The largest trial to date investigating anti-inflammatory and mineralocorticoid receptor antagonist therapies following myocardial infarction has yielded disappointing primary results, according to findings presented at a recent PCT Grand Rounds session.
Dr. Sanjit Jolly, an interventional cardiologist at Hamilton Health Sciences and the Stuart Connolly Chair in Cardiology at McMaster University, shared the late-breaking results of the CLEAR OASIS 9 trial, which examined the effects of colchicine and spironolactone in post-MI patients.
Trial Design and Objectives
The CoLchicine and spironolactonE in patients with myocardial infARction/SYNERGY Stent Registry – Organization to Assess Strategies of Ischemic Syndromes 9 (CLEAR SYNERGY OASIS 9) trial enrolled 7,000 patients with ST-elevation myocardial infarction or large non-ST-elevation myocardial infarction. The study employed a 2×2 factorial design, randomizing participants to either colchicine or placebo, and separately to either spironolactone or placebo.
The primary outcome for the colchicine arm was a composite of cardiovascular death, MI, stroke, or ischemia-driven revascularization. For the spironolactone arm, co-primary outcomes were the effects on 1) a composite of cardiovascular death or heart failure, and 2) a composite of cardiovascular death, heart failure, stroke, or MI.
Colchicine Results: Anti-inflammatory Effects Without Clinical Benefit
Despite successfully reducing C-reactive protein (CRP) levels, colchicine did not reduce the composite primary endpoint compared to placebo. This finding adds complexity to the ongoing investigation of anti-inflammatory approaches in cardiovascular disease.
"CLEAR is the largest trial of colchicine in acute MI, with substantially more events than prior trials," Dr. Jolly noted during his presentation. The trial was initiated before the results of previous colchicine studies (COLCOT and LODOC02) were available, as researchers believed a larger confirmatory trial with greater statistical power was necessary.
Patients receiving colchicine experienced an increase in diarrhea, a known side effect of the medication. Based on these findings, Dr. Jolly concluded that "the role of colchicine post-MI remains uncertain."
Spironolactone Results: No Primary Benefit But Secondary Signal
In the spironolactone arm, the drug failed to reduce either co-primary outcome. However, a secondary analysis revealed a reduction in new or worsening heart failure, and on-treatment analysis suggested a potential benefit that may warrant further investigation.
The results add to the mixed evidence from previous trials examining Mineralocorticoid Receptor Antagonists (MRAs) post-MI in patients without heart failure, including the REMINDER and ALBATROSS studies.
Evolving Landscape of Post-MI Care
A key discussion point following the presentation was the dramatically improved baseline outcomes in contemporary MI care. Dr. Jolly highlighted that heart failure event rates in patients with predominantly ST-elevation MI have dropped from approximately 20% twenty years ago to around 3% today.
"That makes it more difficult to show treatment effects in this population," Dr. Jolly explained, pointing to a challenge facing many cardiovascular trials in the modern era.
Pragmatic Trial Design and Pandemic Challenges
The CLEAR OASIS 9 trial was designed to be applicable to standard clinical practice, with inclusion criteria reflecting real-world patient populations. The global study spanned approximately 70 sites across 11 countries.
The COVID-19 pandemic presented significant challenges to the trial's execution, including spiking shipping expenses, logistics complications regarding material delivery, and a temporary pause in recruitment. Additionally, varying drug approvals across different countries added complexity to this international effort.
Implications for Future Research
The results of CLEAR OASIS 9 highlight the ongoing challenge of finding effective adjunctive therapies for post-MI patients in an era of improved baseline care. While the primary hypotheses were not confirmed, the secondary signals observed with spironolactone may inform future research directions.
The study also underscores the importance of large, well-powered trials to definitively assess therapeutic approaches, particularly when earlier, smaller studies have shown mixed or promising results.
As cardiovascular researchers continue the decades-long quest to reduce residual risk after MI, the CLEAR OASIS 9 results suggest that targeting inflammation with colchicine or routine use of spironolactone may not provide the breakthrough benefits once hoped for, at least in unselected post-MI populations.
