Review of Acute Infarction Ramipril Efficacy (AIRE) Trial
Effect of Ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure
Background The Survival After Ventricular Enlargement (SAVE) trial demonstrated that administration of the angiotensin converting enzyme inhibitor (ACEi) captopril, following MI complicated by LV dysfunction (EF ≤40%) but without clinical heart failure significantly improved morbidity and mortality over 3.5 years of follow-up.
Yet many post-MI patients at the time had clinical heart failure and this represented a vulnerable population of patients with significantly increased morbidity and mortality compared to those without clinical heart failure.
The Acute Infarction Ramipril Efficacy (AIRE) trial sought to test the hypothesis that administration of Ramipril to patients with AMI complicated by acute congestive heart failure would reduce morbidity and mortality vs a placebo.
Patients Eligible patients were 18 years of age or older with a definite AMI occurring 2 to 9 days prior to randomization with clinical evidence of congestive heart failure at any time after the index MI. While clinical evidence of heart failure was mandatory for study entry, it could be transient and not necessarily present at the time of randomization. Patients were excluded with NYHA IV heart failure (these patients would receive ACEi therapy regardless), heart failure of primary valvular or congenital etiology, or patients with any recognized contraindications to ACEi therapy were excluded.
Baseline characteristics The average age of patients was 65 years and 74% were men. Approximately one quarter of patients had had a prior MI, 12% had diabetes, 30% had hypertension and smoking status was not listed. The ejection fraction of study participants was not systematically assessed as part of the study protocol. 62% had a Q wave MI and the predominant location was anterior. The mean time to randomization was 5 days. Approximately 60% of patients received thrombolysis. The average blood pressure and heart rate were not provided. At the time of randomization 22% of patients were receiving a beta blocker and 12% digoxin.
Many more patients (52,019) were reviewed than ultimately enrolled (1,986). The main reasons for exclusion were no definitive MI (21,302) and no definite heart failure (16,989). The authors estimate that among eligible patients with a definitive MI and heart failure that approximately half were enrolled. Information on those enrolled versus not enrolled was not provided.
Procedures Patients were initiated on Ramipril 2.5 mg twice daily or matching placebo for 2 days after which the dose was increased to 5 mg twice daily. If patients could not tolerate the 5 mg twice daily dose they were discharged on 2.5 mg twice daily. For patients who could not tolerate the 2.5 mg dose they were given 1.25 mg twice daily for 2 days with attempts to up-titrate to 2.5 mg and 5 mg at discharge. For patients that could not tolerate at least 2.5 mg twice daily at discharge they were NOT discharged on the 1.25 mg dose. These patients were withdrawn from study treatment but followed up at the prespecified visit intervals and were included in the intention-to-treat analysis.
Outpatient visits were scheduled at 1 month and 3 months following discharge from the index hospitalization and every 3 months thereafter until study close. Monitoring of renal function and electrolytes was done at the discretion of study investigators based on their normal practice. During follow up patients could be started on any medication with exception of an ACEi.
Endpoints The primary study endpoint was all-cause mortality. The secondary endpoint was time to first event including (death, progression to NYHA class 4 heart failure, reinfarction or stroke).
The investigators estimated they would need a sample size of 2,000 patients to detect a 25% relative reduction in the risk of death with 80% power and 2-sided alpha of 5%. This was based on an estimated death rate of 20% at 15 months in the placebo group and 15% in the Ramipril group.
Results 2,006 patients were recruited from 144 centers in 14 countries. However, 20 patients from 1 center were excluded from the final analysis due to inconsistencies in the data. According to investigators the exclusion of these patients did not meaningfully change the final results. The final analysis included 1,986 patients; 1004 in the Ramipril group and 982 in the placebo group.
90% of study participants were discharged from the hospital on study drug. In the Ramipril group, 77% were on the 5 mg dose, 14% were on the 2.5 mg dose and 9% were on no therapy. In the placebo group, 86% were on the 5 mg dose, 7% on the 2.5 mg dose and 7% on no therapy.Patients were followed for an average of 15 months and only 1 was lost to follow-up.
Compared to placebo, Ramipril significantly reduced all cause death by 27% (17% vs 23%; p = 0.002). Ramipril also significantly reduced the secondary composite endpoint of time to first validated event (including death, progression to severe heart failure, reinfarction or stroke) by 19% (28% vs 34%; p = 0.008). Differences in this composite endpoint were mainly driven by death and progression to severe heart failure.
Examination of subgroups showed no evidence of treatment effect heterogeneity but again, similar to the SAVE trial, the size of the trial limits subgroup testing.
Premature withdrawals from study drug, not including death, occurred in 352 patients in the Ramipril group compared to 318 in the placebo group. Intolerance to the drug was cited as a factor in 126 of the Ramipril withdrawals and 68 of the placebo withdrawals whereas progression to severe heart failure was cited in 58 Ramipril withdrawals and 92 placebo. Syncope was more common in Ramipril treated patients compared to placebo (2.4% vs 1.7%) and so was hypotension (4.2% vs 2.3%) but not renal failure (1.5% vs 1.2%).
Conclusions In patients with AMI complicated by clinical congestive heart failure, Ramipril significantly reduced death over 1.3 years of follow-up with a number needed to treat of approximately 17 patients.
Ramipril also significantly reduced a composite of events, which were mainly driven by death and progression to severe heart failure.
Unlike the SAVE trial, which did not estimate a particular sample size for hypothesis testing, AIRE was specifically designed to test whether Ramipril would reduce death by 25% over 15 months and indeed, it did! Thus, results from AIRE not only support but add legitimacy to findings from SAVE.
One perceived limitation of AIRE, particularly when viewed through a contemporary lens, is its lack of ejection fraction estimation. There should be no doubt that these were sick patients in whom, significant LV dysfunction would have been present in most. We base this claim on the observation that the death rate in AIRE at 1.3 years in the placebo group was nearly equal to SAVE at 3.5 years (23% vs 25%). This highlights that development of clinical heart failure (regardless of LV function) confers a worse prognosis than LV dysfunction without heart failure.
In our opinion, the external validity of AIRE is high for a trial performed 30 years ago. The average start date for treatment was 5 days post MI complicated by clinical heart failure. This is longer than we would anticipate in contemporary practice by 2 or 3 days but not unreasonable, especially for post-MI patients with tenuous hemodynamics requiring intravenous diuretic therapy.
Furthermore, the dose titration parameters and follow up schedule in AIRE can be approximated in clinical practice. Also, no obvious treatment effect heterogeneity was noted across important subgroups (e.g., age > vs < 65 years) but these analyses are limited due to the overall sample size. Finally, no strict limits were placed on blood pressure and heart rate at study entry.