Antithrombotic therapy in the primary prevention of acute myocardial infarction

Abstract

The high factor VII coagulant (VIIc) activity in men at high risk of coronary heart disease suggests that restoring normal hemostatic activity with appropriate oral anticoagulants might constitute effective primary prevention. A pilot study was therefore undertaken of a randomized, double-blind, placebo-controlled trial of long-term, low-dose warfarin therapy. Middle-aged men at high risk (mean VIIc 120% of standard) but without clinical coronary heart disease or contraindications to anticoagulants were randomized to warfarin or placebo. The initial warfarin dose (2.5 mg/day) was increased at intervals to lower VIIc to 70% of standard and increase the prothrombin time international normalized ratio to 1.6. The control participants received the same dose sequence of placebo. The pilot study confirmed the feasibility of the design, the absence of any increased risk of serious bleeding, and the high compliance and low withdrawal rate from randomized treatment. Accordingly, a full-scale thrombosis prevention trial has been launched, which, in addition to low-dose warfarin, includes a low-dose aspirin regimen (75 mg/day) in a factorial design. The aim of this trial is to produce a 30% reduction in coronary heart disease in 6,000 high-risk men aged 45 to 69 years. The men will receive either separate or combined therapy and will be followed up for 5 years. Evidence so far indicates that the risk of bleeding in those receiving combined therapy will be no higher than that in those taking aspirin alone.