Authors' objectives

To confirm or refute the theory that aspirin alters the effects of angiotensin-converting enzyme (ACE) inhibitor therapy on major clinical outcomes, by conducting a meta-analysis of individual patient data (IPD) from trials in which the patients were randomised to receive ACE inhibitors or placebo, and either took or did not take aspirin at baseline.

Searching

MEDLINE was searched, although the dates over which the search was conducted were not given. In addition, researchers and colleagues in the pharmaceutical industry were contacted, and reference lists from review articles were scanned (see Other Publications of Related Interest no.1). Principal investigators from each of the large randomised trials (short- and long-term) of ACE inhibitors in MI and the Studies of Left Ventricular Dysfunction (SOLVD) trials were invited to form the ACE-Inhibitor Myocardial Infarction Collaborative Group, which agreed on the data to be collected, and to review the analyses and manuscripts.

Study selection

Assessment of study quality

The collaborative group agreed a prospective protocol for data collection that summarised the methods, pre-specified analyses and a common data-set of 88 variables (see Other Publications of Related Interest no.1). The data sets were rigorously checked for completeness and consistency to ensure no errors occurred during reformatting, and for agreement with the original publications. Any queries were resolved with the principal investigators.

Data extraction

The data sets from each trial were checked for completeness and consistency before being incorporated into a master database for analysis. The baseline characteristics included age, gender, heart rate, blood-pressure, previous MI, diabetes, hypertension, whether currently smoking, and prescribed diuretics or beta-blockers. The outcomes are listed above (see 'Outcomes Assessed in the Review' field).

Methods of synthesis

Results of the review

Six double-blind randomised trials with 22,060 patients were included. A total of 14,410 patients received aspirin; the mean age was 64 years (standard deviation, SD=9) and 21% were women. A total of 7,650 patients did not receive aspirin; the mean age was 62 years (SD=10) and 25% were women.

Differences in the baseline characteristics of the aspirin and no-aspirin subgroups were found, and these varied between the trials. A significant difference (p=0.01) between the proportional reductions in risk with ACE inhibitor therapy was found only for MI with aspirin (OR 0.86, 99% CI: 0.75, 0.99) versus no-aspirin (OR 0.66, 99% CI: 0.54, 0.81). In the primary (composite) outcome, the test for aspirin interaction showed a weak trend (p=0.07) for reduced benefit from aspirin (OR 0.80, 99% CI: 0.73, 0.88) versus no-aspirin (OR 0.71, 99% CI: 0.62, 0.81).

Authors' conclusions

There is only weak evidence of a reduction in benefit when aspirin is added to ACE inhibitor therapy. Both treatments have been shown to be beneficial separately, therefore, both should be used concomitantly in high-risk patients in the absence of clear contraindications.

CRD commentary

This IPD meta-analysis asked a clear question that had been posed in a subgroup analysis in the authors' earlier review (see Other Publications of Related Interest no.1). The search strategy and analysis used previously were reasonably comprehensive, despite being limited to a single database and not including any trial registers; it was updated for the present review. The authors did not achieve their stated aim of confirming or refuting the hypothesis of a reduced benefit from ACE inhibitors when aspirin is given concomitantly.

Implications of the review for practice and research

Practice: The authors state that aspirin and ACE inhibitors should be prescribed together in high-risk patients.

Research: The authors state that the least biased assessment of the possibility of interactions would involve a very large randomised 2x2 factorial trial of aspirin versus placebo, and ACE inhibitors versus placebo. However, they say that such a trial is improbable on ethical and statistical grounds. Both treatments have been shown to be beneficial, and a substantial reduction in risk was still apparent when they were combined.

Bibliographic details

Teo K K, Yusuf S, Pfeffer M, Kober L, Hall A, Pogue J, Latini R, Collins R. Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review. Lancet 2002; 360: 1037-43. [PubMed: 12383982]

Other publications of related interest

1. Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000;355:1575-81. 2. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-71.

This additional published commentary may also be of interest. Cohn JD. Review: concomitant aspirin use does not reduce the effectiveness of ACE inhibitors. ACP J Club 2003;138:64.

Indexing Status

Subject indexing assigned by NLM

MeSH

Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors /therapeutic use; Anticoagulants /therapeutic use; Aspirin /therapeutic use; Drug Therapy, Combination; Female; Heart Failure /complications /drug therapy /mortality; Humans; Logistic Models; Male; Middle Aged; Myocardial Infarction /etiology; Myocardial Revascularization /statistics & numerical data; Patient Admission /statistics & numerical data; Prognosis; Proportional Hazards Models; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Stroke /etiology; Treatment Outcome; Ventricular Dysfunction, Left /complications /drug therapy /mortality

AccessionNumber

12002008548

Database entry date

30/04/2003

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.