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Sex-related differences in response to aspirin in cardiovascular disease: an untested hypothesis

Nature Clinical Practice Cardiovascular Medicine volume 3, pages 4–5 (2006)Cite this article

The recently published aspirin component of the Women's Health Study (WHS) compared low-dose aspirin (100 mg on alternate days) with placebo among 39,876 apparently healthy female healthcare providers for an average duration of around 10 years.1 Aspirin significantly lowered the risk of a first nonfatal stroke by 19% (relative risk [RR], 0.81, 95% CI 0.67–0.97; P = 0.02), but had no significant effect on the risk of first nonfatal myocardial infarction (MI; RR 1.01, 95% CI 0.83–1.24).1 This result was surprising because it appeared to contradict the existing evidence from randomized trials of aspirin in primary prevention. A previous meta-analysis of five published primary prevention trials, predominantly among men, had shown that aspirin significantly reduced the occurrence of nonfatal MI by about a third (RR 0.68, 95% CI 0.59–0.79), but had no significant effect on nonfatal stroke (RR 1.06, 95% CI 0.87–1.29).2 The editorial accompanying the WHS opined that “The investigators of the Physicians' Health Study and the Women's Health Study have produced two landmark studies on the use of aspirin in asymptomatic persons, the results of which segregate according to sex.”3 It is our view, however, that any conclusion that there are sex-related differences in response to aspirin for the prevention of cardiovascular disease in apparently healthy men and women might be premature.

In order to explore the specific effects of aspirin on the coronary and cerebral vasculature, we have analyzed a subset of trials that provided individual patient data for the Antiplatelet Trialists' (APT) Collaboration.4 Detailed data from six trials comparing aspirin with placebo among 11,265 patients with a history of MI, and from nine trials comparing aspirin with placebo among 6,765 patients with a history of cerebrovascular disease (i.e. a transient ischemic attack or stroke) were available for analysis. Aspirin reduced the risk of a major coronary event—nonfatal MI or coronary death—to a similar degree in men and women (19% reduction in men [SE = 5] and 25% reduction in women [SE = 12]; χ2 test for heterogeneity with 1 degree of freedom = 0.3; P = 0.6), and also reduced the risk of stroke (17% reduction in men [SE = 7] and 22% reduction in women [SE = 11]; χ2 test for heterogeneity with 1 degree of freedom = 0.2; P = 0.7). These findings provide evidence against a clinically important difference in the antiplatelet efficacy of aspirin in men and women with previous vascular disease. Thus, any putative explanation for the apparently disparate findings on coronary heart disease and stroke occurrence in men and women within the six primary prevention trials of aspirin versus placebo would have to account for the lack of any cogent evidence of such differences in the meta-analysis of the secondary prevention trials. Sex-specific differences in salicylate levels after aspirin administration5 are an unlikely explanation for these findings, as aspirin irreversibly inhibits platelet thromboxane biosynthesis before it is hydrolyzed in the liver. When compared with development in men, however, atherosclerosis develops later in women and affects cerebral arteries to a greater extent than coronary vessels. So there could be biological differences in the contribution of thromboxane-mediated platelet aggregation in the pathogenesis of atherosclerosis and thrombosis.

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Authors and Affiliations

  1. Center of Excellence, Florida Atlantic University,

    Charles H Hennekens, Danielle Hollar & Colin Baigent

  2. University of Miami School of Medicine,

    Charles H Hennekens, Danielle Hollar & Colin Baigent

  3. Department of Biomedical Science, Center of Excellence, Florida Atlantic University,

    Charles H Hennekens, Danielle Hollar & Colin Baigent

  4. University of Miami School of Medicine, FL, USA

    Charles H Hennekens, Danielle Hollar & Colin Baigent

  5. Clinical Trial Service Unit, University of Oxford, Oxford, UK

    Charles H Hennekens, Danielle Hollar & Colin Baigent

Authors
  1. Charles H Hennekens
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  2. Danielle Hollar
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Correspondence to Charles H Hennekens.

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Competing interests

CH Hennekens is funded by the Department of Biomedical Science and Center of Excellence at Florida Atlantic University (FAU). He is Principal Investigator of two investigator initiated research grants funded by Bayer HealthCare, testing the effects of aspirin dose on platelet biomarkers, inflammatory markers, nitric oxide formation and endothelial function. He is a consultant for Agatston Research Institute, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Chattem, Deaco, the FDA, GlaxoSmithKline, McNeil, the NIH, Novartis, Pfizer, Reliant, TAP and UpToDate. D Hollar receives funding from the Department of Biomedical Science and Center of Excellence at Florida Atlantic University. She is Project Director of two investigator initiated research grants funded by Bayer HealthCare.

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Hennekens, C., Hollar, D. & Baigent, C. Sex-related differences in response to aspirin in cardiovascular disease: an untested hypothesis. Nat Rev Cardiol 3, 4–5 (2006). https://doi.org/10.1038/ncpcardio0420

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