Cholesterol reduction and risk for stroke: a meta-analysis
ACP J Club. 1993 Nov-Dec;119:66. doi:10.7326/ACPJC-1993-119-3-066
Atkins D, Psaty BM, Koepsell TD, Longstreth WT Jr, Larson EB. Cholesterol reduction and the risk for stroke in men: a meta-analysis of randomized, controlled trials. Ann Intern Med. Jul
To evaluate the effectiveness of cholesterol reduction in reducing fatal and nonfatal stroke in middle-aged men by using meta-analysis.
English-language studies published between 1966 and 1992 were identified using MEDLINE searching with the key words cholesterol and clinical trials. Additional studies were identified by reviewing bibliographies of all identified studies and 5 recent meta-analyses examining the effects of cholesterol reduction on ischemic heart disease and mortality.
Studies were selected if they were randomized trials that examined the cardiovascular effects of diets or medications used to lower cholesterol in men, if fatal and nonfatal stroke were reported separately, and if the end-point assessment was blind. 13 studies met the selection criteria.
The study design, intervention, inclusion criteria, change in total cholesterol, and number of strokes and cardiac deaths were extracted. The Mantel-Haenszel method for combining data was used to examine the relation between cholesterol reduction and the risks for fatal stroke, nonfatal stroke, and fatal coronary heart disease.
The 13 trials together randomized 46 538 men. The mean baseline cholesterol level was 6.53 mmol/L, and the mean treatment period was 5.5 years. During > 256 000 patient-years of follow-up, 133 deaths were caused by stroke and 1906 were caused by fatal myocardial infarction (MI) or sudden cardiac death. The overall odds ratio (OR) for cholesterol reduction and the risk for fatal stroke was 1.32 (95% CI 0.94 to 1.86). Heterogeneity of the effect of treatment was not statistically significant. Among the 8 trials reporting nonfatal events, the summary OR for nonfatal stroke for the intervention group compared with the control group was 0.88 (CI 0.70 to 1.11), and the OR for fatal and nonfatal stroke was 0.98 (CI 0.80 to 1.19). The OR for fatal MI or sudden cardiac death was 0.87 (CI 0.79 to 0.95; P = 0.004) for treated patients compared with controls. Heterogeneity among all studies was not statistically significant. Among 3 trials using clofibrate therapy, cholesterol reduction increased the risk for fatal stroke (OR 2.64, CI 1.42 to 4.92) but not for nonfatal stroke (OR 0.87, CI 0.61 to 1.26). Regression analysis showed no association between the magnitude of cholesterol reduction and the risk for fatal stroke.
Serum cholesterol reduction through modified diets or medication did not reduce stroke mortality or morbidity in middle-aged men. Clofibrate was associated with an increased risk for fatal stroke but not nonfatal stroke.
Source of funding: National Institutes of Health National Research Service.
For article reprint: Dr. D. Atkins, Office of Disease Prevention and Health Promotion, Department of Health and Human Services, Switzer 2132, 330 C Street SW, Washington, DC 20201, USA. FAX 202-205-9478.
When patients begin a cholesterol-lowering diet or medication, they do so to reduce their risk for stroke and coronary events. This overview suggests that asymptomatic, middle-aged white men with elevated serum cholesterol who reduce their serum cholesterol by about 7% through diet or medication are unlikely to experience any effect on the risk for stroke (although the 95% CIs of the ORs are wide and are consistent with a 20% reduction and a 19% increase in risk for stroke) but are likely to have a lower risk for fatal MI or sudden death.
The validity of these conclusions depends on the rigor with which the overview was carried out. Ideally, the original data from all randomized controlled trials, both published and unpublished, should be analyzed. The overview by Atkins and colleagues may be somewhat biased because it did not include 5 published studies or any unpublished studies, and the analysis included only the published data and not the original data. It is difficult to know if the conclusions would have been affected if the above criteria had been met.
The conclusions are limited to middle-aged white men with elevated serum cholesterol; they do not apply to older men, women of all ages, and patients with symptoms of cerebrovascular or cardiovascular disease.
The conclusion that clofibrate therapy appears to increase the risk for fatal stroke was based on a post-hoc subgroup analysis of a small number of trials and therefore is not conclusive. All of these points are raised in the paper's well-balanced discussion section.
Graeme J. Hankey, MD
Royal Perth Hospital Perth, Australia