular health at the community level [92,93,94]. The decision to offer or refer adults without cardiovascular risk factors to behavioral counseling should be individualized by the primary care physician [95].

Another aspect of prevention that warrants increased attention is the role of complementary and alternative medicine. Approximately 33% of adults use complementary and alternative medicine therapy (including dietary supplements), and 40% to 70% do not tell their doctors about the therapy [96,97]. Systematic reviews have shown that there is insufficient evidence to support the primary prevention of cardiovascular disease with multivitamins, co-enzyme Q10, selenium supplement, green or black tea, or tai chi [98,99,100,101,102]. Studies have shown that a Mediterranean diet has a beneficial effect on cardiovascular risk factors, although the evidence is limited [103]. The USPSTF recommends against vitamin E supplements and ß-carotene for the prevention of cardiovascular disease [98].

Adherence to guidelines for management of CHD risk and to prevent cardiovascular disease has been suboptimal, especially among patients at low risk for disease [19,20,104]. Clinicians have noted several barriers to adhering to CHD prevention guidelines, including [19,20]:

- Cost of medications

- Lack of reimbursement, especially for lifestyle interventions

- Lack of adequate time for counseling

- Lack of patient education tools

- Existence of multiple guidelines

- Lack of knowledge and skills to recommend dietary changes and facilitate patient adherence

Efforts should be directed at alleviating these barriers to enable healthcare professionals to evaluate patients' risk factors adequately and to develop ways to help patients understand their risk and the importance of prevention strategies. A multidisciplinary team approach is needed to provide expertise in all areas. In addition, initiatives should emphasize the risk of CHD among women.

3. DIAGNOSIS AND RISK STRATIFICATION

Chest pain is the second most common reason for seeking care in the emergency department, accounting for approximately 5% of visits [105]. Patients with chest pain present a tremendous diagnostic challenge for many reasons, including a substantial overlap between characteristics of noncardiac and cardiac pain, misinterpretations of ECG and cardiac biomarker levels, and the lack of typical clinical presentation in many individuals.

Most emergency department clinicians err on the side of caution when evaluating patients with chest pain because of the serious consequences of a missed diagnosis of ACS, in terms of adverse patient outcome as well as threat of medical malpractice [106]. As a result, fewer than 10% of patients who are evaluated for chest pain are ultimately found to have ACS [107].

Both the overdiagnosis and underdiagnosis of ACS have unique consequences. Overdiagnosis leads to unnecessary treatments and high costs, and underdiagnosis has the more serious consequence of increased mortality (compared with hospitalized patients) [106]. The high rate of overdiagnosis indicates that a greater understanding is needed about several aspects of ACS:

- Which individuals are at highest risk for ACS

- How clinical signs and symptoms reflect the likelihood of ACS

- How age, gender, and race/ethnicity are related to differences in signs and symptoms

- How signs, symptoms, and diagnostic testing results should be factored into accurate risk stratification

Not only does a diagnosis of ACS need to be accurate, but it should be timely, as appropriate treatment given early substantially reduces morbidity and mortality [2,3].

To help standardize the diagnosis of patients with chest pain and ACS-related symptoms, the AHA and ACC have jointly developed guidelines on the management of suspected UA/NSTEMI and STEMI, which are updated frequently as new evidence becomes available [2,3]. The approach to diagnosing UA/NSTEMI and STEMI is primarily the same, but each has some unique features. The diagnosis of UA/NSTEMI can be more complex because it lacks the definitiveness of a specific ECG finding. With the diagnosis of STEMI, time is a crucial factor because of the need for reperfusion within tight timeframes. Both guidelines include recommendations for initial evaluation in the emergency department as well as the prehospital setting. The focus here is on initial evaluation in the emergency department setting, and the emphasis throughout is on class I recommendations.

It is imperative to quickly identify patients with chest pain and other symptoms suggestive of ACS, and registration staff and triage nurses should be familiar with their institution's chest pain protocol. High priority should be given to patients with chest pain. Ideally, the emergency department will be notified that a patient with chest pain is arriving, as such patients should be transported by emergency medical services (EMS). Use of EMS transport is associated with substantial decreases in ischemia time and in treatment delays [108]. Unfortunately, studies have shown that 40% to 80% of patients with ACS symptoms do not use emergency medical services, with high rates of self-transport among minority populations [108,109,110].

The two primary goals of the initial evaluation in the emergency department are to determine the likelihood that an individual has ACS and to estimate the short-term risk of adverse outcome(s) [3]. The findings of the history, physical examination, ECG, and cardiac troponin levels have been integrated into risk assessment scores and clinical prediction algorithms to help identify patients at increased risk of adverse outcomes. Identifying patients at high risk is most important, as these patients will gain the greatest absolute benefit from appropriate therapy [2,3]. Because timely, appropriate treatment depends on results of the clinical findings and diagnostic testing, it is essential that this information is obtained as quickly as possible.

Studies have shown that adherence to guidelines for the diagnosis and management of ACS has improved since the early 2000s, but can still be improved [27,111,112,113]. Improving adherence to guideline-directed diagnosis calls for system-wide involvement in quality improvement initiatives. The ACC/AHA recommends participation in a standardized quality-of-care registry that tracks and measures outcomes, complications, and performance measures because of its benefit in improving the quality of care for patients with ACS [3].

HISTORY AND PHYSICAL EXAMINATION

The ACC/AHA guidelines begin with recommendations for a carefully taken history and physical examination. A carefully taken history and physical examination are essential to elicit the details needed to make an accurate diagnosis. The medical history should focus on the type of pain the individual is having, accompanying symptoms, and risk factors that may predispose the patient to ACS. The primary goal of the physical examination is to identify any precursors of acute ischemia and to rule out noncardiac causes of pain, many of which are life-threatening. It is important to determine the time of symptom onset, as timely treatment is essential, especially for patients with STEMI. Other helpful information includes the presence of contraindications to any potential treatment and a history of related events, such as previous episodes of ischemia, MI, CABG, or PCI [2,3].

Given the importance of the patient's history in determining a diagnosis of ACS, it is essential to ensure accurate communication between the patient and healthcare providers, with attention to addressing language and cultural needs. However, the potential for communication challenges can be high. In a London study involving patients with ACS who were of Afro-Caribbean or South East Asian descent, three primary impediments to effective communication were identified: leading questions to define chest pain, patient-clinician conflict related to poor communication, and frank miscommunication as a result of language barriers and translational difficulties [114].

Such communication challenges are prevalent in the United States, as the population of non-English-speaking individuals grows. According to the U.S. Census Bureau, more than 42.1 million Americans are foreign-born, and 25.4 million Americans say they speak English less than "very well" [115]. It has been suggested that patients should be asked what language is spoken at home and what language they prefer for their medical care information, as some patients prefer their native language even though they can understand and discuss symptoms in English [116].

Many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care [117,118]. In addition, the use of professional interpreters is associated with improvements in communication (e.g., errors, comprehension), healthcare use, clinical outcomes, and patient satisfaction with care [117,119]. Despite these findings, professional interpreters are underused in healthcare settings, including the emergency department [118].

"Ad hoc" interpreters (e.g., untrained staff members, family members, friends, or strangers in the hospital) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. However, clinical consequences are more likely with ad hoc interpreters than with professional interpreters [117]. A systematic review of the literature has shown that the use of professional interpreters provides better clinical care than the use of ad hoc interpreters, with the former improving the quality of care for patients with limited English language skills to a level equal to that for patients with no language barriers [119]. In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members [120].

Chest Pain

Chest pain is the most commonly reported symptom in all patients with ACS, regardless of age, gender, race/ethnicity, or the presence of comorbid conditions [11,121]. Despite this fact, up to one-third of patients with ACS have no chest pain or discomfort [121,122]. Thus, the lack of chest pain should not rule out ACS as a diagnosis, especially in the presence of other indicators.

The first step in evaluating chest pain is to determine whether the pain is cardiac or noncardiac. Many other conditions can cause chest pain that is similar to cardiac pain, and the physical examination and imaging tests can aid in the differential diagnosis (Table 6) [3,123]. When discussing chest pain with the patient, the clinician should focus on several aspects of the pain or discomfort, including [106]:

- Characteristics (i.e., severity, location, radiation)

- Time of onset

- Duration

- Alleviating and exacerbating factors

Table 6: DIFFERENTIAL DIAGNOSIS OF CHEST PAIN

Life-Threatening Causes

Aortic dissection

Pulmonary embolism

Pneumothorax

Expanding aortic aneurysm

Other Causes

Pneumonia

Pleuritis

Pericarditis

Costochondritis

Cervical disc disease

Peptic ulcer disease

Gastroesophageal reflux

Biliary disease

Pancreatitis

Panic attack

Source: [3,123]

So-called classic ACS-related chest pain has been described as diffuse pain or pressure in the substernal or epigastric area that frequently radiates to the neck, throat, jaw, back, shoulder, and left arm [124]. Chest pain related to ACS usually begins abruptly and lasts at least 15 to 20 minutes; however, the duration of pain varies among patients [124,125]. The intensity of classic ACS chest pain increases over time, reaching maximal intensity after a few minutes [124]. Pain is usually worse with activity and improves with rest.

Several descriptors are used most often to describe ACS-related chest pain, including [106,124]:

- Tightness

- Pressure

- Heaviness

- Crushing

- Squeezing

The characteristics of ACS-related chest pain are similar to those of stable angina, which has been noted to be deep, poorly localized discomfort of the chest or arm [3]. ACS-related chest pain differs from stable angina in that ACS-related pain occurs at rest, is of new onset, or is of increasing intensity, duration, and/or frequency [3]. An important distinction between stable angina and UA is that the former is exacerbated by activity or emotional stress and relieved by rest and/or nitroglycerin; in contrast, UA occurs at rest [3]. Pain associated with UA may also be pain previously diagnosed as angina that has increased in frequency, duration, or severity or that is prompted by less exertion than in the past [3].

Pain features that are not generally characteristic of ACS-related pain include [3,124,126,127,128]:

- Sharp, stabbing pain

- Pain reproduced with movement or palpation of the chest wall or arms

- Pain of several hours' duration

- Fleeting pain (episodes lasting for a few seconds or less)

- Pain that is of greatest intensity at the onset

- Discomfort primarily (or only) in the middle or lower abdomen

However, the possibility of ACS should not be dismissed because of the presence of atypical pain characteristics. ACS has been diagnosed in 22% of patients who had sharp or stabbing pain and in 13% of patients with pleuritic-type pain, in as many as 15% of patients who had reproducible pain, and in 5% of patients with sharp, stabbing, fleeting pain [3,126].

An increasing number of studies have demonstrated that atypical chest pain occurs more often in several subgroups of patients, especially women, older individuals, and people with diabetes [11,121,129,130,131,132,133]. In addition, the findings of several studies and literature reviews have demonstrated that women with ACS are more likely to have pain or discomfort in the jaw, neck, throat, arm/shoulder, and back [129,134,135].

In the past, it was thought that cardiac pain could be distinguished from some types of noncardiac pain by assessing the relief of chest pain with use of specific drugs, such as nitroglycerin or antacids. However, relief of chest pain after administration of either of these drugs should not be used to distinguish pain as cardiac or noncardiac in nature. Studies have shown that nitroglycerin may relieve both cardiac and noncardiac chest pain [3]. In one study, nitroglycerin relieved chest pain in 35% of patients with ACS and 41% of patients without ACS [3]. Similarly, a gastrointestinal cause of pain should not be assumed if the chest pain is relieved by antacids, as some patients with ACS have reported relief after use of such a drug [3,127].

Associated Symptoms

The classic presentation of ACS includes some symptoms in addition to chest pain, primarily dyspnea, diaphoresis, nausea, abdominal pain, or syncope [2,3]. Again, there is wide variation in the symptoms reported by patients with ACS, as well as differences in subgroups of patients. Patients with STEMI more commonly report nausea, cold sweats, and vomiting [135]. Diaphoresis occurs more often in men with ACS compared with women [129]. In contrast, the likelihood of nonspecific symptoms is greater for women with ACS, with higher rates of fatigue, nausea and/or vomiting, indigestion, palpitations, dyspnea, and dizziness, and lightheadedness [129,130,134,135,136,137]. Among older individuals, dyspnea and fatigue have been noted to be the most common symptoms and diaphoresis has been reported less often [11,126,127].

Patient History

Typically, the patient history can aid in the diagnosis of a current disease. However, in a study of the influence of traditional cardiac risk factors on a diagnosis of ACS, the cardiac risk factor burden (defined as the number of risk factors) had limited value in predicting the likelihood of ACS, especially in patients older than 40 years of age [131]. Research has shown that a history of traditional cardiac risk factors varies among some subgroups. Women with ACS are more likely than men to have a history of diabetes, hypertension, or hyperlipidemia [23,124,134]. (Women are less likely to be smokers, to have a history of angina or MI, and to have had PCI or CABG, regardless of the cardiac history [23,129,138]. According to data from the NCDR, the prevalence of risk factors varies across racial/ethnic subgroups of individuals with ACS (Table 7) [139].

Table 7: RISK FACTORS FOR CHD ACCORDING TO RACE/ETHNICITY AMONG PATIENTS WITH ACS

Patient Characteristics

White

Black

Hispanic

Native American

Asian

Age

63.9 years ±13

59.4 years ±13

61.3 years ±13

58.7 years ±12

63.7 years ±12

Male gender

62%

50%

61%

62%

61%

Risk Factors

Family history of CHD

42%

38%

37%

42%

28%

Hypertension

69%

81%

71%

70%

75%

Diabetes

28%

40%

44%

54%

37%

Current smoker

26%

31%

22%

38%

16%

ACS = acute coronary syndrome; CHD = coronary heart disease.

Source: [139]

The five most important history-related factors that relate to the likelihood of ischemia due to CHD are (in order of importance) [140]:

- Nature of the chest pain

- History of CHD

- Sex/gender

- Age

- Number of traditional risk factors

Physical Examination

Most often, the physical examination is normal for patients being evaluated for possible ACS. Thus, the physical examination is important not to establish a diagnosis of ACS but rather to rule out an alternate diagnosis, identify any precursors of acute ischemia, identify any comorbidities that may have an impact on treatment decisions, and add prognostic information [2,3]. Ruling out a noncardiac cause of chest pain is especially important given the severity of some potential conditions [3,123].

The physical examination should include the following [3]:

- Measurement of vital signs

- Determination of the presence of stroke, pulses, or absence of jugular venous distention

- Pulmonary auscultation for rales

- Cardiac auscultation for murmurs and gallops

- Neurologic evaluation

- Evaluation for signs of cardiogenic shock (hypotension and organ hypoperfusion)

- Identification of contraindications to antiplatelet or fibrinolytic therapy

The presence of bruits or pulse deficits (which would suggest extracardiac disease) is associated with a higher likelihood of significant CHD [3]. Similarly, significant CHD is more likely in a patient who has an S3 or S4 gallop, a new mitral insufficiency murmur, or signs of congestive heart failure (pulmonary rales and elevated jugular venous pressures) [126]. Cardiogenic shock is associated more often with STEMI than NSTEMI, and mortality rates are high [3]. Physical examination should also identify contraindications to antiplatelet or fibrinolytic therapy, which include any prior intracranial hemorrhage, known malignant intracranial neoplasm, suspected aortic dissection, active bleeding or bleeding diathesis (excluding menses), or significant closed-head or facial trauma within the previous three months [2].

DIAGNOSTIC EVALUATION

The integration of the clinical presentation and history with ECG findings, cardiac biomarker levels, and results of cardiac imaging is essential for determining an accurate diagnosis, assessing risk, and guiding subsequent therapy.

ECG

ECG has historically been used to assess myocardial ischemia, and it continues to be an essential diagnostic tool in ACS and an important component in risk stratification. The ECG not only provides documentation of an acute MI but also differentiates between UA/NSTEMI and STEMI. Both UA and NSTEMI are characterized by a lack of ST-segment elevation on ECG. The distinction between the two conditions relies on troponin levels.

New ST-segment depression and symmetrical inverted T-waves both suggest acute ischemia or NSTEMI, and the likelihood is higher for ST-segment depression [3]. As noted, STEMI is associated with complete occlusion (more than 90%) of a coronary artery, and such occlusion is indicated by ST-segment elevation, ranging from less than 1 mm in a single lead to 10 mm in multiple leads [125]. An emergency physician experienced in reading ECGs or a cardiologist should interpret the findings, especially when STEMI is suspected [2]. A diagnosis of acute MI is confirmed with results of serial cardiac biomarker measurements in 90% of patients who have ST-segment elevation of 1 mm or more in at least two contiguous leads [3]. The resultant area of irreversible infarction with STEMI can be large, and immediate reperfusion therapy is needed. Therefore, ECG is essential for therapeutic decision making, and its findings are the primary determinant for treatment of STEMI [2].

The ACC/AHA guidelines recommend that a 12-lead ECG be done and interpreted by an experienced physician within 10 minutes after arrival for patients who have chest pain or other signs suggestive of ACS [2,3]. The diagnostic accuracy of ECG is improved if it is done while the patient is symptomatic, as acute ischemia (and underlying CHD) is strongly suggested by the transient ST-segment changes that occur during symptoms at rest and resolve when symptoms disappear [3]. A 12-lead ECG performed by EMS personnel is recommended for patients who have symptoms consistent with STEMI [2].

A single ECG cannot capture the entire dynamic process of ischemia. As a result, the initial ECG for patients with acute MI can be normal or nondiagnostic in 20% to 55% of cases [124]. Among patients with chest pain and a normal ECG, approximately 1% to 6% will subsequently be found to have MI and about 4% will be found to have UA [3]. Nondiagnostic ECGs are more likely in older patients; according to trial data, the rate of nondiagnostic ECGs was 23% for patients younger than 65 years of age and was 43% for patients 85 years of age and older [11]. In addition, ST-segment elevation on the ECG at presentation has been shown to decrease with age, from 96.3% for patients younger than 65 years of age to 69.9% for patients 85 years of age or older [11].

Thus, the ACC/AHA guidelines state that if the initial ECG is not diagnostic or if the patient remains symptomatic and ACS is suspected, serial ECGs should be done at intervals of 15 to 30 minutes during the first hour [3].

ST-segment and T-wave changes are not specific for ACS and may be the result of another disease or condition. Left ventricular aneurysm, pericarditis, myocarditis, Prinzmetal angina, Takotsubo cardiomyopathy, early repolarization, and Wolff-Parkinson-White syndrome may cause ST-segment elevation [3]. T-wave inversion can be caused by central nervous system events and treatment with tricyclic antidepressants or phenothiazines.

Adherence to the ACC/AHA guidelines for obtaining ECG has been suboptimal, with ECG being performed up to 73% of the time [141,142]. Delay in obtaining the first ECG has been associated with female gender and older age [11,23,143]. This delay may be related to the high rate of atypical presentation of ACS in these populations [11,144]. Increasing the number of nurses or ECG technicians during peak hours and training additional staff to perform ECGs may help to improve timeliness [27,145].

Cardiac Biomarkers

Cardiac biomarkers are detectable intracellular macromolecules released into the circulation after cardiomyocyte injury and death. The biomarkers once used—creatinine kinase (CK)-MB and myoglobin—have been replaced by cardiac-specific troponin (troponin I or T) because of the latter's high concentration in myocardium, near-absolute specificity for myocardial tissue, absence in the blood of healthy individuals, and high clinical sensitivity [2,3,30]. Measurement of CK-MB or myoglobin levels was not useful or cost-effective [146].

Cardiac Troponins

The time to initial elevation of cardiac troponin levels is 2 to 12 hours, with peak elevation at 24 hours (troponin I) and 12 to 48 hours (troponin T) [3,147]. Levels may remain elevated for 5 to 10 days (troponin I) or up to 14 days (troponin T) after an MI [147]. Although the greatest advantage of troponin over earlier biomarkers is their high sensitivity and specificity, their sensitivity is low during the first six hours after the onset of symptoms [147]. For most patients, in whom ACS is suspected, an MI can be ruled out or confirmed within six hours because of the high rate of delayed presentation associated with chest pain [3].

Measurement of troponin levels is crucial for identifying patients who have had an MI. According to the third universal definition of MI, an MI is defined by a rise and/or fall troponin level of at least one level above the 99th percentile of the upper reference level (URL) and evidence of serial increases or decreases in troponin levels [30]. Similarly, the recommendations based on the findings of a Laboratory Medicine Best Practices systematic review are the use of cardiac troponin assays only (no additional biomarkers), with the 99th percentile URL used as the clinical diagnostic threshold for a diagnosis of NSTEMI [148]. The ACC/AHA guideline for UA/NSTEMI states that troponin levels should be measured at the time of presentation and three to six hours after the onset of symptoms in all patients suspected of having ACS [3]. If the time of symptom onset is unclear, the time of presentation should be used instead. When initial serial troponin levels are normal but ECG changes and/or clinical features increase the suspicion for ACS, additional troponin levels should be measured beyond six hours [3]. The lack of elevated troponin levels at the time of presentation should not rule out an MI, as the initial level is normal in as many as 23% of patients with MI [149]. Troponin levels appear to have value in ruling out an MI; the negative predictive value of undetectable troponin levels has been reported to be 99% to 100%.

A diagnosis of MI should not be made on the basis of a single elevated troponin level, as elevated levels may be associated with other cardiac conditions, including tachyarrhythmia, high or low blood pressure, cardiac trauma, heart failure, myocarditis, and pericarditis [3].

Other Markers

As noted earlier, CK-MB, myoglobin, and other biomarkers are no longer useful in diagnosing ACS. B-type natriuretic peptide (BNP) and N-terminal proBNP are also not useful as an aid to diagnosing ACS, but they have demonstrated strong predictive value for short-term and long-term mortality for patients with ACS, and the ACC/AHA guideline notes that these biomarkers may be considered to assess risk in patients in whom ACS is suspected (class IIbB) [3,150,151].

COMPREHENSIVE RISK SCORE AND PROGNOSIS

Risk stratification is an integral component of diagnosis, especially for patients with UA/NSTEMI. The risk of cardiac death and ischemic events varies widely in the UA/NSTEMI population, and the prognosis can help inform decision making regarding treatment [3]. The ACC/AHA guidelines for UA/NSTEMI and STEMI recommend risk assessment with either the Thrombolysis in Myocardial Infarction (TIMI) risk score or the GRACE risk model [2,3]. The TIMI risk score predicts 30-day and 1-year mortality and was developed in a population of patients with STEMI; the GRACE model predicts in-hospital and six-month mortality for all patients with ACS [2,3].

The TIMI risk score is based on seven independent risk factors [152]:

- Advanced age (65 years or older)

- At least three risk factors for CHD

- Previous coronary artery stenosis of 50% or more

- ST-segment deviation on initial ECG

- At least two episodes of angina in the past 24 hours

- Use of aspirin in the past seven days

- Elevated levels of cardiac biomarkers

One point is given for each factor, and the total score corresponds to the risk of all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization through 14 days [152]. That risk ranges from 4.7% for a TIMI risk score of 0 or 1 to 40.9% for a score of 6 or 7. Patients with a higher TIMI score will derive greater benefit from an invasive strategy [3]. The TIMI risk calculator can be accessed online at http://www.timi.org.

The GRACE risk model includes eight variables [153]:

- Age

- Killip class

- Systolic blood pressure

- ST-segment deviation

- Cardiac arrest during presentation

- Serum creatinine level

- Elevated cardiac biomarkers

- Heart rate

Points are assigned to each factor, and the sum total corresponds to a probability of in-hospital death, ranging from 0.2% or less for up to 60 points to more than 52% for a sum of 250 points or more [153]. As with the TIMI score, patients with a higher score gain greater benefit from an invasive strategy [3]. The GRACE risk tool is also available online (http://www.outcomes-umassmed.org/grace).

Clinical features, ECG findings, and troponin levels may also be used to determine both early- and long-term prognosis and direct treatment. For example, patients with elevated troponin levels will gain benefit from intensive management and early revascularization [3]. In addition, elevated troponin levels have been associated with an estimation of infarct size and the risk of death [3]. With regard to ECG findings, after confounding ECG patterns (i.e., bundle-branch block, paced rhythm, left ventricular hypertrophy), the highest risk for death has been associated with ST-segment deviation (elevation or depression) [3]. Isolated T-wave inversion or normal ECG findings were associated with intermediate and low risk, respectively [3]. In another study, the incidence of death or MI at one year was significantly higher for patients who had ST-segment deviation of at least 1 mm and an elevated troponin level (18%) compared with patients who had deviation of less than 1 mm (11%) [154].

FINAL DIAGNOSIS

Four diagnoses are possible after complete evaluation for possible ACS: a noncardiac diagnosis, chronic stable angina, possible ACS, and definite ACS.

Risk assessment factors are used to help identify people who are at low risk of ACS and can thus be discharged safely. In one study, short-term clinically relevant adverse cardiac events were rare among patients who had "nonconcerning" vital signs, nonischemic findings on ECG, and no elevated troponin levels on serial testing [155]. Accelerated diagnostic protocols have been developed to help identify patients who can be safely discharged. According to one such protocol, a TIMI score of 0, no new ECG changes, and nonelevated troponin levels at 0 and 2 hours after the time of presentation indicates a low risk of ACS, with no major adverse cardiac events occurring within 30 days after discharge [156,157]. Another risk stratification tool, the HEART score (consisting of history, ECG findings, age, risk factors, and troponin levels) has been validated in the Netherlands [158]. The HEART score has been shown to identify patients at low risk for ACS and major adverse cardiac events [158]. When compared with care according to ACC/AHA guidelines, a protocol consisting of the HEART score and troponin levels at 0 and 3 hours, led to an increased number of early discharges, with no major adverse cardiac events at 30 days; shorter lengths of stay, and a decrease in objective cardiac testing over 30 days [107].

The ACC/AHA guideline for UA/NSTEMI includes no class I recommendations for discharge from the emergency department. For patients with possible ACS but normal ECG and troponin levels, the guideline notes that it is reasonable to [3]:

- Observe in a chest pain unit or telemetry unit and perform serial ECGs and cardiac troponin levels at intervals of three and six hours (class IIaB)

- Order a treadmill ECG (IIaA), stress myocardial perfusion imaging, or stress echocardiography (IIaB) before discharge or within 72 hours after discharge

- Perform coronary CT angiography to assess coronary artery anatomy (IIaA) or rest myocardial perfusion imaging with a technetium-99m radiopharmaceutical to exclude myocardial ischemia (IIaB)

Patients with chronic stable angina should be treated according to the ACC/AHA guidelines [159]. Patients who are discharged from the emergency department should be told to see their primary care physician as soon as possible, preferably within 72 hours [3]. The results of all diagnostic testing in the emergency department should be sent to the primary care physician to ensure continuity of care. Patients with definite ACS should be treated according to the type of MI.

4. TREATMENT OF UA/NSTEMI

According to data from several studies and quality improvement initiatives, adherence to ACC/AHA guidelines has improved since the early 2000s, but is still not optimal. In addition, time is needed for clinicians to become familiar with updates to clinical practice guidelines; the ACC/AHA guideline for UA/NSTEMI was revised in 2014.

The ACC/AHA guideline reflects the research advances made in ACS. Many more treatment options are available, and clinicians should be familiar with the choices in order to select a strategy on the basis of an individual's status and preference. The most substantial changes in the updated 2014 guideline relate to the following issues [3]:

- More potent antiplatelet and anticoagulant therapy

- Benefit of guideline-directed medical therapy for low-risk patients

- Proper selection of older individuals and women for interventional therapy

- Expanded recommendations on discharge, including patient education, dual antiplatelet therapy, and referral to cardiac rehabilitation

GENERAL CARE

The general care of patients with UA/NSTEMI is directed at the severity of symptoms. Bed rest is recommended while patients have ischemic pain. After symptoms have subsided, patients may move to a chair. The ACC/AHA guideline notes that there is no benefit to the routine use of supplemental oxygen, and it may, in fact, even be harmful [3]. Instead, supplemental oxygen should be given only to patients who have an arterial oxygen saturation of less than 90%, respiratory distress, or other high-risk features of hypoxemia. Continuous ECG monitoring should also be carried out, not only to detect ECG changes that may provide additional diagnostic and prognostic information but also because sudden ventricular fibrillation is the primary preventable cause of death during this initial period [3].

ANALGESIC AND ANTI-ISCHEMIC THERAPY

The goal of immediate treatment for patients with UA/NSTEMI is to provide relief of ischemia and to prevent recurrent adverse ischemic events [3]. This goal is initially achieved through anti-ischemic, antiplatelet, and anticoagulant therapies (Table 8).

Table 8: ADJUNCTIVE TREATMENT INDICATIONS FOR PATIENTS WITH UA/NSTEMI OR STEMI

Adjunctive Therapy

UA/NSTEMI

STEMI

Comments

Analgesia

Nitroglycerin

All patients, unless contraindicated (class IC)

No recommendation

Contraindicated for patients with hypotension or who have used sildenafil or vardenafil within previous 24 hrs or tadalafil within previous 48 hrs (class IIIB).

All patients, unless contraindicated (class IB)

No recommendation

Morphine

Reasonable for patients who have chest pain unrelieved by maximally tolerated anti-ischemic medications (class IIbB)

Not specifically recommended.

Narcotics should be considered if high-dose aspirin fails to relieve pain (class IIbC)

––

Anti-Ischemia Therapy

Beta blocker

All patients, unless contraindicated (class IA)

Continue during and after hospitalization, unless contraindicated (class IC)

Re-evaluate patients with initial contraindications to beta blockers for subsequent use (class IC)

All patients, unless contraindicated (class IB)

Continue during and after hospitalization, unless contraindicated (class IB)

Re-evaluate patients with initial contraindications to beta blockers for subsequent use (class IC)

Administer in the first 24 hours.

Contraindicated for patients with signs of heart failure, evidence of low-output state, increased risk of cardiogenic shock, or other contraindications to beta blockers.

ACE inhibitor

Started and continued in all patients with left ventricular ejection fraction less than 40% and in patients with hypertension, diabetes, or stable CKD, unless contraindicated (class IA)

All patients (within the first 24 hours) with anterior location, HF, or ejection fraction less than or equal to 0.40, unless contraindicated (class IA)

Contraindicated for patients with hypotension (systolic blood pressure of <100 mm Hg or <30 mm Hg below baseline).

An angiotensin receptor blocker should be used for patients intolerant of ACE inhibitors.

Calcium-channel blocker

Patients with continued or recurrent ischemia or with contraindications to beta blockers (class IB)

No recommendation

––

Antiplatelet Therapy

Aspirin (non-enteric coated, chewable)

All patients (class IA)

Continued indefinitely

All patients (class IA)

Continued indefinitely

Should be given as soon as possible at time of evaluation.

Contraindicated for patients who have aspirin allergy or active bleeding.

Lower dose is reasonable during initial period post-stent implantation in patients at risk of bleeding.

Consider clopidogrel or warfarin if aspirin is contraindicated. Monitor closely.

Clopidogrel

All patients (class IB)

Administer to patients who are unable to take aspirin (class IB)

Maintenance dose daily, continued preferably for up to one year (class IB)

All patients (in addition to aspirin), before or at the time of PCI, if not already started and who are undergoing PCI within 24 hours of receiving fibrinolytic therapy (class IC)

Daily dose should be continued for one year (class IC)

Loading dose not recommended for older (>75 years of age) patients with STEMI. Should be withheld for five days in patients to have CABG (class IB). Monitor closely when used in conjunction with warfarin.

Prasugrel

Not recommended for initial platelet therapy.

All patients undergoing PCI with stenting should be given a loading dose and at least one year of maintenance therapy with this or other P2Y inhibitor if not given clopidogrel (class IB).

All patients undergoing PCI with stenting should be given a loading dose and at least one year of maintenance therapy with this or other P2Y inhibitor if not given clopidogrel (class IB).

Should not be given sooner than 24 hours after administration of a fibrin-specific agent or 48 hours after administration of a non-fibrin-specific agent (class IIaB)

Should be withheld for at least seven days in patients to have CABG (class IB).

Should not be administered to patients with history stroke or transient ischemic attack (class IIIB).

Ticagrelor

All patients undergoing PCI with stenting should be given a loading dose and at least one year of maintenance therapy with this or other P2Y inhibitor if not given clopidogrel (class IB).

All patients (in addition to aspirin) undergoing PCI with stenting should be given a loading dose and at least one year of maintenance therapy with this or other P2Y inhibitor if not given clopidogrel (class IB).

Should be withheld for at least five days in patients to have CABG (class IB).

May only be used with lower doses (81 mg) of aspirin.

Requires twice daily administration.

Glycoprotein IIb/IIIa inhibitor

Patients selected for early invasive treatment, along with dual-antiplatelet therapy, who are at intermediate or high risk (high troponin levels) (class IIbB)

Reasonable for selected patients who are receiving unfractionated heparin to have abciximab with primary PCI (class IIaA); eptifibatide or tirofiban may also be considered with primary PCI (class IIaB)

May be reasonable to administer in emergency department to patients selected for primary PCI (class IIbB)

The rate of IV infusion of eptifibatide or tirofiban should be reduced by 50% for patients with estimated creatinine clearance <50 mgL/min.

Eptifibatide or tirofiban should be discontinued two to four hours before CABG (class IB).

Anticoagulant Therapy

Unfractionated heparin (UFH)

Option for patients selected for early invasive treatment (class IB) and early conservative treatment (class IB)

Dose adjusted according to hospital protocol to maintain therapeutic anticoagulation for 48 hrs or until PCI (class IB)

Option for patients selected for primary PCI (class IC) or fibrinolytic therapy (class IC); administer for at least 48 hrs or until revascularization

The UFH dose should be reduced when a glycoprotein IIb/IIIa inhibitor is also given (class IC).

For patients undergoing PCI after receiving anticoagulant regimen, administer additional boluses of UFH as needed to support procedure (class IC).

Enoxaparin

Option for patients selected for early invasive treatment (class IA) and early conservative treatment (class IA)

Option for patients selected for fibrinolytic therapy (class IA); administer for at least 48 hours; for use up to eight days or until revascularization

Discontinue enoxaparin 12 to 24 hrs before CABG (class IB).

Reduce dose for creatinine clearance less than 30 mL/min and/or ≥75 yrs of age.

Bivalirudin

Option for patients selected for early invasive treatment (class IB)

Preferred over UFH with glycoprotein IIb/IIIa inhibitor in patients selected for PCI at high risk of bleeding (class IIaB)

Useful supportive measure for primary PCI with/without prior treatment with UFH (class IB)

Reduce dose for creatinine clearance less than 30 mL/min.

Discontinue bivalirudin three hrs before CABG (class IB).

Fondaparinux

Option for patients selected for early invasive treatment (class IB) and early conservative treatment (IB)

Option for patients selected for fibrinolytic therapy (class IB)

Should not be used as sole anticoagulant to support PCI in patients with NSTE-ACS due to an increased risk of catheter thrombosis.

Avoid for creatinine clearance less than 30 mL/min.

Discontinue 24 hrs before CABG.

ACE = angiotensin-converting enzyme; CABG = coronary artery bypass graft; CKD = chronic kidney disease; HF = heart failure; PCI = percutaneous coronary intervention.

Source: [4,5]

SIZE OF TREATMENT EFFECT FOR RECOMMENDED INTERVENTIONS

Class

Predicted Treatment Effect

I

Benefit >>> Risk

Procedure/treatment should be performed/administered.

IIa

Benefit >> Risk (Additional studies with focused objectives needed)

It is reasonable to perform procedure/administer treatment.

IIb

Benefit ≥ Risk (Additional studies with broad objectives needed; additional registry data would be helpful)

Procedure/treatment may be considered.

III

No Benefit (Procedure/test not helpful; no proven benefit)

OR Harm (Procedure/test excess cost without benefit or harmful; treatment harmful to patients)

LEVEL OF EVIDENCE

Level

Supporting Evidence

A

Multiple randomized clinical trials or meta-analyses

B

Single randomized trial or nonrandomized studies

C

Consensus opinion of experts, case studies, or standard-of-care

Analgesic and anti-ischemic therapy for UA/NSTEMI involves the use of nitroglycerin, morphine, beta blockers, calcium-channel blockers, and angiotensin-converting enzyme (ACE) inhibitors. These agents will help alleviate pain through their mechanisms of action. No nonsteroidal anti-inflammatory drugs (NSAIDs) should be given because of the documented increased risk of major adverse cardiovascular events [3].

Nitroglycerin

Nitroglycerin is a vasodilator that relieves ischemic-related pain by reducing myocardial oxygen demand and enhancing oxygen delivery. Nitroglycerin can be given as sublingual tablets every five minutes for up to three doses. The indications for intravenous nitroglycerin are persistent ischemia, hypertension, or heart failure, following administration of sublingual nitroglycerin and a beta blocker [3]. The administration of intravenous nitroglycerin should be discontinued within 24 hours after the patient's condition has stabilized, at which point oral nitroglycerin can be given. Discontinuation of intravenous nitroglycerin should be gradual, as the abrupt cessation has been associated with exacerbation of ischemic changes on ECG [3]. Nitroglycerine and all nitrates are contraindicated when a phosphodiesterase inhibitor has been used recently [3]. Nitrates are used with caution in patients with right ventricular infarction.

Morphine

The 2014 guideline states that morphine is an option for patients who do not have relief of ischemia-related symptoms during treatment with intravenous nitroglycerin or for patients who have recurrence of symptoms during anti-ischemic therapy [3]. If morphine is used in conjunction with intravenous nitroglycerin, the patient's blood pressure should be closely monitored, as hypotension is a potential adverse effect.

Beta Blockers

The inhibition of beta-1 adrenergic receptors by beta blockers acts to decrease cardiac work and myocardial oxygen demand. Beta blockers also slow the heart rate, which helps enhance coronary blood flow. A beta blocker should be given orally to all patients (unless contraindicated) within 24 hours after presentation [3]. This use of beta blocker therapy has been associated with significantly lower in-hospital mortality [160]. Contraindications include signs of heart failure, low-output state, increased risk of cardiogenic shock, or other relative contraindications to beta blockade.

Beta blockers with intrinsic sympathomimetic activity should be avoided; otherwise, the choice of beta blocker is up to the physician, as no studies have been done to compare single agents with each other. The ACC/AHA guideline recommends the use of sustained-release metoprolol, carvedilol, or bisoprolol as beta-blocker therapy for patients with UA/NSTEMI, stabilized heart failure, and reduced systolic function.

Adherence to guidelines for beta-blocker therapy has ranged from a concordance rate of 56 to 91 (with 100 representing perfect concordance) [8,141]. Patients are more likely to be treated with beta blockers if they have a history of beta-blocker use, a higher systolic blood pressure or lower heart rate on presentation, no signs of heart failure, and have been under the care of a cardiologist [160]. Lower rates of beta blocker therapy have been found for older individuals and women, especially women younger than 55 years of age (compared with men of the same age) [12,161].

Calcium-Channel Blockers

Calcium-channel blockers act to inhibit contraction of myocardial and smooth muscle and to cause vasodilation, although the agents in this drug class vary in the degree of vasodilation and myocardial contractility they produce [3]. They also relieve (or prevent) signs and symptoms of ischemia by decreasing heart rate and blood pressure.

The strongest evidence for a benefit of calcium-channel blockers in the setting of UA/NSTEMI primarily relates to symptom control. Calcium-channel blockers are indicated for patients who have UA/NSTEMI and [3]:

- Ongoing or recurring ischemia-related symptoms despite adequate doses of nitroglycerin and beta blockers

- Intolerance of adequate doses of nitroglycerin or beta blockers

The four agents used most commonly are nifedipine, amlodipine, verapamil, and diltiazem. Although data on comparisons of these four drugs are limited, verapamil and diltiazem are recommended because of their negative inotropic actions and negative chronotropic and dromotropic effects [3]. The ACC/AHA guideline recommends that a nondihydropyridine calcium channel blocker (verapamil or diltiazem) be given to patients with UA/NSTEMI who have continuing or frequently recurring ischemia and a contraindication to beta blockers, provided that clinically significant left ventricular dysfunction, increased risk for cardiogenic shock, a PR interval greater than 0.24 second, or second- or third-degree atrioventricular block without a cardiac pacemaker are not present [3]. In addition, oral nondihydropyridine calcium antagonists are recommended (unless contraindicated) for patients who have recurrent ischemia after appropriate use of beta blockers and nitrates. Immediate-release nifedipine is not recommended for routine use because of a dose-related increase in mortality [3].

Angiotensin-Converting Enzyme (ACE) Inhibitors

An ACE inhibitor should be administered orally within the first 24 hours (unless contraindicated) to patients who have pulmonary congestion or a left ventricular ejection fraction (LVEF) less than 0.40, and to patients who have hypertension, diabetes mellitus, or stable chronic kidney disease [3]. The guidelines also note that an angiotensin-receptor blocker (ARB) should be given to patients who cannot tolerate an ACE inhibitor and have signs of heart failure or LVEF of less than 0.40. The benefits of ACE inhibitors have been demonstrated primarily in the long-term setting after MI, with significant reductions in adverse outcomes, including survival at 30 days [3,162,163]. ARBs have been shown to be noninferior to ACE inhibitors in the prevention of clinical endpoints, including MI and stroke, in high-risk patients [164].

The rate of ACE inhibitor use has been reported to be approximately 77% among patients with UA/NSTEMI [8]. Use has been lower among older individuals and women, especially women younger than 55 years of age (compared with men of the same age) [12,161].

Other Anti-Ischemic Interventions

The ACC/AHA guideline does not make evidence-based recommendations for other anti-ischemic interventions, but does note two additional interventions for persistent or recurrent ischemia [3]. One is ranolazine, an antianginal agent that is indicated for the treatment of chronic angina [165]. The drug has been found to reduce recurrent ischemia in the ACS setting [166,167]. The other intervention is intra-aortic balloon pump counterpulsation, which has historically been used for refractory ischemia. The findings of observational studies have led to its use in the ACS setting, with rigorous randomized controlled trials showing no reduction in adverse events or mortality [3].

Cholesterol Management

Among patients with UA/NSTEMI, treatment with statins has been shown to be associated with lower rates of recurrent MI, CHD-related mortality, need for myocardial revascularization, and stroke [3]. These benefits have been greater with a high-intensity statin (such as atorvastatin) than with low- or moderate-intensity statins. Thus, the 2014 ACC/AHA guideline recommends that all patients receive high-intensity statin therapy, unless contraindicated [3]. Adherence to this recommendation should be improved; in a study in a tertiary care center, 52% of patients eligible for intensive statin therapy received it during hospitalization [168].

ANTIPLATELET THERAPY

Aspirin continues to be a key element of therapy for patients with UA/NSTEMI as part of overall antiplatelet therapy and reduces rates of recurrent MI and death [3]. Antiplatelet therapy reduces platelet formation and aggregation, integral components in the formation of a thrombus after plaque disruption.

Aspirin

The ACC/AHA guideline recommends that aspirin be given as soon as possible after a patient arrives in the emergency department and continued indefinitely in patients who tolerate it [3]. However, adherence by emergency medical personnel to guidelines recommending prompt prehospital aspirin administration is only 45% [169]. Aspirin is contraindicated for patients who are allergic to the drug or who have active bleeding; clopidogrel is recommended for patients who cannot tolerate aspirin [3]. Aspirin should be nonenteric-coated and chewable, and the recommended dose is 162 mg to 325 mg. A maintenance dose of aspirin should be continued indefinitely, at a daily dose of 81 mg to 325 mg. Adherence to the recommended use of aspirin has been better than for other drug therapies for patients with UA/NSTEMI, with rates of 97% to 99% [8,142]. Rates of aspirin use have been reported to be lower for older individuals and women, especially women younger than 55 years of age [12,161].

P2Y12 Inhibitors

P2Y12 inhibitors are added to aspirin as dual-antiplatelet therapy for patients who are managed medically as well as patients treated with PCI. Three inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for use in UA/NSTEMI: clopidogrel, prasugrel, and ticagrelor.

Clopidogrel

Clopidogrel was the first antiplatelet agent to become standard therapy in the ACS setting. The drug was approved by the FDA in 2002 on the basis of the findings of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, in which 12,562 patients with UA/NSTEMI were randomly assigned to treatment with aspirin with or without clopidogrel (loading dose of 300 mg followed by 75 mg daily) and followed up for 3 to 12 months, regardless of the treatment strategy used (conservative or invasive) [170]. The risk of cardiovascular-related death, MI, or stroke was significantly lower for patients who received clopidogrel. The results were similar in many subgroups of patients.

The ACC/AHA guideline recommends clopidogrel as one of two P2Y12 inhibitors to be given in addition to aspirin to all patients (unless contraindicated) with UA/NSTEMI who are to be treated with either an early invasive or ischemia-guided strategy [3]. The recommended dose of clopidogrel is a loading dose of 300 mg or 600 mg, followed by 75 mg daily for up to 12 months. Clopidogrel is also recommended for patients who are unable to take aspirin [3].

Prasugrel

Prasugrel has been shown to be more effective than clopidogrel for patients treated with PCI with stenting. In a comparison of the two drugs in patients with moderate-to-high-risk ACS who were scheduled for PCI, prasugrel was given as a 60-mg loading dose, followed by 10 mg daily, and clopidogrel was given as a 300-mg loading dose, followed by 75 mg daily. Both drugs were given for 6 to 15 months. Prasugrel was associated with a significantly lower rate of the primary composite endpoint of cardiovascular-related death, nonfatal MI, or nonfatal stroke (9.9% vs. 12.1%) [171]. However, the risk of major bleeding was increased with prasugrel (2.4% vs. 1.8%). Overall mortality did not differ significantly between the two drugs [171].

Prasugrel has also been compared with clopidogrel in patients with UA/NSTEMI who are managed medically. In this study, prasugrel was not associated with a decrease in the primary composite endpoint of cardiovascular-related death, MI, or stroke (13.9% vs. 16%) [172]. The rates of major bleeding were similar.

The ACC/AHA guideline recommends prasugrel as one of three options for maintenance antiplatelet therapy (with aspirin) for patients who have PCI and coronary stenting, but prasugrel is not recommended for patients treated with an early-invasive or ischemia-guided strategy [3].

Ticagrelor

Ticagrelor, the first in a new class of antiplatelets known as cyclopentyl-triazolo-pyrimidines, was approved by the FDA in 2011 [173]. Its mechanism of action differs from that of clopidogrel and prasugrel in that it does not require hepatic metabolism for activation and its action is reversible. Ticagrelor achieves greater and more consistent platelet inhibition than clopidogrel [173].

Ticagrelor was compared with clopidogrel in the Study of Platelet Inhibition and Patient Outcomes (PLATO), a randomized, controlled trial involving 18,624 patients, most of whom had UA/NSTEMI [174]. After 12 months, the rate of the primary composite endpoint (i.e., cardiovascular-related death, MI, or stroke) was lower in the ticagrelor and aspirin group than in the clopidogrel and aspirin group (9.8% vs. 11.7%) [174]. In addition, the all-cause death rate was lower in the ticagrelor group than in the clopidogrel group. Although the overall rates of major bleeding did not differ between the two groups, ticagrelor was associated with a higher rate of major bleeding in a subgroup of patients who did not have CABG.

The ACC/AHA guideline recommends ticagrelor as an option (with aspirin) as maintenance antiplatelet therapy for up to 12 months after initial treatment with either an early invasive or ischemia-guided strategy [3]. As a class IIaB recommendation, the ACC/AHA note a preference for ticagrelor over clopidogrel. The recommended dose is 180 mg as a loading dose, followed by 90 mg twice daily. The benefit of ticagrelor compared with clopidogrel is limited to an aspirin dose of 75–100 mg [175].

Adherence to guidelines on the use of a P2Y12 inhibitor has been low, especially for patients with UA/NSTEMI, with rates of 10% to 57% [10]. Rates of use have been lower among women [14]. In addition, some inhibitors have been used inappropriately; for example, in one study, 3% of patients with prior stroke received prasugrel despite its contraindication in that setting [10].

Glycoprotein IIb/IIIa Inhibitors

Glycoprotein IIb/IIIa inhibitors are potent inhibitors of platelet aggregation. Three intravenous glycoprotein IIb/IIIa inhibitors have been approved for clinical use: abciximab, eptifibatide, and tirofiban. Intravenous glycoprotein IIb/IIIa inhibitors are recommended, as oral agents in this class have been associated with increased risk for bleeding and mortality [3].

A meta-analysis (48 trials, 33,513 patients) demonstrated that glycoprotein IIb/IIIa inhibitors were associated with a lower all-cause mortality at 30 days after PCI but not at six months, compared with placebo or usual care [176]. The rate of severe bleeding was increased with glycoprotein IIb/IIIa inhibitors. Less benefit was found when clopidogrel was used. When glycoprotein IIb/IIIa inhibitors were used as part of initial medical treatment of UA/NSTEMI (12 trials, 33,176 patients), there was no decrease in mortality at 30 days, although the rate of death or MI was slightly lower at 30 days and six months [176]. Again, the risk of severe bleeding was higher with glycoprotein IIb/IIIa inhibitors.

The ACC/AHA guideline recommends a glycoprotein IIb/IIIa inhibitor for patients at intermediate-to-high risk (i.e., elevated troponin levels) who are to be treated with an early invasive strategy and dual-antiplatelet therapy [3]. Eptifibatide and tirofiban are the preferred inhibitors (class IIb, B) [3].

The recommended use of glycoprotein IIb/IIIa inhibitors is suboptimal in two ways. First, guideline-recommended use is low, especially among women [14,177,178]. Despite the clear benefit of glycoprotein IIb/IIIa inhibitors for high-risk patients, studies have shown that treatment with the drugs are directed toward patients at lower risk, with its use in high-risk patients ranging from 18% to 35% [179,180]. Use of glycoprotein IIb/IIIa inhibitors has also been suboptimal with respect to dosing; in one study, an excess dose was given to 26.8% of patients [181]. Excess dosing was more likely among older individuals, women, and patients with renal insufficiency, diabetes mellitus, heart failure, or low body weight [181]. Increased risk of major bleeding and mortality were associated with an excess dose.

ANTICOAGULANT THERAPY

Parenteral anticoagulant therapy (in addition to antiplatelet therapy) is recommended for patients with definite or likely UA/NSTEMI, regardless of the initial treatment strategy (early invasive or ischemia-guided) [3].

The anticoagulants used in the UA/NSTEMI setting are enoxaparin, bivalirudin, fondaparinux, and unfractionated heparin [3].

Enoxaparin

Enoxaparin is a low-molecular-weight heparin that offers many pharmacologic advantages compared with unfractionated heparin [40]:

- More predictable anticoagulant effect

- Greater bioavailability

- Lower incidence of heparin-induced thrombocytopenia

- Routine monitoring not required

- Given as a fixed-weight base dose

Compared with unfractionated heparin, enoxaparin has been associated with lower rates of recurrent ischemic events and of invasive procedures in the short term, as well as at one year among patients with UA [182]. Among high-risk patients with UA/NSTEMI treated with an early invasive strategy, the rate of death or MI at 30 days did not differ significantly between enoxaparin and unfractionated heparin, and enoxaparin was associated with an increased risk of major bleeding [183,184].

The ACC/AHA guideline recommends enoxaparin as an option for all patients with NSTE-ACS [3]. The recommended dose is 1 mg/kg, given subcutaneously, every 12 hours, and the drug is continued throughout the hospitalization or until PCI is done [3]. The dose should be decreased to 1 mg/kg daily for patients with a creatinine clearance less than 30 mL/min.

Studies have shown that 14% to 19% of patients with UA/NSTEMI have received an excess dose of low-molecular-weight heparin [181,185]. A higher dose was significantly associated with major bleeding and death [185]. The patients who received excess doses were more likely to be older, smaller, and female [181,185].

Bivalirudin

Bivalirudin is a direct thrombin inhibitor, and it has shown little benefit in lowering the risk of adverse outcomes compared with unfractionated heparin. Bivalirudin has been evaluated only in patients being considered for an early invasive strategy. In a study of 13,819 moderate-risk and high-risk patients, bivalirudin alone was compared with two other regimens: bivalirudin plus a glycoprotein IIb/IIIa inhibitor, and heparin (unfractionated heparin or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor. Bivalirudin plus a glycoprotein IIb/IIIa inhibitor was noninferior to heparin plus a glycoprotein IIb/IIIa inhibitor with respect to composite endpoint (death, MI, or unplanned revascularization) at 30 days [186]. Bivalirudin alone was also noninferior to heparin plus a glycoprotein IIb/IIIa inhibitor, but it offered a significant benefit in terms of major bleeding [186]. At one year, there was no significant difference in the composite endpoint among the three groups [187]. A meta-analysis of 15 trials that included more than 25,000 patients undergoing PCI found that bivalirudin was associated with an increased risk of stent thrombosis, MI, all-cause mortality, and major adverse cardiac events and a reduced risk of major bleeding [188]. When the dose of heparin in the control arm was more than 100 units/kg, bivalirudin was associated with a reduction in major bleeding; when the dose of heparin was less than 75 units/kg, bivalirudin was not associated with reduced major bleeding [188].

The ACC/AHA guideline recommends bivalirudin only for patients who are to have an early invasive strategy [3]. The recommended dose is 0.10 mg/kg as a loading dose, followed by 0.25 mg/kg/hr, to be continued until diagnostic angiography or PCI is performed [3].

Fondaparinux

Fondaparinux is a synthetic polysaccharide molecule that is a selective inhibitor of activated Factor X. It has been compared with enoxaparin in patients with NSTE-ACS and found to have similar efficacy in terms of a primary endpoint of ischemic events, but offering benefit in terms of a significantly lower rate of major bleeding [189,190,191,192]. The ACC/AHA guideline recommends fondaparinux, 2.5 mg subcutaneously daily, for the duration of hospitalization or until PCI is done [3]. When fondaparinux is used alone in this setting, an additional anticoagulant with anti-IIa activity should be given to help prevent catheter thrombosis [3].

Unfractionated Heparin

Unfractionated heparin has been used in the ACS setting since the early 1960s. Heparin prevents the formation of thrombi by accelerating the action of the proteolytic enzyme antithrombin that inactivates Factors IIa, IXa, and Xa [40]. An early meta-analysis (six trials, 1,353 patients) showed that unfractionated heparin plus aspirin reduced the risk for death or MI by 33% compared with aspirin alone among patients with UA [193]. These studies preceded the era of dual-antiplatelet therapy and early catheterization and revascularization.

The ACC/AHA guideline recommends giving unfractionated heparin for 48 hours or until PCI is performed [3]. A weight-adjusted dose is preferred to a fixed initial dose, as anticoagulation is more predictable with such dosing [3]. The recommended dose in the ACC/AHA guideline is an initial loading dose of 60 IU/kg (to a maximum of 4,000 IU) and an initial infusion of 12 IU/kg/h (to a maximum of 1,000 IU/hr), which is adjusted to a therapeutic activated partial thromboplastin time range [3].

CHOICE OF TREATMENT STRATEGY: EARLY INVASIVE VS. ISCHEMIA-GUIDED STRATEGY

As stated, risk stratification is essential to determine the level of treatment: an early invasive or an ischemia-guided strategy. An early invasive approach involves diagnostic angiography, with revascularization performed if appropriate based on coronary anatomy [3]. The procedure is typically done within 24 hours (early invasive) or 25 to 72 hours (delayed invasive) [3]. The optimal timing of angiography has not been established [3]. With an ischemia-guided strategy (previously referred to as a conservative approach or medical management), noninvasive testing is done and angiography is performed only when this testing demonstrates evidence of ischemia. The ACC/AHA guideline provides direction for appropriately selecting an early invasive or ischemia-guided strategy (Table 9) [3].

Table 9: FACTORS ASSOCIATED WITH APPROPRIATE SELECTION OF EARLY INVASIVE STRATEGY OR ISCHEMIA-GUIDED STRATEGY IN PATIENTS WITH NSTE-ACS

Treatment Strategy

Factors Guiding Selection

Immediate invasive (within two hours)

Refractory angina

Signs or symptoms of HF or new or worsening mitral regurgitation

Hemodynamic instability

Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy

Sustained VT or VF

Ischemia-guided strategy

Low-risk score (e.g., TIMI [0 or 1], GRACE [<109])

Low-risk, Tn-negative female patients

Patient or clinician preference in the absence of high-risk features

Early invasive (within 24 hours)

None of the above, but GRACE risk score >140

Temporal change in Tn

New or presumably new ST depression

Delayed invasive (within 25–72 hours)

None of the above, but diabetes mellitus

Renal insufficiency (GFR <60 mL/min/1.73 m^2)

Reduced LV systolic function (EF <40%)

Early postinfarction angina

PCI within six months

Prior CABG

GRACE risk score 109–140; TIMI score ≥2

CABG = coronary artery bypass graft; EF = ejection fraction; GFR = glomerular filtration rate; GRACE = Global Registry of Acute Coronary Events; HF = heart failure; LV = left ventricular; NSTE-ACS = non-ST-elevation acute coronary syndrome; PCI = percutaneous coronary intervention; TIMI = Thrombolysis In Myocardial Infarction; Tn = troponin; VF = ventricular fibrillation; VT = ventricular tachycardia.

Source: [3]

Early Invasive Strategy

The findings of most studies have indicated that a routine early invasive strategy is superior to an ischemia-guided strategy in terms of reducing the rate of cardiovascular-related death or MI, as well as of angina and rehospitalization [15,194,195]. However, a meta-analysis found insufficient evidence to support either approach as having a survival benefit for patients with NSTE-ACS [196]. The greatest advantage of an early invasive strategy has been found among patients at high risk.

An urgent or immediate invasive strategy is recommended for patients with NSTE-ACS with refractory angina or hemodynamic or electrical instability who do not have serious comorbidities or contraindications [3]. An early invasive strategy is recommended for patients with NSTE-ACS who are initially stabilized and at elevated risk for clinical events [3]. The guideline recommends against an early invasive strategy for patients with acute chest pain and a low likelihood of ACS (normal troponin levels) as well as for patients with extensive comorbidities (class III: no benefit).

Ischemia-Guided Strategy

The objective of an ischemia-guided strategy is to avoid unnecessary treatment (and associated costs) for patients at low risk for significant CHD. The ACC/AHA guideline notes that an ischemia-guided strategy may be considered for patients with NSTE-ACS who are initially stabilized and at elevated risk for clinical events (class IIbB) [3]. It is also reasonable to consider clinician and patient preference in decision making about an ischemia-guided strategy (class IIbC). Patients at low or intermediate risk who have had no ischemia at rest or with low-level activity for at least 12 to 24 hours should have noninvasive stress testing (class IB) [3]. Factors to consider when selecting a stress test are the patient's resting ECG and ability to exercise, as well as local resources. An exercise stress test is the easiest, most cost-effective test and should be the choice unless the patient is unable to exercise or has ST changes on resting ECG (class IC) [3]. ST changes on the resting ECG may interfere with interpretation of the stress test findings, and for patients with ST changes, stress testing with an imaging modality (such as cardiac radionuclide imaging or stress echocardiography) is recommended (class IB). Pharmacologic stress testing with imaging should be done for patients who have limited ability to exercise (class IC). Exercise stress testing should be done and interpreted according to the ACC/AHA guidelines, and the results will dictate the need for further therapy [197].

Many factors other than risk influence the use of an early invasive strategy. Such a strategy has been used more often, regardless of patients' risk, when a cardiac catheterization laboratory is available or the treating physician is a cardiologist [179,198,199]. Patient demographic characteristics, such as age, race, and gender, are also factors. Data from trials indicate that an early invasive strategy is used less frequently for older patients, black patients, and women [7,11,139,195,198,200].

The benefit of an early invasive strategy for women is unclear [15,195]. However, when women have high-risk features, such as elevated troponin levels, an early invasive approach does lead to better outcomes; women at low-risk have better outcomes from an ischemia-guided approach [21,201]. These findings led the ACC/AHA to emphasize that an immediate invasive strategy should be used for women who are eligible for that approach and that an early invasive strategy should not be used for women at low risk for ACS [3].

Revascularization Procedures

CABG was once the primary revascularization procedure, but advances in less invasive techniques have contributed to a decline in CABG rates and an increase in the use of PCI for NSTE-ACS [7,202].

A comprehensive comparison of CABG and PCI was carried out in the Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) study, and the findings were considered in the formulation of the 2011 ACC/AHA/Society for Cardiac Angiography and Interventions (SCAI) guideline recommendations for PCI [5]. In a meta-analysis (31 trials, 15,004 patients) published after the guideline, among patients eligible for either PCI or CABG, the latter procedure was associated with lower rates of repeat revascularization, and death; the rate of MI was similar, and the rate of stroke was higher with CABG [203]. Class I recommendations for the use of PCI include patients who have refractory angina or hemodynamic or electrical instability (without comorbidities or contraindications), and initially stabilized patients who have an elevated risk for clinical events [5]. PCI is preferred for patients with discrete lesions, in large-caliber vessels, or one or two vessels, whereas CABG is recommended for more extensive CHD, including left main disease, three-vessel disease, or two-vessel disease with severe involvement of the proximal left anterior descending coronary artery [6]. For patients with multivessel disease, CABG has been associated with higher adjusted rates of long-term survival and lower rates of MI and repeat vascularization compared with PCI with stenting [204,205]. CABG is also recommended for patients with left ventricular systolic dysfunction [6].

5. TREATMENT OF STEMI

Advances in revascularization procedures and antiplatelet and anticoagulant therapies have improved outcomes for patients with STEMI, with significant decreases in the rates of mortality and morbidity [2,206]. The reported mortality rates are approximately 5% to 6% (in-hospital) and 7% to 18% (one-year) [2]. Morbidity includes heart failure, pulmonary edema, reinfarction, cardiogenic shock, and stroke, and rates of these events have also declined significantly [206].

When ECG demonstrates ST-segment elevation, the goal of treatment is to immediately obtain normal coronary perfusion through the occluded infarct-related artery, thus decreasing ischemic time [2]. Re-establishing blood flow through the occluded artery is crucial for limiting the size of the infarct, minimizing myocardial damage, preserving left ventricular function, decreasing morbidity, and improving survival [2,207].

Reperfusion therapy is the cornerstone in the management of STEMI, and antiplatelet and anticoagulant agents are necessary as ancillary therapy. The options for reperfusion include revascularization procedures and/or pharmacologic (fibrinolytic) therapy. As with the treatment for NSTEMI, the use of PCI has become the primary approach to revascularization; approximately 80% to 90% of patients have PCI revascularization based on angiographic findings [208]. In addition, PCI is the preferred strategy for reperfusion because of its superior outcomes compared with fibrinolytic therapy [2,208]. However, gaining the optimal benefit from PCI depends on many factors, and timing is the most important variable in selecting a reperfusion therapy [2,207]. Care should also be taken to evaluate patients for contraindications to fibrinolytic therapy [5].

The ACCF/AHA guideline on the management of STEMI was most recently updated in 2013. The guideline notes that patients with STEMI should be treated in either a coronary care unit or a stepdown unit [2]. Care provided in a coronary care unit should be structured according to evidence-based protocols, and nursing staff should be certified in critical care. Patients who are admitted to a coronary care unit may be transferred to a stepdown unit once they have been clinically stable for 12 to 24 hours [2]. Low-risk patients who have had successful PCI may be admitted directly to a stepdown unit.

TIMING

A familiar adage associated with STEMI is "time is muscle," and every effort should be made to shorten the ischemic time as much as possible. The timing of reperfusion therapy is a complex issue involving the time from the onset of symptoms and the time from presentation to treatment. The time for transfer to another hospital is also a factor for most patients, as most hospitals do not have a cardiac catheterization laboratory and a skilled, readily available PCI team.

Evidence Based Practice Recommendation

As a systems goal, EMS transport directly to a PCI-capable hospital for primary PCI is the recommended triage strategy for patients with STEMI, with an ideal first medical contact-to-device time system goal of 90 minutes or less.

http://circ.ahajournals.org/content/127/4/e362

Last Accessed: June 18, 2018

Strength of Recommendation/Level of Evidence: IB (Procedure/treatment should be performed based on data derived from a single randomized clinical trial or nonrandomized studies evaluating limited populations.)

The 2013 ACCF/AHA guideline indicates that PCI is preferred over fibrinolytic therapy for patients with STEMI when it can be performed in a timely manner by experienced operators [2]. PCI should be done within less than 90 minutes after the patient's first medical contact [2]. If PCI cannot be done within 90 minutes, fibrinolytic therapy should be initiated as the reperfusion strategy within 120 minutes of the first medical contact.

The most significant factor in achieving an optimal outcome from PCI is timing. Findings from hospitals reporting to the Centers for Medicare and Medicaid Services have shown an improvement in the number of patients treated with primary PCI within the recommended 90-minute window, from 44.2% in 2005 to 91.4% in 2010 [209]. In addition, the median door-to-balloon or door-to-device time declined from 96 minutes in 2005 to 64 minutes in 2010 [209].

Improvements in door-to-balloon time have been attributed to national initiatives focused on identification of barriers to appropriate care and implementation of innovative protocols. These initiatives successfully addressed physician and organizational barriers with efforts to develop systems of care that increase patient access to primary PCI based on whether the patient presents to a PCI-capable or non-capable facility [2].

Strategies to Improve Timing of Therapy

Specific strategies that have improved the door-to-device time interval focus on three key components: door-to-ECG time, ECG-to-catheterization laboratory time, and laboratory arrival-to-device time. The ACCF/AHA provides the following steps as a general protocol in improving door-to-device times [2]:

- A prehospital ECG to diagnose STEMI is used to activate the PCI team while the patient is en route to the hospital.

- Emergency physicians activate the PCI team.

- A single call to a central page operator activates the PCI team.

- A goal is set for the PCI team to arrive in the catheterization laboratory within 20 minutes after being paged.

- Timely data feedback and analysis are provided to members of the STEMI care team.

PCI

Evidence Based Practice Recommendation

Reperfusion therapy is reasonable for patients with STEMI and symptom onset within the prior 12 to 24 hours who have clinical and/or ECG evidence of ongoing ischemia. Primary PCI is the preferred strategy in this population.

http://circ.ahajournals.org/content/127/4/e362

Last Accessed: June 18, 2018

Strength of Recommendation/Level of Evidence: IIaB (It is reasonable to perform the procedure based on data derived from a single randomized clinical trial or nonrandomized studies evaluating limited populations.)

As noted, PCI has become more commonly used than CABG for revascularization. PCI for STEMI can be subcategorized according to when the procedure is done and whether it is done in conjunction with fibrinolytic therapy. Primary PCI refers to PCI that is done alone as primary treatment after diagnostic angiography [2]. (As will be described, ancillary treatment with anticoagulant and antiplatelet agents should be given to support PCI.) Facilitated PCI was once a strategy of full- or half-dose fibrinolysis (with or without glycoprotein IIb/IIIa inhibitors) and immediate transfer for planned PCI within 90 to 120 minutes [2]. However, no net clinical benefit has been found with this strategy, and it is not recommended [2]. Rescue PCI refers to transfer for PCI after fibrinolysis has failed. A pharmacoinvasive strategy is the administration of fibrinolytic therapy, in either the prehospital setting or at a non-PCI-capable hospital for early coronary angiography and PCI when appropriate [2].

Primary PCI

Primary PCI is preferred because of the many advantages it offers compared with fibrinolytic therapy, including wider eligibility, better rates of reperfusion, lower risks, and improved outcomes [208,210,211]. PCI is especially preferred for high-risk patients, specifically patients 75 years of age and older, patients with an unclear diagnosis, and patients with cardiogenic shock, heart failure, or ventricular arrhythmias [2]. However, analysis of data has shown that PCI has been done less often among patients at high risk (41%) than among patients at low risk (60%) or intermediate risk (54%) [179].

Class I indications for primary PCI include the following [5]:

- STEMI symptoms within 12 hours (level A)

- Severe heart failure or cardiogenic shock (level B)

- Contraindications to fibrinolytic therapy with ischemic symptoms less than 12 hours (level B)

The ACC/AHA guideline notes that PCI is reasonable for patients with clinical and/or ECG evidence of ongoing ischemia 12-24 hours after onset of symptoms (class IIaB) and might be considered for asymptomatic patients with STEMI and higher risk who presented between 12 and 24 hours after the onset of symptoms (IIbC) [5].

The use of coronary stents during PCI reduces the rates of adverse events such as re-occlusion, restenosis, and target-vessel revascularization [5,208,210]. Drug-eluting stents have been associated with lower long-term rates of target-vessel revascularization and restenosis compared with bare-metal stents, but the reduction has varied among the many types of drug-eluting stents and stent thrombosis was originally a complication [212,213]. Subsequent-generation drug-eluting stents were developed to overcome this complication, and thin-strut fluoropolymer-coated cobalt chromium everolimus-eluting stents have been associated with rates of stent thrombosis that are lower than those for other types of drug-eluting stents or bare-metal stents [213].

The complications of primary PCI include adverse reactions to the contrast medium, volume loading, difficulty with arterial access, and technical complications [210]. Reperfusion injury and hemorrhagic transformation of a bland infarction and hemorrhagic stroke are rare after primary PCI [208].

Primary PCI is supported by antiplatelet and antithrombin therapy. Class I recommendations for this therapy in patients with STEMI include the following [5]:

- Aspirin (level B)

- P2Y12 inhibitors (level A)

- Unfractionated heparin (level C)

- Bivalirudin (level B)

Evidence Based Practice Recommendation

After PCI for STEMI, aspirin should be continued indefinitely.

http://circ.ahajournals.org/content/127/4/e362

Last Accessed: June 18, 2018

Strength of Recommendation/Level of Evidence: IA (Procedure/treatment should be performed based on data derived from multiple randomized clinical trials or meta-analyses evaluating multiple populations.)

The aspirin dose before PCI should be 325 mg for patients who had not been taking aspirin therapy and 81 mg to 325 mg for patients who had already been taking daily aspirin [5]. If stents are to be implanted during PCI, a loading dose of a P2Y12 inhibitor should be given (clopidogrel, 600 mg; prasugrel, 60 mg; or ticagrelor, 180 mg) [5]. For clopidogrel, a 300-mg loading dose is recommended for patients who have PCI within 24 hours after receiving fibrinolytic therapy; a 600-mg loading dose is recommended for patients who have PCI more than 24 hours after receiving fibrinolytic therapy [5]. This recommendation is based on the results of several investigations to explore various loading doses of clopidogrel before or during PCI. A meta-analysis of seven studies demonstrated that a 600 mg loading of clopidogrel reduces the rate of adverse cardiovascular events without an increase in major bleeding compared with 300 mg [5]. The findings of another study suggested that a 600-mg loading dose (compared with a 300-mg dose) is associated with improvements in procedural angiographic endpoints and one-year clinical outcomes in patients with STEMI who undergo primary PCI [5]. No benefit is derived from increasing the loading dose to 900 mg compared with 600 mg [5]. The guideline acknowledges that the safety and efficacy of pretreatment with clopidogrel remains controversial [5].

When compared with clopidogrel, prasugrel was associated with a 2.2% reduction in a composite endpoint of cardiovascular-related death, nonfatal reinfarction, or nonfatal stroke [5]. Prasugrel is contraindicated in patients with active pathologic bleeding or history of transient ischemic attack or stroke. Its use is not recommended for patients older than 75 years of age because of increased risk of fatal intracranial bleeding [5].

If unfractionated heparin is used, it is reasonable to give a glycoprotein IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or high-bolus tirofiban), regardless of whether patients are pretreated with clopidogrel [5]. The ACCF/AHA guideline for STEMI states that it is reasonable to begin treatment with abciximab before or at the time of primary PCI (with or without stenting) [2]. The precise timing of administration has not been defined. Treatment with tirofiban or eptifibatide may also be considered at the time of primary PCI [2].

With regard to anticoagulant therapy, unfractionated heparin is recommended but should not be given to patients already receiving therapeutic enoxaparin (subcutaneously) (class III: harm) [5]. Bivalirudin is also a recommended anticoagulant, with or without previous treatment with unfractionated heparin (class IB) [5]. Bivalirudin or argatroban should be used instead of unfractionated heparin in patients with heparin-induced thrombocytopenia (class IB). Fondaparinux should not be used as the only anticoagulant with PCI (class III: harm) [5]. An additional anticoagulant with anti-Ha activity should be used because of the risk of catheter thrombosis.

FIBRINOLYTIC THERAPY

The benefit of fibrinolytic therapy is its potential to establish reperfusion quickly. The re-establishment of coronary blood flow within the first 30 minutes after occlusion can abort infarction [214]. Reperfusion within 30 minutes to 2 hours can salvage myocardial tissue substantially, and fibrinolytic therapy administered within this timeframe has reduced mortality [215].

Although the focus of treatment for patients presenting with STEMI is often given to PCI, fibrinolytic therapy is the treatment of choice for some patients. If a patient arrives at or is transported by EMS to a non-PCI-capable facility, the decision whether to immediately transfer to a PCI-capable facility or administer fibrinolytic therapy must be made. Factors that affect this decision include the time from onset of symptoms, the risk of complications related to STEMI, the risk of bleeding with fibrinolysis, the presence of shock or severe heart failure, and the time required for transfer to a PCI-capable hospital. The ACCF/AHA guideline recommends that, in the absence of contraindications, fibrinolytic therapy should be given to patients with STEMI and onset of ischemic symptoms within the previous 12 hours when it is anticipated that primary PCI cannot be performed within 120 minutes of first medical contact [2].

Prehospital fibrinolytic therapy may reduce the time delay from symptom onset to treatment and can be administered by a trained EMS unit either with a physician on board or with a hospital-based physician in direct contact. A meta-analysis (six trials) showed a 60-minute reduction in time from symptom onset to treatment with prehospital compared to hospital-based initiation of fibrinolytic therapy [216]. Data from several trials indicate that prehospital fibrinolytic therapy may lower STEMI mortality rates and is considered to be of particular benefit in rural areas [216].

Four fibrinolytic agents have been evaluated and approved in the STEMI setting: tenecteplase, reteplase, alteplase (tPA), and streptokinase (Table 10) [2]. Of these agents, only streptokinase is non-fibrin-specific, and a fibrin-specific agent is preferred [2]. Each agent is associated with risks and benefits, and the choice of an agent is based on several factors, including preferences in the hospital formulary, cost, ease of administration, and the possibility of subsequent PCI. Although streptokinase is the least expensive agent, it is rarely used and no longer marketed in the United States because it is not fibrin-specific and has been shown to be less effective than the other three drugs [2].

Table 10: COMPARISON OF FIBRINOLYTIC AGENTS FOR TREATMENT OF STEMI

Characteristic

Streptokinase

Alteplase

Reteplase

Tenecteplase

Dose

1.5 MU

Up to 100 mg

10 U + 10 U

30–50 mg

Administration

Infusion (over 30 to 60 minutes)

Bolus and infusion (over 90 minutes)

Bolus (over 2 minutes) given 30 minutes apart

Bolus

Weight-based dosing

No

Yes

No

Yes

Antigenic

Yes

No

No

No

Patency ratea

60% to 68%

73% to 84%

84%

85%

Fibrin specificityb

No

Yes (++)

Yes (++)

Yes (++++)

TIMI = Thrombolysis in Myocardial Infarction.

a90-minute grade 2 or 3 TIMI blood flow.

b++++ is stronger than ++.

Source: [42

Alteplase is inconvenient to administer, as it must be given as an initial intravenous bolus over 30 minutes followed by 60 minutes of infusion [2,217]. Reteplase and tenecteplase have both been compared with alteplase. Both have resulted in similar mortality as alteplase, and reteplase has led to better total patency rates or complete perfusion [218,219,220,221]. TIMI 3 flow at 90 minutes has been similar for tenecteplase and alteplase [222]. The use of alteplase has thus declined because of the availability of these more convenient drugs with similar or improved outcomes [217].

The most common complication of fibrinolytic therapy is major bleeding, which occurs in approximately 5% to 6% of patients [207]. Adverse outcomes after fibrinolytic therapy are generally more common among women and older patients [223,224]. Many instances of bleeding can be traced to incorrect dosing, particularly with weight-based agents [217]. In addition, patients who receive an improperly high dose of fibrinolytic agents have increased 30-day mortality.

Repeat fibrinolytic therapy after failed fibrinolytic therapy has not led to significant clinical improvement in terms of all-cause mortality or nonfatal reinfarction and has been associated with an increased risk for bleeding [225]. Rescue PCI is the preferred strategy for failed fibrinolytic therapy, as it has been shown to offer benefit when compared with repeat fibrinolytic therapy [225,226].

Contraindications to Fibrinolytic Therapy

Another factor in selecting a reperfusion approach is whether the patient has contraindications to fibrinolytic therapy. Regardless of timing, PCI should be strongly considered for patients who are at high risk for bleeding complications, especially intracranial hemorrhage. There are several absolute and relative contraindications to fibrinolytic therapy; absolute contraindications include a history of intracranial hemorrhage or of substantial closed head or facial trauma within the past three months, suspected aortic dissection, or active bleeding (Table 11) [2]. Relative contraindications include history of poorly controlled hypertension, recent internal bleeding, and oral anticoagulant therapy [2].

Table 11: CONTRAINDICATIONS AND CAUTIONS FOR FIBRINOLYSIS USE IN ST-ELEVATION MYOCARDIAL INFARCTION (STEMI)a

Absolute Contraindications

Any prior intracranial hemorrhage

Known structural cerebral vascular lesion (e.g., arteriovenous malformation)

Known malignant intracranial neoplasm (primary or metastatic)

Ischemic stroke within three months EXCEPT acute ischemic stroke within 4.5 hours

Suspected aortic dissection

Active bleeding or bleeding diathesis (excluding menses)

Significant closed-head or facial trauma within three months

Intracranial or intraspinal surgery within two months

Severe uncontrolled hypertension (unresponsive to emergency therapy)

For streptokinase, prior treatment within the previous six months

Relative Contraindications

History of chronic, severe, poorly controlled hypertension

Substantial hypertension on presentation (systolic greater than 180 mm Hg or diastolic greater than 110 mm Hg)

History of prior ischemic stroke (greater than three months)

Dementia

Known intracranial pathology not covered in absolute contraindications

Traumatic or prolonged (greater than 10 minutes) CPR

Major surgery (within less than three weeks)

Recent (within two to four weeks) internal bleeding

Noncompressible vascular punctures

Pregnancy

Active peptic ulcer

Oral anticoagulant therapy

aViewed as advisory for clinical decision making and may not be all-inclusive or definitive.

CPR = cardiopulmonary resuscitation, INR = international normalization ratio.

Source: [2]

Ancillary Therapy

As described, a STEMI-associated thrombus consists of a fibrin-rich core and a platelet-rich cap. Because of this, both antiplatelet and anticoagulant therapies play important roles in supporting reperfusion therapy by helping to maintain patency of the infarct-related artery and preventing re-occlusion [2].

Clopidogrel and Aspirin

Recommended antiplatelet therapy has traditionally involved aspirin and clopidogrel. The 2013 ACCF/AHA guideline for STEMI includes a recommendation for clopidogrel (75 mg per day for at least 14 days and up to one year) to be added to aspirin for patients with STEMI, regardless of whether reperfusion with fibrinolytic therapy has been initiated [2]. Although prasugrel has been approved by the FDA for use in patients with STEMI and may be incorporated into the supportive treatment of these patients in place of clopidogrel, it is no longer recommended for use as an adjunct to fibrinolytic therapy [2].

Glycoprotein IIb/IIIa Inhibitor

Evidence Based Practice Recommendation

It may be reasonable to administer intravenous glycoprotein IIb/IIIa receptor antagonist in the precatheterization laboratory setting (e.g., ambulance, emergency department) to patients with STEMI for whom primary PCI is intended.

http://circ.ahajournals.org/content/127/4/e362

Last Accessed: June 18, 2018

Strength of Recommendation/Level of Evidence: IB (Procedure/treatment should be performed based on data derived from a single randomized clinical trial or nonrandomized studies evaluating limited populations.)

A glycoprotein IIb/IIIa inhibitor may also be considered as an ancillary agent for patients who receive fibrinolytic therapy. The 2013 ACCF/AHA guideline for STEMI notes that the use of a glycoprotein IIb/IIIa inhibitor (abciximab, tirofiban, or eptifibatide) is reasonable at the time of primary PCI for selected patients with STEMI; routine use is not recommended [2].

Two meta-analyses of randomized trials that support this recommendation involved a comparison of glycoprotein IIb/IIIa inhibitors in patients with STEMI who had primary PCI. In each case, there was no significant difference in 30-day mortality, reinfarction, TIMI flow grade 3, or ST-segment resolution among the agents [227,228].

Heparin, Fondaparinux, Enoxaparin, or Bivalirudin

Anticoagulant therapy is associated with bleeding complications, so care must be taken in selecting an appropriate agent, with attention paid to the patient's renal function status, the time to an invasive procedure, and overall bleeding risk [229]. Unfractionated heparin, enoxaparin, and fondaparinux are the recommended anticoagulant agents based on studies demonstrating their efficacy [2]. The 2013 ACCF/AHA guideline recommends bivalirudin as an acceptable anticoagulant for primary PCI or for patients undergoing rescue PCI for failed fibrinolysis. Bivalirudin may be useful as a supportive measure for patients undergoing PCI either with or without prior treatment with unfractionated heparin and is particularly useful if patients develop heparin-induced thrombocytopenia and still require anticoagulation [2]. Anticoagulation should be continued for the duration of the index hospitalization (up to eight days) or until revascularization. Enoxaparin is recommended over unfractionated heparin when anticoagulant therapy will extend beyond 48 hours [2].

Unfractionated heparin should be used for patients with severe impairment of renal function, and unfractionated heparin or enoxaparin may be used for patients who are at increased risk of bleeding and who are likely to have early angiography [229]. Researchers reviewed data on 20,479 patients to compare outcomes for unfractionated heparin and enoxaparin [230]. Significantly fewer patients in the enoxaparin group had subsequent PCI within 30 days after fibrinolytic therapy [230]. There were no differences between the two agents with respect to major bleeding in this study, whereas a more recent meta-analysis found enoxaparin to be superior to unfractionated heparin in reducing the incidence of major bleeding [231].

Fondaparinux may also provide benefit for patients who receive fibrinolytic therapy [232,233]. In one trial, 12,092 patients with STEMI were randomly assigned to fondaparinux (2.5 mg once daily for up to eight days) or to placebo. Analysis of a subgroup of 5,436 patients who received fibrinolytic therapy (primarily streptokinase) showed that fondaparinux was associated with significantly lower rates of death or nonfatal MI at 30 days and severe bleeding, yielding a significant overall benefit [232]. As noted, an additional anticoagulant (with anti-IIa activity) should be used in addition to fondaparinux when PCI is to be done after fibrinolytic therapy, and fondaparinux should not be used when creatinine clearance is less than 30 mL/min [2].

NO REPERFUSION THERAPY

Despite the clear benefit of reperfusion, a significant percentage of eligible patients with STEMI do not receive reperfusion therapy and some are mistakenly considered "ineligible" [206,207,234,235]. One study of 8,578 patients with STEMI found that more than 7% of all individuals with no contraindications to reperfusion were not given fibrinolysis or PCI [236]. Patients who are less likely to receive reperfusion therapy are older than 65 years of age, are female, have an atypical clinical presentation, and have a history of cardiovascular disease [207,236,237]. Another study found that 45% of eligible patients with diabetes on dialysis were not treated with reperfusion (i.e., mistakenly considered ineligible) [2]. Compared with in-hospital mortality rates for patients who do receive therapy, the mortality rates are substantially higher for patients who are eligible for reperfusion but do not receive it, and rates have been higher and more discrepant for women, older patients, and patients with prior congestive heart failure, MI, or CABG surgery (Table 12) [234,235,236,238].

Table 12: IN-HOSPITAL MORTALITY RATES FOR PATIENTS WITH ST-ELEVATION MYOCARDIAL INFARCTION (STEMI) BASED ON REPERFUSION THERAPY STATUS

Population

No Reperfusion

Reperfusion

TIMI 9 (1994)

18.9%

10.5%/7.6%a

NRMI (2000–2003)

All patients

14.9%

5.7%

Women

17.9%

9.3%

Older patients (>65 years of age)

18.9%

10.5%

aReperfusion with percutaneous coronary intervention/fibrinolytic therapy.

TIMI = Thrombolysis in Myocardial Infarction; NRMI = National Registry of Myocardial Infarction.

Source: [234,235,236]

Patients with no contraindications to reperfusion should be selected for primary PCI or fibrinolysis. Patients who lack access to PCI or have absolute contraindications to fibrinolysis should receive antithrombotic therapy in the hope of restoring TIMI grade 3 flow to the occluded vessel and preventing complications [239]. Older ACC/AHA guidelines for STEMI included recommendations for the treatment of patients who do not receive reperfusion therapy, including administration of aspirin, clopidogrel, and anticoagulants (low-molecular-weight heparin or fondaparinux rather than unfractionated heparin) to be given for the duration of hospitalization [240]. The 2013 guideline for STEMI does not include a specific recommendation for the treatment of patients who do not receive reperfusion therapy [2]. Despite this, it may be reasonable to administer the additional recommended medications (in the absence of contraindications) in these patients.

Acting on the theory that late revascularization of an infarct-related artery may improve left ventricular function and survival, some researchers have explored the value of late PCI for patients who have not had reperfusion therapy. However, the results of such studies have shown that elective PCI of an occluded infarct-related artery 3 to 28 days after MI offered no incremental benefit (beyond optimal medical therapy) for stable patients. The ACCF/AHA guideline for STEMI includes a recommendation that PCI of a totally occluded infarct-related artery more than 24 hours after STEMI should not be done in asymptomatic, stable patients with one- or two-vessel disease [2].

CABG

Evidence Based Practice Recommendation

Emergency CABG is recommended in patients with acute MI in whom 1) primary PCI has failed or cannot be performed, 2) coronary anatomy is suitable for CABG, and 3) persistent ischemia of a significant area of myocardium at rest and/or hemodynamic instability refractory to nonsurgical therapy is present.

http://circ.ahajournals.org/content/124/23/e652

Last Accessed: June 18, 2018

Strength of Recommendation/Level of Evidence: IB (Procedure/treatment should be performed based on data derived from a single randomized clinical trial or nonrandomized studies evaluating limited populations.)

Although PCI is performed more frequently, several situations call for the use of CABG. The ACCF/AHA guideline for STEMI and the ACC/AHA guideline for CABG surgery recommend emergent or urgent CABG when PCI has failed, for coronary anatomy not amenable to PCI, and at the time of surgical repair of a mechanical defect (e.g., ventricular septal, papillary muscle, free-wall rupture) [2,6].

CABG results in a longer average recovery time and hospital stay compared with PCI (9.2 days and 3.2 days, respectively), and the in-hospital mortality is higher for CABG than for PCI (5.0% to 6.0% and 3.0% to 3.5%, respectively) [238]. However, long-term outcomes, including survival, have been similar for the two procedures. The mortality risk associated with emergent or urgent CABG is greater than that for elective CABG [210]. In addition, there is an increased risk of bleeding associated with clopidogrel and prasugrel given within five to seven days before CABG [210]. Thus, when CABG is planned, clopidogrel should be withheld for at least five days (seven days for prasugrel) unless the urgency for the procedure outweighs the increased risk for bleeding [2,6]. The use of CABG should follow the ACC/AHA guideline for this procedure [6].

NONINVASIVE TESTING

Exercise testing in patients with STEMI is useful for risk stratification and assessment of functional capacity and should be performed to assess the presence and extent of inducible ischemia in patients who have not had angiography and do not have high-risk features [2]. The optimum time to exercise testing after STEMI has not been clearly defined. Exercise testing before discharge can provide reassurance to patients about their functional capacity and can also be used to establish exercise parameters for cardiac rehabilitation [2]. On the other hand, deferring exercise testing until three weeks after discharge in clinically low-risk patients appears to be safe and reasonable [2]. The ACCF/AHA guideline for STEMI suggests that exercise testing should be done before discharge in patients who may be candidates for a revascularization procedure and who have not undergone coronary angiography [2]. The use of exercise testing and the interpretation of its results should follow the guideline developed for this modality [197].

Echocardiography is also recommended for assessing left ventricular function in patients with STEMI who have not had coronary angiography and can be useful for evaluation of RV infarction in patients with inferior STEMI and initial nondiagnostic findings [2]. Patients who have baseline abnormalities that may compromise interpretation of the ECG findings should have stress echocardiography (or myocardial perfusion imaging) to assess inducible ischemia [2]. Echocardiography and stress echocardiography should be performed according to guidelines or criteria developed for their use [241].

GENERAL CARE AND ADJUVANT THERAPIES

In addition to either catheter-based or pharmacologic reperfusion, treatment of patients with STEMI involves the use of some of the same general care principles (such as those regarding bed rest and the use of oxygen) and drugs as those recommended for patients with NSTE-ACS. Adjuvant therapy involves the use of dual-antiplatelet therapy, nitroglycerin, morphine, beta blockers, ACE inhibitors, calcium-channel blockers, and statins; the drugs used depend on whether the patient is treated with PCI or fibrinolytic agents [2].

Antiplatelet Therapy

The 2013 ACCF/AHA guideline for the management of STEMI recommends aspirin at a dose of 162–325 mg as a loading dose before either PCI or fibrinolytic therapy [2]. A P2Y12 inhibitor is used along with aspirin as dual-antiplatelet therapy. For patients treated with PCI, clopidogrel (600 mg), prasugrel (60 mg), or ticagrelor (180 mg) should be given as a loading dose as early as possible or at the time of the PCI [2]. Treatment with a P2Y12 inhibitor is continued for one year. Clopidogrel is the recommended P2Y12 inhibitor to support fibrinolytic therapy; a loading dose of 300 mg is used for patients 75 years of age or younger, and no loading dose is used for patients older than 75 years of age [2]. Treatment with clopidogrel is continued for at least 14 days and up to one year.

Nitroglycerin/Morphine

The benefit of nitroglycerin for patients with STEMI has been modest, but the drug can be given sublingually (0.4 mg every five minutes up to three doses) for persistent or recurrent ischemic discomfort [2]. The use of nitroglycerin should not preclude the use of other drugs that have been shown to have more benefit, such as ACE inhibitors.

The drug of choice to manage the pain associated with STEMI is intravenous morphine sulfate [2]. Morphine sulphate is indicated to relieve ongoing ischemic discomfort, control hypertension, ameliorate anxiety, or manage pulmonary edema. The initial dose should be 4–8 mg, with lower doses in the elderly. Additional doses of 2–8 mg may be given at intervals of 5 to 15 minutes [2].

Beta Blockers

The use of beta blockers has been an established recommendation for patients with STEMI because of the drugs' association with lower mortality [2]. The recommendation was modified in the 2007 focused update of the ACC/AHA guideline because of safety issues related to the use of intravenous beta blockers in conjunction with fibrinolytic therapy as well as emerging data on a lack of survival benefit [240]. The findings were confirmed in the 2013 ACCF/AHA guideline, and it is still recommended that oral beta blockers be used within the first 24 hours, except for those subsets of patients at high risk for complications with use of beta blockers [2]. Beta blockers should not be used in patients with signs of heart failure, evidence of a low output state, increased risk of cardiogenic shock, or other relative contraindications to beta blockade.

ACE Inhibitors

The use of an oral ACE inhibitor is a strong recommendation for all patients recovering from STEMI, including those with anterior infarction, pulmonary congestion, or LVEF of less than 0.40, as well as those with normal LVEF in whom cardiovascular risk factors are well controlled [2]. Adherence to this recommendation has increased since the late 1990s but remains low [179,242,243]. In addition, the doses used in clinical practice have been lower than the target doses used in clinical trials [242].

A meta-analysis of several major trials (more than 100,000 patients) demonstrated that use of an ACE inhibitor was associated with a significant overall odds reduction in mortality of 6.5% [244]. Early treatment is optimal, as reductions in mortality have been greatest within the first five days after the MI [244,245]. The ACCF/AHA guideline for STEMI notes that it is preferable to initiate treatment with an ACE inhibitor within 24 hours [2]. Treatment should start at a low dose that is gradually increased to a full dose within 24 to 48 hours.

ACE inhibitors are of most benefit for patients who are 55 to 74 years of age, have had an anterior infarct, or have a heart rate of at least 80 beats per minute [246]. Contraindications include a systolic blood pressure of less than 100 mm Hg (or more than 30 mm Hg below baseline), the presence of clinically relevant renal failure, a history of bilateral stenosis of the renal arteries, or known allergy. Patients who cannot tolerate an ACE inhibitor should be treated with an ARB [2].

Calcium-Channel Blockers

Early treatment with dihydropyridine calcium antagonists (nifedipine and nicardipine) has not been found to improve rates of mortality or reinfarction [2]. Nifedipine is contraindicated in the treatment of STEMI. Although verapamil and diltiazem may be useful to relieve ongoing or recurrent ischemia, lower blood pressure, or control the ventricular response rate to atrial fibrillation when beta blockers are contraindicated (and the patient has well-preserved left ventricular function and no clinical evidence of congestive heart failure or pulmonary congestion), no specific recommendation for their use exists in the 2013 STEMI guideline [2,3]. Both drugs have been associated with significantly reduced mortality and major cardiovascular events [247,248]. Verapamil should not be used for patients with heart failure or bradyarrhythmias, and diltiazem should not be used for patients with left ventricular dysfunction [2].

6. DISCHARGE PLANNING AND SECONDARY PREVENTION

Appropriate discharge planning and secondary prevention measures are essential, as the morbidity and mortality after UA/NSTEMI or STEMI are high (Table 13). A multidisciplinary team should be involved in preparing the patient for discharge, and detailed discharge instructions should be given to both the patient and family [2]. Discharge instructions should be easily understood, culturally sensitive, given in the patient's preferred language, and reinforced with written instructions. Instructions should include detailed information on the comprehensive care plan, including [2,3]:

- Scheduling the first follow-up visit

- Return to normal activities (driving, work, physical/sexual activities)

- Recommended secondary prevention measures

- Medication dosing, frequency, and adherence

- Plans to obtain prescribed medications immediately after discharge

- Referral to cardiac rehabilitation

Table 13: OUTCOMES WITHIN FIVE YEARS AFTER FIRST MYOCARDIAL INFARCTION IN PATIENTS 45 YEARS OF AGE OR OLDER

Outcome

Prevalence

Men

Women

Recurrent MI or fatal CHD

17%

21%

Heart failure

16%

22%

Stroke

4%

7%

CHD = coronary heart disease, MI = myocardial infarction.

Source: [1]

CARDIAC REHABILITATION

Exercise-based cardiac rehabilitation and secondary prevention programs have been shown to reduce repeat hospital admissions and improve health-related quality of life and function [249,250]. Referral to a cardiac rehabilitation or secondary prevention program is a recommendation in the ACC/AHA guidelines for NSTE-ACS and STEMI [2,3].

SECONDARY PREVENTION STRATEGIES

Substantial evidence has demonstrated that aggressive risk-reduction therapies enhance patient outcomes after ACS, and the 2014 AHA/ACC Guideline for NSTE-ACS, the 2013 ACCF/AHA guideline for STEMI, and the 2011 update of the AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease guideline have made several recommendations for secondary prevention focusing on lifestyle modifications and medications.

Lifestyle Modifications

After an ACS event, patients must address modifiable risk factors associated with atherogenesis by changing certain behaviors. Lifestyle modifications will include improvements in diet and physical activity levels, smoking cessation, blood pressure control, lipid management, and diabetes management [2,251]. Clinicians should involve other healthcare professionals in helping patients to achieve goals and should reinforce patients' positive efforts toward reaching these goals.

Smoking Cessation

Quitting smoking has been described as "probably the most important thing a smoker with acute MI can do to improve future health" [252]. Mortality after an ACS event for a patient who smokes cigarettes is twice that for a patient who does not, but cessation of smoking reduces reinfarction and death rates at one year [2]. Clinicians should use the in-hospital period after MI and each office visit as an opportunity to ask patients who were smokers if they have quit or are ready to quit and should offer counseling, pharmacologic support, and information on formal quit programs. The in-hospital period is unique because many patients are motivated to quit and are typically unable to smoke for three to nine days. Randomized controlled trials have shown that repeated contacts during the hospital stay and at and beyond three months (typically by telephone) are more likely to result in smoking cessation [2]. A Cochrane review showed that only intensive counseling programs work and that nicotine replacement further increases the rates of successful cessation among patients in intensive programs [253]. Another Cochrane review found high-quality evidence for a benefit of combined pharmacotherapy (with any type of nicotine-replacement therapy, bupropion, nortriptyline, or varenicline) and behavioral treatment compared to usual care, brief advice, or less intensive behavioral support [254]. However, many clinicians are reluctant to add another drug to the multitude of medications prescribed after MI.

Diet

Obesity is another well-documented risk factor for CHD, and weight management programs and information on healthy eating/caloric intake should be promoted as appropriate [251]. The patient's body mass index and waist circumference should be measured at each visit. The goal is to attain a body mass index of 18.5–24.9 and a waist circumference of 35 inches (women) or 40 inches (men) [251]. When weight reduction is needed, the initial goal is weight loss of 5% to 10% from baseline [251].

Exercise

Evidence Based Practice Recommendation

Exercise-based secondary prevention programs are recommended for patients with STEMI and UA/NSTEMI.

http://circ.ahajournals.org/content/127/4/e362

Last Accessed: June 18, 2018

Strength of Recommendation/Level of Evidence: IB (Procedure/treatment should be performed based on data derived from a single randomized clinical trial or nonrandomized studies evaluating limited populations.)

The level of exercise should be prescribed according to risk, previous level of exercise, and possibly the results of a stress test [251]. The minimum goal is 30 minutes of aerobic exercise (e.g., walking, cycling, jogging) five times per week, with an optimal goal of 30 to 60 minutes every day [251]. Resistance training two times per week is reasonable to prescribe. Patients should also be encouraged to increase their routine daily activities (such as house cleaning and gardening).

Medications

Four classes of medications are recommended after an ACS event: antiplatelet/anticoagulant agents (aspirin, warfarin, and a P2Y12 inhibitor), beta blockers, ACE inhibitors (or ARBs), and lipid-lowering agents [2,3,251,255]. Treatment with these four classes has been associated with one-year mortality that is significantly lower than that for patients treated with none or one of the medications with a positive impact most apparent at 24 months postdischarge, regardless of revascularization therapy [254,256]. In addition, nitroglycerin should be prescribed for all patients, and they should be instructed on its use for ischemic pain [2]. The medication profile should be tailored to each patient on the basis of the in-hospital events and procedures, risk factors, and drug tolerability.

Antiplatelet/Anticoagulant Agents

The recommended antiplatelet therapy after discharge is a combination of aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) [2,251,255]. The findings of studies have suggested that low-dose aspirin is as effective as higher doses but has a better safety profile [170,257,258]. The recommended daily dose of aspirin is 75–162 mg for all patients, and the ACC/AHA guidelines for the management of STEMI and NSTE-ACS state that it is reasonable to a use an 81-mg dose [2,3,255,258]. However, despite the better safety profile of low-dose aspirin, data have indicated that 325 mg is the most common dose, prescribed for 55.7% of patients with UA/NSTEMI [259].

The addition of clopidogrel to aspirin as maintenance therapy has been found to enhance outcomes for patients [258,260]. Among 12,562 patients with ACS who were taking aspirin (at a dose of 75–325 mg daily) in one trial, one year of treatment with clopidogrel was associated with a lower rate of a composite endpoint of cardiac death, MI, or stroke, regardless of the aspirin dose [258]. Clopidogrel was also associated with an increased risk for major bleeding, but bleeding risks increased with increasing aspirin dose, with or without clopidogrel [258,260]. The 2013 update of the ACCF/AHA guideline for the management of STEMI includes modified recommendations for maintenance therapy with a P2Y12 inhibitor [2]. The guideline indicates that patients with a stent should receive clopidogrel (75 mg daily), prasugrel (10 mg daily), or ticagrelor (90 mg twice a day) for at least one year. Patients not receiving a stent should be treated with clopidogrel (75 mg daily); it is reasonable to prescribe prasugrel (10 mg daily) in patients not receiving a stent and without a history of stroke or transient ischemic attack [2].

Questions about clopidogrel maintenance therapy remain, as the optimal dose and duration of therapy have not been identified [165,255,261,262]. Another concern is the effect of stopping clopidogrel. In a 2008 study of 3,137 patients with ACS (treated either medically or with PCI) who took clopidogrel for a mean of 9 to 10 months, there was a significantly high risk of adverse events in the initial 90 days after stopping treatment with clopidogrel [263]. The reason for this phenomenon is unclear, and the authors suggested that strategies to reduce the incidence of such early events should be identified [263]. Additionally, the response to clopidogrel varies among patients, and diminished responsiveness has been observed [255]. A 2010 retrospective study of 2,017 patients with ACS, conducted to confirm the findings of the 2008 study, found that the 0- to 90-day interval after stopping clopidogrel was associated with higher risk of death/MI compared with the 91- to 360-day interval. There was a similar trend of increased adverse events 0 to 90 days after stopping clopidogrel for various subgroups (i.e., women versus men, medical therapy versus PCI, stent type, and ≥6 months or <6 months of clopidogrel treatment) [264]. Warfarin is recommended as an antithrombotic for patients with UA/NSTEMI or STEMI who are allergic to aspirin [251,255].

Antiplatelet therapy is preferred over anticoagulant therapy with warfarin (or other vitamin K agonists) for treating patients with atherosclerosis [251]. However, warfarin therapy is reasonable for patients with a prosthetic heart valve, persistent or paroxysmal atrial fibrillation, a documented left ventricular thrombus, concomitant venous thromboembolic disease, or other indication. Warfarin should be given to maintain a specific international normalized ratio (INR) depending on the use of stents, underlying cardiac disease, and the concomitant use of clopidogrel [251]. The risk of bleeding is increased when warfarin is used in conjunction with aspirin and/or clopidogrel, and patients treated with the three medications should be monitored closely [251].

Beta Blockers

Treatment with oral beta blockers is recommended for all patients after UA/NSTEMI or STEMI [2]. Treatment should continue indefinitely.

ACE Inhibitors or ARBs

An ACE inhibitor is also recommended as long-term therapy after UA/NSTEMI or STEMI [2,251]. ARBs should be used for patients who are unable to tolerate an ACE inhibitor and have clinical or radiographic signs of heart failure or a left ventricular ejection fraction of less than 40% [2].

Lipid-Lowering Agents

Even before the advent of statins, reducing lipid levels through diet and previously available medications led to significant reductions in MIs. Statins are now the preferred medications for lipid-level management, and several studies have demonstrated their effectiveness in reducing atherogenesis. A fasting lipid profile should be determined within 24 hours after admission, and statin therapy should begin during hospitalization, regardless of this baseline level [2]. Intensive statin therapy appears to be of benefit for patients with recent ACS (but not for patients with stable CHD). In a pooled analysis of data on more than 8,600 patients, intensive statin therapy significantly reduced all-cause mortality compared with standard therapy [265]. This benefit was confirmed in an analysis of data from a total of six trials (28,505 patients), with all-cause mortality at two years of 3.5% for intensive therapy compared with 4.6% for standard therapy [266]. A meta-analysis of 20 trials involving 8,750 patients with ACS undergoing PCI found a time-related benefit to the start of statin therapy. By meta-regression, earlier statin administration correlated significantly with lower risk of MI, major adverse cardiac events, and major adverse cardiac and cerebrovascular events [267].

The 2013 ACCF/AHA guideline for STEMI indicates the need to continue or initiate the use of a statin to manage patients' lipoprotein levels [2]. In particular, the guideline makes a sole recommendation for high-dose atorvastatin (80 mg daily), based primarily on results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. Rates of cardiovascular events did not significantly decrease with tiered simvastatin (40 mg for one month, then 80 mg thereafter), and there are concerns about the safety of the 80-mg dose [2]. The compliance rate of statins may be improved when therapy is initiated before discharge following STEMI.

The goal of statin therapy is to achieve an LDL level less than 100 mg/dL for patients with average risk, and an LDL level of less than 70 mg/dL is reasonable for very-high-risk patients [2]. If the triglyceride level is 200 mg/dL or higher, the non-HDL cholesterol should be less than 130 mg/dL in patients with average risk, whereas a non-HDL cholesterol level of less than 100 mg/dL is reasonable for very-high-risk patients. Statin therapy should be supplemented with dietary modification, weight management, and exercise. Patients should be encouraged to follow a diet with an increase of fresh fruits and vegetables, with less than 7% of total calories as saturated fat, less than 1% of total calories as trans fatty acids, and less than 200 mg per day of cholesterol [2,251].

If statin therapy fails to control lipid levels or patients do not tolerate statins, treatment with niacin or a bile acid sequestrant is reasonable [251]. Ezetimibe should be considered if patients do not tolerate any of the aforementioned medications [268,269,270,271].

Other Therapies

After discharge, patients may need other treatments to manage blood pressure, depression, or diabetes.

Control of Blood Pressure

In addition, blood pressure should be controlled according to the 2017 Guideline for High Blood Pressure in Adults, which recommends treatment when blood pressure is elevated, defined as 120–129/<80 mm Hg [77]. The guideline recommends initial treatment with nonpharmacologic interventions and lifestyle changes. Initiation of pharmacologic treatment is recommended for secondary prevention in patients with clinical CVD and an average systolic blood pressure of 130 mm Hg or greater or an average diastolic blood pressure of 80 mm Hg or greater and for primary prevention in adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 10% or higher and an average systolic blood pressure 130 mm Hg or greater or an average diastolic blood pressure 80 mm Hg or greater. The AHA/ACCF recommends initial treatment with a beta blocker and/or an ACE inhibitor as secondary prevention for patients with CHD [251].

Treatment of Depression

An ACS event can be distressing for many patients, leading to a heightened fear of dying and anxiety about adjusting to life with cardiac disease [272]. These emotions can substantially affect a patient's psychosocial status and lead to depression [273,274]. Some degree of clinically significant depression has been reported to occur in up to half of patients with ACS, with major depression occurring in 15% to 20% of patients [273]. Depression has been found more often in women compared with men and in men with a history of MI [275]. In addition to the negative effect on the patient's quality of life, depression has also been shown to be associated with lack of adherence to secondary prevention measures and with increased mortality [274,276,277].

Evaluation of a patient's psychosocial status, with particular attention paid to signs of depression, is a recommendation in the ACCF/AHA guidelines for STEMI and UA/NSTEMI, and screening for depression and referral and/or treatment is a recommendation in the 2011 AHA/ACCF Secondary Prevention and Risk Reduction Therapy guideline [2,3,251]. At each visit, clinicians should ask patients about anxiety, sleep disorders, social support, and symptoms of depression. Cognitive behavior therapy, sertraline, and selective serotonin reuptake inhibitors may be useful for enhancing the quality of life for patients with symptoms of depression, though treatment does not directly improve cardiovascular disease outcomes [251,273].

Management of Diabetes

CHD is responsible for about 75% of deaths in individuals with diabetes, and more than 30% of patients with NSTE-ACS have diabetes [3]. It is now well known that a reduction in blood glucose levels is associated with improved outcomes in patients with diabetes or prediabetes who have experienced UA/NSTEMI or STEMI. This reduction may be achieved as the result of lifestyle changes (including weight management, physical activity, and medical nutrition therapy) or medication therapy [2,3,278,279]. The patient's primary care physician and/or endocrinologist typically handle the management of diabetes, but it is beneficial for treating physicians to coordinate with a primary care physician or specialist [251].

The goal of diabetes management (aside from reversal of the condition though intensive lifestyle change) is tight glycemic control, as both hyperglycemia and hypoglycemia have a profound impact on in-hospital and six-month mortality rates following a cardiac event [3]. Metformin is the recommended first-line diabetes pharmacotherapy for the prevention of cardiovascular complications [251]. The intensity of blood glucose-lowering medications should be closely tailored to each patient's risk of hypoglycemia during treatment. It may be reasonable to initiate treatment with medications to achieve a hemoglobin A1c of 7% or less [251,280,281].

Adherence and Compliance

Despite the obvious benefit of secondary prevention strategies, physician adherence to guidelines and patient compliance with cardiac rehabilitation, medication regimens, and lifestyle change recommendations are suboptimal [251,252,282,283,284,285,286,287]. According to data from several studies, referrals to cardiac rehabilitation range from 64% to 87% by hospital (mean: 81%) [284]. Quality improvement initiatives have increased referrals. Rates of actual enrollment are more important than referral rates, however, and enrollment has been much lower than referral rates [284,285]. Only 29% of patients with MI who were referred to cardiac rehabilitation enrolled within one month of discharge; this rate raised to just 48.25% after six months [285]. Women are less likely to be enrolled after one month, as are patients with hypertension or peripheral arterial disease and uninsured patients. Older patients are less likely to have participated at six months, as are smokers and patients with economic hardship. White individuals and patients who attained a higher education level were more likely to enroll by six months [285].

Cardiac rehabilitation coordinators have identified several patient-related barriers to participation in rehabilitation programs as well as implementation of other evidence-based guidelines, including coming to terms with a diagnosis of heart disease, challenges in changing behavior, and cost [288]. Others have identified distance from a rehabilitation center (e.g., long travel time, lack of transportation) and high co-pays as significant barriers [285]. Efforts to improve rates of referral to cardiac rehabilitation should continue, and more research is needed to determine how to address barriers to enrollment.

Data have also indicated that rates of dietary change and smoking cessation in patients with ACS need improvement. Research shows that physicians are recommending dietary modification and smoking cessation to patients (91% and 95%, respectively), but rates of compliance are not optimal [252,286,289]. Smoking cessation rates following MI (roughly 30% at six months) are greater than in similar-age patients in the general population but are still too low [252].

Reasons provided for not adhering to dietary modification (and exercise) include not being able to see a physical change, and many individuals express that they are dissatisfied with having to make so many lifestyle changes at once [287]. However, the results of a 2014 study indicate that patients with ACS who comply with nonsmoking, diet, and exercise plans have significantly lower mortality and recurrence of MI despite no change to their waist circumference [290]. Therefore, it is important that patients understand that the benefits of dietary modification are internal (not based on appearance) and that obtaining a regular lipid profile will show their progress.

With regard to medications, studies have shown that up to 57% of patients are not managed optimally, defined as receiving all four classes of medications [25,177,200,243,256,283,289,291]. Optimal medical therapy is less likely among older patients; women; and patients who had CABG during the index hospitalization, had previous heart failure, or had renal dysfunction [256,292,293].

The class I guideline recommendations for all secondary prevention strategies can be organized into a simplified "ABCDE" approach to help clinicians implement guideline-based care [294]:

- A: Aspirin, antianginal agents, antiplatelet therapy, and ACE inhibitors (or ARBs)

- B: Beta blockers and blood pressure control

- C: Cardiac rehabilitation, cholesterol treatment, and cigarette smoking cessation

- D: Diet, depression management, and diabetes management

- E: Exercise and education

Critical pathways, protocols, and other quality improvement tools are valuable for helping to increase implementation of guidelines [25,295]. For example, the GWTG program helps to enhance compliance through a Web-based tool that provides online reminders about discharge management strategies. This tool can be used to send discharge instructions and information on medications to primary care clinicians [25,27]. The GWTG-Coronary Artery Disease program was implemented in 418 U.S. hospitals and was associated with widespread and prolonged adherence to evidence-based guidelines [295].

Lack of patient compliance with medications is also a serious problem and has been referred to as an unrecognized risk factor for CHD, because of its association with significant increases in adverse events and health costs [296,297]. Among individuals with CHD (many of whom had experienced a recent ACS event), compliance with guideline-recommended medications has ranged from 18% to 55%. Approximately 54% of individuals have been compliant with all of their initial medications, and compliance decreases over time [296,298,299]. One study showed that compliance was 60.3% at one year, 53.7% at two years, and 48.8% at five years [300]. Individuals who discontinue medications are more likely to be older, female, unmarried, and less educated [298]. Several other factors have been found to be associated with noncompliance with medications [296,298,299]:

- Choice of medication

- Tolerability

- Duration of treatment

- Dosing frequency

- Higher number of prescribed medications

- Lack of symptoms as indication for the medication

- Uncertainty about how to take the medication

- Lack of transportation to the pharmacy

Patient Education

Patient education is an integral component of treatment for patients with ACS and should begin during hospitalization and continue throughout follow-up care [2]. Adequate time for appropriate education during the index hospitalization has been challenged by shorter hospital stays and reduced staffing [301]. The responsibility of patient education has thus shifted to the healthcare team. Surveys have shown that nearly one-half of individuals are not knowledgeable about ACS-related symptoms or their level of risk, even after having an ACS event [301]. Men, older individuals, and individuals with less formal education were less likely to be knowledgeable about their risk and symptoms [301]. This lack of knowledge can contribute to lack of compliance with recommended secondary prevention strategies.

Research has shown that patient education should focus on the importance of [2,302]:

- Recognition of symptoms

- Timeliness of care

- Acknowledgment of risk factors for ACS

- Compliance with secondary prevention strategies

Education in these areas should be tailored to individuals, as perceptions of cardiac disease and risk differ across subgroups of patients according to age, gender, and race/ethnicity [302,303]. As noted, many clinicians do not feel confident in their effectiveness in helping patients understand their disease and comply with preventive measures [19]. Several strategies can help clinicians educate patients effectively (Table 14) [304,305,306,307,308].

Table 14: STRATEGIES TO HELP ENHANCE EFFECTIVENESS OF PATIENT EDUCATION

Ask the patient what language he or she prefers for educational resources and use that language for oral education and written resources (as much as possible).

Assess the patient's baseline understanding of the disease and treatment.

Ask the patient what and how much he or she wants to know.

Discuss epidemiologic and clinical evidence.

Involve other healthcare specialists in the educational process.

Use a variety of educational resources in a variety of media.

Try innovative approaches, such as interactive modules.

Offer online resources to patients (e.g., the AHA website [https://www.heart.org ] or the NHLBI website [https://www.nhlbi.nih.gov]).

Ascertain potential barriers to compliance.

Develop an action plan.

Have patient focus on one behavior change at a time, if necessary.

Involve family members in educational efforts.

Reinforce recommendations at all office visits.

Provide positive reinforcement for each step toward goals.

Provide telephone follow-up.

Source: [304,305,306,307,308]

Recognition of Symptoms

Many individuals still believe that the onset of an MI will be "dramatic," with chest pain that is severe and crushing [2,309]. Among individuals who had an acute MI, 40% interpreted their symptoms as cardiac in nature [303]. In addition, chest pain and other ACS-related symptoms were interpreted differently by men and women. Men were more likely to think the symptoms were cardiac in nature if the chest pain was severe and if they had a history of CHD. In contrast, women did not relate severity of chest pain with a cardiac origin [303]. Healthcare professionals should talk to patients about the "real" signs and symptoms of ACS, emphasizing the diversity in symptoms [301].

Timeliness of Care

On average, individuals wait 1.5–2 hours before seeking medical care for ACS-related symptoms, and this delay has not changed over time, despite many national public campaigns emphasizing the importance of timely care [2]. Furthermore, up to 50% of individuals with ACS-related symptoms are transported to the hospital by means other than emergency medical services, which can increase delays [2,310]. Individuals have given several reasons for delays in seeking medical care (Table 15) [309]. Individuals and their families or caregivers should be told that immediate action is needed for ACS-related symptoms, including calling emergency medical services, taking nitroglycerin for ischemic pain, and taking aspirin.

Table 15: REASONS FOR DELAY IN SEEKING MEDICAL ATTENTION FOR CHEST PAIN

Expected more severe chest pain

Believed chest pain would resolve

Did not think symptoms were serious

Decided on "wait and see" approach

Thought symptoms were related to another condition (e.g., muscle strain, heartburn)

Was not aware of benefit of rapid action

Feared embarrassment if symptoms were not related to cardiac event

Underestimated personal risk of cardiac event

Source: [2,309]

Acknowledgement of Risk Factors

The need for better understanding of risk among individuals who have had ACS is evidenced by studies that have shown that their perceptions of their personal risk are lower than their actual risk [2,301,309]. Healthcare professionals should reinforce information about modifiable risk factors and provide patients with educational resources that describe risk factors and their effect on the potential for future events. Patients' individual risk factors should be discussed in an ongoing manner, with a focus on positive changes through lifestyle modifications and medications.

Compliance with Secondary Prevention Strategies

Compliance with prevention strategies can be enhanced by identifying the barriers for each individual patient and working together to address the problem. Primary care clinicians and other healthcare professionals should ask patients about medication compliance at each office visit and should emphasize the importance of maintaining drug therapy. Ongoing education about the benefit gained from medications as well as lifestyle modifications is vital to ensuring high compliance and low risk of adverse events.

7. CONCLUSION

The identification of the pathophysiologic process leading to ACS has redefined the treatment of this spectrum of cardiac disorders, and researchers continue to refine therapeutic options to produce optimal patient outcomes. Despite a shared initiating event (plaque rupture or erosion), UA/NSTEMI and STEMI are distinct clinical entities, with differences in pathophysiology, clinical presentation, treatment, and prognosis. The diagnosis of UA/NSTEMI (also known as NSTE-ACS) relies primarily on elevated levels of cardiac troponins and the lack of ST-segment elevation on ECG. By contrast, the diagnosis of STEMI is made solely on ECG findings. After the type of MI has been determined, complex decision making is required to determine the appropriate course of treatment.

The goal of immediate treatment of NSTE-ACS is relief of ischemia and prevention of recurrent ischemic events. Risk stratification is essential for determining whether an early invasive or ischemia-guided strategy is best for the patient. Antiplatelet therapy, P2Y12 inhibitors, and antithrombotic therapy are adjuncts to treatment. With STEMI, the goal of immediate treatment is re-establishment of blood flow to the heart. The crucial factor for determining the treatment approach is timing from the onset of symptoms to treatment and from arrival in the emergency department to treatment. The preferred option for reperfusion is PCI, but the recommended 90-minute door-to-balloon time is difficult to achieve in most cases. However, there is an increased emphasis on developing systems of care that increase patient access to primary PCI. The other option for reperfusion, fibrinolytic therapy, has the advantage of immediately re-establishing blood flow, but it is associated with lower rates of reperfusion and higher risks compared with PCI. Ancillary therapy with antiplatelet therapy, P2Y12 inhibitors, and antithrombotic therapy is used to maintain patency of the infarct-related artery and prevent re-occlusion.

Review of data from several large-scale studies, cardiac registries, and quality improvement initiatives has shown that adherence to guideline recommendations for the diagnosis, treatment, and secondary prevention NSTE-ACS and STEMI are suboptimal, particularly for older individuals, women, and minority populations. In addition, an inverse relationship has been found between risk and treatment, with more low-risk patients than high-risk patients receiving aggressive treatment. The data have also demonstrated a clear benefit in survival and outcomes when guideline recommendations are followed. Thus, clinicians should become more familiar with these guidelines and should encourage hospitals to implement system-wide policies and procedures to facilitate guideline-driven care. The use of protocols, clinical pathways, and standardized order forms can help to ensure that all patients receive appropriate care in a timely manner. After discharge, effective communication among the treating physician, the healthcare team, the patient and family, and the patient's primary care clinician is essential for ensuring long-term compliance with lifestyle modifications and medications, which will help to reduce the risk of future cardiac events.

Works Cited

1. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics—2018 update. A report from the American Heart Association. Circulation. 2018;137(20):e146-e603.

2. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-e425.

3. Amsterdam E, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes. J Am Coll Cardiol. 2014;64(24):e139-228.

4. Tian J, Ren X, Vergallo R, et al. Distinct morphological features of ruptured culprit plaque for acute coronary events compared to those with silent rupture and thin-cap fibroatheroma: a combined optical coherence tomography and intravascular ultrasound study. J Am Coll Cardiol. 2014;63(21):2209-2216.

5. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124:2574-2609.

6. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124:2610-2642.

7. Peterson ED, Shah BR, Parsons L. Trends in quality of care for patients with acute myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J. 2008;156(6):1045-1055.

8. Somma KA, Bhatt DL, Fonarow GC, et al. Guideline adherence after ST-segment elevation versus non-ST segment elevation myocardial infarction. Circ Cardiovasc Qual Outcomes. 2012;5(5):654-661.

9. Maddox TM, Ho PM, Tsai TT, et al. Clopidogrel use and hospital quality in medically managed patients with non-ST-segment-elevation myocardial infarction. Circ Cardiovasc Qual Outcomes. 2012;5(4):523-531.

10. Sherwood MW, Wiviott SD, Peng SA, et al. Early clopidogrel versus prasugrel use among contemporary STEMI and NSTEMI patients in the U.S.: insights from the National Cardiovascular Data Registry. J Am Heart Assoc. 2014;3(2):e000849.

11. Alexander KP, Newby LK, Cannon CP, et al. Acute coronary care in the elderly, part I: non-ST-segment-elevation acute coronary syndromes: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology, in collaboration with the Society of Geriatric Cardiology. Circulation. 2007;115(19):2549-2569.

12. Davis M, Diamond J, Montgomery D, Krishnan S, Eagle K, Jackson E. Acute coronary syndrome in young women under 55 years of age: clinical characteristics, treatment, and outcomes. Clin Res Cardiol. 2015;104;(8):648-655.

13. Grosmaitre P, Le Vavasseur O, Yachouh E, et al. Significance of atypical symptoms for the diagnosis and management of myocardial infarction in elderly patients admitted to emergency departments. Arch Cardiovasc Dis. 2013;106(11):586-592.

14. Poon S, Goodman SG, Yan RT, et al. Bridging the gender gap: insights from a contemporary analysis of sex-related differences in the treatment and outcomes of patients with acute coronary syndromes. Am Heart J. 2012;163:66-73.

15. Alfredsson J, Clayton T, Damman P, et al. Impact of an invasive strategy on 5 years outcome in men and women with non-ST-segment elevation acute coronary syndromes. Am Heart J. 2014;168(4):522-529.

16. Dreyer RP, Wang Y, Strait KM, et al. Gender differences in the trajectory of recovery in health status among young patients with acute myocardial infarction: results from the VIRGO study. Circulation. 2015;131(22):1971-1980.

17. Wang TY, Chen AY, Roe MT, et al. Comparison of baseline characteristics, treatment patterns, and in-hospital outcomes of Asian versus non-Asian white Americans with non-ST-segment elevation acute coronary syndromes from the CRUSADE quality improvement initiative. Am J Cardiol. 2007;100(3):391-396.

18. Patel MR, Chen AY, Roe MT, et al. A comparison of acute coronary syndrome care at academic and nonacademic hospitals.Am J Med. 2007;120(1):40-46.

19. Mosca L, Linfante AH, Benjamin EJ, et al. National study of physician awareness and adherence to cardiovascular disease prevention guidelines. Circulation. 2005;111:499-510.

20. Doroodchi H, Abdolrasulnia M, Foster JA, et al. Knowledge and attitudes of primary care physicians in the management of patients at risk for cardiovascular events. BMC Fam Pract. 2008;9:42.

21. Andreotti F, Marchese N. Women and coronary disease. Heart. 2008;94(1):108-116.

22. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-S45.

23. Blomkalns AL, Roe MT, Peterson ED, Ohman EM, Fraulo ES, Gibler WB. Guideline implementation research: exploring the gap between evidence and practice in the CRUSADE Quality Improvement Initiative. Acad Emerg Med. 2007;14(11):949-954.

24. Peterson ED, Roe MT, Rumsfeld JS, et al. A call to ACTION (Acute Coronary Treatment and Intervention Outcomes Network): a national effort to promote timely clinical feedback and support continuous quality improvement for acute myocardial infarction. Circ Cardiovasc Qual Outcomes. 2009;2:491-499.

25. LaBresh KA, Fonarow GC, Smith SC Jr, et al. Improved treatment of hospitalized coronary artery disease patients with the Get with the Guidelines Program. Crit Pathw Cardiol. 2007;6(3):98-105.

26. Mehta RH, Chen AY, Alexander KP, Ohman EM, Roe MT, Peterson ED. Doing the right things and doing them the right way. Association between hospital guideline adherence, dosing safety, and outcomes among patients with acute coronary syndrome. Circulation. 2015;131:980-987.

27. Miller KL, Pollack CV Jr, Peterson ED. Moving from evidence to practice in the care of patients who have acute coronary syndrome. Cardiol Clin. 2006;24(1):87-102.

28. National Cardiovascular Data Registry. Available at https://cvquality.acc.org/NCDR-Home. Last accessed May 22, 2018.

29. Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med. 2008;358(21):2205-2217.

30. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60(16):1581-1598.

31. Lansky AJ, Ng VG, Maehara A, et al. Gender and the extent of coronary atherosclerosis, plaque composition, and clinical outcomes in acute coronary syndromes. JACC Cardiovasc Imaging. 2012;5(3 Suppl):S62-S72.

32. Leening MJ, Ferket BS, Steyerberg EW, et al. Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort study. BMJ. 2014;349:g5992.

33. Masoudi FA, Ponirakis A, Yeh RW, et al. Cardiovascular care facts: a report from the National Cardiovascular Data Registry, 2011.J Am Coll Cardiol. 2013;62(21):1931-1947.

34. Heron M. Deaths: leading causes for 2014. Natl Vital Stat Rep. 2016;65(5):1-95.

35. Kontos MC, Rennyson SL, Chen AY, Alexander KP, Peterson ED, Roe MT. The association of myocardial infarction process of care measures and in-hospital mortality: a report from the NCDR. Am Heart J. 2014;168(5):766-775.

36. Marceau A, Samson JM, Laflamme N, et al. Short and long-term mortality after STEMI versus non-STEMI: a systematic review and meta-analysis [abstract]. J Am Coll Cardiol. 2013;61(10):e96.

37. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114(12):1852-1866.

38. Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute coronary syndromes: the pathologists' view. Eur Heart J. 2013;34(10):719-728.

39. Sakakura K, Nakano M, Otsuka F, Ladich E, Kolodgie FD, Virmani R. Pathophysiology of atherosclerosis plaque progression.Heart Lung Circ. 2013;22(6):399-411.

40. Bhatheja R, Mukherjee D. Acute coronary syndromes: unstable angina/non-ST elevation myocardial infarction. Crit Care Clin. 2007;23(4):709-735.

41. Stary HC, Blankenhorn DH, Chandler AB, et al. A definition of the intima of human arteries and of its atherosclerosis-prone regions: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1992;85(1):391-405.

42. Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol. 1994;14:840-856.

43. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1995;92(5):1355-1374.

44. Stary HC. Natural history and histological classification of atherosclerotic lesions: an update. Arterioscler Thromb Vasc Biol. 2000;20(5):1177-1178.

45. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20:1262-1275.

46. Schaar JA, Muller JE, Falk E, et al. Terminology for high-risk and vulnerable coronary artery plaques: report of a meeting on the vulnerable plaque, June 17 and 18, 2003, Santorini, Greece. Eur Heart J. 2004;25:1077-1082.

47. Lau J, Kent D, Tatsioni A, et al. Technology Assessment. Vulnerable Plaques: A Brief Review of the Concept and Proposed Approaches to Diagnosis and Management. Rockville, MD: Agency for Healthcare Research and Quality; 2004.

48. Rittersma SZH, van der Wal AC, Koch KT, et al. Plaque instability frequently occurs days or weeks before occlusive coronary thrombosis: a pathological thrombectomy study in primary percutaneous coronary intervention. Circulation. 2005;111:1160-1165.

49. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47(8 suppl):C13-C18.

50. Cheruvu PK, Finn AV, Gardner C, et al. Frequency and distribution of thin-cap fibroatheroma and ruptured plaques in human coronary arteries: a pathologic study. J Am Coll Cardiol. 2007;50(10):940-949.

51. Fuji K, Kawasaki D, Masutani M, et al. OCT assessment of thin-cap fibroatheroma distribution in native coronary arteries.JACC Cardiovasc Imaging. 2010;3(2):168-175.

52. Wykrzykowska JJ, Mintz GS, Garcia-Garcia HM, et al. Longitudinal distribution of plaque burden and necrotic core-rich plaques in nonculprit lesions of patients presenting with acute coronary syndromes. JACC Cardiovasc Imaging. 2012;5(3 Suppl):S10-S18.

53. Xie Y, Mintz GS, Yang J, et al. Clinical outcome of nonculprit plaque ruptures in patients with acute coronary syndrome in the PROSPECT study. JACC Cardiovasc Imaging. 2014;7(4):397-405.

54. Shimamura K, Ino Y, Kubo T, et al. Difference of ruptured plaque morphology between asymptomatic coronary artery disease and non-ST elevation acute coronary syndrome patients: an optical coherence tomography study. Atherosclerosis. 2014;235(2):532-537.

55. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med. 2013;368(21):2004-2013.

56. Motoyama S, Sarai M, Harigaya H, et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol. 2009;54(1):49-57.

57. Ino Y, Kubo T, Tanaka A, et al. Difference of culprit lesion morphologies between ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome: an optical coherence tomography study. JACC Cardiovasc Interv. 2011;4(1):76-82.

58. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97(18):1837-1847.

59. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: executive summary. Circulation. 2010;122:2748-2764.

60. Rodondi N, Locatelli I, Aujesky D, et al. Framingham risk score and alternatives for prediction of coronary heart disease in older adults. PLoS One. 2012;7(3):e34287.

61. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S49-S73.

62. U.S. Preventative Services Task Force. Final Recommendation Statement. High Blood Pressure in Adults: Screening. Available at https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/high-blood-pressure-in-adults-screening#table-of-contents. Last accessed May 22, 2018.

63. U.S. Preventative Services Task Force. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Preventive Medication. Available at https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/statin-use-in-adults-preventive-medication1. Last accessed May 22, 2018.

64. U.S. Preventative Services Task Force. Tobacco Smoking Cessation in Adults, Including Pregnant Women: Behavioral and Pharmacotherapy Interventions. Available at https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/tobacco-use-in-adults-and-pregnant-women-counseling-and-interventions1. Last accessed May 22, 2018.

65. Buckley DI, Fu R, Freeman M, Rogers K, Helfand M. C-reactive protein as a risk factor for coronary heart disease: a systematic review and meta-analyses for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151(7):483-495.

66. Emerging Risk Factors Collaboration. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med. 2012;367(14):1310-1320.

67. Helfand M, Buckley DI, Freeman M, et al. Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151(7):496-507.

68. Emerging Risk Factors Collaboration. Lipid-related markers and cardiovascular disease prediction. JAMA. 2012;307(23):2499-2506.

69. Gepner AD, Young R, Delaney JA, et al. Comparison of coronary artery calcium presence, carotid plaque presence, and carotid intima-media thickness for cardiovascular disease prediction in the Multi-Ethnic Study of Atherosclerosis. Circ Cardiovasc Imaging. 2015;8(1).

70. Zeb I, Budoff M. Coronary artery calcium screening: does it perform better than other cardiovascular risk stratification tools? Int J Mol Sci. 2015;16(3):6606-6620.

71. Taylor AJ, Cerqueira M, Hodgson JMcB, et al. ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac computed tomography: a Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. Circulation. 2010;122(21):e525-e555.

72. Peters SA, den Ruijter HM, Bots ML, Moons KG. Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: a systematic review. Heart. 2012;98(3):177-184.

73. Peters SA, Bakker M, den Ruijter HM, Bots ML. Added value of CAC in risk stratification for cardiovascular events: a systematic review. Eur J Clin Invest. 2012;42(1):110-116.

74. Snow V, Barry P, Fihn SD, et al. Evaluation of primary care patients with chronic stable angina: guidelines from the American College of Physicians. Ann Intern Med. 2004;141(1):57-64.

75. Chou R, for the High Value Care Task Force of the American College of Physicians. Cardiac screening with electrocardiography, stress echocardiography, or myocardial perfusion imaging: advice for high-value care from the American College of Physicians. Ann Intern Med. 2015;162(6):438-447.

76. Moyer VA, on behalf of the U.S. Preventive Services Task Force. Screening for coronary heart disease with electrocardiograpy: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(7):512-518.

77. Whelton PK, Carey RM, Aranow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(6):e1-e487.

78. Navar-Boggan AM, Pencina MJ, Williams K, Sniderman AD, Peterson ED. Proportion of U.S. adults potentially affected by the 2014 hypertension guideline. JAMA. 2014;311(14):1424-1429.

79. Borden WB, Maddox TM, Tang F, et al. Impact of the 2014 expert panel recommendations for management of high blood pressure on contemporary cardiovascular practice: insights from the NCDR PINNACLE registry. J Am Coll Cardiol. 2014;64(21):2196-2203.

80. Murthy VL, Shah RV, Rubenfire M, Brook RD. Comparison of the treatment implications of American Society of Hypertension and International Society of Hypertension 2013 and Eighth Joint National Committee Guidelines: an analysis of National Health and Nutrition Examination Survey. Hypertension. 2014;64(2):275-280.

81. Blood Pressure Lowering Treatment Trialists' Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet. 2014;384(9943):591-598.

82. Moran AE, Odden MC, Thanataveerat A, et al. Cost-effectiveness of hypertension therapy according to 2014 guidelines. N Engl J Med. 2015;372(5):447-455.

83. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497.

84. Hughes LS, Ebell MH. 2013 ACC/AHA cholesterol guideline greatly increases number eligible for statin treatment. Am Fam Physician. 2014;90(4):online.

85. Schoen MW, Salas J, Scherrer JF, Buckhold FR. Cholesterol treatment and changes in guidelines in an academic medical practice. Am J Med. 2015;128(4):403-409.

86. Johnson KM, Dowe DA. Accuracy of statin assignment using the 2013 AHA/ACC Cholesterol Guideline versus the 2001 NCEP ATP III guideline: correlation with atherosclerotic plaque imaging. J Am Coll Cardiol. 2014;64(9):910-919.

87. Martin SS, Sperling LS, Blaha MJ, et al. Clinician-patient risk discussion for atherosclerotic cardiovascular disease prevention: importance to implementation of the 2013 ACC/AHA guidelines. J Am Coll Cardiol. 2015;65(13):1361-1368.

88. Mozaffarian D, Wilson PWF, Kannel WB. Beyond established and novel risk factors: lifestyle risk factors for cardiovascular disease. Circulation. 2008;117:3031-3038.

89. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129(25 Suppl 2):S102-S138.

90. Ebbert JO, Elrashidi MY, Jensen MD. Managing overweight and obesity in adults to reduce cardiovascular disease risk. Curr Athersoscler Rep. 2014;16(10):445.

91. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(Suppl 2):S76-S99.

92. LeFevre ML, on behalf of the U.S. Preventive Services Task Force. Behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults with cardiovascular risk factors: U.S. Preventive Services Task Force Recommendation Statement: behavioral counseling in adults with cardiovascular risk factors. Ann Intern Med. 2014;161(8):587-593.

93. Lin JS, O'Connor E, Evans CV, Senger CA, Rowland MG, Groom HC. Behavioral counseling to promote a healthy lifestyle in persons with cardiovascular risk factors: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;161(8):566-578.

94. Pearson TA, Palaniappan LP, Artinian NT, et al. American Heart Association guide for improving cardiovascular health at the community level, 2013 update: a scientific statement for public health practitioners, healthcare providers, and health policy makers. Circulation. 2013;127:1730-1753.

95. U.S. Preventive Services Task Force, Grossman DC, Bibbins-Domingo K, et al. Behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults without cardiovascular risk factors: U.S. Preventive Services Task Force recommendation statement. JAMA. 2017;318(2):167-174.

96. Ventola CL. Current issues regarding complementary and alternative medicine (CAM) in the United States: part 1: the widespread use of CAM and the need for better-informed health care professionals to provide patient counseling. P T. 2010;35(8):461-468.

97. Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of complementary health approaches among adults: United States, 2001–2012. Natl Health Stat Report. 2015;79:1-15.

98. Moyer VA, LeFevre ML, Siu AL, et al. Vitamin, mineral, and multivitamin supplements for the primary prevention of cardiovascular disease and cancer: U.S. Preventive services Task Force recommendation statement. Ann Intern Med. 2014;160(8):558-564.

99. Flowers N, Hartley L, Todkill D, Stranges S, Rees K. Co-enzyme Q10 supplementation for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2014;12:CD010405.

100. Rees K, Harley L, Day C, Flowers N, Clarke A, Stranges S. Selenium supplementation for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1:CD009671.

101. Hartley L, Flowers N, Holmes J, et al. Green and black tea for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;6:CD009934.

102. Hartley L, Flowers N, Lee MS, Ernst E, Rees K. Tai chi for primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2014;4:CD010366.

103. Rees K, Hartley L, Flowers N, et al. 'Mediterranean' dietary pattern for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;8:CD009825.

104. Hira RS, Kennedy K, Nambi V, et al. Frequency and practice-level variation in inappropriate aspirin use for the primary prevention of cardiovascular disease: insights from the National Cardiovascular Disease Registry's Practice Innovation and Clinical Excellence registry. J Am Coll Cardiol. 2015;65(2):111-121.

105. National Hospital Ambulatory Medical Care Survey: 2015 Emergency Department Summary Tables. Available at https://www.cdc.gov/nchs/data/nhamcs/web_tables/2015_ed_web_tables.pdf. Last accessed May 22, 2018.

106. Kontos MC, Diercks DB, Kirk JD. Emergency department and office-based evaluation of patients with chest pain. Mayo Clin Proc. 2010;85(3):284-299.

107. Mahler SA, Riley RF, Hiestand BC, et al. The HEART Pathway randomized trial: identifying emergency department patients with acute chest pain for early discharge. Circ Cardiovasc Qual Outcomes. 2015;8(2):195-203.

108. Mathews R, Peterson ED, Li S, et al. Use of emergency medical service transport among patients with ST-segment-elevation myocardial infarction: findings from the National Cardiovascular Data Registry Acute Coronary Treatment Intervention Outcomes Network Registry-Get With the Guidelines. Circulation. 2011;124(2):154-163.

109. McGinn AP, Rosamund WD, Goff DC Jr, Taylor HA, Miles JS, Chambless L. Trends in prehospital delay time and use of emergency medical services for acute myocardial infarction: experience in 4 U.S. communities from 1987–2000. Am Heart J. 2005;150(3):392-400.

110. Henderson SO, Magana RN, Korn CS, Genna T, Bretsky PM. Delayed presentation for care during acute myocardial infarction in a Hispanic population of Los Angeles County. Ethn Dis. 2002;12(1):38-44.

111. Nguyen HL, Sacqynski JS, Gore JM, Goldberg RJ. Age and sex differences in duration of prehospital delay in patients with acute myocardial infarction: a systematic review. Circ Cardiovasc Qual Outcomes. 2010;3(1):82-93.

112. Tam LM, Fonarow GC, Bhatt DL, et al. Achievement of guideline-concordant care and in-hospital outcomes in patients with coronary artery disease in teaching and nonteaching hospitals: results from the Get With The Guidelines-Coronary Artery Disease program. Circ Cardiovasc Qual Outcomes. 2013;6(1):58-65.

113. Engel J, Damen NL, van der Wulp I, de Bruijine MC, Wagner C. Adherence to cardiac practice guidelines in the management of non-ST-elevation acute coronary syndromes: a systematic literature review. Curr Cardiol Rev. 2017;13(1):3-27.

114. Farmer SA, Roter DL, Higginson IJ. Chest pain: communication of symptoms and history in a London emergency department. Patient Educ Couns. 2006;63(1-2):138-144.

115. U.S. Census Bureau. Selected Social Characteristics in the United States: 2012–Available at https://factfinder.census.gov/faces/tableservices/jsf/pages/productview.xhtml?pid=ACS_13_5YR_DP02&src=pt. Last accessed May 22, 2018.

116. Karliner LS, Napoles-Springer AM, Schillinger D, Bibbins-Domingo K, Pérez-Stable EJ. Identification of limited English proficient patients in clinical care. J Gen Intern Med. 2008;23(10):1555-1560.

117. Flores G. The impact of medical interpreter services on the quality of health care: a systematic review. Med Care Res Rev. 2005;62(3):255-299.

118. Ramirez D, Engel KG, Tang TS. Language interpreter utilization in the emergency department setting: a clinical review. J Health Care Poor Underserved. 2008;19(2):352-362.

119. Karliner LS, Jacobs EA, Chen AH, Mutha S. Do professional interpreters improve clinical care for patients with limited English proficiency? A systematic review of the literature. Health Serv Res. 2007;42(2):727-754.

120. Ngo-Metzger Q, Massagli MP, Clarridge BR, et al. Linguistic and cultural barriers to care: perspectives of Chinese and Vietnamese immigrants. J Gen Intern Med. 2003;18(1):44-52.

121. Canto JG, Goldberg RJ, Hand MM, et al. Symptom presentation of women with acute coronary syndromes: myth vs reality. Arch Intern Med. 2007;167(22):2405-2413.

122. Brieger D, Eagle KA, Goodman SG, et al. Acute coronary syndromes without chest pain, an underdiagnosed and undertreated high-risk group. Insights from the Global Registry of Acute Coronary Events. Chest. 2004;126(2):461-469.

123. Amsterdam EA, Kirk JD, Bluemke DA, et al. Testing of low-risk patients presenting to the emergency department with chest pain: a scientific statement from the American Heart Association. Circulation. 2010;122:1756-1776.

124. Haro LH, Decker WW, Boie ET, Wright RS. Initial approach to the patient who has chest pain. Cardiol Clin. 2006;24(1):1-17.

125. Smith SW, Whitwam W. Acute coronary syndromes. Emerg Med Clin North Am. 2006;24(1):53-89.

126. Winters ME, Katzen SM. Identifying chest pain emergencies in the primary care setting. Prim Care. 2006;33(3):625-642.

127. Kelly BS. Evaluation of the elderly patient with acute chest pain. Clin Geriatr Med. 2007;23(2):327-349.

128. Butler KH, Swencki SA. Chest pain: a clinical assessment. Radiol Clin North Am. 2006;44(2):165-179.

129. Arslanian-Engoren C, Patel A, Fang J, et al. Symptoms of men and women presenting with acute coronary syndromes. Am J Cardiol. 2006;98(9):1177-1181.

130. Arslanian-Engoren C, Engoren M. Physiological and anatomical bases for sex differences in pain and nausea as presenting symptoms of acute coronary syndromes. Heart Lung. 2010;39(5):386-393.

131. Han JH, Lindsell CJ, Hormung RW, et la. The elder patient with suspected acute coronary syndromes in the emergency department. Acad Emerg Med. 2007;14(8):732-739.

132. Stephen SA, Darney BG, Rosenfeld AG. Symptoms of acute coronary syndrome in women with diabetes: an integrative review of the literature. Heart Lung. 2008;37(3):179-189.

133. Merinopoulos I, Bloore D. But he has no chest pain. Oxf Med Case Reports. 2014;2014(7):129-31.

134. Kosuge M, Kimura K, Ishikawa T, et al. Differences between men and women in terms of clinical features of ST-segment elevation acute myocardial infarction. Circ J. 2006;70(3):222-226.

135. Thuresson M, Jarlöv MB, Lindahl B, Svensson L, Zedigh C, Herlitz J. Symptoms and type of symptom onset in acute coronary syndrome in relation to ST elevation, sex, age, and a history of diabetes. Am Heart J. 2005;150(2):234-242.

136. DeVon HA, Ryan CJ, Ochs AL, Shapiro M. Symptoms across the continuum of acute coronary syndromes: differences between women and men. Am J Crit Care. 2008;17(1):14-24.

137. Carmin CN, Ownby RL, Wiegartz PS, Kondos GT. Women and non-cardiac chest pain: gender differences in symptom presentation. Arch Womens Ment Health. 2008;11(4):287-293.

138. Heer T, Gitt AK, Juenger C, et al. Gender differences in acute non-ST-segment elevation myocardial infarction. Am J Cardiol. 2006;98(2):160-166.

139. Shaw LJ, Shaw RE, Merz CN, et al. Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and in-hospital mortality in the American College of Cardiology-National Cardiovascular Data Registry. Circulation. 2008;117(14):1787-1801.

140. Pryor DB, Shaw L, McCants CB, et al. Value of the history and physical in identifying patients at increased risk for coronary artery disease. Ann Intern Med. 1993;118(2):81-90.

141. Tsai CL, Magid DJ, Sullivan AF, et al. Quality of care for acute myocardial infarction in 58 U.S. emergency departments. Acad Emerg Med. 2010;17(9):940-950.

142. Dasari TW, Roe MT, Chen AY, et al. Impact of time of presentation on process performance and outcomes in ST-segment-elevation myocardial infarction: a report from the American Heart Association: Mission Lifeline program. Circ Cardiovasc Qual Outcomes. 2014;7(5):656-663.

143. Diercks DB, Peacock WF, Hiestand BC, et al. Frequency and consequences of recording an electrocardiogram >10 minutes after arrival in an emergency room in non-ST-segment elevation acute coronary syndromes (from the CRUSADE Initiative). Am J Cardiol. 2006;97(4):437-442.

144. Tricoci P, Peterson ED, Roe MT; CRUSADE Quality Improvement Initiative. Patterns of guideline adherence and care delivery for patients with unstable angina and non-ST-segment elevation myocardial infarction (from the CRUSADE Quality Improvement Initiative). Am J Cardiol. 2006;98(12A):30Q-35Q.

145. Takakuwa KM, Burek GA, Estepa AT, Shofer FS. A method for improving arrival-to-electrocardiogram time in emergency department chest pain patients and the effect on door-to-balloon time for ST-segment elevation myocardial infarction. Acad Emerg Med. 2009;16(10):921-927.

146. Collinson PO, Gaze DC, Thokala P, Goodacre S. Randomised assessment of treatment using panel assay of cardiac markers—contemporary biomarker evaluation (RATPAC CBE). Health Technol Assess. 2013;17(15):v-vi, 1-122.

147. Rosenbaum LS, Januzzi JL. Moving troponin testing into the 21st century: will greater sensitivity be met with greater sensibility? Cardiovasc Hematol Disord Drug Targets. 2008;8(2):118-126.

148. Layfield C, Rose J, Alford A, et al. Effectiveness of practices for improving the diagnostic accuracy of non ST elevation myocardial infarction in the emergency department: a Laboratory Medicine Best Practices systematic review. Clin Biochem. 2015;48(4-5):204-212.

149. Hoeller R, Rubini Giménez M, Reichlin T, et al. Normal presenting levels of high-sensitivity troponin and myocardial infarction. Heart. 2013;99(21):1567-1572.

150. Weber M, Bazzino O, Navarro Estrada JL, et al. N-terminal B-type natriuretic peptide assessment provides incremental prognostic information in patients with acute coronary syndromes and normal troponin T values upon admission. J Am Coll Cardiol. 2008;51(12):1188-1195.

151. Haaf P, Reichlin T, Corson N, et al. B-type natriuretic peptide in the early diagnosis and risk stratification of acute chest pain.Am J Med. 2011;124(5):444-452.

152. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284(7):835-842.

153. Granger CB, Goldberg RJ, Dabbous O, et al. Predictors of hospital mortality in the global registry of acute coronary events.Arch Intern Med. 2003;163(19):2345-2353.

154. Windhausen F, Hirsch A, Tijssen JG, et al. ST-segment deviation on the admission electrocardiogram, treatment strategy, and outcome in non-ST-elevation acute coronary syndromes: a substudy of the Invasive versus Conservative Treatment in Unstable coronary Syndromes (ICTUS) Trial. J Electrocardiol. 2007;40(5):408-415.

155. Weinstock MB, Weingart S, Orth F, et al. Risk for clinically relevant adverse cardiac events in patients with chest pain at hospital admission. JAMA Intern Med. 2015;175(7):1207-1212.

156. Aldous SJ, Richards MA, Cullen L, Troughton R, Than M. A new improved accelerated diagnostic protocol safely identifies low-risk patients with chest pain in the emergency department. Acad Emerg Med. 2012;19(5):510-516.

157. Than M, Aldous S, Lord SJ, et al. A 2-hour diagnostic protocol for possible cardiac chest pain in the emergency department: a randomized clinical trial. JAMA Intern Med. 2014;174(1):51-58.

158. Six AJ, Backus BE, Kelder JC. Chest pain in the emergency room: value of the HEART score. Netherlands Heart Journal. 2008;16(6):191-196.

159. Fraker TJ, Fihn SD. 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina. J Am Coll Cardiol. 2007;50:2264-2274.

160. Miller CD, Roe MT, Mulgund J, et al. Impact of acute beta-blocker therapy for patients with non-ST-segment elevation myocardial infarction. Am J Med. 2007;120(8):685-692.

161. Nguyen HL, Goldberg RJ, Gore JM, et al. Age and sex differences, and changing trends, in the use of evidence-based therapies in acute coronary syndromes: perspectives from a multinational registry. Coron Artery Dis. 2010;21(6):336-344.

162. Buch P, Rasmussen S, Abildstrom SZ, Køber L, Carlsen J, Torp-Pedersen C; TRACE investigators. The long-term impact of the angiotensin-converting enzyme inhibitor trandolapril on mortality and hospital admissions in patients with left ventricular dysfunction after a myocardial infarction: follow-up to 12 years. Eur Heart J. 2005;26(2):145-152.

163. Teo KK, Yusuf S, Pfeffer M, et al. Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review. Lancet. 2002;360(9339):1037-1043.

164. Werner C, Poss J, Bohm M. Optimal antagonism of the renin-angiotensin-aldosterone system: do we need dual or triple therapy? Drugs. 2010;70(10):1215-1230.

165. LexiComp Online. Available at http://online.lexi.com. Last accessed May 22, 2018.

166. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007;297(16):1775-1783.

167. Mega JL, Hochman JS, Scirica BM, et al. Clinical features and outcomes of women with unstable ischemic heart disease: observations from metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndromes-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36). Circulation. 2010;121(16):1809-1817.

168. Shiu JR, Pearson GJ, Charrois TL, Gyenes G, Koshman SL. Frequency of intensive statin therapy in patients with acute coronary syndrome admitted to a tertiary care center. Am J Cardiol. 2012;109:1-5.

169. Tataris KL, Mercer MP, Govindarajan P. Prehospital aspirin administration for acute coronary syndrome (ACS) in the USA: an EMS quality assessment using the NEMSIS 2011 database. Emerg Med J. 2015;32(11):876-881.

170. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.

171. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):2923-2932.

172. Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization.N Engl J Med. 2012;367(14):1297-1309.

173. Gaglia MA Jr, Waksman R. Overview of the 2010 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting regarding ticagrelor. Circulation. 2011;123:451-456.

174. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.

175. Mahaffey KW, Wojdyla DM, Carroll K, et al. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2011;124(5):544-554.

176. Bosch X, Marrugat J, Sanchis J. Platelet glycoprotein IIb/IIIa blockers during percutaneous coronary intervention and as the initial medical treatment of non-ST segment elevation acute coronary syndromes. Cochrane Database Syst Rev. 2013;11:CD002130.

177. Mehta RH, Roe MT, Chen AY, et al. Recent trends in the care of patients with non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE initiative. Arch Intern Med. 2006;166(18):2027-2034.

178. Spinler SA, Managing acute coronary syndrome: evidence-based approaches. Am J Health Syst Pharm. 2007;64(11 suppl 7):S14-S24.

179. Fox KA, Anderson FA Jr, Dabbous OH, et al. Intervention in acute coronary syndromes: do patients undergo intervention on the basis of their risk characteristics? The Global Registry of Acute Coronary Events (GRACE). Heart. 2007;93(2):177-182.

180. Hoekstra JW, Roe MT, Peterson ED, et al. Early glycoprotein IIb/IIIa inhibitor use for non-ST-segment elevation acute coronary syndrome: patient selection and associated treatment patterns. Acad Emerg Med. 2005;12(5):431-438.

181. Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA. 2005;294(24):3108-3116.

182. Goodman SG, Fitchett D, Armstrong PW, Tan M, Langer A. Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation. 2003;107:238-244.

183. Petersen JL, Mahaffey KW, Hasselblad V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: a systematic overview. JAMA. 2004;292(1):89-96.

184. White HD, Kleiman NS, Mahaffey KW, et al. Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial.Am Heart J. 2006;152(6):1042-1050.

185. LaPointe NM, Chen AY, Alexander KP, et al. Enoxaparin dosing and associated risk of in-hospital bleeding and death in patients with non ST-segment elevation acute coronary syndromes. Arch Intern Med. 2007;167(14):1539-1544.

186. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355(21):2203-2216.

187. Stone GW, Ware JH, Bertrand ME, et al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial. JAMA. 2007;298(21):2497-2506.

188. Bavry AA, Elgendy IY, Mahmoud A, Jadhav MP, Huo T. Critical appraisal of bivalirudin versus heparin for percutaneous coronary intervention: a meta-analysis of randomized trials. PLoS One. 2015;10(5):e0127832.

189. Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354(14):1464-1476.

190. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295(13):1519-1530.

191. Steg PG, Jolly SS, Mehta SR, et al. Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial. JAMA. 2010;304(12):1339-1349.

192. Zhao X, Yang XX, Ji SZ, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients undergoing percutaneous coronary intervention treated with the glycoprotein IIb/IIIa inhibitor tirofiban. Mil Med Res. 2016;13.

193. Oler A, Whooley MA, Oler J, et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis. JAMA. 1996;276(10):811-815.

194. Hoenig MR, Aroney CN, Scott IA. Early invasive versus conservative strategies for unstable angina and non-ST elevation myocardial infarction in the stent era. Cochrane Database Syst Rev. 2010;(3):CD004815.

195. Dolor RJ, Melloni C, Chatterjee R, et al. (eds). Treatment Strategies for Women with Coronary Artery Disease. AHRQ Comparative Effectiveness Reviews. Report No.: 12-EHC070-ER. Rockville, MD: Agency for Healthcare Research and Quality; 2012.

196. Navarese EP, Gurbel PA, Andreotti F, et al. Optimal timing of coronary invasive strategy in non-ST-segment elevation acute coronary syndromes: a systematic review and meta-analysis. Ann Intern Med. 2013;158(4):261-270.

197. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circulation. 2002;106:1883-1892.

198. Chan MY, Becker RC, Harrington RA, et al. Noninvasive, medical management for non-ST-elevation acute coronary syndromes. Am Heart J. 2008;155(3):397-407.

199. Carruthers KF, Dabbous OH, Flather MD, et al. Contemporary management of acute coronary syndromes: does the practice match the evidence? Heart. 2005;91:290-298.

200. Sonel AF, Good CB, Mulgund J, et al. Racial variations in treatment and outcomes of black and white patients with high-risk non-ST-elevation acute coronary syndromes: insights from CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines?). Circulation. 2005;111(10):1225-1232.

201. O'Donoghue M, Boden WE, Braunwald E, et al. Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction: a meta-analysis. JAMA. 2008;300(1):71-80.

202. Epstein AJ, Polsky D, Yang F, Yang L, Groeneveld PW. Coronary revascularization trends in the United States: 2001–2008. JAMA. 2011;305(17):1769-1776.

203. Smit Y, Vlayen J, Koppenaal H, Eefting F, Kappetein AP, Mariani MA. Percutaneous coronary invervention versus coronary artery bypass grafting: a meta-analysis. J Thorac Cardiovasc Surg. 2015;149(3):831-838.

204. Hannan EL, Racz MJ, Walford G, et al. Long-term outcomes of coronary-artery bypass grafting versus stent implantation. N Engl J Med. 2005;352(21):2174-2183.

205. Hannan EL, Wu C, Walford G, et al. Drug-eluting stents vs. coronary-artery bypass grafting in multivessel coronary disease. N Engl J Med. 2008;358(4):331-341.

206. Fox KAA, Steg PG, Eagle KA, et al. Decline in rates of death and heart failure in acute coronary syndromes, 1999–2006. JAMA. 2007;297(17):1892-1900.

207. Boden WE, Eagle K, Granger CB. Reperfusion strategies in acute ST-segment elevation myocardial infarction: a comprehensive review of contemporary management options. J Am Coll Cardiol. 2007;50(10):917-929.

208. Stone GW. Angioplasty strategies in ST-segment-elevation myocardial infarction: part I: primary percutaneous coronary intervention. Circulation. 2008;118(5):538-551.

209. Krumholz HM, Herrin J, Miller LE, et al. Improvements in door-to-balloon time in the United States, 2005 to 2010. Circulation. 2011;124(9):1038-1045.

210. Peacock WF, Hollander JE, Smalling RW, Bresler MJ. Reperfusion strategies in the emergency treatment of ST-segment elevation myocardial infarction. Am J Emerg Med. 2007;25(3):353-366.

211. Boden WE. Management of chronic coronary disease: is the pendulum returning to equipoise? Am J Cardiol. 2008;101(10A): 69D-74D.

212. Bangalore S, Kumar S, Fusaro M, et al. Short- and long-term outcomes with drug-eluting and bare-metal coronary stents: a mixed-treatment comparison analysis of 117 762 patient-years of follow-up from randomized trials. Circulation. 2012;125(23):2873-2891.

213. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Clinical outcomes with drug-eluting and bare-metal stents in patients with ST-segment elevation myocardial infarction: evidence from a comprehensive network meta-analysis. J Am Coll Cardiol. 2013;62(6):496-504.

214. Giugliano RP, Braunwald E. Selecting the best reperfusion strategy in ST-elevation myocardial infarction: it's all a matter of time. Circulation. 2003;108(23):2828-2830.

215. Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet. 1996;348(9030):771-775.

216. Bowling A, Culliford L, Smith D, Rowe G, Reeves BC. What do patients really want? Patients' preferences for treatment for angina. Health Expect. 2008;11(2):137-147.

217. Hilleman DE, Tsikouris JP, Seals AA, Marmur JD. Fibrinolytic agents for the management of ST-segment elevation myocardial infarction. Pharmacotherapy. 2007;27(11):1558-1570.

218. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med. 1997;337(16):1118-1123.

219. Sinnaeve P, Alexander J, Belmans A, et al. One-year follow-up of the ASSENT-2 trial: a double-blind, randomized comparison of single-bolus tenecteplase and front-loaded alteplase in 16,949 patients with ST-elevation acute myocardial infarction. Am Heart J. 2003;146(1):27-32.

220. Bode C, Smalling RW, Berg G, et al. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. The RAPID II Investigators. Circulation. 1996;94(5):891-898.

221. Jinatongthai P, Kongwatcharapong J, Foo CY, et al. Comparative efficacy and safety of reperfusion therapy with fibrinolytic agents in patients with ST-segment elevation myocardial infarction: a systematic review and network meta-analysis. Lancet. 2017;390(10096):747-759.

222. Cannon CP, Gibson CM, McCabe CH, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Circulation. 1998;98(25):2805-2814.

223. Reynolds HR, Farkouh ME, Lincoff AM, et al. Impact of female sex on death and bleeding after fibrinolytic treatment of myocardial infarction in GUSTO V. Arch Intern Med. 2007;167(19):2054-2060.

224. Ahmed S, Antman EM, Murphy SA, et al. Poor outcomes after fibrinolytic therapy for ST-segment elevation myocardial infarction: impact of age (a meta-analysis of a decade of trials). J Thromb Thrombolysis. 2006;21(2):119-129.

225. Wijeysundera HC, Vijayaraghavan R, Nallamothu BK, et al. Rescue angioplasty or repeat fibrinolysis after failed fibrinolytic therapy for ST-segment myocardial infarction: a meta-analysis of randomized trials. J Am Coll Cardiol. 2007;49(4):422-430.

226. Collet JP, Montalescot G, Le May M, Borentain M, Gershlick A. Percutaneous coronary intervention after fibrinolysis: a multiple meta-analyses approach according to the type of strategy. J Am Coll Cardiol. 2006;48(7):1326-1335.

227. Gurm H, Tamhane U, Meier P, et al. A comparison of abciximab and small molecule glycoprotein IIb/IIIa inhibitors in patients undergoing primary percutaneous coronary intervention: a meta-analysis of contemporary randomized controlled trials. Circ Cardiovasc Intervent. 2009;2(3):230-236.

228. De Luca G, Ucci G, Cassetti E, et al. Benefits from small molecule administration as compared with abciximab among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-analysis. J Am Coll Cardiol. 2009;53(18):1668-1673.

229. Fitchett D. Tailored antithrombotic therapy for acute coronary syndromes. Expert Rev Cardiovasc Ther. 2008;6(7):935-944.

230. Gibson CM, Murphy SA, Montalescot G, et al. Percutaneous coronary intervention in patients receiving enoxaparin or unfractionated heparin after fibrinolytic therapy for ST-segment elevation myocardial infarction in the ExTRACT-TIMI 25 trial. J Am Coll Cardiol. 2007;49(23):2238-2246.

231. Silvain J, Beygui F, Barthélémy O, et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ. 2012;344:e553.

232. Peters RJG, Joyner C, Bassand JP, et al. The role of fondaparinux as an adjunct to thrombolytic therapy in acute myocardial infarction: a subgroup analysis of the OASIS-6 trial. Eur Heart J. 2008;29(3):324-331.

233. Brito V, Ciapponi A, Kwong J. Factor Xa inhibitors for acute coronary syndromes. Cochrane Database Syst Rev. 2011;1):CD007038.

234. Cannon CP, Bahit MC, Haugland JM, et al. Underutilization of evidence-based medications in acute ST elevation myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 9 registry. Crit Pathw Cardiol. 2002;1(1):44-52.

235. Cohen M, Boiangiu C, Abidi M. Therapy for ST-segment elevation myocardial infarction patients who present late or are ineligible for reperfusion therapy. J Am Coll Cardiol. 2010;55(18):1895-1906.

236. Gharacholou SM, Alexander KP, Chen AY, et al. Implications and reasons for the lack of use of reperfusion therapy in patients with ST-segment elevation myocardial infarction: findings from the CRUSADE initiative. Am Heart J. 2010;159(5):757-763.

237. Alexander KP, Newby LK, Armstrong PW, et al. Acute coronary care in the elderly, part II: ST-segment-elevation myocardial infarction: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology. Circulation. 2007;115:2570-2589.

238. Sugiyama T, Hasegawa K, Kobayashi Y, et al. Differential time trends of outcomes and costs of care for acute myocardial infarction hospitalizations by ST elevation and type of intervention in the United States, 2001–2011. J Am Heart Assoc. 2015;4(3):e001445.

239. Mega JL, Morrow DA. ST-elevation myocardial infarction: management. In: Mann DL, Zipes DP, Libby P, Bonow RO (eds). Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: Elsevier/Saunders; 2015: 1095-1146.

240. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation. 2008;117(2):296-329.

241. Douglas PS, Garcia MJ, Haines DE, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 appropriate use criteria for echocardiography: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance endorsed by the American College of Chest Physicians. J Am Coll Cardiol. 2011;57(9):1126-1166.

242. Gibson CM. NRMI and current treatment patterns for ST-elevation myocardial infarction. Am Heart J. 2004;148(5 suppl):S29-S33.

243. Roe MT, Parsons LS, Pollack CV Jr, et al. Quality of care by classification of myocardial infarction: treatment patterns for ST-segment elevation vs non-ST-segment elevation myocardial infarction. Arch Intern Med. 2005;165(14):1630-1636.

244. Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G. ACE inhibitor use in patients with myocardial infarction: summary of evidence from clinical trials. Circulation. 1995;92(10):3132-3137.

245. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet. 1995;345(8951):669-685.

246. ACE Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. Circulation. 1998;97(22):2202-2212.

247. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med. 1988;319(7):385-392.

248. Effect of verapamil on mortality and major events after acute myocardial infarction: the Danish Verapamil Infarction Trial II (DAVIT II). Am J Cardiol. 1990;66(10):779-785.

249. Clark AM, McAlister FA, Hartling L, Vandermeer B. Randomized Trials of Secondary Prevention Programs in Coronary Artery Disease: A Systematic Review. Rockville, MD: Agency for Healthcare Research and Quality; 2005.

250. Anderson L, Taylor RS. Cardiac rehabilitation for people with heart disease: an overview of Cochrane systematic reviews. Cochrane Database Syst Rev. 2014;12:CD011273.

251. Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011. Circulation. 2011;124:2458-2473.

252. Benowitz NL, Prochaska JJ. Smoking cessation after acute myocardial infarction. J Am Coll Cardiol. 2013;61(5):533-555.

253. Rigotti NA, Clair C, Munafò MR, Stead LF. Interventions for smoking cessation in hospitalised patients. Cochrane Database Syst Rev. 2012;5:CD001837.

254. Stead LF, Klilpillai P, Fanshawe TR, Lancaster T. Combined pharmacotherapy and behavioural interventions for smoking cessation. Cochrane Database Syst Rev. 2016;3:CD008286.

255. Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients With unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2012;60(7):645-681.

256. Yan AT, Yan RT, Tan M, et al. Optimal medical therapy at discharge in patients with acute coronary syndromes: temporal changes, characteristics, and 1-year outcome. Am Heart J. 2007;154(6):1108-1115.

257. Antithrombotics Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86.

258. Peters RJ, Mehta SR, Fox KA, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003;108(14):1682-1687.

259. Tickoo S, Roe MT, Peterson ED. Patterns of aspirin dosing in non-ST-elevation acute coronary syndromes in the CRUSADE Quality Improvement Initiative. Am J Cardiol. 2007;99(11):1496-1499.

260. Squizzato A, Bellesini M, Takeda A, Middeldorp S, Donadini MP. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;12:CD005158.

261. Depta JP, Bhatt DL. Aspirin and platelet adenosine diphosphate receptor antagonists in acute coronary syndromes and percutaneous coronary intervention: role in therapy and strategies to overcome resistance. Am J Cardiovasc Drugs. 2008;8(2):91-112.

262. Braunwald E, Angiolillo D, Bates E, et al. Antiplatelet strategies: evaluating their current role in the setting of acute coronary syndromes. Clin Cardiol. 2008;31(S1):I2-I9.

263. Ho PM, Peterson ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA. 2008;299(5):532-539.

264. Ho PM, Tsai TT, Wang TY, et al. Adverse events after stopping clopidogrel in post-acute coronary syndrome patients: insights from a large integrated healthcare delivery system. Circ Cardiovasc Qual Outcomes. 2010;3(3):303-308.

265. Murphy SA, Cannon CP, Wiviott SD, et al. Effect of intensive lipid-lowering therapy on mortality after acute coronary syndrome (a patient-level analysis of the Aggrastat to Zocor and Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 Trials). Am J Cardiol. 2007;100(7):1047-1051.

266. Afilalo J, Majdan AA, Eisenberg MJ. Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials. Heart. 2007;93(8):914-921.

267. Navarese EP, Kowalewski M, Andreotti F, et al. Meta-analysis of time-related benefits of statin therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Am J Cardiol. 2014;113(10):1753-1764.

268. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

269. Japaridze L, Sadunishvili M, Megreladze I. Combination therapy effectiveness of ezetimibe and atorvastatin in patients with acute coronary syndrome. Georgian Med News. 2016;(252):15-22.

270. Japaridze L, Sandunishvili M. The short-term effect of atorvastatin plus ezetimibe therapy versus atorvastatin monotherapy on clinical outcomes in acute coronary syndrome patients by gender. Kardiol Pol. 2017;75(8):770-778.

271. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1—full report. J Clin Lipidol. 2015;9:129-169.

272. Whitehead DL, Strike P, Perkins-Porras L, Steptoe A. Frequency of distress and fear of dying during acute coronary syndromes and consequences for adaptation. Am J Cardiol. 2005;96(11):1512-1516.

273. Swenson JR, O'Connor CM, Barton D, et al. Influence of depression and effect of treatment with sertraline on quality of life after hospitalization for acute coronary syndrome. Am J Cardiol. 2003;92(11):1271-1276.

274. Grace SL, Abbey SE, Kapral MK, Fang J, Nolan RP, Stewart DE. Effect of depression on five-year mortality after an acute coronary syndrome. Am J Cardiol. 2005;96(9):1179-1185.

275. Naqvi TZ, Rafique AM, Andreas V, Rahban M, Mirocha J, Naqvi SS. Predictors of depressive symptoms post-acute coronary syndrome. Gend Med. 2007;4(4):339-351.

276. Kronish IM, Rieckmann N, Halm EA, et al. Persistent depression affects adherence to secondary prevention behaviors after acute coronary syndromes. J Gen Intern Med. 2006;21(11):1178-1183.

277. Rieckmann N, Gerin W, Kronish IM, et al. Course of depressive symptoms and medication adherence after acute coronary syndromes: an electronic medication monitoring study. J Am Coll Cardiol. 2006;48(11):2218-2222.

278. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2007;30(1):162-172.

279. Golden SH, Anderson C, Bray GA, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence. A scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2015;132:691-718.

280. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the study of diabetes. Diabetes Care. 2015;38(1):140-149.

281. American Diabetes Association. Standards of medical care in diabetes—2018. Diabetes Care. 2018;41(Suppl 1):S55-S64.

282. Cheng K, Ingram N, Keenan J, Choudhury RP. Evidence of poor adherence to secondary prevention after acute coronary syndromes: possible remedies through the application of new technologies. Open Heart. 2015;2(1):e000166.

283. Bradley SM, Bryson CL, Maynard C, Maddox TM, Fihn SD. Recent hospitalization for non-coronary events and use of preventive medications for coronary artery disease: an observational cohort study. BMC Cardiovasc Disord. 2011;11:42.

284. Beatty AL, Li S, Thomas L, Amsterdam EA, Alexander KP, Whooley MA. Trends in referral to cardiac rehabilitation after myocardial infarction: data from the National Cardiovascular Data Registry 2007 to 2012. J Am Coll Cardiol. 2014;63(23):2582-2583.

285. Parashar S, Spertus JA, Tang F, et al. Predictors of early and late enrollment in cardiac rehabilitation, among those referred, after acute myocardial infarction. Circulation. 2012;126(13):1587-1595.

286. Peterson ED, Roe MT, Rumsfeld JS, et al. A call to ACTION (acute coronary treatment and intervention outcomes network): a national effort to promote timely clinical feedback and support continuous quality improvement for acute myocardial infarction. Circ Cardiovasc Qual Outcomes. 2009;2(5):491-499.

287. Condon C, McCarthy G. Lifestyle changes following acute myocardial infarction: patients' perspectives. Eur J Cardiovasc Nurs. 2006;5(1):37-44.

288. Fernandez RS, Davidson P, Griffiths R. Cardiac rehabilitation coordinators' perceptions of patient-related barriers to implementing cardiac evidence-based guidelines. J Cardiovasc Nurs. 2008;23(5):449-457.

289. Peterson ED, Roe MT, Mulgund J, et al. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA. 2006;295(16):1912-1920.

290. Booth JN 3rd, Levitan EB, Brown TM, Farkouh ME, Safford MM, Muntner P. Effect of sustaining lifestyle modifications (nonsmoking, weight reduction, physical activity, and mediterranean diet) after healing of myocardial infarction, percutaneous intervention, or coronary bypass (from the REasons for Geographic and Racial Differences in Stroke Study). Am J Cardiol. 2014;113(12):1933-1940.

291. Blomkalns AL, Chen AY, Hochman JS, et al. Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-scale observations from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) National Quality Improvement Initiative. J Am Coll Cardiol. 2005;45(6):832-837.

292. Lewis WR, Ellrodt AG, Peterson E, et al. Trends in the use of evidence-based treatments for coronary artery disease among women and the elderly: findings from the Get With the Guidelines quality improvement program. Circ Cardiovasc Qual Outcomes. 2009;2(6):633-641.

293. Lee HY, Cooke CE, Robertson TA. Use of secondary prevention drug therapy in patients with acute coronary syndrome after hospital discharge. J Manag Care Pharm. 2008;14(3):271-280.

294. Gluckman TJ, Sachdev M, Schulman SP, Blumenthal RS. A simplified approach to the management of non-ST-segment elevation acute coronary syndromes. JAMA. 2005;293(3):349-357.

295. Birtcher KK, Pan W, Labresh KA, Cannon CP, Fonarow GC, Ellrodt G. Performance achievement award program for Get With the Guidelines—Coronary Artery Disease is associated with global and sustained improvement in cardiac care for patients hospitalized with an acute myocardial infarction. Crit Pathw Cardiol. 2010;9(3):103-112.

296. Munger MA, Van Tassell BW, LaFleur J. Medication nonadherence: an unrecognized cardiovascular risk factor. MedGenMed. 2007;9:58.

297. Ho PM, Magid DJ, Shetterly SM, et al. Medication nonadherence is associated with a broad range of adverse outcomes in patients with coronary artery disease. Am Heart J. 2008;155(4):772-779.

298. Kulkarni SP, Alexander KP, Lytle B, Heiss G, Peterson ED. Long-term adherence with cardiovascular drug regimens. Am Heart J. 2006;151(1):185-191.

299. Kripalani S, Henderson LE, Jacobson TA, Vaccarino V. Medication use among inner-city patients after hospital discharge: patient-reported barriers and solutions. Mayo Clin Proc. 2008;83(5):529-535.

300. Blackburn DF, Dobson RT, Blackburn JL, Wilson TW, Stang MR, Semchuk WM. Adherence to statins, beta-blockers and angiotensin-converting enzyme inhibitors following a first cardiovascular event: a retrospective cohort study. Can J Cardiol. 2005;21(6):485-488.

301. Dracup K, McKinley S, Doering LV, et al. Acute coronary syndrome: what do patients know? Arch Intern Med. 2008;168(10):1049-1054.

302. Ratner PA, Tzianetas R, Tu AW, et al. Myocardial infarction symptom recognition by the lay public: the role of gender and ethnicity. J Epidemiol Community Health. 2006;60(7):606-615.

303. Fukuoka Y, Dracup K, Moser DK, et al. Is severity of chest pain a cue for women and men to recognize acute myocardial infarction symptoms as cardiac in origin? Prog Cardiovasc Nurs. 2007;22(3):132-137.

304. Wang WW. The educational needs of myocardial infarction patients. Prog Cardiovasc Nurs. 1994;9(4):28-36.

305. Theis SL, Johnson JH. Strategies for teaching patients: a meta-analysis. Clin Nurse Spec. 1995;9(2):100-105, 120.

306. Boyd MD. Strategies for effective health teaching. In: Boyd MD, Graham BA, Gleit CJ, Whitman NI (eds). Health Teaching in Nursing Practice: A Professional Model. 3rd ed. Stamford, CT: Appleton and Lange; 1998: 201-229.

307. Kingsbury K. Taking AIM: how to teach primary and secondary prevention effectively. Can J Cardiol. 1998;14(suppl A):22A-26A.

308. Cooper H, Booth K, Fear S, Gill G. Chronic disease patient education: lessons from meta-analyses. Patient Educ Couns. 2001;44(2):107-117.

309. Finnegan JR Jr, Meischke H, Zapka JG, et al. Patient delay in seeking care for heart attack symptoms: findings from focus groups conducted in five U.S. regions. Prev Med. 2000;31(3):205-213.

310. Thuresson M, Jarlöv MB, Lindahl B, Svensson L, Zedigh C, Herlitz J. Factors that influence the use of ambulance in acute coronary syndrome. Am Heart J. 2008;156(1):170-176.

Evidence-Based Practice Recommendations Citations

1. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-e140. Available at http://circ.ahajournals.org/content/127/4/e362. Last accessed June 18, 2018.

2. American College of Cardiology Foundation, American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery. J Am Coll Cardiol. 2011;58(24):e123-e210. Available at http://circ.ahajournals.org/content/124/23/e652. Last accessed June 18, 2018.

96441 • Suicide Assessment and Prevention

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

Suicide is a major preventable public health problem and cause of mortality. This course will review the major aspects of suicide assessment, management, and prevention, with a special focus on military veterans. Primary care contact may represent the last opportunity for intervention in the severely depressed suicidal patient, making the thorough comprehension of identification and treatment of depression and suicide risk imperative.

Table of Contents

96441 • Suicide Assessment and Prevention

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. EPIDEMIOLOGY OF SUICIDE

THE MISREPORTING OF DEATH BY SUICIDE

SUICIDE REPORTING IN THE MEDIA

3. PATHOPHYSIOLOGY OF SUICIDAL BEHAVIOR

4. SUICIDE AND SPECIAL POPULATIONS

WOMEN

YOUTH

OLDER ADULTS (65 YEARS OF AGE AND OLDER)

LESBIAN, GAY, BISEXUAL, AND TRANSGENDER (LGBT+) INDIVIDUALS

MILITARY WAR VETERANS

HEALTHCARE PROFESSIONALS

5. RISK AND PROTECTIVE FACTORS FOR SUICIDE

PROTECTIVE FACTORS

RISK FACTORS

MILITARY VETERANS

6. IMMINENT SUICIDE

WARNING SIGNS

7. SUICIDE ATTEMPTS

LETHAL MEANS

MOTIVES BEHIND SUICIDAL BEHAVIOR

8. SCREENING AND ASSESSMENT OF SUICIDE RISK

SCREENING IN THE PRIMARY CARE SETTING: EXPERT CONSENSUS

ASSESSMENT OF SUICIDE RISK

DETERMINING LEVEL OF RISK AND APPROPRIATE ACTIONS

DOCUMENTATION

9. MANAGEMENT OF SUICIDAL PATIENTS

PHARMACOTHERAPY TO REDUCE SUICIDE RISK

PSYCHOTHERAPY TO REDUCE SUICIDE RISK

MENTAL HEALTH REFERRAL

REFERRAL TO BE HOSPITALIZED

ADDITIONAL OPTIONS FOR CONTINUITY OF CARE

SAFETY PLANNING

CONSIDERATIONS FOR VETERANS

CONSIDERATIONS FOR HEALTHCARE PROFESSIONALS

10. SUICIDE PREVENTION

HISTORY OF SUICIDE PREVENTION IN THE UNITED STATES

SUICIDE PREVENTION THAT TARGETS AT-RISK POPULATIONS

STIGMA AND SUICIDE

11. SUICIDE SURVIVORS: TREATMENT AND RESOURCES

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

96441 • Suicide Assessment and Prevention

Education Category. Psychiatric / Mental Health

Release Date. 04/01/2020

Expiration Date. 03/31/2023

Course Overview

Suicide is a major preventable public health problem and cause of mortality. This course will review the major aspects of suicide assessment, management, and prevention, with a special focus on military veterans. Primary care contact may represent the last opportunity for intervention in the severely depressed suicidal patient, making the thorough comprehension of identification and treatment of depression and suicide risk imperative.

Audience

This course is designed for physicians, nurses, pharmacists, and other healthcare professionals who may identify persons at risk for suicide and intervene to prevent or manage suicidality.

Course Objective

The purpose of this course is to provide health and mental health professionals with an appreciation of the impact of depression and suicide on patient health as well as the skills necessary to identify and intervene for patients at risk for suicide.

Learning Objectives

Upon completion of this course, you should be able to:

1. Review the epidemiology of suicide.

2. Describe the impact of suicide in the treatment of special populations, including among military veterans.

3. Identify risk and protective factors for suicide.

4. Discuss warning signs of imminent suicide and the importance of lethal means.

5. Evaluate tools available for the assessment and evaluation of suicide risk.

6. Outline key components of an effective suicide prevention plan.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Abimbola Farinde, PharmD, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

In 2017, there were 47,173 reported suicide deaths in the United States, making it the 10th leading overall cause of mortality [1]. Every day, approximately 129 Americans take their own life, and one person dies by suicide every 11.2 minutes. An estimated 90% of persons who die by suicide have a diagnosable psychiatric disorder at the time of death, although only 46% have a documented diagnosis [2,3].

For the approximately 39,000 suicide deaths each year, an estimated 200,000 additional individuals are affected by the loss of a loved one or acquaintance by suicide [5,46]. This translate to about six survivors intimately affected per suicide. However, a 2016 study estimated that the rate is much higher, projecting a rate of 115 individuals exposed to a single suicide in addition to those intimately affected (equaling more than 5 million individuals) [13,14]. Among these, 20% (or more than 1 million individuals) reported that the experience had a devastating impact or caused a major-life disruption [4]. A similar study published in 2019 estimated rates of those affected to be 135 individuals per suicide, illustrating the much wider effects of suicide [14]. These figures do not take into account the physical and emotional pain and trauma endured by persons who survive suicide attempts [5].

The total economic burden of suicide is estimated to be $69 billion annually, with the costs falling most heavily on adults of working age [2]. Depression causes an estimated 200 million lost workdays each year at a cost to employers of $17 to $44 billion [6]. However, the accuracy of attempts to quantify such costs on a national scale is hampered by incomplete data, such as the under-reporting of suicides and an absence of reliable data on suicide attempts [5].

Among persons with a mood disorder, 12% to 20% will ultimately die by suicide. The first three months after diagnosis is the period of highest risk for a first attempt, with the three months following the first attempt being the highest risk period for a second attempt [7].

Case Scenario: Patient A

Two case studies will be referenced throughout the text to illustrate the challenges of assessing and treating patients with possible suicide attempt.

Patient A, 19 years of age, is brought to the local emergency department by ambulance after being found unconscious on the floor of her mother's living room, an empty pill bottle nearby. She exhibits quiet, shallow breathing but otherwise no spontaneous movement; she does react to deep, noxious stimuli by opening her eyes and moving her extremities but does not speak or respond to questioning. Her neck is supple, and a screening cranial nerve and motor exam shows no focal neurologic deficits. Her blood pressure is 110/70 mm Hg, pulse is 114 beats per minute, respiration 12 breaths per minute, and temperature 98.8°F; the lungs are clear. The empty bottle is a prescription for a tricyclic antidepressant made out to Patient A's mother. The friend who found her has followed and provides some context: she is not working at present, lives with a boyfriend who recently left her ("they fight a lot"), and has been living at her mother's home for several days. She is admitted to the intensive care unit and intubated, primarily to protect her airway from aspiration should she vomit.

2. EPIDEMIOLOGY OF SUICIDE

Every year, more than 800,000 people around the world die by suicide, accounting for 1.4% of all deaths and ranking as the 18th leading cause of death. This suicide rate has increased by more than 60% in the past 45 years, with suicide rates among young people increasing at alarming rates in both developed and developing countries [8]. However, since 2000, the overall rate appears to have decreased slightly.

Suicide rates vary according to race, ethnicity, sex, and many other factors, including age [8]. In almost every country, suicide is predominated by male victims, with the exception of China, which is the only country in which the female suicide rate (14.8 per 100,000) exceeds the male rate (13 per 100,000) [9]. In the United States, the number of deaths by suicide is nearly four times greater among men (36,782) than among women (10,391). Overall, suicide accounts for 1.7% of all deaths in the United States [1].

From the mid-1950s to the late 1970s in the United States, the suicide rate tripled among men 15 to 24 years of age and doubled among women 15 to 24 years of age. The suicide rate reached a plateau during the 1980s and early 1990s and began decreasing during the mid-1990s [10]. However, the age-adjusted suicide rate has increased 33% between 1999 and 2017, with increases in all age groups younger than 75 years of age [11]. Among the elderly, the suicide rate peaked in 1987, at 21.8 per 100,000 people, and has since declined nearly 13% (to 19.0 per 100,000 in 2017) [11,13]. Despite the growing recognition of suicide as a problem demanding public health attention, the overall rates of suicide in the United States have increased over the last half-century [13].

Although official national statistics are not compiled on attempted suicide (i.e., nonfatal actions), it is estimated that 1.4 million adults (18 years of age and older) attempted suicide in 2018 [13]. Overall, there are roughly 25 attempts for every death by suicide; this ratio changes to 100 to 200:1 for the young and 4:1 for the elderly [13,16]. The risk of attempted (nonfatal) suicide is greatest among women and the young, and the ratio of female-to-male nonfatal suicide attempts is 3.5:1 [2,10].

THE MISREPORTING OF DEATH BY SUICIDE

There is broad agreement that not all suicide deaths are accurately recorded and reported. Reasons for under-reporting include [5,18,19,20,21]:

- Families or family physicians may hide evidence due to the stigma of suicide.

- The determination of death is judged by local standards, which can vary widely.

- Ambiguous cases involving suicide may end up classified as "accidental" or "undetermined."

- Compared with the "accidental" or "undetermined" motive categories, a larger number of deaths are officially classified as "ill-defined and unknown causes of mortality," in which even the actual cause of death is uncertain and some of which are undoubtedly suicides.

- The frequency of physician-assisted suicide for the terminally ill is unknown but is probably both substantial and increasing.

In contrast, some ambiguous cases are classified as suicides, often in institutions such as prisons, hospitals, religious orders, and the military, where the verdict of suicide is likely to be less embarrassing than homicide. Other motivations for declaring a death a suicide, despite much doubt surrounding a case, are that homicides must be investigated and a murderer sought and accidental death may be the basis of negligence lawsuits [5].

SUICIDE REPORTING IN THE MEDIA

Suicide rates may temporarily spike with intense media coverage of a suicide, especially among youth, and both news reports and fictional accounts of suicide in movies and television can produce this effect [22,23,24]. Imitation is often the key factor and is most powerful with the highly publicized suicides of entertainment celebrities [5,25].

Media coverage of suicide can lead to misinformation, as when suicide is attributed to a single event, such as the loss of a job or a relationship, without mention of a broader context involving ongoing problems with depression, substance abuse, or lack of access to treatment for these conditions. On the other hand, responsible coverage of suicide can educate audiences about the causes, warning signs, and treatment advances and prevention of suicide [5].

Thirty-six hours after admission, Patient A has been extubated and is awake, sitting up, and talking to a young man (the boyfriend) at her bedside. As you approach, she smiles sheepishly and asks, "Can I go home now?" Before answering, which of the following management options would you consider appropriate at this juncture?

- Have physical therapy assess strength and ambulation. If normal, discharge her home to the care of her family.

- Ask the young man to step out, then take a careful medical and social history, exploring in detail her mindset, actions, and intent in the period leading up to admission.

- Anticipate transfer out of the intensive care unit and the need for an around-the-clock "sitter" in her room as a suicide prevention precaution.

- Request social service consult to assess her resources and support system and a psychiatry consult to assess the need for further inpatient care and recommend a plan for outpatient follow-up.

3. PATHOPHYSIOLOGY OF SUICIDAL BEHAVIOR

Although suicide is a potential complication of all psychiatric disorders, serious suicidal actions have a neurobiologic basis that is distinct from the psychiatric illnesses with which they are associated [26].

Alterations in several neurobiologic systems are associated with suicidal behavior, most prominently hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, serotonergic system dysfunction, and excessive activity of the noradrenergic system. While the first and the last system appear to be involved in the response to stressful events, serotonergic dysfunction is thought to be trait-dependent and associated with disturbances in the regulation of anxiety, impulsivity, and aggression [27,28]. Altered functioning of these systems may stem from both genetic and developmental causes. Exposure to extreme or chronic stress during childhood has developmental consequences on these systems that persist into adulthood. Genetic differences may also contribute to alterations in the functioning of these neurobiologic systems, and the interactive effect of adverse childhood experiences, such as physical abuse, sexual abuse, or caregiver abandonment, with genetic vulnerability is increasingly believed to play a role in suicidal behavior [27,29].

Neurobiologic and psychologic perspectives have converged to identify the most prominent risk factors for suicidal behavior: dysregulated impulse control and a propensity to intense psychologic pain that includes hopelessness, often in the context of a mood disorder. These factors are believed to largely reflect serotonergic system dysregulation [30]. Investigation into the role played by serotonergic dysfunction in suicidal behavior has identified two prominent regions: the dorsal and median raphe nuclei in the midbrain, which host the main serotonergic cell bodies, and the prefrontal cortex, particularly the ventral prefrontal cortex, which is innervated by the serotonergic system. In vivo and postmortem examinations have revealed serotonergic hypofunction in these two brain systems in persons who have died by suicide or made serious suicide attempts. The deficient serotonergic input in the ventral prefrontal cortex stemming from this serotonin hypofunction can result in a breakdown in inhibitory function leading to a predisposition to impulsive and aggressive behavior. This vulnerability to deficient impulse control coupled with the development of psychiatric illness or other life stressors elevates the risk of acting on suicidal thoughts [31].

4. SUICIDE AND SPECIAL POPULATIONS

WOMEN

A woman takes her own life every 49.7 minutes in the United States [1]. Suicide is more common among women who are single, recently separated, divorced, or widowed, and the suicide rates for women peak between the ages of 45 to 54 years, and again after 75 years of age. Precipitating life events for women who attempt suicide often involve interpersonal losses or crises in significant social or family relationships. As noted, more women attempt suicide than men, and there is a 3.5:1 ratio of women versus men with a history of attempted suicide. The higher rates of attempted suicide among women are likely due to the higher rates of mood disorders such as major depression, persistent depressive disorder (dysthymia), and seasonal affective disorder. Factors that may contribute to the lower rates of suicide deaths in women relative to men include stronger social supports, feeling that their relationships are a deterrent to suicide, differences in preferred suicide method, and greater willingness to seek psychiatric and medical intervention [2,13].

YOUTH

In 2017, suicide was the second leading cause of death for young people 10 to 24 years of age, exceeded only by unintentional injury [32]. As noted, an estimated 100 to 200 attempts are made for every suicide completion in this age group. Between 2008 and 2015, encounters for suicide ideation and/or attempt at children's hospitals nearly doubled [51]. Risk factors for suicide among the young include suicidal thoughts, psychiatric disorders (e.g., depression, impulsive aggressive behavior, bipolar disorder, panic disorder), drug and/or alcohol abuse, and previous suicide attempts. The risk is further elevated with situational stress or access to firearms [2,13].

Children 10 to 14 Years of Age

In 2017, 2.5 per 100,000 children 10 to 14 years of age died of suicide in the United States. As a percent of total deaths, suicide was highest among Native American/Alaska Native youth, at 25.5%. White youth were next highest with 16.8%, followed by Hispanics with 11.3% [2].

College Students

More than 1,000 suicides occur each year on college campuses, and 1 in 10 college students have made a suicide plan [34]. A 2011 survey of 27,774 college students from 44 campuses found that 6.6% had seriously contemplated suicide and 1.1% had attempted suicide [16]. In the 12 months before the survey, 60.5% reported feeling very sad, 45.2% reported feeling hopeless, and 30.3% reported feeling so depressed they were unable to function [16]. More than 45% reported feelings of hopelessness; however, only 6.7% of men and 13.1% of women reported a diagnosis of depression, suggesting that many students are not receiving adequate diagnosis and/or treatment [16]. A 2015 follow-up survey including 93,034 college students from 108 campuses found a much higher rate of suicidality, with 24% of the survey population reporting seriously contemplating suicide, nearly 20% reporting self-injury, and 9% reporting a suicide attempt [33]. Rates of suicidality were highest among racial/ethnic, sexual, and gender minorities.

Students with a pre-existing mental health condition or who develop mental health conditions in college are at highest risk of suicide. In the 2015 study, 25% students were diagnosed with and/or received treatment for a mental health condition in the previous 12 months [33]. Risk factors for suicide among college students include depression, sadness, hopelessness, and stress [13].

Other Considerations in Youth Suicide

Most adolescent suicides occur at home after school hours. Adolescent nonfatal suicide attempters are typically girls who ingest pills, while those who die by suicide are typically boys who die from gunshot wounds. Intentional self-harm should be considered serious and in need of further evaluation because not all adolescent attempters admit their intent. Most adolescent suicide attempts are triggered by interpersonal conflicts and are motivated by the desire to change the behavior or attitude of others. Repeat attempters may use this behavior as a coping mechanism for stress and tend to exhibit more chronic symptomatology, worse coping histories, and higher rates of suicidal and substance abuse behaviors in their family histories [13]. The presence of multiple emotional, behavioral, and/or cognitive problems may be a more important predictor of suicide behavior risk than a specific type of problem (e.g., an addictive behavior or an emotional problem) [13,33]. The presence of acne is associated with social and psychologic problems, and certain acne medications have been linked with an increased risk of suicidal ideation [36].

OLDER ADULTS (65 YEARS OF AGE AND OLDER)

The elderly account for roughly 18.8% of suicides but only 16% of the population [13]. Suicide rates rise with age for men, especially after 65 years of age, and the suicide rate in elderly men is 4.96 times that of same-aged women; more than 83% of elderly suicides are among men [13,35]. The overall rate of elderly suicide is 18 per 100,000. However, the rate is 31.2 per 100,000 among elderly white men and 51.8 per 100,000 among white men older than 85 years of age, a rate that is almost 2 times the rate for men of all ages. In contrast, the suicide rate of women declines after 60 years of age [13,35].

Although undiagnosed and/or untreated depression is the primary cause of suicide in the elderly, suicide completion is rarely preceded by only one factor. Risk factors for suicide in this population include a previous suicide attempt; mental illness; physical illness or uncontrollable pain; fear of a prolonged illness; major changes in social roles, such as retirement; loneliness and social isolation (especially in older men who have recently lost a loved one); and access to means, such as firearms in the home [13].

LESBIAN, GAY, BISEXUAL, AND TRANSGENDER (LGBT+) INDIVIDUALS

The true incidence of suicide among lesbian, gay, bisexual, transgender, and other gender and sexual minority (LGBT+) youth is unknown, but research indicates higher rates of suicidal behavior among LGBT+ youth (15 to 24 years of age) compared with heterosexual youth [33,43]. Among adolescents and young adults, the lifetime prevalence of suicide attempts ranges from 20.5% to 52.4% among LGB individuals versus 4.2% to 24.8% among same-aged heterosexuals [39,40,42]. Among adolescents and young adults, past-year suicide attempts are more than 4.5 times higher among LGB youth than same-aged heterosexual youth [13,37,47].

Evidence Based Practice Recommendation

The American Academy of Child and Adolescent Psychiatry asserts that family connectedness, adult caring, and school safety are highly significant protective factors against suicidal ideation and attempts in gay, lesbian, and gender-variant youth.

https://jaacap.org/article/S0890-8567(12)00500-X/fulltext

Last Accessed: March 30, 2020

Level of Evidence: Expert Opinion/Consensus Statement

LGBT+ youth generally have more risk factors, more severe risk factors, and fewer protective factors, such as family support and safe schools, than heterosexual youth. There are also risks unique to this population related to sexual orientation, such as disclosure to family or friends [13]. The impact of stigma and discrimination against LGBT+ individuals is enormous and is directly tied to risk factors for suicide such as isolation, alienation and rejection from family, and lack of access to culturally competent care [43]. Family connectedness, perceived caring from other adults, and feeling safe at school were reported as significant protective factors in a survey of 6th-, 9th-, and 12th-grade LGBT+ students [37,38]. It has also been noted that LGBT+ adults have a two-fold excess risk of suicide than their heterosexual counterparts [37].

The affect of race/ethnicity and other demographic characteristics on suicidal behavior in the LGB population has also been studied little, but reports suggest high suicide attempt rates among African American gay/bisexual men, among gay/bisexual men of lower socioeconomic status, and among LGB Latinx [35].

Depression and suicide are also common among transgender individuals. One survey assessed transgender individuals' school experiences from kindergarten through grade 12. Of the individuals who were out as transgender during their school years, 77% reported at least one negative experience, including physical attacks, verbal abuse, and mistreatment by teachers and/or administrators. Among those with negative school experiences, 58% attempted suicide, compared with 37% of transgender individuals without negative school experiences. Among out transgender college students, 24% reported that they were physically, verbally, or sexually harassed. [38]. Across all age groups, 39% of transgender individuals reported experiencing serious psychologic distress in the past month, compared with 5% of the general U.S. population. In addition, 40% of individuals reported attempting suicide, more than nine times the rate in the United States [38,47].

MILITARY WAR VETERANS

Although the true incidence of suicide among military war veterans is difficult to estimate due to the lack of national suicide surveillance data, the U.S. Department of Veterans Affairs (VA) estimates that 18% of all deaths from suicide in the United States are in military war veterans [79]. Despite preventive measures taken by the military, the number of suicides in this population continues to increase [52,54,56,79]. Although the majority of military suicides occur among young men shortly after their discharge from military service, military women 18 to 35 years of age commit suicide nearly three times more frequently than nonveteran women of the same age group [57,58].

Patient A is transferred to a regular floor and a sitter is assigned to her room. With the aid of additional clinical observation and consultations, a clearer picture emerges. In the presence of staff, Patient A appears open and optimistic and takes initiative; when her boyfriend or family are present, she becomes passive, more withdrawn, and demanding, expecting others to attend to her needs. Patient A's parents divorced when she was 11 years of age, and two years later, she came under psychiatric care, followed by counseling, because of depression and a brief period of suicide ideation. She had attended college but dropped out after two years. In recent months, her life had become more chaotic. She was unhappy in her job and subject to fits of anger and despondency. She was often at odds with her live-in boyfriend, who, on occasion, threatened to leave her and in fact did so four days prior to her admission. The decision to take an overdose of her mother's medication was judged to have been abrupt and impulsive, perhaps a "suicide gesture" — partly misdirected anger and partly designed to win back the attention of her boyfriend. Nevertheless, she almost succeeded in taking her life. The consultant's diagnosis is borderline personality disorder and likely major depression. She is transferred to the inpatient psychiatry service for further evaluation and care. Some days later, she is discharged to a mental health clinic for psychiatric and social service follow-up combined with ongoing counseling.

HEALTHCARE PROFESSIONALS

Some occupations are known to have higher rates of suicide than others. Job factors, including chronic stress, vicarious trauma, low job security, and low pay, can contribute to risk of suicide, as can easy access to lethal means (e.g., medications, firearms) among people at risk. Other factors that can influence the link between occupation and suicide include gender, socioeconomic status, economic environment, cultural factors, and stigma [115].

Healthcare workers have historically been at disproportionate risk of suicide, due to a variety of factors, including difficult working conditions, such as [115]:

- Long work hours

- Irregular shifts

- Emotionally difficult situations

- Risk for exposure to infectious diseases and other hazards on the job, including workplace violence

- Routine exposure to human suffering and death (vicarious or secondary trauma)

- Access to lethal means (e.g., medications) and knowledge about using them

In 2019, a large review of more than 60 scientific studies was conducted to address conflicting data on the nature of suicide among healthcare workers. The researchers found that physicians were at a significant and increased risk for suicide, with female physicians at particularly high risk [116]. A cross-sectional survey involving 7,378 nurses found that nurses were at increased risk for past-year suicidal ideation (5.5%) [117]. In addition, nurses with suicidal ideation were less likely to be willing to seek help (72.6%) than nurses without suicidal ideation (85%). Burnout was strongly associated with suicidal ideation, even after controlling for other personal and professional characteristics [117].

5. RISK AND PROTECTIVE FACTORS FOR SUICIDE

Suicide is now understood to be a multidimensional disorder stemming from a complex interaction of biologic, genetic, psychologic, sociologic, and environmental factors [59,60]. One of the first social scientists to empirically investigate contributing factors to suicide was Émile Durkheim. Instead of focusing only on shared traits among persons who had died by suicide, Durkheim compared one group with another and originated the scientific study of suicide risk factors [5,61]. Protective factors reduce suicide risk by enhancing resilience and counterbalancing risk factors, while risk factors increase the potential for suicidal behavior. Protective and risk factors may be biopsychosocial, environmental, or sociocultural in nature [5].

PROTECTIVE FACTORS

Several protective factors against suicide behavior have been identified [5,62]. These include:

- Access to effective clinical care for mental, physical, and substance use disorders, and support for help-seeking

- Restricted access to highly lethal means of suicide

- Strong connections to family and community support

- Emotionally supportive connections with medical and mental health providers

- Effective problem-solving and conflict-resolution skills

- Cultural and religious beliefs that discourage suicide and support self-preservation

- Reality testing ability

- Pregnancy, children in the home, or sense of family responsibility

- Life satisfaction

RISK FACTORS

In addition to risk factors specific to special populations, there are many general risk factors common among most populations. General biopsychosocial risk factors include [2,5,62]:

- Psychiatric disorders

- Alcohol and other substance use disorders

- Hopelessness

- Impulsive and/or aggressive tendencies

- History of physical or sexual trauma or abuse, especially in childhood

- Medical illness involving the brain or central nervous system (CNS)

- Family history of suicide

- Suicidal ideas, plans, or attempts (current or previous)

- Lethality of suicidal plans or attempts

Evidence Based Practice Recommendation

According to the American Psychiatric Association, the assessment and treatment of major depressive disorder should consider the impact of language barriers, as well as cultural variables that may influence symptom presentation, treatment preferences, and the degree to which psychiatric illness is stigmatized.

https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf

Last Accessed: March 30, 2020

Strength of Recommendation: I (Recommended with substantial clinical confidence)

In addition, environmental factors can impact an individual's suicide risk. Attention to the presence of job or financial loss, relationship or social loss, easy access to lethal means, and local clusters of suicide (due to contagious influence) is necessary.

Lack of social support and sense of isolation are risk factors for suicide, along with cultural factors. Some cultural practices and/or beliefs can predispose an individual to suicide, such as stigma associated with help-seeking behavior; barriers to accessing mental health care and substance abuse treatment; certain cultural and religious beliefs (e.g., suicide as an honorable act); and media exposure to and the influence of others who have died by suicide [2,5,62].

Psychiatric Disorders

At least 90% of people who die by suicide have diagnosable psychiatric illness [2,3]. The psychiatric conditions with the greatest association with suicidal behavior are depression, bipolar disorder, substance abuse, schizophrenia, and personality disorders.

Depression

Major depression is the psychiatric diagnosis most commonly associated with suicide. The lifetime risk of suicide among patients with untreated and treated depressive disorder is nearly 20% and 141 per 100,000, respectively [13,63]. About 30% of all patients with major depression attempt suicide, half of whom ultimately take their own lives. More than 60% of persons who die by suicide are clinically depressed at the time of their deaths, although this climbs to 75% when patients with comorbid depression and alcohol use disorder are added. Seven of every 100 men and 1 of every 100 women diagnosed with depression will die by suicide [13]. Among persons 18 years of age and older who experienced depression in the previous year, 56.3% thought it would be better if they were dead during their worst or most recent episode, 40.3% contemplated suicide, 14.5% made a suicide plan, and 10.4% attempted suicide [65].

The risk of suicide in persons with major depression is roughly 20 times that of the general population [13]. Among persons with depression, those with a history of multiple episodes of depression and those with an alcohol or other substance use disorder are at greatest risk [2]. Persons with depression who exhibit the following symptoms are at heightened risk for suicide [2,13]:

- Extreme hopelessness or desperation

- A lack of interest in previously pleasurable activities

- Intense anxiety and/or panic attacks

- Insomnia

- Talk of suicide or history of attempts

- Irritability, agitation, or enraged behavior

- Isolation

Feelings of hopelessness (e.g., belief that there is no solution) are more predictive of suicide risk than a diagnosis of depression per se. It is also important to remember that patients who desire an early death during a serious or terminal illness are usually experiencing a treatable depressive illness [2].

Bipolar Disorder

Between 5 and 10 million Americans currently have bipolar disorder. Of these, as many as 1 in 5 will die by suicide [67]. Like depression, bipolar disorder is treatable, and effective treatment decreases the risk of suicide.

Alcohol and Substance Abuse

Alcohol and drug abuse are second only to depression and other mood disorders as conditions most associated with suicide. The suicide risk among patients with alcohol use disorder is 50% to 70% higher than the general population. Alcohol abuse is a factor in roughly 30% of suicides, and about 7% of persons with alcohol dependence die by suicide [2,13,68].

In 2011, an estimated 228,366 emergency department admissions were made for alcohol- or drug-related suicide attempts. Almost all (94.7%) involved either a prescription drug or an over-the-counter medication [69]. Approximately 64.4% involved multiple drugs, and 29% involved alcohol [69].

As mentioned, comorbid psychiatric and substance use disorders substantially increase the risk of suicide behavior. Combined data from 2004 and 2005 indicated that 16.4 million adults 18 years of age and older experienced a major depressive episode in the previous year. Of these persons, more than 10% attempted suicide. But when alcohol abuse or illicit drug use occurred with major depression, the proportion of suicide attempts rose to nearly 14% for alcohol abuse and close to 20% for illicit drug use [65]. A 2017 study conducted among more than 10,000 individuals in a prison population showed that those with a documented substance abuse disorder or other psychiatric disorder had a higher rate of attempted suicide (2.0 and 9.2 greater odds, respectively) than those without a diagnosis [41].

There are several possible explanations for the association between alcohol/drug use and suicide. Alcoholism can cause loss of friends, family, or job, leading to social isolation; however, the reverse is equally plausible. Alcohol abuse and suicide may also both represent attempts to deal with depression and misery. Alcohol increases the sedating effects of some drugs that are frequently used in suicide attempts and may increase impulsive actions, making suicide attempts and completions more common [18,70]. To claim that alcoholism "causes" suicide is simplistic; while the association of alcohol and suicide is clear, a causal relationship is not. Both alcoholism and suicide may be responses to the same pain [18].

Schizophrenia

Suicide is the largest cause of premature death among individuals with schizophrenia, and young, unemployed men are at highest risk. Other risk factors include recurrent relapses; fear of deterioration, especially among persons with high intellectual ability; positive symptoms of suspiciousness and delusions; and depressive symptoms [59,60]. The suicide risk is highest during early stages of the illness, early relapse, and early recovery. The risk decreases with prolonging illness duration [59,60].

Personality Disorders

An estimated 20% to 50% of young people who die by suicide have a diagnosable personality disorder, with borderline personality and antisocial personality disorders being most frequently associated with suicide. Histrionic and narcissistic personality disorders and certain psychologic traits, such as impulsivity and aggression, are also associated with suicide [59,60].

Medical Disorders

Illnesses affecting the brain and CNS have a greater effect on suicide risk compared with other medical conditions. These conditions include epilepsy, AIDS, Huntington disease, traumatic head injury, and cerebrovascular accidents. In contrast, cancer and other potentially fatal conditions carry a more modest suicide risk [71].

Sociodemographic Factors

Suicide is an individual act that also occurs in the context of a broader culture, and specific sociodemographic factors are associated with suicide risk, including marital status, occupation, and previous suicide attempt(s) [59,60].

Marital Status

Divorced, widowed, and single people have a higher suicide risk. Marriage appears to be protective for men, but not so for women. Marital separation also increases the risk of suicide [59,60].

Occupation

Certain occupational groups, such as veterinary surgeons, pharmacists, dentists, farmers, and medical practitioners, have higher rates of suicide. Although obvious explanations are lacking, access to lethal means, work pressure, social isolation, and financial difficulties may account for the heightened risk [59,60].

Unemployment and suicide are also correlated, although the nature of the association is complex. Poverty, social deprivation, domestic difficulties, and hopelessness likely mediate the effect of unemployment, but persons with psychiatric illness and personality disorders are also more likely to be unemployed. Recent job loss is a greater risk factor than long-term unemployment.

Previous Suicide Attempt

Approximately 20% of people who kill themselves had made a previous attempt, making previous serious suicide attempts a very high risk factor for future attempts [2].

Incarceration

Suicide is the single most common cause of death in correctional settings, and collectively, inmates have higher suicide rates than their community counterparts. One study found that the rate of suicide among male prisoners is 5 to 6 times higher than in the general population and as much as 20 times higher among women prisoners. Also, for every suicide death there are many more suicide attempts [44,72].

Inmates at highest risk of suicide include young men, the mentally ill, the socially disenfranchised and socially isolated, substance abusers, previous suicide attempters, and juveniles placed in adult correctional facilities. Factors that increase the likelihood of suicidal behavior include the psychologic impact of arrest and incarceration; the stresses of prison life, including physical and sexual predation and assault from other inmates; and the absence of formal policies regarding managing suicidal patients, staff training, or access to mental health care [44,72].

Vicarious Trauma and Burnout

Compassion fatigue is comprised of two components: burnout and vicarious traumatic stress [118]. The first component consists of characteristic negative feelings such as frustration, anger, exhaustion, and depression. The second component, vicarious traumatic stress, may result when the professional is negatively affected through vicarious or indirect exposure to trauma material through their work. Compassion fatigue is associated with a variety of negative mental health repercussions, including increased risk for depression and suicidal ideation.

Being aware of the factors that increase a professional's risk of burnout is very valuable in contributing to a prevention strategy. Contributing factors may be individual/personal, systemic, or frequently a combination of both. It is important to know what does not work (or what makes a toxic environment) first in order to prevent exposure and the associated fallout from such exposure.

Creative Personalities

Anecdotes of famous painters, writers, and musicians who were depressed and died by suicide have occurred for centuries, but only recently has science been able to identify the underlying basis of vulnerability to depression and suicide among creative people. Treatment of major depressive or bipolar illness in artists presents unique problems, one of which is the concern that creativity and the disorder are so intertwined that treatment might suppress the artist's unique talent [73,74,76].

Holiday Suicide Myth

The idea that suicide occurs more frequently during the holiday season is a myth perpetuated in part by the media and has been debunked [2]. The National Center for Health Statistics of the Centers for Disease Control and Prevention (CDC) reports that the suicide rate is actually lowest in December, with peak rates in the spring and the fall. This pattern has remained constant for many years [77]. The holiday suicide myth has been considered important to counter because it provides misinformation about suicide that might ultimately hamper prevention efforts [78].

MILITARY VETERANS

Protective Factors

Several general protective factors may be more prevalent among veterans, including strong interpersonal bonds, responsibilities/duties to others, steady employment, sense of belonging/identity, and access to health care [79]. Historically, the selection bias for healthy recruits, employment, purposefulness, access to health care and a strong sense of belonging were believed to be protective against suicide, but increasing rates have challenged this assumption [79]. In one study, having a service-connected disability was associated with a lower risk of suicide in veterans, likely due to greater access to VA health care and regular compensation payments [52]. It is interesting to note that many of these protective factors do not apply to discharged or retired veterans. Other potentially protective factors include older age, African American/black race, and admission to a nursing home [79].

Risk Factors

Veterans often possess many risk factors for attempting or completing suicide. This includes combat exposure (particularly deployment to a combat theater and/or adverse deployment experiences), combat wounds, post-traumatic stress disorder (PTSD) and other mental health problems, comorbid major depression, traumatic brain injury, poor social support, feelings of not belonging or of being a burden to others or society, acquired ability to inflict lethal self-injury, and access to lethal means [52,58,81,82,83]. There is conflicting evidence of the role of PTSD in suicide risk, with some studies finding PTSD diagnosis to be protective while others indicated it increased risk. Other possible risk factors include [79]:

- Disciplinary actions

- Reduction in rank

- Career threatening change in fitness for duty

- Perceived sense of injustice or betrayal (unit/command)

- Command/leadership stress, isolation from unit

- Transferring duty station

- Administrative separation from service/unit

Case Scenario: Patient B

Patient B is 56 years of age, married with one grown daughter. She consults a primary care physician because of a gradual decline in health over the past 12 to 18 months. She has come at the insistence of her daughter, who accompanies her. Her given purpose is vague: a "check-up" and perhaps laboratory work. Her daughter tells the nurse, "My mother's not well. She's home alone, doesn't get enough sleep, and won't eat right. She complains about her stomach and thinks she has food allergies; she has tried special diets, supplements, and herbal remedies and claims she's getting better, but she's not." The patient is petite, well-groomed, and smiles readily. She tells the physician, "I'll be okay, but I do want to be sure I'm not anemic or have a thyroid problem." She gives a history of chronic, recurrent abdominal discomfort, bloating, periodic constipation, and intolerance to many foods. As a young woman, she was told she has irritable bowel syndrome and was given trials of medication, but she reports being unable to take these medications and being "very sensitive to any prescription medication." She thinks she has lost maybe 5 pounds in the past year. Her examination is unrevealing, except she is thin and there is a hint of generalized muscle atrophy. Over the course of the interview, she appears tired and to have a slightly blunt affect. The following laboratory tests are ordered: complete blood count, chemistry profile, vitamin D and B12 levels, and thyroid function tests. She is given an appointment to return in five days to discuss the results and plan a course of treatment.

6. IMMINENT SUICIDE

While risk factors for suicide represent broader, durable, and ongoing factors, a suicide crisis is a time-limited event that signals an immediate danger of suicide. A suicide crisis can be triggered by a particularly distressing event, such as loss of a loved one or career failure, and involve an intense emotional state in addition to depression, such as desperation (anguish plus urgent need for relief), rage, psychic pain or inner tension, anxiety, guilt, hopelessness, or acute sense of abandonment. Changes in behavior or speech can suggest that suicide is imminent; speech may be indirect, with statements such as, "My family would be better off without me." Persons contemplating suicide may also talk as if they are saying goodbye or going away, exhibit actions ranging from buying a gun to suddenly putting one's affairs in order, or deterioration in social or occupational functioning, increasing use of alcohol, other self-destructive behavior, loss of control, or rage explosions [2].

WARNING SIGNS

Most people who are suicidal exhibit warning signs, whether or not they are in an acute suicide crisis. These warning signs should be taken seriously and include observable signs of serious depression, such as unrelenting low mood, pessimism, hopelessness, desperation, anxiety, psychic pain, and inner tension; withdrawal from friends and/or social activities; sleep problems; and loss of interest in personal appearance, hobbies, work, and/or school [2,13]. Other signs include:

- Increased alcohol and/or other drug use

- Recent impulsiveness and taking unnecessary risks

- Talk about suicide, death, and/or no reason to live

- Making a plan (e.g., giving away prized possessions, sudden or impulsive purchase of a firearm, or obtaining other means of killing oneself, such as poisons or medications)

- Unexpected rage, anger, or other drastic behavior change

- Recent humiliation, failure, or severe loss (especially a relationship)

- Unwillingness to "connect" with potential helpers.

The following expressions of thoughts, feelings, or behaviors may also be warning signs of suicidal behavior [13]:

- Can't stop the pain

- Can't think clearly

- Can't make decisions

- Can't see any way out

- Can't sleep, eat, or work

- Can't get out of the depression

- Can't make the sadness go away

- Can't see the possibility of change

- Can't see themselves as worthwhile

- Can't get someone's attention

- Can't seem to get control

A mnemonic device, IS PATH WARM, has been developed for use in identifying suicide risk [84]. This mnemonic device was derived from the consensus of internationally renowned clinical researchers held under the auspices of the American Association of Suicidology. It consists of the following [84]:

- Ideation

- Substance abuse

- Purposelessness

- Anxiety

- Trapped

- Hopelessness

- Withdrawal

- Anger

- Recklessness

- Mood change

Intentional Self-Harm

Intentional self-harm is behavior related to, but distinct from, suicide behavior and includes suicide attempts and nonsuicidal self-injurious behaviors, such as burning, cutting, and hair pulling, that does not have fatal intent [85]. Self-injurious behavior falls into three categories [85]:

- Major self-injury: Infrequent, usually associated with psychosis or intoxication

- Stereotypic self-injury: Repetitive and reflects a biologic drive of self-harm

- Superficial-to-moderate self-injury: The most common form and is used by self-mutilators to relieve tension, release anger, regain self-control, escape from misery, or terminate a state of depersonalization

Patients with a history of intentional and repetitive self-harm are likely to be highly impulsive with a diagnosis of borderline personality disorder, and distress over their inability to curtail the behavior may heighten suicide risk [85,86,87]. It is essential to recognize that previous nonlethal self-harm does not preclude the development of suicidal ideation or plans with serious intent and lethality [62]. It is important to assess the intent of self-harm behaviors during the risk assessment.

Five days after the initial visit, in anticipation of follow-up later that day, the physician reviews Patient B's laboratory results, all of which are normal. That afternoon, the patient is a "no-show," and no further action is taken. Some time the following week, the office nurse asks her colleague about Patient B, stating "Something about her really bothered me." She recommends that the physician call the patient to follow-up, which he does. The daughter answers with a mix of concern and relief. She states, "I'm really worried about my mother. She's not making sense at times, seems really down, and says we'd all be better off if she just went to sleep and didn't wake up…I didn't mention it last week, but she and my dad are not doing well. He's busy, on the road a lot, and I get the feeling she thinks he's unfaithful to her." At this juncture what do you do?

- Ask the daughter to bring her mother to the office today, along with all supplements and herbal medicines she may have been taking.

- Consider the key issue(s) and give some thought to your clinical approach (e.g., sequencing the encounter and useful tools that will help to identify major depression and assess suicide risk).

- Anticipate logistical barriers in relation to time of day and the possible need for immediate psychiatric consultation and/or hospitalization.

7. SUICIDE ATTEMPTS

LETHAL MEANS

In the United States in 2017, use of a firearm was the cause of death in 50.6% of suicides and is the number one means among all individuals 15 years of age and older. Gun use accounts for 58.8% of all suicide deaths in individuals 15 to 24 years of age, reaching a low of 42.4% in those 35 to 44 years of age, and increasing to 52.8% in those 55 to 64 years of age. Firearm use for suicide completion is extremely high among the elderly, with individuals 75 to 84 having the highest rate at 77%, followed by 74.4% among those 85 years of age and older. Gun use is also the most common suicide method among youth, accounting for 47.2% of all suicide deaths [1].

Although most gun owners report keeping a firearm in their home for the purpose of protection or self-defense, 83% of gun-related deaths in these homes are the result of a suicide, usually by someone other than the gun owner. Guns are involved in more deaths by suicide than by homicide, and overall, death by firearm is the most common suicide method [12].

The suicide rates among youths 15 to 24 years of age by firearm decreased from 7.3 per 100,000 in 1992 to 6.8 per 100,000 in 2017, while the suicide rates by suffocation (e.g., hanging) increased from 1.9 per 100,000 in 1992 to 5.4 per 100,000 in 2017. This trend among older teens has been mirrored by children 5 to 14 years of age, who since 1993 have increasingly used suffocation and decreasingly used guns in suicide deaths. In this group, suicides by suffocation have occurred more frequently than those by firearms since 1999 [1,78].

The most common method of suicide among women in all age groups from 2001 to 2017 was poisoning (31.4%); however, in 2018, firearms surpassed poisoning for the first time since 2000 among female victims [15,78]. Although intentional overdose is the next most common method for suicide attempt, it is much less likely to result in death. Overdose may be achieved with over-the-counter medications, prescription drugs, dietary supplements/herbal medications, or illicit drugs. Ibuprofen is a popular over-the-counter analgesic and a common drug of choice in intentional overdoses. There were more than 12,490 intentional overdose ingestions of ibuprofen reported by U.S. poison control centers in 2018, resulting in one death [89]. Opioid analgesics may result in deaths due to intentional overdose. The rates of fatal toxicity involving opioid analgesics have escalated in tandem with the increased rates in opioid analgesic prescribing, abuse, addiction, and diversion in the past several years. In one study, researchers found that the percentage of individuals who died by suicide and had opioids in their system more than doubled, from 8.8% to 17.7%, between 2006 and 2017 [45].

Ingestion of other toxic substances (including bleach, poisons, and agricultural chemicals), jumps from tall heights, hanging/suffocation, and exsanguination are also relatively common methods of suicide attempt and completion. When assessing risk, it is important to consider the patient's level of impulsivity and the potential lethality of available means.

MOTIVES BEHIND SUICIDAL BEHAVIOR

Although thousands of books have explored the question of why people kill themselves, in most cases the answer can be summed up in three words: to stop pain. The pain may be physical, as in chronic or terminal illness, but is usually emotional. However, Stone has delineated a more elaborate description of the motivations for suicide, including [18]:

- Altruistic/heroic suicide: Occurs when someone (more or less) voluntarily dies for the benefit of the group. Examples include the Japanese kamikaze pilots in WWII and the Buddhist monks who burned themselves to death protesting the Vietnam war.

- Philosophical suicide: Various philosophical schools, such as the stoics and existentialists, have advocated suicide under some circumstances.

- Religious suicide: Often as martyrdom, this type of suicide has a long history that spans from early Christianity to the Branch Davidians in Waco, Texas, and some members at Jonestown, Guyana.

- Escape: This type of suicide represents an escape from an unbearable situation, such as persecution, a terminal illness, or chronic misery.

- Excess alcohol and other drug use

- Romantic suicide: This includes suicide pacts (dual suicide), which constitute about 1% of suicides in Western Europe. Participants are usually older than 51 years of age, except in Japan, where 75% of dual suicides are "lovers' pacts."

- "Anniversary" suicide: Suicide involving the same method or date as a deceased loved one.

- "Contagion" suicide: Occurs when one suicide appears to trigger others (e.g., "cluster" and "copycat" suicides), most often among adolescents.

- Manipulation: Usually involving the theme "If you don't do what I want, I'll kill myself." The word "manipulative" does not imply a lack of seriousness, as fatal suicide attempts can be made by people hoping to influence or manipulate the feelings of others even though they will not be around to witness the outcome. However, the intent of manipulative attempts is to produce guilt in the other person, and a nonfatal result is usually intended.

- Call for help: An expression of unbearable pain and misery that is more frequent in the young.

- "Magical thinking" and vengeance: Associated with a feeling of power and complete control. This motivation to attempt suicide is driven by a "you'll be really sorry when I'm dead" fantasy. A fatal outcome is intended, and this is sometimes called "aggressive suicide."

- Cultural approval: In some cultures, such as Japanese culture, society has traditionally accepted or encouraged suicide when matters of honor were concerned.

- Lack of an outside source to blame for one's misery: Evidence exists that rage and homicide is the extreme response when an external cause of one's unhappiness can be identified, and depression and suicide is the extreme response in the absence of a perceived or identifiable external source.

8. SCREENING AND ASSESSMENT OF SUICIDE RISK

Many persons who die by suicide have contact with healthcare providers in the time preceding their deaths. Roughly 45% of all persons who die by suicide had contact with a mental health professional in the year before their deaths, and 75% of elderly persons who die by suicide had visited their physician in the month before their death [2,5]. Although close to 90% of these cases had diagnosable psychiatric illness at the time of death, only 30% reported suicidal ideation or intent to a health professional before their suicide attempt [2]. These figures suggest a widespread inadequacy in identifying and assessing at-risk persons by healthcare professionals, and numerous studies have concluded that health professionals often lack sufficient training in the proper assessment, treatment, management, or referral of suicidal patients [2,5]. Many health professionals also lack training in identifying grieving family members of loved ones who have died by suicide [5]. Primary care providers occupy a niche in the healthcare system and have perhaps the greatest opportunity to impact suicidal persons through educational means [5,46,59,60,91].

SCREENING IN THE PRIMARY CARE SETTING: EXPERT CONSENSUS

Many organizations have issued consensus statements regarding screening for suicide risk in the primary care setting. The U.S. Preventive Services Task Force states that although suicide screening is of high national importance, it is very difficult to predict who will die from suicide and has found insufficient evidence for routine screening by primary care clinicians to detect suicide risk and limited evidence of the accuracy of screening tools to identify suicide risk in the primary care setting [92]. The Canadian Task Force on Preventive Health Care found insufficient evidence for routine screening by primary care clinicians to detect depression and suicide risk [93].

However, the American Academy of Pediatrics recommends asking about depression, substance abuse, suicidal thoughts, sexual abuse, and other suicide risk factors during the routine history in all ages throughout adolescence [94]. The American Academy of Child and Adolescent Psychiatry recommends clinician awareness of patients at high risk for suicide (i.e., older male adolescents and all adolescents with current psychiatric illness or disordered mental state), especially when complicated by comorbid substance abuse, irritability, agitation, or psychosis [95]. Finally, the American Medical Association recommends that all adolescents be asked annually about behaviors or emotions that indicate risk for suicide [96].

ASSESSMENT OF SUICIDE RISK

Initial Inquiry

Healthcare providers may encounter a patient they suspect is suicidal. This suspicion may be prompted by the presence of one or more of the risk factors for suicide described previously, patient history, a statement expressed by the patient, or by their intuition. This scenario may present a dilemma of how to proceed. Although some healthcare professionals are uncomfortable with suicidal patients, it is essential not to ignore or deny the suspicion of suicide risk. The first and most immediate step is to allocate adequate time to the patient, even though many others may be scheduled. Showing a willingness to help begins the process of establishing a positive rapport with the patient. Closed-ended and direct questions at the beginning of the interview are not very helpful; instead, use open-ended questions such as, "You look very upset; tell me more about it." Listening with empathy is in itself a major step in reducing the level of suicidal despair and overall distress [59,60]. It is helpful to lead into the topic gradually with a sequence of useful questions, such as [59,60]:

- Do you feel unhappy and helpless?

- Do you feel desperate?

- Do you feel unable to face each day?

- Do you feel life is a burden?

- Do you feel life is not worth living?

- Have you had thoughts of ending your own life?

It is important to ask these questions after rapport has been established, when the patient feels comfortable expressing his or her feelings, and when the patient is in the process of expressing negative feelings [59,60].

After the patient confirms an initial suspicion of suicidal ideation, the next step is to assess the frequency and severity of the ideation and the possibility of suicide. It is important to ask the patient about whether a method has been developed and planned, the accessibility to the means to attempt suicide, and the magnitude of lethal intent in a manner that is not demanding or coercive, but is asked in a warm and caring way that demonstrates empathy with the patient. Such general questions might include [59,60]:

- Have you made any plans for ending your life?

- How are you planning to do it?

- Do you have in your possession [pills/guns/other means]?

- Have you considered when to do it?

In general, the more an individual has thought about suicide, made specific plans, and intends to act on those plans, the greater the suicide risk. Thus, as part of the assessment of suicide risk it is essential to inquire specifically about the patient's suicidal thoughts, plans, behaviors, and intent. Such questions may often flow naturally from discussion of the patient's current situation, but in other cases they should be explicitly asked [62].

Other questions may help further elucidate suicidal thoughts, plans, or behaviors, including [62]:

Patient's Feelings about Living

- Have you ever felt that life was not worth living?

- Did you ever wish you could go to sleep and just not wake up?

Thoughts of Death, Self-Harm, or Suicide

- Is death something you've thought about recently?

- Have things ever reached the point that you've thought of harming yourself?

Follow-Up Questions

- When did you first notice such thoughts?

- What led up to the thoughts (e.g., interpersonal and psychosocial precipitants, including real or imagined losses; specific symptoms such as mood changes, anhedonia, hopelessness, anxiety, agitation, psychosis)?

- How often have those thoughts occurred (including frequency, obsessional quality, controllability)?

- How close have you come to acting on those thoughts?

- How likely do you think it is that you will act on them in the future?

- Have you ever started to harm (or kill) yourself but stopped before doing something (e.g., holding knife or gun to your body but stopping before acting, going to edge of bridge but not jumping)?

- What do you envision happening if you actually killed yourself (e.g., escape, reunion with significant other, rebirth, reactions of others)?

- Have you made a specific plan to harm or kill yourself? If so, what does the plan include?

- Do you have guns or other weapons available to you?

- Have you made any particular preparations (e.g., purchasing specific items, writing a note or a will, making financial arrangements, taking steps to avoid discovery, rehearsing the plan)?

- Have you spoken to anyone about your plans?

- How does the future look to you?

- What things would lead you to feel more (or less) hopeful about the future (e.g., treatment, reconciliation of relationship, resolution of stressors)?

- What things would make it more (or less) likely that you would try to kill yourself?

- What things in your life would lead you to want to escape from life or be dead?

- What things in your life make you want to go on living?

- If you began to have thoughts of harming or killing yourself again, what would you do?

For persons with previous suicidal or self-harm behavior, the following questions address the antecedents, methods, and aftermath [62]:

- Can you describe what happened (e.g., circumstances, precipitants, view of future, use of alcohol or other substances, method, intent, seriousness of injury)?

- What thoughts were you having beforehand that led up to the attempt?

- What did you think would happen (e.g., going to sleep versus injury versus dying, getting a reaction out of a particular person)?

- Were other people present at the time?

- Did you seek help afterward yourself, or did someone get help for you?

- Had you planned to be discovered, or were you found accidentally?

- How did you feel afterward (e.g., relief versus regret at being alive)?

- Did you receive treatment afterward (e.g., medical versus psychiatric, emergency department, inpatient versus outpatient)?

- Has your view of things changed, or is anything different for you since the attempt?

- Are there other times in the past when you've tried to harm (or kill) yourself?

Repeated Suicidal Thoughts or Attempts

- About how often have you tried to harm (or kill) yourself?

- When was the most recent time?

- Can you describe your thoughts at the time that you were thinking most seriously about suicide?

- When was your most serious attempt at harming or killing yourself?

- What led up to it, and what happened afterward?

Persons with Psychosis, Hallucinations, and Delusions

- Can you describe the voices (e.g., single versus multiple, male versus female, internal versus external, recognizable versus unrecognizable)?

- What do the voices say (e.g., positive remarks, negative remarks, threats)? If the remarks are commands, determine if they are for harmless versus harmful acts; ask for examples.

- How do you cope with (or respond to) the voices?

- Have you ever done what the voices ask you to do? What led you to obey the voices? If you tried to resist them, what made it difficult?

- Have there been times when the voices told you to hurt or kill yourself? How often? What happened?

- Are you worried about having a serious illness or that your body is rotting?

- Are you concerned about your financial situation even when others tell you there is nothing to worry about?

- Are there things that you have been feeling guilty about or blaming yourself for?

Potential to Harm Others

- Are there others who you think may be responsible for what you are experiencing (e.g., persecutory ideas, passivity experiences)? Are you having any thoughts of harming them?

- Are there other people you would want to die with you?

- Are there others who you think would be unable to go on without you?

When assessing for suicide, it is important to be cautious of misleading information or false improvement [59,60]. When an agitated patient suddenly appears calm, he or she may have made the decision to attempt suicide and feels calm after making the decision. Denial is another important consideration. Patients may deny harboring very serious intentions of killing themselves.

All patients at acute risk for suicide who are under the influence (intoxicated by drugs or alcohol) should be evaluated in an urgent care setting and be kept under observation until they are sober. If the patient is intoxicated when the initial assessment is completed, it should be repeated after he or she is sober [79].

Lethal Means

All persons at risk for suicide should be assessed for availability or intent to acquire lethal means, including firearms and ammunition, drugs, poisons, and other means in the patient's home [79].

Clinicians should always inquire about access to firearms and ammunition and how they are stored. For military members and veterans, this includes assessing privately owned firearms. In addition, medication reconciliation should be performed for all patients. For any current and/or proposed medications, consider the risk/benefit of any medications that could be used as a lethal agent to facilitate suicide. Consider prescribing limited supplies for those at elevated risk for suicide or with histories of overdose or the availability of a caregiver to oversee the administration of the medications. In addition to medications, the availability of chemical poisons, especially agricultural and household chemicals, should be assessed, as many of these are highly toxic [79].

DETERMINING LEVEL OF RISK AND APPROPRIATE ACTIONS

The formulation of the level of risk for suicide guides the most appropriate care environment in which to address the risk and provide safety and care needs. The first priority is safety. Patients assessed as having a clear intention of taking their lives will require higher levels of safety protection than those with less inclination toward dying. Patients who are at high risk for suicide may require inpatient care to provide for increased level of supervision and higher intensity of care. Those at intermediate and low acute risk may be referred to an outpatient care setting and, with appropriate supports and safety plans, may be able to be followed-up in the community (Table 1) [79].

Table 1: DETERMINE LEVEL OF RISK FOR SUICIDE AND APPROPRIATE ACTION

Risk of Suicide Attempt

Indicators of Suicide Risk

Contributing Factorsa

Initial Action Based on Level of Risk

High acute risk

Persistent suicidal ideation or thoughts

Strong intention to act or plan

Not able to control impulse

Recent suicide attempt or preparatory behaviorb

Acute state of mental disorder or acute psychiatric symptoms

Acute precipitating event(s)

Inadequate protective factors

Maintain direct observational control of the patient

Limit access to lethal means

Immediate transfer with escort to urgent/emergency care setting for hospitalization

Intermediate acute risk

Current suicidal ideation or thoughts

No intention to act

Able to control the impulse

No recent attempt or preparatory behavior or rehearsal of act

Existence of warning signs or risk factorsb and limited protective factors

Refer to behavioral health provider for complete evaluation and interventions

Contact behavioral health provider to determine acuity of referral

Limit access to lethal means

Low acute risk

Recent suicidal ideation or thoughts

No intention to act or plan

Able to control the impulse

No planning or rehearsing a suicide act

No previous attempt

Existence of protective factors and limited risk factors

Consider consultation with behavioral health to determine need for referral and treatment

Treat presenting problems

Address safety issues

Document care and rationale for action

aModifiers that increase the level of risk for suicide of any defined level include acute state of substance use, access to means (e.g., firearms, medications), and existence of multiple risk factors or warning signs or lack of protective factors.

bEvidence of suicidal behavior warning signs in the context of denial of ideation should call for concern (e.g., contemplation of plan with denial of thoughts or ideation).

Source: U.S. Department of Veterans Affairs. VA/DoD Clinical Practice Guideline for Assessment and Management of Patients at Risk for Suicide. Available at http://www.healthquality.va.gov/guidelines/MH/srb.

Risk Assessment Tools

Rating scales can be helpful in the assessment process. However, a clinical assessment by a trained professional is required to assess suicide risk. This professional should have the skills to engage patients in crisis and to elicit candid disclosures of suicide risk in a non-threatening environment. The assessment should comprise a physical and psychiatric examination, including a comprehensive history (with information from patient, parents, and significant others whenever possible) to obtain information about acute psychosocial stressors, psychiatric diagnoses, current mental status, and circumstances of prior suicide attempts. Assessment tools may be used to evaluate risk factors, in addition to the clinical interview, although there is insufficient evidence to recommend one tool over another.

High Acute Risk

Considering all the information gathered in the assessment, the clinician will formulate the level of risk in one of the following categories: high acute risk, intermediate acute risk, low acute risk, not at elevated risk [79].

High acute risk patients include those with warning signs, serious thoughts of suicide, a plan and/or intent to engage in lethal self-directed violence, a recent suicide attempt, and/or those with prominent agitation, impulsivity, and/or psychosis. In such cases, clinicians should ensure constant observation and monitoring before arranging for immediate transfer for psychiatric evaluation or hospitalization [79]. Patients at high acute risk should be immediately referred for a specialty evaluation with particular concern for ensuring the patient's safety and consideration for hospitalization.

Intermediate Acute Risk

Intermediate acute risk patients include those with suicidal ideation and a plan but with no intent or preparatory behavior. Combination of warning signs and risk factors to include history of self-directed violence (suicide attempt) increases a person's risk for suicide. Patients at intermediate risk should be evaluated by a behavioral health provider. The decision whether to urgently refer a patient to a mental health professional or emergency department depends on that patient's presentation. The patient who is referred may be hospitalized if further evaluation reveals that the level of illness or other clinical findings warrant it. The patient may be managed in outpatient care if patient and provider collectively determine that the individual is capable of maintaining safety by utilizing non-injurious coping methods and utilize a safety plan [79].

Low Acute Risk

Low acute risk patients include those with recent suicidal ideation who have no specific plans or intent to engage in lethal self-directed violence and have no history of active suicidal behavior. Consider consultation with behavioral health to determine need for referral to treatment addressing symptoms and safety issues. These patients should be followed up for reassessment. Patients at low acute risk should be considered for consultation with or referral to a behavioral health practitioner [79].

Not at Elevated Acute Risk or Risk Unknown

Persons with a mental disorder who are managed appropriately according to evidence-based guidelines and do not report suicidal thoughts are outside the scope of the classification of risk for suicide. Patients who at some point in the past have reported thoughts about death or suicide but currently do not have any of these symptoms are not considered to be at acute risk of suicide. There is no indication to consult with behavioral health specialty in these cases, and the patients should be followed in routine care, continue to receive treatment for their disorder, and be re-evaluated periodically for thoughts and ideation. Patients at no elevated acute risk should be followed in routine care with treatment of their underlying condition, and evaluated periodically for ideation or suicidal thoughts. Patients for whom the risk remains undetermined (i.e., no collaboration of the patient or provider concerns about the patients despite denial of risk) should be evaluated by a behavioral health practitioner [79].

DOCUMENTATION

In order to ensure optimal patient care and to prevent miscommunication and litigation, the results of any suicide risk assessment should be fully documented. At a minimum, documentation should include the following points, noted by the mnemonic SUICIDE [17]:

- Suicide assessment: The results of suicide screening or assessment, including any relevant history (personal or family), access to lethal means, suicide plans, recent history of stressful events, and protective factors, should be noted.

- Unpredictable: Family members and/or other supportive third parties should be alerted that suicide can be unpreventable, even given the best efforts and plans.

- Interventions: All interventions planned and undertaken should be included in the patient's record.

- Clear and comprehensive: It is important to ensure that all documentation is clear and comprehensive, with specific notes regarding the patient's own words.

- Intent: The intentions of any suicide attempt(s) or intentional self-harm should be noted.

- Discussions with family members and/or other supportive third parties: Supportive third parties can be invaluable to the treatment process, and their inclusion in risk assessments and treatment planning should be documented.

- Educate, engage, empathize: Documentation should include notes regarding the patient's involvement in treatment planning and the creation of a safety plan.

Patient B arrives at the office with her daughter. She appears withdrawn and preoccupied, having a look of resignation and despair. Seated together, you begin the interview in a positive, affirming manner: "I'm pleased that all your laboratory work, including your thyroid tests, is normal. You know you told me you would be okay, and I believe if we work together, so as to know and understand better what you are going through, we can relieve many of your symptoms and get you to a much better place." She is receptive, and after further discussions, the following picture emerges: Patient B has been unhappy for "a very long time." There is little to add to the somatic complaints related on the first visit. She sleeps poorly and is tired all the time; she has lost interest in what was previously an active social life and rarely "goes out." There is a good deal of psychic stress and pain attached to the relationship with her husband, and a sense of hopelessness has been building for months. In recent days, she has not slept and has periods of confusion. She wishes not to be a burden to those closest to her and has thought often of ending her life. Recently she has been thinking about just how to do this, the options available to her, and how it might be done so as to mask her intent. At the conclusion of the interview, you glance at the nurse with an expression of appreciation, and shudder to think how easily you might have missed all this.

- Recall the mnemonic device IS PATH WARM. How many of the elements are positive for Patient B? Which ones?

- Would you rate Patient B's suicide risk as low? Intermediate? High?

- Which of the following management options is the LEAST appropriate at this juncture?

- Send the patient home with a prescription for an antidepressant and a plan for regular return psychotherapy sessions in your office.

- Refer her to a psychiatrist (appointment in 48 to 72 hours) and negotiate a "contract" with the patient that she is not to take matters into her own hands but will call you immediately if she has thoughts of doing so.

- Arrange admission to the hospital medical service with a "sitter" and place an urgent psychiatry consultation.

- Call your psychiatry consultant to summarize the case and request immediate consultation or admission to the inpatient psychiatry service.

9. MANAGEMENT OF SUICIDAL PATIENTS

The opportunity for an emotionally disturbed patient with vague suicidal ideation to vent his or her thoughts and feelings to an understanding health or mental health provider may bring a degree of relief such that no further intervention is needed. However, in all cases the encouragement of further contact and follow-up should be conveyed to the patient, especially when inadequate social support is present. Independent of the actual catalyst, most suicidal persons possess feelings of helplessness, hopelessness, and despair and a triad of three cognitive/emotional conditions [59,60]:

- Ambivalence: Most suicidal patients are ambivalent, with alternating wishes to die and to live. The healthcare provider can use patient ambivalence to increase the wish to live, thus reducing suicide risk.

- Impulsivity: Suicide is usually an impulsive act, and impulse, by its nature, is transient. A suicide crisis can be defused if support is provided at the moment of impulse.

- Rigidity: Suicidal people experience constricted thinking, mood, and action and dichotomized black-and-white reasoning to their problems. The provider can help the patient understand alternative options to death through gentle reasoning.

Healthcare professionals should assess the strength and availability of emotional support to the patient, help the patient identify a relative, friend, acquaintance, or other person who can provide emotional support, and solicit the person's help [59,60]. The engagement of supportive third parties in the patient's life can be a useful tool in preventing suicide completion.

Adherence to established best practices general assures that assessment and care will be ethical and legal. It is important to consider and document informed consent. Underlying key ethical principles include respect for persons, autonomy, and beneficence [121].

PHARMACOTHERAPY TO REDUCE SUICIDE RISK

Abundant evidence has demonstrated that lithium reduces the rate of suicidal behavior in patients with bipolar disorder and recurrent major depression and that clozapine reduces suicidal behavior in schizophrenia [97,98,99,100,101,102]. Both drugs reduce suicide risk independently of their effect on the primary psychiatric disorder. Although the exact anti-suicide mechanism of both drugs has yet to be identified, lithium enhances serotonergic activity and clozapine is a potent 5-HT2A antagonist. Serotonergic modulation is a likely explanation of the suicide-reducing effects of both medications, because aggression levels and suicide are correlated with prefrontal cortical 5-HT2A binding [71,104,105].

PSYCHOTHERAPY TO REDUCE SUICIDE RISK

In addition to pharmacotherapy, various psychotherapy approaches have been shown to decrease suicide risk in patients at low or intermediate risk for suicide [55]. Post-admission cognitive therapy is a cognitive-behavioral therapy approach designed to help patients who have suicide-related thoughts and/or behaviors. It consists of three phases of therapy for outpatients or inpatients [55]:

- The patient is asked to tell a story associated with her or his most recent episode of suicidal thoughts, behavior, or both.

- The patient is assisted with modifying underdeveloped or overdeveloped skills that are most closely associated with the risk of triggering a suicidal crisis.

- The patient is guided through a relapse-prevention task.

Another cognitive-behavioral approach is cognitive-behavioral psychotherapy for suicide prevention, which involves "acute and continuation phases, each lasting about 12 sessions, and includes a chain analysis of the suicidal event, safety plan development, skill building, psychoeducation, family intervention, and relapse prevention" [53].

Dialectical behavior therapy was originally designed to address the self-harm impulses of patients with borderline personality disorder, but it has good evidence for use in most suicidal individuals. Dialectical behavioral therapy is an adaptation of cognitive-behavioral therapy and is based on the theoretical principle that maladaptive behaviors, including self-injury, are attempts to manage intense overwhelming affect of biosocial origin. It consists of the two key elements of a behavioral, problem-solving approach blended with acceptance-based strategies and an emphasis on dialectical processes. Dialectical behavioral therapy emphasizes balancing behavioral change, problem-solving, and emotional regulation with validation, mindfulness, and acceptance of patients. Therapeutic targets are ranked in hierarchical order, with life-threatening behaviors addressed first, followed by therapy-interfering behaviors, and then behaviors that interfere with quality of life.

MENTAL HEALTH REFERRAL

Depending on the level of suicide risk, referral to a mental health professional (e.g., psychologist, counselor, therapist), psychiatrist, or hospitalization may be warranted. Long-term treatment and follow-up will be required for many patients, and appropriate referral to outpatient facilities is often necessary. If the person is currently in therapy, the therapist should be called and involved in the management decision. If the patient does not have a therapeutic relationship with a mental health professional, referral to one should be made. Suicidal patients should be referred to a psychiatrist when any of the following are present: psychiatric illness; previous suicide attempt; family history of suicide, alcoholism, and/or psychiatric disorder; physical illness; or absence of social support [59,60]. After deciding to refer a patient to a mental health professional, the clinician should explain to the patient the reason for the referral and help alleviate patient anxiety over stigma and psychotropic medications. It is also important to help the patient understand that pharmacologic and psychologic therapies are both effective and to emphasize to the patient that referral does not mean "abandonment." The referring clinician should also arrange an appointment with the mental health professional, allocate time for the patient following the initial appointment with the therapist or psychiatrist, and ensure the ongoing relationship with the patient [59,60].

REFERRAL TO BE HOSPITALIZED

Evidence Based Practice Recommendation

The Department of Veterans Affairs recommends choosing the appropriate care setting that provides the patient at risk of suicide maximal safety in the least restrictive environment. Despite insufficient evidence to demonstrate the effectiveness of acute hospitalization in the prevention of suicide, hospitalization is indicated in suicidal patients who cannot be maintained in less restrictive care settings.

https://www.healthquality.va.gov/guidelines/MH/srb

Last Accessed: March 30, 2020

Level of Evidence: Expert Opinion/Consensus Statement

Some indications for immediate hospitalization include recurrent suicidal thoughts, high levels of intent of dying in the immediate future (the next few hours or days), the presence of agitation or panic, or the existence of a plan to use a violent and immediate suicide method [59,60]. When hospitalizing a patient, she or he should not be left alone; the hospitalization and transfer of the patient by ambulance or police should be arranged and the family, and any appropriate authorities should be informed [59,60].

A patient may be discharged to a less restrictive level of care from an acute setting (emergency department/hospital/acute specialty care) after a behavioral health clinician evaluated the patient, or a behavioral health clinician was consulted, and all three of the following conditions have been met [79]:

- Clinician assessment indicates that the patient has no current suicidal intent.

- The patient's active psychiatric symptoms are assessed to be stable enough to allow for reduction of level of care.

- The patient has the capacity and willingness to follow the personalized safety plan (including having available support system resources).

ADDITIONAL OPTIONS FOR CONTINUITY OF CARE

It is important to ensure that the patient has follow-up contact even after discharge to another provider. At the point of discharge, information should be provided on crisis options (referred to as "crisis cards") and free, universally available help, such as hotlines. There is evidence that follow-up outreach in the form of letters or postcards expressing care and concern and continuing for up to three years may be helpful in suicide prevention [75]. These letters should generally be non-demanding, allowing the opportunity but not the requirement for patients to respond.

Alternatively, patients may be followed-up with phone calls from a mental health professional or suicide crisis volunteer [75]. If phone follow-up is preferred, calls should be made weekly or biweekly, in some cases supplemented with a home visit, and should continue for a period of three to six months.

In many cases, partnering with a community crisis center can be helpful [66]. Crisis call centers are a crucial resource in linking patients to services and providing emotional support. According to the Suicide Prevention Lifeline, crisis center follow-up before a service appointment is associated with improved motivation, a reduction in barriers to accessing services, improved adherence to medication, reduced symptoms of depression, and higher attendance rates [64].

SAFETY PLANNING

The VA recommends establishing an individualized safety plan for all persons who are at high acute risk for suicide as part of discharge planning, regardless of inpatient or outpatient status [79]. The safety plan is designed to empower the patient, manage the suicidal crisis, and engage other resources. Safety should also be discussed with patients at intermediate and low risk, with appropriate patient education and a copy of a safety plan handout [79].

Stressful events, challenging life situations, mental/substance use disorders, and other factors can precipitate a crisis of suicidal thoughts and behaviors leading directly to self-injury. Advance anticipation of challenging situations and envisioning how one can identify and break a cycle of suicidal crises can reduce risk of self-injury and enhance a patient's sense of self-efficacy. Open dialogue between patients and clinicians to establish a therapeutic alliance and develop strategies and skills supporting the patient's ability to avoid acting on thoughts of suicide (including minimizing access to lethal means) is an essential component of suicide prevention in clinical settings. Putting this thinking-through process in writing for the anticipation of a suicidal crisis and how to manage it constitutes a patient's safety (action) plan [79].

Safety planning is a provider-patient collaborative process—not a "no harm" contract. The safety planning process results in a written plan that assists the patient with restricting access to means for completing suicide, problem-solving and coping strategies, enhancing social supports and identifying a network of emergency contacts including family members and friends, and ways to enhance motivation. These plans are tailored to the patient by assisting with identifying his or her specific warning signs and past effective coping strategies [79].

The safety plan should include the following elements, as appropriate:

- Early identification of warning signs or stressors

- Enhancing coping strategies (e.g., to distract and support)

- Utilizing social support contacts (discuss with whom to share the plan)

- Contact information about access to professional help

- Minimizing access to lethal means (e.g., weapons and ammunition or large quantities of medication)

The safety plan should be reviewed and updated by the healthcare team working with the patient as needed and shared with family and other supportive third parties if the patient consents. Safety plans should be updated to remain relevant during changes in clinical state and transitions of care [79].

Providers should document the safety plan or reasons for not completing such a plan in the medical record. In addition, patients should receive a copy of the plan [79].

Limiting Access to Lethal Means

Restricting at-risk patients from access to lethal means is considered an essential part of suicide prevention and safety planning. Methods of ensuring persons with suicidal intent do not have access to lethal means include restriction of access to firearms and ammunition, safer prescribing and dispensing of medications to prevent intentional overdoses, and modifying the environment of care in clinical settings to prevent fatal hangings [79]. For military service members, concerns about firearms should include privately owned guns and ammunition. It is also important to educate caregivers, family members, and/or other supportive third parties regarding the potential dangers of lethal means and how to keep these items or substances from the patient.

CONSIDERATIONS FOR VETERANS

With military service members, the command element should also be involved in education, safety planning, treatment planning, and implementation of duty limitations. Additional areas to address are the patient's medical and other specific needs. These may be psychosocial, socioeconomic, or spiritual in nature [79].

The VA has made the following recommendations when creating a treatment plan for veterans and active service members [79]:

- Providers should take reasonable steps to limit the disclosure of protected health information to the minimum necessary to accomplish the intended purpose.

- Providers should involve command in the treatment plan of service members at high acute risk for suicide to assist in the recovery and the reintegration of the patient to the unit. For service members at other risk levels, the provider should evaluate the risk and benefit of involving command and follow service department policies, procedures, and local regulations.

- When performing a medical profile, the provider should discuss with command the medical recommendation and the impact on the service member's limitations to duty and fitness for continued service.

- Providers should discuss with service members the benefit of having command involved in their plan and assure them their rights to protected health information, with some exceptions, regarding to the risk for suicide.

- As required by pertinent military regulations, communicate to the service member's chain of command regarding suicidal ideation along with any recommended restrictions to duty, health and welfare inspection, security clearance, deployment, and firearms access. Consider redeployment to home station any service member deployed to a hazardous or isolated area.

- Service members at high acute risk for suicide who meet criteria for hospitalization and require continuous (24-hour) direct supervision should be hospitalized in almost all instances. If not, the rationale should specifically state why this was not the preferred action, with appropriate documentation.

- During operational deployment conditions or other extreme situations during which hospitalization or evacuation is not possible, "unit watch" may be considered as appropriate in lieu of a high level care setting (hospitalization), and service department policies, procedures, and local regulations should be followed.

- Because of the high risk of suicide during the period of transition, providers should pay particular attention to ensure follow-up, referral, and continuity of care during the transition of service members at risk for suicide to a new duty station or after separation from a unit or from military service.

CONSIDERATIONS FOR HEALTHCARE PROFESSIONALS

Although confidentiality is crucial when caring for any patient, this is heightened for healthcare providers who would potentially be seeking assessment and treatment in their workplace. All healthcare providers should be offered the opportunity for anonymous screening for depression and suicide. The healer education assessment and referral (HEAR) screening program is a sustainable suicide prevention program that uses an anonymous method to provide screening for untreated depression or suicide [119,121]. The American Foundation for Suicide Prevention also provides services specifically for healthcare providers, accessible at https://afsp.org/suicide-prevention-for-healthcare-professionals.

10. SUICIDE PREVENTION

Understanding the interactive relationship between risk and protective factors in suicidal behavior and how this interaction can be modified forms the basis of suicide prevention [5,106]. The characteristics shared by effective suicide prevention programs include clear identification of the intended population, definition of desired outcomes, use of interventions known to effect a particular outcome, and use of community coordination and organization to achieve an objective. Prevention efforts are based on a clear plan with goals, objectives, and implementation steps [5,45].

HISTORY OF SUICIDE PREVENTION IN THE UNITED STATES

In the United States, large-scale suicide prevention efforts began in 1958. Funding from the U.S. Public Health Service established the first suicide prevention center in Los Angeles, and other crisis intervention centers replicating this model were opened across the country [5]. The risk factor approach to suicide prevention was first implemented in 1966, and the American Association of Suicidology and the American Foundation for Suicide Prevention were established over the next two decades. Their activities included increasing the scientific understanding of suicide as the basis for effective prevention activities [5]. In 1983, the CDC established a violence prevention division that alerted the public to the disturbing increase in youth suicide rates.

In 1996, survivors of suicide loss mobilized to form the Suicide Prevention Advocacy Network USA (SPAN USA) and launched a campaign to advocate for the development of a national suicide prevention strategy [107]. In 2009, SPAN USA merged with the American Foundation for Suicide Prevention to raise awareness, fund research, and provide resources and aid to those affected by suicide [48].

The National Strategy for Suicide Prevention (NSSP) was released by the Surgeon General of the United States in 2001 and updated in 2012. The NSSP describes a series of goals and objectives designed to reduce the incidence of suicide behaviors in the United States [46]. Although activity in the field of suicide prevention has increased exponentially since publication of the NSSP, the overall rate of suicide since 2000 continues to increase [1].

SUICIDE PREVENTION THAT TARGETS AT-RISK POPULATIONS

College Students

Colleges and universities are increasingly challenged to identify and manage mental health and substance use problems in students. Because the risk and protective factors for suicide among young adults include substance abuse and interpersonal violence, suicide prevention may best be integrated within broader prevention efforts [5,108,109].

Inmates in Jails and Correctional Settings

As discussed, jails and juvenile justice facilities have exceptionally high suicide rates. The highest rates of jail suicide occur within the first 24 to 48 hours of arrest, suggesting an important role of medical assessment of substance abuse and suicide proneness at intake. Comprehensive prevention programs targeting inmate suicide include training, screening, effective communication methods, intervention, use of reporting protocols, and mortality review [5,110].

Elderly Persons

Almost 70% of elderly patients who take their own lives see their primary care physician within a few months of their death [111,112]. This represents an absolutely vital, yet narrow, window for accurate screening and assessment of suicide risk [2]. Unfortunately, healthcare and mental health professionals are not immune from harboring the stereotypes of the elderly often found among society in general. These can include attitudes that a depressive response to interpersonal loss, physical limitation, or changing societal role is an inevitable and even normal aspect of aging [111,113,114]. Suicidal thoughts may even be considered age-appropriate in the elderly [112]. When held by patients and family members, these erroneous beliefs can lead to under-reporting of symptoms and lack of effort on the part of family members to seek care for patients [114]. When held by clinicians, these beliefs can result in delayed or missed diagnoses, less effective treatment, or suicide in the elderly patient.

Because the elderly have the highest overall suicide rate of all age groups, organizations with special access to older persons have an important role in suicide prevention. State aging networks exist in every state, and these networks develop and fund a variety of in-home and community-based services. States organize the provision of such services through area agencies on aging, which coordinate a broad range of services for older people [5].

Patients with Bipolar Disorder

Although 20% of patients with bipolar disorder have their first episode during adolescence, diagnosis is often delayed for years, which can result in problems such as substance abuse and suicidal behaviors. Thus, early recognition and aggressive treatment may prevent years of needless suffering and death by suicide. In particular, lithium is effective in preventing suicidal behavior in patients with bipolar disorder. Maintaining treatment is essential in preventing suicide, and the suicide rate in the first year of discontinuation of lithium treatment is 20 times higher than during lithium treatment [103].

Patients with Schizophrenia

There are approximately 3.5 million people in the United States with schizophrenia [49]. One study of patients with schizophrenia showed a lifetime prevalence of suicide attempt of 39.2%, versus 2.8% of nonafflicted individuals; furthermore, more than 10% of patients with schizophrenia will eventually die of suicide [50,90]. Depression is the most important risk factor for suicide in patients with schizophrenia; only 4% of patients with schizophrenia who exhibit suicidal behavior do so in response to instructions from "command" voices. Clozapine is effective in reducing suicide and attempted suicide in patients with schizophrenia, and effective suicide prevention involves the early recognition and prompt treatment of schizophrenia and all comorbid conditions [2].

Military Veterans

Assessment of suicide risk and protective factors in military personnel is vital, particularly at times of transition (e.g., deployment, separation from service/unit). It is important to include life planning, referral information, and resources for patients who experience suicidal ideation, and there are military-specific resources available for current or former members of the military. The Veterans Crisis Line, at 800-273-8255, is free to all active service members, including members of the National Guard and Reserve, and veterans, even if they are not registered with the VA or enrolled in VA health care [81].

STIGMA AND SUICIDE

The stigma of mental illness and substance abuse, both of which are closely linked to suicide, prevents many persons from seeking help out of a fear of prejudice and discrimination [88]. People who have a substance use disorder face additional stigma because many people believe that abuse and addiction are moral failings and that individuals are fully capable of controlling these behaviors if they want to [5,80]. The stigma of suicide, while deterring some from attempting suicide, is also a barrier to treatment for many persons who have suicidal thoughts or have attempted suicide. Family members of suicide attempters often hide the behavior from friends and relatives, because they may believe that it reflects badly on their own relationship with the suicide attempter or that suicidal behavior itself is shameful or sinful. Persons who attempt suicide may have many of these same feelings [5].

On a systems level, the stigma surrounding mental illness, substance use disorders, and suicide has contributed to inadequate funding for preventive services and inadequate insurance reimbursement for treatments. Substance use and mental health conditions, including those associated with suicide, will remain undertreated and services tailored to persons in crisis will remain limited as long as stigma persists, resulting in an unnecessarily high rate of suicidal behavior and suicide [5]. Additionally, the stigma associated with mental illness and substance abuse has led to separate systems for physical health and mental health care, a consequence being that preventive and treatment services for mental illness and substance abuse are much less available than for other health problems. This separation has also led to bureaucratic and institutional barriers between the two systems that impede and complicate access to care and service implementation [5].

11. SUICIDE SURVIVORS: TREATMENT AND RESOURCES

Family members and friends affected by the death of a loved one through suicide are referred to as "suicide survivors." Conservative estimates suggesting a ratio of six survivors for every suicide deaths indicate that an estimated 6 million Americans became suicide survivors in the past 25 years; however, as noted, many more individuals are affected by a single suicide [4,13,14].

The death of a loved one by suicide can be shocking, painful, and unexpected for survivors. The ensuing grief can be intense, complex, chronic, and nonlinear. Working through grief is a highly individual and unique process that survivors experience in their own way and at their own pace. Grief does not always move in a forward direction, and there is no timeframe for grief. Survivors should not expect their lives to return to their previous state and should strive to adjust to life without their loved one. The initial emotional response may be overwhelming, and crying is a natural reaction and an expression of sadness following the loss of a loved one [13].

Survivors often struggle with trying to comprehend why the suicide occurred and how they could have intervened. Feelings of guilt are likely when the survivor believes he or she could have prevented the suicide. The survivor may even experience relief at times, especially if the loved one had a psychiatric illness. The stigma and shame that surround suicide may cause difficulty among the family members and friends of survivors in knowing what to say and how to support the survivor and might prevent the survivor from reaching out for help. Ongoing support remains important to maintain family and other relationships during the grieving process [13].

Many survivors find that the best help comes from attending a support group for survivors of suicide in which they can openly share their own story and their feelings with fellow survivors without pressure or fear of judgment and shame. Support groups can be a helpful source of guidance, understanding, and support through the healing process [13]. The American Foundation for Suicide Prevention maintains an international directory of suicide bereavement support groups on their website, https://afsp.org.

12. CONCLUSION

Suicide is a major preventable public health problem and cause of mortality. This course has reviewed the major aspects of suicide assessment, management, and prevention, with a special focus on military veterans. Primary care contact may represent the last opportunity for intervention in the severely depressed suicidal patient, making the thorough comprehension of identification and treatment of depression and suicide risk imperative.

Works Cited

1. Kochanek KD, Murphy SL, Xu J, Arias E. Deaths: final data for 2017. Natl Vital Stat Rep. 2019;68(9):1-76.

2. American Foundation for Suicide Prevention. Suicide Statistics. Available at https://afsp.org/about-suicide/suicide-statistics. Last accessed February 13, 2020.

3. National Alliance on Mental Illness. Risk of Suicide. Available at https://www.nami.org/Learn-More/Mental-Health-Conditions/Related-Conditions/Suicide. Last accessed February 13, 2020.

4. Cerel J, Maple M, van de Venne J, et al. Exposure to suicide in the community: prevalence and correlates in one U.S. state.Public Health Rep. 2016;131(1):100-107.

5. U.S. Department of Health and Human Services, Office of the Surgeon General, and National Action Alliance for Suicide Prevention. 2012 National Strategy for Suicide Prevention: Goals and Objectives for Action. Washington, DC: U.S. Department of Health and Human Services; 2012.

6. Centers for Disease control and Prevention. Depression Evaluation Measures. Available at https://www.cdc.gov/workplacehealthpromotion/health-strategies/depression/evaluation-measures/index.html. Last accessed February 17, 2020.

7. Randall JR, Walld R, Finlayson G, Sareen J, Martens PJ, Bolton JM. Acute risk of suicide and suicide attempts associated with recent diagnosis of mental disorders: a population-based, propensity score-matched analysis. Can J Psychiatry. 2014;59(10): 531-538.

8. World Health Organization. Suicide Data. Available at https://www.who.int/mental_health/prevention/suicide/suicideprevent/en. Last accessed February 17, 2020.

9. Värnik P. Suicide in the world. Int J Environ Res Public Health. 2012;9(3):760-771.

10. Xu JQ, Kochanek KD, Murphy SL, Tejada-Vera B. Deaths: final data for 2007. Natl Vital Stat Rep. 2010;58(19):1-135.

11. Hedegaard H, Curtin SC, Warner M. Increase in suicide in the United States, 1999–2017. NCHS Data Brief. 2018;330:1-7.

12. Hoyert DL, Xu J. Deaths: preliminary data for 2011. Nat Vital Stat Rep. 2012;61(6):1-52.

13. American Association of Suicidology. Facts and Statistics. Available at https://suicidology.org/facts-and-statistics. Last accessed February 17, 2020.

14. Cerel J, Brown MM, Maple M, et al. How many people are exposed to suicide? Not six. Suicide Life Threat Behav. 2019;49:529-534.

15. Centers for Disease Control and Prevention. Suicide: Facts at a Glance. Available at https://www.cdc.gov/violenceprevention/pdf/suicide-datasheet-a.pdf. Last accessed February 25, 2020.

16. American College Health Association. American College Health Association-National College Health Assessment II: Reference Group Executive Summary Fall 2011. Hanover, MD: American College Health Association; 2012.

17. Francois D, Madva EN, Goodman H. How to document SUICIDE risk. Current Psychiatry. 2014;13(10):33-34.

18. Stone G. Suicide and Attempted Suicide. New York, NY: Carroll & Graf; 2001.

19. Clark DC, Horton-Deutsch SL. Assessment in absentia: the value of the psychological autopsy method for studying antecedents of suicide and predicting future suicides. In: Maris RW, Berman AL, Maltsberger JT, Yufit RI (eds). Assessment and Prediction of Suicide. New York, NY: Guilford Press; 1992: 144-182.

20. Hawton K, Saunders KE, O'Connor RC. Self-harm and suicide in adolescents. Lancet. 2012;379(9834):2373-2382.

21. Bebbington PE, Minot S, Cooper C, et al. Suicidal ideation, self-harm and attempted suicide: results from the British psychiatric morbidity survey 2000. Eur Psychiatry. 2010;25(7):427-431.

22. Schmidtke A, Schaller S. The role of mass media in suicide prevention. In: Hawton K, van Heeringen K (eds). The International Handbook of Suicide and Attempted Suicide. New York, NY: Wiley; 2000: 675-697.

23. Velting DM, Gould MS. Suicide contagion. In: Maris RW, Silverman MM, Canetto SS (eds). Review of Suicidology. New York, NY: Guilford Press; 1997: 96-136.

24. Zenere EFJ. Suicide clusters and contagion. Principal Leadership. 2009;10(2):12-16.

25. National Institute of Mental Health. Crisis and Suicide Prevention Services Struggle with Demand after Celebrity Suicides. Available at https://www.nimh.nih.gov/news/science-news/2019/crisis-and-suicide-prevention-services-struggle-with-demand-after-celebrity-suicides.shtml. Last accessed February 18, 2020.

26. van Heeringen K, Mann JJ. The neurobiology of suicide. Lancet Psychiatry. 2014;1(1):63-72.

27. Mann JJ, Currier DM. Stress, genetics and epigenetic effects on the neurobiology of suicidal behavior and depression. Eur Psychiatry. 2010;25(5):268-271.

28. Costanza A, D'Orta I, Perroud N, et al. Neurobiology of suicide: do biomarkers exist? Int J Legal Med. 2014;128(1):73-82.

29. Fiori LM, Ernst C, Turecki G. Genetic and neurobiological approaches to understanding suicidal behaviors. In: Nock M (ed).The Oxford Handbook of Suicide and Self-Injury. Oxford: Oxford University Press; 2014: 155-182.

30. Joiner TE Jr, Brown JS, Wingate LR. The psychology and neurobiology of suicidal behavior. Annu Rev Psychol. 2005;56:287-314.

31. Ernst C, Mechawar N, Turecki G. Suicide neurobiology. Prog Neurobiol. 2009;89(4):315-333.

32. Centers for Disease Control and Prevention. Ten Leading Causes of Death and Injury. Available at https://www.cdc.gov/injury/wisqars/leadingcauses.html. Last accessed February 18, 2020.

33. Liu CH, Stevens C, Wong SHM, Yasui M, Chen JA. The prevalence and predictors of mental health diagnoses and suicide among U.S. college students: implications for addressing disparities in service use. Depress Anxiety. 2019;36(1):8-17.

34. Wilcox HC, Arria AM, Caldeira KM, et al. Prevalence and predictors of persistent suicide ideation, plans, and attempts during college. J Affect Disord. 2010;127(1-3):287-294.

35. Centers for Disease Control and Prevention. WONDER Databases. Available at https://wonder.cdc.gov. Last accessed February 22, 2020.

36. Halvorsen JA, Stern RS, Dalgard F, Thoresen M, Bjertness E, Lien L. Suicidal ideation, mental health problems, and social impairment are increased in adolescents with acne: a population-based study. J Invest Dermatol. 2011;131(2):363-370.

37. National LGBT Health Education Center. Suicide Risk and Prevention for LGBTQ People. Available at https://www.lgbthealtheducation.org/wp-content/uploads/2018/10/Suicide-Risk-and-Prevention-for-LGBTQ-Patients-Brief.pdf. Last accessed February 22, 2020.

38. National Center for Transgender Equality. The Report of the 2015 U.S. Transgender Survey. Available at https://www. transequality.org/sites/default/files/docs/USTS-Full-Report-FINAL.PDF. Last accessed February 22, 2020.

39. Hatzenbuehler ML. The social environment and suicide attempts in lesbian, gay, and bisexual youth. Pediatrics. 2011;127(5): 896-903.

40. Haas AP, Eliason M, Mays VM, et al. Suicide and suicide risk in lesbian, gay, bisexual, and transgender populations: review and recommendations. J Homosex. 2011;58(1):10-51.

41. Gates ML, Turney A, Ferguson E, Walker V, Staples-Horne M. Associations among substance use, mental health disorders, and self-harm in a prison population: examining group risk for suicide attempt. Int J Environ Res Public Health. 2017;14(3):317.

42. Mustanski B, Liu RT. A longitudinal study of predictors of suicide attempts among lesbian, gay, bisexual, and transgender youth. Arch Sex Behav. 2013;42(3):437-448.

43. Kann L, Olsen EO, McManus T, et al. Sexual identity, sex of sexual contacts, and health-related behaviors among students in grades 9–12—United States and selected sites, 2015. MMWR. 2016;65(9):1-202.

44. Fazel S, Ramesh T, Hawton K. Suicide in prisons: an international study of prevalence and contributory factors. Lancet Psychiatry. 2017;4(12):946-952.

45. American Psychiatric Association. New Research: Opiates May Be Playing an Increasing Role in Suicides, Even Outside of Overdoses. Available at https://www.psychiatry.org/newsroom/news-releases/new-research-opiates-may-be-playing-an-increasing-role-in-suicides-even-outside-of-overdoses. Last accessed February 25, 2020.

46. National Action Alliance for Suicide Prevention. Transforming Health Systems Initiative Work Group. Recommended Standard Care for People with Suicide Risk: Making Health Care Suicide Safe. Washington, DC: Education Development Center, Inc.; 2018.

47. Grant JM, Mottet LA, Tanis J, Harrison J, Herman JL, Keisling M. Injustice at Every Turn: A Report of the National Transgender Discrimination Survey. Available at https://www.transequality.org/sites/default/files/docs/resources/NTDS_Report.pdf. Last accessed February 22, 2020.

48. American Foundation for Suicide Prevention. Available at https://afsp.org. Last accessed February 25, 2020.

49. Schizophrenia and Related Disorders Alliance of America. About Schizophrenia. Available at https://sardaa.org/resources/about-schizophrenia. Last accessed February 25, 2020.

50. Fuller-Thomson E, Hollister B. Schizophrenia and suicide attempts: findings from a representative community-based Canadian sample. Schizophr Res Treatment. 2016;2016:3165243.

51. Plemmons G, Hall M, Doupnik S, et al. Hospitalization for suicide ideation or attempt: 2008–2015. Pediatrics. 2018;141(6):1-12.

52. Sundararman R, Panangala SV, Loster SA. CRS Report for Congress: Suicide Prevention Among Veterans. Available at https://www.fas.org/sgp/crs/misc/RL34471.pdf. Last accessed February 24, 2020.

53. Stanley B, Brown G, Brent DA, et al. Cognitive-behavioral therapy for suicide prevention (CBT-SP): treatment model, feasibility, and acceptability. J Am Acad Child Adolesc Psychiatry. 2009;48(10):1005-1013.

54. Cogan J. US Military Suicide Rates at Record High. Available at https://www.wsws.org/en/articles/2009/02/suic-f04.html. Last accessed February 22, 2020.

55. Ghahramanlou-Holloway M, Neely LL, Tucker J. A cognitive-behavioral strategy for preventing suicide. Curr Psychiatr. 2014; 13(8):18-25, 28.

56. Sher L. Suicide in war veterans: the role of comorbidity of PTSD and depression. Expert Rev Neurother. 2009;9:921-923.

57. McFarland BH, Kaplan MS, Huguet N. Datapoints: self-inflicted deaths among women with U.S. military service: a hidden epidemic? Psychiatr Serv. 2010;61(12):1177.

58. Rozanov V, Carli V. Suicide among war veterans. Int J Environ Res Public Health. 2012;9(7):2504-2519.

59. World Health Organization. Preventing Suicide: A Resource for General Physicians. https://www.who.int/mental_health/media/en/56.pdf. Last accessed February 22, 2020.

60. World Health Organization. Preventing Suicide: A Resource for Primary Health Care Workers. Geneva: World Health Organization Department of Mental Health; 2000.

61. Durkheim E. Suicide: A Study in Sociology. New York, NY: Free Press; 1951.

62. American Psychiatric Association. Practice Guideline for the Assessment and Treatment of Patients with Suicidal Behaviors. Washington, DC: American Psychiatric Association; 2010.

63. Gotlib IH, Hammen CL (eds). Handbook of Depression. 3rd ed. New York, NY: Guilford Press; 2015.

64. National Suicide Prevention Lifeline. Crisis Center Guidance: Follow-up with Callers and Those Discharged from Emergency Department and Inpatient Settings. Available at https://suicidepreventionlifeline.org/wp-content/uploads/2016/09/Lifeline-Follow-Up-Guidance1214.pdf. Last accessed February 25, 2020.

65. Office of Applied Studies. The OAS Report: Suicidal Thoughts, Suicide Attempts, Major Depressive Episode and Substance Use Among Adults. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2006.

66. Suicide Prevention Resource Center. Continuity of Care for Suicide Prevention: The Role of Emergency Departments. Available at http://www.sprc.org/sites/default/files/migrate/library/ContinuityCare_Suicide_Prevention_ED.pdf. Last accessed February 25, 2020.

67. Depression and Bipolar Support Alliance. Bipolar Disorder Statistics. Available at https://www.dbsalliance.org/education/bipolar-disorder/bipolar-disorder-statistics. Last accessed February 23, 2020.

68. Goldsmith SK, Pellmar TC, Kleinman AM, Bunney WE (eds). Reducing Suicide: A National Imperative. Washington, DC: National Academy Press; 2002.

69. Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2013.

70. Miranda J, Schoenbaum M, Sherbourne C, Duan N, Wells K. Effects of primary care depression treatment on minority patients' clinical status and employment. Arch Gen Psychiatry. 2004;61(8):827-834.

71. Mann JJ. Neurobiology of suicidal behavior. Nat Rev Neuroscienc. 2003;4(10):819-828.

72. World Health Organization. Preventing Suicide in Jails and Prisons. Available at https://www.who.int/mental_health/prevention/suicide/resource_jails_prisons.pdf. Last accessed February 24, 2020.

73. Tremblay CH, Grosskopf S, Yang K. Brainstorm: occupational choice, bipolar illness and creativity. Econ Human Biol. 2010;8(2): 233-241.

74. Liu A, Werner K, Roy S, et al. A case study of an emerging visual artist with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurocase. 2009;15(3):235-247.

75. Brown GK, Green KL. A review of evidence-based follow-up care for suicide prevention: where do we go from here? Am J Prev Med. 2014;47(3 Suppl 2):S209-S215.

76. Figueroa CG. Virginia Woolf as an example of a mental disorder and artistic creativity [article in Spanish]. Rev Med Chil. 2005; 133(11):1381-1388.

77. Annenberg Public Policy Center. Holiday-Suicide Link: The Myth Persists. Available at https://www.annenbergpublicpolicycenter.org/holiday-suicide-link-the-myth-persists. Last accessed February 24, 2020.

78. Centers for Disease Control and Prevention. Injury Prevention and Control: Data and Statistics. Available at https://www.cdc.gov/injury/wisqars/index.html. Last accessed February 24, 2020.

79. U.S. Department of Veterans Affairs. VA/DoD Clinical Practice Guideline for Assessment and Management of Patients at Risk for Suicide. Available at https://www.healthquality.va.gov/guidelines/MH/srb. Last accessed February 22, 2020.

80. Murphy GE. Suicide in Alcoholism. New York, NY: Oxford University Press; 1992.

81. Veterans Crisis Line. Available at https://www.veteranscrisisline.net. Last accessed February 25, 2020.

82. Selby EA, Anestis MD, Bender TW, et al. Overcoming the fear of lethal injury: evaluating suicidal behavior in the military through the lens of the Interpersonal-Psychological Theory of Suicide. Clin Psychol Rev. 2010; 30(3):298-307.

83. Boscarino JA. Posttraumatic stress disorder and mortality among U.S. Army veterans 30 years after military service. Ann Epidemiol. 2006;16(4):248-256.

84. Association of Suicidology. Know the Warning Signs of Suicide. Available at http://www.suicidology.org/resources/warning-signs. Last accessed February 24, 2020.

85. Favazza A. Self-mutilation. In: Jacobs DG (ed). The Harvard Medical School Guide to Suicide Assessment and Intervention. San Francisco, CA: Jossey-Bass; 1999: 125-145.

86. Evans J, Platts H, Liebenau A. Impulsiveness and deliberate self-harm: a comparison of "first-timers" and "repeaters." Acta Psychiatr Scand. 1996;93(5):378-380.

87. Stanford S, Jones MP. Psychological subtyping finds pathological, impulsive, and "normal" groups among adolescents who self-harm. J Child Psychol Psychiatry. 2009;50(7):807-815.

88. Najt P, Fusar-Poli P, Brambilla P. Co-occurring mental and substance abuse disorders: a review on the potential predictors and clinical outcomes. Psychiatry Res. 2011;186(2-3):159-164.

89. Gummin DD, Mowry JB, Spyker DA, et al. 2018 annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 36th annual report. Clin Toxicol (Phila). 2019;57(12):1220-1413.

90. Internet Mental Health Initiative. Schizophrenia Facts and Statistics. Available at http://www.schizophrenia.com/szfacts.htm. Last accessed February 25, 2020.

91. Kleespies PM (ed). Emergencies in Mental Health Practice: Evaluation and Management. New York, NY: Guilford Press; 2000.

92. U.S. Preventive Services Task Force. Screening for Suicide Risk in Primary Care: A Systematic Evidence Review for the U.S. Preventive Services Task Force: Evidence Synthesis, No. 103. Rockville, MD: Agency for Healthcare Research and Quality; 2013.

93. Canadian Task Force on Preventive Health Care. Recommendations on screening for depression in adults. CMAJ. 2013;185(9): 775-782.

94. Shain BN, Committee on Adolescents. Suicide and suicide attempts in adolescents. Pediatrics. 2007;120(3):669-676.

95. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with suicidal behavior. J Am Acad Child Adolesc Psychiatry. 2001;40(7 suppl):24S-51S.

96. American Medical Association. Guidelines for Adolescent Preventive Services (GAPS): Recommendations Monograph. 3rd ed. Chicago, IL: American Medical Association; 1996.

97. Lewitzka U, Severus E, Bauer R, Ritter P, Müller-Oerlinghausen B, Bauer M. The suicide prevention effect of lithium: more than 20 years of evidence-a narrative review. Int J Bipolar Disord. 2015;3(1):32.

98. Tondo L, Baldessarini RJ. Long-term lithium treatment in the prevention of suicidal behavior in bipolar disorder patients. Epidemiol Psychiatr Soc. 2009;18(3):179-183.

99. Asenjo Lobos C, Komossa K, Rummel-Kluge C, et al. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010;(11):CD006633.

100. Kasckow J, Felmet K, Zisook S. Managing suicide risk in patients with schizophrenia. CNS Drugs. 2011;25(2):129-143.

101. Riesselman A, Johnson E, Palmer E. Lithium and clozapine in suicidality: shedding some light to get out of the dark. Ment Health Clin. 2015;5(5):237-243.

102. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646.

103. Rihmer Z, Gonda X. The effect of pharmacotherapy on suicide rates in bipolar patients. CNS Neurosci Ther. 2012;18(3):238-242.

104. Underwood MD, Kassir SA, Bakalian MJ, Galfalvy H, Mann JJ, Arango V. Neuron density and serotonin receptor binding in prefrontal cortex in suicide. Int J Neuropsychopharmacol. 2012;15(4):435-447.

105. Oquendo MA, Russob SA, Underwood MD, et al. Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide. Biol Psychiatry. 2006;59(3):235-243.

106. Wasserman D, Wasserman C. Oxford Textbook of Suicidology and Suicide Prevention: A Global Perspective. Oxford: Oxford University Press; 2009.

107. Suicide Prevention Resource Center, SPAN USA. Charting the Future of Suicide Prevention: A 2010 Progress Review of the National Strategy and Recommendations for the Decade Ahead. Washington, DC: Education Development Center, Inc.; 2010.

108. Brent DA, Johnson BA, Perper J, et al. Personality disorder, personality traits, impulsive violence, and completed suicide in adolescents. J Am Acad Child Adolesc Psychiatry. 1994;33(8):1080-1086.

109. Hunt J, Eisenberg D. Mental health problems and help-seeking behavior among college students. J Adolesc Health. 2010;46(1):3-10.

110. Pompili M, Lester D, Innamorati M, et al. Preventing suicide in jails and prisons: suggestions from experience with psychiatric inpatients. J Forensic Sci. 2009;54(5):1155-1162.

111. Substance Abuse and Mental Health Services Administration. The Treatment of Depression in Older Adults: Depression and Older Adults: Key Issues. Rockville, MD: Center for Mental Health Services, Substance Abuse and Mental Health Services Administration, US Department of Health and Human Services; 2011.

112. Fischer LR, Wei F, Solberg LI, Rush WA, Heinrich RL. Treatment of elderly and other adult patients for depression in primary care. J Am Geriatr Soc. 2003;51(11):1554-1562.

113. Mitchell AJ, Rao S, Vaze A. Do primary care physicians have particular difficulty identifying late-life depression? A meta-analysis stratified by age. Psychother Psychosom. 2010;79(5):285-94.

114. Law J, Laidlaw K, Peck D. Is depression viewed as an inevitable consequence of age? The "understandability phenomenon" in older people. Clinical Gerontologist. 2010;33(3):194-209.

115. Tiesman H, Weissman D, Stone D, Quinlan K, Chosewood LC. Suicide Prevention for Healthcare Workers. Available at https://blogs.cdc.gov/niosh-science-blog/2021/09/17/suicide-prevention-hcw. Last accessed June 2, 2022.

116. Dutheil F, Aubert C, Pereira B, Dambrun M, Moustafa F, Mermillod M, et al. Suicide among physicians and health-care workers: a systematic review and meta-analysis. PLoS ONE. 2019;14(12):e0226361.

117. Kelsey EA, West CP, Cipriano PF, et al. Original research: suicidal ideation and attitudes toward help seeking in U.S. nurses relative to the general working population. Am J Nurs. 2021;121(11):24-36.

118. Stamm BH, Figley CR. Advances in the theory of compassion satisfaction and fatigue and its measurement with the ProQOL 5. Presented at the International Society for Traumatic Stress Studies Annual Conference. Atlanta, GA; 2009.

119. Davidson JE, Zisook S, Kirby B, DeMichele G, Norcross W. Suicide prevention: a healer education and referral program for nurses. J Nurs Adm. 2018;48(2):85-92.

120. American Nurses Association. Nurse Suicide Prevention/Resilience. Available at https://www.nursingworld.org/practice-policy/nurse-suicide-prevention. Last accessed June 2, 2022.

121. Bernert RA, Roberts LW. Suicide risk: ethical considerations in the assessment and management of suicide risk. Focus. 2012;10(4):467-472.

Evidence-Based Practice Recommendations Citations

1. Adelson SL, American Academy of Child and Adolescent Psychiatry Committee on Quality Issues. Practice parameter on gay, lesbian, or bisexual sexual orientation, gender nonconformity, and gender discordance in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2012;51(9):957-974. Available at https://jaacap.org/article/S0890-8567(12)00500-X/fulltext. Last accessed March 30, 2020.

2. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Arlington, VA: American Psychiatric Association; 2010. Available at https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Last accessed March 30, 2020.

3. Assessment and Management of Risk for Suicide Working Group. VA/DoD Clinical Practice Guideline for Assessment and Management of Patients at Risk for Suicide. Washington, DC: Department of Veterans Affairs, Department of Defense; 2019. Available at https://www.healthquality.va.gov/guidelines/MH/srb/. Last accessed March 30, 2020.