Generic anti-inflammatory drug lowers ischemic events in patients with recent MI
The COLchicine Cardiovascular Outcomes Trial (COLCOT)
Presented during the AHA Scientific Sessions 2019 by Jean-Claude Tardif (Montreal Heart Inst, Montreal, QC, Canada).
Introduction and methods
Ample evidence, from both experimental and clinical studies, supports the role of inflammation in atherosclerosis and its complications. Therefore, the search for a widely used anti-inflammatory treatment that may reduce the risk of atherosclerotic events in patients with coronary artery disease continues.
Colchicine is an orally administered, potent anti-inflammatory medication currently indicated for gout and pericarditis. COLCOT evaluates the efficacy of colchicine in patients with a recent myocardial infarction (MI) on CV outcomes and its long-term safety and tolerability. 4745 Patients with an MI less than 30 days prior to inclusion, who were treated according to guidelines with PCI completed if planned, were randomized to colchicine 0.5 mg daily or placebo. The primary endpoint was a composite of time to first of CV death, cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization. Randomization was within 14 days after the index MI in both treatment groups (13.4 and 13.5 days for colchicine and placebo, respectively). Baseline characteristics were well balanced between groups, as did existing treatments.
- The primary composite efficacy endpoint occurred less frequent in the colchicine group (ITT analysis: HR: 0.77, 95%CI: 0.61-0.96, P=0.02).
- Looking at individual components of the primary endpoint showed that stroke (HR: 0.26, 95%CI: 0.10-0.70, with n=5 [0.2%] and n=19 [0.8%] in treatment groups, respectively) and urgent hospitalization for angina requiring revascularization (HR: 0.50, 95%CI: 0.31-0.81) were significantly reduced with colchicine treatment.
- CV death (HR: 0.84, 95%CI: 0.46-1.52), resuscitated cardiac arrest (HR: 0.83, 95%CI: 0.25-2.73) and MI (HR: 0.91, 95%CI: 0.68-1.21) were not significantly altered by colchicine vs. placebo treatment.
- The secondary composite endpoint of CV death, cardiac arrest, MI or stroke was not significantly altered by colchicine treatment (HR: 0.85, 95%CI: 0.66-1.10).
- The per-protocol analysis showed a reduction of the primary efficacy endpoint of 29% (HR: 0.71, 95%CI: 0.56-0.90, P=0.004). A pattern of significance similar to that in the ITT analysis was seen for the individual components.
- A total events analysis in a negative binomial model showed that first and recurrent events were reduced by 34% (HR: 0.66, 95%CI: 0.51-0.86).
- Regarding adverse events, nausea (1.8% vs. 1.0%), flatulence (0.6% vs. 0.2%) and pneumonia (0.9% vs. 0.4%) occurred significantly more often with colchicine vs. placebo.
These data showed that colchicine 0.5 mg/day significantly lowered the risk of first and total ischemic CV events by 23% and 34% respectively, compared to placebo, in patients with a recent MI. Rates of adverse events were low. These effects were seen on background therapy with aspirin, a second antiplatelet agent and a statin in almost all patients. The effect of colchicine will be further assessed in patients with T2DM without known coronary disease, in the COLCOT-T2D.
A limitation of the study is its relative short duration, of approximately 23 months. Risks and benefits of longer-term treatment with colchicine were therefore not evaluated.
Aruna D Pradhan (Brigham and Women’s Hospital Harvard Medical School, Boston, MA, USA), as a discussant, called the COLCOT study a large simple and well-designed event-driven trial. She considers this landmark results that provide confirmation that inflammation management lowers CV risk. It also represents successful repurposing of a broadly available and relatively safe generic drug for a new application.
She did point out that cardiologists like herself would like to see reductions in MI and CV death. The components now only showed numerical reductions. The largest benefit was seen in urgent revascularization. Stroke was reduced, but these numbers were very low.
Use of colchicine was generally well-tolerated for the measured adverse events and drug discontinuation rates were similar in the placebo and active treatment arms (18% at 2 years). She did note that complete ascertainment of adverse events was not performed. It is therefore unknown if unmeasured adverse effects that could have led to study drug discontinuation will limit long-term adherence.
Pradhan pointed out other relevant considerations with regard to use of colchicine, such as the fact that it is renally cleared. Caution is therefore advised during chronic use. Will sufficient data be available on safety in these patients from COLCOT and future trials? She also noted that the mechanism of CV risk reduction was not elucidated in this trial, as large declines in measured inflammation markers were seen in both groups and the sample size was too limited to discern differences. Several ongoing trials will further evaluate the inflammation hypothesis (COLCOT, Colchicine-PCI, LoDoCo2, CLEAR-Synergy and CONVINCE), and hopefully replicate the current findings.
In the discussion, the question was brought up where these data bring us today, in light of the CANTOS trial with canakinumab that was seen as a proof-of-concept trial, and the CERT trial with methotrexate that failed to show clinical benefit. Methotrexate did not show an effect on inflammatory biomarkers. Colchicine is known to have a benefit on inflammatory signs. Donal Lloyd-Jones, the moderator of the press conference, noted that an interesting conversation is now coming up, namely whether we should give it to all, or are there subgroups that benefit more. He said, when there is a safe drug that is readily available, it is hard to hold back. Pradhan added that cardiologists need to learn how and when to use it. Results need confirmation in other trials, but the pathways make sense.
- Our reporting is based on the information provided during AHA Scientific Sessions 2019 -