Spironolactone Fails to Lower Heart Failure and Cardiovascular Deaths in Acute MI Patients: CLEAR SYNERGY trial

The CLEAR SYNERGY trial has dealt a second setback to the 2x2 factorial design study. Following the disappointing results from the colchicine arm last month—where the anti-inflammatory agent failed to reduce major cardiovascular (CV) events after acute myocardial infarction (MI)—new findings from the spironolactone arm show a similar lack of impact.

Dr. Sanjit Jolly from Hamilton Health Sciences/Population Health Research Institute, Canada, presented the latest data at the American Heart Association (AHA) 2024 Scientific Sessions. These results were simultaneously published in the New England Journal of Medicine alongside the full colchicine trial results.

Despite hopes that a mineralocorticoid receptor antagonist (MRA) like spironolactone might show benefits where colchicine did not, the trial results were disappointing. Dr. Jolly referenced previous studies like EPHESUS, which demonstrated that eplerenone, another MRA, reduced all-cause mortality in patients with heart failure (HF) following MI. However, two other conflicting trials, REMINDER and ALBATROSS, left the potential benefits of early MRA use in modern settings unclear.

In the current study, 7,062 patients from 14 countries were randomized to receive either spironolactone or a placebo immediately after PCI for STEMI or large NSTEMI. Less than 1% had prior heart failure, as noted by Dr. Jolly. While there was a numerically lower incidence of cardiovascular deaths and new or worsening HF in the spironolactone group over three years (183 vs. 220 events), the difference was not statistically significant. Similarly, there were no significant differences in the first occurrence of MI, stroke, new or worsening heart failure, or cardiovascular death (280 versus 294 events; HR 0.95).

Discontinuation of treatment was a notable issue in the trial, mirroring what was observed in the colchicine arm, with 26% of patients stopping their medication. Serious adverse events occurred in around 7% of patients in both the spironolactone and placebo groups. In the spironolactone group, 1.1% of patients discontinued treatment due to hyperkalemia, while 2.3% developed gynecomastia.

Given the high rate of discontinuations, the investigators performed an on-treatment analysis, which revealed what Dr. Jolly described as an "exploratory and hypothesis-generating" signal. In the analysis, patients treated with spironolactone showed better outcomes than the placebo group, particularly due to a reduction in new or worsening heart failure.

"In patients with myocardial infarction, spironolactone did not lower the rates of cardiovascular death, new or worsening heart failure, or the combined incidence of cardiovascular death, myocardial infarction, stroke, or new or worsening heart failure," the researchers concluded.

Reference:

DOI: 10.1056/NEJMoa2405923