Stroke Prevention In Nonrheumatic Atrial Fibrillation - SPINAF


Warfarin vs. placebo for ischemic stroke in atrial fibrillation.


Low-intensity anticoagulation is not only equal in efficacy to anticoagulation at a higher intensity in preventing thromboembolic episodes but also associated with a lower risk of bleeding.

Study Design

Study Design:

Patients Screened: 7,982
Patients Enrolled: 571 (including 46 with a previous cerebral infarction)
Mean Follow Up: 3 years
Mean Patient Age: 67
Female: 0
Mean Ejection Fraction: 48 ±14 (placebo) to 48 ±7 (warfarin)

Patient Populations:

Male veterans of any age, without echocardiographic evidence of rheumatic heart disease.
Atrial fibrillation documented by two ECGs at least four weeks apart.
Baseline prothrombin-time ratio within the normal range.
Previous warfarin therapy discontinued at least six months before randomization.


Intermittent atrial fibrillation.
Definite indication for anticoagulation or antiplatelet agents (prosthetic heart valve, mitral stenosis, active thromboembolic disease, coronary-artery bypass surgery [CABG], intracardiac thrombus, myocardial infarction [MI] within one month).
Contraindication to anticoagulation.
Inappropriate for the study (administrative criteria).

Primary Endpoints:

Clinically evident cerebral infarction

Secondary Endpoints:

Cerebral hemorrhage and death (not related to a cerebral endpoint)

Drug/Procedures Used:

Warfarin, 2 mg tablets to maintain an international normalized ratio of 1.4 to 2.8, or placebo.

Principal Findings:

Among the patients with no history of stroke, cerebral infarction occurred in 19 of the 265 patients in the placebo group during an average follow-up of 1.7 years (4.3 percent per year) and in 4 of the 260 patients in the warfarin group during an average follow-up of 1.8 years (0.9 percent per year).

The reduction in risk with warfarin therapy was 0.79 (95 percent confidence interval, 0.52 to 0.90; P = 0.001). The annual event rate among the 228 patients over 70 years of age was 4.8 percent in the placebo group and 0.9 percent in the warfarin group (risk reduction, 0.79; P = 0.02).

The only cerebral hemorrhage occurred in a 73-year-old patient in the warfarin group. Other major hemorrhages, all gastrointestinal, occurred in 10 patients: 4 in the placebo group, for a rate of 0.9 percent per year, and 6 in the warfarin group, for a rate of 1.3 percent per year.

There were 37 deaths that were not preceded by a cerebral end point--22 in the placebo group and 15 in the warfarin group (risk reduction, 0.31; P = 0.19).

Cerebral infarction was more common among patients with a history of cerebral infarction (9.3 percent per year in the placebo group and 6.1 percent per year in the warfarin group) than among those without such a history.


Low-intensity anticoagulation with warfarin prevented cerebral infarction in patients with nonrheumatic atrial fibrillation without producing an excess risk of major hemorrhage. This benefit extended to patients over 70 years of age.


1. N Engl J Med 1992;327:1406-12 [published erratum appears in N Engl J Med 1993;328:148]. Final results

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Rheumatic Heart Disease, Stroke, Follow-Up Studies, Risk Reduction Behavior, Reference Values, Warfarin, Prothrombin, International Normalized Ratio, Veterans, Cerebral Infarction, Atrial Fibrillation, Confidence Intervals, Cerebral Hemorrhage

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