Dyslipidemia: Rational Use of the Statins
Dyslipidemia: Rational Use of the Statins
Although the cardiovascular death rate has declined in the United States, the number of hospitalizations for cardiac disease has not. The improvement in care has been offset by an increase in the number of older Americans. By 2050, more than 100 million Americans will be 60 years of age or older, and about 30 million will be older than 80 years.
As the number of older persons rises, clinicians will see more patients with chronic conditions-such as obesity, diabetes mellitus, and uncontrolled hypertension-that increase the risk of coronary heart disease (CHD). These risk factors have been well established by the Framingham Study1 and other epidemiologic reports. The combination of increased caloric intake and reduced physical activity that has become prevalent in our society will also contribute to a higher incidence of the metabolic syndrome-a condition whose manifestations include increased abdominal girth, low levels of high-density lipoprotein (HDL) cholesterol, hypertension, and elevated blood glucose and triglyceride levels.
All of these factors and others suggest that we must actively pursue strategies-such as global risk assessment and the aggressive control of modifiable risk factors-to protect our patients from CHD, which continues to be the leading cause of death in this country. In recent years, aggressive therapy has resulted in a major improvement in the outlook for patients at risk. Yet many of these persons fail to achieve the treatment goals set forth by the National Cholesterol Education Program (NCEP).2 Moreover, many asymptomatic patients at increased risk who would benefit from treatment are not receiving it.
In this article I highlight data from important clinical trials that demonstrate the benefits of lipid-lowering therapy. I also discuss the major causes of undertreatment.
ROLE OF STATINS IN REDUCING CHD RISK
Cardiovascular risk assessment must include intensive scrutiny of a patient's lipid profile, with particular attention to low-density lipoprotein (LDL) cholesterol, the most atherogenic cholesterol (Table 1). Although very high LDL levels secondary to genetic hyperlipidemia present a significant risk, this condition is rare. In fact, initial coronary events occur much more frequently in persons with serum LDL cholesterol levels between 130 and 160 mg/dL (ie, values below those that warrant drug therapy according to the NCEP guidelines).
The rationale for lowering elevated LDL cholesterol levels is supplied by a host of double-blind, placebo-controlled trials that have demonstrated a reduction in primary and secondary cardiac events in patients who are given HMG-CoA reductase inhibitors (statins)
Primary prevention. The degree of absolute risk-the likelihood that CHD will develop within a specific period- guides the intensity of primary prevention efforts. Patients are considered at high risk if the probability that they will suffer a myocardial infarction (MI) in the next 10 years is greater than 20%. According to the NCEP guidelines, risk factors in addition to elevated LDL cholesterol levels include hypertension, cigarette smoking, low levels of HDL cholesterol, CHD, and CHD risk equivalents. The latter group consists of other clinical forms of atherosclerotic disease-such as peripheral arterial disease, previous abdominal aortic aneurysm, and symptomatic carotid artery disease-and diabetes. The NCEP guidelines emphasize that although persons at higher risk are candidates for drug therapy, lifestyle changes are the foundation of primary prevention. The NCEP recommendations are summarized in Table 2.
Two major randomized, doubleblind, placebo-controlled trials evaluated the effectiveness of statin therapy in primary prevention. In the West of Scotland Coronary Prevention Study (WOSCOPS), pravastatin was compared with placebo in men who had elevated LDL cholesterol levels and no known heart disease.3 In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/ TexCAPS), lovastatin was compared with placebo in adults with average total cholesterol and low levels of HDL cholesterol.4 Hospital admission for unstable angina was considered an endpoint cardiac event.
Both studies demonstrated a significant reduction in first cardiacevents in otherwise healthy persons treated with statins. Neither trial was powered to provide statistically significant evidence of a mortality benefit because the number of deaths was small.
Secondary prevention. A host of studies have demonstrated the value of reducing the level of LDL cholesterol in patients with established CHD and hyperlipidemia. The Scandinavian Simvastatin Survival Study (4S) examined data from 4444 patients with known CHD who were randomized to drug therapy or placebo and followed for 5 years.5 The results showed a dramatic reduction in cardiac deaths, stroke, hospitalizations, and need for revascularization in the treated group. This was the first major study to demonstrate a statin-associated reducreduction in all-cause mortality in patients with CHD who had high serum LDL cholesterol. Most previous trials were not powered to demonstrate a difference in an infrequent event end point.
The Cholesterol and Recurrent Events (CARE) trial followed 4159 men and women with average cholesterol levels who had had an acute MI.6 They were randomly assigned to pravastatin or placebo and followed for 5 years. There was a significant reduction in the incidence of cardiovascular events and stroke in the treated patients. Lowering the LDL cholesterol below 124 mg/dL did not seem to provide additional benefits.
Both 4S and CARE recruited patients several months after they had recovered from an acute MI. These studies excluded patients in the immediateperiod after an acute event, when recurrent ischemia and death are most likely to occur.
Subsequently, the Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) study randomized 3086 patients with acute coronary syndrome (ACS) within 24 to 96 hours after hospital admission to either atorvastatin, 80 mg/d, or placebo with a 16-week follow-up.7 The treated group had a lower risk of ischemia requiring hospitalization and had fewer strokes; there were, however, no significant differences in risk of death, nonfatal MI, or cardiac arrest between the groups.
The value of statin therapy is not limited to patients with acute MI or even unstable ACS. In the Atorvastatin Versus Revascularization Treatment (AVERT) trial, 341 patients with stable coronary artery disease, relatively normal left ventricular function, asymptomatic or mild to moderate angina, and an LDL cholesterol level of at least 115 mg/dL who were referred for percutaneous transluminal coronary angioplasty (PTCA) were randomized to atorvastatin, 80 mg/d, or PTCA followed by usual care.8
After 18 months, the incidence of ischemic events-as well as PTCA and coronary artery bypass graft procedures and hospitalizations for worsening angina-was lower in the atorvastatin group. There was no mortality benefit for PTCA. After adjustment for interim analysis, the results just missed statistical significance. At the end of the study, more patients who had undergone PTCA reported improvement in angina; however, these patients were more likely to have started or increased antianginal medication. The researchers concluded that in low-risk patients with stable coronary artery disease, aggressive lipid-lowering therapy was at least as effective as PTCA and usual care in reducing the incidence of ischemic events.