Chapter 7. Unstable Angina/Non-ST Elevation Myocardial Infarction

Background

Unstable angina and non-ST elevation myocardial infarction (USA/NSTEMI) are a part of the wide spectrum of clinical manifestations of atherosclerotic coronary artery disease (Table 7–1). Compared with ST elevation myocardial infarction (STEMI), the incidence of USA/NSTEMI has been increasing. According to the National Registry of Myocardial Infarction (NRMI) database, from 1994 to 1999, the prevalence of STEMI decreased from 36.4% to 27.1% with concomitant rise of NSTEMI from 45% to 63%. Similar trends were also observed in a population study from 1999 to 2008. Despite this, the age-adjusted mortality for NSTEMI patients has been gradually declining, likely due to advancement in the treatment for acute coronary syndrome.

Pathophysiology

Angina pectoris is the symptomatic equivalent of transient myocardial ischemia, which results from a temporary imbalance in the myocardial oxygen demand and supply. Most episodes of myocardial ischemia are generally believed to result from an absolute reduction in regional myocardial blood flow below basal levels, with the subendocardium carrying a greater burden of flow deficit relative to the epicardium, whether triggered by a primary reduction in coronary blood flow or an increase in oxygen demand. USA/NSTEMI shares a more or less common pathophysiologic substrate with STEMI, which is usually due to ruptured or unstable atherosclerotic plaques with overlying thrombus formation, leading to reduced coronary blood flow. The differences in clinical presentation result largely from the differences in the magnitude of coronary occlusion, the duration of the occlusion, the modifying influence of local and systemic blood flow, and the adequacy of coronary collaterals.

Symptoms

USA/NSTEMI is a clinical syndrome characterized by symptoms of ischemia, which may include classic retrosternal chest pain or such pain surrogates as a burning sensation, feeling of indigestion, or dyspnea (Table 7–2). Anginal symptoms may also be felt primarily or as radiation in the neck, jaw, teeth, arms, back, or epigastrium. The pain of unstable angina typically lasts 15–30 minutes; it can last longer in some patients. In some patients, particularly the elderly, dyspnea, fatigue, diaphoresis, light-headedness, a feeling of indigestion and the desire to burp or defecate, or nausea and emesis may accompany other symptoms or may be the only symptoms. It has been estimated that about 43.6% of patients with USA/NSTEMI presented without chest pain. The clinical presentation of unstable angina can take any one of several forms.

There may be an onset of ischemic symptoms in a patient who had been previously free of angina, with or without a history of coronary artery disease. If symptoms are effort-induced, they are often rapidly progressive, with more frequent, easily provoked, and prolonged episodes. Rest pain may follow a period of crescendo effort angina or may exist from the beginning.

Symptoms may intensify or change in a patient with antecedent angina. Pain may be provoked by less effort and be more frequent and prolonged than before. The response to nitrates may decrease and their consumption increase. The appearance of new pain at rest or with minimal exertion is particularly ominous. On the other hand, recurrent long-standing ischemic symptoms at rest do not necessarily constitute an acute ischemic syndrome. Ischemic symptoms may recur shortly after (usually within 4 weeks) an acute myocardial infarction (MI), coronary artery bypass surgery, or catheter-based coronary artery intervention. In some patients, an acute unstable coronary syndrome may manifest as acute pulmonary edema or sudden cardiac death.

Physical Examination

No physical finding is specific for USA/NSTEMI, and when the patient is free of pain, the examination may be entirely normal. During episodes of ischemia, a dyskinetic left ventricular apical impulse, a third or fourth heart sound, or a transient murmur of ischemic mitral regurgitation may be detected. Similarly, during episodes of prolonged or severe ischemia, there may be transient evidence of left ventricular failure, such as pulmonary congestion or edema, diaphoresis, or hypotension. Arrhythmias and conduction disturbances may occur during episodes of myocardial ischemia.

The findings from physical examination, especially as they relate to signs of heart failure, provide important prognostic information. An analysis of data from four randomized clinical trials (GUSTO IIb, PURSUIT, and PARAGON A and B) revealed that Killip classification, a commonly used classification based on physical examination of patients at presentation of STEMI, is a strong independent predictor for short- and long-term mortality, with higher Killip class associated with higher mortality rate. This has also been recently confirmed using data from the Canadian Acute Coronary Syndrome Registries.

Diagnostic Studies

USA/NSTEMI is a common reason for admission to the hospital, and the diagnosis, in general, rests entirely on clinical grounds. In a patient with typical effort-induced chest discomfort that is new or rapidly progressive, the diagnosis is relatively straightforward, particularly (but not necessarily) when there are associated electrocardiogram (ECG) changes. Often, however, the symptoms are less clear-cut. The pain may be atypical in terms of its location, radiation, character, and intensity, or the patient may have had a single, prolonged episode of pain, which may or may not have resolved by the time of presentation. The physician should strongly suspect unstable angina, particularly when coronary artery disease or its risk factors are present. When in doubt, it is safer to err on the side of caution and consider the diagnosis to be unstable angina until proven otherwise. Even though dynamic ST-T changes on the ECG make the diagnosis more certain, between 5% and 10% of patients with a compelling clinical history (especially middle-aged women) have no critical coronary stenosis on coronary angiography. In rare instances, especially in women, spontaneous coronary artery dissection, unrelated to coronary atherosclerosis, may be the basis for an acute coronary syndrome. In general, the more profound the ECG changes, the greater the likelihood of an ischemic origin for the pain and the worse the prognosis.

ECG and Holter Monitoring

ECG abnormalities are common in patients with USA/NSTEMI. In view of the episodic nature of ischemia, however, the changes may not be present if the ECG is recorded during an ischemia-free period or the ischemia involves the myocardial territories (eg, the circumflex coronary artery territory) that are not well represented on the standard 12-lead ECG. Therefore, it is not surprising that 40–50% of patients admitted with a clinical diagnosis of unstable angina have no ECG abnormalities on initial presentation. The ECG abnormalities tend to be in the form of transient ST segment depression or elevation and, less frequently, T-wave inversion, flattening, peaking, or pseudo-normalization (ie, the T wave becomes transiently upright from a baseline state of inversion or vice versa). It must be emphasized, however, that a normal or unremarkable ECG should never be used to disregard the diagnosis of unstable angina in a patient with a compelling clinical history and an appropriate risk-factor profile.

Continuous ambulatory ECG recording reveals a much higher prevalence of transient ST-T wave abnormalities, of which 70–80% are not accompanied by symptoms (silent ischemia). These episodes, which may be associated with transient ventricular dysfunction and reduced myocardial perfusion, are much more prevalent in patients with ST-T changes on their admission tracings (up to 80%) than in persons without such changes. Frequent and severe ECG changes on ECG monitoring, in general, indicate an increased risk of adverse clinical outcome.

Angiography

More than 90–95% of patients with a clinical syndrome of unstable angina have angiographically detectable atherosclerotic coronary artery disease of varying severity and extent. The prevalence of single-, two-, and three-vessel disease is roughly equal, especially in patients older than 55 and those with a past history of stable angina. In relatively younger patients and in those with no prior history of stable angina, the frequency of single-vessel disease is relatively higher (50–60%). Left main coronary disease is found in 10–15% of patients with unstable angina. A subset of patients (5–10%) with angiographically normal or near normal coronary arteries may have noncardiac symptoms masquerading as unstable angina, the clinical syndrome X (ischemic symptoms with angiographically normal arteries and possible microvascular dysfunction), or the rare primary vasospastic syndrome of Prinzmetal (variant) angina. It should be recognized, however, that most patients (even those with Prinzmetal angina) tend to have a significant atherosclerotic lesion on which the spasm is superimposed. In general, the extent (number of vessels involved, location of lesions) and severity (the percentage of diameter narrowing, the minimal luminal diameter, or the length of the lesion) of coronary artery disease and the prevalence of collateral circulation, as judged by traditional angiographic criteria, do not differ between patients with unstable angina and those with stable coronary artery disease. The morphologic features of the culprit lesions do tend to differ, however. The culprit lesion in patients with unstable angina tends to be more eccentric and irregular, with overhanging margins and filling defects or lucencies. These findings (on autopsy or in vivo angioscopy) represent a fissured plaque, with or without a superimposed thrombus. Such unstable features in the culprit lesion are detected more frequently when angiography is performed early in the clinical course.

Noninvasive Tests

Any form of provocative testing (exercise or pharmacologic stress) is clearly contraindicated in the acute phase of the disease because of the inherent risk of provoking a serious complication. Several studies of patients who had been pain-free and clinically stable for more than 3–5 days, however, have shown that such testing, using ECG, scintigraphic, or echocardiographic evaluation, may be safe. Provocative testing is used primarily to stratify patients into low- and high-risk subsets. Aggressive diagnostic and therapeutic interventions can then be selectively applied to the high-risk patients; the low-risk patients are treated more conservatively. In general, these studies have shown that patients who have good exercise duration and ventricular function, without significant inducible ischemia or ECG changes on admission, are at a very low risk and can be managed conservatively. On the other hand, patients with ECG changes on admission, a history of prior MI, evidence of inducible ischemia, and ventricular dysfunction tend to be at a higher risk for adverse cardiac events and therefore in greater need of further and more invasive evaluation.

Biomarkers

Blood levels of specific myocardial biomarkers such as cardiac troponins are, by definition, not elevated in unstable angina; if they are elevated without evolution of Q waves, the diagnosis is generally an NSTEMI. This distinction is somewhat arbitrary, however. Patients with negative biomarkers within 6 hours of symptom onset need to have them remeasured within 8–12 hours.

Elevated levels of circulating biomarkers, such as high-sensitivity C-reactive protein, fibrinogen, brain natriuretic peptide, and glucose, have been reported in patients presenting with USA/NSTEMI. The presence of such markers may be useful in risk stratification for clinical outcomes; however, their roles in diagnosing USA/NSTEMI and determining whether treatment strategies based on these biomarkers would alter clinical outcomes have not been established.

Conditions that simulate or masquerade as unstable angina include acute MI, acute aortic dissection, acute pericarditis, pulmonary embolism, esophageal spasm, hiatal hernia, and chest wall pain. Careful attention to the history, risk factors, and objective findings of ischemia (transient ST-T changes and mild elevations of troponins in particular) remain the cornerstones for the diagnosis.

Acute Myocardial Infarction

Although MI often produces more prolonged pain, the clinical presentation can be indistinguishable from that of unstable angina. As stated earlier, this distinction should be considered somewhat arbitrary because abnormal myocardial technetium-99m pyrophosphate uptake, mild creatine kinase elevations detected on very frequent blood sampling, and increases in troponin T and I levels (released from necrotic myocytes) are observed in some patients with otherwise classic symptoms of unstable angina.

Acute Aortic Dissection

The pain of aortic dissection is usually prolonged and severe. It frequently begins in or radiates to the back and tends to be relatively unrelenting and often tearing in nature; transient ST-T changes are rare. An abnormal chest radiograph showing a widened mediastinum, accompanied by asymmetry in arterial pulses and blood pressure, can provide clues to the diagnosis of aortic dissection, which can be verified by bedside echocardiography (transesophageal, with or without transthoracic echocardiography), magnetic resonance imaging (MRI), computed tomography (CT) scanning, or aortography.

Acute Pericarditis

Acute pericarditis may be difficult to differentiate from unstable angina. A history of a febrile or respiratory illness suggests the former. The pain of pericarditis is classically pleuritic in nature and worsens with breathing, coughing, deglutition, truncal movement, and supine posture. A pericardial friction rub is diagnostic, but is often evanescent, and frequent auscultation may be needed. Prolonged, diffuse ST elevation that is not accompanied by reciprocal ST depression or myocardial necrosis is typical of pericarditis. Leukocytosis and an elevated erythrocyte sedimentation rate are common in pericarditis but not in unstable angina. Echocardiography may detect pericardial effusion in patients with pericarditis; diffuse ventricular hypokinesis may imply associated myocarditis. Regional dysfunction, especially if transient, is more likely to reflect myocardial ischemia.

Acute Pulmonary Embolism

Chest pain in acute pulmonary embolism is also pleuritic in nature and almost always accompanied by dyspnea. Arterial hypoxemia is common, and the ECG may show sinus tachycardia with a rightward axis shift. Precordial ST-T wave abnormalities may simulate patterns of anterior myocardial ischemia or infarction. A high index of suspicion, combined with a noninvasive assessment of pulmonary ventilation-perfusion mismatch, evidence of lower extremity deep venous thrombosis, CT angiography, and possibly pulmonary angiography, is necessary to exclude the diagnosis.

Gastrointestinal Causes of Pain

Various gastrointestinal pathologies can mimic unstable angina. These include esophageal spasm, peptic ulcer, hiatal hernia, cholecystitis, and acute pancreatitis. A history compatible with those conditions, the response to specific therapy, and appropriate biochemical tests and imaging procedures should help clarify the situation. It should be noted that these abdominal conditions may produce ECG changes that simulate acute myocardial ischemia.

Other Causes of Chest Pain

Many patients present with noncardiac chest pain that mimics unstable angina, and sometimes no specific diagnosis can be reached. The pain may be musculoskeletal, or there may be nonspecific changes on the ECG that increase the diagnostic confusion. In these patients, a definite diagnosis often cannot be reached despite careful clinical observation. When the pain has abated and the patient is stable, a provocative test for myocardial ischemia may help rule out ischemic heart disease. Although coronary angiography may provide evidence of atherosclerotic coronary artery disease, anatomic evidence does not necessarily prove an ischemic cause for the symptoms. In some patients, acute myocarditis may also produce chest pain syndromes simulating unstable angina and acute MI. Recreational drug use (cocaine and methamphetamine) may also produce clinical syndromes of chest pain, sometimes related to drug-induced acute coronary syndrome precipitated by the vasoconstrictor and prothrombotic effects of these drugs.

In treating unstable angina, the initial objective is to stratify patients for their short-term morbidity and mortality risks based on their clinical presentations. After risk stratification, management objectives include eliminating episodes of ischemia and preventing acute MI and death.

Initial Management

During this early in-hospital phase, therapy is primarily aimed at stabilizing the patient by stabilizing the culprit coronary lesion and thus preventing a recurrence of myocardial ischemia at rest and progression to MI.

General Measures

Patients whose history is compatible with a diagnosis of unstable angina should be promptly hospitalized in an intensive or intermediate care unit. General supportive care includes bed rest with continuous monitoring of cardiac rate and rhythm and frequent evaluation of vital signs; relief of anxiety with appropriate reassurance and, if necessary, anxiolytic medication; and treatment of associated precipitating or aggravating factors such as hypoxia, hypertension, dysrhythmias, heart failure, acute blood loss, or thyrotoxicosis. A 12-lead ECG should be repeated if it is initially unrevealing or if any significant change has occurred in symptoms or clinical stability. Serial cardiac biomarker evaluation should be performed as a part of an NSTEMI rule-out protocol and to evaluate the extent of myocardial damage and used for outcome risk stratification.

Outcome Risk Stratification

The Global Registry of Acute Coronary Events (GRACE) and Thrombolysis in Myocardial Infarction (TIMI) risk scores are the two commonly used risk scores to predict short-term risk of events and are helpful for clinical decision making. GRACE score is calculated based on the sum of the scores assigned to clinical parameters such as age, heart rate, systolic blood pressure, serum creatinine, Killip classification, presence of cardiac arrest, ST segment deviation, and elevation of cardiac enzymes. The score predicts outcome events reasonably well both in test and validation cohorts, predicting greater than 3% in-hospital death with a score higher than 140. Calculation of GRACE score is somewhat complex, but an online version of the GRACE risk score calculator is available at www.outcomes.org/grace. The TIMI score contains less clinical variables with 1 point assigned to each variable; hence, it is easier for clinical usage and performs relatively well in predicting outcome. However, the TIMI score lacks several key factors compared to the GRACE score, and thus is not as accurate in predicting outcomes as the GRACE score. The TIMI calculator is available at www.timi.org.

Anti-Ischemic Medications

Nitrates

Nitrates are generally considered one of the cornerstones of therapy (Table 7–3); however, their use is largely based on clinical experience, not on randomized clinical trials. Nitrates relieve and prevent ischemia by improving subendocardial blood flow in the ischemic zone through their vasodilator actions, predominantly on the large epicardial vessels, including the stenotic segments and the coronary collaterals. Nitrates directly stimulate cyclic guanosine monophosphate (GMP) production, achieving vasodilatory effect in the vascular smooth muscle without requiring an intact or functional endothelium; hence, their effects are generally well preserved in atherosclerosis. Reduction of left ventricular preload and afterload by peripheral vasodilator actions may contribute to the reduction of myocardial ischemia. Although nitrates may reduce the number of both symptomatic and asymptomatic episodes of myocardial ischemia in unstable angina, no effect has yet been demonstrated on the incidence of progression to MI or death.

In the very acute phase, it is preferable to use intravenous nitroglycerin to ensure adequate bioavailability, a rapid onset and cessation of action, and easy titration of doses. Oral, sublingual, transdermal, and transmucosal preparations are better suited for subacute and chronic use. To minimize the chances of abrupt hypotension, nitroglycerin infusion should be started at 10 mcg/min and the infusion rate titrated according to symptoms and blood pressure. The goal is to use the lowest dose that will relieve ischemic symptoms without incurring side effects. The side effects of nitrates include hypotension, reflex tachycardia associated with hypotension; occasional profound bradycardia, presumably related to vagal stimulation; headaches; and facial flushing. Rare side effects include methemoglobinemia, alcohol intoxication, and an increase in intraocular and intracranial pressure. Because the magnitude of reduced arterial pressure that a patient can tolerate without developing signs of organ hypoperfusion varies, it is difficult to define an absolute cut-off point. A reasonable approach in normotensive patients without heart failure is to maintain the arterial systolic blood pressure no lower than 100–110 mm Hg; in hypertensive patients, reduction below 120–130 mm Hg may be unwise.

Continuous and prolonged administration of intravenous nitroglycerin for more than 24 hours may lead to the attenuation of both its peripheral and coronary dilator actions. This effect is due to the development of tolerance in some patients. At the present time, however, there is no easy and practical way to avoid or overcome this problem other than escalating the dose to maintain reduction in measurable end points (eg, the arterial blood pressure).

With the increasing use of phosphodiesterase-5 inhibitors (such as sildenafil) for erectile dysfunction among patients with coronary artery disease or the recreational use of such medication, it is important to obtain a history of whether the patient has taken such medication 24 hours prior to presentation of USA/NSTEMI. Nitrate-mediated vasodilation in the presence of phosphodiesterase-5 inhibition can lead to prolonged hypotension or even death.

β-Blockers

The evidence for use of β-blockers in USA/NSTEMI extrapolates mostly from studies in STEMI or stable angina patients. Use of β-blockers has been shown to reduce the frequency of both symptomatic and asymptomatic ischemic episodes in stable as well as unstable angina. These protective effects are generally attributed to their negative chronotropic and inotropic effects, which reduce the imbalance of myocardial oxygen demand and supply. Their ability to reduce the risk of infarct development is less clear, but they do decrease reinfarction and mortality rates in postinfarction patients. The mechanism of their protective effect against reinfarction remains unexplained, although it has been speculated that they reduce the risk of plaque rupture by reducing mechanical stress on the vulnerable plaque. It is also unclear whether β-blockers offer any additional benefit in unstable angina patients who are already receiving nitrates and antiplatelet-anticoagulant therapy.

β-blockers administered orally, not intravenously, can be started early (within 24 hours after admission) in the absence of contraindications such as congestive heart failure, hemodynamic instability, heart block, or active reactive airway disease. The choice of β-blockers depends on pharmacokinetic consideration as well as physician familiarity; however, β-blockers without intrinsic sympathomimetic activity, such as propranolol, atenolol, or metoprolol, are preferred.

Calcium Channel Blockers

Calcium channel blockers are also frequently used in managing ischemic heart disease. Their beneficial effects in myocardial ischemia are generally attributed to their ability to improve myocardial blood flow by reducing coronary vascular tone and dilation of large epicardial vessels and coronary stenoses through an endothelium-independent action. They also reduce myocardial workload through their negative chronotropic (diltiazem and verapamil) and inotropic and peripheral vasodilator effects. Because exaggerated vasoconstriction may play a role in unstable angina, calcium channel blockers have been used in its management. In general, although calcium channel blockers have been shown to reduce the frequency of ischemic episodes in unstable angina, their protective effect against the development of acute MI has not been definitively demonstrated. In fact, the use of such calcium channel blockers as nifedipine tends to increase the risk of ischemic complications in unstable angina. Such adverse effects may well be due to reflex tachycardia or coronary steal caused by the arteriole-dilating actions of dihydropyridine calcium channel blockers. The protective effects of the heart rate-slowing calcium channel blocker diltiazem have been reported in patients with a non-Q wave MI and preserved ventricular function. As in the case of β-blockers, the additive benefits of calcium channel blockers in patients with unstable angina who are receiving nitrates and antithrombotic therapy have not been defined, and their use should also be considered an adjunct to such drugs.

Antiplatelet Therapy

Platelet activation and aggregation leading to coronary thrombosis is the hallmark feature underlying the pathophysiology of acute coronary syndrome. Hence, inhibition of platelet activation via pharmacologic blockade of signaling pathways such as cyclooxygenase-1 or P2Y12 receptor plays a central role in managing acute coronary syndrome.

Aspirin

Aspirin irreversibly inhibits cyclooxygenase-1 and reduces thromboxane A2 production; hence, it reduces platelet aggregation by this pathway. It has been shown to reduce the risk of developing MI by about 50% in at least four randomized trials. The protective effect of aspirin in unstable angina has been comparable, in the dosage range of 75–1200 mg/day. Because of the potential for gastrointestinal side effects, low doses of aspirin (75–81 mg/day) are preferable for daily maintenance. A higher loading dose of 160–325 mg on the first day is recommended in order to initiate the antiplatelet effect more rapidly.

P2Y12 Receptor Inhibitors

Adenosine diphosphate (ADP) is one of the inducers of platelet activation by binding to a G-protein–coupled P2Y12 receptor with subsequent activation of GP IIbIIIa receptor and stabilization of platelet aggregation. Currently available P2Y12 receptor inhibitors include ticlopidine, clopidogrel, prasugrel, and ticagrelor.

Ticlopidine

Ticlopidine was the first P2Y12 receptor inhibitor that was approved for use for secondary prevention of stroke and MI and for prevention of stent closure after percutaneous coronary intervention (PCI). Ticlopidine is a prodrug and requires biotransformation to active metabolite in liver. Its use can cause rare, but life-threatening side effects including thrombotic thrombocytopenic purpura or neutropenia; hence, its use has been replaced by other P2Y12 receptor inhibitors.

Clopidogrel

Clopidogrel is also a prodrug requiring hepatic metabolism to form active metabolite to irreversibly inhibit P2Y12 receptor. Extrapolation based on the CURE trial suggested that the combination of aspirin and clopidogrel appears to modestly reduce the combined incidence of cardiovascular death, MI, or stroke in USA/NSTEMI patients who are not undergoing revascularization procedures. However, this small additional benefit is at the expense of increased major or minor bleeding and cost.

The majority of clinical trials (CREDO, PCI-CURE, CLARITY, and COMMIT) testing the efficacy of aspirin and clopidogrel focus on high-risk acute coronary syndrome patients undergoing PCI. Based on these trials, current guidelines recommend treatment with aspirin and clopidogrel for 12 months for acute coronary syndrome patients undergoing PCI. The suggested loading and daily maintenance dose for clopidogrel are 300 mg and 75 mg, respectively. A higher loading dose (600 mg) and higher daily maintenance dose (150 mg) of clopidogrel for the first 7 days, using a dose of 75 mg/day thereafter, did not reduce the composite end point of cardiovascular death, MI, or stroke at 30 days when compared with the conventional dosing regimen but did result in a higher major bleeding rate, as demonstrated by the CURRENT-OASIS 7 trial. However in the subgroup of patients undergoing PCI, the high-dose clopidogrel approach reduced the risk of stent thrombosis and MI at the cost of excess bleeding risk.

Given that clopidogrel requires hepatic transformation into active metabolite, the gene polymorphism involving the key enzymes in the biotransformation has been detected, and such polymorphism may account for the variable platelet inhibition response in individual patients. It has been proposed that testing the degree of platelet inhibition after clopidogrel administration may identify patients with poor response to clopidogrel, and dosing of clopidogrel based on such results may improve clinical outcome. However, the results from the GRAVITAS trial failed to confirm this hypothesis. Hence, routine use of a platelet function test to dose clopidogrel in acute coronary syndrome patients is not recommended.

Prasugrel

Prasugrel is a third-generation thienopyridine and a prodrug and, like clopidogrel, requires hepatic biotransformation to active metabolites. The biotransformation of prasugrel is more efficient compared to clopidogrel; hence, the onset of action is faster and the degree of platelet inhibition more potent.

The approved use of prasugrel is only for acute coronary syndrome patients undergoing PCI as tested in TRITON-TIMI 38 trial, with clinical benefit largely driven by reduction of non-fatal MI, not death or stroke, and at the expense of increasing life-threatening bleeding when compared to clopidogrel. The bleeding risk is increased in patients with history of stroke or transient ischemic attack, age greater than 75 years, or a body weight of less than 60 kg; hence, the use of prasugrel in these patient populations should be avoided. The recommended dose in current guidelines is a loading dose of prasugrel 60 mg given promptly or no later than 1 hour after PCI with 10 mg daily as maintenance dose for at least 12 months. The benefit of prasugrel in medically managed patients with USA/NSTEMI has not been established and is undergoing clinical testing.

Ticagrelor

Ticagrelor is a cyclopentyltriazolopyrimidine that directly and reversibly inhibits P2Y12 receptors on platelets. It has several unique pharmacologic features including fast absorption and short half-life with rapid onset and offset. Based on the PLATO trial, its use in acute coronary syndrome patients, regardless of treatment strategy (medical management, revascularization via PCI or coronary artery bypass graft [CABG]), was approved by U.S. Food and Drug Administration in July 2012 using a regimen with a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. This approval is accompanied with a warning stating that use of ticagrelor with aspirin with a dose greater than 100 mg/day decreases its effectiveness.

GP IIBIIIA Receptor Inhibitor

Activation of GP IIbIIIa receptors leads to interaction of receptors with ligands such as fibrinogen followed by platelet aggregation. Currently available intravenous GP IIbIIIa receptor inhibitors are abciximab, a monoclonal antibody against the receptor; nonpeptidic inhibitors, lamifiban and tirofiban; and a peptidic inhibitor, eptifibatide.

Four major randomized clinical trials (PRISM, PRISM-PLUS, PURSUIT, and PARAGON) evaluated the efficacy of intravenous GP IIbIIIa receptor inhibitors in reducing clinical events (death, MI, or refractory angina) in patients with USA/NSTEMI. Different inhibitors were tested in the trials (tirofiban in PRISM and PRISM-PLUS, eptifibatide in PURSUIT, and lamifiban in PARAGON). These trials differed in tested patient population, experimental designs, angiographic strategies, and end point measurement, but these trials showed consistent, although small, reductions in short-term composite event rates in the management of the acute phase of USA/NSTEMI when they were added to the background treatment of aspirin and heparin as a part of initial medical management. Meta-analysis of these trials indicated that patients with high-risk features would benefit more from the use of GP IIbIIIa inhibitors, especially when undergoing PCI.

The efficacy of intravenous abciximab on clinical outcome in patients with USA/NSTEMI without early intervention was tested in GUSTO-IV acute coronary syndrome trial. There was no survival benefit in patients receiving abciximab when compared with placebo at 30 days or at 1 year.

The efficacy of intravenous GP IIbIIIa inhibitors in reducing clinical events in patients with USA/NSTEMI undergoing PCI was also tested—abciximab in EPILOG and CAPTURE and tirofiban in RESTORE. These trials consistently showed a reduction of short-term clinical events (composite end point of death, MI, or urgent or repeat revascularization). The major benefit appears to be in nonfatal adverse events rather than mortality.

Thus, overall data suggest that intravenous GP IIbIIIa inhibitors used judiciously, along with aspirin and heparin, are beneficial in high-risk patients with USA/NSTEMI undergoing PCI.

In the modern era of frequent use of dual antiplatelet therapy (mostly aspirin and clopidogrel), routine addition of eptifibatide to aspirin and clopidogrel in managing USA/NSTEMI patients does not confer clinical benefit but increases bleeding risk as demonstrated by the EARLY-ACS trial. Current U.S. guidelines recommend use of GP IIbIIIa inhibitors as an alternative to clopidogrel as a second antiplatelet agent or in addition to clopidogrel as a third antiplatelet agent in high-risk patients undergoing initial invasive strategy. These agents are especially useful if invasive therapy is planned but must be delayed.

Anticoagulant Therapy

Unfractionated Heparin and Low-Molecular-Weight Heparin

The protective effect of intravenous unfractionated heparin (UFH) in treating unstable angina has been demonstrated in randomized trials. During short-term use, the risk of MI in unstable angina is reduced by about 90%, and ischemic episodes are reduced by about 70%. Current guidelines recommend intravenous administration of a bolus of 60–70 U/kg followed by 12–15 U/kg/h titrated to an activated partial thromboplastin time of 1.5 to 2 times normal for a duration of 2–5 days in patients with USA/NSTEMI.

Recently, low-molecular-weight heparin (LMWH) was tested to examine its role as an alternative anticoagulation therapy to UFH in patients with USA/NSTEMI. LMWH has certain pharmacologically superior features to UFH: longer half-life, weaker binding to plasma protein, higher bioavailability with subcutaneous injection, more predictable dose response, and less incidence of heparin-induced thrombocytopenia. Dalteparin has been shown to be superior to placebo and equivalent to UFH for immediate, short-term treatment of USA/NSTEMI in reducing composite end points in the FRISC and FRIC trials, respectively. In the FRISC II trial, dalteparin also lowered the risk of death or MI in patients receiving invasive procedures, especially in high-risk patients. In the ESSENCE and Thrombolysis in Myocardial Infarction (TIMI) 11B trials, enoxaparin (modestly but significantly) reduced the combined incidence of death, MI, or recurrent angina over UFH. This reduction is mainly due to a decrease in recurrent angina. But in the SYNERGY trial, enoxaparin was not superior to UFH in reducing mortality or nonfatal MI in high-risk patients undergoing early invasive therapy. Taken together, acute treatment with LMWH is likely as effective as UFH in USA/NSTEMI patients receiving aspirin. However, because LMWH is easier to use and does not require partial thromboplastin time monitoring, it is being increasingly preferred over UFH. Enoxaparin is the most studied LMWH, and its dose is 1 mg/kg subcutaneously twice daily with a treatment duration up to 8 days.

Direct Thrombin Inhibitors

Compared with heparin, direct thrombin inhibitors appear to offer a small reduction in death or MI in patients with USA/NSTEMI. Currently only bivalirudin is available for clinical use.

Bivalirudin was tested in the ACUITY trial in the setting of USA/NSTEMI. Bivalirudin was shown to be noninferior to heparin in composite ischemia end points (death, MI, or unplanned revascularization) in USA/NSTEMI patients with moderate- or high-risk features undergoing invasive therapy when it was used in conjunction with a GP IIbIIIa inhibitor. Taken together, direct thrombin inhibitors have not been routinely used in the medical management of USA/NSTEMI; however, they are alternative antithrombotics for patients with heparin-induced thrombocytopenia.

Fondaparinux

Fondaparinux is an indirect factor Xa inhibitor that works by reversible binding to antithrombin. When compared to enoxaparin in the OASIS-5 trial, fondaparinux was observed to have similar efficacy in reducing primary outcome of death, MI, or refractory ischemia with less major bleeding. However, catheter thrombus was noted to be more frequent than with enoxaparin, requiring additional bolus of UFH with empirically determined dose at the time of catheterization. Because of this disadvantage, fondaparinux is seldom used in USA/NSTEMI patients with planned early invasive approach. Fondaparinux is given at a dose of 2.5 mg/day subcutaneously and is contraindicated in patients with a creatinine clearance < 20 mL/min because its excretion is predominantly by kidneys.

Figure 7–1 summarizes the use of various antiplatelet, antithrombotic, and GP IIbIIIa inhibitors in different USA/NSTEMI settings.

Definitive Management

Catheter-Based Interventions

Endovascular interventions such as percutaneous coronary angioplasty and stenting are commonly performed in patients with unstable angina to reduce the critical stenosis in the culprit artery or in multiple coronary arteries. Although these interventions accomplish an acute reduction in the severity of stenosis in patients with unstable angina, they carry a somewhat higher risk of acute complications, including death (0–2%), abrupt closure (0–17%), acute MI (0–13%), and the need for urgent coronary artery bypass surgery (0–12%), than in patients with stable angina. The risk is especially great when the procedure is performed soon after the onset of symptoms, in the absence of prior treatment with heparin, or in the presence of an angiographically visible intracoronary thrombus. In the current era of stent placement for coronary intervention, the angiographic restenosis rate at 6- to 7-month follow-up with bare metal stents ranges from 22% to 32%, whereas it is less than 10% for drug-eluting stents even at longer follow-up, as demonstrated in clinical trials for uncomplicated lesions.

One of the important clinical decisions in treating USA/NSTEMI patients is whether to choose a “conservative” versus “invasive” approach based on patients' clinical risk profile. Patients demonstrating highest risk for short-term morbidity or mortality from USA/NSTEMI are those with refractory angina despite intensive antianginal treatment, severe heart failure or unstable hemodynamics, and life-threatening ventricular arrhythmias, and these patients should undergo immediate angiography with intention for revascularization within 2 hours of presentation. Patients without the aforementioned high-risk features but with elevated troponin level, dynamic ST-T changes on ECG, diabetes mellitus, renal insufficiency, left ventricular ejection fraction < 40%, early post-MI angina, PCI within 6 months, prior CABG, or intermediate to high GRACE score (> 140) should undergo invasive evaluation within 72 hours of admission. Other low-risk patients can undergo noninvasive evaluation for inducible ischemia before hospital discharge (conservative approach). If inducible ischemia is detected, patients should undergo coronary angiography.

Coronary Artery Bypass Surgery

Randomized trials and observational series have shown that surgical myocardial revascularization in patients with unstable angina is relatively superior to medical therapy for controlling symptoms and improving effort tolerance and ventricular function.

There is no clinical trial comparing PCI with CABG in patients with USA/NSTEMI. Surgical revascularization can be considered an appropriate option for patients with unstable angina who do not stabilize with aggressive medical therapy or for whom angioplasty is unsuccessful or is followed by acute complications not amenable to additional catheter-based intervention. It is also applicable to patients who have severe multivessel or left mainstem coronary artery disease, particularly when left ventricular function is also impaired. Although multivessel angioplasty is performed in many centers, the Bypass Angioplasty Revascularization Investigation (BARI) trial showed that CABG offered a lower repeat revascularization rate and a reduced incidence of clinical angina compared with multivessel percutaneous transluminal coronary angioplasty. The BARI trial also revealed that CABG has a better long-term survival benefit compared with multivessel percutaneous transluminal coronary angioplasty, especially in diabetic patients.

Intra-Aortic Balloon Counterpulsation

Intra-aortic balloon counterpulsation is a useful adjunct in managing selected cases of unstable angina. It helps maintain or improve coronary artery blood flow and myocardial perfusion by augmenting diastolic aortic pressure; at the same time, systolic unloading contributes to a reduction in ventricular wall tension and myocardial oxygen demand and an improvement in ventricular function. These beneficial effects on myocardial oxygen supply and demand help stabilize patients with recurrent myocardial ischemia and those with serious intermittent or persistent hemodynamic or electrical instability. Cardiac catheterization and revascularization can then be carried out with relative safety.

Intra-aortic balloon counterpulsation (and the percutaneous method of insertion) carries a significant risk of vascular complications involving the lower extremities, especially in women, in patients older than 70 years, and in the presence of diabetes or aortoiliac disease. It should be viewed as a temporary stabilizing measure, pending definitive revascularization.

With the advances in treatment strategies, clinical event rates for refractory angina, MI, and death have been reduced substantially. For example, in patients who were not treated with aspirin and heparin, the rates of refractory angina, MI, and death were 23%, 12%, and 1.7%, respectively, within the first week of treatment, and the rates became 10.7%, 1.6%, and 0%, respectively, if the patients were treated with aspirin and heparin. With the addition of a GP IIbIIIa receptor inhibitor, the rates of refractory angina, MI, or death were 10.6%, 8.3%, and 6.9%, respectively, at 6 months in the PRISM-PLUS trial. With the combination of early invasive strategy, GP IIbIIIa inhibitor, heparin, and aspirin, the 6-month mortality rate decreased further to 3.3% in the TACTICS-TIMI 18 trial. Even with such decreases in the event rates, a substantial number of patients still continue to suffer from USA/NSTEMI and its complications due to the high prevalence of atherosclerosis. All patients should become acquainted with risk factor modification strategies, which include lipid lowering, smoking cessation, an exercise program, diabetes control, blood pressure control, dietary counseling, and weight control. Recently, the use of angiotensin-converting enzyme inhibitors has also been shown to reduce atherothrombotic events in patients with coronary artery disease especially in the presence of diabetes. With the advancement of therapies and risk factor modification, patients' short- and long-term outcomes can be further improved. The simple mnemonic ABCDE (Table 7–4) summarizes the long-term risk-reducing approach for patients with unstable coronary artery disease.