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Cholesterol Reduction and Stroke
- David Atkins, MD, MPH;
- Bruce M. Psaty, MD, PhD; and
- Eric B. Larson, MD, MPH
- Department of Health and Human Services; Office of Disease Prevention and Health Promotion; Washington, DC 20201 University of Washington; Seattle, WA 98195
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should:
•Include no more than 300 words of text, three authors, and five references
•Type with double-spacing
•Send three copies of the letter, an authors' form signed by all authors, and a cover letter describing any conflicts of interest related to the contents of the letter.
Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
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IN RESPONSE:
Most of the criticisms raised by Dr. Davey Smith and colleagues were specifically addressed in our report [1]. The primary conclusion of our analysis was, and remains, that cholesterol reduction does not have a beneficial effect on stroke mortality in middle-aged men. The more inclusive data Davey Smith and colleagues provide support this conclusion.
The difference between the pooled risk they report and our original finding (1.10 compared with 1.34) is small, appears consistent with chance, and is unlikely to represent “publication bias” (that is, under-reporting negative results). We created selection criteria to reduce the potential sources of heterogeneity among studies, but it is possible that trials we excluded (such as short-term angiography trials and trials in patients who have had a stroke) differ systematically from longer trials. Nonetheless, our results provide an unbiased estimate for the interventions and populations most relevant to clinicians—moderate reductions of cholesterol in hypercholesterolemic middle-aged men who have not had stroke—and we took pains to restrict our conclusions to the specific interventions and populations we studied.
We fully agree that subgroup analyses should be treated with caution, and we explicitly stated that we did these analyses solely to generate hypotheses. When speaking with several news organizations, we declined to discuss the clofibrate finding for the very reason that it was not our primary hypothesis and was based on limited data. However, unlike Davey Smith and colleagues' cautionary example, our subgroups were defined before the analysis was done and were based on biologic plausibility. We greatly appreciate the unpublished data they obtained from other clofibrate trials. These data, and the revised World Health Organization results published after the acceptance of our manuscript, reduce the likelihood that total stroke mortality is greatly increased in all patients who have ever been treated with clofibrate. However, the data do not address our more specific hypothesis that treatment with fibrate medications may increase the risk for hemorrhagic stroke because of the effects on hemostasis. “In-trial” rather than “intention-to-treat” results may provide the most meaningful data to answer this question.
The assumption that lowering cholesterol has identical effects on coronary heart disease and stroke is not supported by data from clinical trials in middle-aged men. Better data are needed to determine whether cholesterol reduction in general, or individual lipid-lowering therapies, have favorable or unfavorable effects on specific types of stroke. We encourage investigators to collect and report precise data on all fatal and nonfatal cerebrovascular events in future studies of cholesterol-lowering therapies.
David Atkins, MD, MPH
Department of Health and Human Services; Office of Disease Prevention and Health Promotion; Washington, DC 20201
Bruce M. Psaty, MD, PhD
Eric B. Larson, MD, MPH
University of Washington; Seattle, WA 98195
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should:
•Include no more than 300 words of text, three authors, and five references
•Type with double-spacing
•Send three copies of the letter, an authors' form signed by all authors, and a cover letter describing any conflicts of interest related to the contents of the letter.
Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
Annals welcomes electronically submitted letters.
- Copyright ©2004 by the American College of Physicians
