Michael B. Rothberg, MD, MPH; Carmel Celestin, MD; Louis D. Fiore, MD, MPH; Elizabeth Lawler, MPH; James R. Cook, MD, MPH
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Michael B. Rothberg, MD, MPH, Division of General Medicine and Geriatrics, Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199; e-mail, Michael.Rothberg@bhs.org.
Current Author Addresses: Dr. Rothberg: Division of General Medicine and Geriatrics, Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199.
Dr. Celestin: Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199.
Dr. Fiore and Ms. Lawler: Massachusetts Veterans Epidemiology Research and Information Center, 150 South Huntington Avenue, Boston, MA 02130.
Dr. Cook: Cardiac Services, Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199.
Author Contributions: Conception and design: M.B. Rothberg, C. Celestin.
Analysis and interpretation of the data: M.B. Rothberg, L.D. Fiore, E. Lawler, J.R. Cook.
Drafting of the article: M.B. Rothberg, J.R. Cook.
Critical revision of the article for important intellectual content: M.B. Rothberg, C. Celestin, L.D. Fiore, E. Lawler, J.R. Cook.
Final approval of the article: M.B. Rothberg, C. Celestin, L.D. Fiore, E. Lawler, J.R. Cook.
Provision of study materials or patients: L.D. Fiore, E. Lawler.
Statistical expertise: J.R. Cook.
Collection and assembly of data: M.B. Rothberg, C. Celestin, L.D. Fiore.
After the acute coronary syndrome, adding warfarin to standard aspirin therapy decreases myocardial infarction and stroke but increases major bleeding.
To quantify the risks and benefits of warfarin therapy after the acute coronary syndrome.
MEDLINE from 1990 to October 2004. Additional data were obtained from study authors. Clinical risk factors were used to classify hypothetical patients into cardiovascular and bleeding risk groups on the basis of published data.
Randomized trials comparing intensive warfarin therapy (international normalized ratio > 2.0) plus aspirin with aspirin alone after the acute coronary syndrome.
Two reviewers independently selected studies and extracted data on study design; quality; and clinical outcomes, including myocardial infarction, stroke, revascularization, death, and major and minor bleeding. Rate ratios for outcomes were calculated and pooled by using the method of DerSimonian and Laird.
Ten trials involving a total of 5938 patients (11 334 patient-years) met the study criteria. Compared with aspirin alone, warfarin plus aspirin was associated with a decrease in the annual rate of myocardial infarction (0.022 vs. 0.041; rate ratio, 0.56 [95% CI, 0.46 to 0.69]), ischemic stroke (0.004 vs. 0.008; rate ratio, 0.46 [CI, 0.27 to 0.77]), and revascularization (0.115 vs. 0.135; rate ratio, 0.80 [CI, 0.67 to 0.95]). Warfarin was associated with an increase in major bleeding (0.015 vs. 0.006; rate ratio, 2.5 [CI, 1.7 to 3.7]). Mortality did not differ.
Two large studies provided most of the data. Studies did not include coronary stenting, and results should not be applied to patients with stents. Relative risk reductions may not be consistent across risk groups.
For patients with the acute coronary syndrome who are at low or intermediate risk for bleeding, the cardiovascular benefits of warfarin outweigh the bleeding risks.
Continued thrombin generation persists for several months after acute cardiac events.
Data from 10 randomized trials involving 5938 patients with the acute coronary syndrome who were not stented showed that, compared with aspirin alone, warfarin plus aspirin decreased annual rates of myocardial infarction, ischemic stroke, and revascularization and increased major bleeding rates. In patients with low or average bleeding risks, numbers of cardiovascular events prevented by warfarin plus aspirin exceeded numbers of major bleeding episodes caused by it.
Benefits of warfarin plus aspirin may exceed harms in patients with the acute coronary syndrome who are not stented and do not have high bleeding risks.
Table 1. Baseline Events and Rates for 6 Outcomes in the Aspirin and Combination Aspirin and Warfarin Groups
Forest plot showing rate ratios of myocardial infarction for warfarin plus aspirin compared with aspirin alone.
Forest plot showing rate ratios of ischemic stroke for warfarin plus aspirin compared with aspirin alone.
Forest plot showing rate ratios of death for warfarin plus aspirin compared with aspirin alone.
Forest plot showing rate ratios of major bleeding for warfarin plus aspirin compared with aspirin alone.
Table 2. Projected 1-Year Rates for Myocardial Infarction and Bleeding, by Indication
Appendix Table 1. Design of Trials Included in the Meta-Analysis
Appendix Table 2. Tests of Heterogeneity
Predicted myocardial infarctions (MIs) and thrombotic strokes averted and excess bleeding episodes caused in 1000 patients as a result of adding warfarin to aspirin for 1 year, stratified by bleeding and MI risk.
Process of study selection.
Forest plot showing rate ratios of percutaneous transluminal coronary angioplasty or coronary artery bypass grafting for warfarin plus aspirin compared with aspirin alone.
Forest plot showing rate ratios of minor bleeding for warfarin plus aspirin compared with aspirin alone.
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Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. Warfarin plus Aspirin after Myocardial Infarction or the Acute Coronary Syndrome: Meta-Analysis with Estimates of Risk and Benefit. Ann Intern Med. ;143:241–250. doi: 10.7326/0003-4819-143-4-200508160-00005
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Published: Ann Intern Med. 2005;143(4):241-250.
Acute Coronary Syndromes, Cardiology, Coronary Heart Disease, Emergency Medicine.
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