Insights from CLEAR SYNERGY (OASIS 9): Spironolactone and Myocardial Infarction

 The CLEAR SYNERGY (OASIS 9) trial unveiled pivotal findings on spironolactone, a mineralocorticoid receptor antagonist, in patients with myocardial infarction (MI). Contrary to earlier evidence, spironolactone did not reduce deaths from cardiovascular (CV) causes, new or worsening heart failure (HF), or other major adverse cardiovascular events (MACE).

The study enrolled 3,537 patients who received spironolactone versus 3,525 who received a placebo. The average left ventricular ejection fraction (LVEF) across participants was 49%, indicating preserved or mildly reduced systolic function in most patients.

The RALES and EPHESUS trials previously established significant mortality and HF hospitalization benefits of mineralocorticoid receptor antagonists in acute MI complicated by depressed LVEF. However, the ALBATROSS trial, which evaluated spironolactone post-MI regardless of LVEF, showed an overall negative outcome, with a subgroup analysis suggesting potential benefits only in STEMI patients.

In CLEAR SYNERGY, where STEMI patients were overwhelmingly represented, spironolactone failed to demonstrate reductions in MACE or CV death. HF events were numerically lower in the spironolactone arm (1.6% vs. 2.4%), aligning partially with prior findings. However, adjustment for competing risks diminished the significance of these estimates.

Advances in contemporary MI management, such as angioplasty techniques, modern stent technology, and optimized pharmacological therapies, may have reduced the incremental benefit of routine spironolactone use in broader MI populations. This study does not support an expanded indication for mineralocorticoid receptor antagonists beyond post-MI LV systolic dysfunction.

Adverse events in the spironolactone group were notable for a higher incidence of hyperkalemia (1.1% vs. 0.05%), which led to more frequent medication discontinuation. Serious adverse events were comparable between groups (7.2% vs. 6.8%).

The colchicine arm of the trial similarly failed to demonstrate significant reductions in primary outcomes. Over a 3-year median follow-up, MACE occurred in 9.1% of colchicine patients and 9.3% of placebo patients. C-reactive protein (CRP) levels were modestly reduced in colchicine users, but diarrhea was more frequent (10.2% vs. 6.6%), while serious infections remained similar.

Take-Home Points

• Spironolactone did not reduce MACE or CV death but lowered HF events numerically, though this benefit was attenuated by risk adjustments.
• Advances in MI treatment may have reduced the incremental benefit of routine mineralocorticoid receptor antagonists in a broad MI population.
• The study does not support spironolactone use beyond patients with post-MI LV systolic dysfunction, aligning with RALES and EPHESUS trial findings.
• Hyperkalemia occurred more frequently with spironolactone, emphasizing the need for monitoring.
• The colchicine arm showed no significant reductions in MACE, though CRP levels decreased modestly.

These findings reinforce the importance of personalized treatment approaches and the evolving role of adjunct therapies in modern cardiac care.