Cardiologist explores why colchicine failed to help heart attack patients

He said replicating results in studies is needed to confirm scientific findings, and in this trial he was unable to replicate the findings of the previous COLCOT and LODOCO2 trials for colchicine.

"I think one of the most important messages here is that replication is really important. The most similar trial to this is the COLCOT trial. But this trial actually had more than twice the number of events, so significantly more power. So the fact that we weren't were able to replicate it makes me uncertain on what the role of colchicine therapy is in this population," Jolly explained.

Study design and methodology

The CLEAR SYNERGY trial was the largest trial to date on colchicine in the context of acute myocardial infarction. Launched in 2018, the trial enrolled about 7,000 patients who were randomized within 72 hours of experiencing an myocardial infarction to receive either colchicine or a placebo. The study's primary focus was to determine if routine colchicine administration would reduce a composite of cardiovascular death, MI, stroke or ischemia-driven revascularization.

One of the main measures was C-reactive protein (CRP), a marker of inflammation known to be elevated during heart attacks. Results showed that while colchicine effectively reduced CRP levels after three months, this reduction did not translate into better cardiovascular outcomes.

Colchicine’s biological activity was confirmed by an observed increase in the common side effect of diarrhea. Despite this activity, the rates of cardiovascular events were nearly identical across both groups, with a hazard ratio of 0.99, indicating no benefit of colchicine therapy.

Colchicine previously hailed as a major drug 

Colchicine, traditionally used to treat caused by gout, has been the focus of cardiovascular research due to its anti-inflammatory properties. It was thought to potentially reduce coronary artery inflammation following heart attacks to help lower the risk of recurrent events. Coronary inflammation has been implicated as one of the primary causes of plaques rupturing and causing heart attacks, but until colchicine gained FDA clearance in June 2023, there were no drugs indicated to treat cardiovascular inflammation.

"There has been encouraging evidence suggesting colchicine could play a role in heart disease prevention," Jolly explained, noting the recent surge in interest in colchicine after FDA approval for cardiovascular use. He said CLEAR SYNERGY aimed to conduct a comprehensive analysis to assess colchicine's true effect on cardiovascular outcomes.

Addressing potential confounding factors in the trial

Given the unexpected findings, the research team examined various factors that could have affected the results. They conducted an on-treatment analysis, which only included patients who consistently took the drug, but still observed no difference in outcomes. Additionally, they considered the potential impact of the COVID-19 pandemic on reporting and event rates, yet saw no significant variation across different periods.

"The data remained consistent, even when adjusted for pandemic-related factors, which confirmed the robustness of our results," Jolly noted.

Implications for clinical practice and future research

The CLEAR SYNERGY findings may be surprising to those who were optimistic about colchicine's potential based on earlier studies. Jolly said inflammation is still an important area of research in cardiovascular disease, even if colchicine is not the answer. He pointed to other anti-inflammatory agents, such as canakinumab and IL-6 inhibitors, as possible avenues to explore.

Jolly suggested that future research could focus on understanding whether specific patient subgroups might benefit from colchicine, particularly those with high initial CRP levels. Another possibility could involve larger trials with 10,000 or more patients, though he acknowledged the logistical challenges involved.

The CLEAR SYNERGY (OASIS 9) trial actually tested two drugs in two factorials. The first colchicine factorial was presented at TCT, and the second one comparing the hypertension/heart failure drug spironolactone vs. placebo will be presented as a late-breaking trial at the American Heart Association Scientific Sessions 2024 meeting in Chicago.

Click here to read more details from TCT and hear reactions from other cardiologists.