Coumadin - Clinical Pharmacology

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Clinical Trials Atrial Fibrillation (AF):

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 1). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which stopped early due to pub-lished positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6 to 2.7% (See Table 1).

Meta-analysis findings of these studies revealed that the effects of warfarin in reducing throm-boembolic events including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available.

TABLE 1. CLINICAL STUDIES OF WARFARIN IN NON-RHEUMATIC AF PATIENTS*

Study n Thromboembolism % Major Bleeding

Warfarin-Warfarin-Treated Control PT %Risk Treated Control

Patients Patients Ratio INR Reduction p-value Patients Patients

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

*All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhage and transient ischemic attacks.

Myocardial Infarction:

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. [But note that a lower INR was achieved and increased bleeding was associated with INR's above 4.0; (see DOSAGE AND ADMINISTRATION)]. The primary endpoint was a combination of total mortality and recurrent infarction. A secondary endpoint of cere-brovascular 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 the following table: