Elsevier

The Lancet

Volume 351, Issue 9098, 24 January 1998, Pages 233-241
The Lancet

Articles
Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk

https://doi.org/10.1016/S0140-6736(97)11475-1Get rights and content

Summary

Background

We aimed to evaluate low intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease (IHD).

Methods

5499 men aged between 45 years and 69 years at high risk of IHD were recruited from 108 practices in the UK that belong to the Medical Research Council's General Practice Research Framework. Initially, warfarin or placebo was randomly allocated to 1427 men; 1013 of these men later moved to a factorial stage of the trial, 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 four 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 placebo aspirin (P, n=1272). The primary end-point was all IHD defined as the sum of coronary death and fatal and non-fatal myocardial infarction (Ml).

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 reduction in all IHD of 21% (95% Cl 4–35, p=0·02) chiefly due to a 39% reduction (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 non-fatal events. Absolute reductions in all IHD due to warfarin or aspirin were 2·6 and 2·3 per 1000 person years, respectively. WA reduced all IHD by 34% (11–51, p=0·006) compared with P. WA increased haemorrhagic and fatal strokes. Ruptured aortic or dissecting aneurysms occurred in 15 of those who were or had been on warfarin compared with three of those who had not (p=0·01).

Interpretation

These results add to evidence that aspirin reduces non-fatal IHD. Warfarin reduced all IHD chiefly because of an effect on fatal events. Combined treatment with warfarin and aspirin is more effective in the reduction of IHD than either agent on its own.

Introduction

An association between the level of activity of factor VII, VIIC, and the incidence of ischaemic heart disease (IHD), particularly fatal episodes, was found in the first Northwick Park Heart Study.1, 2, 3 Factor VII is a vitamin K dependent clotting factor the activity of which is lowered by warfarin. The thrombosis prevention trial started with screening examinations in 1983. At this stage, the trial's objective was to reduce VIIC from the level found in the men in the Northwick Park Heart Study who developed IHD (about 117%), to a value characteristic of groups at low risk (about 70%) and to see whether this would lower the incidence of IHD.4 Preliminary studies in men aged 45 years to 69 years showed that this reduction in VIIC corresponds to raising the International Normalised Ratio (INR) with warfarin by about 0·5 (ie, to 1·5). This is a modest intensity of anticoagulation, being less than that recommended for the prophylaxis of venous thrombosis5 but likely to cause less serious bleeding than conventional intensities and supported by evidence that lower than conventional levels of anticoagulation are equally effective in prevention of venous thromboembolism while resulting in less bleeding.6 Another reason for this trial is the proven effectiveness of warfarin in the secondary prevention of IHD.7, 8, 9

During the early stages of this trial, the value of aspirin in secondary prevention of IHD was becoming increasingly clear10 and is now firmly established.11 There was also growing evidence that the simultaneous modification of platelet activity and of fibrin formation may be more effective than modifying either process alone and that it may be possible to achieve this without an unacceptable increase in serious bleeding.12, 13 However, the effect of aspirin in primary prevention is uncertain, a reduction in myocardial infarction (MI) being partly offset by a possible increase in the incidence of stroke14 so that further information on aspirin in this setting was needed. After a preliminary study,15 the trial was therefore expanded in 1989 into a factorial comparison of low-intensity oral anticoagulation with warfarin and of low-dose aspirin, 75 mg daily in a controlled release formulation intended to maximise thromboxane inhibition while sparing prostacyclin.16 Besides assessing the effects of warfarin and aspirin separately, an additional purpose of the factorial trial was to see if it is possible to decrease the incidence of major IHD using their combination.

The four groups established by the factorial design were active warfarin and active aspirin (WA), active warfarin and placebo aspirin (W), placebo warfarin and active aspirin (A), and placebo warfarin and placebo aspirin (P).

Section snippets

Methods

The methods we used have been described elsewhere.17, 18 The trial was done through 108 group practices in the Medical Research Council's (MRC) General Practice Research Framework in men aged between 45 years and 69 years. All parts of the UK are represented. An initial search of some 135 000 practice notes was done to exclude those not eligible for the trial, the main reasons being a current or recent history of possible peptic ulceration (27% of exclusions), a history of possible or definite

Results

The flow of patients throughout the trial is given in figure 1. A total of 5499 men were recruited of whom 5085 contributed to the factorial stage.

The risk-factor profile for those eligible for the trial but who did not enter it was virtually identical with that of the men who did (data not shown). Table 1 gives the entry characteristics of the four treatment groups in the factorial stage. The mean INR of those on active warfarin at stable dose was 1·47 (IQR 1·41–1·54)—ie, a separation of 0·47

Discussion

The incidence of IHD was 62% of that considered likely and only a little more than the rate found in a trial of aspirin in unselected British doctors, who were at generally low risk.23 Figures from the Office of Population Censuses and Surveys and the Office of National Statistics show that between 1983 and 1995, mortality from IHD (ICD 410–414) in men in the relevant age groups declined considerably (more than the 10% we assumed in estimating the sample size). It is probable that referral of

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