Current issues of ACP Journal Club are published in Annals of Internal Medicine


Warfarin reduced the risk for stroke in patients with nonrheumatic atrial fibrillation

ACP J Club. 1993 Mar-April;118:42. doi:10.7326/ACPJC-1993-118-2-042

Source Citation

Ezekowitz MD, Bridgers SL, James KE, et al., for the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med. 1992 Nov 12;327:1406-12.



To evaluate the effectiveness of warfarin in reducing the risk for stroke in patients with nonrheumatic atrial fibrillation.


Randomized, double-blind, placebo-controlled, multicenter trial with a mean follow-up of 1.8 years.


16 Department of Veterans Affairs medical centers.


525 men who were veterans (mean age 67 y) with constant nonrheumatic atrial fibrillation and no history of stroke. Exclusion criteria were a definite indication for or current use of anticoagulation or antiplatelet agents, contraindication to anticoagulation, use of anticoagulation within the past 6 months for > 1 continuous month, or inability to complete follow-up.


260 patients were assigned to receive sodium warfarin, 4 mg/d, for the first 12 weeks followed by dose adjustment in 1-mg increments to maintain the prothrombin-time ratio at 1.2 to 1.5. 265 patients were assigned to receive placebo.

Main outcome measures

The primary outcome measure was cerebral infarction, and the secondary outcome measures were cerebral hemorrhage and death.

Main results

The study was terminated soon after interim analyses showed a significant benefit of warfarin. All analyses were on an intention-to-treat basis. Data on 74 patients who withdrew (33 in the placebo group and 41 in the warfarin group) were included to the point of withdrawal. The 19 patients who were lost to follow-up were assessed for mortality through a national death registry. Cerebral infarction occurred in 19 patients (4.3%/y) assigned to placebo compared with 4 patients (0.9%/y) in the warfarin group (P = 0.001) (Table). The combined endpoint of death or cerebral ischemia was also lower in the warfarin group than the placebo group (P = 0.03) (Table). Only 1 cerebral hemorrhage occurred (a 73-year-old patient in the warfarin group). 4 major gastrointestinal hemorrhages occurred in the placebo group and 6 in the warfarin group. The groups did not differ for death: 22 patients (5.0%/y) in the placebo group and 15 patients (3.3%/y) in the warfarin group died without a preceding cerebral event (P = 0.19).


Anticoagulation with warfarin reduced the risk for cerebral infarction without producing an excess risk for serious hemorrhage in patients with constant nonrheumatic atrial fibrillation and no previous history of stroke.

Source of funding: Department of Veterans Affairs Cooperative Studies Program.

For article reprint: Dr. M.D. Ezekowitz, Cardiovascular Section, 111B, Department of Veterans Affairs Medical Center, Clinical Campus, Yale University School of Medicine, 950 Campbell Avenue, West Haven, CT 06516, USA. FAX 203-937-3884.

Table. Warfarin vs placebo for patients with nonrheumatic atrial fibrillation

Outcomes at 1.8 y Warfarin Placebo RRR (95% CI) NNT (CI)
Stroke 1.5% 7.2% 79% (41 to 92) 18 (10 to 43)
Death or cerebral ischemia 7.3% 15.5% 53% (22 to 72) 12 (7 to 36)

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


The study by Ezekowitz and colleagues is the fifth randomized study comparing warfarin with control or placebo in patients with nonrheumatic atrial fibrillation. The design of the studies and their results were remarkably similar (1). Warfarin decreases the relative risk for stroke by approximately 70% (from 5% to 2% per year), with little increase in the frequency of major bleeding. This effect is clinically important, and all patients with atrial fibrillation who are eligible for anticoagulation should seriously be considered for warfarin therapy.

At least 4 important questions still remain about antithrombotic therapy in patients with atrial fibrillation. First, are some patients at such low risk for stroke that anticoagulation is not needed? Current data suggest that patients < 60 years of age, with no associated cardiovascular disease, have a low risk for stroke and that anticoagulation may not be warranted.

Second, how does the efficacy of aspirin compare with that of warfarin? At present, the data about the efficacy of aspirin (2, 3) are not as convincing as those for warfarin. Two direct comparisons of aspirin and warfarin are currently under way.

Third, what is the optimal dose of warfarin? The intensity of anticoagulation in the 5 studies varied from an International Normalized Ratio (INR) of 2.8 to 4.2, to an INR of 1.4 to 2.8. A randomized study comparing 2 intensities of anticoagulation is under way in the Netherlands. In the meantime, an INR between 2.0 and 3.0 seems reasonable.

Finally, what is the role of warfarin in patients who have already had a stroke? Because warfarin is so effective in patients who have not had a stroke, it seems sensible to give warfarin to patients who have had a previous stroke, pending the results of a recently completed study.

Andreas Laupacis, MD
Ottawa Civic HospitalOttawa, Ontario, Canada


1. Laupacis A, Albers G, Dunn M, Feinberg W. Antithrombotic therapy in atrial fibrillation. Chest. 1992;102(Suppl):426S-33S.

2. Petersen P, Boysen G, Godtredsen J, et al. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet. 1989;1:175-9.

3. The Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991;84:527-39.