Studies with Warfarin

Despite the use of aspirin, the long-term risk of MI or death continues to be high in patients with UA. Consequently, additional treatments are constantly being considered. One candidate is warfarin.

In the Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) substudy (82) warfarin anticoagulant therapy was compared with conventional therapy, for up to 5 mo, on the primary composite end point of cardiovascular death, MI, or stroke, and on the secondary composite end point of cardiovascular death, MI, stroke, and readmission to hospital for UA. Of the 10,141 patients entering the main trial, 3712 were randomized, 12-48 h later, to receive oral anticoagulant therapy (n = 1848) or standard therapy (n = 1864). Countries represented in the study were defined as being good or poor compliers (based on the use of oral anticoagulants at a rate of above or below 70% at 35 d). In the good-complier countries, both the primary and secondary composite outcomes were significantly reduced with oral anticoagulants compared with standard therapy (primary end point: 6.1 vs 8.9%, p = 0.02; secondary endpoint 11.9 vs 16.5%, p = 0.005). There were no significant differences in end points in the poor-complier countries. In the overall study, there was a significantly higher incidence of major bleeding, which was larger in the good-complier countries (relative risk 2.71) than in the poor-complier countries (relative risk 1.58). Additionally, in the good-complier countries, there were significant reductions in the number of cardiac catheterization procedures (p = 0.004) and reductions in revascularization procedures approached statistical significance (p = 0.06). Hence, considering participating countries according to their rate of compliance to anticoagulant therapy suggests that high compliance has the potential to lead to clinically significant reductions in major ischemic cardiovascular events.

In another study, conducted by Huynh et al. (83), the potential benefit of secondary prevention with warfarin in patients with NSTE ACS and prior coronary artery bypass grafting (CABG) was investigated. In this double-blind trial, 135 patients with UA or NSTEMI, who had already undergone CABG, and were poor candidates for revascularization, were randomized to receive: (i) aspirin and placebo; (ii) warfarin and placebo; or (iii) aspirin and warfarin for 12 mo. A primary composite end point of death, MI, or UA requiring admission to hospital 1 yr after randomization was used in the study. This was reached in 14.6% of the patients in the warfarin alone group, 11.5% in the aspirin alone group, and in 11.3% in the combination therapy group (p = 0.76) Subgroup analysis by risk factors was unable to provide any indication that warfarin on its own, or in combina tion with aspirin, could be more beneficial than aspirin on its own. Additionally, in the two groups of patients receiving warfarin there was a greater frequency of bleeding.

In the ATACS trial (84), 214 UA/NSTEMI patients were randomized to receive either aspirin alone (162.5 mg daily) or a combination of aspirin (162.5 mg daily) plus UFH (aPTT, 2X control) followed by warfarin (internation normalized ration [INR], 2 to 3) as antithrombotic therapy. Therapy began within 9.5 ± 8.8 h of qualifying pain and continued for 12 wk. At 14 d, there was a significant decrease in the frequency of ischaemic events in the group treated with the combination therapy compared to the group treated with aspirin alone (10.5 vs 27%; p = 0.004). At 12 wk, however, there was a nonsignificant decrease in total ischemic events in the combination therapy group vs aspirin alone. From these results, Cohen et al. (84) concluded that the combination of antithrombotic therapy with aspirin plus anticoagulation with warfarin leads to a significant reduction in ischemic events in the early phase of UA.

In the recently presented Warfarin-Aspirin Reinfarction Study (WARIS)-II study, 3626 MI patients were randomized to treatment with aspirin 160 mg od, or warfarin INR 2.8-4.2, or both warfarin INR 2.0-2.5 and aspirin 75 mg once daily (85). Patients were followed-up for up to 4 yr. The combined warfarin and aspirin treatment was significantly more effective than aspirin alone at reducing death, nonfatal MI, and stroke. Warfarin treatment alone was also significantly more effective than aspirin alone, but to a lesser degree. One disadvantage of warfarin treatment was that major bleeding was 4X more common than with aspirin alone, but the overall bleeding rate in the study was relatively low.

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