Cholesterol and the Heart
The Scandinavian Simvastatin Trial
Coronary atherosclerosis is a leading cause of cardiovascular mortality, and high serum cholesterol is thought to be a major factor in the development of coronary atherosclerosis. Fortunately, there has been a consistent decline in cholesterol levels in US adults over the last three decades. Data from four National Health and Nutrition Surveys conducted between 1960 and 1991 show that cholesterol levels have declined from 5.69 mol/L (220 mg/dL) in 1960 to 1962 to 5.3 mmol/L (205 mg/dL) in 1988 to 1991.
The National Cholesterol Education Program recommends that all adults 20 years of age and older be screened for cholesterol levels, and treated if these levels are high. However, a metaanalysis of randomized, controlled cholesterol-lowering trials demonstrated that only patients with a very high initial risk of coronary artery disease (CAD) mortality benefitted from cholesterol reduction. Total mortality (from all causes other than heart disease) was actually increased for those at low risk of death from heart disease. For this reason, many experts recommend that cholesterol-lowering drugs be used only in patients with established CAD or other factors leading to a very high risk of death from coronary artery disease.
Recently results were reported for a randomized, double- blind, multicenter simvastatin trial involving 4444 Scandinavians (aged 35 to 70 years) at high risk of CAD. The investigators-Pedersen et al. at Oslo University’s Aker Hospital-studied the effects of simvastatin 20 to 40 mg/day on cardiovascular morbidity and mortality and total mortality in residents of Denmark, Iceland, Sweden, and Finland having established CAD (previous myocardial infarction (MI) or stable angina pectoris). The drug was administered at a dosage of 20 mg daily with the evening meal. Depending on response, the dosage was increased to 40 mg daily (37% of patients) or reduced to 10 mg daily (only 2 patients). Patients were observed for a median of 5.4 years.
Simvastatin (trade names Zocor, Simlup, Simcard, Simvacor) reduced mean total cholesterol by 25% and low- density lipoprotein (LDL) cholesterol by 35%, and it elevated high-density lipoprotein (HDL) cholesterol by 8%. There were 256 deaths in the placebo group (12%), 189 of which were coronary deaths, and 182 deaths in the simvastatin group (8%), 111 of which were coronary deaths (giving a relative risk of 0.58). A total of 622 patients (28%) had one or more major coronary events in the placebo group, compared with 431 patients (19%) in the simvastatin group (relative risk 0.66). Excluding silent myocardial infarction, the overall risk of coronary death plus nonfatal MI was reduced by 37%. Beneficial effects began after about 1 year of therapy and increased steadily thereafter; risk of coronary artery disease death was reduced by 26% in the first 2 years, and by 46% after that. Other benefits of treatment included a 37% reduction in the risk of undergoing myocardial revascularization procedures, and a slight reduction in fatal and nonfatal cerebrovascular events.
Only 19% of the participants were women, too few to determine whether the drug prolonged their lives. The effects on other measures matched those in men: a 38% average drop in serum levels of LDL cholesterol and an 8% average increase in high-density lipoprotein cholesterol after 6 weeks of simvastatin therapy. Patients were excluded who had unstable (Prinzmetal’s) angina; MI within 6 months of study initiation; congestive heart failure requiring treatment with digitalis, diuretics, or vasodilators; or arrhythmias requiring antiarrhythmic therapy. Also excluded were patients with secondary hypercholesterolemia, tendon xanthomata, planned coronary artery surgery or angioplasty, persistent atrial fibrillation, cardiomegaly, hemodynamically important valvular heart disease, history of completed stroke, impaired hepatic function, partial ileal bypass, history of drug or alcohol abuse, poor mental function, or any other serious disease.
Simvastatin is a member of the class of drugs that inhibit hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. When this enzyme is blocked, the liver produces additional cholesterol receptors that pull cholesterol out of the bloodstream, reducing serum cholesterol levels. Simvastatin was well tolerated in the Scandinavian trial. The overall frequency of adverse events was similar in the simvastatin and placebo groups (6% of both groups withdrew from the study because of adverse events). There were 61 nonfatal cases of cancer in the placebo group and 57 in the simvastatin group (excluding cases of nonmelanoma skin cancer, which occurred in 6 placebo patients and 13 simvastatin patients). Rhabdomyolysis, the most important adverse effect of HMG-CoA reductase inhibitors, occurred in one patient who recovered when treatment was discontinued. Isolated cases of elevated creatine kinase, aspartate aminotransferase, and alanine aminotransferase were noted.
In this trial, overall mortality as well as cardiac mortality were reduced. Does this mean that individuals who are not at risk of CAD should reduce cholesterol levels? Not necessarily. Participants in this study were at high risk of death from CAD, the very group already recommended for cholesterol-reduction therapy. There is still little evidence that cholesterol reduction benefits people who are not at high risk of CAD death. But the results of this study provide good evidence that simvastatin can reduce morbidity and mortality in patients with established coronary artery disease. The investigators concluded that the addition of simvastatin at a dosage of 20 to 40 mg daily to the treatment regimens of patients with CAD can be expected to save the lives of 4 of the 9 patients who otherwise would die from coronary artery disease, to prevent nonfatal MI in 21 patients expected to have an myocardial infarction, and to avoid myocardial revascularization procedures in 6 of the 19 patients expected to require such procedures.
Is Cholesterol Reduction Necessary in the Elderly?
The National Cholesterol Education Program has stated that “high-risk elderly patients who are otherwise in good health are candidates for cholesterol-lowering therapy.” However, evidence from the New Haven, CT, EPESE study (Established Population for the Epidemiologic Study of the Elderly) indicates that this may not be true. Krumholz et al. (Yale University and the University of Connecticut) evaluated 997 EPESE subjects over age 70, interviewed in 1988 and observed for 4 years. They found a lack of association between cholesterol levels (total serum cholesterol and HDL cholesterol) and coronary artery disease morbidity and mortality and all-cause mortality in this cohort. Indeed, in women the best survival occurred in the group with total serum cholesterol levels of 6.2 mmol/L (240 mg/dL) or more, followed by the group with levels between 5.2 and 6.2 mmol/L (200 to 240 mg/dL), with the worst survival in the group with levels less than 5.2 mmol/L (less than 200 mg/dL).
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