Concise Clinical Review Unstable Angina and Non–ST Elevation Myocardial Infarction Eugene Braunwald1,2 1

The TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; and 2Department of Medicine, Harvard Medical School, Boston, Massachusetts

Non–ST elevation acute coronary syndromes are responsible for approximately 1 million admissions to U.S. hospitals and twice as many to European hospitals each year. Thus, they are among the most common serious illnesses in adults, and are associated with an in-hospital mortality of approximately 5%. The most common cause is rupture of an atherosclerotic coronary plaque, resulting in subtotal coronary occlusion. Diagnosis is based on the clinical picture of retrosternal chest pain, aided by electrocardiographic findings of ST segment deviations and biomarker abnormalities (elevation of troponin and natriuretic peptides) and cardiac imaging (myocardial scans showing perfusion defects). Treatment involves antiischemic agents (nitrates and b blockers), antiplatelet drugs (aspirin, P2Y12, and glycoprotein IIb/IIIa receptor blockers), and anticoagulants (unfractionated and low-molecular-weight heparins). Patients should undergo risk stratification, and those with high-risk factors should undergo coronary arteriography promptly with the intent to carry out coronary revascularization. Those at low risk should continue to receive intensive antiischemic and antithrombotic therapy. At discharge, patients should receive intensive lipid-lowering therapy with high doses of a statin, as tolerated. Keywords: antiplatelet drugs; invasive strategy; anticoagulants; coronary revascularization; ST segment deviations

The clinical manifestations of ischemic heart disease include chronic stable angina and acute coronary syndromes (ACS) (Figure 1); the latter consist of a spectrum of three related conditions—ST-segment elevation myocardial infarction (STEMI), non–ST-segment elevation myocardial infarctions (NSTEMI), and unstable angina (UA). The latter two manifestations, termed non–ST elevation acute coronary syndromes (NSTE-ACS), are the subject of this review. While the incidence of STEMI is declining, that of NSTE-ACS appears to be stable in the United States (Figure 2) (1), presumably because of a balance between more intensive preventive measures, which reduce the incidence of ACS, on the one hand, and on the other, the enhanced risk profile resulting from aging of the population and the increasing prevalence of diabetes and chronic kidney disease.

(Received in original form September 28, 2011; accepted in final form December 4, 2011) Correspondence and requests for reprints should be addressed to Eugene Braunwald, M.D., TIMI Study Group, 350 Longwood Avenue, Boston, MA 02115. E-mail: [email protected] This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org CME will be available for this article at http://ajrccm.atsjournals.org or at http:// cme.atsjournals.org Am J Respir Crit Care Med Vol 185, Iss. 9, pp 924–932, May 1, 2012 Copyright ª 2012 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201109-1745CI on December 28, 2011 Internet address: www.atsjournals.org

The clinical syndromes of UA and NSTEMI are similar, except that by definition the latter is associated with myocardial necrosis, and has a worse prognosis. As a result of the widespread use of increasingly sensitive troponin assays, a marker of myocardial necrosis, the apparent incidence of NSTEMI is rising while that of UA is declining (2).

PATHOGENESIS A number of processes have been identified in the pathogenesis of NSTE-ACS. (1) Rupture or erosion of an unstable, vulnerable atheromatous plaque with a superimposed nonocclusive thrombus, causing reduced myocardial perfusion, ischemia, and ultimately necrosis. Plaque instability is accelerated by inflammation of the arterial wall and by the expression of metalloproteinases present in T cells in the shoulder of the plaque; these enzymes are thought to attack the thin fibrous wall of the plaque (3). Both limbs of the clotting process, that is, the platelets and the coagulation cascade, play critical roles in thrombus formation. Plaque rupture or erosion exposes platelets to subendothelial collagen, which initiates the process of platelet adhesion to the damaged endothelial process. This adhesion of platelets leads to their activation and shape changes. Multiple platelet agonists, such as adenosine diphosphate (ADP), thromboxane, and epinephrine, lead to a conformational change of the glycoprotein (GP) IIb/IIIa receptor on the platelets’ surface that binds them to fibrinogen, resulting in platelet aggregation and the formation of a “platelet plug.” Downstream microembolization of platelet aggregates and plaque debris (Figure 3) often causes distal myocardial necrosis. The exposure of tissue factor activates the coagulation cascade; its combination with factor V leads to the activation of coagulation factor X to form factor Xa, which in turn leads to the conversion of factor II (prothrombin) into factor IIa (thrombin); the latter is responsible for the conversion of fibrinogen to fibrin, which traps platelet aggregates, thereby forming a thrombus. (2) Coronary artery vasoconstriction, which may involve both large and small vessels, as occurs in a adrenergic–mediated constriction, in cocaine abuse, and in constriction of small coronary arteries, that is, the microcirculation, in patients with so-called coronary syndrome X (3). It also occurs in the spasm of epicardial arteries in Prinzmetal’s angina, a condition that appears to be declining in North America and Western Europe, but remains prevalent in Asia. (3) An imbalance between myocardial O2 supply and demand, caused by increased O2 demand—secondary to conditions such as tachyarrhythmias, fever, anemia, or sepsis—in the presence of severe, fixed atherosclerotic narrowing of coronary arteries (4). These three pathogenetic processes of NSTE-ACS are not mutually exclusive. Any two and sometimes all three are simultaneously present.

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Figure 3. Culprit lesion of unstable angina. Shown is plaque rupture with superimposed dynamic thrombosis. The layering of thrombus reveals the stepwise progression. Microscopic distal emboli are seeded to the myocardium supplied by the artery. Reprinted by permission from Reference 43.

Figure 1. Spectrum of coronary artery disease. ACS ¼ acute coronary syndrome.

CLINICAL MANIFESTATIONS Like STEMI, NSTE-ACS secondary to coronary atherosclerosis is uncommon in men under 45 years and in women under 55 years, but its incidence rises steadily thereafter. The majority of patients with NSTE-ACS have a history of chronic stable angina, myocardial infarction (MI), and/or myocardial revascularization. However, NSTE-ACS may also be the first clinical manifestation of ischemic heart disease. It may present as the new onset of severe (>Canadian Class III) angina, the sudden acceleration and intensification of existing angina (crescendo angina), or the development of prolonged (.20 min) rest pain in patients with or without a recent MI (4). The discomfort in most patients with NSTE-ACS is described as frank pain, pressure, or heaviness, usually most prominent in the retrosternal region, with variable transmission to the ulnar aspect of the left arm, either shoulder, neck, and as high as the mandible or as low as the epigastrium (5). The pain occurs

Figure 2. Age- and sex-adjusted incidence rates of acute MI, 1999– 2008. I bars represent 95% confidence intervals. MI ¼ myocardial infarction; STEMI ¼ ST-segment elevation MI. Based on a population of 3 3 106 persons enrolled in Kaiser Permanente Northern California. The mortality rates are age and sex adjusted. Reprinted by permission from Reference 1.

at rest, or when it is precipitated by exertion, it is not usually relieved rapidly by rest and/or nitroglycerine, as chronic stable angina usually is. The pain may occur at night and awaken the patient from sleep (nocturnal angina). NSTE-ACS may be painless or be atypical, with so-called “anginal equivalents”— dyspnea, nausea, diaphoresis, abdominal pain, weakness, or syncope. Physical examination may be entirely normal, but in patients with large areas of ischemic myocardium, S3 and/or S4 gallop sounds and pulmonary rales may be audible; occasionally hypotension or frank cardiogenic shock occurs, although the latter features are far more common in STEMI. Laboratory

ECG changes, most commonly persistent ST segment depression, may be present especially if the recording is made at a time that the patient is experiencing pain. Transient ST-segment elevation may also occur. Deep, symmetrical (.2 mm) T-wave inversions are compatible with, but are not diagnostic of, NSTE-ACS; lesser T-wave inversions are nonspecific and not helpful in diagnosis. A biomarker profile of NSTE-ACS that reflects the pathogenesis is shown in Figure 4. Cardiac-specific troponins (cTn), I or T, are the biomarkers of choice and reflect myonecrosis. They are considered to be abnormally elevated if they are above the 99th percentile of the normal range of the specific assay used. While an abnormally elevated cTn generally signifies myocardial necrosis, this may occur in conditions causing myonecrosis other than MI, including heart failure, chest trauma, myocarditis, pericarditis, pulmonary embolism, or following cancer chemotherapy; cTnI may also be elevated in renal failure. Patients with suspected NSTE-ACS should have a troponin measured at presentation. Since it may take several hours after the onset of necrosis to become elevated, if negative on presentation it should be repeated 6 to 9 hours later. Two negative tests 6 to 9 hours apart usually exclude NSTEMI, but do not exclude UA, in which by definition there is no myocardial necrosis. Ultrasensitive troponins rise within 3 hours after the onset of chest pain, and the absence of the very low concentrations detected by these tests makes it possible to rule out NSTEMI rapidly (6). A number of other biomarkers may be elevated, including the C-reactive protein (considered to be a “barometer” of inflammation), which when elevated, is associated with increased long-term risk (7). Elevation of a natriuretic peptide (brain natriuretic peptide [BNP] or N-terminal proBNP) reflecting

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Figure 4. Biomarker profile in acute coronary syndromes. CrCl ¼ creatine clearance; HbA1c ¼ hemoglobin A1c; hsCRP ¼ high-sensitivity C-reactive protein; Lp-PLA2 ¼ lipoprotein-associated phospholipase A2. Adapted by permission from Reference 44.

hemodynamic stress is also associated with increased risk (8). Fasting hyperglycemia—particularly if recurrent—and elevation of hemoglobin A1c, reflecting chronic elevation of glucose and the diagnosis of diabetes, are associated with accelerated atherogenesis and a high incidence of both early and late recurrence. An increased risk of adverse outcomes is also present in patients with renal dysfunction, reflected in elevations of creatinine or cystatin C, and with a reduction of estimated glomerular filtration rate. Cardiac Imaging

Echocardiography is useful in assessing ventricular function, but regional dysfunction may be present in acute ischemia and old infarction. 99mTc-sestamibi myocardial perfusion imaging at rest identifies one or more areas of hypoperfusion in almost all patients with NSTE-ACS, but as is the case with echocardiography cannot distinguish clearly between acute ischemia and old infarction (9). Contrast-enhanced computed tomographic angiography can identify vulnerable plaques, which are characterized by positive (outward) remodeling, low plaque density, and spotty calcification (Figure 5a). Computed tomographic angiography is being used with increasing frequency in emergency departments, especially in patients deemed to be at low risk of having ACS (10). A test that does not show a severe stenosis (.50% in luminal diameter) has a high negative predictive value and thus helps in ruling out a coronary cause of chest pain. Cardiac magnetic resonance imaging can simultaneously assess global and regional left ventricular function, perfusion, and myocardial viability. It can identify areas of myocardial hypoperfusion and left ventricular dysfunction. Delayed enhancement after contrast injection is present in areas of MI and scar (11). Coronary Angiography

Approximately 85% of patients with the clinical diagnosis of NSTE-ACS have significant coronary obstruction (i.e., >50% luminal diameter stenosis) (Figure 5b); approximately 25% have obstruction in one major coronary artery, 30% in two arteries, and 20% in all three major arteries; approximately 10% of these patients also have obstruction of the left main coronary artery (3). The remaining 15% have no evidence of significant coronary obstruction on angiography; this occurs more frequently in women than in men and in African Americans than in whites. In such patients, NSTE-ACS, if present, may be related to microvascular coronary obstruction or

Figure 5. (a) Multiplanar reconstructions with dual-source computed tomographic coronary angiography demonstrating a noncalcified severe lesion with outward remodeling (arrow) of right coronary artery. Reprinted by permission from Reference 45. (b) Coronary artery thrombus in a 60-year-old patient with unstable angina. Coronary angiography shows an irregular hazy filling defect in the left anterior descending artery at the level of the second diagonal branch (arrow). Contrast medium surrounds the globular thrombus, which extends into the diagonal branch. Reprinted by permission from Reference 3.

coronary artery spasm. The absence of coronary obstruction on angiography should prompt a search for causes of the presenting symptoms other than coronary atherosclerosis. Estimation of Risk

Table 1 enumerates clinical indicators of increased risk that have been combined in several ways. The thrombolysis in myocardial ischemia (TIMI) risk score (Figure 6) identifies seven independent risk factors; their sum correlates directly with risk (12). The accuracy of this score has been confirmed in several independent studies. It is easy to obtain very rapidly at the time of presentation and does not require a physician or computer. It has been shown that a high risk score identifies patients who derive benefit from an early invasive strategy (see below). The Global Registry of Acute Coronary Events (GRACE) risk score (13) has also identified a number of independent risk factors that are associated with increased mortality. It is more complex than the TIMI risk score and requires a computer. Three biomarkers (troponin, C-reactive protein, and BNP) independently predict adverse outcomes in patients with NSTE-ACS. The incidence of these outcomes is closely related to the number of abnormal biomarkers, from 0 to 3 (14).

Concise Clinical Review TABLE 1. HIGH-RISK FEATURES OF NSTE-ACS Patient Characteristics Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy Elevated cardiac biomarkers (TnT or TnI) New or presumably new ST-segment depression Signs or symptoms of HF or new or worsening mitral regurgitation High-risk findings from noninvasive testing Hemodynamic instability Sustained ventricular tachycardia PCI within 6 mo Prior CABG High risk score (e.g., TIMI, GRACE) Reduced left ventricular function (LVEF less than 40%) CABG ¼ coronary artery bypass graft surgery; GRACE ¼ Global Registry of Acute Coronary Events; HF ¼ heart failure; LVEF ¼ left ventricular ejection fraction; PCI ¼ percutaneous coronary intervention; TIMI ¼ thrombolysis in myocardial infarction; TnI ¼ troponin I; TnT ¼ troponin T. Adapted by permission from Reference 5.

MANAGEMENT Patients with chest pain at rest suspected of having ACS should be taken immediately to a hospital emergency department (if possible by ambulance) for rapid evaluation (15). This includes a directed clinical examination and a 12-lead ECG, both of which should be completed within 10 minutes of presentation (16). A blood specimen should be sent for serum troponin determination, which should be completed within 60 minutes. If the clinical examination is compatible with NSTE-ACS and the ECG shows ST segment depression or transient elevation and/ or the cardiac troponin is abnormally elevated, the patient should be admitted to a coronary, chest pain, or medical ICU. If both the ECG and the troponin are negative, but the pain continues, the patient may be admitted to an intermediate care or step-down unit for further observation and testing. Whenever possible, continuous ECG monitoring should be performed for 48 hours to detect transient ST segment changes, which characterize recurrent ischemia and which help in assessing the tempo of the ischemic process. Frequent ventricular extrasystoles identify patients who are at risk of more serious ventricular tachyarrhythmias and sudden cardiac death (17). Arterial O2 saturation should be assessed by oximetry. Patients should be placed on bed rest, and supplemental O2 is advisable in patients with a reduced arterial O2 saturation (,90%), and/or those with heart failure and pulmonary rales. In patients experiencing ischemic chest pain, sublingual nitroglycerine (0.3–0.6 mg up to three times) should be administered. If the pain persists, and/or the patient is hypertensive or in heart failure, intravenous nitroglycerine (5–10 mg/min with the dose increased gradually up to 200 mg/min, as needed, should be administered as long as the systolic pressure remains above 100 mm Hg). Patients with pain persisting despite administration of nitrates should receive intravenous morphine sulfate in boluses of 2 to 5 mg every 10 min 3 3 (5). Oral b blockers may be initiated or continued in patients without severe heart failure, hypotension or atrioventricular block. Calcium channel antagonists can be substituted for or added to b blockers in patients who cannot tolerate the latter because of a history of asthma or obstructive pulmonary disease or the presence of severe (New York Heart Association Class IV) heart failure, or whose ischemia is not controlled by maximal doses of b blockers (3). Nifedipine and other short-acting dihydropyridines should not be administered in the absence of b blockers. All patients with NSTE-ACS should have their risk assessed (see above). The presence of any of the markers of high risk (Table 1) should accelerate consideration of an invasive strategy (see below).

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Patients without troponin elevation who have had no evidence of recurrent ischemia, symptomatic or electrocardiographic, for at least 24 to 48 hours and who are considered to be at low risk may undergo stress testing, either with pharmacologic (e.g., dobutamine) stress echocardiography or stress myocardial perfusion scintigraphy to confirm the presence of ischemic heart disease and, if it is present, to assess the clinical risk to guide subsequent management (5).

ANTIPLATELET THERAPY Given the importance of platelet activation in the pathogenesis of NSTE-ACS, antiplatelet therapy is an important component of management (Figure 7). Three groups of antiplatelet drugs— aspirin, P2Y12 receptor blockers, and GP IIb/IIIa antagonists— have been found to be useful in these patients. Aspirin

This drug irreversibly blocks the platelet enzyme cyclooxygenase (COX) 1 and prevents collagen-induced platelet activation as well as the synthesis and release of thromboxane A2, a potent platelet activator. Aspirin has been found to be efficacious across the entire spectrum of coronary artery disease, ranging from primary prevention in high-risk subjects to patients with STEMI, including patients with NSTE-ACS (18). This drug forms the foundation for all antiplatelet therapy in these patients. In patients who are aspirin-naı¨ve, a loading dose of 162 to 325 mg should be given, followed by a daily dose of 75 to 100 mg. The Organization to Assess Strategies in Ischemic Syndromes (OASIS-7) trial showed that a higher maintenance dose (300–325 mg) is not necessary, and indeed was associated with excessive bleeding (19). Aspirin is contraindicated in patients with allergy and intolerance, active bleeding, active peptic ulcer, or another source of gastrointestinal bleeding. Aspirin “resistance” has been described, but it appears that most cases are related to poor patient compliance.

Figure 6. TIMI risk score for unstable angina or non–ST elevation myocardial infarction. The individual risk factors are shown at the bottom, and the composite of the risk of D, MI, or UR is shown along the vertical axis. Adapted by permission from Reference 12. CAD ¼ coronary artery disease; D ¼ death; MI ¼ myocardial infarction; TIMI ¼ thrombolysis in myocardial ischemia; UR ¼ urgent revascularization.

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Figure 7. Platelet activation mechanisms and sites of blockade of antiplatelet therapies. Platelet activation is initiated by soluble agonists, such as thrombin, thromboxane A2, 5-HT (hydroxytryptamine), ADP (via P2Y1 and P2Y12), and ATP, and by adhesive ligands, such as collagen and von Willebrand factor. Consequently, dense granule secretion of platelet agonists and secretion of thromboxane A2 lead to amplification of platelet activation, which causes a conformational change in the GP IIb/IIIa receptor leading it to bind to fibrinogen, resulting in platelet aggregation. The P2Y12 receptor plays a major role in the amplification of platelet activation. ADP ¼ adenosine diphosphate; cAMP ¼ cyclic adenosine monophosphate; COX ¼ cyclooxygenase diphosphate; GP ¼ glycoprotein; TxA2 ¼ thromboxane A2; PAR ¼ protease receptor protein. Shown also are the sites of action of antiplatelet agents. ASA ¼ aspirin; TRA ¼ thrombin receptor antagonist. Adapted by permission from References 46 and 47.

P2Y12 Blockers

The drugs in this class fall into two groups, the thienopyridines (clopidogrel and prasugrel) and a triazolopyrimidine (ticagrelor). The former are pro-drugs that require oxidation by the hepatic CYP P-450 system to form the active metabolites, which irreversibly block the activation of the platelet P2Y12 receptor by ADP, and they thereby inhibit platelet activation. Ticagrelor is a direct-acting and reversible blocker. One of the three available P2Y12 blockers should be added immediately to aspirin in patients with NSTE-ACS. Clopidogrel. In the CURE trial, 12,562 patients with NSTEACS received aspirin and were randomized to clopidogrel (300-mg loading dose, 75-mg daily maintenance dose) or placebo (19). The addition of clopidogrel reduced the composite endpoint of cardiovascular death, MI, or stroke by 20% (absolute reduction ¼ 2.2%) compared with aspirin alone and also reduced the incidence of in-hospital severe ischemia and the need for coronary revascularization. The combination was superior to aspirin alone, irrespective of the treatment strategy employed— medical (i.e., noninterventional), percutaneous coronary intervention (PCI), or surgical revascularization (see Figure E1 in the online supplement). There was an absolute 1% excess of major bleeding when clopidogrel was added to aspirin and excessive bleeding when coronary surgery was performed within 5 days of clopidogrel administration. Clopidogrel is a moderately potent blocker of the P2Y12 receptor, but about 20% of patients show little, if any, efficacy. Two steps are required in the formation of the active metabolite of the thienopyridines, and the onset of action following the Food and Drug Administration (FDA)–approved loading dose, 300 mg, is relatively slow, requiring 4 to 6 hours. A higher loading dose (600 mg) results in an earlier (2 or 3 hr) and somewhat greater potency. The OASIS-7 trial, performed in 25,086 patients with NSTE-ACS referred for an invasive strategy, found no significant difference in outcome between 300-mg and 600-mg loading doses, but in the large subgroup of patients in this trial who actually underwent PCI, the higher dose, followed by 150 mg/day 3 7 followed by 75 mg/day was superior to the loading dose of 300 mg followed by 75 mg/day (20). The higher doses used in the OASIS-7 trial, although not

approved by the FDA, are now generally used by interventional cardiologists (15, 21). The CYP2C19 enzyme is involved in both metabolic steps required to convert clopidogrel to its active metabolite. The gene that encodes this enzyme has a relatively common allele that is associated with reduced function, (CYP2C19*2). Approximately 30% of whites, 40% of African Americans, and 55% of East Asians have at least one copy of this reduced function allele. The presence of one copy is associated with about a 30% reduction of platelet inhibition and a similar relative reduction in the clinical efficacy of clopidogrel, resulting in a higher incidence of adverse events, including stent thrombosis (22). Homozygosity is rare (z2.2% of whites) and results in almost total lack of efficacy of clopidogrel. In the clopidogrel group of the Trial to Assess Improvement in Therapeutic Options by Optimizing Platelet Inhibition (TRITON-TIMI 38) trial, carriers of the reduced function allele showed an increased risk of stent thrombosis with one (hazard ratio [HR] ¼ 2.67, P ¼ 0.0001) or two (HR ¼ 3.97, P ¼ 0.001) alleles (22). In a metaanalysis of nine trials comprising 9,685 patients with ACS who underwent PCI, Mega and colleagues reported a significantly increased risk of adverse coronary outcomes in heterozygous patients (HR ¼ 1.57, P ¼ 0.01), whereas those who were homozygous for the reduced function gene showed a higher risk when compared with subjects who had one reduced function allele (23). There is no general agreement whether patients who are to be placed on clopidogrel should receive genetic testing for this allele or platelet function measurement or neither of these. Clopidogrel is widely used worldwide and is expected to go off patent in the United States in April, 2012. It is likely to be used even more widely when it becomes generic. Prasugrel. Like clopidogrel, prasugrel is a pro-drug, but unlike clopidogrel, it is oxidized rapidly in one step to its active metabolite, and it becomes active within 30 minutes of ingestion. Prasugrel is a more powerful P2Y12 inhibitor than clopidogrel (Figure E2a), there is less variability in the response, and the CYP2 C19 reduced-function allele does not appear to affect its action (24). In the TRITON-TIMI 38 trial, conducted in 13,608 patients, of whom 10,074 had NSTE-ACS and the remainder had STEMI, all patients received aspirin. Following coronary arteriography and after the decision had been made to carry out PCI, patients were

Concise Clinical Review

randomized to either the FDA-approved dose of clopidogrel (300mg loading dose, 75-mg daily maintenance dose) or a 60-mg loading dose of prasugrel followed by a 10-mg daily maintenance dose. A significant 19% risk reduction in the primary endpoint (cardiovascular death, MI, and stroke) was observed, and the rates of stent thrombosis were reduced from 2.4% to 1.1% in the group receiving prasugrel (25). However, there was a 0.6% increase in major bleeding, including fatal bleeding. The risk reduction was particularly striking (30%) in patients with diabetes mellitus (26). Three subgroups of patients did not exhibit a net clinical benefit with prasugrel compared with clopidogrel—patients with a previous stroke or transient ischemic attack, patients older than 75 years, and those weighing less than 60 kg. The FDA has approved prasugrel for patients with ACS (including STEMI) in whom the decision has been made to proceed to PCI, but it is contraindicated in patients with a history of stroke or transient ischemic attack and should not be used in those older than 75 years and/ or less than 60 kg or in patients with any other risks of bleeding unless the risk of ischemia is high; a 5 mg/day maintenance dose may be used in these patients. Indeed, in the TRITON-TIMI 38 trial, in the “core” group of patients, which excluded these three groups, prasugrel was associated with a robust 26% absolute reduction in the primary endpoint (Figure E2b) (27). Ticagrelor. This cyclopentyl-triazolopyrimidine is an orally active, reversible P2Y12 blocker that, like prasugrel, has a rapid onset of action and produces almost complete blockade of the receptor. However, it has a plasma half-life of only approximately 12 hours and has a more rapid offset of action than do the thienopyridines. The Platelet Inhibition and Platelet Outcomes (PLATO) trial compared ticagrelor (180-mg loading dose followed by 90 mg twice a day) to clopidogrel (300-mg or 600-mg loading dose, 75-mg daily maintenance dose) in 18,624 patients, 11,067 of whom had moderate to high risk of NSTE-ACS, whereas the remainder had STEMI and were to be treated with primary PCI; all patients received aspirin. When compared with clopidogrel, the composite endpoint (cardiovascular death, MI, and stroke at 1 yr) was reduced by 16%; there was a 22% significant reduction in total mortality and a 21% reduction in vascular death (28). The rate of stent thrombosis was reduced significantly from 1.9% to 1.3%. There was a 15% higher incidence of non–coronary artery bypass graft surgery (CABG)-related major bleeding and an increase in fatal intracranial bleeding. An excess of dyspnea and of ventricular pauses was observed. The benefits of ticagrelor were observed in patients with STEMI and NSTE-ACS, as well as in patients in whom invasive or conservative management strategies were planned. No benefit was observed with ticagrelor in patients in the United States, and this may have been due to the play of chance or related to higher doses of aspirin received in this country (29); hence, the FDA has recommended that the dose of concomitant aspirin not exceed 100 mg. Irrespective of which P2Y12 inhibitor is employed, in the absence of bleeding or a high risk thereof, dual antiplatelet therapy should be continued for 1 year after an episode of NSTE-ACS (and after insertion of a drug-eluting stent for any indication). Low-dose aspirin (75–100 mg/d) should then be continued for an indefinite period. In patients at risk of gastrointestinal bleeding, a protein pump inhibitor (other than omeprazole) should be used concomitantly. GP IIb/IIIa Blockers

These agents block the final common pathway of platelet aggregation, that is, the fibrinogen-mediated cross-linkage of platelets through the GP IIb/IIIa receptor. Three GP IIb/IIIa inhibitors are available. Two small molecular blockers recognize the

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binding site of platelet GP IIb/IIIa; tirofiban is a nonpeptide mimetic, and eptifibatide is a synthetic heptapeptide (5). These drugs are similar in many ways. They are administered intravenously as a bolus followed by a continuous infusion. Their short plasma half-lives (z2 h) restore platelet function in about 4 hours after discontinuation of the infusion. The third drug in this class is abciximab, a Fab fragment of a monoclonal antibody. This drug is no longer the most frequently used IIb/IIIa inhibitor because of its prolonged action (z12 h) that cannot be rapidly reversed when necessary because of serious bleeding (5). Early trials with these drugs demonstrated that when added to aspirin, they exerted a beneficial effect in patients with NSTEMIACS, especially those with an elevated troponin and who underwent PCI (30). However, the role of these agents in patients who receive a P2Y12 receptor blocker is less evident. To assess the role of eptifibatide in the presence of frequent (90%) clopidogrel use, the Early Glycoprotein IIb/IIIa Inhibition in Non-ST Segment Elevation Acute Coronary Syndrome (EARLY-ACS) trial randomized 9,492 patients with NSTE-ACS who were assigned to an invasive strategy (31). More than 90% of the patients received clopidogrel. They were then randomized to either routine therapy with eptifibatide for more than 12 hours or placebo with selective eptifibatide (by decision of the interventional cardiologist) after angiography. No significant benefit of routine early eptifibatide was noted, although the routine use of the GP IIb/IIIa inhibitor was associated with an increase in non–life-threatening bleeding requiring transfusion. Based on this trial, routine early use of a GP IIb/IIIa inhibitor can no longer be recommended in NSTE-ACS patients receiving aspirin and clopidogrel, although selective use during PCI may still be warranted. Indeed, it is current practice among many interventional cardiologists to selectively add a GPIIb/IIIa inhibitor to aspirin and clopidogrel at the time of PCI in high-risk patients (with elevated troponin, diabetes, and/or anatomically difficult lesions) who are not at a high risk of bleeding.

ANTICOAGULANT THERAPY These drugs, like antiplatelet agents, play a critical role in the management of patients with NSTEMI-ACS (5, 32, 33). Unfractionated Heparin

Unfractionated heparin (UFH) is a mixture of polysaccharide chains of varying lengths that activates antithrombin and by blocking circulating factors IIa (thrombin) and, to a lesser extent, Xa, prevents coagulation. It also binds nonspecifically to plasma proteins and endothelial cells and is responsible for an unpredictable anticoagulant response. Intravenous administration of a bolus of 60 to 70 U/kg is followed by 12–15 U/kg/hour titrated to an activated partial thromboplastin time that is 1.5 to 23 normal. UFH should be administered for 2 to 5 days in patients with NSTE-ACS. Rebound reactivation may occur when UFH is discontinued. A metaanalysis of clinical trials showed a 33% reduction of death or MI when UFH was added to aspirin (34). While UFH is the least expensive anticoagulant, its disadvantages are that it requires continuous intravenous infusion as well as repeated monitoring and dose adjustments; its major complication is bleeding. Immunogenic heparin-induced thrombocytopenia is an infrequent but serious complication that can cause both thrombosis and bleeding. Low-Molecular-Weight Heparins

Low-molecular-weight heparins (LMWHs) combine inhibition of factors Xa and IIa, thereby inhibiting both the generation

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Figure 8. Cumulative incidence of cardiac death in patients following non–ST elevation acute coronary syndromes receiving guidelineapproved therapy including aspirin and a thienopyridine and placebo (5,114 pts) or rivaroxaban 2.5 mg twice daily (5,113 pts). Adapted by permission from Reference 37.

and the action of thrombin, and they have a greater relative antiXa action than UFH. When compared with UFH, LMWH binds less to plasma proteins and endothelial cells, it inhibits plateletbound factor Xa, has more predictable bioavailability, can be administered by subcutaneous injection on a weight basis, and does not usually require dose adjustments (32). The incidence of heparin-induced thrombocytopenia is about 10% of that observed with UFH. LMWHs are cleared by the kidneys, and therefore, their dose must be reduced in patients with renal dysfunction. Their properties make them much easier to use than UFH. Enoxaparin, the most widely studied LMWH, has been shown to be equivalent to UFH in NSTE-ACS patients (35) but has the advantages mentioned above. The dose is 1 mg/kg subcutaneously twice daily. Treatment for up to 8 days has been utilized; longer therapy has not proven to be of benefit. The major complication is bleeding, which occurs with slightly greater frequency with enoxaparin than UFH. Bivalirudin

This polypeptide is a direct inhibitor of thrombin, with a short (z25 min) plasma half-life. Bivalirudin, with provisional GP IIb/IIIa inhibitor, was compared with intravenous UFH or enoxaparin plus routine use of a GP IIb/IIIa inhibitor in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, which was performed in 9,207 patients with NSTE-ACS who were scheduled for treatment with an early invasive strategy (36). The efficacy outcomes were similar, but the bivalirudintreated patients had significantly less bleeding. Bivalirudin is given at a dose of 0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/hour during PCI and may be discontinued shortly thereafter. It is not cleared by the kidneys and therefore can be used in patients with renal dysfunction.

Figure 9. Decision-making algorithm for the management of non– ST-segment elevation acute coronary syndromes. BNP ¼ brain natriuretic peptide; CABG ¼ coronary artery bypass graft surgery; CAD ¼ coronary artery disease; CT ¼ computed tomography; GFR ¼ glomerular filtration rate; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; MRI ¼ magnetic resonance imaging; NST-ACS ¼ non-ST acute coronary syndromes; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction. Adapted by permission from Reference 48.

Patients on fondaparinux exhibited less bleeding, but those that underwent cardiac catheterization showed an excess of catheterrelated thrombosis. To avoid the latter, small doses of unfractionated heparin must be used. Because of this thrombotic tendency, fondaparinux is infrequently used in patients with NSTE-ACS in whom an early invasive approach (see below) is planned. Rivaroxaban

This orally administered novel anticoagulant inhibits the action of factor Xa, which is critical to the production of thrombin. In the Anti-Xa Therapy to Lower Cardiac Events (ATLAS-2 TIMI 51) trial, a placebo-controlled, double-blind trial performed in 15,526 patients with ACS, a very low dose of rivaroxaban (2.5 mg twice daily) reduced cardiovascular death by 34% from 4.1% to 2.7% (P ¼ 0.002) (Figure 8), and all-cause death by 32% from 4.5% to 2.9% (P ¼ 0.002). Although major bleeding and intracranial bleeding were increased, fatal bleeding was not (38). Rivaroxaban will be considered by the FDA for the treatment of ACS.

Fondaparinux

This is a synthetic pentasaccharide whose anticoagulant property is based on the inactivation of factor Xa by antithrombin. Fondaparinux is administered subcutaneously at a dose of 2.5 mg/day and is cleared almost entirely by the kidneys. In the large (20,078 patient) OASIS 5 trial in patients with NSTE-ACS, it was compared with enoxaparin (37). The primary endpoint, a composite of death, MI, or refractory ischemia, was similar in the two groups.

EARLY INVASIVE VERSUS CONSERVATIVE THERAPY Selecting one of the two basic strategies is one of the most important decisions that must be made in the management of patients with NSTE-ACS (Figure 9). A metaanalysis of 8,375 patients enrolled into the seven more recent trials showed a highly significant (P ¼ 0.001) 25% reduction in the incidence of death, MI, or rehospitalization with early invasive therapy (39).

Concise Clinical Review

Early Invasive Strategy

An early invasive strategy consists of diagnostic angiography performed soon after presentation, with the intention, on the basis of the coronary anatomy, to perform revascularization. Patients at very high risk, such as those with ischemic pain that is refractory to the usual antiischemic therapy, as well as those with hemodynamic or electrical instability should have arteriography performed immediately (5, 15, 40), with a view to proceeding with coronary revascularization within 2 hours of presentation. Other patients who have been stabilized but are at high risk, such as those with a high TIMI or GRACE risk score (see above), risk factors shown in Table 1 and Figure 9, should have coronary arteriography performed within 72 hours of presentation. Once revascularization has been decided upon, the selection of the technique, i.e., PCI or CABG, is dependent on the coronary anatomy (5, 16). The majority of patients with critical obstruction of one or two major epicardial arteries can be treated successfully with PCI. Patients with three-vessel disease and ejection fraction less than 40%, as well as those with obstruction of the left main coronary artery or patients with lesions that are anatomically unsuitable for PCI, should undergo CABG. Surgical revascularization may also be indicated in patients with two-vessel disease who have severe obstruction of the proximal left anterior descending coronary artery and left ventricular dysfunction and/or diabetes (41). However, as more experience is being gathered, PCI is being used successfully even in such patients in some centers. Conservative Strategy

A conservative strategy should be used in patients at low risk, as shown in Figure 9, and having none of the risk factors enumerated in Table 1. Contraindications for an early invasive strategy also include serious comorbidities, such as active cancer, infection, recent stroke, other serious life-threatening illnesses, advanced Alzheimer’s disease, and serious intracranial pathology that could contraindicate potent anticoagulant and antiplatelet therapy as well as absence of critical less than 50% luminal diameter. Conservative therapy consists of vigorous antiischemic therapy with nitrates, b blockers, and sometimes calcium channel blockers as well as antithrombotic therapy with aspirin, clopidogrel, or ticagrelor, and an LMWH while the patients are in the hospital. Low-risk patients should undergo noninvasive cardiac stress testing, as well as echocardiography. Severe ischemia on such testing and/or a depressed ejection fraction (,40%) provide an indication for coronary arteriography, with the decision regarding revascularization dependent on the arteriographic findings. Patients who are managed according to a conservative strategy should be followed closely and considered for transfer to an invasive strategy if they develop any of the high-risk features enumerated in Table 1 and/or experience recurrent ischemia with chest pain and/or ST segment changes while on antiischemic therapy, appropriate dual antiplatelet therapy, and an LMWH. Experiences in a large registry have recorded in-hospital mortality rates of approximately 5% (42).1 Author disclosures are available with the text of this article at www.atsjournals.org.

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