Although many risk factors for coronary artery disease are not modifiable, it is now clear that interventions such as smoking cessation, treatment of dyslipidemia, and lowering of blood pressure can both prevent coronary disease and delay its progression and complications after it is manifest. Treatment of lipid abnormalities delays the progression of atherosclerosis and in some cases produces regression. Even in the absence of regression, fewer new lesions develop, endothelial function may be restored, and coronary event rates are markedly reduced in patients with clinical evidence of atherosclerosis.

A series of clinical trials has demonstrated the efficacy of lowering LDL cholesterol with HMG-CoA reductase inhibitors (statins) in preventing death, coronary events, and strokes. Beneficial results have been found in patients who have already experienced coronary events (secondary prevention), in those at particularly high risk for events (diabetics and patients with peripheral artery disease), and those with elevated LDL cholesterol without multiple risk factors.

Benefits occurred regardless of age, race, or the presence of hypertension. Therefore, aggressive lipid-lowering therapy should be implemented in all patients with dyslipidemia and coronary artery, cerebrovascular, or peripheral vascular disease. Furthermore, there is now clear evidence that reduction of LDL cholesterol can prevent coronary events and stroke in patients without clinically manifest atherosclerosis (primary prevention) and LDL levels as low as 130 mg/dL. The recently reported Heart Protection Study demonstrated more than 20% reductions in vascular events in patients with prior myocardial infarction, stroke, peripheral vascular disease, or diabetes with total cholesterol levels as low as 135 mg/dL, a substantial number of whom had LDL cholesterol levels under 100 mg/dL. This result suggests that all patients at significant risk for vascular events should receive a statin regardless of their cholesterol level - and, by implication, that these agents may work by additional mechanisms that are unrelated to lipid lowering.

Treatment of abnormally low HDL levels or elevations of lipoprotein(a) and small, dense LDL particles is more difficult, but oral niacin in high dosages (2-3 g/d or more) may be effective. A trial in postinfarction patients has demonstrated that an increase in HDL levels with gemfibrozil (600 mg twice daily) in patients with relatively low LDL levels prolongs reinfarction-free survival. The value of reducing elevated triglyceride levels is less clear, but since elevated triglycerides are often associated with other lipid abnormalities, treatment of high-risk patients with niacin, gemfibrozil, or fenofibrate for levels above 400 mg/dL is appropriate.

Since LDL oxidation appears to play a role in the atherogenicity of lipid molecules that have passed into the vessel wall, antioxidant therapy has been advocated as a preventive measure. Thus far, however, there are few data to support this popular concept, and many large, well-controlled studies have failed to demonstrate a benefit with vitamin E therapy. Indeed, there have been no positive prospective trials with any antioxidant agent. Antioxidant therapy may hinder the effectiveness of niacin and statin therapy.

Elevated plasma homocysteine levels are associated with an increased risk of vascular events. Although homocysteine levels can be reduced with dietary supplements of folic acid (1 mg/d) in combination with vitamin B₆ and vitamin B₁₂, it is not clear that this reduces clinical events in individuals with coronary artery disease.

Antiplatelet therapy is another very effective preventive measure. Aspirin (325 mg every other day) in males over the age of 50 reduces the incidence of myocardial infarction. Whether this approach should be employed in the general population or only in those at higher risk is unclear, and the optimal dosage is not known. A prudent approach would be to administer 81-325 mg daily to men with multiple coronary risk factors or concomitant diabetes starting at age 45-50 if no contraindication is present. The same approach is probably warranted for women, commencing 5-10 years later. The previously mentioned GISSI Prevention Trial found a significant mortality reduction with omega-3 fatty acid administration (1 g daily) - which has an antiplatelet effect - in postinfarction patients.

The effect of hormone replacement therapy in postmenopausal women has now been clarified, and it is clear that combined estrogen-progesterone therapy is not protective. Control of blood pressure has now been shown to prevent infarctions in older patients. Although unproved, it seems likely that control of blood pressure in younger individuals also prevents subsequent coronary events. The role of exercise remains controversial. Although individuals who exercise for at least 30 minutes a week are at lower risk for subsequent coronary events, it is difficult to be certain that this outcome relates specifically to exercise rather than a generally healthy lifestyle.

The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that the ACE inhibitor ramipril reduces fatal and nonfatal vascular events (cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes) by 20-25% in patients at high risk, including diabetics with additional risk factors or patients with clinical coronary, cerebral, or peripheral arterial atherosclerotic disease. Thus, the role of ACE inhibitors in secondary prevention appears to be expanding beyond patients with heart failure or left ventricular systolic dysfunction.

The decrease in number of coronary deaths over the last 2 decades may be due to a decrease in the prevalence of risk factors but probably also reflects improvements in medical therapy, the role of coronary care units, better treatment of angina, arrhythmias, and heart failure, and improved survival after coronary revascularization in some patient subsets.

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