Elsevier

The Lancet

Volume 360, Issue 9327, 13 July 2002, Pages 109-113
The Lancet

Articles
Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial

https://doi.org/10.1016/S0140-6736(02)09409-6Get rights and content

Summary

Background

Antiplatelet treatment with aspirin and oral anticoagulants reduces reocurrence of ischaemic events after myocardial infarction. We aimed to investigate which of these drugs is more effective in the long term after acute coronary events, and whether the combination of aspirin and oral anticoagulants offers greater benefit than either of these agents alone, without excessive risk of bleeding.

Methods

In a randomised open-label trial in 53 sites, we randomly assigned 999 patients to low-dose aspirin, high-intensity oral anticoagulation, or combined low-dose aspirin and moderate intensity oral anticoagulation. Patients were followed up for a maximum of 26 months. The primary composite endpoint was first occurrence of myocardial infarction, stroke, or death.

Findings

The primary endpoint was reached in 31 (9%) of 336 patients on aspirin, in 17 (5%) of 325 on anticoagulants (hazard ratio 0·55 [95% CI 0·30–1·00], p=0·0479), and in 16 (5%) of 332 on combination therapy (0·50 [0·27–0·92], p=0·03). Major bleeding was recorded in three (1%) patients on aspirin, three (1%) on anticoagulants (1·03 [0·21–5·08], p=1·0), and seven (2%) on combination therapy (2·35 [0·61–9·10], p=0·2). Frequency of minor bleeding was 5%, 8% (1·68 [0·92–3·07], p=0·20), and 15% (3·13 [1·82–5·37], p=<0·0001), in the three groups, respectively. 164 patients permanently discontinued the study drug. Analyses were done by intention to treat.

Interpretation

In patients recently admitted with acute coronary events, treatment with high-intensity oral anticoagulants or aspirin with medium-intensity oral anticoagulants was more effective than aspirin on its own in reduction of subsequent cardiovascular events and death.

Introduction

The beneficial effect of antithrombotic treatment in patients with acute coronary events suggests that prevention of thrombus formation after plaque rupture reduces subsequent cardiovascular events. Short-term use of aspirin and long-term use of oral anticoagulants are effective in patients who have had myocardial infarction.1, 2, 3 Compared with placebo, antiplatelet treatment, especially aspirin, reduces vascular events by 25% after myocardial infarction,1 and long-term treatment with coumadin reduced vascular events by 35%.2, 3 Indirect comparison of these trials suggests that coumadin could be more beneficial than aspirin. Aspirin has been compared directly with coumadin in patients who have had myocardial infarction, but only in two small clinical trials in the early 1980s,4, 5 in which no difference was recorded for reinfarction and mortality. Since then, lower doses of aspirin have been used, making combination treatment with anticoagulants more realistic than previously. At the start of our trial, aspirin with low-intensity coumadin (international normalised ratio [INR] values <1·5) was no more effective in prevention of ischaemic events in coronary artery disease than aspirin on its own.6 However, aspirin with moderate intensity coumadin (INR 2·0–3·0) was more effective than aspirin on its own.7

In the Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 (ASPECT-2) study, we assessed the effect of high-intensity coumadin and aspirin plus moderate-intensity coumadin, compared with aspirin on its own in patients who had had an acute coronary event.

Section snippets

Study design

The ASPECT-2 study was a prospective, multicentre, randomised, open-label trial. The study was done in accordance with the Declaration of Helsinki. The protocol was approved by the Netherlands National Health Insurance Council and by all local institutional ethics committees. All patients gave written informed consent.

Patients

Eligible patients were men or non-pregnant women who were admitted with acute myocardial infarction or unstable angina within the preceding 8 weeks. Myocardial infarction was

Results

In February, 1999, we stopped the study early because of slow patient recruitment. By that time, 999 patients had been enrolled in 53 hospitals across the Netherlands (figure 1). Five patients assigned to coumadin and one assigned to aspirin and coumadin were excluded because they refused to participate directly after randomisation, but before use of the study drug. Median length of follow-up was 12 months (range 0–26). The study drug was discontinued in 34 (10%) of 336 on aspirin, in 62 (19%)

Discussion

Plaque rupture and superimposed thrombus caused by platelet aggregation and activation of the coagulation cascade are major factors in the pathophysiology of acute coronary events. After the acute event, activation of anticoagulation is raised for several months,8 and this increase has been associated with increased risk of unfavourable outcome. In outpatients, a persistent effect can be achieved with oral anticoagulants.

In our study, high-intensity oral anticoagulation and the combination of

References (14)

  • Collaborative overview of randomised trials of anti-platelet therapy-I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients

    BMJ

    (1994)
  • P Smith et al.

    The effect of warfarin on mortality and reinfarction after myocardial infarction

    N Engl J Med

    (1990)
  • Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction

    Lancet

    (1994)
  • K Breddin et al.

    The German-Austrian aspirin trial

    Circulation

    (1980)
  • A controlled comparison of aspirin and oral anticoagulants in prevention of death after myocardial infarction

    N Engl J Med

    (1982)
  • Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction

    Lancet

    (1997)
  • M Cohen et al.

    Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users

    Circulation

    (1994)
There are more references available in the full text version of this article.

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