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Any cardiovascular protection from colchicine in heart attack survivors seemed to be debunked with a better-powered randomized trial, researchers found.

Between acute MI patients randomized to colchicine or placebo right after percutaneous coronary intervention (PCI) in the CLEAR OASIS 9 trial, there were statistically indistinguishable rates of combined cardiovascular death, myocardial infarction (MI), stroke, or ischemia-driven revascularization at 5 years (9.1% vs 9.3%, HR 0.99, 95% CI 0.85-1.16), according to Sanjit Jolly, MD, of Hamilton Health Sciences and McMaster University in Ontario, at the Transcatheter Cardiovascular Therapeutics (TCT) meeting.

The only clinically significant signal his group reported was more diarrhea with colchicine (10.2% vs 6.6%, P<0.001).

"I was a believer in colchicine," Jolly revealed during a TCT press conference. He shared his experience putting his own father (a retired cardiologist) on colchicine and only recently taking him off the drug, given the results of CLEAR OASIS 9. "As a patient you can decide for yourself, would you want to take this therapy? I decided to stop it in my parent."

As this is the largest trial of routine long-term colchicine in acute MI to date -- boasting 649 primary outcome events -- "the role of colchicine post myocardial infarction long term is uncertain," he concluded.

Available generically, colchicine is derived from the autumn crocus plant used medicinally for thousands of years in Egypt.

Last year, the FDA approved brand-name colchicine (Lodoco) as the first anti-inflammatory agent indicated for cardiovascular prevention in adults with established atherosclerotic disease or multiple risk factors. Colchicine currently stands at a class IIb recommendation in American guidelines and IIa in the European ones.

TCT session discussant Roxana Mehran, MD, of Mount Sinai Health System in New York City, said she believed that colchicine's place in the guidelines may be re-evaluated based on the new data. "I would say there's some evidence to downgrade, but that would be up to the guideline group."

"Colchicine may be considered in patients under optimal medical therapy who remain at very high risk for ischemic events. It's not for everyone," Mehran said.

CLEAR OASIS 9 contradicts two major trials on the anti-inflammatory drug. In 2019, the COLCOT group had found that low-dose colchicine worked for secondary prevention after MI, with the most substantial reductions observed for stroke and revascularization in follow-up of nearly 2 years. Colchicine again reduced cardiovascular events, this time in stable ischemic heart disease, in the LoDoCo2 trial from 2020.

Jolly pointed out COLCOT's 301 primary endpoint events and LoDoCo2's 451 -- both lower than the present report.

"We had double the events, so I think it's just regression to the mean," he explained. "As time goes on, with more data, the truth may be there is no effect or a very modest effect [of colchicine]."

"This medicine is not well tolerated ... I would not want to start it in a patient. I never did, and now there's good rationale not to," commented Ajay Kirtane, MD, of New York-Presbyterian/Columbia University Irving Medical Center in New York City, as a panelist during the press conference.

The sentiment was echoed by fellow panelist Wayne Batchelor, MD, MHS, of Inova Health System in Fairfax, Virginia. However, Batchelor warned against "throwing the baby out with the bathwater" as the concept of suppressing inflammation may still prove clinically beneficial with a different drug such as an interleukin 6 inhibitor.

CLEAR OASIS 9 was a 2x2 factorial randomized trial that included 7,000 acute MI patients. Within 72 hours following PCI, participants were randomly assigned colchicine (0.5 mg once daily) versus placebo and spironolactone (25 mg once daily) vs placebo.

The overall cohort had a mean age just over 60 years, with only one in five being women. Reflecting the study having initially been limited to patients with ST-segment elevation myocardial infarction (STEMI) until a protocol amendment to ease enrollment, the study population ended up presenting with 95% STEMI and 5% large non-ST elevation MI. The prevalence of diabetes was around 18%, and prior MI around 9%.

For the index PCI, operators used the Synergy stent when available. The procedure consisted of a median one stent per patient, the stent averaging 23.8 mm long and having a diameter of 3.2 mm. Nearly half of patients had multivessel coronary disease, the vast majority of whom had staged procedures.

Medications at discharge were standard fare including aspirin, statins, and ticagrelor (Brilinta; 45%) as the preferred P2Y12 inhibitor over clopidogrel (Plavix; 42%) or prasugrel (Effient; 11%).

Colchicine's lack of benefit was consistent in on-treatment analysis and in the individual components of the composite primary endpoint:

• Cardiovascular death: 3.3% with colchicine vs 3.2% with placebo
• MI: 2.9% vs 3.1%
• Stroke: 1.4% vs 1.2%
• Ischemia-driven revascularization: 4.6% vs 4.7%

This was irrespective of the patient's MI type and whether they had multivessel disease, Jolly noted.

All-cause mortality was statistically similar between colchicine and placebo groups (4.6% vs 5.1%), while there was a signal of significant reduction in non-cardiovascular death by colchicine (1.3% vs 1.9%) that Jolly downplayed as a statistical anomaly.

In any case, colchicine did reduce inflammation better than placebo (-1.3 mg/L mean difference in CRP between groups at 3 months).

The medication was also not associated with excess serious adverse events (6.7% vs 7.4%).

Mehran pointed out that limitations of CLEAR OASIS 9 include its conduct during the COVID-19 pandemic and deviations from the original study protocol. She also highlighted the underrepresentation of women as a limitation of the trial, though she acknowledged that many women may have been missed due to the cutoff of acute MIs within 72 hours.

Jolly noted that the full CLEAR OASIS 9 manuscript has been accepted at the New England Journal of Medicine and will be published when the spironolactone arm of the 2x2 factorial trial is presented at the American Heart Association meeting later this month.

This is not the first negative trial for colchicine.

Cardiovascular benefits apparently did not extend to colchicine administered at the time of PCI in an older trial, nor did the drug work as a perioperative treatment to reduce atrial fibrillation and myocardial injury after major non-cardiac thoracic surgery. Additionally, the CONVINCE trial had been stopped before investigators could show whether long-term colchicine use had cardiovascular benefits in .

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