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Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation

Robert G. Hart, MD; Lesly A. Pearce, MS; and Maria I. Aguilar, MD
[+] Article and Author Information

From the University of Texas Health Science Center, San Antonio, Texas, and Mayo Clinic Scottsdale, Scottsdale, Arizona.


Note: Dr. Hart and Ms. Pearce were leaders of the SPAF trials (1987 to 1999), which were funded by the National Institute of Neurologic Disorders and Stroke. Dr. Hart also served on the data and safety monitoring boards of the SPORTIF III and V trials, which were sponsored by AstraZeneca Pharmaceuticals (Wilmington, Delaware), and on the stroke advisory committee of the ACTIVE-W trial. Drs. Hart and Aguilar and Ms. Pearce are coauthors on the Cochrane Stroke Group modules on this topic.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Robert G. Hart, MD, Department of Medicine (Neurology), University of Texas Health Science Center, 7703 Floyd Curl Drive, MC# 7883, San Antonio, TX 78229-3900; e-mail, hartr@uthscsa.edu.

Current Author Addresses: Dr. Hart: Department of Medicine (Neurology), University of Texas Health Science Center, 7703 Floyd Curl Drive, MC# 7883, San Antonio, TX 78229-3900.

Ms. Pearce: 2509 Bel Air Court, Minot, ND 58703.

Dr. Aguilar: Department of Neurology, Division of Cerebrovascular Disease, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054.


Ann Intern Med. 2007;146(12):857-867. doi:10.7326/0003-4819-146-12-200706190-00007
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Background: Atrial fibrillation is a strong independent risk factor for stroke.

Purpose: To characterize the efficacy and safety of antithrombotic agents for stroke prevention in patients who have atrial fibrillation, adding 13 recent randomized trials to a previous meta-analysis.

Data Sources: Randomized trials identified by using the Cochrane Stroke Group search strategy, 1966 to March 2007, unrestricted by language.

Study Selection: All published randomized trials with a mean follow-up of 3 months or longer that tested antithrombotic agents in patients who have nonvalvular atrial fibrillation.

Data Extraction: Two coauthors independently extracted information regarding interventions; participants; and occurrences of ischemic and hemorrhagic stroke, major extracranial bleeding, and death.

Data Synthesis: Twenty-nine trials included 28 044 participants (mean age, 71 years; mean follow-up, 1.5 years). Compared with the control, adjusted-dose warfarin (6 trials, 2900 participants) and antiplatelet agents (8 trials, 4876 participants) reduced stroke by 64% (95% CI, 49% to 74%) and 22% (CI, 6% to 35%), respectively. Adjusted-dose warfarin was substantially more efficacious than antiplatelet therapy (relative risk reduction, 39% [CI, 22% to 52%]) (12 trials, 12 963 participants). Other randomized comparisons were inconclusive. Absolute increases in major extracranial hemorrhage were small (≤0.3% per year) on the basis of meta-analysis.

Limitation: Methodological features and quality varied substantially and often were incompletely reported.

Conclusions: Adjusted-dose warfarin and antiplatelet agents reduce stroke by approximately 60% and by approximately 20%, respectively, in patients who have atrial fibrillation. Warfarin is substantially more efficacious (by approximately 40%) than antiplatelet therapy. Absolute increases in major extracranial hemorrhage associated with antithrombotic therapy in participants from the trials included in this meta-analysis were less than the absolute reductions in stroke. Judicious use of antithrombotic therapy importantly reduces stroke for most patients who have atrial fibrillation.

Figures

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Figure.
Relative effects of antithrombotic therapies on all stroke from randomized trials in patients with atrial fibrillation.

Horizontal lines represent 95% CIs around point estimates. Please see footnote in Table 1 for definitions of study acronyms. A. Adjusted-dose warfarin compared with placebo or no treatment in 6 randomized trials. B. Antiplatelet agents compared with placebo or no treatment in 8 randomized trials. In SAFT (23), aspirin was combined with low, inefficacious dosages of warfarin. In ESPS II (13), combination refers to aspirin plus dipyridamole. C. Adjusted-dose warfarin compared with antiplatelet agents in 11 randomized trials. Nonaspirin antiplatelet agents were indobufen (SIFA [12]), clopidogrel plus aspirin (ACTIVE-W [28]), and triflusal (NASPEAF [25]). *The Vemmos et al. (27) and WASPO (31) trials are not shown; however, the information is shown in Table 4.

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Adjusted-dose warfarin vs. aspirin for prevention of stroke in patients with atrial fibrillation
Posted on August 20, 2007
Robert G. Hart
University of Texas Health Science Center
Conflict of Interest: None Declared

To The Editor: The recently published randomized Birmingham Atrial Fibrillation Trial of the Aged (BAFTA) compared adjusted-dose warfarin (target INR 2-3) with aspirin (75 mg per day) in 973 atrial fibrillation patients age >75 years (mean = 81.5 years) managed by U.K. general practitioners (1). The important results indicate that the relative efficacy and safety of warfarin for stroke prevention can be extended to very elderly patients managed by non-specialists. Since BAFTA appears likely to be the last large trial comparing adjusted-dose warfarin with aspirin (and addition of BAFTA results increases the total number of stroke events available for meta-analysis by 42%), here we add the BAFTA results to our updated meta- analysis of antithrombotic trials in patients who have atrial fibrillation (2).

Including BAFTA, nine randomized trials enrolling 4620 participants compared adjusted-dose warfarin with aspirin. By meta-analysis, the relative risk reduction by warfarin over aspirin is 39% (CI 19 to 53) in these eight predominantly primary prevention trials and single secondary prevention trial and remained at 39% when three comparisons of warfarin with non-aspirin antiplatelet agents were included (1). The meta-analytic estimate for the absolute risk reduction by warfarin over aspirin for primary prevention is about 1% per year (Table).

Based on all available randomized data, the relative risk reduction in all strokes by adjusted-dose warfarin vs. antiplatelet therapy is about 40%. Despite some inconsistencies in results of earlier, smaller trials (Figure will appear in print), this number appears to be stable and is the best available estimate.

StudyNStrokes / Patients / Patient-YearsRelative Risk Reduction (95% CI)Absolute Risk Reduction for Primary Prevention (%/yr)#
Adjusted-dose warfarin vs. aspirin
8 previous trials (2)364791/1803/3740 vs. 142/1844/373038% (18 to 52)0.7% per yr
BAFTA ^(1)97335/488/1333 vs. 62/485/126347% (19 to 66)2.3% per yr
9 aspirin trials+4620126/2291/5073 vs. 204/2329/499339% (19 to 53)0.9% per yr
Adjusted-dose warfarin vs. aspirin or non-aspirin antiplatelet agents
12 antiplatelet trials+12721215/6353/10279 vs. 344/6368/1020939% (27 to 49)1.0% per yr

Robert G. Hart, M.D. Lesly A. Pearce, M.S. Maria I. Aguilar, M.D.

References:

1. Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GYH et al. on behalf of the BAFTA investigators and the Midland Research Practices Network. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007; 370: 493-503.

2. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007: 146: 857-67.

Conflict of Interest:

None declared

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