Management of stable angina includes eliminating or controlling specific coronary risk factors, implementing lifestyle changes to reduce the risk of coronary artery disease, controlling precipitating factors and prescribing appropriate anti-ischemic medicines.1 Measures for eliminating or modifying risk factors include control of hypertension and diabetes, a reduction of the cholesterol level, smoking cessation, weight reduction to the patient's ideal body weight, regular exercise and avoidance of strenuous activities that are known to precipitate angina. Correction of precipitating conditions such as anemia, valvular disease and arrhythmias is also important.
The goals of drug therapy in the management of chronic stable angina are to eliminate ischemia, abolish or reduce the frequency and severity of anginal attacks, prevent myocardial infarction and potentially improve the patient's long-term survival. Because a pivotal aspect in the pathophysiology of angina is a mismatch of oxygen supply and oxygen demand, drug therapy is directed at decreasing the myocardial oxygen demand and increasing the myocardial oxygen supply. Antianginal agents such as nitrates, calcium channel blockers, beta-adrenergic blockers and aspirin have been shown to decrease cardiac ischemia or prevent myocardial infarction.
The vascular endothelium, once thought to be merely a passive barrier that separates the lumen from the vessel wall, is actively involved in the response to noxious environmental stimuli. These defense mechanisms include release of endothelium-derived relaxing factor (EDRF), which is now known to be nitric oxide.2 Nitric oxide relaxes vascular smooth muscle and also inhibits platelet aggregation and adhesion. The various forms of nitrate therapy provide an exogenous source of nitric oxide.
Nitrates are potent venodilators and, at higher doses, they are also arterial dilators. Nitrate-induced venodilation causes a decrease in venous return to the heart, thereby reducing left ventricular wall stress, which leads to a decrease in myocardial oxygen demand. Dilatation of the stenotic vessel, as well as dilatation of the intracoronary collateral arteries, increases blood flow to ischemic myocardium. Nitrates have also been shown to relieve coronary spasm.
Nitrates in all of the different forms of administration—sublingual, spray, buccal, oral, intravenous and topical—are effective anti-ischemic agents. They differ primarily in their onset of action and rate of elimination (Table 1). The onset of action of sublingual nitrates, intravenous nitrates and nitrate spray occurs within minutes of administration, making these formulations useful for immediate relief of angina. Alternatively, the spray and the sublingual forms of nitroglycerin can be used as a prophylactic measure before the patient begins an activity that usually precipitates angina. Oral or transdermal nitrates may be practical for use in patients who have frequent episodes of angina or cannot predict an attack. Newer long-acting mononitrates offer the advantage of improved bioavailability, as they avoid first-pass hepatic elimination. They are at least as effective as the isosorbide dinitrates in relieving angina and in allowing an increased duration of exercise before the onset of ischemia. Long-acting mononitrates also require less frequent dosing.
Tolerance, and with it loss of antianginal effect, develops with long-term use of any form of nitrate. It is therefore important to assure a 10- to 12-hour nitrate-free interval. If overnight protection against angina is needed, a trial of nighttime dosing, with a nitrate-free interval during the daytime, may be appropriate. Alternatively, such patients may benefit from the addition of another class of antianginal agents, as may patients who continue to have angina despite nitrate therapy.
Beta-adrenergic blockers have been shown to be effective in reducing the frequency of symptomatic and silent episodes of ischemia and the rate of cardiac events in patients with stable ischemia.3 They exert their actions by blocking beta1 and beta2 receptors on myocardial and smooth muscle cells (Table 2). Inhibition of beta receptors on the myocardium decreases both the heart rate, especially during exercise, and the force of contraction, leading to a decrease in myocardial oxygen demand. As the heart rate slows, the diastolic period is prolonged, enabling increased oxygen delivery by improving myocardial perfusion.
Initial titration of the beta-blocker dose to achieve a resting heart rate of 50 to 60 beats per minute is a good indication that the drug is working. Further modification of the dose to eliminate symptoms is the usual goal in the treatment of angina. Beta-blocker therapy must be discontinued gradually over five to 10 days to avoid rebound angina or hypertension.
Selection of a specific beta blocker often depends on other clinical factors. Cardioselective formulations, such as acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone) and metoprolol (Lopressor), mainly block beta1 cardiac receptors and are advantageous in patients with reactive airways disease or peripheral vascular disease. All beta blockers, however, become nonselective at higher dosages. Thus, the safest approach in patients with asthma is avoidance of beta blockers altogether. Beta blockers with intrinsic sympathomimetic activity, such as acebutolol and pindolol (Visken), may be useful if sinus bradycardia is a problem.
Calcium Channel Blockers
The calcium channel blockers are a diverse group of compounds that block calcium entry into the myocardial and smooth muscle cells, causing muscular relaxation and vascular dilatation. Some of the calcium channel blockers also exert an inhibitory effect on the sinus and atrioventricular nodes, causing the heart rate to slow.
Calcium channel blockers are divided into three structural classes: the papaverine derivatives (i.e., verapamil [Calan]), the benzothiazapine derivatives (i.e., diltiazem [Cardizem]) and the dihydropyridines (e.g., nifedipine [Adalat]). Drugs in each class affect the vasculature, myocardium and conduction system to a different degree (Table 3). Dilatation of the peripheral vasculature is the predominant effect of the dihydropyridines. This may provoke a reflex tachycardia that can often be minimized with use of a long-acting compound. In contrast, slowing of the heart rate and depression of contractility predominate with verapamil, a papaverine derivative. Diltiazem has properties in between those of the drugs in the other two categories.
Calcium channel blockers in each of the three classes have demonstrated efficacy in reducing silent and overt ischemia.4 A slowing of the heart rate, decreased contractility and a reduction in the afterload all serve to reduce myocardial oxygen demand. Dilatation of the coronary arteries improves oxygen delivery. Rarely, coronary steal can occur and may exacerbate angina.
Caution needs to be exercised when prescribing any negative inotropic agent to patients with impaired left ventricular function. The dihydropyridines have the least effect on contractility and appear to be safer in such situations. In particular, amlodipine5 (Norvasc) and felodipine6 (Plendil) have been shown to be safe in patients with compensated congestive heart failure. As with beta blockers, calcium channel blockers should be withdrawn gradually to avoid rebound effects.
Recently, a case-controlled study7 and a meta-analysis8 ignited a debate over the safety of calcium channel blockers in patients with coronary heart disease. The authors of these two articles suggested that use of a calcium channel blocker increased mortality in such patients. A subsequent review of the data, however, revealed possible flaws in the study methods and conclusions.9 Yet there is one point of general consensus from these studies: the use of short-acting dihydropyridines should be avoided in patients with coronary artery disease. However, many well-designed trials have demonstrated the safety and efficacy of the other calcium channel blockers in the treatment of stable angina. Calcium channel blockers play an important role in the management of angina, particularly in patients with contraindications to beta blockers (Table 4).
While minimizing the number of medicines required for control of angina is preferred, combination therapy is indicated if the patient is intolerant to or continues to experience angina despite the optimal dosage of a single drug (Table 5). Combination therapy with beta blockers and nitrates10 or calcium channel blockers11 decreases the degree of cardiac ischemia and improves exercise tolerance. However, use of diltiazem or verapamil with a beta blocker requires careful monitoring of the heart rate and blood pressure, as this combination has additive effects on the sinus and atrioventricular nodes. If prohibitive bradycardia develops, a dihydropyridine calcium channel blocker is an effective alternative to diltiazem or verapamil.
Monotherapy with a beta blocker or a nitrate is the first choice for patients with stable angina if there are no contraindications. If monotherapy fails to produce improvement, the combination of a beta blocker and a dihydropyridine calcium channel blocker or a nitrate may relieve symptoms and mitigate ischemia. If combination therapy fails to relieve symptoms, invasive approaches to treatment should be considered.
Measures to Improve Survival
With the exception of the use of beta blockers after myocardial infarction, antianginal medications have been shown to ameliorate symptoms only; they do not reduce mortality.12 This is in contradistinction to the use of aspirin and lipid-lowering agents in patients with chronic stable angina, which have been shown to improve survival.
Aspirin inhibits the synthesis of prostaglandins, notably thromboxane A2, a potent vasoconstrictor and platelet activator. Aspirin has been shown to improve short- and long-term mortality and to reduce the rate of cardiac events, stroke and acute myocardial syndromes in which platelets contribute to thrombus formation, such as in myocardial infarction and unstable angina.13
A meta-analysis of 25 studies, which included 29,000 patients, demonstrated that antiplatelet therapy was associated with a statistically significant (30 percent) reduction in nonfatal infarctions or strokes and a 15 percent reduction in total vascular mortality.14 Specifically, aspirin in a daily dose of 300 to 325 mg resulted in a 24 percent risk reduction in total vascular events. This effect was equivalent to that occurring with higher dosages of aspirin. A similar conclusion was drawn from a subsequent meta-analysis of studies that included a significant number of high-risk patients, elderly patients and women with chronic stable angina, as well as those with unstable angina.15 Also notable in this study was the finding that aspirin dosages as low as 75 mg per day achieved a significant 29 percent reduction in the vascular event rate, a reduction that is not substantially different from that achieved with higher dosages.
As a primary preventive measure, aspirin has been shown to decrease fatal and nonfatal cardiac events. The Physicians' Health Study,16 a prospective randomized study of approximately 22,000 male physicians without known coronary disease, demonstrated that 325 mg of aspirin every other day decreased the risk of a first heart attack by 44 percent. This dosage also significantly decreased fatal and nonfatal vascular events.
Another primary prevention trial, the Swedish Angina Pectoris Aspirin Trial,17 showed that aspirin is beneficial in patients with chronic stable angina. A daily dosage of 75 mg was associated with a 34 percent reduction in the combined incidence of nonfatal myocardial infarction and cardiac death.
Thus, the evidence is overwhelmingly in favor of the use of aspirin, in the absence of contraindications, as secondary prevention in all patients with heart disease—young and old, men and women. Aspirin therapy may also play a role in primary prevention in otherwise healthy men with cardiac risk factors. Although the results of clinical trials of primary prevention in women are not yet available, it seems logical to recommend prophylactic use of aspirin in women if these findings are confirmed.
Finally, no medicine is without side effects. Some studies have shown an increased risk of nonfatal strokes and gastrointestinal side effects in patients receiving aspirin. Therefore, as always, the risks and benefits must be weighed for each individual patient. While the most common dosage of aspirin for primary and secondary prevention is 325 mg daily, the evidence is substantial that a dosage as low as 75 mg per day results in a similar reduction in cardiac events and mortality rate, and may be associated with fewer side effects.
Primary and secondary prevention trials have proved that a reduction in an elevated serum low-density lipoprotein (LDL) level decreases the risk of fatal and nonfatal cardiac events.18–20 One of the more impressive secondary prevention trials, the Scandinavian Simvistatin Survival Study (4S),19 evaluated the effect of simvistatin in hypercholesterolemic patients 35 to 75 years of age with coronary artery disease and stable symptoms. Significant reductions in LDL and total cholesterol levels were achieved, as well as a significant increase in high-density lipoprotein (HDL) levels. Five-year follow-up revealed a 42 percent reduction in the risk of coronary death, a 34 percent reduction in the risk of major coronary events (cardiac deaths, non-fatal myocardial infarction and resuscitated cardiac arrest) and a 37 percent reduction in the risk of myocardial revascularization.21 Data from the Cholesterol and Recurrent Events (CARE) trial20 convincingly documented that a reduction in the LDL cholesterol level to 100 mg per dL (2.60 mmol per L) in men and women with known coronary artery disease but only mildly elevated cholesterol levels also significantly reduces the risk of fatal and nonfatal coronary events.
Similar benefits were observed in the West of Scotland Coronary Prevention Study.18 This prospective, randomized, placebo-controlled, primary prevention trial included over 6,000 men with hypercholesterolemia but no known heart disease. After five years of follow-up, pravastatin was found to have achieved significant reductions in total cholesterol, triglycerides and LDL levels, along with a significant decrease in the frequency of angiography and revascularization. Compared with the placebo group, the pravastatin treatment group had a significant (31 percent) reduction in nonfatal myocardial infarctions and cardiovascular death, and an overall reduction (22 percent) in all-cause mortality.
Studies of the effect of statin drugs on coronary artery diameter and plaque size, as documented by angiographic monitoring, have demonstrated that cholesterol reduction with these agents slows progression of plaque and occasionally even induces its regression.22,23 While the changes in lumen diameter were statistically significant in these trials, the absolute changes were relatively small (less than 5 percent) compared to the impressive reduction in clinical events and mortality. The significant reduction in the number of new, complete occlusions in these studies has generated the hypothesis that the statin drugs deplete the lipid-rich core of the plaque, thereby making it less likely to fissure, rupture and develop into a complete occlusion.
The weight of the evidence demonstrating improved survival and fewer cardiac events following cholesterol reduction in patients with and without heart disease has prompted the expert panel of the National Cholesterol Education Program (NCEP) to recommend the following goals for cholesterol reduction (Table 6): all patients with known coronary artery disease should aim for a serum LDL cholesterol level of less than 100 mg per dL, those without coronary disease but with two or more cardiac risk factors should aim for an LDL level of less than 130 mg per dL (3.35 mmol per L) and all other patients should aim for an LDL of less than 160 mg per dL (4.15 mmol per L).
Methods of reducing the serum cholesterol level include diet, exercise and drug therapy. The NCEP guidelines provide the details for a stepwise approach, beginning with dietary modifications and then initiating drug therapy as indicated to achieve the desired cholesterol level. A review of the data on dietary therapy alone, however, suggests that a low-fat diet results in a cholesterol reduction ranging from 1 to 17 percent.24 Further analysis of dietary therapy in physicians' offices found that in common practice, dietary therapy produces, on average, less than a 10 percent reduction in the cholesterol level.25 Considering how commonly the cholesterol level is over 200 mg per dL (5.15 mmol per L), most patients will require far more than a 10 percent reduction. Thus, dietary therapy alone is often insufficient.
In recognition of this limitation, the NCEP guidelines suggest initiation of drug therapy as first-line treatment in anyone with markedly elevated cholesterol (LDL over 190 mg per dL [4.90 mmol per L]) and in higher-risk patients with coronary disease but lower cholesterol levels.
The value of a healthy, low-fat diet cannot be overemphasized. It is well to remember that the long-term effects of cholesterol-reducing agents are not well known, and there may be as yet unforeseen risks from lifelong lipid-lowering therapy. A low-cholesterol diet should be encouraged, even in patients who are receiving cholesterol-lowering agents. The combination of a low-fat diet and medication has been shown to lower cholesterol levels more than either intervention alone.
Antioxidants, such as vitamins A and E, are a plausible but as yet unproven means of decreasing cardiovascular disease. The theoretic benefit of antioxidants is based on data that implicate oxidized LDL as a crucial factor in the development of atherosclerosis.26 Antioxidants, by inhibiting the conversion of LDL to oxidized LDL or by interfering with the actions of oxidized LDL, may prevent atherosclerosis.
A number of large-scale observational studies support the beneficial role of antioxidants, showing lower cardiovascular mortality in healthy women and men with the highest intake of vitamin E and beta carotene, and in elderly men and women with a high intake of beta carotene.27 A primary prevention study28 of over 29,000 male smokers who were followed for as long as eight years reported no reduction in coronary events among those receiving vitamin E, and an increased overall mortality in those participants taking beta carotene. The implication from this large study is that in certain subgroups the risk:benefit ratio of beta carotene may be too high to warrant its routine use in coronary disease prevention.
A study of the effects of vitamin E suggests that it may be a useful adjunct to a cardioprotective regimen. The Cambridge Heart Antioxidant Study (CHAOS)29 demonstrated that vitamin E in dosages of 400 and 800 IU daily in high-risk patients with overt coronary artery disease significantly decreased the combined incidence of death and nonfatal myocardial infarction. No effect was found on the incidence of cardiovascular death alone. The clinical implication is that 400 IU of vitamin E may reduce the incidence of cardiac events in patients with known heart disease, but beta carotene should probably be avoided. While vitamin E seems promising, definite guidelines for its use await the results of other trials.
Medical treatment of patients with heart disease is an all-encompassing endeavor involving lifestyle modification and drug therapy. Regarding behavioral changes, the American Heart Association recommends complete smoking cessation, a low-cholesterol diet, a minimum of 30 minutes of physical activity three to four times a week and maintenance of ideal body weight.1
Clearly, all patients with coronary artery disease should be taking aspirin daily if there are no contraindications. In addition, any patient who has had a prior myocardial infarction should receive a beta blocker (assuming no contraindications). Finally, those who cannot achieve adequate LDL reduction by diet alone should receive a cholesterol-lowering agent. Because the benefits of HMG-CoA reductase inhibitors have been so impressive in the postmyocardial infarction population, it has become common practice to initiate this therapy at hospital discharge (even without an initial trial of diet alone).
In addition to prolonging survival, the goal in treating patients with angina is to relieve symptoms and improve quality of life. Selecting the appropriate antianginal regimen for each individual patient and knowing when to consider palliative interventional treatment is a challenge that requires mixing the art and science of medicine.