ArticlesFollow-up study of patients randomly allocated ramipril or placebo for heart failure after acute myocardial infarction: AIRE Extension (AIREX) Study
Introduction
The long-term survival of patients after acute myocardial infarction (AMI) remains a major objective for doctors and public health officials. Important advances in treatment options available for secondary prevention of AMI have occurred over the past two decades. Their acceptance into clinical practice has followed several well-executed, large-scale, collaborative, randomised and controlled clinical trials.
Eight major survival studies to investigate the effects of five different ACE inhibitors have collectively randomised more than 100 000 patients who have had an AMI to receive either active or control treatments.1, 2, 3, 4, 5, 6, 7, 8, 9 In all but the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) trial10 double-blind, placebo-controlled methods were used. Collectively, these investigations represent one of the most comprehensive evaluations of a medical treatment strategy ever done. However, some important questions remain unanswered. There continues to be a variety of opinions as to whether, when, and for how long individual patients should receive treatment.11, 12 This variation may be contributing to an apparent under-use of these drugs in routine clinical practice.13, 14, 15 However, further placebo-controlled survival studies are unlikely because withholding a treatment of accepted clinical value would be unethical.
We thought that an extended follow-up of patients, with AMI and clinically defined heart failure, who took part in the AIRE Study, and who had been recruited from hospitals in the UK, would provide useful information for clinicians when electing to prescribe these agents. Arrangements had been made for long-term observation to be done when the AIRE Study started as a trial in 1989, in the UK;16 however, subsequent international extension of the trial meant that comprehensive long-term flagging of survival status of all patients could not be done. Here we report on the long-term survival status of all 603 patients from the UK recruited to the AIRE Study between 1989 and 1992.
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Patients and methods
The rationale, design, organisation, outcome definitions, and results of the AIRE Study have already been published.4, 17, 18, 19, 20 Briefly, this was an independent, multinational, multicentre, double-blind, randomised, placebo-controlled, parallel-group study. Patients were eligible for inclusion in the study if they had evidence, on electrocardiograms and by testing for enzyme changes, of a myocardial infarction complicated by clinical transient or persisting evidence of heart failure (left
Statistical analyses
Data collection, management, entry, and statistical analyses were done at the Leeds University Institute for Cardiovascular Research. The predetermined statistical endpoint of the study was death from all causes, which was assessed with strict intention-to-treat methods. Survival curves for patients assigned placebo or ramipril were obtained by Kaplan-Meier estimates and compared by the log-rank test (two-sided p value). All patients alive at 0000 h March 1, 1996, were censored at that time.
Results
603 patients with persistent or transient clinical evidence of heart failure after confirmed AMI were randomly assigned treatment with either ramipril (302 patients) or matching placebo (301 patients). The mean time from AMI to the start of treatment initiation was 5 days in both groups. The two groups were similar in terms of age, sex distribution, medical history, site and type of AMI, rates of thrombolytic treatment, time to treatment initiation, and use of concomitant medication at time of
Sensitivity analyses
To assess the robustness of our prestated primary evaluation of all-cause mortality, we did a series of additional analyses. Each of these were designed to test the reliability of the observed reduction in mortality seen with ramipril.
To assess the net effect of minor variations in the characteristics of patients allocated placebo or ramipril, appropriately adjusted survival curves were compared. All key variables recorded at the time of randomisation and treatment allocation were
Discussion
The findings of the AIREX Study extend earlier observations, underlining the long-term effectiveness of ramipril therapy for patients with transient or persistent clinical evidence of heart failure after AMI. The recommended treatment regimen (oral ramipril 2·5 mg twice a day increasing to 5 mg twice a day) was assessed by strict intention-to-treat methods. Furthermore, the protocol stipulated discontinuation of double-blind treatment in the event that overt chronic congestive heart failure
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