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Therapeutics

Warfarin plus aspirin prevented ischemic heart disease in high-risk men

ACP J Club. 1998 Jul-Aug;129:4. doi:10.7326/ACPJC-1998-129-1-004


Source Citation

The Medical Research Council's General Practice Research Framework. 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. Lancet. 1998 Jan 24;351:233-41.


Abstract

Question

Can low-intensity oral anticoagulation with warfarin and low-dose aspirin, together or individually, prevent ischemic heart disease (IHD) in high-risk men?

Design

Randomized, placebo-controlled trial using a factorial design.

Setting

108 U.K. practices belonging to the Medical Research Council's General Practice Research Framework.

Patients

5085 men (mean age 57.5 y) at high risk for IHD on the basis of smoking, family history of premature IHD, body mass index, blood pressure, total cholesterol and plasma fibrinogen levels, and plasma factor VII coagulant activity. Exclusion criteria were history of possible peptic ulceration, myocardial infarction (MI), or stroke or use of drugs incompatible with trial medications.

Intervention

1277 men were allocated to warfarin and aspirin, 1268 to warfarin alone, 1268 to aspirin alone, and 1272 to placebo. Warfarin was started at 2.5 mg/d and adjusted monthly to maintain an International Normalized Ratio of approximately 1.5. Aspirin, 75 mg/d, was given in a controlled-release formulation.

Main outcome measures

Total IHD (coronary death and fatal and nonfatal MI), fatal IHD (coronary death and fatal MI [death within 1 month]), and nonfatal IHD.

Main results

344 IHD events occurred in the factorial component of the trial. Men who received warfarin and aspirin had fewer total IHD events { P = 0.005}* and fewer nonfatal IHD events { P = 0.014}* than men who received placebo only (Table). Men who received warfarin (alone or with aspirin) had fewer total IHD events { P = 0.04}* and fewer fatal IHD events { P = 0.01}* than men who did not receive warfarin. Men who received aspirin (alone or with warfarin) had fewer total IHD events { P = 0.04}* and fewer nonfatal IHD events { P = 0.004}* than men who did not receive aspirin. Incidence of IHD for warfarin alone {6.5%}† and aspirin alone {6.5%}† was lower than that for placebo {8.4}†, but the differences were not statistically significant { P = 0.07}†.

Conclusions

In high-risk men, warfarin combined with low-dose aspirin reduced ischemic heart disease events. Combined treatment was more effective than either warfarin or aspirin alone.

Sources of funding: Medical Research Council; British Heart Foundation; DuPont Pharma and Bayer Corporation; Glaxo; in part, Boehringer-Ingelheim Ltd.

For correspondence: Professor T.W. Meade, MRC Epidemiology and Medical Care Unit, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, England, UK. FAX 44-171-982-6253.

* Information supplied by authors.

† Calculated from data in article.


Table. Warfarin and aspirin vs placebo for ischemic heart disease (IHD)†

Outcomes Warfarin and aspirin Placebo RR (95% CI) NT (CI)
Total IHD 5.6% 8.4% 33.9% (12 to 51) 36 (21 to 114)
Nonfatal IHD 3.7% 5.7% 35.9% (8 to 55) 49 (27 to 238)
Fatal IHD 1.9% 2.7% 29.7% (-17 to 58) Not significant

†Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

The study by the Medical Research Council is the first to suggest that a combined antithrombotic regimen is useful in the primary prevention of death caused by IHD. Treatment with warfarin alone or warfarin and aspirin was associated with reduced IHD mortality compared with aspirin alone, which only reduced nonfatal events. The results of aspirin therapy are consistent with a meta-analysis of studies on primary prevention with aspirin in patients at relatively low risk (1).

Although this study defines the potential value of antithrombotic therapy in the primary prevention of IHD, several factors should be considered before using the combination of warfarin and aspirin. First, the data were mostly collected at a time when aggressive control of cholesterol levels was not widely done. It is difficult to determine the extent to which optimal management of hypertension and hypercholesterolemia would affect the results of this trial. Second, the identification of appropriate high-risk patients for treatment with this more aggressive regimen is also problematic because plasma fibrinogen levels and factor VII coagulant activity are not commonly used in clinical practice. An increased risk for cerebral hemorrhage was also seen in patients who had hypertension and were allocated to warfarin and aspirin.

Nonetheless, the results suggest that the combination of a relatively safe, low dose of warfarin with a low dose of aspirin should be considered in patients thought to be at particularly high risk for IHD events.

Paul R. Eisenberg, MD, MPH
Washington University School of MedicineSt. Louis, Missouri, USA


Reference

1. Collaborative overview of randomised trials of antiplatelet therapy-I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81-106. Erratum BMJ. 1994;308:1540.