Elsevier

The Lancet

Volume 349, Issue 9064, 24 May 1997, Pages 1493-1497
The Lancet

Articles
Follow-up study of patients randomly allocated ramipril or placebo for heart failure after acute myocardial infarction: AIRE Extension (AIREX) Study

https://doi.org/10.1016/S0140-6736(97)04442-5Get rights and content

Summary

Background

In the Acute Infarction Ramipril Efficacy (AIRE) Study, the effect of angiotensin-converting-enzyme (ACE) inhibition on the survival of patients with clinical heart failure after acute myocardial infarction (AMI), was assessed. At an average follow-up time of 15 months after randomisation, all-cause mortality was reduced from 22·6% (placebo group) to 16·9% (ramipril group) representing an absolute mortality reduction of 5·7% and a relative risk reduction of 27% (95% Cl 11–40%; p=0·002). Our aim in this study was to assess the long-term (3 years after the AIRE Study closed) magnitude, duration, and reliability of the survival benefits observed after treatment with ramipril (target dose 5 mg twice a day) when compared with placebo.

Methods

We investigated the mortality status of all 603 patients recruited from the 30 UK centres involved in the AIRE Study. Through government records we were able to confirm the death or survival of all 603 patients exactly 3 years after the close of the AIRE Study. Follow-up was for a minimum of 42 months and a mean of 59 months. The average duration of treatment with masked trial medication was 13·4 months for placebo and 12·4 months for ramipril.

Findings

By 0000 h March 1, 1996, death from all causes had occurred in 117 (38·9%) of 301 patients randomly assigned placebo and 83 (27·5%) of 302 patients randomly assigned ramipril, representing a relative risk reduction of 36% (95% Cl 15–52%; p=0·002) and an absolute reduction in mortality of 11·4% (114 additional 5-year survivors per 1000 patients treated for an average of 12·4 months).

Interpretation

Our data provide robust evidence that administration of ramipril to patients with clinically defined heart failure after AMI results in a survival benefit that is not only large in magnitude, but also sustained over many years.

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.

Section snippets

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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