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.
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.
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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.
Upon completion of this course, you should be able to:
- Discuss the prevalence and definition of coronary heart disease (CHD) and acute coronary syndrome (ACS).
- Explain the pathophysiology of ACS, including the role of plaque formation and rupture.
- Discuss screening and evaluation of asymptomatic individuals for ACS.
- Describe the various clinical presentations of ACS and the differential diagnosis of chest pain, including considerations for non-English-proficient patients.
- Describe the role of 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).
- Discuss the factors involved in risk stratification of individuals with suspected ACS.
- Outline the adherence to guidelines for the acute treatment of UA/NSTEMI.
- List the optimal anti-ischemic, antiplatelet, and anticoagulant agents for the treatment of UA/NSTEMI.
- Distinguish between the clinical indications for an ischemia-guided or invasive strategy for patients with UA/NSTEMI.
- Discuss the issue of timing in selecting reperfusion therapy for patients with STEMI.
- Describe the role of percutaneous coronary intervention (PCI) for STEMI.
- Identify contraindications and cautions for fibrinolysis in the treatment of STEMI.
- List other reperfusion therapies used in the treatment of STEMI, and identify the appropriate therapy for individual patients.
- Outline appropriate secondary prevention measures for patients with ACS.
- Discuss the relationship between guideline adherence in practice and patient outcomes.
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.
Contributing faculty, Lori L. Alexander, MTPW, ELS, MWC, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
John M. Leonard, MD
John V. Jurica, MD, MPH
The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
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#40941: Acute Coronary Syndrome
Coronary heart disease (CHD), which encompasses angina pectoris (stable angina), coronary insufficiency (unstable angina or UA), and myocardial infarction (MI) affects nearly 27% of men and 16% of women 20 years and older in the United States . CHD is the leading cause of death in the United States, accounting for 24% of all deaths . 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 .
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). More than 1.1 million hospitalizations in 2010 were associated with a primary or secondary discharge diagnosis of ACS . As with CHD, the financial cost associated with ACS is high; the mean cost for the first ACS admission is more than $71,000 .
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 [4,5,6]. 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 [4,5,7,8]. 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 [9,10,11,12]. 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 [9,13,14,15,16,17,18,19,20]. 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 . 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 [21,22,23,24]. 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) [25,26]. Data from these initiatives have shown that adherence to guidelines enhances outcomes [9,27,28].
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.
SOURCES OF DATA ON CORONARY ARTERY DISEASE AND ACUTE CORONARY SYNDROME (ACS)
|Community Surveillance Programs|
|1948 to present||
|Identify common factors or characteristics contributing to cardiovascular disease by following its development over a long period of time|
|1987–1989 to present||
|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|
|1989 through 1999||
|Observe risk factors for cardiovascular disease in individuals 65 years of age or older|
|National Registry of Myocardial Infarction (NRMI) 1-4||1990–2006||2.2 million men and women with acute MI||Tracked the characteristics, treatment, and outcomes for patients with acute myocardial infarction (MI) (largest observational registry of ACS)|
|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 (including the United States)|
|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|
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.
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" . 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.
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) . 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 .
UA is closely related to NSTEMI, and the two entities are often indistinguishable from each other, especially during the initial evaluation of a patient . 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" . 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 . In contrast, STEMI is associated with myocardial damage, with both elevated serum cardiac biomarker levels and persistent ST-segment elevation on ECG .
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 . 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 :
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" . 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 (eg, coronary artery spasm, arrhythmias); or sudden cardiac death .
The overall prevalence of CHD among adults is 6.2%, with a higher prevalence among men compared with women (7.6% vs. 5.0%) . The prevalence increases with age, with the highest rates found among people 80 years and older (Figure 1) . Women tend to be older than men at the time of a first cardiac event [16,33,34].
The prevalence of CHD, MI, and angina vary considerably according to gender and race/ethnicity. For CHD, the rate is highest for white men (7.8%) and lowest for white women (4.6%); similarly, the prevalence of MI is highest for white men (4.1%) and lowest for Hispanic and white women (1.7% and 1.8%, respectively) (Table 2) . The prevalence of angina is highest for black women (5.0%) and lowest for white women (2.9%) .
ACS is also more prevalent among men; 653,000 of the more than 1.4 million unique hospitalizations for ACS (as a primary or secondary discharge diagnosis) occurred among men, compared with 488,000 among women . Of all of these unique hospitalizations, 813,000 were for MI alone, 322,000 were for UA alone, and 6,000 were for both . 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 . In addition, approximately 5% were of Hispanic or Latino ethnicity .
The incidence of STEMI has decreased since 2003, while the incidence of NSTEMI has increased . STEMI continues to be less prevalent than NSTEMI, accounting for 29% to 47% of MIs documented in various registries . 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 . 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) .
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|
|AI = American Indian, AN = Alaskan Native, PI = Pacific Islander.|
As noted, CHD-related mortality rates continue to decrease; the annual rate decreased 39% from 2001 to 2011, and the actual number of deaths decreased approximately 25% during that time . 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 (24.9% vs 23.5%) . CHD-related mortality increases with age, with CHD accounting for 21% of all deaths among people 45-64 years old, approximately 27% of all deaths among people 65 years and over, and approximately 31% of all deaths among people 85 years and older .
With regard to race, CHD is the leading cause of death in the white and black populations, and the second leading cause of death in the American Indian/Alaska Native and Asian/Pacific Islander populations (Table 4) . 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.
CORONARY HEART DISEASE (CHD) AS A PERCENTAGE OF ALL DEATHS ACCORDING TO RACE AND ETHNICITY
|Racial/Ethnic Population||CHD as Percentage of All Deaths|
|American Indian/Alaska Native||17.9%|
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 [35,36]. 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) . At 1 year, however, the risk of mortality is similar for STEMI and NSTEMI .
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 . Plaque erosion is another primary cause of ACS . The mechanisms underlying plaque erosion are not as well understood as those for plaque rupture, but inflammation plays a central role in both [38,39,40].
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 .
The gradual process of atherosclerosis usually causes no symptoms over the course of many years, with most plaques causing no symptoms . 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 . 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 [42,43,44,45]. A simpler classification, based on morphologic characteristics, was later introduced . 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 . Pathologic intimal thickening or a thick-cap fibroatheroma is usually involved in plaque erosion . Erosion is often the cause of thrombosis in young patients, particularly women younger than 50 years of age [33,40]. The least often cause of thrombosis is a calcified nodule, which is usually found in older patients with substantially calcified and tortious arteries .
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 . Vulnerable plaque has the following hallmark characteristics [38,48]:
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
Because of its high lipid content, vulnerable plaque is associated with the progressive development of ischemic disease . 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 . 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 . 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 . 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 . In one study, the thrombus was days or weeks old in 49% of patients with STEMI . 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 [50,51,52]. 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 .
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 . Plaque rupture in combination with large plaque burden and luminal narrowing appears to lead to ACS . Lipid-rich plaque and intracoronary thrombus have been found significantly less often in patients with asymptomatic CHD compared with patients with NSTEMI .
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 . 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 . 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 [57,58].
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.
The Framingham Heart Study identified the first risk factors, and these factors were integrated into a risk-assessment tool, the Framingham Risk Score . 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) . The use of one of these risk calculators is a class IB recommendation from the American College of Cardiology Foundation and American Heart Association . 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 . 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) . These equations were developed on the basis of data on participants from several large racially and geographically diverse studies . 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) .
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 [63,64,65].
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) [60,62]. 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.
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||
|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)|
|Testing for microalbuminuria||
|Lipoprotein-associated phospholipase A2||Might be reasonable for asymptomatic adults at intermediate risk (IIbB)|
|Resting electrocardiography (ECG)||
|Transthoracic echocardiography (to detect left ventricular hypertrophy)||
|Measurement of carotid intima-media thickness||
|Brachial/peripheral flow-mediated dilation||Not recommended (IIIB)|
|Measurement of arterial stiffness||Not recommended outside of research settings (IIIC)|
|Measurement of ankle-brachial index||
|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||
|Coronary artery calcium scoring||
|Coronary computed tomography angiography||Not recommended for asymptomatic adults (IIIC)|
|Magnetic resonance imaging of plaque||Not recommended for asymptomatic adults (IIIC)|
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 [60,66]. The ACCF/AHA guideline does not recommend a CRP level for asymptomatic adults at high risk . One study suggested improved 10-year risk prediction when a CRP or fibrinogen level was added to a traditional risk score . 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 .
The USPSTF found no evidence that homocysteine levels or leukocyte counts were useful in further stratifying risk among individuals at intermediate risk .
The 2010 ACCF/AHA guideline for assessment of cardiovascular risk does not recommend assessment of lipoprotein or apolipoprotein levels . Measurement of a lipoprotein-associated phospholipase A2 level "might be reasonable" for asymptomatic adults at intermediate risk . 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 . However, the 2013 ACCF/AHA guideline notes that the contribution of apolipoprotein B is uncertain .
According to the 2010 ACCF/AHA guideline, natriuretic peptide levels are not recommended for the evaluation of risk among asymptomatic adults . A hemoglobin A1C "may be reasonable" for assessing risk in asymptomatic adults without diabetes and "may be considered" for asymptomatic adults with diabetes . 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 . However, in its 2013 guideline, the ACCF/AHA expert panel notes that the contribution of albuminuria is uncertain .
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 [70,71]. 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%) . 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 . 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 [73,74]. 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 .
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 . 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 [60,62]. The 2010 ACCF/AHA guideline does not recommend measurement of flow-mediated dilation or arterial stiffness as part of risk assessment . 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 [73,74]. Magnetic resonance imaging of plaque is not recommended .
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 [60,75,76,77]. 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 [60,77].
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 [60,76]. 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 [60,76].
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 report from the Eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC8) sets goals for systolic and diastolic blood pressure and provides evidence-based recommendations on treatment approaches . One study showed that fewer adults in the United States would need antihypertension treatment according to these recommendations, compared with the JNC7 recommendations, while another study indicated that more cardiology patients with hypertension would be treated [79,80]. Differences in treatment and target blood pressures, especially among older individuals (60 to 79 years of age) exist between the JNC8 guideline and guidelines from the American Society of Hypertension and the International Society of Hypertension . 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 . A study to evaluate the cost-effectiveness of treating hypertension according to the 2014 guidelines indicated that approximately 56,000 fewer cardiovascular events and 13,000 fewer deaths would occur each year, with overall cost savings .
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 [24,84,85,86]. 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 . 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 . 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 . 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/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 [90,91]. The AHA/ACC also published a guideline on lifestyle management to reduce cardiovascular risk in 2013 . In its guideline of cardiac screening, the ACP notes that strategies to improvement lifestyle behaviors should be emphasized . 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 [93,94,95].
Another aspect of prevention that warrants increased attention is the role of complementary and alternative medicine. Approximately 40% 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 . The USPSTF recommends against vitamin E supplements and ß-carotene for the prevention of cardiovascular disease .
Adherence to guidelines for management of CHD risk and to prevent cardiovascular disease has been suboptimal, especially among patients at low risk for disease [21,22,104]. Clinicians have noted several barriers to adhering to CHD prevention guidelines, including [21,22]:
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.
Chest pain is the second most common reason for seeking care in the emergency department, accounting for approximately 9% of visits . 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 . As a result, fewer than 10% of patients who are evaluated for chest pain are ultimately found to have ACS .
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) . 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
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 [4,5]. 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 . 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) . 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 [4,5]. 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 [29,111,112]. 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 .
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 [4,5].
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 .
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 40.3 million Americans are foreign-born, and more than 25 million Americans say they speak English less than "very well" . 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 .
Many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care [116,117]. 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 [116,118]. Despite these findings, professional interpreters are underused in healthcare settings, including the emergency department .
"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 . 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 . In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members .
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 [13,120]. Despite this fact, up to one-third of patients with ACS have no chest pain or discomfort [120,121]. 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) [5,122]. When discussing chest pain with the patient, the clinician should focus on several aspects of the pain or discomfort, including :
Characteristics (i.e., severity, location, radiation)
Time of onset
Alleviating and exacerbating factors
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 . Chest pain related to ACS usually begins abruptly and lasts at least 15 to 20 minutes; however, the duration of pain varies among patients [123,124]. The intensity of classic ACS chest pain increases over time, reaching maximal intensity after a few minutes . Pain is usually worse with activity and improves with rest.
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 . 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 . 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 . 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 .
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 [5,125].
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 [13,120,128,129,130,131,132]. 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 [128,133,134].
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 . In one study, nitroglycerin relieved chest pain in 35% of patients with ACS and 41% of patients without ACS . 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 [5,126].
The classic presentation of ACS includes some symptoms in addition to chest pain, primarily dyspnea, diaphoresis, nausea, abdominal pain, or syncope [4,5]. 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 . Diaphoresis occurs more often in men with ACS compared with women . 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 [128,129,133,134,135,136]. Among older individuals, dyspnea and fatigue have been noted to be the most common symptoms and diaphoresis has been reported less often [13,125,126].
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 . 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 [25,123,133]. (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 [25,128,137]. According to data from the NCDR, the prevalence of risk factors varies across racial/ethnic subgroups of individuals with ACS (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|
|Family history of CHD||42%||38%||37%||42%||28%|
|ACS = acute coronary syndrome; CHD = coronary heart disease.|
The five most important history-related factors that relate to the likelihood of ischemia due to CHD are (in order of importance) :
Nature of the chest pain
History of CHD
Number of traditional risk factors
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 [4,5]. Ruling out a noncardiac cause of chest pain is especially important given the severity of some potential conditions [5,122].
The physical examination should include the following :
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
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 . 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) . Cardiogenic shock is associated more often with STEMI than NSTEMI, and mortality rates are high . 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 3 months .
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 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 . 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 . An emergency physician experienced in reading ECGs or a cardiologist should interpret the findings, especially when STEMI is suspected . 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 . 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 .
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 [4,5]. 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 . A 12-lead ECG performed by EMS personnel is recommended for patients who have symptoms consistent with STEMI .
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 . 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 . 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 . 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 .
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 .
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 . 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 [140,141]. Delay in obtaining the first ECG has been associated with female gender and older age [13,25,142]. This delay may be related to the high rate of atypical presentation of ACS in these populations [13,143]. Increasing the number of nurses or ECG technicians during peak hours and training additional staff to perform ECGs may help to improve timeliness [29,144].
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 [4,5,32]. Measurement of CK-MB or myoglobin levels was not useful or cost-effective .
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) [5,146]. Levels may remain elevated for 5 to 10 days (troponin I) or up to 14 days (troponin T) after an MI . Although the greatest advantage of troponin over earlier biomarkers is their high sensitivity and specificity, their sensitivity is low during the first 6 hours after the onset of symptoms . For most patients, in whom ACS is suspected, an MI can be ruled out or confirmed within 6 hours because of the high rate of delayed presentation associated with chest pain .
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 . 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 . The ACC/AHA guideline for UA/NSTEMI states that troponin levels should be measured at the time of presentation and 3 to 6 hours after the onset of symptoms in all patients suspected of having ACS . 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 6 hours . 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 . 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 .
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) [5,149,150].
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 . 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 [4,5]. 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 6-month mortality for all patients with ACS [4,5].
The TIMI risk score is based on seven independent risk factors :
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 7 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 . 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 . The TIMI risk calculator can be accessed online at http://www.timi.org.
The GRACE risk model includes eight variables :
Systolic blood pressure
Cardiac arrest during presentation
Serum creatinine level
Elevated cardiac biomarkers
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 . As with the TIMI score, patients with a higher score gain greater benefit from an invasive strategy . The GRACE risk tool is also available online (www.outcomes-umassmed.org/grace/).
Clinical features, ECG findings, and troponin levels 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 . In addition, elevated troponin levels have been associated with an estimation of infarct size and the risk of death . 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) . Isolated T-wave inversion or normal ECG findings were associated with intermediate and low risk, respectively . In another study, the incidence of death or MI at 1 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%) .
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 . 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 [155,156]. Another risk stratification tool, the HEART score (consisting of history, ECG findings, age, risk factors, and troponin levels) has been validated in the Netherlands . The HEART score has been shown to identify patients at low risk for ACS and major adverse cardiac events . 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 .
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 :
Observe in a chest pain unit or telemetry unit and perform serial ECGs and cardiac troponin levels at intervals of 3 and 6 hours (class IIaB)
Order a treadmill ECG (IIaA), stress myocardial perfusion imaging, or stress echocardiography (IIaB) before discharge or with 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 . 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 . 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.
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 :
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
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 . 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 .
The goal of immediate treatment for patients with UA/NSTEMI is to provide relief of ischemia and to prevent recurrent adverse ischemic events . This goal is initially achieved through anti-ischemic, antiplatelet, and anticoagulant therapies (Table 8).
ADJUNCTIVE TREATMENT INDICATIONS FOR PATIENTS WITH UA/NSTEMI OR STEMI
|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)||
|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)||
|Calcium-channel blocker||Patients with continued or recurrent ischemia or with contraindications to beta blockers (class IB)||No recommendation||––|
|Aspirin (non-enteric coated, chewable)||
|Loading dose not recommended for older (>75 years of age) patients with STEMI. Should be withheld for 5 days in patients to have CABG (class IB). Monitor closely when used in conjunction with warfarin.|
|Ticagrelor||All patients undergoing PCI with stenting should be given a loading dose and at least 1 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 1 year of maintenance therapy with this or other P2Y inhibitor if not given clopidogrel (class IB).||
|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)||
|Unfractionated heparin (UFH)||
|Option for patients selected for primary PCI (class IC) or fibrinolytic therapy (class IC); administer for at least 48 hrs or until revascularization||
|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 8 days or until revascularization||
|Bivalirudin||Option for patients selected for early invasive treatment (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)||
|ACE = angiotensin-converting enzyme; CABG = coronary artery bypass graft; CKD = chronic kidney disease; HF = heart failure; PCI = percutaneous coronary intervention.|
SIZE OF TREATMENT EFFECT FOR RECOMMENDED INTERVENTIONS
|Class||Predicted Treatment Effect|
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 .
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 5 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 . 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 . Nitroglycerine (and all nitrates) are contraindicated when a phosphodiesterase inhibitor has been used recently . Nitrates are used with caution in patients with right ventricular infarction.
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 . 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.
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 . This use of beta blocker therapy has been associated with significantly lower in-hospital mortality . 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) [10,140]. 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 . 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) [14,160].
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 . 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 :
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 . 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 . 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 nifidipine is not recommended for routine use because of a dose-related increase in mortality .
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 . 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 [5,161,162]. ARBs have been shown to be noninferior to ACE inhibitors in the prevention of clinical endpoints, including MI and stroke, in high-risk patients .
The rate of ACE inhibitor use has been reported to be approximately 77% among patients with UA/NSTEMI . Use has been lower among older individuals and women, especially women younger than 55 years of age (compared with men of the same age) [14,160].
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 . One is ranolazine, an antianginal agent that is indicated for the treatment of chronic angina. The drug has been found to reduce recurrent ischemia in the ACS setting [164,165]. 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 .
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 . 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 . 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 .
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 . Antiplatelet therapy reduces platelet formation and aggregation, integral components in the formation of a thrombus after plaque disruption.
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 . However, adherence by emergency medical personnel to guidelines recommending prompt prehospital aspirin administration is only 45% . 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 . 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% [10,141]. Rates of asprin use have been reported to be lower for older individuals and women, especially women younger than 55 years of age [14,160].
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 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) . 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 . 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 .
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%) . 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 .
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%) . 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 .
Ticagrelor, the first in a new class of antiplatelets known as cyclopentyl-triazolo-pyrimidines, was approved by the FDA in 2011 . 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 .
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 . 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%) . 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 . 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 mg to 100 mg .
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% . Rates of use have been lower among women . 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 .
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 .
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 6 months, compared with placebo or usual care . 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 . 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 . Eptifibatide and tirofiban are the preferred inhibitors (class IIb, B) .
The recommended use of glycoprotein IIb/IIIa inhibitors is suboptimal in two ways. First, guideline-recommended use is low, especially among women [16,175,176]. 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% [177,178]. 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 . Excess dosing was more likely among older individuals, women, and patients with renal insufficiency, diabetes mellitus, heart failure, or low body weight . Increased risk of major bleeding and mortality were associated with an excess dose.
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) .
The anticoagulants used in the UA/NSTEMI setting are enoxaparin, bivalirudin, fondaprinux, and unfractionated heparin .
Enoxaparin is a low-molecular-weight heparin that offers many pharmacologic advantages compared with unfractionated heparin :
More predictable anticoagulant effect
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 1 year among patients with UA . 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 [181,182].
The ACC/AHA guideline recommends enoxaparin as an option for all patients with NSTE-ACS . 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 . 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 [179,183]. A higher dose was significantly associated with major bleeding and death . The patients who received excess doses were more likely to be older, smaller, and female [179,183].
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 . Bivalirudin alone was also noninferior to heparin plus a glycoprotein IIb/IIIa inhibitor, but it offered a significant benefit in terms of major bleeding . At 1 year, there was no significant difference in the composite endpoint among the three groups .
The ACC/AHA guideline recommends bivalirudin only for patients who are to have an early invasive strategy . 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 .
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 [186,187,188]. The ACC/AHA guideline recommends fondaparinux, 2.5 mg subcutaneously daily, for the duration of hospitalization or until PCI is done . When fondaparinux is used alone in this setting, an additional anticoagulant with anti-IIa activity should be given to help prevent catheter thrombosis .
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 . 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 . 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 . A weight-adjusted dose is preferred to a fixed initial dose, as anticoagulation is more predictable with such dosing . 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 aPTT range .
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 . The procedure is typically done within 24 hours (early invasive) or 25 to 72 hours (delayed invasive) . The optimal timing of angiography has not been established . 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) .
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 2 hours)||
|Early invasive (within 24 hours)||
|Delayed invasive (within 25–72 hours)||
|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.|
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 [17,190,191]. However, a meta-analysis found insufficient evidence to support either approach as having a survival benefit for patients with NSTE-ACS . 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 . An early invasive strategy is recommended for patients with NSTE-ACS who are initially stabilized and at elevated risk for clinical events . 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).
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) . 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) . 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) . 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 .
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 [177,194,195]. 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 [9,13,138,191,194,196].
The benefit of an early invasive strategy for women is unclear [17,191]. 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 [23,197]. 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 .
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 . 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 .
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 . 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 . 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 [200,201]. CABG is also recommended for patients with left ventricular systolic dysfunction .
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 [4,202]. The reported mortality rates are approximately 5% to 6% (in-hospital) and 7% to 18% (1-year) . Morbidity includes heart failure, pulmonary edema, reinfarction, cardiogenic shock, and stroke, and rates of these events have also declined significantly .
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 . 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 [4,203].
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 . In addition, PCI is the preferred strategy for reperfusion because of its superior outcomes compared with fibrinolytic therapy [4,204]. However, gaining the optimal benefit from PCI depends on many factors, and timing is the most important variable in selecting a reperfusion therapy [4,203]. Care should also be taken to evaluate patients for contraindications to fibrinolytic therapy .
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 . 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 . Low-risk patients who have had successful PCI may be admitted directly to a stepdown unit.
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.
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 . PCI should be done within less than 90 minutes after the patient's first medical contact (door-to-device time) . 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 . In addition, the median door-to-balloon or door-to-device time declined from 96 minutes in 2005 to 64 minutes in 2010 .
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 .
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 :
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.
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 . (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 . However, no net clinical benefit has been found with this strategy, and it is not recommended . 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 .
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 [204,206,207]. 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 . 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%) .
Class I indications for primary PCI include the following :
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) .
The use of coronary stents during PCI reduces the rates of adverse events such as reocclusion, restenosis, and target-vessel revascularization [7,204,206]. 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 [208,209]. 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 .
The complications of primary PCI include adverse reactions to the contrast medium, volume loading, difficulty with arterial access, and technical complications . Reperfusion injury and hemorrhagic transformation of a bland infarction and hemorrhagic stroke are rare after primary PCI .
Primary PCI is supported by antiplatelet and antithrombin therapy. Class I recommendations for this therapy in patients with STEMI include the following :
Aspirin (level B)
P2Y12 inhibitors (level A)
Unfractionated heparin (level C)
Bivalirudin (level B)
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 . 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) . 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 . 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 . 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 1-year clinical outcomes in patients with STEMI who undergo primary PCI . No benefit is derived from increasing the loading dose to 900 mg compared with 600 mg . The guideline acknowledges that the safety and efficacy of pretreatment with clopidogrel remains controversial .
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 . 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 .
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 . 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) . The precise timing of administration has not been defined. Treatment with tirofiban or eptifibatide may also be considered at the time of primary PCI .
With regard to anticoagulant therapy, unfractionated heparin is recommended but should not be given to patients already receiving therapeutic enoxaparin (subcutaneously) (class III: harm) . Bivalirudin is also a recommended anticoagulant, with or without previous treatment with unfractionated heparin (class IB) . 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) . An additional anticoagulant with anti-Ha activity should be used because of the risk of catheter thrombosis.
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 . Reperfusion within 30 minutes to 2 hours can salvage myocardial tissue substantially, and fibrinolytic therapy administered within this timeframe has reduced mortality .
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 .
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 . 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 .
Four fibrinolytic agents have been evaluated and approved in the STEMI setting: tenecteplase, reteplase, alteplase (tPA), and streptokinase (Table 10) . Of these agents, only streptokinase is non-fibrin-specific, and a fibrin-specific agent is preferred . 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 in the United States because it is not fibrin-specific and has been shown to be less effective than the other three drugs .
COMPARISON OF FIBRINOLYTIC AGENTS FOR TREATMENT OF STEMI
|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|
|Patency ratea||60% to 68%||73% to 84%||84%||85%|
|Fibrin specificityb||No||Yes (++)||Yes (++)||Yes (++++)|
Alteplase is inconvenient to administer, as it must be given as an initial intravenous bolus over 30 minutes followed by 60 minutes of infusion [4,213]. 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 [214,215,216]. TIMI 3 flow at 90 minutes has been similar for tenecteplase and alteplase . The use of alteplase has thus declined because of the availability of these more convenient drugs with similar or improved outcomes .
The most common complication of fibrinolytic therapy is major bleeding, which occurs in approximately 5% to 6% of patients . Adverse outcomes after fibrinolytic therapy are generally more common among women and older patients [218,219]. Many instances of bleeding can be traced to incorrect dosing, particularly with weight-based agents . 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 . Rescue PCI is the preferred strategy for failed fibrinolytic therapy, as it has been shown to offer benefit when compared with repeat fibrinolytic therapy [220,221].
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 3 months, suspected aortic dissection, or active bleeding (Table 11) . Relative contraindications include history of poorly controlled hypertension, recent internal bleeding, and oral anticoagulant therapy .
CONTRAINDICATIONS AND CAUTIONS FOR FIBRINOLYSIS USE IN ST-ELEVATION MYOCARDIAL INFARCTION (STEMI)a
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 reocclusion .
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 1 year) to be added to aspirin for patients with STEMI, regardless of whether reperfusion with fibrinolytic therapy has been initiated . 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 .
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 .
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 [222,223].
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 . Unfractionated heparin, enoxaparin, and fondaparinux are the recommended anticoagulant agents based on studies demonstrating their efficacy . 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 . Anticoagulation should be continued for the duration of the index hospitalization (up to 8 days) or until revascularization. Enoxaparin is recommended over unfractionated heparin when anticoagulant therapy will extend beyond 48 hours .
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 . Researchers reviewed data on 20,479 patients to compare outcomes for unfractionated heparin and enoxaparin . Significantly fewer patients in the enoxaparin group had subsequent PCI within 30 days after fibrinolytic therapy . There were no differences between the two agents with respect to major bleeding.
Fondaparinux may also provide benefit for patients who receive fibrinolytic therapy . In one trial, 12,092 patients with STEMI were randomly assigned to fondaparinux (2.5 mg once daily for up to 8 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 . 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 .
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" [202,203,227,228]. 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 . 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 [203,229,230]. Another study found that 45% of eligible patients with diabetes on dialysis were not treated with reperfusion (i.e., mistakenly considered ineligible) . 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) [227,228,229,231].
IN-HOSPITAL MORTALITY RATES FOR PATIENTS WITH ST-ELEVATION MYOCARDIAL INFARCTION (STEMI) BASED ON REPERFUSION THERAPY STATUS
|TIMI 9 (1994)||18.9%||10.5%/7.6%a|
|Older patients (>65 years of age)||18.9%||10.5%|
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 . 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 . The 2013 guideline for STEMI does not include a specific recommendation for the treatment of patients who do not receive reperfusion therapy . 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 .
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) [4,8].
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) . 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 . In addition, there is an increased risk of bleeding associated with clopidogrel and prasugrel given within 5 to 7 days before CABG . Thus, when CABG is planned, clopidogrel should be withheld for at least 5 days (7 days for prasugrel) unless the urgency for the procedure outweighs the increased risk for bleeding [4,8]. The use of CABG should follow the ACC/AHA guideline for this procedure .
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 . 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 . On the other hand, deferring exercise testing until 3 weeks after discharge in clinically low-risk patients appears to be safe and reasonable . 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 . The use of exercise testing and the interpretation of its results should follow the guideline developed for this modality .
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 . 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 . Echocardiography and stress echocardiography should be performed according to guidelines or criteria developed for their use .
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 .
The 2013 ACCF/AHA guideline for the management of STEMI recommends aspirin at a dose of 162 to 325 mg as a loading dose before either PCI or fibrinolytic therapy . 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 . Treatment with a P2Y12 inhibitor is continued for 1 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 . Treatment with clopidogrel is continued for at least 14 days and up to 1 year.
The benefit of nitroglycerin for patients with STEMI has been modest, but the drug can be given sublingually (0.4 mg every 5 minutes up to three doses) for persistent or recurrent ischemic discomfort . 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 . 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 .
The use of beta blockers has been an established recommendation for patients with STEMI because of the drugs' association with lower mortality . 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 . 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 . 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.
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 . Adherence to this recommendation has increased since the late 1990s but remains low [177,235,236]. In addition, the doses used in clinical practice have been lower than the target doses used in clinical trials .
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% . Early treatment is optimal, as reductions in mortality have been greatest within the first 5 days after the MI [237,238]. The ACCF/AHA guideline for STEMI notes that it is preferable to initiate treatment with an ACE inhibitor within 24 hours . 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 . 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 .
Early treatment with dihydropyridine calcium antagonists (nifedipine and nicardipine) has not been found to improve rates of mortality or reinfarction . 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 [4,5]. Both drugs have been associated with significantly reduced mortality and major cardiovascular events [240,241]. Verapamil should not be used for patients with heart failure or bradyarrhythmias, and diltiazem should not be used for patients with left ventricular dysfunction .
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 . 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 [4,5]:
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
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 [242,243]. Referral to a cardiac rehabilitation or secondary prevention program is a recommendation in the ACC/AHA guidelines for NSTE-ACS and STEMI [4,5].
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.
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 [4,244]. Clinicians should involve other healthcare professionals in helping patients to achieve goals and should reinforce patients' positive efforts toward reaching these goals.
Quitting smoking has been described as "probably the most important thing a smoker with acute MI can do to improve future health" . 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 1 year . 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 3 months (typically by telephone) are more likely to result in smoking cessation . 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 . Adding a smoking cessation medication (e.g., bupropion, varenicline) is not more effective than intensive counseling alone, and many clinicians are reluctant to add another drug to the multitude of medications prescribed after MI.
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 . 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 kg/m2 and a waist circumference of 35 inches (women) or 40 inches (men) . When weight reduction is needed, the initial goal is weight loss of 5% to 10% from baseline .
The level of exercise should be prescribed according to risk, previous level of exercise, and possibly the results of a stress test . 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 . 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).
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 [4,5,244,247]. Treatment with these four classes has been associated with 1-year mortality that is significantly lower than that for patients treated with none or one of the medications . In addition, nitroglycerin should be prescribed for all patients, and they should be instructed on its use for ischemic pain . The medication profile should be tailored to each patient on the basis of the in-hospital events and procedures, risk factors, and drug tolerability.
The recommended antiplatelet therapy after discharge is a combination of aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) [4,244,247]. The findings of studies have suggested that low-dose aspirin is as effective as higher doses but has a better safety profile [168,249,250]. 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 [4,5,247,250]. 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 .
The addition of clopidogrel to aspirin as maintenance therapy has been found to enhance outcomes for patients . Among 12,562 patients with ACS who were taking aspirin (at a dose of 75–325 mg daily) in one trial, 1 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 . Clopidogrel was also associated with an increased risk for major bleeding, but bleeding risks increased with increasing aspirin dose, with or without clopidogrel .
The 2013 update of the ACCF/AHA guideline for the management of STEMI includes modified recommendations for maintenance therapy with a P2Y12 inhibitor . 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 1 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 .
Questions about clopidogrel maintenance therapy remain, as the optimal dose and duration of therapy have not been identified [247,252,253,254]. 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 . The reason for this phenomenon is unclear, and the authors suggested that strategies to reduce the incidence of such early events should be identified . Additionally, the response to clopidogrel varies among patients, and diminished responsiveness has been observed . Warfarin is recommended as an antithrombotic for patients with UA/NSTEMI or STEMI who are allergic to aspirin [244,247].
Antiplatelet therapy is preferred over anticoagulant therapy with warfarin (or other vitamin K agonists) for treating patients with atherosclerosis . 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 . 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 .
Treatment with oral beta blockers is recommended for all patients after UA/NSTEMI or STEMI . Treatment should continue indefinitely.
An ACE inhibitor is also recommended as long-term therapy after UA/NSTEMI or STEMI [4,244]. 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% .
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 . 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 . This benefit was confirmed in an analysis of data from a total of six trials (28,505 patients), with all-cause mortality at 2 years of 3.5% for intensive therapy compared with 4.6% for standard therapy .
The 2013 ACCF/AHA guideline for STEMI indicates the need to continue or initiate the use of a statin to manage patients' lipoprotein levels . 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 . 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 . 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 [4,244].
If statin therapy fails to control lipid levels or patients do not tolerate statins, treatment with niacin or a bile acid sequestrant is reasonable . Ezetimibe should be considered if patients do not tolerate any of the aforementioned medications .
After discharge, patients may need other treatments to manage blood pressure, depression, or diabetes.
In addition, blood pressure should be controlled according to the JNC8 guideline, which recommends treatment when blood pressure is higher than 150/90 mm Hg in individuals 60 years or older or higher than 140/90 mm Hg in individuals younger than 60 years . The JNC8 panel recommends initial treatment with a thiazide-type diuretic, calcium channel blocker, ACE inhibitor, or ARB for the general nonblack population and a thiazide-type diuretic or calcium channel blocker for the general black population . The AHA/ACCF recommends initial treatment with a beta blocker and/or an ACE inhibitor as secondary prevention for patients with CHD .
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 . These emotions can substantially affect a patient's psychosocial status and lead to depression [260,261]. 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 . Depression has been found more often in women compared with men and in men with a history of MI . 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 [261,263,264].
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 [4,5,244]. 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 [244,260].
CHD is responsible for about 75% of deaths in individuals with diabetes, and more than 30% of patients with NSTE-ACS have diabetes . 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 [4,5,265]. 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 .
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 6-month mortality rates following a cardiac event . Metformin is the recommended first-line diabetes pharmacotherapy for the prevention of cardiovascular complications . 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 .
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 [244,245,266,267,268,269,270,271]. According to data from several studies, referrals to cardiac rehabilitation range from 64% to 87% by hospital (mean: 81%) . 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 [268,269]. Only 29% of patients with MI who were referred to cardiac rehabilitation enrolled within 1 month of discharge; this rate raised to just 48.25% after 6 months . Women are less likely to be enrolled after 1 month, as are patients with hypertension or peripheral arterial disease and uninsured patients. Older patients are less likely to have participated at 6 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 6 months .
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 . Others have identified distance from a rehabilitation center (e.g., long travel time, lack of transportation) and high co-pays as significant barriers . 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 [245,270,273]. Smoking cessation rates following MI (roughly 30% at 6 months) are greater than in similar-age patients in the general population but are still too low .
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 . 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 . 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 [27,175,196,236,248,267,273,275]. 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 [248,276,277].
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 :
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 [27,279]. 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 [27,29]. 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 .
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 [280,281]. 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 [280,282,283]. One study showed that compliance was 60.3% at 1 year, 53.7% at 2 years, and 48.8% at 5 years . Individuals who discontinue medications are more likely to be older, female, unmarried, and less educated . Several other factors have been found to be associated with noncompliance with medications [282,280,283]:
Choice of medication
Duration of treatment
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 is an integral component of treatment for patients with ACS and should begin during hospitalization and continue throughout follow-up care . Adequate time for appropriate education during the index hospitalization has been challenged by shorter hospital stays and reduced staffing . 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 . Men, older individuals, and individuals with less formal education were less likely to be knowledgeable about their risk and symptoms . This lack of knowledge can contribute to lack of compliance with recommended secondary prevention strategies.
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 [286,287]. As noted, many clinicians do not feel confident in their effectiveness in helping patients understand their disease and comply with preventive measures . Several strategies can help clinicians educate patients effectively (Table 14) [288,289,290,291,292].
STRATEGIES TO HELP ENHANCE EFFECTIVENESS OF PATIENT EDUCATION
Many individuals still believe that the onset of an MI will be "dramatic," with chest pain that is severe and crushing [4,293]. Among individuals who had an acute MI, 40% interpreted their symptoms as cardiac in nature . 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 . Healthcare professionals should talk to patients about the "real" signs and symptoms of ACS, emphasizing the diversity in symptoms .
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 . 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 [4,294]. Individuals have given several reasons for delays in seeking medical care (Table 15) . 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.
REASONS FOR DELAY IN SEEKING MEDICAL ATTENTION FOR CHEST PAIN
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 [4,285,293]. 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 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.
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 reocclusion.
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.
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