Weekly Journal Scan: A CLEAR message questions the routine use of spironolactone in acute myocardial infarction

This comment refers to ‘Routine spironolactone in acute myocardial infarction’, published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2405923. CLEAR is an investigator-initiated, multicentre, prospective, blinded, randomized, placebo-controlled trial with a 2 × 2 factorial design which randomly assigned patients with acute myocardial infarction (AMI) who had undergone percutaneous coronary intervention (PCI) to receive spironolactone or placebo and colchicine or placebo. The spironolactone vs. placebo comparison aimed to determine whether spironolactone reduces the incidence of cardiovascular (CV) death or new or worsening heart failure (HF) in this setting.1 A total of 7062 patients with acute ST-segment elevation or large non-ST-segment elevation myocardial infarction (STEMI or NSTEMI, respectively) were enrolled at 104 centres in 14 countries and randomized in a factorial 1:1:1:1 allocation to receive spironolactone (25 mg daily) and colchicine (.5 mg daily), colchicine and placebo, spironolactone and placebo, or placebo only as soon as possible after the index PCI. The primary efficacy outcomes were a composite of CV deaths or new or worsening HF, evaluated as the total number of first and recurrent events, and a composite of the first occurrence of myocardial infarction (MI), stroke, new or worsening HF, or death from CV causes, evaluated in a time-to-event analysis. Safety outcomes, including hyperkalaemia, death from renal causes, dialysis, renal transplantation, or a drop in the estimated glomerular filtration rate of at least 40%, were also evaluated. The trial was initially designed to detect a 25% relative risk reduction in the primary outcome, based on an estimated 15% event rate at 3 years in the placebo group. After a blinded interim analysis in April 2020 that identified a lower-than-expected event rate (3% per patient-year), the sample size was increased from 4000 to 7000 patients to maintain 80% power, and it was estimated that 546 primary outcome events would be needed to detect a 25% relative risk reduction. Of the patients, 3537 were assigned to receive spironolactone and 3525 to receive placebo. The mean age of the patients was 61 years, with 20% women and the vast majority from North America and Europe. Of the patients, 95% had STEMI at presentation, and more than 96% received treatment with at least one drug-eluting stent and statin and dual antiplatelet therapy at discharge. The median time from symptom onset to the first dose of the trial product was 29 h. The median duration of follow-up was 3 years. Of the patients, 28% in the spironolactone group and 24% in the placebo group discontinued the trial regimen. There were 183 events of the first primary outcome (1.7 per 100 patient-years) in the spironolactone group as compared with 220 events (2.1 per 100 patient-years) in the placebo group hazard ratio (HR) adjusted for the competing risk of death from non-CV causes, .91; 95% confidence interval (CI), .69 to 1.21; P = .51. For the second primary outcome, an event occurred in 280 patients (7.9%) in the spironolactone group and 294 patients (8.3%) in the placebo group (HR adjusted for competing risk, .96; 95% CI, .81 to 1.13; P = .60). Serious adverse events were reported in 255 patients (7.2%) in the spironolactone group and 241 (6.8%) in the placebo group (P = .54). Hyperkalaemia leading to trial regimen discontinuation and gynaecomastia were significantly more common in the spironolactone group than in the placebo group. The on-treatment analyses, which excluded patients who discontinued the trial regimen on the day of randomization and censored patients 7 days after permanent discontinuation of the trial regimen, included 131 events in the spironolactone group vs. 179 events in the placebo group for the first primary outcome (HR, .79; 95% CI, .63 to 1.00). The second primary outcome occurred in 6% of the spironolactone group vs. 7% of the placebo group (HR, .83; 95% CI, .69 to 1.00). Moreover, the analysis revealed a reduction in new or worsening HF events in the spironolactone group (1.3% vs. 2.0%, HR, .67; 95% CI, .46 to .98; the widths of the CIs have not been adjusted for multiplicity, and the intervals may not be used in place of hypothesis testing). Aldosterone has been long viewed as a detrimental factor in MI due to its negative influence on cardiac tissue remodelling and function.2 Aldosterone antagonism, in turn, represents a cornerstone of HF therapy, irrespective of ejection fraction at clinical presentation, and is associated with reduced CV events.3,4 High aldosterone levels after MI have been linked to increased mortality; however, whether aldosterone antagonism benefits all patients post-MI remains uncertain.5 The EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial demonstrated that eplerenone improved outcomes in patients with AMI and HF with reduced ejection fraction.6 In contrast, the ALBATROSS (Aldosterone Lethal Effects Blockade in Acute Myocardial Infarction Treated with or without Reperfusion to Improve Outcome and Survival at Six Months Follow-Up) trial failed to show a reduction in CV events for patients with MI without HF who received spironolactone.7 A subsequent meta-analysis suggested potential benefits from mineralocorticoid antagonism in patients with AMI without HF.8 According to the CLEAR trial, spironolactone had no statistically significant effects on mortality from CV causes or CV events, including new or worsening HF, in patients with AMI undergoing PCI.1 As the authors pointed out, however, other recent trials testing drugs proven to be effective in HF have failed to demonstrate benefits in early post-MI, including PARADISE-MI with sacubitril/valsartan and EMPACT-MI with empagliflozin.9,10 This may be attributable, at least in part, to the remarkable improvement in outcomes after AMI over the past decades, directly related to the extensive use of early revascularization and advancements in drug therapy, which may reduce the feasibility of detecting further benefits with additional treatments after AMI, short of performing very large trials to detect moderate benefits. Some limitations need to be considered when interpreting the results of CLEAR. The incidence of primary outcome events was lower than expected, and the discontinuation rate was twice as high as anticipated, thereby reducing the statistical power of the study. The on-treatment analysis, suggesting a 20% reduction in both primary endpoints, may be interpreted as hypothesis-generating to suggest that, with increased adherence to the trial regimen and a lower rate of discontinuation, a benefit of aldosterone antagonism may indeed exist. Unfortunately, left ventricular ejection fraction was not measured in this study, and NYHA class data are not available to explore any differential effects of spironolactone as a function of these variables. In addition, women were underrepresented in the trial population, along with some racial and ethnic groups, thereby limiting generalizability of the CLEAR findings. Finally, whether these results reflect a class effect cannot be determined, and future studies may help clarifying the role of the novel non-steroidal mineralocorticoid antagonists in this clinical setting, given the benefits shown with finerenone across the range of ejection fraction in HF, along with a better safety profile.11 The results of this trial come at a time when some of the drugs considered cornerstones in the treatment of patients with MI (such as beta-blockers)12 are being re-evaluated and help reinforce the message that a tailor-made approach is needed in the management of MI. Routine use of spironolactone in patients with AMI does not appear to be beneficial, but further studies are needed to clarify the effects of this class of drugs in different subgroups of patients. D.P. received speaker’s fees from Daiichi-Sankyo, outside the submitted work. M.V. reports personal fees for speaker bureau and/or consulting in advisory boards from Astra Zeneca, Bayer, GSK, Menarini Int., Novartis Pharma, Novo Nordisk, Pfizer, Sanofi Pasteur, and Servier. M.V. is supported by a research grant from Italian Ministry of Health (‘Ricerca corrente’).