THROMBOSIS PREVENTION TRIAL - RANDOMIZED TRIAL OF LOW-INTENSITY ORAL ANTICOAGULATION WITH WARFARIN AND LOW-DOSE ASPIRIN IN THE PRIMARY PREVENTION OF ISCHEMIC-HEART-DISEASE IN MEN AT INCREASED RISK

Background We aimed to evaluate low intensity oral anticoagulation wit h warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease (IHD). Methods 5499 men aged between 45 years and 69 ye ars at high risk of IHD were recruited from 108 practices in the UK th at belong to the Medical Research Council's General Practice Research Framework. Initially, warfarin or placebo was randomly allocated to 14 27 men; 1013 of these men later moved to a factorial stage of the tria l, retaining their warfarin or placebo warfarin allocation and adding randomly allocated active or placebo aspirin. Another 4072 men entered directly into the factorial stage making a total of 5085 men. The fou r factorial treatment groups were: active warfarin and active aspirin (WA, n=1277), active warfarin and placebo aspirin (W, n=1268), placebo warfarin and active aspirin (A, n=1268), and placebo warfarin and pla cebo aspirin (P, n=1272). The primary end-point was all IHD defined as the sum of coronary death and fatal and nonfatal myocardial infarctio n(MI). Findings The mean International Normalised Ratio (INR) of those on active warfarin was 1.47. The mean warfarin dose was 4.1 mg a day (range 0.5 mg-12.5 mg). There were 410 IHD events (142 fatal, 268 non- fatal). The main effect of warfarin (ie, WA and W vs A and P) was a re duction in all IHD of 21% (95% CI 4-35, p=0.02) chiefly due to a 39% r eduction (15-57, p=0.003) in fatal events so that warfarin reduced the death rate from all causes by 17% (1-30, p=0.04). The main effect of aspirin (ie, WA and A vs W, and P) was a reduction in all IHD of 20% ( 1-35, p=0.04) almost entirely due to a 32% reduction (12-48, p=0.004) in nonfatal events, Absolute reductions in all IHD due to warfarin; or aspirin were 2.6 and 2.3 per 1000 person years, respectively. WA redu ced all IHD by 34% (11-51, p=0.006) compared with P. WA increased haem orrhagic and fatal strokes. Ruptured aortic or dissecting aneurysms oc curred in 15 of those who were or had been on warfarin compared with t hree of those who had not (p=0.01). Interpretation These results add t o evidence that aspirin reduces non-fatal IHD, Warfarin reduced all IH D chiefly because of an effect on fatal events. Combined treatment wit h warfarin and aspirin is more effective in the reduction of IHD than either agent on its own.