In patients with acute myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI), spironolactone did not meet its primary composite endpoints but showed a potential reduction in new or worsening heart failure (HF), according to data from the CLEAR SYNERGY (OASIS-9) trial presented at the American Heart Association Scientific Sessions. The trial, a 2x2 factorial design, randomized patients post-MI to spironolactone or placebo, alongside colchicine or placebo.
The CLEAR SYNERGY trial involved 7,062 patients (mean age 61 years, 20% women, 95% with STEMI, <1% with prior HF) across 104 centers in 14 countries, with a median follow-up of 3 years. Sanjit Jolly, MD, MSc, from McMaster University, noted the uncertainty around the routine administration of mineralocorticoid receptor antagonists in MI patients without existing heart failure.
The intention-to-treat analysis revealed no significant difference in the primary outcome of cardiovascular (CV) death or new/worsening HF between the spironolactone and placebo groups (1.7% vs. 2.1%; HR = 0.89; 95% CI, 0.73-1.08; P = 0.23). Similarly, no difference was observed in the second primary outcome of CV death, MI, stroke, or new/worsening HF (7.9% vs. 8.3%; HR = 0.95; 95% CI, 0.8-1.12; P = 0.52).
On-Treatment Analysis Suggests Benefit
However, an on-treatment analysis, excluding patients who discontinued the study drug early, showed that spironolactone favored the first primary outcome (1.5% vs. 2%; HR = 0.79; 95% CI, 0.63-1; P = 0.047) and the second primary outcome (5.8% vs. 7.2%; HR = 0.83; 95% CI, 0.69-1; P = 0.046).
High Discontinuation Rates
Dr. Jolly highlighted a significant 26% drug discontinuation rate, higher than anticipated, which emphasizes the importance of the on-treatment analysis. He also noted the challenges inherent in 2x2 factorial designs when one study drug is less tolerable.
Impact on Heart Failure Outcomes
Both intention-to-treat and on-treatment analyses favored spironolactone for the secondary outcome of new or worsening HF (intention to treat: 1.6% vs. 2.4%; HR = 0.69; 95% CI, 0.49-0.96; on-treatment: 1.3% vs. 2%; HR = 0.67; 95% CI, 0.46-0.98).
Serious adverse events occurred at similar rates between groups (spironolactone, 7.2%; placebo, 6.8%; P = 0.54). However, the spironolactone group experienced higher rates of hyperkalemia leading to drug discontinuation (P = 0.01) and gynecomastia (P < 0.001).
Clinical Implications
Dr. Jolly concluded that routine spironolactone post-MI did not reduce the co-primary outcomes but did show a one-third reduction in new or worsening heart failure. He also noted that improved post-MI outcomes over the last 20 years make it more challenging to demonstrate a difference with new interventions, with heart failure event rates now at 2-3% compared to 10-15% historically.
Roxana Mehran, MD, from Mount Sinai School of Medicine, commented on the low event rates in the trial, noting that most patients were STEMI patients who were stable with little left ventricular dysfunction or heart failure at presentation. She agreed that spironolactone reducing the risk for new or worsening HF "makes sense" but that more granular data are needed to identify which patients might benefit the most. She also suggested that the results may have been impacted by the lower-than-expected event rate and the concomitant administration of colchicine, which may have led to higher drug discontinuation due to diarrhea.
