2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

In the United States, the median age at ACS presentation is 68 years (interquartile range 56 to 79), and the male-to-female ratio is approximately 3:2.⁴⁰ Some patients have a history of stable angina, whereas in others, ACS is the initial presentation of coronary artery disease (CAD). It is estimated that in the United States, each year, >780 000 persons will experience an ACS. Approximately 70% of these will have NSTE-ACS.⁹ Patients with NSTE-ACS typically have more comorbidities, both cardiac and noncardiac, than patients with STEMI.

The hallmark of ACS is the sudden imbalance between myocardial oxygen consumption (MVO₂) and demand, which is usually the result of coronary artery obstruction. The imbalance may also be caused by other conditions, including excessive myocardial oxygen demand in the setting of a stable flow-limiting lesion; acute coronary insufficiency due to other causes (eg, vasospastic [Prinzmetal] angina [Section 7.11], coronary embolism, coronary arteritis); noncoronary causes of myocardial oxygen supply-demand mismatch (eg, hypotension, severe anemia, hypertension, tachycardia, hypertrophic cardiomyopathy, severe aortic stenosis); nonischemic myocardial injury (eg, myocarditis, cardiac contusion, cardiotoxic drugs); and multifactorial causes that are not mutually exclusive (eg, stress [Takotsubo] cardiomyopathy [Section 7.13], pulmonary embolism, severe heart failure [HF], sepsis).⁴¹

Patients with suspected ACS and high-risk features should be transported to the ED by emergency medical services when available. Hospitals and outpatient facilities should provide clearly visible signage directing patients transported by private vehicle to the appropriate triage area. Outpatient facilities should have the capacity for ECG and cardiac troponin measurements with immediate ED referral for those considered to have ACS.

NSTE-ACS most commonly presents as a pressure-type chest pain that typically occurs at rest or with minimal exertion lasting ≥10 minutes.⁴¹ The pain most frequently starts in the retrosternal area and can radiate to either or both arms, the neck, or the jaw. Pain may also occur in these areas independent of chest pain. Patients “with NSTE-ACS may also present with diaphoresis, dyspnea, nausea, abdominal pain, or syncope. Unexplained new-onset or increased exertional dyspnea is the most common angina equivalent. Less common presentations include nausea and vomiting, diaphoresis, unexplained fatigue, and syncope. Factors that increase the probability of NSTE-ACS are older age, male sex, positive family history of CAD, and the presence of peripheral arterial disease, diabetes mellitus, renal insufficiency, prior MI, and prior coronary revascularization. Although older patients (≥75 years of age) and women usually present with typical symptoms of ACS, the frequency of atypical presentations is increased in these groups as well as in patients with diabetes mellitus, impaired renal function, and dementia.^54,55 Atypical symptoms, including epigastric pain, indigestion, stabbing or pleuritic pain, and increasing dyspnea in the absence of chest pain should raise concern for NSTE-ACS.⁵⁶ Psychiatric disorders (eg, somatoform disorders, panic attack, anxiety disorders) are noncardiac causes of chest pain that can mimic ACS.⁵⁷

The physical examination in NSTE-ACS can be normal, but signs of HF should expedite the diagnosis and treatment of this condition. Acute myocardial ischemia may cause a S₄, a paradoxical splitting of S₂, or a new murmur of mitral regurgitation due to papillary muscle dysfunction. However, these signs may also exist without NSTE-ACS and thus are nonspecific. The coupling of pain on palpation suggesting musculoskeletal disease or inflammation with a pulsatile abdominal mass suggesting abdominal aortic aneurysm raises concern for nonischemic causes of NSTE-ACS. The physical examination can indicate alternative diagnoses in patients with chest pain, several of which are life threatening. Aortic dissection is suggested by back pain, unequal palpated pulse volume, a difference of ≥15 mm Hg between both arms in systolic blood pressure (BP), or a murmur of aortic regurgitation. Acute pericarditis is suggested by a pericardial friction rub. Cardiac tamponade can be reflected by pulsus paradoxus. Pneumothorax is suspected when acute dyspnea, pleuritic chest pain, and differential breath sounds are present. A pleural friction rub may indicate pneumonitis or pleuritis.

A 12-lead ECG should be performed and interpreted within 10 minutes of the patient’s arrival at an emergency facility to assess for cardiac ischemia or injury.²¹ Changes on ECG in patients with NSTE-ACS include ST depression, transient ST-elevation, or new T-wave inversion.^21,58 Persistent ST-elevation or anterior ST depression indicative of true posterior MI should be treated according to the STEMI CPG.¹⁷ The ECG can be relatively normal or initially nondiagnostic; if this is the case, the ECG should be repeated (eg, at 15- to 30-minute intervals during the first hour), especially if symptoms recur.²¹ A normal ECG does not exclude ACS and occurs in 1% to 6% of such patients.^59–61 A normal ECG may also be associated with left circumflex or right coronary artery occlusions, which can be electrically silent (in which case posterior electrocardiographic leads [V₇ to V₉] may be helpful). Right-sided leads (V₃R to V₄R) are typically performed in the case of inferior STEMI to detect evidence of right ventricular infarction. Left ventricular (LV) hypertrophy, bundle-branch blocks with repolarization abnormalities, and ventricular pacing may mask signs of ischemia/injury.⁶²

Cardiac troponins are the most sensitive and specific biomarkers for NSTE-ACS. They rise within a few hours of symptom onset and typically remain elevated for several days (but may remain elevated for up to 2 weeks with a large infarction). A negative cardiac troponin obtained with more sensitive cardiac troponin assays on admission confers a >95% negative predictive value for MI compared with high-sensitivity assays that confer a negative predictive value ≥99%.^63–65 See Section 3.4 for a detailed review of biomarkers for the diagnosis of MI.

A chest roentgenogram is useful to identify potential pulmonary causes of chest pain and may show a widened mediastinum in patients with aortic dissection. Computed tomography (CT) of the chest with intravenous contrast can help exclude pulmonary embolism and aortic dissection. Transthoracic echocardiography can identify a pericardial effusion and tamponade physiology and may also be useful to detect regional wall motion abnormalities. Transesophageal echocardiography can identify a proximal aortic dissection. In low-risk patients with chest pain, coronary CT angiography can result in a more rapid, more cost-effective diagnosis than stress myocardial perfusion imaging.⁶⁶

Assessment of prognosis guides initial clinical evaluation and treatment and is useful for selecting the site of care (coronary care unit, monitored step-down unit, or outpatient monitored unit), antithrombotic therapies (eg, P2Y₁₂ inhibitors, platelet glycoprotein [GP] IIb/IIIa inhibitors [Sections 4.3.1.2 and 5.1.2.2]), and invasive management (Sections 4.4.2.1, 4.3.1, 4.4, 4.4.4, 4.4.5). There is a strong relationship between indicators of ischemia due to CAD and prognosis (Table 3 and Figure 2). Patients with a high likelihood of ischemia due to CAD are at greater risk of a major adverse cardiac event (MACE) than patients with a lower likelihood of ischemia due to CAD. Risk is highest at the time of presentation but remains elevated past the acute phase. By 6 months, NSTE-ACS mortality rates may equal or exceed those of STEMI.⁵⁸ By 12 months, rates of death, MI, and recurrent instability in contemporary registries are >10%. Early events are related to the ruptured coronary plaque and thrombosis, and later events are more closely associated with the pathophysiology of chronic atherosclerosis and LV systolic function.^92–98

At initial presentation, the clinical history, anginal symptoms and equivalents, physical examination, ECG, renal function, and cardiac troponin measurements can be integrated into an estimation of the risk of death and nonfatal cardiac ischemic events (Table 3 and Figure 2).^42,78

Cardiac troponins are the mainstay for diagnosis of ACS and for risk stratification in patients with ACS. The primary diagnostic biomarkers of myocardial necrosis are cardiac troponin I and cardiac troponin T. Features that favor troponins for detection of ACS include high concentrations of troponins in the myocardium; virtual absence of troponins in nonmyocardial tissue; high-release ratio into the systemic circulation (amount found in blood relative to amount depleted from myocardium); rapid release into the blood in proportion to the extent of myocardial injury; and the ability to quantify values with reproducible, inexpensive, rapid, and easily applied assays. The 2012 Third Universal Definition of MI provides criteria that classify 5 clinical presentations of MI on the basis of pathological, clinical, and prognostic factors.²¹ In the appropriate clinical context, MI is indicated by a rising and/or falling pattern of troponin with ≥1 value above the 99th percentile of the upper reference level and evidence for serial increases or decreases in the levels of troponins.^67,68,156 The potential consequences of emerging high-sensitivity troponin assays include increases in the diagnosis of NSTEMI^152,172,173 influenced by the definition of an abnormal troponin.^{67,153,174,175} The recommendations in this section are formulated from studies predicated on both the new European Society of Cardiology/ACC/AHA/World Health Organization criteria²¹ and previous criteria/ redefinitions of MI based on earlier-generation troponin assays (Appendix 4, Table A).

Of the 3 troponin subunits, 2 subunits (troponin I and troponin T) are derived from genes specifically expressed in the myocardium. Cardiac troponin measurements provide highly sensitive results specific for detecting cardiomyocyte necrosis.^34,173 Highly sensitive assays can identify cardiac troponin not only in the blood of patients with acute cardiac injury, but also in the blood of most healthy people.^{64,68,70,166,176,177} As assay sensitivity increases, a greater proportion of patients will have detectable long-term elevations in troponin, thus requiring consideration of serial changes for the diagnosis of MI. Clinicians should be aware of the sensitivity of the tests used for troponin evaluation in their hospitals and cutpoint concentrations for clinical decisions. Markedly elevated values are usually related to MI, myocarditis, rare analytical factors, or chronic elevations in patients with renal failure and in some patients with HF.

CPGs endorse the 99th percentile of the upper reference level as the appropriate cutpoint for considering myocardial necrosis.^21,22 For the diagnosis of acute myocardial necrosis, it is important to determine not only the peak troponin value, but also serial changes:

Absolute changes in nanograms per liter of high-sensitivity cardiac troponin T levels appear to have a significantly higher diagnostic accuracy for AMI than relative changes and may distinguish AMI from other causes of high-sensitivity cardiac troponin T elevations.⁷¹ This has also been suggested for some contemporary assays.⁷¹ Troponins are elevated in MI as early as 2 to 4 hours after symptom onset,^64,70 and many medical centers obtain troponins at 3 hours. Depending on the assay, values may not become abnormal for up to 12 hours. In the vast majority of patients with symptoms suggestive of ACS, MI can be excluded or confirmed within 6 hours, because very few patients present immediately after symptom onset. In high-risk patients, measurements after 6 hours may be required to identify ACS.

Solitary elevations of troponin cannot be assumed to be due to MI, because troponin elevations can be due to tachyarrhythmia, hypotension or hypertension, cardiac trauma, acute HF, myocarditis and pericarditis, acute pulmonary thromboembolic disease, and severe noncardiac conditions such as sepsis, burns, respiratory failure, acute neurological diseases, and drug toxicity (including cancer chemotherapy). Chronic elevations can result from structural cardiac abnormalities such as LV hypertrophy or ventricular dilatation and are also common in patients with renal insufficiency.³⁴ Patients with end-stage renal disease and no clinical evidence of ACS frequently have elevations of cardiac troponin.^180–182 With conventional assays, this is more common with cardiac troponin T than with cardiac troponin I.¹⁸⁰ In the diagnosis of NSTEMI, cardiac troponin values must manifest an acute pattern consistent with the clinical events, including ischemic symptoms and electrocardiographic changes. Troponin elevations may persist for up to 14 days or occasionally longer. There is a paucity of guidelines for establishment of reinfarction during the acute infarct period on the basis of troponin measurements. References suggest that an increase of >20% of previous troponin levels or an absolute increase of high-sensitivity cardiac troponin T values (eg, >7 ng/L over 2 hours) may indicate reinfarction.^183–185

During pregnancy, troponin values are within the normal range in the absence of cardiovascular morbidities. There is controversy as to whether troponin levels are elevated in pre-eclampsia, eclampsia, or gestational hypertension.^186–189 When present, cardiac troponin elevations reflect myocardial necrosis.

Point-of-care troponin values may provide initial diagnostic information, although their sensitivity is substantially below that of central laboratory methods.^{154,155,190–192} In addition, the rigorous quantitative assay standardization needed for routine diagnosis favors central laboratory testing.

Previously, CK-MB was used for early evidence of myocardial injury. Because myoglobin is a relatively small molecule, it is rapidly released from infarcted myocardium. CK-MB is much less sensitive for detection of myocardial injury than troponin, and substantially more tissue injury is required for its detection. With the availability of cardiac troponin, CK-MB, myoglobin, and other diagnostic biomarkers are no longer necessary.^{158,160–163,196–198} CK-MB may be used to estimate MI size. Detection of MI after percutaneous coronary intervention (PCI) remains an area of controversy. Because of the increased sensitivity of cardiac troponin, the prognostic value associated with varying degrees of elevation remains unclear.

The majority of patients presenting to the ED with chest pain do not have ACS (Figure 1), and most are at low risk for major morbidity and mortality.³⁵ Low-risk patients are usually identified by an absence of history of cardiovascular disease, normal or near-normal initial ECG, normal initial troponin, and clinical stability.^35,202 The utility of an accelerated diagnostic protocol for detecting patients with benign conditions versus those who require admission for serious disease has been established.³⁵ At minimum, these protocols involve serial ECGs and troponin measurements, both of which can be performed in the ED, a separate chest pain unit, or a telemetry unit. A 30-day negative predictive value >99% for ACS has been reported for patients presenting to the ED with chest pain who undergo a 2-hour accelerated diagnostic protocol composed of a TIMI risk score of 0, normal ECG, and normal high-sensitivity troponin at 0 hours and 2 hours (assuming appropriate follow-up care).^65,210 Some protocols also call for a functional or anatomic test (eg, treadmill test, rest scintigraphy, coronary CT angiography, stress imaging). Coronary CT angiography is associated with rapid assessment, high negative predictive value, decreased length of stay, and reduced costs^205–207; however, in the latter studies, it increased the rate of invasive coronary angiography and revascularization with uncertain long-term benefits in low-risk patients without ECG or troponin alterations.²¹¹ Accelerated diagnostic protocols are also potentially applicable in intermediate-risk patients, whose presentation includes a history of cardiovascular disease, diabetes mellitus, chronic kidney disease (CKD), and/or advanced age.²⁰²

Patients with cyanosis, arterial oxygen saturation <90%, respiratory distress, or other high-risk features of hypoxemia are treated with supplemental oxygen. The 2007 UA/NSTEMI CPG recommended the routine administration of supplemental oxygen to all patients with NSTE-ACS during the first 6 hours after presentation on the premise that it is safe and may alleviate hypoxemia.²¹² The benefit of routine supplemental oxygen administration in normoxic patients with NSTE-ACS has never been demonstrated. At the time of GWC deliberations, data emerged that routine use of supplemental oxygen in cardiac patients may have untoward effects, including increased coronary vascular resistance, reduced coronary blood flow, and increased risk of mortality.^213–215

ACE inhibitors reduce mortality in patients with recent MI, primarily those with LV dysfunction (LVEF <0.40) with or without pulmonary congestion.^283–285 In patients with normal LV function (including patients with diabetes mellitus), total mortality and MACE (including HF) are reduced. It has been found that approximately 15% of patients with NSTEMI develop HF during hospitalization, with the rate increasing to 24% of patients 1 year later.²⁸⁶ A metaanalysis demonstrated a small but significant (0.48%) absolute benefit of early initiation of an ACE inhibitor on survival at 30 days, with benefit seen as early as 24 hours after admission for AMI.²⁸³ An ACE inhibitor should be used cautiously in the first 24 hours of AMI, because it may result in hypotension or renal dysfunction.²⁸³ It may be prudent to initially use a short-acting ACE inhibitor, such as captopril or enalapril, in patients at increased risk of these adverse events. In patients with significant renal dysfunction, it is sensible to stabilize renal function before initiating an ACE inhibitor or an ARB, with re-evaluation of creatinine levels after drug initiation. An ARB may be substituted for an ACE inhibitor with similar benefits on survival.^277,278 Combining an ACE inhibitor and an ARB may result in an increase in adverse events.^277,278 In a study in which patients with AMI with LV dysfunction (LVEF <0.40) with or without HF were randomized 3 to 14 days after AMI to receive eplerenone (a selective aldosterone blocker), eplerenone was efficacious as an adjunct to ACE inhibitors and beta blockers in decreasing long-term mortality.^279,287 In a study of patients with HF, >50% of whom had an ischemic etiology, spironolactone (a nonselective aldosterone inhibitor) was beneficial²⁷⁹; however, RCT data on MI are not available.

See Table 7 for a summary of recommendations from this section and Online Data Supplement 15 for additional information on initial oral and intravenous antiplatelet therapy in patients with definite or likely NSTE-ACS treated with an early invasive or an ischemia-guided strategy.

Despite the large number of new antiplatelet and antithrombotic agents, aspirin, which targets COX and subsequent thromboxane A₂ inhibition, is the mainstay of antiplatelet therapy. Multiple other pathways of platelet activation can be targeted by agents that inhibit the platelet P2Y₁₂ receptor, including thienopyridine prodrug agents, such as clopidogrel and prasugrel, which require conversion into molecules that bind irreversibly to the P2Y₁₂ receptor. Additional pyrimidine derivatives, including ticagrelor, do not require biotransformation and bind reversibly to the P2Y₁₂ receptor, antagonizing adenosine diphosphate platelet activation. In addition to these oral agents, intravenous GP IIb/IIIa receptor inhibitors, including abciximab, eptifibatide, and tirofiban, target the final common pathway of platelet aggregation. In the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome) trial, patients were randomly assigned to either early, pre–PCI double-bolus eptifibatide or delayed, provisional eptifibatide. Seventy-five percent of the patients received upstream, preprocedure clopidogrel. The risk of TIMI major bleeding in the early eptifibatide group was 2.6% compared with 1.8% (P=0.02) in the delayed provisional group.²⁹⁵ In the GUSTO IV-ACS (Global Use of Strategies To Open Occluded Coronary Arteries IV-Acute Coronary Syndromes) trial, there was no clinical benefit of abciximab in this population; in troponin-negative patients, mortality was 8.5% compared with 5.8% in controls (P=0.002).^{288,289,296,297}

See Table 7 for a summary of recommendations regarding antiplatelet/anticoagulant therapy in patients with definite or likely NSTE-ACS and Online Data Supplement 16 for additional information on combined oral anticoagulant therapy and antiplatelet therapy in patients with definite NSTE-ACS.

There is no role for fibrinolytic therapy in patients with NSTE-ACS. Fibrinolysis with or without subsequent PCI in patients with NSTE-ACS was evaluated by the Fibrinolytic Trialists and TIMI investigators.^93,329 There was no benefit for mortality or MI. Intracranial hemorrhage and fatal and nonfatal MI occurred more frequently in patients treated with fibrinolytic therapy.

Two treatment pathways have emerged for all patients with NSTE-ACS. The invasive strategy triages patients to an invasive diagnostic evaluation (ie, coronary angiography). In contrast, the initial ischemia-guided strategy calls for an invasive evaluation for those patients who 1) fail medical therapy (refractory angina or angina at rest or with minimal activity despite vigorous medical therapy), 2) have objective evidence of ischemia (dynamic electrocardiographic changes, myocardial perfusion defect) as identified on a noninvasive stress test, or 3) have clinical indicators of very high prognostic risk (eg, high TIMI or GRACE scores). In both strategies, patients should receive optimal anti-ischemic and antithrombotic medical therapy as outlined in Section 4.1. A subgroup of patients with refractory ischemic symptoms or hemodynamic or rhythm instability are candidates for urgent coronary angiography and revascularization.

This strategy seeks to rapidly risk stratify patients by assessing their coronary anatomy. The major advantages of invasive therapy when appropriate are 1) the rapid and definitive nature of the evaluation, 2) the potential for earlier revascularization in appropriate patients that might prevent occurrence of further complications of ACS that could ensue during medical therapy, and 3) facilitation of earlier discharge from a facility.

The ischemia-guided strategy seeks to avoid the routine early use of invasive procedures unless patients experience refractory or recurrent ischemic symptoms or develop hemodynamic instability. When the ischemia-guided strategy is chosen, a plan for noninvasive evaluation is required to detect severe ischemia that occurs at a low threshold of stress and to promptly refer these patients for coronary angiography and revascularization as indicated. The major advantage offered by the ischemia-guided strategy is that some patients’ conditions stabilize during medical therapy and will not require coronary angiography and revascularization. Consequently, the ischemia-guided strategy may potentially avoid costly and possibly unnecessary invasive procedures.

Several studies^{93,138,334–337} and meta-analyses^{141, 340} have concluded that a strategy of routine invasive therapy is generally superior to an ischemia-guided strategy or selectively invasive approach. One study reported that the routine invasive strategy resulted in an 18% relative reduction in death or MI, including a significant reduction in MI alone.³⁴¹ The routine invasive arm was associated with higher in-hospital mortality (1.8% versus 1.1%), but this disadvantage was more than compensated for by a significant reduction in mortality between discharge and the end of follow-up (3.8% versus 4.9%). The invasive strategy was also associated with less angina and fewer rehospitalizations. Patients undergoing routine invasive treatment also had improved quality of life. In an analysis of individual patient data³⁴⁰ that reported 5-year outcomes from the FRISC (Framingham and Fast Revascularization During Instability in Coronary Artery Disease)-II trial,³³⁹ ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes) trial,³³⁸ and RITA (Randomized Trial of a Conservative Treatment Strategy Versus an Interventional Treatment Strategy in Patients with Unstable Angina)-3 trial,³³⁴ 14.7% of patients (389 of 2721) randomized to a routine invasive strategy experienced cardiovascular death or nonfatal MI versus 17.9% of patients (475 of 2746) in the selective invasive strategy (HR: 0.81; 95% CI: 0.71 to 0.93; P=0.002). The most marked treatment effect was on MI (10.0% routine invasive strategy versus 12.9% selective invasive strategy), and there were consistent trends for fewer cardiovascular deaths (HR: 0.83; 95% CI: 0.68 to 1.01; P=0.068) and all-cause mortality (HR: 0.90; 95% CI: 0.77 to 1.05). There were absolute reductions of 2.0% to 3.8% in cardiovascular death or MI in the low- and intermediate-risk groups and an 11.1% absolute risk reduction in the highest-risk patients. The invasive strategy demonstrated its greatest advantage in the highest-risk stratum of patients with no significant benefit on mortality over the noninvasive approach in moderate- and low-risk patients.³⁴² An ischemia-guided strategy has been used with favorable results in initially stabilized patients with NSTE-ACS at elevated risk for clinical events, including those with positive troponin levels.³³⁸ One limitation of these studies is the absence of adherence to optimal medical therapy in non-invasively treated patients during long-term management. In addition, in FRISC-II, invasive management was delayed and patients with markedly positive stress tests (up to 2.9-mm exercise-induced ST depression) were randomized to noninvasive or invasive therapy.³³⁸

The TACTICS-TIMI (Treat Angina With Tirofiban and Determine Cost of Therapy With an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction) 18 trial demonstrated a reduction in the 6-month endpoint of death or MI in older adults with ACS.¹³⁸ Controversy exists over revascularization treatment differences between men and women with ACS. The FRISC-II trial showed a benefit of revascularization in men for death or MI that was not observed for women.³⁴⁴ In contrast, death, MI, or rehospitalization rates were reduced for both men and women in TACTICS-TIMI 18.¹³⁸ RITA-3 showed that the routine strategy of invasive evaluation resulted in a beneficial effect in high-risk men that was not seen in women.³⁴² A meta-analysis suggests that in NSTE-ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite endpoint of death, MI, or rehospitalization.^141,345,346 In contrast, an ischemia-guided strategy is preferred in low-risk women.¹⁴¹ Another collaborative meta-analysis of randomized trials reported that an early invasive strategy yielded similar RR reductions in overall cardiovascular events in patients with and without diabetes mellitus.³⁴⁷ However, an invasive strategy appeared to reduce recurrent nonfatal MI to a greater extent in patients with diabetes mellitus.

Coronary angiography is designed to provide detailed information about the size and distribution of coronary vessels, the location and extent of atherosclerotic obstruction, and the suitability for revascularization. The LV angiogram, usually performed with coronary angiography, provides an assessment of the extent of focal and global LV dysfunction and of the presence and severity of coexisting disorders (eg, valvular or other associated lesions). Patients with NSTE-ACS can be divided into risk groups on the basis of their initial clinical presentation. The TIMI, PURSUIT, and GRACE scores are useful tools for assigning risk to patients with NSTE-ACS.

Risk stratification identifies patients who are most likely to benefit from subsequent revascularization. Patients with left main disease or multivessel CAD with reduced LV function are at high risk for adverse outcomes and are likely to benefit from CABG. Clinical evaluation and noninvasive testing aid in the identification of most patients at high risk because they often have ≥1 of the following high-risk features: advanced age (>70 years of age), prior MI, revascularization, ST deviation, HF, depressed resting LV function (ie, LVEF ≤0.40) on noninvasive study, or noninvasive stress test findings, including magnetic resonance imaging.³⁴⁸ Any of these risk factors or diabetes mellitus may aid in the identification of high-risk patients who could benefit from an invasive strategy.

Some patients with NSTE-ACS are not in the very high-risk group and do not have findings that portend a high risk for adverse outcomes. They are not likely to receive the same degree of benefit from routine revascularization afforded to high-risk patients, and an invasive study is optional for those at lower risk and can be safely deferred pending further clinical evidence. Decisions about coronary angiography in patients who are not at high risk according to findings on clinical examination and noninvasive testing can be individualized on the basis of patient preferences and/or symptoms.

The goals of noninvasive testing in patients with a low or intermediate likelihood of CAD and high-risk patients who did not have an early invasive strategy are to detect ischemia and estimate prognosis. This information guides further diagnostic steps and therapeutic measures.

Because of its simplicity, lower cost, and widespread familiarity with its performance and interpretation, the standard low-level exercise electrocardiographic stress test remains the most reasonable test in patients who are able to exercise and who have a resting ECG that is interpretable for ST shifts. There is evidence that imaging studies are superior to exercise electrocardiographic evaluation in women for diagnosis of CAD.³⁵⁰ However, for prognostic assessment in women, treadmill exercise testing has provided comparable results to stress imaging.³⁵⁴ Patients with an electrocardiographic pattern that would interfere with interpretation of the ST segment (baseline ST abnormalities, bundle-branch block, LV hypertrophy with ST-T changes, intraventricular conduction defect, paced rhythm, pre-excitation, and digoxin) should have an exercise test with imaging. Patients who are unable to exercise should have a pharmacological stress test with imaging. Low- and intermediate-risk patients with NSTE-ACS may undergo symptom-limited stress testing, provided they have been asymptomatic and clinically stable at 12 to 24 hours for those with UA and 2 to 5 days for patients at similar risk with NSTEMI.³⁴⁹ The optimal testing strategy in women is less well defined than in men.

In contrast to noninvasive tests, coronary angiography provides detailed structural information for assessment of prognosis and appropriate management. When combined with LV angiography, it also provides an assessment of global and regional LV function. Coronary angiography is usually indicated in patients with NSTE-ACS who have recurrent symptoms or ischemia despite adequate medical therapy or who are at high risk as categorized by clinical findings (HF, serious ventricular arrhythmias), noninvasive test findings (significant LV dysfunction with EF <0.40, large anterior or multiple perfusion defects or wall motion abnormalities on echocardiography, high-risk Duke treadmill score ≤−11), high-risk TIMI or GRACE scores, or markedly elevated troponin levels. Patients with NSTE-ACS who have had previous PCI or CABG should also be considered for early coronary angiography, unless prior coronary angiography data indicate that no further revascularization is feasible.

The general indications for coronary angiography and revascularization should be tempered by individual patient characteristics and preferences (a patient-centered approach). Patient and clinician judgments about risks and benefits are important for patients who might not be candidates for coronary revascularization, such as very frail older adults and those with serious comorbid conditions (eg, severe hepatic, pulmonary, or renal failure; active or inoperable cancer).

Approximately half of all PCI procedures are performed in patients with UA or NSTEMI, and approximately 32% to 40% of patients with NSTE-ACS will undergo PCI.³⁶⁵ As discussed previously, in patients with NSTE-ACS, a strategy of early angiography and revascularization (primarily with PCI) results in lower rates of recurrent UA, recurrent reho-spitalization, MI, and death.^366,367 Although PCI of a nonculprit lesion is not advocated in patients with STEMI,²⁶ there is less agreement on whether nonculprit lesions should undergo intervention at the time of culprit-lesion PCI for NSTE-ACS. Most reports,^359–364 but not all,³³⁰ comparing culprit lesion–only PCI with multivessel PCI (eg, PCI of multiple vessels performed at the same time) in patients with NSTE-ACS did not find an increased risk of MACE with multivessel PCI and found a reduction in the need for repeat revascularization. However, the data consist predominantly of post hoc analysis of nonrandomized data with variable duration of follow-up. This question has not been resolved and is an area of current investigation.

The combination of oral antiplatelet therapy and oral anticoagulant therapy significantly increases the risk of bleeding. This risk varies widely, but on average, the addition of a single antiplatelet agent increased the risk of bleeding from a range of 2% to 3% to a range of 4% to 6%, whereas the addition of DAPT to oral anticoagulant therapy (“triple therapy”) increased the risk of bleeding from a range of 4% to 6% to a range of 10% to 14%.^432–435 This risk was also related to the duration of triple therapy.

In patients with NSTE-ACS in whom there are indications for triple therapy, the benefit of such therapy in terms of prevention of stent thrombosis, thromboembolic events, and recurrent MI must be weighed against the risk of bleeding complications. Similarly, DAPT, in addition to anticoagulant therapy, requires consideration of the increased risk of bleeding. It is essential that therapeutic decision making in this critical area include discussion with the patient about the options, advantages, and limitations of available approaches.

Recommendations about the management of patients treated with triple therapy have been published in ACC/AHA CPGs and by other organizations.^{17,26,430,433,436} Although some organizations have recommended a target INR of 2.0 to 2.5 in patients with atrial fibrillation (AF) who require triple therapy,⁴³⁷ others continue to recommend a target INR of 2.0 to 3.0.^12,436 The HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score has relevance in these deliberations.⁴³⁹ No prospective study to date has demonstrated that a target INR of 2.0 to 2.5 reduces bleeding complications.

Whenever possible, shorter durations of triple therapy are favored in preference to longer durations of triple therapy. In patients with NSTE-ACS who require oral anticoagulation for AF, mechanical heart valve, deep venous thrombosis, or other conditions, a bare-metal stent may offer the advantages of lower bleeding risk over a DES because of the potentially shorter duration of triple antithrombotic therapy. The WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting) trial is the first published study to address the question of optimal antiplatelet therapy in patients taking oral anticoagulant medication.⁴⁴⁰ WOEST was a randomized, open-label trial of 563 patients (approximately 25% of whom had NSTE-ACS) receiving oral anticoagulant therapy and undergoing coronary stenting. Patients randomized to single antiplatelet treatment with clopidogrel had significantly fewer bleeding complications and no increase in thrombotic events compared with those randomized to DAPT with aspirin and clopidogrel. Larger clinical trials are needed to compare double versus triple therapy in the setting of coronary stenting and NSTE-ACS. One such study that has been initiated is PIONEER AF-PCI (an Open-Label, Randomized, Controlled, Multicenter Study Exploring two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation who Undergo Percutaneous Coronary Intervention).

Although there are some data on therapy with aspirin, clopidogrel, and warfarin, there is sparse information on the use of newer P2Y₁₂ inhibitors (prasugrel, ticagrelor), direct thrombin inhibitor (dabigatran), or factor-Xa inhibitors (rivaroxaban, apixaban) in patients receiving triple therapy. Prasugrel³⁰² and ticagrelor⁴¹² produce a greater degree of platelet inhibition than clopidogrel and are associated with greater rates of bleeding.^{300,302,412,441} These are important potential disadvantages in patients requiring triple therapy, a group in which the inherent risks of bleeding are significantly increased. (Overall bleeding risk was not increased with ticagrelor, although there was increased bleeding in certain subgroups on this drug).⁴¹² Because there are no well-established therapies to reverse the anticoagulant effects of the newer oral antiplatelet agents, caution is required when considering the use of these agents in patients who require triple therapy and are at significantly increased risk of bleeding. This admonition is especially important in elderly patients, a group in which bleeding risk is inherently increased (Section 7.1).

Proton pump inhibitors decrease the risk of gastrointestinal bleeding in patients treated with DAPT⁴³¹ and are used in patients treated with DAPT who have a history of gastrointestinal bleeding and those at increased risk of bleeding, which is associated with oral anticoagulation therapy even if there is no history of gastrointestinal bleeding.⁴³⁰ On the basis of these results, proton pump inhibitors are also used in patients receiving triple antithrombotic therapy who have a history of gastrointestinal bleeding. Although the clinical evidence that omeprazole and esomeprazole diminish the antiplatelet efficacy of clopidogrel is weak,⁴³⁰ the US Food and Drug Administration has issued a warning to avoid concomitant use of these 2 proton pump inhibitors with clopidogrel.⁴⁴²

Although higher platelet reactivity has been associated with a greater incidence of adverse events in patients undergoing stent implantation, a strategy of adjusting antiplatelet therapy based on routine platelet function testing has not been beneficial in reducing ischemic complications.^26,443–445 Similarly, a strategy of routine genetic phenotype testing has also not been beneficial and thus is not recommended.^26,446–448 A more detailed discussion of these issues and current recommendations about platelet function testing and genetic testing are in the 2011 PCI CPG.²⁶

The US Public Health Service emphasizes comprehensive cardiac rehabilitation programs,⁴⁴⁹ and the 2011 secondary prevention CPG underscores referral to cardiac rehabilitation for survivors of ACS.²⁷ Since 2007, referral to these programs has been designated a quality performance measure.^453–455 Barriers to referral can be obviated by discussion with the patient and referral by the patient’s primary care clinician and/or cardiovascular caregiver. These comprehensive programs provide patient education, enhance regular exercise, monitor risk factors, and address lifestyle modification.⁴⁵⁶ Aerobic exercise training can generally begin 1 to 2 weeks after discharge in patients treated with PCI or CABG.⁴⁵⁷ Mild-to-moderate resistance training can be considered and started 2 to 4 weeks after aerobic training.⁴⁵⁸ Unsupervised exercise may target a heart rate range of 60% to 75% of maximum age-predicted heart rate based on the patient’s exercise stress test. Supervised training may target a higher heart rate (70% to 85% of age-predicted maximum).⁴⁵⁷ Additional restrictions apply when residual ischemia is present. Daily walking can be encouraged soon after discharge for most patients. Resource publications on exercise prescription in cardiovascular patients are available.^456,457 Regular physical activity reduces symptoms in patients with cardiovascular disease, enhances functional capacity, improves other risk factors such as insulin resistance and glucose control, and is important in weight control.⁴⁵⁶ Questionnaires and nomograms for cardiac patients have been developed to guide exercise prescription if an exercise test is unavailable.^459–462 See Section 6.4 and Table 10 for more information.

Results of testing should be discussed with the patient, the patient’s family, and/or the patient’s advocate in an understandable manner. Test results should be used to help determine the advisability of coronary angiography, the need for adjustments in the medical regimen, and the specifics for secondary prevention measures. See Section 6.4 and Table 10 for more information on plan of care.

Vaccination with the 23-valent pneumococcal polysaccharide vaccine is recommended for all adults ≥65 years of age. Adults of any age who are at increased risk, including smokers and those with asthma, should also be given the vaccine. Immunocompromised adults should receive the 13-valent conjugate vaccine in addition to the 23-valent vaccine.^464–466 The influenza vaccine is discussed in Section 6.4.

Selective COX-2 inhibitors and other nonselective NSAIDs have been associated with increased cardiovascular risk, and the risk appears to be amplified in patients with established. cardiovascular disease.^{17,234,235,467,469} In a large Danish observational study of patients with first MI (n=58 432), the HR and 95% CI for death were 2.80 (2.41 to 3.25) for rofecoxib, 2.57 (2.15 to 3.08) for celecoxib, 1.50 (1.36 to 1.67) for ibuprofen, 2.40 (2.09 to 2.80) for diclofenac, and 1.29 (1.16 to 1.43) for other NSAIDs.²³⁴ There were dose-related increases in risk of death and non–dose-dependent trends for rehospitalization for MI for all drugs.^234,467 An AHA scientific statement on the use of NSAIDs concluded that the risk of cardiovascular events is proportional to COX-2 selectivity and the underlying risk in the patient.²³⁷ Non-pharmacological approaches were recommended as the first line of treatment, followed by the stepped-care approach to pharmacological therapy, as shown in Figure 4.

Although prior observational data suggested a protective effect of hormone therapy for coronary events, a randomized trial of hormone therapy for secondary prevention of death and MI (the HERS [Heart and Estrogen/Progestin Replacement] study) failed to demonstrate a beneficial effect.⁴⁷³ There was an excess risk for death and MI early after initiation of hormone therapy. The Women’s Health Initiative included randomized primary prevention trials of estrogen plus progestin and estrogen alone.⁴⁷² Both trials were stopped early owing to an increased risk related to hormone therapy that was believed to outweigh the potential benefits of further study.^470–472 It is recommended that post-menopausal women receiving hormone therapy at the time of a cardiovascular event discontinue its use and that hormone therapy should not be initiated for the primary or secondary prevention of coronary events. However, there may be other permissible indications for hormone therapy in postmenopausal women (eg, treatment of perimenopausal symptoms such as flushing or prevention of osteoporosis) if the benefits are believed to outweigh the increased cardiovascular risk. Postmenopausal women who are >1 to 2 years past the initiation of hormone therapy who wish to continue such therapy for another compelling indication should weigh the risks and benefits, recognizing the greater risk of cardiovascular events and breast cancer (combination therapy) or stroke (estrogen).⁴⁷³

Although there is an association of elevated homocysteine blood levels and CAD, a reduction in homocysteine levels with routine folate supplementation did not reduce the risk of CAD events in 2 trials (the NORVIT [Norwegian Vitamin Trial] and the HOPE [Heart Outcomes Prevention Evaluation] study) that included post–MI or high-risk stable patients^476–478 and produced poorer outcomes in another study.⁴⁷⁹ Additionally, in the NORVIT trial, there was a trend toward increased cardiovascular events (95% CI: 1.00 to 1.50; P=0.05) in the cohort receiving the combination of folic acid, vitamin B6, and vitamin B12; the authors cautioned against using the treatment for secondary prevention.⁴⁷⁶ Similarly, experience in large clinical trials with antioxidant vitamins has failed to demonstrate benefit for primary or secondary prevention.^474,475,480

There has been improved understanding of the system changes necessary to achieve safer care.⁴⁹⁷ This includes adoption by all US hospitals of a standardized set of “Safe Practices” endorsed by the National Quality Forum,⁴⁹⁸ which overlap with the National Patient Safety Goals espoused by The Joint Commission.⁴⁹⁹ Examples of patient safety standards for all patients after AMI include improved communication among clinicians, nurses, and pharmacists; medication reconciliation; careful transitions between care settings; and consistent documentation. The National Quality Forum has also endorsed a set of patient-centered “Preferred Practices for Care Coordination,”⁵⁰⁰ which detail comprehensive specifications that are necessary to achieve successful care coordination for patients and their families. Systems of care designed to support patients with NSTE-ACS, STEMI, and other cardiac diseases can result in significant improvement in patient outcomes. Table 10 provides reference documents for multiple risk-reduction strategies for secondary prevention in the posthospital phase of NSTE-ACS. These include the 2013 ACC/AHA CPGs on management of blood cholesterol,¹⁸ obesity,¹⁶ and lifestyle¹⁵ and the 2014 recommendations for management of hypertension,⁵⁰¹ which were published during the development of this CPG. To provide the interventions and services listed in Table 10, appropriate resources must be used so that patients with MI have full access to evidence-based therapies and follow-up care. There is a growing emphasis on penalizing hospitals for avoidable hospital readmissions. It is imperative for health systems to work with clinicians, nurses, pharmacists, communities, payers, and public agencies to support the interventions that achieve comprehensive care. Several patient characteristics have been predictors of readmission after AMI.^502,503

Ventricular arrhythmias are common early after onset of NSTE-ACS, and not all require intervention. The mechanisms for these arrhythmias include continuing ischemia, hemodynamic and electrolyte abnormalities, reentry, and enhanced automaticity. Approximately 5% to 10% of hospitalized patients may develop ventricular tachycardia (VT)/ventricular fibrillation (VF), usually within 48 hours of presentation.⁵⁷⁴ The incidence of VF in otherwise uncomplicated AMI appears to have decreased within the past few years from >4% to <2%, of which 59% of patients had non–Q-wave MI.⁵⁷⁴ A study of 277 consecutive patients with NSTE-ACS who underwent cardiac catheterization within 48 hours found VT/VF occurring in 7.6% of patients, 60% of which developed within 48 hours after admission.⁵⁷⁵ Risk factors for VT/VF include HF, hypotension, tachycardia, shock, and low TIMI flow grade. Treatment consists of immediate defibrillation or cardioversion for VF or pulseless sustained VT. Early administration of beta blockers has been associated with reduction in incidence of VF.⁵⁷⁶ The prophylactic use of lidocaine is not recommended. Although VT/VF is associated with higher 90-day mortality risk, premature ventricular contractions not associated with hemodynamic compromise and accelerated ventricular rhythms do not confer higher mortality risks and do not require specific therapy other than maintaining electrolyte balance. NSTE-ACS non-sustained VT occurring >48 hours after admission indicates an increased risk of cardiac and sudden death, especially when associated with accompanying myocardial ischemia.⁵⁷⁷ Life-threatening ventricular arrhythmias that occur >48 hours after NSTE-ACS are usually associated with LV dysfunction and signify poor prognosis. RCTs in patients with ACS have shown consistent benefit of implantable cardioverter-defibrillator therapy for survivors of VT or VF arrest.^578–582 For other at-risk patients, especially those with significantly reduced LVEF, candidacy for primary prevention of sudden cardiac death with an implantable cardioverter-defibrillator should be readdressed ≥40 days after discharge.⁵⁸³ A life vest may be considered in the interim.

AF, atrial flutter, and other supraventricular arrhythmias may be triggered by excessive sympathetic stimulation, atrial stress due to volume overload, atrial infarction, pericarditis, electrolyte abnormalities, hypoxia, or pulmonary disease. AF is the most common of these arrhythmias and may develop in >20% of patients. AF is associated with shock, HF, stroke, and increased 90-day mortality.⁵⁸⁴ Management of AF requires rate control and adequate anticoagulation according to the 2014 AF CPG.¹² For hemodynamically unstable patients and those with continuing ischemia, treatment should be implemented according to the 2010 advanced cardiac life support CPGs.⁵⁸⁵

Sinus bradycardia is especially common with inferior NSTEMI. Symptomatic or hemodynamically significant sinus bradycardia should be treated with atropine and, if not responsive, temporary pacing. The incidence of complete heart block is 1.0% to 3.7% in NSTEMI, based on anterior or posterior/inferior location, respectively.⁵⁸⁶ Atrioventricular block and bundle-branch block develop in approximately 5% of patients.⁵⁸⁷ High-degree atrioventricular block or bundle-branch block in anterior NSTEMI is more ominous because of a greater extent of myocardial injury and involvement of the conduction system.⁵⁸⁷

First-degree atrioventricular block does not require treatment. High-grade atrioventricular block after inferior NSTEMI usually is transient, with a narrow QRS complex and a junctional escape rhythm that can be managed with an ischemia-guided strategy. Prophylactic placement of a temporary pacemaker is recommended for high-grade atrioventricular block, new bundle-branch block, or bifascicular block with anterior infarction. Indications for permanent pacing are reviewed in the 2012 device-based therapy CPG.²⁰

AMI is the leading cause of cardiogenic shock. Early revascularization is a mainstay in the treatment of cardiogenic shock.^560,589 Compared with medical therapy, early revascularization is associated with improved 6-month mortality⁵⁶⁰ and 13% absolute mortality reduction at 6 years.⁵⁸⁸ Urgent revascularization with CABG may be indicated for failed PCI, coronary anatomy not amenable to PCI, and at the time of surgical repair of a mechanical defect (eg, septal, papillary muscle, free-wall rupture). Age alone is not a contraindication to urgent revascularization for cardiogenic shock.^589,590 Mortality after cardiogenic shock has steadily improved,⁵⁹¹ including in older adults,^589,590 with 30-day mortality ranging from approximately 40% with milder forms of shock²⁶⁸ to >45% with refractory shock.⁵⁹² Approximately 30% of patients in the IABP-SHOCK (Intra-Aortic Balloon Pump in Cardiogenic Shock) II trial presented with NSTEMI,²⁶⁸ and 22% of patients in the TRIUMPH (Tilarginine Acetate Injection in a Randomized International Study in Unstable Acute Myocardial Infarction Patients With Cardiogenic Shock) trial had ST depression on presentation.⁵⁹² Of the 23% of patients with ACS who had NSTEMI in the GRACE registry, 4.6% of patients experienced cardiogenic shock.⁵⁹³ Of the 2992 patients in shock, 57% underwent cardiac catheterization, and in-hospital revascularization was performed in 47% of this group.

In-hospital mortality of all patients with shock was 59%.⁵⁹⁴ Patients with NSTEMI developed cardiogenic shock later than patients with STEMI, and had higher-risk clinical characteristics, more extensive CAD, and more recurrent ischemia and infarction before developing shock compared with patients with STEMI, and shock developed later in patients with NSTEMI.¹⁵¹ Patients with NSTEMI constituted >17% of those in the SHOCK trial registry.⁵⁹⁵ They were also older and had more comorbidities but had comparable mortality to patients with STEMI. The left circumflex coronary artery was the culprit vessel in 30% of patients with NSTEMI, suggesting the presence of true posterior MI.⁵⁹⁵ Dopamine in patients with cardiogenic shock may be associated with increased mortality compared with norepinephrine.⁵⁹⁶ The use of percutaneous ventricular assist devices has been hampered by the need for interventional expertise, cost, and lack of supportive evidence.⁵⁹⁷ IABP has been used for decades,^265,598 and it may facilitate intervention in patients who are hemodynamically unstable, but it did not reduce mortality or secondary endpoints in 1 RCT of 598 patients with cardiogenic shock complicating AMI.²⁶⁸ Newer devices with higher levels of support have provided better hemodynamic support but without improved clinical outcomes compared with IABP.^599,600

A meta-analysis (6 trials: 23 072 patients without diabetes mellitus, 6458 patients with diabetes mellitus) of the effect of GP IIb/IIIa platelet receptor inhibitors (abciximab, eptifibatide, and tirofiban) on mortality in NSTEMI revealed that for the entire patient group, a GP IIb/IIIa inhibitor was associated with reduced 30-day mortality (6.2% to 4.6%; P=0.007).³⁹² This benefit was particularly large in the 1279 patients with diabetes mellitus who underwent PCI (4.0% to 1.2%; P=0.002). The ACUITY trial in ACS (13 819 patients, 3852 with diabetes mellitus) reported that 30-day adverse clinical outcomes (death, MI, or unplanned revascularization) or major bleeding were increased in patients with diabetes mellitus (12.9% versus 10.6%; P<0.001).⁶¹⁷ Bivalirudin plus a GP IIb/IIIa inhibitor resulted in increased similar rates of the composite ischemia compared with heparin plus a GP IIb/IIIa inhibitor. Bivalirudin alone was associated with a similar increased rate of composite ischemia but less major bleeding (3.7% versus 7.1%; P<0.001).

Several studies evaluated the benefit of oral antiplatelet therapy during ACS in patients with diabetes mellitus. In TRITON-TIMI 38, patients with diabetes mellitus had a greater reduction in ischemic events without an observed increase in TIMI major bleeding with prasugrel compared with clopidogrel.⁶¹⁸ In PLATO, ticagrelor compared with clopidogrel reduced ischemic events irrespective of diabetic status and glycemic control, without an increase in major bleeding.⁶¹⁹

Patients with CKD with ACS are at increased risk for ischemic complications, including stent thrombosis and post–PCI ischemic events.⁶⁶³ They are also predisposed to higher bleeding complications, which, in addition to the lack of clinical trial data, result in their undertreatment with antiplatelet therapy. Patients with advanced CKD exhibit high residual platelet reactivity despite treatment with clopidogrel independent of the presence of diabetes mellitus.⁶⁶⁴ Hyporesponsiveness to thienopyridines is associated with increased adverse cardiovascular outcomes, including cardiovascular mortality,⁶⁶⁵ and higher dosing regimens of clopidogrel do not appear to further suppress adenosine diphosphate-induced platelet aggregation.^664,666

Although prasugrel may be more efficient than doubling the dose of clopidogrel in achieving adequate platelet inhibition,⁶⁶⁷ no clinical studies have demonstrated its efficacy in patients with CKD with ACS. Ticagrelor, however, was studied in a prespecified analysis from the PLATO trial.⁶⁶⁸ In patients with an estimated GFR <60 mL per minute (nearly 21% of patients in PLATO with available central laboratory serum creatinine levels), ticagrelor significantly reduced the primary cardiovascular endpoint (17.3% versus 22.0%; HR: 0.77; 95% CI: 0.65 to 0.90) compared with clopidogrel.⁶⁶⁷ Notably, this was associated with a 4% absolute risk reduction in all-cause mortality favoring ticagrelor and with no differences in major bleeding, fatal bleeding, and non–CABG-related major bleeding events, demonstrating its utility in patients with renal insufficiency.