Spironolactone ineffective for patients with preserved ejection fraction after myocardial infarction

1. In this randomized controlled trial, spironolactone did not significantly reduce death from cardiovascular causes or new or worsening heart failure in patients with preserved ejection fraction after acute myocardial infarction.

2. Spironolactone was associated with significantly higher rates of hyperkalemia, breast tenderness, and gynecomastia compared to placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Mineralocorticoid receptor antagonists, such as spironolactone, are a mainstay treatment for chronic heart failure with reduced ejection fraction and have shown efficacy in reducing heart failure in those with preserved ejection fraction. Previous research demonstrated the benefits of aldosterone antagonism in patients with reduced ejection fraction after acute myocardial infarction, but it was unclear if this benefit extends to all post-myocardial infarction patients regardless of ejection fraction. The CLEAR trial evaluated spironolactone’s role in this population. The results showed no significant reduction in death from cardiovascular causes, recurrent myocardial infarction, stroke, or new or worsening heart failure with spironolactone treatment. Although there was a non-significant trend towards lower overall mortality, spironolactone did not reduce death from renal causes, the need for dialysis or renal transplantation, or preserve eGFR above or equal to 40%. There was also no significant difference in the occurrence of arrhythmias or atrial fibrillation. However, spironolactone was associated with significantly higher rates of hyperkalemia (>5.5 mmol/L) leading to discontinuation, breast tenderness, and gynecomastia. The trial was limited by its inability to detect a relative risk reduction of 30% or smaller, a low overall incidence of events, high discontinuation rates, and underrepresentation of women and some racial and ethnic groups. In conclusion, the study did not demonstrate a significant benefit of spironolactone in patients following myocardial infarction.

Click here to read the study in NEJM

Relevant Reading: Colchicine in Acute Myocardial Infarction

In-Depth [randomized controlled trial]: This randomized controlled trial investigated the efficacy and safety of spironolactone, a mineralocorticoid receptor antagonist, in patients with preserved ejection fraction following acute myocardial infarction. Initially, inclusion criteria required patients to have experienced STEMI and undergone percutaneous coronary intervention. This was later expanded to include patients with large NSTEMI who had undergone percutaneous intervention and met at least one of the following: left ventricular ejection fraction below 45%, diabetes mellitus, multivessel coronary artery disease, previous myocardial infarction, or age over 60. A total of 7,062 patients from 14 countries were enrolled, with 3,537 assigned to spironolactone and 3,525 to placebo. The primary outcomes were two composites: death from cardiovascular causes or worsening heart failure, and the first occurrence of myocardial infarction, stroke, new or worsening heart failure, or cardiovascular death. In the spironolactone group, 183 events of cardiovascular death or worsening heart failure occurred compared to 220 in the placebo group, but this difference was not statistically significant (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.69–1.21; p = 0.51). For the second composite outcome, there were 280 events in the spironolactone group versus 294 in the placebo group, also not statistically significant (HR, 0.96; 95% CI, 0.96; p = 0.60). Secondary outcomes assessed the safety of spironolactone. Patients in the spironolactone group experienced higher rates of clinically significant arrhythmias (HR, 1.45; 95% CI, 0.67–3.12) and atrial fibrillation (HR, 1.14; 95% CI, 0.84–1.55), though these findings were not statistically significant. Overall mortality was lower in the spironolactone group (HR, 0.84; 95% CI, 0.54–1.30). However, spironolactone was associated with significantly higher rates of hyperkalemia leading to trial discontinuation (p=0.001), breast tenderness (p<0.001), and gynecomastia (p<0.001). Overall, these findings suggest that spironolactone does not improve outcomes in patients with preserved ejection fraction following acute myocardial infarction.

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