Improving Outcomes in Unstable Angina

Three cardiologists discuss how to provide the best possible care to patients with unstable angina—a potentially critically ill population—by speeding up diagnosis, refining risk stratification, optimizing medical management, and making the right call on invasive procedures.

By P. K. Shah, MD, Sanjay Kaul, MD, and Bojan Cercek, MD

Dr. Shah is director of the division of cardiology and the Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles, California. He is also Shapell and Webb Family Chair in Cardiology there. Dr. Kaul is director of the vascular physiology laboratory and cardiology training program and associate director of the coronary care unit at Cedars-Sinai, and is associate professor of medicine at the University of California-Los Angeles (UCLA). Dr. Cercek is director of the Cedars-Sinai coronary care unit and professor of medicine at UCLA School of Medicine.

Acute coronary syndromes of unstable angina, myocardial infarction (MI), and many cases of sudden cardiac death reflect the most lethal complications of atherosclerotic coronary artery disease. Each year in the United States, approximately 1.5 million patients are admitted to the hospital with a clinical diagnosis of unstable angina or non#151;ST-segment elevation myocardial infarction (NSTEMI), making unstable angina one of the most common reasons for admission to cardiac care units. Timely diagnosis, accurate risk stratification, and appropriate medical management with cardiac interventions in selected cases can substantially influence the outcome for these potentially critically ill patients.

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How Angina Presents

Patients with unstable angina may present to the hospital with one of three clinical syndromes.

New and abrupt onset. The patient has suddenly developed symptoms of myocardial ischemia (chest pain, pressure, or discomfort, or sensations like those of indigestion or heartburn) with no prior history of coronary artery disease. Often the symptoms will have begun while the patient was at rest, but sometimes they are reported to have been triggered by physical activity. Usually the syndrome is of less than four weeks' duration.

Escalation of symptoms. A patient with known or established coronary artery disease reports worsening of previously stable or infrequent ischemic symptoms. They may be more frequent, more prolonged, more readily provoked, or more severe.

Recurrence of symptoms. The patient's previous ischemic syndrome returns soon after an acute MI or endovascular coronary intervention (usually within four to six weeks).

The diagnosis of unstable angina should be considered when a patient presents with any of these three clinical syndromes. It is most certain in patients who also have known atherosclerotic vascular disease or risk factors for atherosclerotic vascular disease or both. (It is important to note, though, that the patient with unstable angina and no risk factors occasionally turns out to have acute myocarditis or primary dissection involving a coronary artery.) Electrocardiographic abnormalities with transient ST-T-wave changes tend to be present in about 30% to 50% of patients on initial presentation. Evidence of myocardial necrosis (without associated Q waves) in the form of CK-MB elevation or, more specifically, troponin T or troponin I elevation is observed in 30% of cases. Strictly speaking, patients with unstable angina who exhibit signs of myocardial necrosis should be considered to have acute MI, but by convention they are often lumped under the combined entity of unstable angina and NSTEMI.

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Pathophysiology of Unstable Angina

About 9 in 10 patients with the clinical presentation of unstable angina have atherosclerotic coronary artery disease with severe luminal narrowing involving one or more coronary arteries. Approximately 10% of cases have no significant luminal obstruction; most of these have some sort of nonischemic or noncardiac pain masquerading as unstable angina, while a minority have the rare vasospastic or Prinzmetal angina. Patients in the latter group will exhibit transient ST-segment elevation. As previously noted, rare cases of unstable angina may result from other nonatherosclerotic causes of coronary artery obstruction, such as coronary artery dissection.

A considerable body of evidence suggests that unstable angina results from episodic reduction in coronary blood flow due to superimposition of a platelet-fibrin thrombus on a disrupted atherosclerotic plaque (see photos, below). The intermittent nature of ischemia is probably related to the dynamic nature of thrombosis. Myocardial necrosis in unstable angina can result from prolonged thrombotic occlusion of the epicardial coronary artery, downstream microvascular occlusion related to platelet embolism, or both. Although exaggerated vasoconstriction may also play a role in the dynamic obstruction of coronary blood flow, it is generally accepted that thrombus is a dominant player.

Arterial obstruction. Ruptured lipid-rich plaque with a superimposed thrombus (A, arrow pointing to thrombus) and an embolus made of thrombus obstructing a small artery downstream from an epicardial coronary artery that had a plaque rupture and thrombus (B).

Plaque disruption and thrombosis tend to occur in atherosclerotic lesions that are lipid rich, with increased inflammatory cell infiltration. Inflammation is believed to contribute to the process of plaque disruption through elaboration of matrix-degrading proteases and to thrombosis through the production of procoagulant tissue factor.

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Identifying High-Risk Patients

Patients with unstable angina face three major risks related to the underlying disease: progression to acute MI, death, and recurrent ischemia requiring invasive therapeutic intervention. Over the past several years, diverse variables have been correlated with the risk of complications in this patient population. These include advancing age, postinfarction unstable angina, evidence of left ventricular dysfunction or hemodynamic instability, transient ST-segment shifts, diabetes, biochemical evidence of myocardial damage, and ongoing inflammation as indicated by elevated systemic markers such as C-reactive protein.

Recent studies have shown that an increased circulating level of cardiac troponin is a significant predictor of adverse outcome in unstable angina even in the absence of ECG changes or CK-MB elevations. These studies have also demonstrated an incremental clinical benefit to using potent antithrombotic therapies (such as platelet glycoprotein IIb/IIIa receptor blockers and low- molecular-weight heparins) in this high-risk cohort of patients. Recently it has been shown that risk scores as calculated in the Thrombolysis in Myocardial Infarction (TIMI) studies provided a sound basis for categorization of patients with unstable angina into subsets by degree of risk (see graph, below). This scoring system may be useful in identifying patients likely to benefit from the more aggressive interventions.

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Therapeutic Options and Considerations

The immediate goals of management in unstable angina include prevention of progression to acute MI and death and of recurrent episodes of ischemia. Long-term goals include stabilization and prevention of progression of underlying atherosclerotic vascular disease (see figures below).

All are served by antithrombotic therapy, since thrombosis plays a critical role in the pathophysiology of unstable angina and its major complications. This therapy consists of an antiplatelet agent (aspirin, clopidogrel, or a platelet glycoprotein IIb/IIIa receptor blocker) or an antithrombin agent (heparin) or both.

Aspirin. Aspirin inhibits platelet aggregation by irreversible acetylation of platelet cyclooxygenase, resulting in inhibition of thromboxane A2 synthesis. Four large-scale, controlled, randomized trials have shown that aspirin in doses ranging from 81 to 1200 mg/day reduces the relative risk of acute MI and death in patients with unstable angina by about 50% when used alone or with heparin. Aspirin in doses of 81 to 321 mg/day should be considered for all patients with unstable angina. In patients with true aspirin sensitivity, other effective oral antiplatelet agents that work by platelet adenosine diphosphate (ADP) receptor antagonism, such as ticlopidine or its better tolerated congener, clopidogrel, can be used as aspirin substitutes with comparable efficacy.

Recent results of the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial suggest that a combination of aspirin and clopidogrel may be more efficacious in reducing adverse events than aspirin alone, albeit at a slightly higher risk of nonintracranial bleeding complications.

Platelet glycoprotein IIb/IIIa receptor blockers or "superaspirins." Platelets contain dimeric glycoprotein IIb/IIIa receptors which, when activated, mediate platelet aggregation by their interaction with adhesive ligands such as fibrinogen and von Willebrand factor. This receptor-mediated aggregation represents the final common pathway for all platelet agonists that induce aggregation. Several recent studies have examined the role of blockers of these receptors, both in patients with unstable angina and those with acute coronary syndromes undergoing endovascular interventions. Three such blockers are in clinical use: abciximab, a long-acting chimeric monoclonal antibody fragment, and the short-acting synthetic compounds tirofiban and eptifibatide. In several clinical trials of unstable coronary syndromes, the addition of an intravenous infusion of these agents has been shown to result in a greater reduction of spontaneous and interventional procedure-related clinical events than that achieved with aspirin and heparin alone. The benefit is more pronounced in patients with high-risk characteristics (continuing instability during routine therapy, elevated troponin, and pronounced ECG abnormalities) and those undergoing endovascular interventions.

Unfractionated heparin. Heparin reduces thrombin action by its interaction with antithrombin III and by inhibiting factor Xa. A number of clinical trials have shown that early intravenous unfractionated heparin (UFH) reduces the risk of acute MI and ischemia in patients with unstable angina, and one comparative study suggested that it was more effective than aspirin for this purpose. Meta-analyses of several small studies have found that the combined use of aspirin and UFH produces a 33% reduction in the incidence of death or MI compared with aspirin alone. The combination of aspirin (indefinitely) and heparin (for the first three to five days) is considered standard treatment for patients with unstable angina. When using UFH, a protocol of weight-adjusted dosing with close monitoring should be followed to maintain activated partial thromboplastin time within 1.5 to 2.0 times the control value and thereby avoid an increased risk of bleeding.

Low-molecular-weight heparins. In an attempt to overcome the multiple limitations of unfractionated heparin, several low-molecular-weight heparins (LMWHs) have been produced by methods involving enzymatic or chemical degradation of UFH. All heparins produce their anticoagulant effect after binding antithrombin. Unfractionated heparin binds both thrombin and factor Xa with the same potency (1:1), whereas LMWHs vary in their anti-Xa potency. Unlike UFH, LMWHs do not bind avidly to circulating proteins or inflammatory cells, which makes their bioavailability and dose response more predictable and stable and their effect more sustained in duration.

The LMWH formulations can be given in fixed doses, subcutaneously once or twice a day, eliminating the need for intravenous dosing, frequent dose adjustments, or aPTT monitoring. Another comparative benefit is reduced frequency of heparin-induced thrombocytopenia (HIT) syndrome. However, because of cross-reactivity, LMWH cannot be substituted for UFH when UFH has produced HIT. Clinical trials have shown that LMWH, like UFH, produces an additive benefit when combined with aspirin.

Studies involving dalteparin (120 IU/kg every 12 hours in the FRISC trial) or nadroparin (FRAXIS trial) as the LMWH have not shown either to be superior to UFH in terms of clinical efficacy. However, studies involving enoxaparin (1 mg/kg every 12 hours in the ESSENCE and TIMI-11B trials) have suggested that it has a modest advantage over UFH, due mainly to a decrease in recurrent ischemia rather than a substantive difference in the rate of acute MI or death. Adverse effects of LMWH in terms of major bleeding have been similar to those of UFH. However, since the use of LMWH is logistically simpler and potentially cost-saving (because of reduced resource utilization, which more than offsets the higher cost of the drug), it is preferable to UFH#151;especially in high-risk patients#151;even if there is no difference in clinical efficacy.

Prolonged postdischarge home use of LMWH in treating unstable angina has been examined in three clinical trials and not found to improve clinical outcome compared with short-term in-hospital use.

Direct antithrombins. Heparin has been shown to be less effective in inhibiting thrombin bound to vessel walls than it is against circulating thrombin, whereas direct thrombin inhibitors such as hirudin and hirudin analogues are equally effective in inhibiting both forms of thrombin. These direct thrombin inhibitors have been tested in unstable angina, but no clear superiority over standard heparin has been demonstrated.

Adjunctive therapies. Nitrates (by various routes) are useful in reducing the frequency of angina in patients with unstable angina, although reduction in the risk of acute MI or death has never been demonstrated. Their use should therefore be considered primarily palliative. Beta-blockers also reduce the frequency of angina and are associated with a modestly decreased incidence (about 10% to 15%) of MI or death. Thus, in addition to nitrates, beta-blockers may be considered adjunctive therapy for unstable angina unless specific contraindications exist.

In addition to nitrates and beta-blockers, heart rate-reducing calcium channel blockers such as diltiazem and verapamil can be used as adjuncts, especially if beta-blockers are contraindicated, to control symptoms. Short-acting dihydropyridines such as nifedipine, which increase heart rate, should not be used. Overall results from clinical trials suggest that in acute MI, there tends to be a higher mortality with the use of heart rate-increasing agents such as nifedipine, while the use of long-acting agents that decrease heart rate (verapamil and diltiazem) is associated with a trend toward better survival, but none of the trends appears to be important.

Coronary angiography and invasive intervention. It is generally accepted that coronary angiography is appropriate for patients with unstable angina who continue to have recurrent instability or are in a state of severe hemodynamic compromise. What is less clear is whether a patient who has been stabilized is better off with conservative follow-up, risk stratification, and provocative testing or with routine coronary angiography. One clinical trial (VANQUISH) conducted in an era when glycoprotein IIb/IIIa blockers were not used and coronary stents were not in vogue showed a better outcome with conservative management, while two others (TIMI-IIIB and MATE) showed comparable outcomes for the two approaches. However, two more recent studies (FRISC II and TACTICS-TIMI 18) have provided data suggesting that a routine invasive strategy may yield better clinical outcomes. In the FRISC II trial, the six-month composite end point (nonfatal MI or death) was 9.4% for the invasive arm versus 12.1% (P = 0.03) for the conservative arm. In the TIMI 18 trial, death or nonfatal MI occurred in 7.4% of patients in the invasive arm compared to 10.5% (P = 0.009) in the conservative arm.

Our own clinical practice is to recommend early coronary angiography in the majority of patients with unstable angina, especially if they show one or more markers of high risk and have no comorbidity that would preclude a reasonable outcome. Coronary angiography may indicate percutaneous transluminal coronary angioplasty, and possibly stenting of culprit lesions, or referral for CABG if there is critical multivessel or left main-stem disease, especially in the presence of left ventricular dysfunction.

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Long-term Strategy

Since about 85% to 90% of patients with unstable angina have atherosclerotic vascular disease, risk-factor modification must be initiated in the hospital and continued long-term. Patients must adopt a healthy lifestyle, which would include smoking cessation, weight loss as needed, a diet rich in fruits, vegetables, and fish and low in saturated fat, regular aerobic exercise, and stress reduction. In addition, hypertension, diabetes, and dyslipidemia must be brought under control. Recent studies have suggested, also, that angiotensin-converting enzyme inhibitors may reduce vascular events in patients with established coronary artery disease, especially in those with glucose intolerance or left ventricular dysfunction. We have found that "ABCDE" is a useful mnemonic capturing the essence of long-term management for this patient population (see box, below).

The short and long-term outcomes of patients with unstable angina can be improved with early diagnosis, risk stratification, and effective antithrombotic and adjunctive therapies, supplemented with judicious use of invasive assessment and treatment and aggressive risk factor modification.

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