#40944: Acute Coronary Syndrome

The gradual process of atherosclerosis usually causes no symptoms over the course of many years, with most plaques causing no symptoms [41]. 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 [41]. 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 [45,46,47,48]. A simpler classification, based on morphologic characteristics, was later introduced [49]. 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 [49]. Pathologic intimal thickening or a thick-cap fibroatheroma is usually involved in plaque erosion [43]. Erosion is often the cause of thrombosis in young patients, particularly women younger than 50 years of age [34,43]. The least often cause of thrombosis is a calcified nodule, which is usually found in older patients with substantially calcified and tortuous arteries [43].

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 [50]. Vulnerable plaque has the following hallmark characteristics [41,51]:

Because of its high lipid content, vulnerable plaque is associated with the progressive development of ischemic disease [41]. The high level of macrophage infiltration reflects the important role of inflammation in plaque rupture as well as early plaque formation. 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 [41]. 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 [41]. 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 [41]. 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 [41]. In one study, the thrombus was days or weeks old in 49% of patients with STEMI [52]. 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 [53,54,55]. 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 [56].

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 [57]. Plaque rupture in combination with large plaque burden and luminal narrowing appears to lead to ACS [4]. Lipid-rich plaque and intracoronary thrombus have been found significantly less often in patients with asymptomatic CHD compared with patients with NSTEMI [58].

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 [59]. 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 [59]. 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 [60,61].

The Framingham Heart Study identified the first risk factors, and these factors were integrated into a risk-assessment tool, the Framingham Risk Score [62]. 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) [63]. The use of one of these risk calculators is a class IB recommendation from the American College of Cardiology Foundation and American Heart Association [63]. 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 [64]. 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) [65]. These equations were developed on the basis of data on participants from several large racially and geographically diverse studies [65]. 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) [65].

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 [66,67,68]. The adult prevalence of hypertension in the United States is 46.7% and the prevalence of hypercholesterolemia (total cholesterol >200 mg/dL) is 33.9% [1].

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) [63,65]. A positive family history is considered a nontraditional risk factor for CHD, and approximately 14% of adults report having a parent or sibling who had a heart attack or angina before 50 years of age [1]. Family history of premature angina, MI, angioplasty, or bypass surgery increases the lifetime risk about 50% for both heart disease (from 8.9% to 13.7%) and CVD mortality (from 14.1% to 21%) [1]. Other nontraditional risk factors lend themselves to quantitative measure that may be used to predict risk. Those that have been evaluated most often are inflammatory markers, lipid-related markers, other biochemical markers, testing for subclinical atherosclerosis, electrocardiography (ECG), and imaging studies.

Inflammatory Markers

The recognition of the important role of inflammation in the development of CHD has led to increased research on the value of inflammatory markers in predicting risk. C-reactive protein (CRP) is the marker that has been most rigorously studied. The USPSTF found moderate, consistent evidence that adding a CRP level to a risk algorithm improves risk stratification for individuals at intermediate risk, and the 2010 ACCF/AHA guideline subsequently noted that measuring the CRP level may be reasonable for asymptomatic men (50 years of age or younger) or women (60 years of age or younger) who are at intermediate risk for cardiovascular disease [63,69]. The ACCF/AHA guideline does not recommend a CRP level for asymptomatic adults at high risk [63]. One study suggested improved 10-year risk prediction when a CRP or fibrinogen level was added to a traditional risk score [70]. 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 [65].

The USPSTF found no evidence that homocysteine levels or leukocyte counts were useful in further stratifying risk among individuals at intermediate risk [71].

Lipid-Related Markers

The 2010 ACCF/AHA guideline for assessment of cardiovascular risk does not recommend assessment of lipoprotein or apolipoprotein levels [63]. Measurement of a lipoprotein-associated phospholipase A2 level "might be reasonable" for asymptomatic adults at intermediate risk [63]. 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 [72]. However, the 2013 ACCF/AHA guideline notes that the contribution of apolipoprotein B is uncertain [65].

Other Biochemical Markers

According to the 2010 ACCF/AHA guideline, natriuretic peptide levels are not recommended for the evaluation of risk among asymptomatic adults [63]. A hemoglobin A1C "may be reasonable" for assessing risk in asymptomatic adults without diabetes and "may be considered" for asymptomatic adults with diabetes [63]. 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 [63]. However, in its 2013 guideline, the ACCF/AHA expert panel notes that the contribution of albuminuria is uncertain [65].

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 is combined with traditional risk factors [73,74]. 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%) [63]. 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 [75]. 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 [76,77]. 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 [65].

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 [71]. 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 [63,65]. The 2010 ACCF/AHA guideline does not recommend measurement of flow-mediated dilation or arterial stiffness as part of risk assessment [63]. 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 [76,77]. Magnetic resonance imaging of plaque is not recommended [63].

ECG

The ACC/AHA, ACP, and USPSTF have all recommended against routine screening with resting ECG and exercise treadmill test for asymptomatic individuals at low risk [63,78,79,80]. 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 [63,80].

Imaging Studies

The 2010 ACCF/AHA guideline and the ACP screening guideline note that stress echocardiography is not indicated for asymptomatic adults at low or intermediate risk [63,79]. 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 [63,79].

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 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease was commissioned to consolidate existing recommendations and clinical practice guidelines into a single document for primary prevention of CVD [81]. The document includes new guidance for aspirin use, exercise/physical therapy, and tobacco use, and recommendations for interprofessional team-based care, shared decision-making, and assessment of social determinants of health. Calculation of an age-specific 10-year CVD risk assessment should guide decision making, matching the intensity of preventive interventions to the patient's absolute risk. Effective prevention strategies promote a healthy lifestyle throughout life emphasizing optimal diet, physical activity, and avoidance of tobacco and exposure to secondhand smoke. Other major points of emphasis include the following [81]:

The 2017 Guideline for High Blood Pressure in Adults sets goals for systolic and diastolic blood pressure and provides evidence-based recommendations on treatment approaches [82]. These recommendations are included and adapted in the ACC/AHA 2019 Guideline on Primary Prevention of Cardiovascular Disease [81]. 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 [83,84].

With regard to the treatment of cholesterol levels, ACC/AHA guidelines published in 2013, and updated in 2018, 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 [23,85,86,87]. 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 [88]. 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 [89]. This approach also has the potential to enhance patient adherence to medication. The 2018 guideline recommendations for management of blood cholesterol are included and adopted in the ACC/AHA Guideline on Primary Prevention of Cardiovascular Disease [81].

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 [90]. Lifestyle management is a key component of the new guidelines for the treatment of cholesterol levels and hypertension, and several other guidelines have addressed issues related to lifestyle behaviors, such as obesity, diet, and physical activity. The ACC/AHA/TOS (The Obesity Society) developed a guideline on the management of overweight and obesity, and some members of the Expert Panel authored a separate review on the evidence statements related to cardiovascular risk [91,92]. The AHA/ACC also published a guideline on lifestyle management to reduce cardiovascular risk in 2013 [93]. The decision to offer or refer adults without cardiovascular risk factors to behavioral counseling should be individualized by the primary care physician [94].

Another aspect of prevention that warrants increased attention is the role of complementary and alternative medicine. Approximately 33% of adults use complementary and alternative medicine therapy (including dietary supplements), and 40% to 70% do not tell their doctors about the therapy [95,96]. 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 [97,98,99,100,101]. Studies have shown that a Mediterranean diet has a beneficial effect on cardiovascular risk factors, although the evidence is limited [102]. The USPSTF recommends against vitamin E supplements and ß-carotene for the prevention of cardiovascular disease [97].

Adherence to guidelines for management of CHD risk and to prevent cardiovascular disease has been suboptimal, especially among patients at low risk for disease [20,21,103]. Clinicians have noted several barriers to adhering to CHD prevention guidelines, including [20,21]:

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 most commonly reported symptom in all patients with ACS, regardless of age, gender, race/ethnicity, or the presence of comorbid conditions [11,120]. 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) [3,122]. When discussing chest pain with the patient, the clinician should focus on several aspects of the pain or discomfort, including [105]:

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 [123]. 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 [123]. Pain is usually worse with activity and improves with rest.

Several descriptors are used most often to describe ACS-related chest pain, including [105,123]:

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

Pain features that are not generally characteristic of ACS-related pain include [3,123,125,126,127]:

However, the possibility of ACS should not be dismissed because of the presence of atypical pain characteristics. ACS has been diagnosed in 22% of patients who had sharp or stabbing pain and in 13% of patients with pleuritic-type pain, in as many as 15% of patients who had reproducible pain, and in 5% of patients with sharp, stabbing, fleeting pain [3,125].

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 [11,120,128,129,130,131,132]. 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 [3]. In one study, nitroglycerin relieved chest pain in 35% of patients with ACS and 41% of patients without ACS [3]. Similarly, a gastrointestinal cause of pain should not be assumed if the chest pain is relieved by antacids, as some patients with ACS have reported relief after use of such a drug [3,126].

The classic presentation of ACS includes some symptoms in addition to chest pain, primarily dyspnea, diaphoresis, nausea, abdominal pain, or syncope [2,3]. Again, there is wide variation in the symptoms reported by patients with ACS, as well as differences in subgroups of patients. Patients with STEMI more commonly report nausea, cold sweats, and vomiting [134]. Diaphoresis occurs more often in men with ACS compared with women [128]. 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 [11,125,126].

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 [130]. 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 [24,123,133]. (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 [24,128,137]. According to data from the NCDR, the prevalence of risk factors varies across racial/ethnic subgroups of individuals with ACS (Table 7) [138].

The five most important history-related factors that relate to the likelihood of ischemia due to CHD are (in order of importance) [139]:

Most often, the physical examination is normal for patients being evaluated for possible ACS. Thus, the physical examination is important not to establish a diagnosis of ACS but rather to rule out an alternate diagnosis, identify any precursors of acute ischemia, identify any comorbidities that may have an impact on treatment decisions, and add prognostic information [2,3]. Ruling out a noncardiac cause of chest pain is especially important given the severity of some potential conditions [3,122].

The physical examination should include the following [3]:

The presence of bruits or pulse deficits (which would suggest extracardiac disease) is associated with a higher likelihood of significant CHD [3]. Similarly, significant CHD is more likely in a patient who has an S3 or S4 gallop, a new mitral insufficiency murmur, or signs of congestive heart failure (pulmonary rales and elevated jugular venous pressures) [125]. Cardiogenic shock is associated more often with STEMI than NSTEMI, and mortality rates are high [3]. Physical examination should also identify contraindications to antiplatelet or fibrinolytic therapy, which include any prior intracranial hemorrhage, known malignant intracranial neoplasm, suspected aortic dissection, active bleeding or bleeding diathesis (excluding menses), or significant closed-head or facial trauma within the previous three months [2].

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

New ST-segment depression and symmetrical inverted T-waves both suggest acute ischemia or NSTEMI, and the likelihood is higher for ST-segment depression [3]. As noted, STEMI is associated with complete occlusion (more than 90%) of a coronary artery, and such occlusion is indicated by ST-segment elevation, ranging from less than 1 mm in a single lead to 10 mm in multiple leads [124]. An emergency physician experienced in reading ECGs or a cardiologist should interpret the findings, especially when STEMI is suspected [2]. A diagnosis of acute MI is confirmed with results of serial cardiac biomarker measurements in 90% of patients who have ST-segment elevation of 1 mm or more in at least two contiguous leads [3]. The resultant area of irreversible infarction with STEMI can be large, and immediate reperfusion therapy is needed. Therefore, ECG is essential for therapeutic decision making, and its findings are the primary determinant for treatment of STEMI [2].

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

A single ECG cannot capture the entire dynamic process of ischemia. As a result, the initial ECG for patients with acute MI can be normal or nondiagnostic in 20% to 55% of cases [123]. Among patients with chest pain and a normal ECG, approximately 1% to 6% will subsequently be found to have MI and about 4% will be found to have UA [3]. Nondiagnostic ECGs are more likely in older patients; according to trial data, the rate of nondiagnostic ECGs was 23% for patients younger than 65 years of age and was 43% for patients 85 years of age and older [11]. In addition, ST-segment elevation on the ECG at presentation has been shown to decrease with age, from 96.3% for patients younger than 65 years of age to 69.9% for patients 85 years of age or older [11].

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

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

Adherence to the ACC/AHA guidelines for obtaining ECG has been suboptimal, with ECG being performed up to 73% of the time [140,141]. Delay in obtaining the first ECG has been associated with female gender and older age [11,24,142]. This delay may be related to the high rate of atypical presentation of ACS in these populations [11,143]. Increasing the number of nurses or ECG technicians during peak hours and training additional staff to perform ECGs may help to improve timeliness [28,144].

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 [2,3,31]. Measurement of CK-MB or myoglobin levels was not useful or cost-effective [145].

Cardiac Troponins

As noted, cardiac troponin I and T are sensitive and specific biomarkers of myocardial injury, and serum measurements are used to identify whether patients with ACS have had an MI. A variety of troponin assays are in use. Contemporary ("sensitive") troponin assays have been in use for many years, while "highly sensitive" assays were only approved in 2017 for use in the United States. The Fourth Universal Definition of MI recommends using highly sensitive troponin assays when available [31]. The time to initial elevation of cardiac troponin levels following MI is 2 to 12 hours when measured by sensitive assays, with peak elevation at 24 hours (troponin I) and 12 to 48 hours (troponin T) [3,146]. Levels may remain elevated for 5 to 10 days (troponin I) or up to 14 days (troponin T) after an MI [146]. Highly sensitive assays detect significant elevations of cardiac troponin within one hour, which has the advantage of more rapid diagnosis and triage. The sensitivity of cardiac troponin for the diagnosis of MI is relatively low during the first six hours, especially in patients who present shortly after symptom onset [146]. However, for most patients with ACS, MI can be ruled out or confirmed within six hours, in part because of the high rate of delayed presentation associated with chest pain [3].

For the diagnosis of MI, the Fourth Universal Definition of MI defines myocardial injury as a rise and/or fall in cardiac troponin of at least one level above the 99th percentile of the upper reference level (URL) for normal values, including evidence of serial increases or decreases of troponin levels [31]. 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 [147].

It is important to bear in mind that chronic elevations of troponin are present in some patients unrelated to acute events, which is why a rise or fall of troponin is required to establish the diagnosis of MI. Baseline troponin levels are often higher in the elderly than in younger adults; 20% of adults older than 70 years of age have, as baseline, a cardiac troponin level above the 99th percentile URL [32]. Troponin assays are not standardized; the value reported will vary depending on the assay used, and comparison of reported results across different laboratories may not be reliable for diagnostic purposes [31]. Clinicians should familiarize themselves with the specific assay used in their own clinical facility.

The ACC/AHA guideline for UA/NSTEMI states that troponin levels should be measured at the time of presentation and three to six hours after the onset of symptoms in all patients suspected of having ACS [3]. If the time of symptom onset is unclear, the time of presentation should be used instead. When initial serial troponin levels are normal but ECG changes and/or clinical features increase the suspicion for ACS, additional troponin levels should be measured beyond six hours [3]. The lack of elevated troponin levels at the time of presentation should not rule out an MI, as the initial level is normal in as many as 23% of patients with MI [148]. Troponin levels appear to have value in ruling out an MI; the negative predictive value of undetectable troponin levels has been reported to be 99% to 100%.

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

Other Markers

As noted earlier, CK-MB, myoglobin, and other biomarkers are no longer useful in diagnosing ACS. B-type natriuretic peptide (BNP) and N-terminal proBNP are also not useful as an aid to diagnosing ACS, but they have demonstrated strong predictive value for short-term and long-term mortality for patients with ACS, and the ACC/AHA guideline notes that these biomarkers may be considered to assess risk in patients in whom ACS is suspected (class IIbB) [3,149,150].

Nitroglycerin is a vasodilator that relieves ischemic-related pain by reducing myocardial oxygen demand and enhancing oxygen delivery. Nitroglycerin can be given as sublingual tablets every five minutes for up to three doses. The indications for intravenous nitroglycerin are persistent ischemia, hypertension, or heart failure, following administration of sublingual nitroglycerin and a beta blocker [3]. The administration of intravenous nitroglycerin should be discontinued within 24 hours after the patient's condition has stabilized, at which point oral nitroglycerin can be given. Discontinuation of intravenous nitroglycerin should be gradual, as the abrupt cessation has been associated with exacerbation of ischemic changes on ECG [3]. Nitroglycerine and all nitrates are contraindicated when a phosphodiesterase inhibitor has been used recently [3]. Nitrates are used with caution in patients with right ventricular infarction.

The 2014 guideline states that morphine is an option for patients who do not have relief of ischemia-related symptoms during treatment with intravenous nitroglycerin or for patients who have recurrence of symptoms during anti-ischemic therapy [3]. If morphine is used in conjunction with intravenous nitroglycerin, the patient's blood pressure should be closely monitored, as hypotension is a potential adverse effect.

The inhibition of beta-1 adrenergic receptors by beta blockers acts to decrease cardiac work and myocardial oxygen demand. Beta blockers also slow the heart rate, which helps enhance coronary blood flow. A beta blocker should be given orally to all patients (unless contraindicated) within 24 hours after presentation [3]. This use of beta blocker therapy has been associated with significantly lower in-hospital mortality [159]. The evidence for the benefit of beta-blocker therapy is well established, but it diminishes as the time from the index cardiac event elapses [160]. Contraindications include signs of heart failure, low-output state, increased risk of cardiogenic shock, or other relative contraindications to beta blockade.

Beta blockers with intrinsic sympathomimetic activity should be avoided; otherwise, the choice of beta blocker is up to the physician, as no studies have been done to compare single agents with each other. The ACC/AHA guideline recommends the use of sustained-release metoprolol, carvedilol, or bisoprolol as beta-blocker therapy for patients with UA/NSTEMI, stabilized heart failure, and reduced systolic function.

Adherence to guidelines for beta-blocker therapy has ranged from a concordance rate of 56 to 91 (with 100 representing perfect concordance) [8,140]. 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 [159]. Lower rates of beta blocker therapy have been found for older individuals and women, especially women younger than 55 years of age (compared with men of the same age) [12,161].

Calcium-channel blockers act to inhibit contraction of myocardial and smooth muscle and to cause vasodilation, although the agents in this drug class vary in the degree of vasodilation and myocardial contractility they produce [3]. They also relieve (or prevent) signs and symptoms of ischemia by decreasing heart rate and blood pressure.

The strongest evidence for a benefit of calcium-channel blockers in the setting of UA/NSTEMI primarily relates to symptom control. Calcium-channel blockers are indicated for patients who have UA/NSTEMI and [3]:

The four agents used most commonly are nifedipine, amlodipine, verapamil, and diltiazem. Although data on comparisons of these four drugs are limited, verapamil and diltiazem are recommended because of their negative inotropic actions and negative chronotropic and dromotropic effects [3]. The ACC/AHA guideline recommends that a nondihydropyridine calcium channel blocker (verapamil or diltiazem) be given to patients with UA/NSTEMI who have continuing or frequently recurring ischemia and a contraindication to beta blockers, provided that clinically significant left ventricular dysfunction, increased risk for cardiogenic shock, a PR interval greater than 0.24 second, or second- or third-degree atrioventricular block without a cardiac pacemaker are not present [3]. In addition, oral nondihydropyridine calcium antagonists are recommended (unless contraindicated) for patients who have recurrent ischemia after appropriate use of beta blockers and nitrates. Immediate-release nifedipine is not recommended for routine use because of a dose-related increase in mortality [3].

An ACE inhibitor should be administered orally within the first 24 hours (unless contraindicated) to patients who have pulmonary congestion or a left ventricular ejection fraction (LVEF) less than 0.40, and to patients who have hypertension, diabetes mellitus, or stable chronic kidney disease [3]. The guidelines also note that an angiotensin-receptor blocker (ARB) should be given to patients who cannot tolerate an ACE inhibitor and have signs of heart failure or LVEF of less than 0.40. The benefits of ACE inhibitors have been demonstrated primarily in the long-term setting after MI, with significant reductions in adverse outcomes, including survival at 30 days [3,162,163]. ARBs have been shown to be noninferior to ACE inhibitors in the prevention of clinical endpoints, including MI and stroke, in high-risk patients [164].

The rate of ACE inhibitor use has been reported to be approximately 77% among patients with UA/NSTEMI [8]. Use has been lower among older individuals and women, especially women younger than 55 years of age (compared with men of the same age) [12,161].

The ACC/AHA guideline does not make evidence-based recommendations for other anti-ischemic interventions, but does note two additional interventions for persistent or recurrent ischemia [3]. One is ranolazine, an antianginal agent that is indicated for the treatment of chronic angina [165]. The drug has been found to reduce recurrent ischemia in the ACS setting [166,167]. The other intervention is intra-aortic balloon pump counterpulsation, which has historically been used for refractory ischemia. The findings of observational studies have led to its use in the ACS setting, with rigorous randomized controlled trials showing no reduction in adverse events or mortality [3].

Among patients with UA/NSTEMI, treatment with statins has been shown to be associated with lower rates of recurrent MI, CHD-related mortality, need for myocardial revascularization, and stroke [3]. These benefits have been greater with a high-intensity statin (such as atorvastatin) than with low- or moderate-intensity statins. Thus, the 2014 ACC/AHA guideline recommends that all patients receive high-intensity statin therapy, unless contraindicated [3]. Adherence to this recommendation should be improved; in a study in a tertiary care center, 52% of patients eligible for intensive statin therapy received it during hospitalization [168].

The ACC/AHA guideline recommends that aspirin be given as soon as possible after a patient arrives in the emergency department and continued indefinitely in patients who tolerate it [3]. However, adherence by emergency medical personnel to guidelines recommending prompt prehospital aspirin administration is only 45% [169]. Aspirin is contraindicated for patients who are allergic to the drug or who have active bleeding; clopidogrel is recommended for patients who cannot tolerate aspirin [3]. Aspirin should be nonenteric-coated and chewable, and the recommended dose is 162 mg to 325 mg. A maintenance dose of aspirin should be continued indefinitely, at a daily dose of 81 mg to 325 mg. Adherence to the recommended use of aspirin has been better than for other drug therapies for patients with UA/NSTEMI, with rates of 97% to 99% [8,141]. Rates of aspirin use have been reported to be lower for older individuals and women, especially women younger than 55 years of age [12,161].

P2Y12 inhibitors 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. In addition, cangrelor is approved for patients treated with PCI [161].

Clopidogrel

Clopidogrel was the first antiplatelet agent to become standard therapy in the ACS setting. The drug was approved by the FDA in 2002 on the basis of the findings of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, in which 12,562 patients with UA/NSTEMI were randomly assigned to treatment with aspirin with or without clopidogrel (loading dose of 300 mg followed by 75 mg daily) and followed up for 3 to 12 months, regardless of the treatment strategy used (conservative or invasive) [170]. The risk of cardiovascular-related death, MI, or stroke was significantly lower for patients who received clopidogrel. The results were similar in many subgroups of patients.

The ACC/AHA guideline recommends clopidogrel as one of two P2Y12 inhibitors to be given in addition to aspirin to all patients (unless contraindicated) with UA/NSTEMI who are to be treated with either an early invasive or ischemia-guided strategy [3]. The recommended dose of clopidogrel is a loading dose of 300 mg or 600 mg, followed by 75 mg daily for up to 12 months. Clopidogrel is also recommended for patients who are unable to take aspirin [3].

Prasugrel

Prasugrel has been shown to be more effective than clopidogrel for patients treated with PCI with stenting. In a comparison of the two drugs in patients with moderate-to-high-risk ACS who were scheduled for PCI, prasugrel was given as a 60-mg loading dose, followed by 10 mg daily, and clopidogrel was given as a 300-mg loading dose, followed by 75 mg daily. Both drugs were given for 6 to 15 months. Prasugrel was associated with a significantly lower rate of the primary composite endpoint of cardiovascular-related death, nonfatal MI, or nonfatal stroke (9.9% vs. 12.1%) [171]. However, the risk of major bleeding was increased with prasugrel (2.4% vs. 1.8%). Overall mortality did not differ significantly between the two drugs [171].

Prasugrel has also been compared with clopidogrel in patients with UA/NSTEMI who are managed medically. In this study, prasugrel was not associated with a decrease in the primary composite endpoint of cardiovascular-related death, MI, or stroke (13.9% vs. 16%) [172]. The rates of major bleeding were similar.

The ACC/AHA guideline recommends prasugrel as one of three options for maintenance antiplatelet therapy (with aspirin) for patients who have PCI and coronary stenting, but prasugrel is not recommended for patients treated with an early-invasive or ischemia-guided strategy [3].

Ticagrelor

Ticagrelor, the first in a new class of antiplatelets known as cyclopentyl-triazolo-pyrimidines, was approved by the FDA in 2011 [173]. Its mechanism of action differs from that of clopidogrel and prasugrel in that it does not require hepatic metabolism for activation and its action is reversible. Ticagrelor achieves greater and more consistent platelet inhibition than clopidogrel [173].

Ticagrelor was compared with clopidogrel in the Study of Platelet Inhibition and Patient Outcomes (PLATO), a randomized, controlled trial involving 18,624 patients, most of whom had UA/NSTEMI [174]. After 12 months, the rate of the primary composite endpoint (i.e., cardiovascular-related death, MI, or stroke) was lower in the ticagrelor and aspirin group than in the clopidogrel and aspirin group (9.8% vs. 11.7%) [174]. In addition, the all-cause death rate was lower in the ticagrelor group than in the clopidogrel group. Although the overall rates of major bleeding did not differ between the two groups, ticagrelor was associated with a higher rate of major bleeding in a subgroup of patients who did not have CABG.

The ACC/AHA guideline recommends ticagrelor as an option (with aspirin) as maintenance antiplatelet therapy for up to 12 months after initial treatment with either an early invasive or ischemia-guided strategy [3]. As a class IIaB recommendation, the ACC/AHA note a preference for ticagrelor over clopidogrel. The recommended dose is 180 mg as a loading dose, followed by 90 mg twice daily. The benefit of ticagrelor compared with clopidogrel is limited to an aspirin dose of 75–100 mg [175].

Adherence to guidelines on the use of a P2Y12 inhibitor has been low, especially for patients with UA/NSTEMI, with rates of 10% to 57% [10]. Rates of use have been lower among women [14]. In addition, some inhibitors have been used inappropriately; for example, in one study, 3% of patients with prior stroke received prasugrel despite its contraindication in that setting [10].

Glycoprotein IIb/IIIa inhibitors are potent inhibitors of platelet aggregation. Three intravenous glycoprotein IIb/IIIa inhibitors have been approved for clinical use: abciximab, eptifibatide, and tirofiban. Intravenous glycoprotein IIb/IIIa inhibitors are recommended, as oral agents in this class have been associated with increased risk for bleeding and mortality [3].

A meta-analysis (48 trials, 33,513 patients) demonstrated that glycoprotein IIb/IIIa inhibitors were associated with a lower all-cause mortality at 30 days after PCI but not at six months, compared with placebo or usual care [176]. The rate of severe bleeding was increased with glycoprotein IIb/IIIa inhibitors. Less benefit was found when clopidogrel was used. When glycoprotein IIb/IIIa inhibitors were used as part of initial medical treatment of UA/NSTEMI (12 trials, 33,176 patients), there was no decrease in mortality at 30 days, although the rate of death or MI was slightly lower at 30 days and six months [176]. Again, the risk of severe bleeding was higher with glycoprotein IIb/IIIa inhibitors.

The ACC/AHA guideline recommends a glycoprotein IIb/IIIa inhibitor for patients at intermediate-to-high risk (i.e., elevated troponin levels) who are to be treated with an early invasive strategy and dual-antiplatelet therapy [3]. Eptifibatide and tirofiban are the preferred inhibitors (class IIb, B) [3].

The recommended use of glycoprotein IIb/IIIa inhibitors is suboptimal in two ways. First, guideline-recommended use is low, especially among women [14,177,178]. Despite the clear benefit of glycoprotein IIb/IIIa inhibitors for high-risk patients, studies have shown that treatment with the drugs are directed toward patients at lower risk, with its use in high-risk patients ranging from 18% to 35% [179,180]. Use of glycoprotein IIb/IIIa inhibitors has also been suboptimal with respect to dosing; in one study, an excess dose was given to 26.8% of patients [181]. Excess dosing was more likely among older individuals, women, and patients with renal insufficiency, diabetes mellitus, heart failure, or low body weight [181]. Increased risk of major bleeding and mortality were associated with an excess dose.

Enoxaparin is a low-molecular-weight heparin that offers many pharmacologic advantages compared with unfractionated heparin [44]:

Compared with unfractionated heparin, enoxaparin has been associated with lower rates of recurrent ischemic events and of invasive procedures in the short term, as well as at one year among patients with UA [182]. Among high-risk patients with UA/NSTEMI treated with an early invasive strategy, the rate of death or MI at 30 days did not differ significantly between enoxaparin and unfractionated heparin, and enoxaparin was associated with an increased risk of major bleeding [183,184]. A 2023 assessment of bleeding and associated risk factors among a cohort of 602 patients treated with enoxaparin found that the incidence of bleeding was 15.8%; 5.7% involved major bleeding. The risk factors associated with bleeding were age 65 years or older, history of bleeding, and history of oral anticoagulant exposure [185].

The ACC/AHA guideline recommends enoxaparin as an option for all patients with NSTE-ACS [3]. The recommended dose is 1 mg/kg, given subcutaneously, every 12 hours, and the drug is continued throughout the hospitalization or until PCI is done [3]. The dose should be decreased to 1 mg/kg daily for patients with a creatinine clearance less than 30 mL/min.

Studies have shown that 14% to 19% of patients with UA/NSTEMI have received an excess dose of low-molecular-weight heparin [181,186]. A higher dose was significantly associated with major bleeding and death [186]. The patients who received excess doses were more likely to be older, smaller, and female [181,186].

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 [187]. Bivalirudin alone was also noninferior to heparin plus a glycoprotein IIb/IIIa inhibitor, but it offered a significant benefit in terms of major bleeding [187]. At one year, there was no significant difference in the composite endpoint among the three groups [188]. A meta-analysis of 15 trials that included more than 25,000 patients undergoing PCI found that bivalirudin was associated with an increased risk of stent thrombosis, MI, all-cause mortality, and major adverse cardiac events and a reduced risk of major bleeding [189]. When the dose of heparin in the control arm was more than 100 units/kg, bivalirudin was associated with a reduction in major bleeding; when the dose of heparin was less than 75 units/kg, bivalirudin was not associated with reduced major bleeding [189].

The ACC/AHA guideline recommends bivalirudin only for patients who are to have an early invasive strategy [3]. The recommended dose is 0.10 mg/kg as a loading dose, followed by 0.25 mg/kg/hr, to be continued until diagnostic angiography or PCI is performed [3].

Fondaparinux 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 [190,191,192,193]. The ACC/AHA guideline recommends fondaparinux, 2.5 mg subcutaneously daily, for the duration of hospitalization or until PCI is done [3]. When fondaparinux is used alone in this setting, an additional anticoagulant with anti-IIa activity should be given to help prevent catheter thrombosis [3].

Unfractionated heparin 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 [44]. 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 [194]. These studies preceded the era of dual-antiplatelet therapy and early catheterization and revascularization.

The ACC/AHA guideline recommends giving unfractionated heparin for 48 hours or until PCI is performed [3]. A weight-adjusted dose is preferred to a fixed initial dose, as anticoagulation is more predictable with such dosing [3]. The recommended dose in the ACC/AHA guideline is an initial loading dose of 60 IU/kg (to a maximum of 4,000 IU) and an initial infusion of 12 IU/kg/h (to a maximum of 1,000 IU/hr), which is adjusted to a therapeutic activated partial thromboplastin time range [3].

The findings of most studies have indicated that a routine early invasive strategy is superior to an ischemia-guided strategy in terms of reducing the rate of cardiovascular-related death or MI, as well as of angina and rehospitalization [15,195,196]. However, a meta-analysis found insufficient evidence to support either approach as having a survival benefit for patients with NSTE-ACS [197]. The greatest advantage of an early invasive strategy has been found among patients at high risk.

An urgent or immediate invasive strategy is recommended for patients with NSTE-ACS with refractory angina or hemodynamic or electrical instability who do not have serious comorbidities or contraindications [3]. An early invasive strategy is recommended for patients with NSTE-ACS who are initially stabilized and at elevated risk for clinical events [3]. The guideline recommends against an early invasive strategy for patients with acute chest pain and a low likelihood of ACS (normal troponin levels) as well as for patients with extensive comorbidities (class III: no benefit).

The objective of an ischemia-guided strategy is to avoid unnecessary treatment (and associated costs) for patients at low risk for significant CHD. The ACC/AHA guideline notes that an ischemia-guided strategy may be considered for patients with NSTE-ACS who are initially stabilized and at elevated risk for clinical events (class IIbB) [3]. It is also reasonable to consider clinician and patient preference in decision making about an ischemia-guided strategy (class IIbC). Patients at low or intermediate risk who have had no ischemia at rest or with low-level activity for at least 12 to 24 hours should have noninvasive stress testing (class IB) [3]. Factors to consider when selecting a stress test are the patient's resting ECG and ability to exercise, as well as local resources. An exercise stress test is the easiest, most cost-effective test and should be the choice unless the patient is unable to exercise or has ST changes on resting ECG (class IC) [3]. ST changes on the resting ECG may interfere with interpretation of the stress test findings, and for patients with ST changes, stress testing with an imaging modality (such as cardiac radionuclide imaging or stress echocardiography) is recommended (class IB). Pharmacologic stress testing with imaging should be done for patients who have limited ability to exercise (class IC). Exercise stress testing should be done and interpreted according to the ACC/AHA guidelines, and the results will dictate the need for further therapy [198].

Many factors other than risk influence the use of an early invasive strategy. Such a strategy has been used more often, regardless of patients' risk, when a cardiac catheterization laboratory is available or the treating physician is a cardiologist [179,199,200]. Patient demographic characteristics, such as age, race, and gender, are also factors. Data from trials indicate that an early invasive strategy is used less frequently for older patients, Black patients, and women [7,11,138,196,199,201].

The benefit of an early invasive strategy for women is unclear [15,196]. 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 [22,202]. These findings led the ACC/AHA to emphasize that an immediate invasive strategy should be used for women who are eligible for that approach and that an early invasive strategy should not be used for women at low risk for ACS [3].

CABG was once the primary revascularization procedure, but advances in less invasive techniques have contributed to a decline in CABG rates and an increase in the use of PCI for NSTE-ACS [7,203].

A comprehensive comparison of CABG and PCI was carried out in the Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) study, and the findings were considered in the formulation of the 2011 ACC/AHA/Society for Cardiac Angiography and Interventions (SCAI) guideline recommendations for PCI [5]. In a meta-analysis (31 trials, 15,004 patients) published after the guideline, among patients eligible for either PCI or CABG, the latter procedure was associated with lower rates of repeat revascularization, and death; the rate of MI was similar, and the rate of stroke was higher with CABG [204]. Class I recommendations for the use of PCI include patients who have refractory angina or hemodynamic or electrical instability (without comorbidities or contraindications), and initially stabilized patients who have an elevated risk for clinical events [5]. PCI is preferred for patients with discrete lesions, in large-caliber vessels, or one or two vessels, whereas CABG is recommended for more extensive CHD, including left main disease, three-vessel disease, or two-vessel disease with severe involvement of the proximal left anterior descending coronary artery [6]. For patients with multivessel disease, CABG has been associated with higher adjusted rates of long-term survival and lower rates of MI and repeat vascularization compared with PCI with stenting [205,206]. CABG is also recommended for patients with left ventricular systolic dysfunction [6].

Specific strategies that have improved the door-to-device time interval focus on three key components: door-to-ECG time, ECG-to-catheterization laboratory time, and laboratory arrival-to-device time. The ACCF/AHA provides the following steps as a general protocol in improving door-to-device times [2]:

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 [209,211,212]. PCI is especially preferred for high-risk patients, specifically patients 75 years of age and older, patients with an unclear diagnosis, and patients with cardiogenic shock, heart failure, or ventricular arrhythmias [2]. However, analysis of data has shown that PCI has been done less often among patients at high risk (41%) than among patients at low risk (60%) or intermediate risk (54%) [179].

Class I indications for primary PCI include the following [5]:

The ACC/AHA guideline notes that PCI is reasonable for patients with clinical and/or ECG evidence of ongoing ischemia 12-24 hours after onset of symptoms (class IIaB) and might be considered for asymptomatic patients with STEMI and higher risk who presented between 12 and 24 hours after the onset of symptoms (IIbC) [5].

After PCI for STEMI, aspirin should be continued indefinitely.

(https://www.ahajournals.org/doi/10.1161/CIR.0b013e3182742c84 Last Accessed: June 24, 2024)

Strength of Recommendation/Level of Evidence: IA (Procedure/treatment should be performed based on data derived from multiple randomized clinical trials or meta-analyses evaluating multiple populations.)

The use of coronary stents during PCI reduces the rates of adverse events such as re-occlusion, restenosis, and target-vessel revascularization [5,209,211]. 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 [213,214]. 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 [214]. One small study that included 372 patients compared the efficacy of drug-eluting stents with drug-coated balloons for use during PCI [215]. The primary outcome was a composite of major adverse cardiovascular events (e.g., cardiac death, MI, target lesion revascularization) at one year [215]. Major adverse events occurred in 10 patients (12%) in the drug-coated balloon group and in 50 patients (13.4%) in the drug-eluting stent group. Other studies have confirmed the potential benefit of using drug-coated balloons during PCI [216,217].

The complications of primary PCI include adverse reactions to the contrast medium, volume loading, difficulty with arterial access, and technical complications [211]. Reperfusion injury and hemorrhagic transformation of a bland infarction and hemorrhagic stroke are rare after primary PCI [209].

Primary PCI is supported by antiplatelet and antithrombin therapy. Class I recommendations for this therapy in patients with STEMI include the following [5]:

The aspirin dose before PCI should be 325 mg for patients who had not been taking aspirin therapy and 81 mg to 325 mg for patients who had already been taking daily aspirin [5]. If stents are to be implanted during PCI, a loading dose of a P2Y12 inhibitor should be given (clopidogrel, 600 mg; prasugrel, 60 mg; or ticagrelor, 180 mg) [5]. For clopidogrel, a 300-mg loading dose is recommended for patients who have PCI within 24 hours after receiving fibrinolytic therapy; a 600-mg loading dose is recommended for patients who have PCI more than 24 hours after receiving fibrinolytic therapy [5]. This recommendation is based on the results of several investigations to explore various loading doses of clopidogrel before or during PCI. A meta-analysis of seven studies demonstrated that a 600 mg loading of clopidogrel reduces the rate of adverse cardiovascular events without an increase in major bleeding compared with 300 mg [5]. The findings of another study suggested that a 600-mg loading dose (compared with a 300-mg dose) is associated with improvements in procedural angiographic endpoints and one-year clinical outcomes in patients with STEMI who undergo primary PCI [5]. No benefit is derived from increasing the loading dose to 900 mg compared with 600 mg [5]. The guideline acknowledges that the safety and efficacy of pretreatment with clopidogrel remains controversial [5].

When compared with clopidogrel, prasugrel was associated with a 2.2% reduction in a composite endpoint of cardiovascular-related death, nonfatal reinfarction, or nonfatal stroke [5]. Prasugrel is contraindicated in patients with active pathologic bleeding or history of transient ischemic attack or stroke. Its use is not recommended for patients older than 75 years of age because of increased risk of fatal intracranial bleeding [5].

If unfractionated heparin is used, it is reasonable to give a glycoprotein IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or high-bolus tirofiban), regardless of whether patients are pretreated with clopidogrel [5]. The ACCF/AHA guideline for STEMI states that it is reasonable to begin treatment with abciximab before or at the time of primary PCI (with or without stenting) [2]. The precise timing of administration has not been defined. Treatment with tirofiban or eptifibatide may also be considered at the time of primary PCI [2].

With regard to anticoagulant therapy, unfractionated heparin is recommended but should not be given to patients already receiving therapeutic enoxaparin (subcutaneously) (class III: harm) [5]. Bivalirudin is also a recommended anticoagulant, with or without previous treatment with unfractionated heparin (class IB) [5]. Bivalirudin or argatroban should be used instead of unfractionated heparin in patients with heparin-induced thrombocytopenia (class IB). Fondaparinux should not be used as the only anticoagulant with PCI (class III: harm) [5]. An additional anticoagulant with anti-Ha activity should be used because of the risk of catheter thrombosis.

Another factor in selecting a reperfusion approach is whether the patient has contraindications to fibrinolytic therapy. Regardless of timing, PCI should be strongly considered for patients who are at high risk for bleeding complications, especially intracranial hemorrhage. There are several absolute and relative contraindications to fibrinolytic therapy; absolute contraindications include a history of intracranial hemorrhage or of substantial closed head or facial trauma within the past three months, suspected aortic dissection, or active bleeding (Table 11) [2]. Relative contraindications include history of poorly controlled hypertension, recent internal bleeding, and oral anticoagulant therapy [2].

As described, a STEMI-associated thrombus consists of a fibrin-rich core and a platelet-rich cap. Because of this, both antiplatelet and anticoagulant therapies play important roles in supporting reperfusion therapy by helping to maintain patency of the infarct-related artery and preventing re-occlusion [2].

Clopidogrel and Aspirin

Recommended antiplatelet therapy has traditionally involved aspirin and clopidogrel. The 2013 ACCF/AHA guideline for STEMI includes a recommendation for clopidogrel (75 mg per day for at least 14 days and up to one year) to be added to aspirin for patients with STEMI, regardless of whether reperfusion with fibrinolytic therapy has been initiated [2]. Although prasugrel has been approved by the FDA for use in patients with STEMI and may be incorporated into the supportive treatment of these patients in place of clopidogrel, it is no longer recommended for use as an adjunct to fibrinolytic therapy [2].

Glycoprotein IIb/IIIa Inhibitor

It may be reasonable to administer intravenous glycoprotein IIb/IIIa receptor antagonist in the precatheterization laboratory setting (e.g., ambulance, emergency department) to patients with STEMI for whom primary PCI is intended.

(https://www.ahajournals.org/doi/10.1161/CIR.0b013e3182742c84 Last Accessed: June 24, 2024)

Strength of Recommendation/Level of Evidence: IB (Procedure/treatment should be performed based on data derived from a single randomized clinical trial or nonrandomized studies evaluating limited populations.)

A glycoprotein IIb/IIIa inhibitor may also be considered as an ancillary agent for patients who receive fibrinolytic therapy. The 2013 ACCF/AHA guideline for STEMI notes that the use of a glycoprotein IIb/IIIa inhibitor (abciximab, tirofiban, or eptifibatide) is reasonable at the time of primary PCI for selected patients with STEMI; routine use is not recommended [2].

Two meta-analyses of randomized trials that support this recommendation involved a comparison of glycoprotein IIb/IIIa inhibitors in patients with STEMI who had primary PCI. In each case, there was no significant difference in 30-day mortality, reinfarction, TIMI flow grade 3, or ST-segment resolution among the agents [233,234].

Heparin, Fondaparinux, Enoxaparin, or Bivalirudin

Anticoagulant therapy is associated with bleeding complications, so care must be taken in selecting an appropriate agent, with attention paid to the patient's renal function status, the time to an invasive procedure, and overall bleeding risk [235]. Unfractionated heparin, enoxaparin, and fondaparinux are the recommended anticoagulant agents based on studies demonstrating their efficacy [2]. The 2013 ACCF/AHA guideline recommends bivalirudin as an acceptable anticoagulant for primary PCI or for patients undergoing rescue PCI for failed fibrinolysis. Bivalirudin may be useful as a supportive measure for patients undergoing PCI either with or without prior treatment with unfractionated heparin and is particularly useful if patients develop heparin-induced thrombocytopenia and still require anticoagulation [2]. Anticoagulation should be continued for the duration of the index hospitalization (up to eight days) or until revascularization. Enoxaparin is recommended over unfractionated heparin when anticoagulant therapy will extend beyond 48 hours [2].

Unfractionated heparin should be used for patients with severe impairment of renal function, and unfractionated heparin or enoxaparin may be used for patients who are at increased risk of bleeding and who are likely to have early angiography [235]. Researchers reviewed data on 20,479 patients to compare outcomes for unfractionated heparin and enoxaparin [236]. Significantly fewer patients in the enoxaparin group had subsequent PCI within 30 days after fibrinolytic therapy [236]. There were no differences between the two agents with respect to major bleeding in this study, whereas a more recent meta-analysis found enoxaparin to be superior to unfractionated heparin in reducing the incidence of major bleeding [237]. In patients with obesity, enoxaparin was associated with significantly lower risks of in-hospital venous thromboembolism and in-hospital mortality, major bleeding, mortality related to pulmonary embolism, and hospitalization costs when compared with unfractionated heparin [238].

Fondaparinux may also provide benefit for patients who receive fibrinolytic therapy [239,240]. In one trial, 12,092 patients with STEMI were randomly assigned to fondaparinux (2.5 mg once daily for up to eight days) or to placebo. Analysis of a subgroup of 5,436 patients who received fibrinolytic therapy (primarily streptokinase) showed that fondaparinux was associated with significantly lower rates of death or nonfatal MI at 30 days and severe bleeding, yielding a significant overall benefit [239]. As noted, an additional anticoagulant (with anti-IIa activity) should be used in addition to fondaparinux when PCI is to be done after fibrinolytic therapy, and fondaparinux should not be used when creatinine clearance is less than 30 mL/min [2].

The 2013 ACCF/AHA guideline for the management of STEMI recommends aspirin at a dose of 162–325 mg as a loading dose before either PCI or fibrinolytic therapy [2]. A P2Y12 inhibitor is used along with aspirin as dual-antiplatelet therapy. For patients treated with PCI, clopidogrel (600 mg), prasugrel (60 mg), or ticagrelor (180 mg) should be given as a loading dose as early as possible or at the time of the PCI [2]. Treatment with a P2Y12 inhibitor is continued for one year. Clopidogrel is the recommended P2Y12 inhibitor to support fibrinolytic therapy; a loading dose of 300 mg is used for patients 75 years of age or younger, and no loading dose is used for patients older than 75 years of age [2]. Treatment with clopidogrel is continued for at least 14 days and up to one year.

The benefit of nitroglycerin for patients with STEMI has been modest, but the drug can be given sublingually (0.4 mg every five minutes up to three doses) for persistent or recurrent ischemic discomfort [2]. The use of nitroglycerin should not preclude the use of other drugs that have been shown to have more benefit, such as ACE inhibitors.

The drug of choice to manage the pain associated with STEMI is intravenous morphine sulfate [2]. Morphine sulphate is indicated to relieve ongoing ischemic discomfort, control hypertension, ameliorate anxiety, or manage pulmonary edema. The initial dose should be 4–8 mg, with lower doses in the elderly. Additional doses of 2–8 mg may be given at intervals of 5 to 15 minutes [2].

The use of beta blockers has been an established recommendation for patients with STEMI because of the drugs' association with lower mortality [2]. The recommendation was modified in the 2007 focused update of the ACC/AHA guideline because of safety issues related to the use of intravenous beta blockers in conjunction with fibrinolytic therapy as well as emerging data on a lack of survival benefit [247]. The findings were confirmed in the 2013 ACCF/AHA guideline, and it is still recommended that oral beta blockers be used within the first 24 hours, except for those subsets of patients at high risk for complications with use of beta blockers [2]. Beta blockers should not be used in patients with signs of heart failure, evidence of a low output state, increased risk of cardiogenic shock, or other relative contraindications to beta blockade.

The use of an oral ACE inhibitor is a strong recommendation for all patients recovering from STEMI, including those with anterior infarction, pulmonary congestion, or LVEF of less than 0.40, as well as those with normal LVEF in whom cardiovascular risk factors are well controlled [2]. Adherence to this recommendation has increased since the late 1990s but remains low [179,249,250]. Results of a 2022 study of 260 patients indicated adherence to guideline recommendations was achieved in less than 71% of study subjects, with women less likely to receive guideline-directed treatment. During the one-year follow-up, 23 patients died; adherence to guideline-directed therapy was associated with fewer deaths [251]. In addition, the doses used in clinical practice have been lower than the target doses used in clinical trials [249].

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% [252]. Early treatment is optimal, as reductions in mortality have been greatest within the first five days after the MI [252,253]. The ACCF/AHA guideline for STEMI notes that it is preferable to initiate treatment with an ACE inhibitor within 24 hours [2]. Treatment should start at a low dose that is gradually increased to a full dose within 24 to 48 hours.

ACE inhibitors are of most benefit for patients who are 55 to 74 years of age, have had an anterior infarct, or have a heart rate of at least 80 beats per minute [254]. Contraindications include a systolic blood pressure of less than 100 mm Hg (or more than 30 mm Hg below baseline), the presence of clinically relevant renal failure, a history of bilateral stenosis of the renal arteries, or known allergy. Patients who cannot tolerate an ACE inhibitor should be treated with an ARB [2]. Data indicate that ARBs might be associated with lower all-cause mortality and hospitalization for heart failure compared with ACE inhibitors among patients with acute MI [255].

Early treatment with dihydropyridine calcium antagonists (nifedipine and nicardipine) has not been found to improve rates of mortality or reinfarction [2]. Nifedipine is contraindicated in the treatment of STEMI. Although verapamil and diltiazem may be useful to relieve ongoing or recurrent ischemia, lower blood pressure, or control the ventricular response rate to atrial fibrillation when beta blockers are contraindicated (and the patient has well-preserved left ventricular function and no clinical evidence of congestive heart failure or pulmonary congestion), no specific recommendation for their use exists in the 2013 STEMI guideline [2,3]. Both drugs have been associated with significantly reduced mortality and major cardiovascular events [256,257]. Verapamil should not be used for patients with heart failure or bradyarrhythmias, and diltiazem should not be used for patients with left ventricular dysfunction [2].

After an ACS event, patients must address modifiable risk factors associated with atherogenesis by changing certain behaviors. Lifestyle modifications will include improvements in diet and physical activity levels, smoking cessation, blood pressure control, lipid management, and diabetes management [2,260]. Clinicians should involve other healthcare professionals in helping patients to achieve goals and should reinforce patients' positive efforts toward reaching these goals.

Smoking Cessation

Quitting smoking has been described as "probably the most important thing a smoker with acute MI can do to improve future health" [261]. Mortality after an ACS event for a patient who smokes cigarettes is twice that for a patient who does not, but cessation of smoking reduces reinfarction and death rates at one year [2]. Clinicians should use the in-hospital period after MI and each office visit as an opportunity to ask patients who were smokers if they have quit or are ready to quit and should offer counseling, pharmacologic support, and information on formal quit programs. The in-hospital period is unique because many patients are motivated to quit and are typically unable to smoke for three to nine days. Randomized controlled trials have shown that repeated contacts during the hospital stay and at and beyond three months (typically by telephone) are more likely to result in smoking cessation [2]. An updated 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 [262]. Another Cochrane review found high-quality evidence for a benefit of combined pharmacotherapy (with any type of nicotine-replacement therapy, bupropion, nortriptyline, or varenicline) and behavioral treatment compared to usual care, brief advice, or less intensive behavioral support [263]. However, many clinicians are reluctant to add another drug to the multitude of medications prescribed after MI.

Diet

Obesity is another well-documented risk factor for CHD, and weight management programs and information on healthy eating/caloric intake should be promoted as appropriate [260]. The patient's body mass index and waist circumference should be measured at each visit. The goal is to attain a body mass index of 18.5–24.9 and a waist circumference of 35 inches (women) or 40 inches (men) [260]. When weight reduction is needed, the initial goal is weight loss of 5% to 10% from baseline [260].

Exercise

Exercise-based secondary prevention programs are recommended for patients with STEMI and UA/NSTEMI.

(https://www.ahajournals.org/doi/10.1161/CIR.0b013e3182742c84 Last Accessed: June 24, 2024)

Strength of Recommendation/Level of Evidence: IB (Procedure/treatment should be performed based on data derived from a single randomized clinical trial or nonrandomized studies evaluating limited populations.)

The level of exercise should be prescribed according to risk, previous level of exercise, and possibly the results of a stress test [260]. 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 [260]. 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 [2,3,260,264]. Treatment with these four classes has been associated with one-year mortality that is significantly lower than that for patients treated with none or one of the medications with a positive impact most apparent at 24 months postdischarge, regardless of revascularization therapy [263,265]. In addition, nitroglycerin should be prescribed for all patients, and they should be instructed on its use for ischemic pain [2]. The medication profile should be tailored to each patient on the basis of the in-hospital events and procedures, risk factors, and drug tolerability.

Antiplatelet/Anticoagulant Agents

The recommended antiplatelet therapy after discharge is a combination of aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) [2,260,264]. The findings of studies have suggested that low-dose aspirin is as effective as higher doses but has a better safety profile [170,266,267]. The recommended daily dose of aspirin is 75–162 mg for all patients, and the ACC/AHA guidelines for the management of STEMI and NSTE-ACS state that it is reasonable to a use an 81-mg dose [2,3,264,267]. 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 [268].

The addition of clopidogrel to aspirin as maintenance therapy has been found to enhance outcomes for patients [267,269]. Among 12,562 patients with ACS who were taking aspirin (at a dose of 75–325 mg daily) in one trial, one year of treatment with clopidogrel was associated with a lower rate of a composite endpoint of cardiac death, MI, or stroke, regardless of the aspirin dose [267]. Clopidogrel was also associated with an increased risk for major bleeding, but bleeding risks increased with increasing aspirin dose, with or without clopidogrel [267,269]. The 2013 update of the ACCF/AHA guideline for the management of STEMI includes modified recommendations for maintenance therapy with a P2Y12 inhibitor [2]. The guideline indicates that patients with a stent should receive clopidogrel (75 mg daily), prasugrel (10 mg daily), or ticagrelor (90 mg twice a day) for at least one year. Patients not receiving a stent should be treated with clopidogrel (75 mg daily); it is reasonable to prescribe prasugrel (10 mg daily) in patients not receiving a stent and without a history of stroke or transient ischemic attack [2].

Questions about clopidogrel maintenance therapy remain, as the optimal dose and duration of therapy have not been identified [165,270,271,272]. 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 [272]. The reason for this phenomenon is unclear, and the authors suggested that strategies to reduce the incidence of such early events should be identified [272]. Additionally, the response to clopidogrel varies among patients, and diminished responsiveness has been observed [264]. A 2010 retrospective study of 2,017 patients with ACS, conducted to confirm the findings of the 2008 study, found that the 0- to 90-day interval after stopping clopidogrel was associated with higher risk of death/MI compared with the 91- to 360-day interval. There was a similar trend of increased adverse events 0 to 90 days after stopping clopidogrel for various subgroups (i.e., women versus men, medical therapy versus PCI, stent type, and ≥6 months or <6 months of clopidogrel treatment) [273]. Warfarin is recommended as an antithrombotic for patients with UA/NSTEMI or STEMI who are allergic to aspirin [260,264].

Antiplatelet therapy is preferred over anticoagulant therapy with warfarin (or other vitamin K agonists) for treating patients with atherosclerosis [260]. 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 [260]. 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 [260].

Beta Blockers

Treatment with oral beta blockers is recommended for all patients after UA/NSTEMI or STEMI [2]. Treatment should continue indefinitely.

ACE Inhibitors or ARBs

An ACE inhibitor is also recommended as long-term therapy after UA/NSTEMI or STEMI [2,260]. ARBs should be used for patients who are unable to tolerate an ACE inhibitor and have clinical or radiographic signs of heart failure or a left ventricular ejection fraction of less than 40% [2].

Lipid-Lowering Agents

Even before the advent of statins, reducing lipid levels through diet and previously available medications led to significant reductions in MIs. Statins are now the preferred medications for lipid-level management, and several studies have demonstrated their effectiveness in reducing atherogenesis. A fasting lipid profile should be determined within 24 hours after admission, and statin therapy should begin during hospitalization, regardless of this baseline level [2]. Intensive statin therapy appears to be of benefit for patients with recent ACS (but not for patients with stable CHD). In a pooled analysis of data on more than 8,600 patients, intensive statin therapy significantly reduced all-cause mortality compared with standard therapy [274]. This benefit was confirmed in an analysis of data from a total of six trials (28,505 patients), with all-cause mortality at two years of 3.5% for intensive therapy compared with 4.6% for standard therapy [275]. A meta-analysis of 20 trials involving 8,750 patients with ACS undergoing PCI found a time-related benefit to the start of statin therapy. By meta-regression, earlier statin administration correlated significantly with lower risk of MI, major adverse cardiac events, and major adverse cardiac and cerebrovascular events [276].

The 2013 ACCF/AHA guideline for STEMI indicates the need to continue or initiate the use of a statin to manage patients' lipoprotein levels [2]. In particular, the guideline makes a sole recommendation for high-dose atorvastatin (80 mg daily), based primarily on results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. Rates of cardiovascular events did not significantly decrease with tiered simvastatin (40 mg for one month, then 80 mg thereafter), and there are concerns about the safety of the 80-mg dose [2]. The compliance rate of statins may be improved when therapy is initiated before discharge following STEMI.

The goal of statin therapy is to achieve an LDL level less than 100 mg/dL for patients with average risk, and an LDL level of less than 70 mg/dL is reasonable for very-high-risk patients [2]. If the triglyceride level is 200 mg/dL or higher, the non-HDL cholesterol should be less than 130 mg/dL in patients with average risk, whereas a non-HDL cholesterol level of less than 100 mg/dL is reasonable for very-high-risk patients. Statin therapy should be supplemented with dietary modification, weight management, and exercise. Patients should be encouraged to follow a diet with an increase of fresh fruits and vegetables, with less than 7% of total calories as saturated fat, less than 1% of total calories as trans fatty acids, and less than 200 mg per day of cholesterol [2,260].

If statin therapy fails to control lipid levels or patients do not tolerate statins, treatment with niacin or a bile acid sequestrant is reasonable [260]. Ezetimibe should be considered if patients do not tolerate any of the aforementioned medications [277,278,279,280].

After discharge, patients may need other treatments to manage blood pressure, depression, or diabetes.

Control of Blood Pressure

In addition, blood pressure should be controlled according to the 2017 Guideline for High Blood Pressure in Adults, which recommends treatment when blood pressure is elevated, defined as 120–129/<80 mm Hg [82]. The guideline recommends initial treatment with nonpharmacologic interventions and lifestyle changes. Initiation of pharmacologic treatment is recommended for secondary prevention in patients with clinical CVD and an average systolic blood pressure of 130 mm Hg or greater or an average diastolic blood pressure of 80 mm Hg or greater and for primary prevention in adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 10% or higher and an average systolic blood pressure 130 mm Hg or greater or an average diastolic blood pressure 80 mm Hg or greater. The AHA/ACCF recommends initial treatment with a beta blocker and/or an ACE inhibitor as secondary prevention for patients with CHD [260].

Treatment of Depression

An ACS event can be distressing for many patients, leading to a heightened fear of dying and anxiety about adjusting to life with cardiac disease [281]. These emotions can substantially affect a patient's psychosocial status and lead to depression [282,283]. 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 [282]. Depression has been found more often in women compared with men and in men with a history of MI [284]. 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 [283,285,286].

Evaluation of a patient's psychosocial status, with particular attention paid to signs of depression, is a recommendation in the ACCF/AHA guidelines for STEMI and UA/NSTEMI, and screening for depression and referral and/or treatment is a recommendation in the 2011 AHA/ACCF Secondary Prevention and Risk Reduction Therapy guideline [2,3,260]. 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 [260,282].

Management of Diabetes

CHD is responsible for about 75% of deaths in individuals with diabetes, and more than 30% of patients with NSTE-ACS have diabetes [3]. It is now well known that a reduction in blood glucose levels is associated with improved outcomes in patients with diabetes or prediabetes who have experienced UA/NSTEMI or STEMI. This reduction may be achieved as the result of lifestyle changes (including weight management, physical activity, and medical nutrition therapy) or medication therapy [2,3,287,288]. 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 [260].

The goal of diabetes management (aside from reversal of the condition though intensive lifestyle change) is tight glycemic control, as both hyperglycemia and hypoglycemia have a profound impact on in-hospital and six-month mortality rates following a cardiac event [3]. Metformin is the recommended first-line diabetes pharmacotherapy for the prevention of cardiovascular complications [260]. 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 [260,289,290].

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 [260,261,291,292,293,294,295,296]. According to data from several studies, referrals to cardiac rehabilitation range from 64% to 87% by hospital (mean: 81%) [293]. 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 [293,294]. Only 29% of patients with MI who were referred to cardiac rehabilitation enrolled within one month of discharge; this rate raised to just 48.25% after six months [294]. Women are less likely to be enrolled after one month, as are patients with hypertension or peripheral arterial disease and uninsured patients. Older patients are less likely to have participated at six months, as are smokers and patients with economic hardship. White individuals and patients who attained a higher education level were more likely to enroll by six months [294].

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 [297]. Others have identified distance from a rehabilitation center (e.g., long travel time, lack of transportation) and high co-pays as significant barriers [294]. 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 [261,295,298]. Smoking cessation rates following MI (roughly 30% at six months) are greater than in similar-age patients in the general population but are still too low [261].

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 [296]. 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 [299]. 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 [26,177,201,250,265,292,298,300]. 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 [265,301,302].

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 [303]:

Critical pathways, protocols, and other quality improvement tools are valuable for helping to increase implementation of guidelines [26,304]. 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 [26,28]. 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 [304].

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 [305,306]. 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 [305,307,308]. One study showed that compliance was 60.3% at one year, 53.7% at two years, and 48.8% at five years [309]. Individuals who discontinue medications are more likely to be older, female, unmarried, and less educated [307]. Several other factors have been found to be associated with noncompliance with medications [305,307,308]:

Patient education is an integral component of treatment for patients with ACS and should begin during hospitalization and continue throughout follow-up care [2]. Adequate time for appropriate education during the index hospitalization has been challenged by shorter hospital stays and reduced staffing [310]. 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 [310]. Men, older individuals, and individuals with less formal education were less likely to be knowledgeable about their risk and symptoms [310]. This lack of knowledge can contribute to lack of compliance with recommended secondary prevention strategies.

Research has shown that patient education should focus on the importance of [2,311]:

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 [311,312]. As noted, many clinicians do not feel confident in their effectiveness in helping patients understand their disease and comply with preventive measures [20]. Several strategies can help clinicians educate patients effectively (Table 13) [313,314,315,316,317].

Recognition of Symptoms

Many individuals still believe that the onset of an MI will be "dramatic," with chest pain that is severe and crushing [2,318]. Among individuals who had an acute MI, 40% interpreted their symptoms as cardiac in nature [312]. 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 [312]. Healthcare professionals should talk to patients about the "real" signs and symptoms of ACS, emphasizing the diversity in symptoms [310].

Timeliness of Care

On average, individuals wait 1.5–2 hours before seeking medical care for ACS-related symptoms, and this delay has not changed over time, despite many national public campaigns emphasizing the importance of timely care [2]. Furthermore, up to 50% of individuals with ACS-related symptoms are transported to the hospital by means other than emergency medical services, which can increase delays [2,319]. Individuals have given several reasons for delays in seeking medical care (Table 14) [318]. 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.

Acknowledgement of Risk Factors

The need for better understanding of risk among individuals who have had ACS is evidenced by studies that have shown that their perceptions of their personal risk are lower than their actual risk [2,310,318]. Healthcare professionals should reinforce information about modifiable risk factors and provide patients with educational resources that describe risk factors and their effect on the potential for future events. Patients' individual risk factors should be discussed in an ongoing manner, with a focus on positive changes through lifestyle modifications and medications.

Compliance with Secondary Prevention Strategies

Compliance with prevention strategies can be enhanced by identifying the barriers for each individual patient and working together to address the problem. Primary care clinicians and other healthcare professionals should ask patients about medication compliance at each office visit and should emphasize the importance of maintaining drug therapy. Ongoing education about the benefit gained from medications as well as lifestyle modifications is vital to ensuring high compliance and low risk of adverse events.