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Cholesterol Reduction and the Risk for Stroke in Men: A Meta-Analysis of Randomized, Controlled Trials

David Atkins, MD, MPH; Bruce M. Psaty, MD, PhD; Thomas D. Koepsell, MD, MPH; W. T. Longstreth, MD, MPH; and Eric B. Larson, MD, MPH
[+] Article, Author, and Disclosure Information

From the Cardiovascular Health Research Unit and Department of Medicine, University of Washington and Harborview Medical Center, Seattle, Washington. Requests for Reprints: David Atkins, MD, MPH, Office of Disease Prevention and Health Promotion, Department of Health and Human Services, Switzer 2132, 330 C Street SW, Washington, DC 20201. Acknowledgments: The authors thank Kristan Geissel and Judy Sanders for help in preparing this manuscript. Grant Support: By a National Institutes of Health National Research Service Award (5T32PE1002).

Copyright 2004 by the American College of Physicians

Ann Intern Med. 1993;119(2):136-145. doi:10.7326/0003-4819-119-2-199307150-00008
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Objective: Reducing serum cholesterol lowers the risk for ischemic heart disease, but its effects on other vascular diseases are unknown. Published trials were reviewed to determine the effect of cholesterol-lowering interventions on fatal and nonfatal stroke.

Design: Meta-analysis of randomized, controlled trials.

Data Identification: A literature search of English-language studies examining the effect of modified diets or medications on cardiovascular end points from 1965 to 1992 using MEDLINE and a review of references of five quantitative overviews of cholesterol reduction and coronary disease.

Data Analysis: Thirteen studies met three eligibility criteria: patients randomized to intervention or control; fatal or nonfatal stroke reported separately; and end points assessed without knowledge of treatment status. Heterogeneity among studies and overall effects of treatment on fatal and nonfatal stroke were estimated using the Mantel-Haenszel-Peto method to combine independent study results. The influence of various study designs and interventions was explored using subgroup comparisons.

Results: For fatal stroke, the overall odds ratio associated with cholesterol-lowering interventions in 13 trials was 1.32 (95% CI, 0.94 to 1.86), and the odds ratio for the 10 single-intervention trials was 1.34 (CI, 0.91 to 1.96). Among eight trials reporting nonfatal events, the summary odds ratio for nonfatal stroke for treated participants compared with controls was 0.88 (CI, 0.70 to 1.11), and the odds ratio for total strokes was 0.98 (CI, 0.80 to 1.19). Among three trials using clofibrate, treatment significantly increased the risk for fatal stroke (odds ratio, 2.64; CI, 1.42 to 4.92) but not for nonfatal stroke (odds ratio, 0.87; CI, 0.61 to 1.26). Regression analysis showed no statistical association between the magnitude of cholesterol reduction and the risk for fatal stroke.

Conclusions: Lowering serum cholesterol through modified diets or medications does not reduce stroke mortality or morbidity in middle-aged men. Clofibrate appears to increase the risk for fatal strokes, but the mechanism for this effect is unknown.


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Figure 1.
Individual study and summary odds ratios for individual trials.[51][47, 52, 57]

Two arms of one study are depicted as separate trials; three trials , which observed a total of three strokes, cannot be depicted because the estimated odds ratio was zero or infinite. Point estimates and lines indicate odds ratios and 95% confidence intervals for fatal stroke in treated patients compared with controls. An odds ratio greater than 1.0 indicates that cholesterol-lowering treatment increases the risk for fatal stroke. N = number of pooled trials; total stroke = fatal plus nonfatal strokes; CHD = coronary heart disease.

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