The methods have been described in detail elsewhere, including the fulfilment of CONSORT criteria.2,5,6
—The trial was carried out through 108 group practices in the Medical Research Council's general practice research framework in men aged between 45 and 69 years. At screening, history of smoking and family history of premature coronary heart disease were elicited, body mass index calculated, blood pressure measured, and blood samples taken for measurement of concentrations of total cholesterol and plasma fibrinogen and determination of plasma factor VII coagulant activity (VIIc). These variables were weighted according to their associations with coronary heart disease in the Northwick Park heart study,7
apart from family history which was not recorded in this study and which for the thrombosis prevention trial was considered to increase risk by 50%. Within each practice, those men in the top 20% of the distribution of the risk score or in the top 25% in regions with particularly high mortality from coronary heart disease were considered to be at increased risk and eligible for the trial. Of the 10
557 men considered to be at high risk and eligible for the treatment phase, 5499 (52%) entered the trial. Men came from all parts of the United Kingdom. Their mean (SD) age was 57.5 (6.7) years and just over 41% were current smokers. Their mean (SD) body mass index was 27.4 (3.6), and there was a family history of premature coronary heart disease in 15.5%. Mean (SD) systolic blood pressure at entry was 139 (18) mm Hg.2
Antihypertensive drugs were being used by 245 men at the time of recruitment and were used by 1421 men at some stage during the trial. Mean systolic pressure during follow up was about 135 mm Hg.
Trial treatment—The factorial design of the trial, which was double blind and placebo controlled, resulted in four treatment groups—that is, active warfarin and active aspirin, active warfarin and placebo aspirin, placebo warfarin and active aspirin, and placebo warfarin and placebo aspirin. Warfarin was started at 2.5 mg daily and adjusted by increments or decreases of 0.5 mg or 1.0 mg daily at monthly intervals until the international normalised ratio was about 1.5. Dose changes were matched in men on placebo warfarin. Aspirin was given as 75 mg daily in a controlled release formulation. The main effect of aspirin was determined by comparing results in the combined warfarin and aspirin and aspirin only groups with those in the warfarin only and placebo groups and “main” is used only in this technical sense. (The main effects of warfarin, combined warfarin and aspirin, and warfarin only compared with aspirin only and placebo were not considered. See below).
Terminating events—The primary end point was all coronary heart disease, defined as the sum of fatal and non-fatal events (coronary death and all myocardial infarction). Stroke was a secondary end point.
—The records of men in the trial were flagged in the NHS central register, thus ensuring automatic notification of death and the cause of death. Men were reviewed by their general practitioners each year, in addition to which the research nurse annually searched the notes of all those taking part for possible terminating events whether or not the man was still taking trial treatment. The independent assessment of end points was carried out according to World Health Organization (WHO) criteria8
as previously described.2
—Information about episodes of bleeding was obtained and classified as major, intermediate, or minor.2
Here, major and intermediate episodes are referred to as clinically significant.
Statistics—Rates are shown per 1000 person years together with relative risks. Interactions between the treatment effect of aspirin and all the variables used in the risk scoring were computed. As we had no prior hypotheses for most of the ensuing associations we restricted the principal findings to age and cholesterol concentration, for comparison with the US physicians health study, and to the only interaction terms significant at the 1% level or less, which were between aspirin treatment and blood pressure. (There were no interactions at less than the 1% level between the effect of warfarin treatment and any of the risk variables.) For tabular presentation we used arbitrary cut off values. The significance of interactions between the treatment effect of aspirin and the three risk factors, however, was assessed by using the full range of values for all variables. Findings for each variable under consideration were corrected for intercorrelations between age (except when age itself was under consideration) and all of the other seven risk factors used in the risk scoring procedure. All analyses were by intention to treat.