PDF: SPAF
(1991)Objective
Warfarin versus aspirin compared to placebo in preventing ischemic stroke and systemic embolism in patients with atrial fibrillation.
Study Summary
Intervention
Randomized controlled trial; 1,330 patients with nonvalvular atrial fibrillation. Group 1 (warfarin-eligible): randomized to warfarin, aspirin 325 mg, or placebo. Group 2 (warfarin-ineligible): randomized to aspirin 325 mg or placebo. Mean follow-up: 1.3 years.
Study Design
Arms: Array
Outcome
- Warfarin: 2.3%/year vs. placebo 7.4%/year; RR reduction 67%; P=0.01
- Aspirin: 3.6%/year vs. placebo 6.3%/year; RR reduction 42%; P=0.02
• Stroke or death:
- Warfarin: 3.8%/year vs. 9.8%/year; RR reduction 58%; P=0.01
- Aspirin: 7.9%/year vs. 11.8%/year; RR reduction 32%; P=0.02
• Major bleeding:
- Warfarin: 1.5%/year
- Aspirin: 1.4%/year
- Placebo: 1.6%/year
Bottom Line
Both aspirin and warfarin significantly reduced the risk of ischemic stroke and systemic embolism in patients with atrial fibrillation compared to placebo. Warfarin provided a greater risk reduction in warfarin-eligible patients. Prophylactic antithrombotic therapy should be considered for patients with nonrheumatic atrial fibrillation who can safely take either aspirin or warfarin.
Major Points
- 1,330 inpatients and outpatients with constant or intermittent atrial fibrillation were included.
- Mean follow-up was 1.3 years.
- The rate of primary events (ischemic stroke and systemic embolism) in patients assigned to placebo was 6.3% per year and was reduced by 42% in those assigned to aspirin (3.6% per year, p=0.02; 95% CI, 9-63%).
- In warfarin-eligible patients, warfarin (INR 1.3-1.8) reduced the risk of primary events by 67% (warfarin vs. placebo, 2.3% vs. 7.4% per year; p=0.01; 95% CI, 27-85%).
- Primary events or death were reduced 58% (p=0.01) by warfarin and 32% (p=0.02) by aspirin.
- The risk of significant bleeding was 1.5% per year in the warfarin group, 1.4% in the aspirin group, and 1.6% in the placebo group.
- The trial highlights the effectiveness of both aspirin and warfarin in reducing thromboembolic events in this population.
Study Design
- Study Type
- Multicenter, randomized clinical trial
- Randomization
- Yes
- Blinding
- Aspirin vs. placebo was double-blind. Warfarin was open-label. Primary and secondary events were adjudicated by an Events Committee unaware of treatment allocation.
- Sample Size
- 1330
- Follow-up
- Mean 1.3 years.
- Centers
- 15
Primary Outcome
Definition: Prevention of ischemic stroke and systemic embolism (primary events).
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo: 6.3% per year | Aspirin: 3.6% per year; Warfarin: 2.3% per year | - (9-63% for aspirin; 27-85% for warfarin) | 0.02 for aspirin; 0.01 for warfarin |
Limitations & Criticisms
- The magnitude of reduction in events by warfarin versus aspirin cannot be directly compared because warfarin-eligible patients formed a subset of all aspirin-eligible patients.
- The trial was terminated early for the placebo arm when the superiority of both warfarin and aspirin relative to placebo was established, but the trial is continuing to directly assess the relative benefit of aspirin compared with warfarin.
- Warfarin was administered open-label, which could introduce bias, though outcomes were adjudicated by a blinded committee.
- The study design for warfarin used an approximate INR of 2.0-4.5, which is a broader range than later standard recommendations.
- The percentage of patients lost to follow-up was not explicitly stated for the final results, although 98.5% of scheduled visits were completed.
Citation
Circulation 1991;84:527-539