Jean-Claude Tardif, MD; Michel Zeitouni, MD, MSc DISCLOSURES January 27, 2020

This interview is a translation of a video discussion posted on Medscape France. It has been edited for clarity.

Michel Zeitouni, MD, MSc: Hello. I am Michel Zeitouni, a cardiologist at the Pitié-Salpêtrière Hospital and a researcher with the organization ACTION Cœur (Allies in Cardiovascular Trials, Initiatives and Organized Networks). Today I have the pleasure of welcoming Prof Jean-Claude Tardif to Medscape; we are speaking from the American Heart Association (AHA) 2019 meeting in Philadelphia, Pennsylvania.

Prof Tardif is the research director at the Montreal Heart Institute. He presented a study that made a lot of noise at the AHA, the COLCOT study. COLCOT included more than 4000 patients with myocardial infarction (MI) and found a reduction in cardiovascular events in those who received colchicine compared with the placebo group. Prof Tardif, tell us about the results.

Jean-Claude Tardif, MD: Colchicine is a potent anti-inflammatory drug, and there is an accumulation of data suggesting that inflammation is relevant to the progression of atherosclerosis. The COLCOT study included 4745 patients who were recruited within 30 days of their MI. They all received two antiplatelet agents and a statin, and they underwent angioplasty if necessary. Then they were assigned colchicine at a low dose of 0.5 mg/day or placebo. The average follow-up was 23 months, and we found a 23% reduction in the primary efficacy outcome, which was the combination of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring revascularization.

Zeitouni: The inflammation pathway has been in the spotlight ever since the CANTOS study, which used canakinumab, a drug that we have known well for decades and with which we found some benefits for patients with MI. You also looked at tolerability, since it’s a question we ask about colchicine; ultimately, it was tolerated rather well.

Tardif: Perhaps it’s in part because we used a low dose of 0.5 mg/day, but we saw no difference in the incidence of adverse effects of any cause or severity, and no difference in the occurrence of diarrhea compared with placebo. There was a very slight increase in nausea, with 1.8% in the active group vs 1.0% in the placebo group. There also was a little more pneumonia in the colchicine group (0.9% vs 0.4%).

Zeitouni: You used a rather broad composite endpoint and saw a consistent effect on each component. One thing that struck those who saw your presentation was colchicine’s effect on stroke. How do you explain the reduction in stroke? Do you anticipate a COLCOT STROKE study? 

Tardif: I’m not sure I have all the answers, but we were not the first to see this. There was a meta-analysis of very small, previously published studies that also suggested a benefit for stroke. Now, is this an anti-atherosclerotic effect related to the anti-inflammatory effect of colchicine?  Is it an effect that has something to do specifically with the cerebral arteries?  Could there be unsuspected effects on central blood pressure?  This remains to be seen. It opens up questions that have yet to be answered but deserve to be tested in clinical trials. So, yes, there will be clinical studies on colchicine in stroke.

Zeitouni: Someone mentioned COLCOT-2 in one of the late-breaking trials. Would you tell us about this trial? Colchicine will be used in primary prevention for diabetics.

Tardif: Exactly. Now that COLCOT-1 has been conducted in patients with a recent MI, there is another study called LoDoCo2, in patients with stable coronary disease, that will be presented in 2020. The next frontier will be the high-risk, primary-prevention patients in what we call COLCOT-T2D. This study will involve 10,000 patients with type 2 diabetes who do not have known coronary heart disease. We will assess cardiovascular efficacy, but we will also look at the occurrence of cancer, cognitive disorders, and dementia, because we will be following these patients for 4 years; the COLCOT-1 patients were followed for an average of 23 months. 

Zeitouni: So, colchicine may be the new aspirin in these high-risk patients. You saw a reduction in infarct size in the acute phase or the time of remodeling, and a reduction, perhaps, in rhythm disorders. How do you explain the effectiveness?

Tardif: I believe that it is an anti-atherosclerotic effect via the anti-inflammatory effect. I say this because patients were, on average, 13 days post-MI. And when we look at the time at which the events occur—the effect on the stroke, the effect on urgent hospitalizations for angina—it seems more related to the anti-atherosclerotic effect than to an effect on ventricular remodeling.

Zeitouni: Another study that was presented at AHA was COLCHICINE-PCI. Those investigators studied patients undergoing angioplasty, to learn whether the administration of colchicine reduced the rate of infarction or periprocedural myocardial damage. The outcomes assessed were biomarkers of myocardial injury. They did not find any difference in these markers, but they did find that inflammation decreased in the colchicine arm as measured by interleukin-6 levels. What are your thoughts on this?  Is there a role for colchicine in angioplasty to reduce periprocedural events? 

Tardif: The concept was interesting. I think there were, unfortunately, significant methodologic problems in COLCHICINE-PCI. First, the study included only about 400 patients, so the power was extremely limited. Second, the investigators chose to give only one dose of colchicine before angioplasty and not to repeat it afterwards. It was unlikely that we would see any significant longer-term effects. In contrast, COLCOT had not 400 but 4700 patients, and we treated the patients for 23 months. I am struggling to learn from COLCHICINE-PCI. If we want to repeat the experiment, we should do it with longer treatment duration. The finding of a reduction in periprocedural inflammation is the interesting part for me.

Zeitouni: With all of these results from COLCOT, are we a step further in the fight against the residual risk of our coronary patients. Which postinfarction patients would you treat and for how long? 

Tardif: First, which patients?  If you remember, at the trial presentation people were saying, “Oh, my goodness, are we now going to add another drug on top of the two antiplatelet agents, the statin, and maybe even an ACE inhibitor?” My answer is, really, is this the most intelligent way to practice medicine?

Zeitouni: It should be personalized.

Tardif: Exactly. Instead of saying, “We will give all medicines to everyone,” why not try to tailor them by clinical characteristics? We will obviously do subgroup analyses in COLCOT. It is important to understand that not all the data were analyzed because it became available only a few weeks before the conference. We had put a manuscript together for the New England Journal of Medicine and for the AHA presentation. However, we have work to do in the coming months, analyzing the subgroups as well as others, looking at  biomarkers—is there a particular genetic profile that could show us the patients who would benefit from colchicine?

Personally, I think it’s a bad idea to say that we will give six drugs to everyone. In some patients the disease will be mediated by inflammation, whereas in others it will be mediated by diabetes. So I believe it will be necessary to move toward personalized medicine.

Zeitouni: Precisely, with patients who have inflammation and progressive atherothrombotic disease, and occasionally with some young people, who also relapse despite optimal medical treatment. We have a drug now that is well tolerated, accessible, and with strong evidence.

Tardif: I think we could give it to everyone, but with any medications we give, we should make an effort to understand who in particular benefits.

As to your question about duration of treatment, the average follow-up was 23 months, so perhaps we should treat these patients for 2 years. As I noted, COLCOT-T2D will follow patients for 4 years, but for now I would recommend at least 2 years of treatment.

Zeitouni: Prof Tardif, thank you very much for your explanations and for this study, which will improve the prognosis of our patients. We now know more about inflammation and atherothrombosis, thanks to this type of research.