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).
*All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhagic stroke and transient ischemic attacks.
|Study||N||Thromboembolism||% Major Bleeding|
|Warfarin – Treated Patients||Control Patients||PT Ratio||INR||% Risk Reduction||p – value||Warfarin – Treated Patients||Control Patients|
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|
|Event||Warfarin||Dipyridamole / Aspirin||Pentoxifylline / Aspirin|
|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) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4 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 Therapy INR 2 . 65||High Intensity Warfarin Therapy INR 9|
|Thromboembolism||4/100 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 to 2.25 vs. INR 2.5 to 4) for a three month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2 % 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.
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