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Colchicine cut post-MI CVD events

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Landmark colchicine results confirm CANTOS findings

The landmark results from COLCOT confirm that managing inflammation reduces cardiovascular risk, and the results successfully repurpose colchicine, a broadly available and relatively safe branded generic drug for a new application. Colchicine was also generally well tolerated for measured adverse effects, but we do not know whether unmeasured adverse effects may cause discontinuations that would limit long-term adherence. Clinicians should exercise caution using colchicine in patients with chronic kidney disease because of its renal clearance, and the 0.5-mg daily dosage used in COLCOT does not exactly align with the 0.6-mg colchicine formulation that’s available on the U.S. market.

Dr. Aruna D. Pradhan, medical epidemiologist, Brigham and Women's Hospital, Boston. Mitchel L. Zoler/MDedge News

Dr. Aruna D. Pradhan

The COLCOT results are the only statistically significant effect of an anti-inflammatory drug on cardiovascular disease outcomes since the report from CANTOS. The statistically significant result in COLCOT in the composite primary endpoint notably did not show substantial incremental benefit for several of the individual endpoints that made up the composite. Colchicine treatment linked with a significant reduction in angina resulting in urgent hospitalization and revascularization, and in stroke, but this tallied a small number of 24 total events in both treatment arms: 5 strokes in the colchicine group and 19 strokes among patients on placebo. The between-group differences were small for the individual endpoints of cardiovascular death, MI, and nonfatal cardiac arrest.

The adverse effect profile of colchicine showed a concerning, statistically significant increased rate of serious pneumonia infections, which occurred at a 0.9% rate among patients on colchicine and a 0.4% rate among patients on placebo. But the patients on colchicine showed no excess of fatal infections or episodes of septic shock. This increase in the rate of serious pneumonias may be the price paid for using an anti-inflammatory drug in these patients.

A similar, earlier study of methotrexate designed to follow on the CANTOS findings with a less expensive and easier to administer drug failed to show significant benefit. CIRT (Cardiovascular inflammation reduction trial) enrolled 4,786 patients with either a prior MI or multivessel coronary disease plus diabetes or metabolic syndrome, and the CIRT results highlight that not all anti-inflammatory drugs work the same way or have similar effects on cardiovascular disease. The COLCOT findings need replication, and three large studies now in progress are also assessing colchicine in patients with cardiovascular disease. Cardiologists will need to learn how to use colchicine, but the COLCOT results are promising and show an overall low level of adverse effects.

The COLCOT findings followed a prior report from a study without a placebo control that showed a rather dramatic, 67% reduction in cardiovascular events with colchicine treatment in 532 patients with stable coronary disease (J Amer Coll Cardiol. 2013 Jan 29;61[4]:404-10).

Aruna D. Pradhan, MD , is a medical epidemiologist at Brigham and Women’s Hospital in Boston. She has received research funding from Kowa. She made these comments as designated discussant for the COLCOT report.



– The proof of concept shown by the CANTOS study in 2017 that an anti-inflammatory drug could cut the incidence of cardiovascular events has now been replicated in a study with more than 4,700 post-MI patients who received the much more affordable oral anti-inflammatory drug colchicine.

Dr. Jean-Claude Tardif, professor of medicine, University of Montreal Mitchel L. Zoler/MDedge News

Dr. Jean-Claude Tardif

Daily treatment with a single, 0.5-mg/day colchicine tablet cut cardiovascular disease events by a statistically significant 23%, compared with placebo patients during nearly 20 months on treatment when colchicine was added on top of a regimen that included aspirin, a second antiplatelet drug, a statin, and in many patients a beta-blocking drug, Jean-Claude Tardif, MD, said at the American Heart Association scientific sessions.

Adding colchicine to the treatment of patients within 30 days of having a MI led to an absolute reduction in the study’s primary endpoint of 1.6% during a median 19.6 months on treatment. In a secondary analysis that looked at total cardiovascular events and not just first events, adding colchicine to background therapy was associated with a relative 34% decline, said Dr. Tardif, professor of medicine at the University of Montreal and director of the Research Centre at the Montreal Heart Institute. In addition to his report at the meeting, the results also appeared concurrently in an article published online (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388).

The dramatic efficacy and overall safety shown by colchicine in COLCOT (Colchicine Cardiovascular Outcomes Trial) appeared to replicate the benefit seen with the relatively expensive monoclonal antibody canakinumab (Ilaris) in CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study), where a canakinumab injection every 3 months led to a 15% reduction in the incidence of cardiovascular events, compared with placebo, during a median 3.7 years of follow-up in a study with just over 10,000 post-MI patients (N Engl J Med. 2017 Sep 21;377[12]:1119-31).

“One of the limitations of CANTOS was that canakinumab is a very expensive, injectable drug. We followed in the footsteps of CANTOS with a less expensive, oral drug,” Dr. Tardif explained during a press briefing. “Colchicine is a known, potent anti-inflammatory drug,” and as of November 2019, the average U.S. cost of a 30-day supply of 0.6-mg capsules was $147. The colchicine formulation used in COLCOT delivered a 0.5-mg daily dose to patients, a formulation that’s not currently on the U.S. market.

Dr. Donald M. Lloyd-Jones, professor and chairman of preventive medicine, Northwestern University, Chicago Mitchel L. Zoler/MDedge News

Dr. Donald M. Lloyd-Jones

“Having a safe drug that’s easily available; it will be hard to hold this one back,” commented Donald M. Lloyd-Jones, MD, professor and chairman of preventive medicine at Northwestern University in Chicago. “What the guidelines will need to wrestle with is there are five drugs” already recommended to use after an MI; “is colchicine number six?” The existing guideline-directed drugs for post-MI patients include aspirin, a second antiplatelet agent, a statin, a beta-blocker, and an angiotensin-converting enzyme inhibitor, Dr. Lloyd-Jones noted. The incremental benefit from adding colchicine to background regimen was “modest, but statistically significant,” he said, and “importantly, this was not an industry-sponsored trial.” Dr. Lloyd-Jones said that he has recently heard from a patient of his in the Chicago area who takes colchicine for gout that the monthly cost for the drug has risen to as high as $270. By comparison, the price in Montreal is less than $9/month, Dr. Tardif said.

COLCOT enrolled 4,745 patients at a median of about 13.5 days following an acute MI at 167 centers in 12 countries. The study’s primary endpoint was the combination of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization in a time-to-event analysis. The combined endpoint occurred in 5.5% of the patients on colchicine and 7.1% of those on placebo during a median of nearly 20 months on treatment. The adverse effects data showed generally similarly rates among patients on colchicine and in the control group, including their rates of gastrointestinal effects. The one exception was the rate of serious pneumonias, which were more than double in the colchicine recipients, a statistically significant difference.

COLCOT received no commercial support. Dr. Tardif has received honoraria from Amarin, DalCor, Sanofi, and Servier; he has an ownership interest in DalCor; and he has received research funding from Amarin, AstraZeneca, DalCor, Esperion, Ionis, RegenxBio, Sanofi, and Servier. Dr. Lloyd-Jones had no disclosures.

SOURCE: Tardif J-C et al. AHA 2019, Abstract.

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