COLCOT: Colchicine Shows Promise to Reduce Events After MI

PHILADELPHIA — Addition of the anti-inflammatory agent colchicine to standard of care within 30 days of a myocardial infarction (MI) significantly reduced a composite endpoint of cardiovascular events compared with placebo in a large, randomized study.

In the evaluation of 4745 people who experienced a recent MI, low-dose colchicine, 0.5 mg daily, significantly decreased the risk for first ischemic cardiovascular events by 23% compared with placebo. Researchers also report that colchicine reduced combined first and recurrent ischemic cardiovascular events by 34%.

"By repurposing well-known medications like colchicine, we can help address the major public health issue of subsequent cardiovascular events after an MI in a cost-effective manner, to help patients worldwide overcome the cost barriers of their treatment," lead study author Jean-Claude Tardif, MD, from the Montreal Heart Institute in Montreal, Quebec, Canada, told theheart.org | Medscape Cardiology.

The COLchicine Cardiovascular Outcomes Trial (COLCOT) study was reported at the American Heart Association (AHA) Scientific Sessions 2019 and simultaneously published online November 16 in the New England Journal of Medicine.

Anti-Inflammatory Effect Could Be Key

Tardif and his colleagues evaluated colchicine because "there is ample evidence that supports the role of inflammation in atherosclerosis initiation, progression and complications…that leads to acute coronary syndromes," he said here during a news briefing on late-breaking research.

Colchicine has been available for decades and is generally used short term to treat gout and pericarditis.

A previous trial, CANTOS, showed the anti-inflammatory drug canakinumab was linked to a relative risk reduction of 15%. However, the agent was a "very expensive" injectable that was not ultimately developed for heart disease, Tardif said.

Because colchicine is more available and less expensive, it is "probably more readily translatable to the clinic," he added.

Other relevant prior research included the CIRT study, which failed to show a similar benefit with methotrexate. Specifically, in that trial, methotrexate did not reduce inflammatory biomarkers.

"So, it appears that when you reduced inflammation in CANTOS, there was benefit. When you did not, there was no benefit," Tardif said.

High Standard of Care

In COLCOT, Tardif and colleagues randomly assigned 2366 patients to 0.5 mg colchicine daily and another 2379 to placebo. The mean time between MI and randomization was 13 days.

Mean age of participants was 60 years, 20% were women, and approximately half had hypertension. Standard of care included high rates of angioplasty (93%). In addition, 99% of patients were receiving aspirin therapy, 98% were taking a secondary antiplatelet agent, and 99% were taking a statin.

"We conducted COLCOT in patients with recent myocardial infarction because there is intense inflammation at that point in time," Tardif said.

The primary endpoint was a composite of first event of cardiovascular death, resuscitated cardiac arrest, acute MI, stroke, or urgent hospitalization for angina necessitating coronary revascularization.

Significant Primary Findings

In the colchicine group, 5.5% experienced the primary endpoint vs 7.1% of the placebo group, a 23% reduction (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 - 0.96). This reduction was statistically significant compared with placebo (P = 0.02).

Tardif and colleagues also looked at the individual contribution of each of the five outcomes as secondary endpoints. The overall findings were driven by a lower incidence of stroke and urgent hospitalizations for angina leading to coronary revascularization, the researchers note.

Table. Individual Endpoint Findings

Endpoint	Hazard Ratio (95% CI)
Cardiovascular death	0.84 (0.46-1.52)
Resuscitated cardiac arrest	0.83 (0.25-2.73)
Myocardial infarction	0.91 (0.68-1.21)
Stroke	0.26 (0.10-0.70)
Urgent hospitalization for angina leading to revascularization	0.50 (0.31-0.81)

"Certainly, for the primary composite endpoint, there was a 23% reduction and the trial concluded at the accumulation 301 events, as planned," invited commentator Aruna D. Pradham, MD, MPH, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, said at the news briefing.

"However, for the secondary endpoints, there was no significant benefit," she added. "Although numerically there was a significant difference in events for the primary composite, for the individual events they were numerically lower but not statistically significant. And certainly, as cardiologists, we want to see reductions in myocardial infarction, cardiovascular disease death, and all-cause mortality — those things that are more robust."

The point estimates for the benefit was "in the right direction in all five components," Tardif said. "That tells me that colchicine is having an effect…and more research is coming."

COLCOT also evaluated the total burden of first and recurrent cardiac ischemic events. The rate ratio for total events was 0.66, or a 34% relative risk reduction for all first and recurrent primary events compared with placebo.

"I was particularly excited when we saw the 34% overall reduction in burden," Tardif said.

"Although the risk of the primary composite end point…was lower in the colchicine group than in the placebo group, this result was driven predominantly by lower risks of angina and stroke," L. Kristen Newby, MD, MHS, from the Division of Cardiology and Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, writes in an accompanying editorial.

"A significant effect on death from cardiovascular causes or myocardial infarction was not shown."

Too Soon for Stroke Prevention?

While the reduction in strokes and urgent hospitalizations drove most of the benefit seen in the primary composite outcome, it may be premature to suggest colchicine be used for prevention of ischemic stroke.

"There was a benefit in stroke, but the numbers were small and [there was] a weak benefit there," Pradham said.

"We have to look at primary composite endpoint, and after that we have to look for consistency among the other endpoints," commented Donald Lloyd-Jones, MD, chair of the American Heart Association Committee on Scientific Sessions Programming. "I would be very careful to suggest that this study should be used for stroke prevention because it was a very small number of events."

"We need to keep this at the top line of the primary outcomes and not weigh any particular [individual endpoint] too heavily. We do that at our peril," Lloyd-Jones added.

Colchicine was well tolerated, Tardif said. Nausea occurred more often in the colchicine group than the placebo group: 1.8% vs 1.0%. In addition, the pneumonia rate was 0.9% in the colchicine group vs 0.4% in the placebo participants.

Cost a Consideration?

Some patients report issues with the cost, Lloyd-Jones said. "I saw a patient on Thursday that has both stable coronary heart disease and gout. He told me his out-of-pocket cost recently went from $50 to $270 a month in Chicago. The reason behind the jump in price was unclear and could be a function of the patient's insurance plan, he added.

"That is very concerning to me. I wonder if there is some gaming going on here. I don't want to see that with this drug," Lloyd-Jones said. "Importantly, this was not an industry-sponsored trial."

"Montreal is a 90-minute flight from here," Tardif agreed. "I had a patient with gout 2 days ago also who told me colchicine costs 27 cents a day."

Colchicine is a branded drug and not a traditional generic, which could affect the cost.

The Big Picture

Putting the findings into the context of combination treatment after an MI, Lloyd-Jones wondered whether colchicine might be someday join the "standard five drug cocktail" after a myocardial infarction of aspirin, dual antiplatelet therapy, a statin, an angiotensin-converting enzyme inhibitor, and a β-blocker.

"When you have a safe drug that is easily available, it's going to be hard to hold this one back, I would have to think," said Lloyd-Jones, who is also director of Northwestern University Clinical and Translational Sciences Institute, and the Eileen M. Foell Professor of Preventive Medicine (Epidemiology), Medicine (Cardiology) and Pediatrics at the Feinberg School of Medicine at Northwestern University in Chicago, Illinois.

"It's an important result and important study," Ivar J. Benjamin, MD, past president of the AHA and director of the Cardiovascular Center at the Medical College of Wisconsin in Milwaukee, told theheart.org | Medscape Cardiology when asked to comment.

Benjamin added that any potential long-term effects of the agent will need to be determined if it is used for secondary prevention.

Furthermore, he said, he has also encountered patients who start colchicine in the hospital, but after discharge "all of a sudden they have significant costs associated with a branded generic."

"It's in those instances that the next thing they do, is they come back to the hospital because they have a recurrence of their pericarditis."

"This will be a landmark study," Pradham said. "COLCOT was a large, simple and well-designed, event-driven trial. These results provide confirmation that Inflammation management reduces cardiovascular risk."

"Obviously the COLCOT results apply to patients who have recently suffered a myocardial infarction," Tardif said. "Further research is needed in our opinion to assess the benefits of colchicine in other high-risk patients."

With that in mind, Tardif announced that a COLCOT-T2D trial will be launched to study 10,000 people with diabetes without known coronary disease.

The Government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations supported the study. Tardif received a grant from the Government of Quebec related to the study. Pradham, Benjamin, and Newby had no relevant disclosures.

American Heart Association (AHA) Scientific Sessions 2019. Presented November 16, 2019.

N Engl J Med. Published online November 16, 2019. Article, Editorial

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