Colchicine Scores for Secondary Prevention After MI

PHILADELPHIA -- A low oral dose of gout medication colchicine reduced ischemic events in heart attack survivors, the COLCOT trial showed, further affirming the inflammatory hypothesis.

The potent anti-inflammatory drug reduced the primary composite endpoint of cardiovascular (CV) death, resuscitated cardiac arrest, myocardial infarction (MI), stroke, or urgent hospitalization for angina leading to coronary revascularization by 27% relative to placebo (rate 5.5% vs 7.1%, P=0.02).

The effect was especially driven by stroke and revascularization but trended in the same direction for the other components, reported Jean-Claude Tardif, MD, of the Montreal Heart Institute, at the American Heart Association (AHA) meeting.

"The benefits of colchicine with regard to cardiovascular end points in COLCOT were at least as large as those of canakinumab in CANTOS," the researchers noted in a paper simultaneously published online in the New England Journal of Medicine.

Trial Details

COLCOT has been eagerly anticipated as a follow-on to the CANTOS trial with canakinumab (Ilaris), which cut nonfatal MI or stroke and CV death by 15%, although in a different setting -- as noted by Tardif's group -- "early after myocardial infarction in COLCOT and stable coronary disease in CANTOS."

But that pricey injectable monoclonal antibody was turned down by the FDA for a CV prevention indication, and a cheaper potential anti-inflammatory alternative, methotrexate, subsequently failed for prevention in the CIRT trial.

CIRT tempered enthusiasm for the inflammatory hypothesis, that targeting an inflammatory pathway can reduce heart attacks and stroke independent of lipids, noted Robert Harrington, MD, of Stanford University in California and AHA president.

That the biggest driver was stroke -- not MI -- was unexpected, he said. In CANTOS and most other trials in the post-MI setting, "the predominant effect of a therapy that works has been on reducing recurrent myocardial infarction," he said, "and that's not what we see here."

In the COLCOT trial, the hazard ratios for colchicine compared with placebo were:

• 0.26 (95% CI, 0.10 to 0.70) for stroke
• 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to revascularization
• 0.91 (95% CI, 0.68 to 1.21) for MI
• 0.84 (95% CI, 0.46 to 1.52) for death from CV causes
• 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest

'Sixth Drug?'

"When you have a safe drug that's easily available, it's going to be hard to hold this one down," suggested AHA press conference chair Donald Lloyd-Jones, MD, of Northwestern University in Chicago. While it's only one trial, guidelines committees will have to wrestle with the question of "is this the sixth drug in our cocktail for our MI patients?" he said.

However, "I don't think it has a strength of evidence that would compel me to go out and say I have to start using colchicine in my patients," Harrington said. However, it's worth more study in a larger trial, perhaps by the National Heart, Lung, and Blood Institute or Patient-Centered Outcomes Research Institute, given that it's a generic medication, he noted.

Stroke is an important endpoint to patients, so "it's very promising that we can show a reduction," commented Laxmi Mehta, MD, director of preventive cardiology at The Ohio State University in Columbus, who was not involved in the trial.

Questions that now need to be answered are the mechanism behind that sizable stroke benefit, and how much of the reduction in revascularization might have been accounted for by the 7% of patients who didn't have percutaneous coronary intervention for their index MI, she told MedPage Today.

Also, the 4,745 patients in COLCOT were randomized to colchicine (0.5 mg once daily) or placebo a mean of 13.5 days after their acute MI.

"Inflammation is highest right around the time of the myocardial infarction," Mehta noted. "In future studies, does it warrant [looking at] not only the dose of colchicine, but the timing of colchicine? Is 13 days good enough or should we be doing it sooner?"

However, the researchers noted that this timing made clear that the effects seen with colchicine were not due to the drug's known benefits for pericarditis.

"Postinfarction pericarditis typically occurs within the first few days after the injury," they wrote. "There were only two patients with a first positively adjudicated event of urgent hospitalization for angina leading to coronary revascularization within 14 days after randomization, and the median time to this clinical end point was 258 days."

Both arms in a subgroup with C-reactive protein measurements showed large decreases in the inflammatory marker, without a difference between them.

But there was a limited sample size to discern differences, noted AHA discussant Aruna Pradhan, MD, Brigham and Women's and Hospital Harvard Medical School in Boston.

There was an increased risk of pneumonia reported as a serious adverse event (AE) with colchicine based on 21 versus 9 events (0.9% vs 0.4%, P=0.03). Overall AEs and serious events as well as GI events were similar between groups.

Patients were followed for a median of 22.6 months. Inclusion criteria included MI within 30 days of enrollment and treatment according to national guidelines with intensive use of statins. Exclusion criteria included severe heart failure, a left ventricular ejection fraction of <35%, stroke within the prior 3 months, type 2 MI as the index event, and coronary bypass surgery either within the prior 3 years or planned.

Three other large-scale trials with colchicine -- LoDoCo2 in stable coronary disease, CLEAR-Synergy in ST-segment elevation MI with primary PCI, and CONVINCE in stroke survivors -- are underway and will show whether the benefits can be replicated, Pradhan noted.

Cost Concerns

"One caveat: I saw a patient in clinic on Thursday, who has long-standing, now-stable coronary heart disease as well as gout, as many of our patients do with coronary heart disease. He told me that just in the last month his colchicine out-of-pocket costs went from $50 a month to $27o a month in Chicago," Lloyd-Jones said. "That is very concerning to me. I really wonder whether there is some gaming going on here. I do not want to see that with this drug."

Tardif countered that in Montreal, the drug costs just $0.27 a day (around $8 for a 30-day supply). "There's something wrong with a system where 90 minutes [by air] away you get a drug for 50 times less than others are paying."

"Amen," responded Lloyd-Jones, adding, "It's unacceptable, especially for very low-cost, inexpensively produced drugs to be seeing price increases like this. There's no reason for it other than the profit."

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