Carcinogenicity, mutagenicity, or fertility studies have not been performed with warfarin.
In five prospective, randomized, controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 4). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6% to 2.7% (see Table 4).
|N||Thromboembolism||% Major Bleeding|
|Study||Warfarin-TreatedPatients||ControlPatients||PT Ratio||INR||% RiskReduction||p -value||Warfarin-TreatedPatients||ControlPatients|
Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with warfarin sodium [see Dosage and Administration (2.2)].
In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirintreated patients (p<0.005) and pentoxifylline/aspirin-treated patients (p<0.05). The results of this study are presented in Table 5.
|Patients Treated With|
|Thromboembolism||2.2/100 py||8.6/100 py||7.9/100 py|
|Major Bleeding||2.5/100 py||0.0/100 py||0.9/100 py|
In a prospective, open-label, clinical study comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events per 100 patient years, respectively). Major bleeding was more common in the high intensity group. The results of this study are presented in Table 6.
|Event||Moderate Warfarin TherapyINR 2.65||High Intensity Warfarin TherapyINR 9.0|
|Thromboembolism||4.0/100 py||3.7/100 py|
|Major Bleeding||0.95/100 py||2.1/100 py|
In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25 vs. INR 2.5-4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively, and minor embolic events 10.8% vs. 10.2%, respectively). Major hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group.
WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. The primary endpoint was a composite of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in Table 7:
|Event||Warfarin(N=607)||Placebo(N=607)||RR (95% CI)||% Risk Reduction(p -value)|
|Total Patient Years of Follow-up||2018||1944|
|Total Mortality||94 (4.7/100 py)||123 (6.3/100 py)||0.76 (0.60, 0.97)||24 (p=0.030)|
|Vascular Death||82 (4.1/100 py)||105 (5.4/100 py)||0.78 (0.60, 1.02)||22 (p=0.068)|
|Recurrent MI||82 (4.1/100 py)||124 (6.4/100 py)||0.66 (0.51, 0.85)||34 (p=0.001)|
|Cerebrovascular Event||20 (1.0/100 py)||44 (2.3/100 py)||0.46 (0.28, 0.75)||54 (p=0.002)|
WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin to a target INR 2.8 to 4.2, aspirin 160 mg per day, or warfarin to a target INR 2.0 to 2.5 plus aspirin 75 mg per day prior to hospital discharge. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in the Table 8.
|Event||Aspirin(N=1206)||Warfarin(N=1216)||Aspirin plusWarfarin(N=1208)||Rate Ratio(95% CI)||p -value|
|No. of Events|
|Major Bleeding *||8||33||28||3.35† (ND)4.00‡ (ND)||NDND|
|Minor Bleeding §||39||103||133||3.214 (ND)2.555 (ND)||NDND|
|Composite Endpoints ¶||241||203||181||0.81 (0.69-0.95)40.71 (0.60-0.83)5||0.030.001|
|Reinfarction||117||90||69||0.56 (0.41-0.78)40.74 (0.55-0.98)5||<0.0010.03|
|Thromboembolic Stroke||32||17||17||0.52 (0.28-0.98)40.52 (0.28-0.97)5||0.030.03|
There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group.
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