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COLCOT: Low-dose colchicine reduces CV risk after MI
PHILADELPHIA — Adults with a recent MI were less likely to experience an ischemic CV event over 2 years when assigned the anti-inflammatory gout medication colchicine compared with assignment to placebo, according to new results of the COLCOT trial presented at the American Heart Association Scientific Sessions.
“In addition to standard of care in patients with a recent MI, colchicine 0.5 mg daily significantly reduces the risk for first ischemic CV events by 23% and total ischemic cardiovascular events by 34%,” Jean-Claude Tardif, MD, director of research at the Montreal Heart Institute, told Healio. “By repurposing well-known medications like colchicine, we can help address the major public health issue of subsequent CV events after an MI in a cost-effective manner, to help patients worldwide overcome the cost barriers of their treatment.”
Efficacy, safety
The COLCOT researchers analyzed data from 4,745 adults recruited within 30 days after MI who were randomly assigned colchicine 0.5 mg once daily (n = 2,366) or placebo (n = 2,379) and followed for a median of 22.6 months. The mean age was 61 years, 19% were women and 20% had diabetes.
The primary endpoint — CV death, resuscitated cardiac arrest, MI, stroke or hospitalization for angina leading to coronary revascularization — occurred in 5.5% of participants in the colchicine arm and 7.1% of participants in the placebo arm, for an HR of 0.77 (95% CI, 0.61-0.96).
The researchers observed risk reduction across the five individual endpoints for patients in the colchicine arm: HR = 0.84 for CV death (95% CI, 0.46-1.52), 0.83 for resuscitated cardiac arrest (95% CI, 0.25-2.73), 0.91 for MI (95% CI, 0.68-1.21), 0.26 for stroke (95% CI, 0.1-0.7) and 0.5 for urgent hospitalization for angina (95% CI, 0.31-0.81).
In a per-protocol analysis, the benefits of colchicine were magnified, Tardif said, with a relative risk reduction of 29% for the primary endpoint (HR = 0.71; 95% CI, 0.56-0.9).
Colchicine was well tolerated and there were no between-group differences for adverse events, Tardif said. Rates of diarrhea (9.7% vs. 8.9%; P = .35) and pneumonia (0.9% vs. 0.4%; P = .03) were higher among patients assigned colchicine.
“The magnitude of colchicine's benefits, 23% and 34% for first and total — including recurrent — primary endpoint CV events, on a background of excellent standard of care, is surprising,” Tardif said in an interview. “The excellent tolerability profile of colchicine is also very reassuring.”
Mean index MI-to-randomization time was 13.4 days, and 93% of participants underwent PCI for the index MI. Aspirin, a different antiplatelet agent and a statin were taken by 98.8%, 97.9% and 99% of participants, respectively.
A ‘ landmark study ’
The COLCOT results provide confirmation that inflammation management reduces CV risk, Aruna Pradhan, MD, associate physician at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, said during a discussion of the findings.
“This will be a landmark study,” Pradhan said during a press conference, adding that it is an example of successful repurposing of a broadly available, relatively safe generic drug for a new application.
Pradhan noted that individual endpoints in the primary composite outcome were numerically lower, but did not rise to statistical significance.
“The major benefit seemed to be in urgent revascularization, which was significantly lower in those with colchicine,” Pradhan said, adding the observed signal for a stroke benefit was weak.
Drug discontinuation rates were similar in both arms at 2 years, with rates of 18.4% and 18.7% with colchicine and placebo, respectively, Pradhan said.
Other considerations
Cardiologists are not typically familiar with the use of colchicine for long-term therapy, Pradhan said. Caution should be advised for the use of colchicine in patients with chronic kidney disease, as the drug is renally cleared, she said. The 0.5 mg dose is not available in the U.S., and the implications for off-label use with the currently available 0.6 mg generic formulations are not known.
The mechanism of CV risk reduction was also not elucidated, although researchers observed large declines in inflammation markers for participants in the colchicine arm.
“We now have a drug that is already available, and the question for the guideline writers that they will have to wrestle with is, is this the sixth drug in our cocktail for post-MI patients?” Donald M. Lloyd-Jones, MD, ScM, associate dean for clinical and translational research, chair of the department of preventive medicine and director of Northwestern University Clinical and Translational Sciences Institute, said during a question-and-answer session during the press conference. “We have now one trial, modestly sized, but with a significant reduction in endpoints. This is going to start a very important conversation in understanding: Should we be using this for everyone? When you have a safe drug that is easily available, it is going to be hard to hold it back.”
Tardif said more research is needed to assess the benefits of colchicine in other high-risk groups. A new trial, COLCOT-TD2, will randomly assign 10,000 individuals with type 2 diabetes but without known coronary disease to receive colchicine 0.5 mg or placebo, Tardif said. – by Regina Schaffer
References:
Tardif JC, et al. Late Breaking Science I. Outside the Box: New Approaches to CVD Risk Reduction. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.
Tardif JC, et al. N Engl J Med. 2019; doi:10.1056/NEJMoa1912388.
Disclosures: Tardif reports he has received grants or personal fees from Amarin, AstraZeneca, DalCor, Esperion, Ionis, Pfizer, Sanofi and Servier, and has a patent for genetic markers predicting responsiveness to therapy with HDL-raising agents. Please see the study for all other authors’ relevant financial disclosures. Lloyd-Jones reports no relevant financial disclosures. Pradhan reports she receives research grants from Denka Seiken and Kowa Research Institute.
Perspective
Back to TopI find this study interesting in many regards; it clearly was a positive study and generally well done in terms of the conduct of the trial. There was a good number of people who discontinued therapy, but they still had follow-up on a significant proportion of patients.
We know the outcome, and it was a positive study in terms of decreasing several key events, but the major events that drove the whole positivity were representation with acute coronary syndrome or angina and decrease in stroke, which are clinically significant. I think that’s important, and it shows that there’s promise in this therapy.
The couple of things that were really striking to me, however, were:
1. The population of people that were studied. All these people had an MI, and almost all of them were stented and were stable, and then followed. But this is a clearly diseased population who had stents placed in vulnerable lesions. That’s important because prior studies of colchicine that were smaller, but also had positive outcomes, showed that the stented population seemed to be less responsive to colchicine than the nonstented population. So, the positive outcome of this may be the tip of the iceberg in terms of the efficacy of colchicine. We really need to see a large study of patients treated with colchicine who were not stented, maybe with stable coronary disease, because that, to me, may be where the real benefit of this drug comes into play.
2. This is taken as proof of concept that atherosclerosis is an inflammatory disease and inflammation drives the outcomes. I don’t think I’d argue with that, but all inflammation is not the same. For instance, methotrexate didn’t have a benefit on coronary outcomes from a large trial — maybe the dose was too low, but it didn’t show. Directly blocking IL-6 with canakinumab (Ilaris, Novartis) did have some benefit — albeit not huge — and colchicine may share that blocking of IL-1-driven inflammation. It contributes to our understanding in a way that certain types of inflammation may be reasonable targets to add to patients with coronary disease.
How does this come to play in routine rheumatology practice? Patients with gout and often with pseudo gout are placed on colchicine. With gout, we tend to limit the chronic use of colchicine because once you get rid of all the deposits, we don’t need it to treat the gouty arthritis. But this says, maybe we should leave them on longer because we do know that the population of patients with gout also have more coronary disease. So that’s a population in which I think it’s not unreasonable to change our practice patterns and say, those patients who have tolerated colchicine when it was given as prophylaxis against gout attacks, if they have multiple risk factors for coronary disease, why not continue therapy at a low dose? I think that’s the practice implication that’s reasonable to consider. I don’t think I would put everyone on colchicine right now.
Surprises from this study were how well this was tolerated. In those who maintained it, there were not a lot of GI issues complicating long-term therapy. And that’s a bit of a surprise because we know that it does that. But there was a significant proportion of folks who had the colchicine discontinued very early on, and that was probably the GI-intolerant group. So maybe it wasn’t so surprising, but a large proportion of people who were able to get past the first couple weeks of therapy seemed to do well on it, which is good. Once you exclude the people who are intolerant of colchicine, it’s no surprise in terms of how well it was tolerated once you get past the first couple of weeks.
Cardiologists prescribing colchicine need to be wary of patients who have some degree of renal insufficiency, which could be based just on age alone. And the one thing cardiologists need to be aware of is neuromuscular toxicity of the drug, particularly in patients who have renal insufficiency. Numbness, tingling and weakness have to be taken exceedingly seriously. There are some drug interactions that they need to be aware of pharmacokinetically, including statins, but in this study virtually all of these patients were on statin therapy. That’s the other thing about this study — patients were treated very aggressively, as they should be, for their coronary disease and yet still there was a small benefit of colchicine but there weren’t issues of any significance with neuromuscular toxicity. I don’t think this in any way requires that somebody see a rheumatologist before they get treated with colchicine; cardiologists are treating people with pericarditis with this now.
Lastly, this is not the first study that’s shown benefit of colchicine as secondary prevention. There was a very nice study — the LoDoCo study — from Nidorf et al, that showed benefit of colchicine primarily in patients who had not had stents placed. In an observational study done even earlier, Pillinger et al, published data suggesting that colchicine was a benefit at reducing coronary events. This is not new, but it’s the largest study to date. But we definitely need to see the studies of patients with coronary disease who have not had stents placed because I think, with maybe some sense of optimism, that it will look even better than what this study showed because this was a modest benefit, but clearly positive.
Perspective
Back to Top
This is an external and independent confirmation that the inflammation hypothesis is real. That is really crucial. When we presented our CANTOS data 2 years ago, it was the first study. Like any field, we need replication, and this clearly provides it. It is going to dictate what is going to happen in atherosclerosis. Down the road, I would like to see cardiologists treating all atherosclerosis patients with some combination of powerful lipid-lowering drugs and powerful anti-inflammatory drugs. It is clear now that we need to do both. One can imagine using colchicine in high-risk patients in whom we are already doing the recommended things. Right now, that is probably the group I would consider using this in because the evidence is positive, and I don’t have an alternative anti-inflammatory drug that is proven. Additionally, there will be at least three more large colchicine trials coming out in the next year or 2. If they are all consistent, this could well become a new therapy for atherosclerosis, so it is very exciting.
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