Key Takeaways:
- The CLEAR SYNERGY trial was a multicenter trial with a 2-by-2 factorial design which randomly assigned patients with myocardial infarction who had undergone percutaneous coronary intervention to receive either a) spironolactone or placebo and b) either colchicine or placebo.
- Among patients with myocardial infarction, spironolactone did not reduce the incidence of death from cardiovascular causes or new or worsening heart failure or the incidence of a composite of death from cardiovascular causes, myocardial infarction, stroke, or new or worsening heart failure.
- Safety outcomes, including hyperkalemia and gynecomastia, were more common in the spironolactone group compared to placebo.
Spironolactone, a mineralocorticoid receptor antagonist, has demonstrated efficacy in reducing mortality in heart failure with reduced ejection fraction. However, its role in routine post-myocardial infarction management without established heart failure remains unclear. The CLEAR SYNERGY trial was conducted to evaluate whether routine spironolactone use after MI could improve cardiovascular outcomes (CLEAR ClinicalTrials.gov number, NCT03048825). The results were presented at AHA Scientific Sessions 2024 with simultaneous publication in the New England Journal of Medicine.
In this multicenter trial with a 2-by-2 factorial design, authors randomly assigned patients with myocardial infarction who had undergone percutaneous coronary intervention to receive either a) spironolactone or placebo and b) either colchicine or placebo. The results of the colchicine trial were previously presented. The two primary outcomes were a composite of death from cardiovascular causes or new or worsening heart failure, evaluated as the total number of events; and a composite of the first occurrence of myocardial infarction, stroke, new or worsening heart failure, or death from cardiovascular causes. Safety was also assessed.
A total of 7,062 patients across 104 centers in 14 countries. Patients with acute MI who had undergone percutaneous coronary intervention (PCI) were randomized to receive spironolactone (n=3,537) or placebo (n=3,525). The primary outcomes were the composite of cardiovascular death or new or worsening heart failure, as well as the broader composite including recurrent MI and stroke. Safety outcomes such as hyperkalemia, renal dysfunction, and gynecomastia were also assessed.
The primary outcome of cardiovascular death or new or worsening heart failure occurred in 183 patients (1.7 per 100 patient-years) in the spironolactone group compared to 220 patients (2.1 per 100 patient-years) in the placebo group (HR, 0.91; 95% CI, 0.69–1.21; P=0.51). For the broader composite outcome, events occurred in 280 patients (7.9%) in the spironolactone group and 294 patients (8.3%) in the placebo group (HR, 0.95; 95% CI, 0.80–1.12; P=0.52). New or worsening heart failure was reported in 58 patients (1.6%) in the spironolactone group and 84 patients (2.4%) in the placebo group (HR, 0.77; 95% CI, 0.51–1.16; P=0.24). Safety outcomes revealed higher rates of hyperkalemia leading to trial regimen discontinuation in the spironolactone group (1.1% vs. 0.6%; P=0.01) and gynecomastia (2.3% vs. 0.5%; P<0.001). Serious adverse events occurred in 7.2% of the spironolactone group versus 6.8% in the placebo group (P=0.54).
Dr. Sanjit Jolly, the study’s lead investigator, noted, “Participants fared much better in this trial than in previous ones. This reflects the advances in angioplasty techniques in the overall care for heart attacks. Modern treatment approaches, including medication, stent technology and more timely interventions, have positively impacted patient outcomes. While spironolactone didn’t reduce deaths or other major heart complications after a heart attack, it did reduce the likelihood of heart failure, which is an important finding for patients and health care professionals.” These results suggest the routine use of spironolactone in patients after MI without heart failure is unlikely to confer substantial clinical benefits. Further research may clarify its role in specific subgroups.