Speaker
Sanjit S. Jolly, MD, MSc, FRCPC
Interventional Cardiologist, Hamilton Health Sciences
Stuart Connolly Chair in Cardiology
Professor of Medicine, McMaster University
Keywords
Myocardial Infarction; Cardiology; Heart Failure; Colchicine; Spironolactone
Key Points
- 20 years ago, an article published in Nature hypothesized that if we could find a cardioprotective drug to lower cardio-reactive protein (CRP), we could eliminate heart disease.
- Over the last 2 decades, there have been successes and failures on that front. The Cardiovascular Inflammation Reduction Trial (CIRT) found that methotrexate did not reduce the rate of major adverse cardiovascular events. The Canakinimab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) found that higher doses of canakinumab reduced cardiovascular (CV) death, myocardial infarction (MI), or stroke by over 15% during follow-up.
- 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 was a large, simple, randomized trial of 7,000 patients with ST-elevation myocardial infarction or large non-ST-elevation myocardial infarction. Participants were randomized in a 2×2 factorial; first to either colchicine or placebo, then to either spironolactone or placebo.
- The primary outcome in the first factorial was the effect was treatment with colchicine vs placebo on a composite of CV death, MI, stroke, or IDR. The co-primary outcomes in the subsequent factorial were the effects of spironolactone vs a placebo on 1) a composite of CV death or heart failure (HF) and 2) a composite of CV death, HF, stroke, or MI.
- There have been 2 large trials looking at colchicine in cardiovascular disease: COLCOT and LODOC02. The CLEAR trial started before the results of the COLCOT trial, as the research team believed a larger confirmatory trial with more power was needed and replication of power results were important for Class 1 indications in guidelines. CLEAR is the largest trial of colchicine in acute MI, with substantially more events than prior trials.
- In the first factorial, they found that while CRP was reduced with colchicine, acute and long-term colchicine did not reduce the composite of CV death, MI, stroke, or ischemia-driven revascularization. Colchicine was also associated with an increase in diarrhea, a known side effect of the drug. The research team believes the role of colchicine post-MI remains uncertain.
- There have been 2 trials looking at Mineralocorticoid Receptor Antagonists (MRA) post-MI in patients without HF: REMINDER and ALBATROSS. Their results left some questions unanswered.
- In the second factorial, they found that routine spironolactone post-MI did not reduce either co-primary outcome. There was a reduction in new or worsening heart failure, and on-treatment analysis suggests a potential benefit.
Discussion Themes
Outcomes have improved remarkably over the last 20 years, such that HF event rates in a population with predominantly ST-elevation MI are around 3%; a significant drop from the roughly 20% HF event rate in that population 20 years ago. That makes it more difficult to show treatment effects in this population.
The study team developed their inclusion criteria to select for a study population that would be applicable in standard clinical practice. The trial became more pragmatic as the study went on as a result of pivots they made in response to the COVID-19 pandemic.
Key challenges were driven by the COVID-19 pandemic. These included shipping expenses, which spiked significantly; shifting logistics, regarding who would receive the materials; and a pause in recruitment. The study team also came up against varying drug approvals in different locations; this was a global trial, taking place over roughly 70 sites in 11 countries.