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A Meta-analysis of Randomized Trials

Jeffrey S. Berger, MD, MS; Mori J. Krantz, MD; John M. Kittelson, PhD; William R. Hiatt, MD

JAMA. 2009;301(18):1909-1919.

Context  Randomized trials have shown that aspirin decreases the risk of cardiovascular events in patients with symptomatic coronary and cerebrovascular disease. Despite guideline recommendations for secondary prevention in peripheral artery disease (PAD), the effect of aspirin in this population is not well established.

Objective  To investigate the effect of aspirin on cardiovascular event rates in patients with PAD.

Data Sources and Study Selection  MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, Science Citation Index (1966 to December 2008), and unpublished studies from the supplemental index of the Antithrombotic Trialists' Collaboration. Eligible studies were prospective, randomized controlled trials of aspirin therapy, with or without dipyridamole that reported cardiovascular event rates. Eighteen trials involving 5269 individuals were identified.

Data Extraction  Studies were reviewed to determine the number of participants, mean follow-up, and the primary end point of cardiovascular events (nonfatal myocardial infarction [MI], nonfatal stroke, and cardiovascular death). Data on the secondary end points of all-cause mortality, major bleeding, and the individual components of the primary outcome measure were also abstracted. For the primary end point, the analysis had 88% power to detect a 25% reduction and 70% power to detect a 20% reduction in cardiovascular events in the aspirin group compared with the control group.

Data Synthesis  Among 5269 participants, cardiovascular events were experienced by 251 (8.9%) of 2823 patients taking aspirin (alone or with dipyridamole) and by 269 (11.0%) of 2446 in the control group (pooled relative risk [RR], 0.88; 95% confidence interval [CI], 0.76-1.04). Aspirin therapy was associated with a reduction in the secondary outcome of nonfatal stroke (52 of 2823 vs 76 of 2446; RR, 0.66; 95% CI, 0.47-0.94) but was not associated with significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding. In the subset of 3019 participants taking aspirin alone vs control, aspirin was associated with a nonsignificant reduction in cardiovascular events (125 of 1516 vs 144 of 1503; RR, 0.75; 95% CI, 0.48-1.18), a significant reduction in nonfatal stroke (32 of 1516 vs 51 of 1503; RR, 0.64; 95% CI, 0.42-0.99), but no statistically significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding.

Conclusions  In patients with PAD, treatment with aspirin alone or with dipyridamole resulted in a statistically nonsignificant decrease in the primary end point of cardiovascular events and a significant reduction in nonfatal stroke. Results for the primary end point may reflect limited statistical power. Additional randomized controlled trials of aspirin therapy are needed to establish the net benefit and bleeding risks in PAD.

Author Affiliations: Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia (Dr Berger); Duke Clinical Research Institute, Durham, North Carolina (Dr Berger); Department of Medicine, Section of Vascular Medicine, Divisions of Geriatrics (Dr Hiatt) and Cardiology (Drs Krantz and Hiatt), University of Colorado Denver School of Medicine, Denver; Department of Biostatistics and Informatics, Colorado School of Public Health (Dr Kittelson); and Colorado Prevention Center (Drs Krantz and Hiatt), Denver.

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RELATED LETTERS

Aspirin for Prevention of Stroke and Cardiovascular Events Among Patients With Peripheral Artery Disease
Hisato Takagi and Takuya Umemoto
JAMA. 2009;302(11):1165.
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Aspirin for Prevention of Stroke and Cardiovascular Events Among Patients With Peripheral Artery Disease—Reply
John M. Kittelson, Mori J. Krantz, and William R. Hiatt
JAMA. 2009;302(11):1165-1166.
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