Acute Coronary Artery Syndromes

Despite advances in both the prevention and the treatment of acute coronary artery syndromes—unstable angina and Q wave and non-Q wave myocardial infarction—the actual cause of atherosclerosis and thrombus formation in coronary arteries has not yet been fully elucidated. In the past 6 years, however, a new basic science called vascular biology has provided a much better understanding of the manner in which a coronary artery plaque becomes a life-threatening thrombus.

About 60% of the time, coronary artery disease manifests itself clinically as an acute coronary artery syndrome. Stable angina is the presenting condition in about 26% of cases, and the remaining cases present as sudden death.

Atherosclerosis Is Similar to Chronic Inflammation

Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995; 91:2844-50.

This review of recent laboratory findings helps explain some of the clinical and pathologic observations made during the past 10 years in patients with the acute coronary syndromes. Using molecular biological techniques, researchers have examined the presence of cytokines, immunologically activated cells, and changes in the extracellular matrix in vulnerable areas of atherosclerotic plaques.

Atherosclerosis shares many characteristics with chronic inflammatory processes. For example, oxidized lipoproteins probably contribute to smoldering inflammation within atherosclerotic plaques. Other agents that may help incite this inflammatory process include infectious agents (such as viruses and chlamydia) and autoantigens (such as heat-shock proteins). Activated T cells in plaques secrete interferon-, which may impair collagen synthesis, whereas activated macrophages and smooth-muscle cells release enzymes that weaken the connective tissue framework of a plaque's fibrous cap. This weakening sets the stage for plaque disruption and eventual thrombosis.

These findings provide bases for clinical studies of prophylactic therapy with anti-inflammatory drugs. They may also suggest a possible mechanism by which aspirin acts within plaques as an anti-inflammatory agent as well as a platelet antiaggregation factor.

Transition from Plaque to Thrombus

Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995; 92:657-71.

These authors review the laboratory evidence on why, after years of indolent growth, atherosclerotic plaque suddenly disrupts to form a thrombus. Atherosclerosis without thrombosis appears to be a benign disease. It is the acute thrombotic event in addition to a disrupted atherosclerotic plaque that leads to unstable angina and myocardial infarction.

The risk for plaque disruption depends more on plaque composition and structure than on the severity of arterial stenosis. Major determinants of the vulnerability of plaque to rupture include the consistency of the plaque's atherosclerotic core, the thickness of the plaque's fibrous cap, and inflammation near the plaque, as described above.

Plaque disruption tends to occur at "weak" points within the plaque that coincide with hemodynamic and biochemical "stress" points. Thus, plaque vulnerability depends on both the plaque itself and the external forces that act on it. Any clinical intervention that can strengthen the plaque or reduce the stress on it reduces the likelihood that a patient will develop unstable angina or myocardial infarction.

Various "triggers" that disrupt plaque include sudden surges in blood pressure, such as those caused by exercise or exposure to cold. Beta-blockers are thought to decrease the sympathetic surges. Other triggers include cigarette smoking and coronary artery vasospasm. Once a plaque disrupts, the makeup of the coronary artery thrombosis depends on the composition of the interior of the plaque, fibrinolytic enzyme levels, platelet activation, and other factors. This process is clearly a complex interplay of physical, physiologic, and biochemical elements.

The studies described in the reviews by Libby and by Falk and coworkers provide more insight into the "Virchow triad" of intravascular coagulation. The first factor, stasis, can occur as a result of either proximal coronary artery occlusion or vasospasm. The second, hypercoagulability, comes from platelet activation and from the reduction of thrombolytic enzyme levels. The third, injury to the vascular wall, results from the tissue factors released near the vulnerable plaque.

Cholesterol Reduction

It is clear that disruption of vulnerable plaque is the event that leads to an unstable ischemic syndrome. Both laboratory studies and clinical research have focused on the role of cholesterol in the development of plaques and, possibly, in their stability.

It has been known for 50 years that elevated cholesterol levels are highly associated with unstable ischemic syndromes. However, it has been difficult to show a change in total mortality associated with the reduction of total cholesterol or low-density lipoprotein (LDL) cholesterol levels. Carefully done studies have shown that reducing cholesterol levels stabilizes or even slightly reduces vascular occlusion caused by plaque. Studies of large groups of patients have shown a reduction in the number of unstable ischemic events that is out of proportion to the change seen in the plaque.

Several studies have recently provided more clinical evidence that decreasing lipid levels produces a beneficial effect overall.

Cholesterol Level Reduction and Treatment with Antioxidants Decreased Coronary Vasomotion

Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med. 1995; 332:488-93.

Studies of the effect of cholesterol level reduction have shown a more robust effect in patients with established coronary artery disease than in persons without known disease. These findings suggest that some of the effect of lowering cholesterol levels may be related to the coronary artery vasomotion associated with atherosclerosis rather than to plaque formation itself. Anderson and colleagues sought to determine whether cholesterol reduction or antioxidant therapy could restore endothelium-dependent coronary vasodilation in patients with hypercholesterolemia and coronary atherosclerosis.

The 49 study patients (37 men and 12 women) had a mean serum cholesterol level of 209 mg/dL and a mean age of 56 years. Angiographic evidence of coronary atherosclerosis was shown in 92%. The patients were randomly assigned to one of three groups. Group I (11 patients) received a low-cholesterol diet; group II (21 patients) received LDL cholesterol-lowering agents (lovastatin and cholestyramine); and group III (17 patients) received an LDL cholesterol-lowering agent (lovastatin) and an antioxidant (probucol).

Endothelium-dependent coronary artery vasomotion in response to intracoronary infusion of acetylcholine (10^–8 to 10^–6 M) was assessed by coronary angiography at baseline and after 1 year of therapy.

Low-density lipoprotein cholesterol levels were reduced by 38% in group II and 41% in group III (both compared with group I) (P < 0.001). At base-line and at follow-up, maximal changes in coronary artery diameter with acetylcholine were – 15% and – 6% in group II, – 19% and – 2% in group III (P < 0.01 for group III compared with group I), and – 14% and – 19% in group I (P = 0.08 compared with group II). Negative values indicate vasoconstriction.

Thus, endothelium-dependent vasodilation improves with cholesterol reduction and antioxidant therapy, and the effect is greatest when antioxidant therapy is added to an LDL cholesterol-lowering drug. This may partly explain the reduced incidence of coronary events seen with cholesterol-lowering therapy.

Simvastatin Was Effective in Secondary Prevention

Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344:1383-9.

Cholesterol-lowering maneuvers have been controversial in primary prevention. However, several small studies and some expert panels have indicated that there may be stronger evidence for such maneuvers among persons with known coronary artery disease. This study evaluated the effect of cholesterol reduction with simvastatin on mortality and morbidity in patients with established coronary heart disease (secondary prevention).

Physicians at 94 Scandinavian clinical centers recruited 4444 patients (82% men, 51% older than 60 years of age) who had angina pectoris or previous myocardial infarction and whose serum cholesterol levels were 213 to 309 mg/dL (5.5 to 8.0 mmol/L) while they received a lipid-lowering diet. The patients were randomly assigned to receive double-blind treatment with simvastatin or placebo. The dose was adjusted on the basis of cholesterol levels at 6 and 18 weeks to achieve serum cholesterol levels of 116 to 201 mg/dL (3.0 to 5.2 mmol/L). The maximum dosage was 40 mg/d.

After a mean follow-up of 5.4 years, the following changes were seen in the simvastatin group: Total cholesterol levels had decreased by a mean of 25%, LDL cholesterol levels had decreased by a mean of 35%, and high-density lipoprotein cholesterol levels had increased by a mean of 8%. Eight percent of simvastatin recipients compared with 12% of the control patients had died (from all causes). This produced a relative risk of 0.70 (95% CI, 0.58 to 0.85; P = 0.0003); the number of patients who had to be treated to prevent one death was about 25 in the 5.4 years (Table 1). The 6-year probabilities of survival in the placebo and simvastatin groups were 87.6% and 91.3%, respectively. The relative risk for death from coronary artery disease in the simvastatin group was 0.58 (CI, 0.46 to 0.73). The risk for death from noncardiovascular causes was the same in both groups. Side effects occurred in 6% of patients in both groups.

In this study, long-term treatment with simvastatin was safe and improved survival in patients with known coronary artery disease. The use of simvastatin was associated with fewer systemic and coronary ischemic events. This study was the first to show a decrease in all-cause mortality, and its results are generally accepted as adequate evidence that secondary prevention of elevated cholesterol levels is effective in reducing the risk for further death and disability from coronary artery disease.

Pravastatin Was Effective in Primary Prevention

Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995; 333:1301-7.

Treatment of hypercholesterolemia as primary prevention for coronary artery disease remains controversial. Studies have generally shown that treating elevated cholesterol levels reduces the incidence of myocardial infarction, but overall death rates among treated patients have not differed greatly. In this study from Scotland, researchers asked whether administering pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary artery disease.

Physicians at coronary screening clinics throughout western Scotland examined 81 161 men 45 to 64 years of age. Men with nonfasting plasma cholesterol levels of at least 252 mg/dL (6.5 mmol/L) were given dietary advice and were re-examined 4 weeks later. If LDL cholesterol levels were greater than 155 mg/dL (4.0 mmol/L) at that time, the patients were asked to return 4 weeks later. If LDL cholesterol levels were still at least 155 mg/dL and were not greater than 174 mg/dL (4.5 mmol/L) and if no major electrocardiographic abnormalities were seen, patients were randomly assigned to receive simvastatin (4 mg/d) or placebo. The 6596 patients had a mean plasma total cholesterol level of 272 mg/dL. The patients were then seen every 3 months; at each visit, electrocardiography was done, lipoprotein levels were measured, and dietary advice was given. Physical examinations were done annually. The mean duration of follow-up was 4.9 years.

Primary end points were nonfatal myocardial infarction, death from coronary heart disease, or both. Secondary end points were death from cardiovascular disease, death from any cause, or coronary revascularization.

In patients given pravastatin, cholesterol levels decreased 20% and LDL cholesterol levels decreased 26% (Figure 1). No change occurred in the placebo group. The rate of withdrawal from the study was the same in both groups. Two hundred forty-eight definite coronary events (nonfatal myocardial infarction or death from coronary disease) occurred in the placebo group, and 174 occurred in the pravastatin group. The relative risk reduction with pravastatin was 31% (CI, 17% to 43%; P < 0.001). Reduction in the risk for nonfatal myocardial infarction was also 31% (P < 0.001) (Figure 2). The risk for death from all cardiovascular causes was reduced by 32% (P = 0.03). Because no excess of deaths from noncardiovascular causes was seen in the pravastatin group, the overall reduction in the relative risk for death in the pravastatin group was 22% (CI, 0% to 40%; P = 0.05). The number needed to treat to prevent one death was 111.

View larger version (19K): [in this window] [in a new window]   Figure 1. Effects of pravastatin therapy on plasma low-density lipoprotein (LDL) cholesterol levels.

View larger version (24K): [in this window] [in a new window]   Figure 2. Kaplan-Meier analysis of the time to a definite nonfatal myocardial infarction or death from coronary heart disease, according to treatment.

Pravastatin reduced the incidence of myocardial infarction and the rate of death from cardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction. There were no excess deaths from other causes among men taking pravastatin, and these men had no adverse effects caused by pravastatin.

We believe that the evidence is great enough to warrant the initiation of primary prevention therapy with pravastatin in men who are 45 to 64 years of age and have high cholesterol levels. This is in some contrast to the recent recommendations of the American College of Physicians, which advocate primary prevention if patients have at least one other cardiac risk factor [1].

In summary, when we combine the data from the studies described above with those from older studies, such as the Framingham study, we arrive at the following recommendations, which are particularly important in persons with known coronary artery disease. First, adipose body mass should be minimized, and a low-fat, low-carbohydrate diet should be pursued. Second, in general, the lower the cholesterol level, the better. Some studies show positive effects at a total level as low as 140 mg/dL, but targets of 90 mg/dL or less for LDL cholesterol and 45 mg/dL or more for HDL cholesterol are adequate. Finally, cessation of smoking is critical.

Aortic Regurgitation

In 1988, it was shown that hydralazine improved the markers of outcome in patients with asymptomatic aortic regurgitation. Left ventricular end-systolic and end-diastolic volume were reduced, whereas ejection fraction was increased. Therefore, afterload reduction—decreasing the resistance to forward flow from the left ventricle—appeared to make good sense. However, no study had examined actual clinical outcome, and, since 1988, the use of other afterload reducers that have theoretical advantages over hydralazine have been introduced.

Enalapril Appeared To Be Superior to Hydralazine

Lin M, Chiang HT, Lin SL, Chang MS, Chiang BN, Kuo HW, et al. Vasodilator therapy in chronic asymptomatic aortic regurgitation: enalapril versus hydralazine therapy. J Am Coll Cardiol. 1994; 24:1046-53.

The increased use of angiotensin-converting enzyme inhibitors as afterload reducers in patients with heart failure highlights the question of whether drugs in this class are more helpful as afterload reducers in patients with aortic regurgitation. These researchers sought to compare the long-term efficacy of enalapril with that of hydralazine therapy on left ventricular end-diastolic and end-systolic volumes, ejection fraction, left ventricular mass, and the renin-angiotensin system in patients with moderate to severe asymptomatic aortic regurgitation.

Seventy-six asymptomatic patients with moderate to severe nonrheumatic chronic aortic regurgitation were randomly assigned in a double-blind study comparing the effects of hydralazine ( 50 mg twice daily) with those of enalapril ( 20 mg twice daily). At 12 months, two-dimensional echocardiography was done to measure left ventricular end-diastolic and end-systolic volumes, left ventricular mass, and left ventricular wall stress. Plasma renin activity and aldosterone and antidiuretic hormone levels were also measured at this time.

Seventy patients completed the study. Those receiving enalapril had significantly reduced left ventricular end-diastolic volume (124 to 108 mL/m²), left ventricular end-systolic volume (50 to 40 mL/m²), and left ventricular mass (131 to 113 J/m²) (P < 0.01 for all comparisons). Hydralazine was associated with no significant changes. Both drugs reduced left ventricular wall stress. At 1 year, patients receiving hydralazine had increased plasma renin activity and plasma aldosterone levels compared with patients receiving enalapril.

Although both drugs effectively reduced left ventricular wall stress, enalapril appeared to be superior for the treatment of chronic aortic regurgitation because it more effectively decreased left ventricular mass and volumes. Whether this translates into better patient survival beyond 1 year is still unknown.

Nifedipine Delayed the Need for Valve Replacement

Scognamiglio R, Rahimtoola SH, Fasoli G, Nistri S, Dalla Volta S. Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function. N Engl J Med. 1994; 331:689-94.

Previous studies have shown that vasodilator therapy with hydralazine or nifedipine confers short-term benefits on patients with aortic regurgitation. However, as noted above, no long-term benefits of afterload reduction therapy have been shown. This study attempted to assess whether vasodilator therapy would reduce or delay the need for aortic valve replacement in asymptomatic patients with severe aortic regurgitation and normal ejection fraction.

Researchers randomly assigned 143 asymptomatic patients with normal left ventricular systolic function and high-grade aortic regurgitation measured by color Doppler ultrasonography to a control group or an intervention group. The control group received digoxin, 0.25 mg/d, and the intervention group received nifedipine, 20 mg twice daily. Left ventricular function, volume, and mass were evaluated every 6 months. Patients were referred for valve replacement for the following reasons: ejection fraction less than 50% for 1 month, change in clinical condition to New York Heart Association class II or greater, development of angina, or increase in left ventricular end-diastolic volume index of 15% or more.

Actuarial analyses indicated that, after 6 years, 34% of patients in the digoxin group and 15% of those in the nifedipine group had had valve replacement (P < 0.001). In the digoxin group, symptoms necessitated valve replacement in 25% of patients, whereas left ventricular dysfunction only accounted for surgical referral. In the nifedipine group, all patients having valve replacement had it only because of left ventricular dysfunction. In all patients who had valve replacement, the left ventricular end-diastolic volume had increased by 15%. After valve replacement, 75% of the patients in the digoxin group and all patients in the nifedipine group with preoperative abnormal ejection fraction had normal ejection fraction after surgery.

Long-term vasodilator therapy with nifedipine reduces or delays the need for aortic valve replacement in asymptomatic patients with severe aortic regurgitation and normal left ventricular systolic function.

In summary, good evidence now shows that reducing afterload improves outcomes for patients with asymptomatic aortic regurgitation. Early treatment of these patients delays and may even prevent the need for surgical repair. Whether such therapy could be generalized to mitral insufficiency is now being studied. In addition, it remains unknown whether the theoretical advantage of angiotensin-converting enzyme inhibitors over the calcium channel blockers will prove to be a clinical advantage.

Atrial Fibrillation

Atrial fibrillation is the most common sustained arrhythmia; it affects about 1.5 million Americans. For most patients, the danger lies not in the arrhythmia but in the sequelae—emboli to the brain and subsequent stroke. The risks for both atrial fibrillation and stroke increase with age, and numerous trials have shown the efficacy of anticoagulation therapy.

Prevention of Emboli after Cardioversion

Kinch JW, Davidoff R. Prevention of embolic events after cardioversion of atrial fibrillation. Current and evolving strategies. Arch Intern Med. 1995; 155:1353-60.

This review examines the incidence of embolic events that occur after cardioversion of atrial fibrillation and the effect of antithrombotic therapy. The use of transesophageal echocardiography in this setting is also examined. The authors of this paper reviewed 9 studies involving 2363 patients who had had cardioversion with quinidine and 16 studies of 2606 patients who had had cardioversion with electricity. The anticoagulation status of these patients was mixed.

Overall, cardioversion of atrial fibrillation to sinus rhythm was associated with a 1.55% incidence of thromboembolic events. In three nonrandomized, controlled trials that studied the effect of anticoagulation with warfarin in 848 patients, the risk for embolism was 4.6% in the untreated group and 0.5% in the treated group. After cardioversion, anticoagulation therapy was most effective if continued for 2 to 3 weeks, presumably because normal atrial contraction does not return immediately after electrical reversion to sinus rhythm. In most studies, patients received anticoagulation therapy for 3 to 4 weeks before cardioversion.

The use of transesophageal echocardiography to rule out intra-atrial thrombus and thus to identify low-risk patients who are candidates for immediate cardioversion remains controversial. Four uncontrolled studies of 283 patients have supported the use of transesophageal echocardiographic studies. At least two other studies, however, have shown that embolic events are possible even after the results of transesophageal echocardiographic study are normal.

Optimal Oral Anticoagulation Therapy

Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. The European Atrial Fibrillation Trial Study Group. N Engl J Med. 1995; 333:5-10.

Patients with chronic atrial fibrillation being treated with warfarin are at risk for ischemic (embolic) events if anticoagulation is ineffective, but they are also at risk for bleeding complications when anticoagulation is too aggressive.

This European group studied 214 patients with nonrheumatic chronic atrial fibrillation to determine which intensity of oral anticoagulation with warfarin would provide the best balance. This was a secondary prevention study; all patients had previously had a minor cerebral ischemic event. Incidence rates for both ischemic and major hemorrhagic events were calculated (Table 2).

The optimal intensity of anticoagulation lay between international normalized ratios of 2.0 and 3.9. Treatment was ineffective when the international normalized ratios were less than 2.0. Most major bleeding complications occurred when the international normalized ratios were greater than 5.0.

In summary, with the exception of young persons who have lone, paroxysmal atrial fibrillation, every person with atrial fibrillation should be receiving warfarin if they can tolerate it and should have an international normalized ratio of 2.0 to 3.0. Some controversy surrounds the treatment of very old persons because of their higher risk for bleeding, but this recommendation certainly applies to patients younger than 75 years of age. It appears that keeping the international normalized ratio between 2.0 and 3.0 is relatively safe even in older patients, as long as their risks for bleeding are not obviously higher. In persons 65 to 75 years of age, the risks and benefits of warfarin should be carefully assessed. For most persons older than 75 years of age, aspirin may be the drug of choice.

About 25% of patients who convert to sinus rhythm remain in sinus rhythm 1 year later. Treatment with antiarrhythmic drugs can improve this percentage to as high as 50%, but the side effects can be severe. A reasonable clinical strategy would be to attempt cardioversion at least once for persons in stable atrial fibrillation. Reversion to atrial fibrillation is associated with the duration of the arrhythmia and the size of the left atrium. If atrial fibrillation recurs relatively soon and the patient tolerates the arrhythmia, it would then be reasonable to try to control the heart rate and continue the anticoagulation. Before cardioversion, patients should receive 3 to 4 weeks of warfarin-produced anticoagulation, and warfarin therapy should be continued for 4 weeks after cardioversion.

Myocarditis

A common practice has been to obtain myocardial biopsy specimens from patients with myocarditis to assess the activity of myocardial inflammation because it has been believed that immunosuppressive therapy probably improves outcomes in patients with evidence of active inflammation.

Immunosuppression Appeared Ineffective

Mason JW, O'Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med. 1995; 333:269-75.

Myocarditis is a precursor of dilated cardiomyopathy. It has been proposed that aberrant immune responses are the cause of myocarditis that follows viral illness. This study sought to determine whether immunosuppressive therapy would improve left ventricular function in patients with myocarditis. The secondary objective was to determine the usefulness of myocardial biopsy in patients with suspected myocarditis.

In a randomized trial, immunosuppressive drugs (prednisone with cyclosporine or azathioprine) were compared with conventional therapy for heart failure in 111 patients with biopsy-proven myocarditis. All patients had a left ventricular ejection fraction less than 45% by radionuclide gated blood-pool imaging. Therapeutic intervention lasted 24 weeks. The primary outcome measure was a change in left ventricular ejection fraction at week 28.

Mean left ventricular ejection fraction improved equally in both groups, increasing by 25% to 34% at 28 weeks. Independent predictors of improved left ventricular ejection fraction included higher left ventricular ejection fraction at baseline, less intense conventional therapy, and shorter duration of disease. No difference in mortality rates was seen between the two groups. Mortality rates for the entire cohort were 20% at 1 year and 56% at 4.3 years. The study suggested that a robust inflammatory response was associated with less severe initial disease.

This study offers three important conclusions: 1) Immunosuppression seems to have no effect on the prognosis of myocarditis; 2) about half of patients with myocarditis will die within 5 years; and 3) myocardial biopsy is therefore unnecessary. There is some theoretical support for the use of afterload reducers, especially captopril, but the effectiveness of this drug has not been shown in clinical studies.

Dr. Cheitlin: San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, CA 94110-3594.

Dr. Roberts (Series Editor): York Health System, York, PA 17403.