Jantoven (Page 5 of 7)

NONCLINICAL TOXICOLOGY

Carcinogenicity, mutagenicity, or fertility studies have not been performed with warfarin.

CLINICAL STUDIES

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).

Table 4: Clinical Studies of Warfarin in Non-Rheumatic AF Patients *
N Thromboembolism % Major Bleeding
Study Warfarin-TreatedPatients ControlPatients PT Ratio INR % RiskReduction p -value Warfarin-TreatedPatients ControlPatients
AFASAK 335 336 1.5-2.0 2.8-4.2 60 0.027 0.6 0.0
SPAF 210 211 1.3-1.8 2.0-4.5 67 0.01 1.9 1.9
BAATAF 212 208 1.2-1.5 1.5-2.7 86 <0.05 0.9 0.5
CAFA 187 191 1.3-1.6 2.0-3.0 45 0.25 2.7 0.5
SPINAF 260 265 1.2-1.5 1.4-2.8 79 0.001 2.3 1.5

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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.

Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves
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 9.0) 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.

Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves
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:

Table 7: WARIS — Endpoint Analysis of Separate Events
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.

Table 8: WARIS II — Distribution of Events According to Treatment Group
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
Death 92 96 95 0.82

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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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