The parent trial was conducted in patients with a recent MI because of the intense inflammation present at that time, and added colchicine 0.5 mg daily to standard care within 30 days following MI.
As previously reported, colchicine significantly reduced the risk of the primary end point — a composite of cardiovascular (CV) death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring revascularization — by 23% compared with placebo.
This new analysis shows the risk was reduced by 48% in patients receiving colchicine within 3 days of an MI (4.3% vs 8.3%; adjusted hazard ratio [HR], 0.52; 95% CI, 0.32 – 0.84, P = .007).
Risk of a secondary efficacy end point — CV death, resuscitated cardiac arrest, MI, or stroke — was reduced by 45% over an average follow up of 22.7 months (3.3% vs 6.1%; adjusted HR, 0.55; 95% CI, 0.32 – 0.95, P = .031).
“We believe that our results support an early, in-hospital initiation of adjunctive colchicine for post-MI prevention,” Nadia Bouabdallaoui, MD, Montreal Heart Institute, Quebec, Canada, said during an online session devoted to colchicine at the European Society of Cardiology (ESC) Congress 2020.
Session moderator Massimo Imazio, MD, professor of cardiology at the University of Turin, Italy, said the improved outcomes suggest that earlier treatment is better — a finding that parallels his own experience using colchicine in patients with pericarditis.
“This substudy is very important because this is probably also the year in cardiovascular applications [that] early use of the drug could improve outcomes,” he said.
Positive data have been accumulating for colchicine from COLCOT, LoDoCo, and, most recently, the LoDoCo2 trial, even as another anti-inflammatory drug, methotrexate, flamed out as secondary prevention in the CIRT trial.
The new COLCOT substudy included 4661 of the 4745 original patients and examined treatment initiation using three strata: within 0-3 days (n = 1193), 4-7 days (n = 720), and 8-30 days (n = 2748). Patients who received treatment within 3 days were slightly younger, more likely to be smokers, and to have a shorter time from MI to randomization (2.1 days vs 5.1 days vs 20.8 days, respectively).
In the subset receiving treatment within 3 days, those assigned to colchicine had the same number of cardiac deaths as those given placebo (2 vs 2) but fewer resuscitated cardiac arrests (1 vs 3), MIs (17 vs 29), strokes (1 vs 5), and urgent hospitalizations for angina requiring revascularization (6 vs 17).
“A larger trial might have allowed for a better assessment of individual endpoints and subgroups,” observed Bouabdallaoui.
Although there is growing support for colchicine, experts caution that the drug many not be for everyone. In COLCOT, 1 in 10 patients were unable to tolerate the drug, largely because of gastrointestinal (GI) issues.
A second COLCOT substudy aimed to identify genetic markers predictive of colchicine response and to gain insights into the mechanisms behind this response. It included 767 patients treated with colchicine and another 755 treated with placebo — or about one-third the patients in the original trial.
A genome-wide association study did not find a significant association for the primary CV endpoint, although a prespecified subgroup analysis in men identified an interesting region on chromosome 9 (variant: rs10811106), which just missed reaching genome-wide significance, said Marie-Pierre Dubé, PhD, director of the Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre at the Montreal Heart Institute.
In addition, the genome-wide analysis found two significant regions for GI events: one on chromosome 6 (variant: rs6916345) and one on chromosome 10 (variant: rs74795203).
For each of the identified regions, the researchers then tested the effect of the allele in the placebo group and the interaction between the genetic variant and treatment with colchicine. For the chromosome 9 region in males, there was no effect in the placebo group and a significant interaction in the colchicine group.
For the significant GI event findings, there was a small effect for the chromosome 6 region in the placebo group and a very significant interaction with colchicine, Dubé said. Similarly, there was no effect for the chromosome 10 region in the placebo group and a significant interaction with colchicine.
Additional analyses in stratified patient populations showed that males with the protective allele (CC) for the chromosome 9 region represented 83% of the population. The primary CV endpoint occurred in 3.2% of these men treated with colchicine and 6.3% treated with placebo (HR, 0.46; 95% CI, 0.24 – 0.86).
For the gastrointestinal events, 25% of patients carried the risk allele (AA) for the chromosome 6 region and 36.9% of these had GI events when treated with colchicine vs 18.6% when treated with placebo (HR, 2.42; 95% CI, 1.57 – 3.72).
Similarly, 13% of individuals carried one or two copies of the risk allele (AG+GG) for the chromosome 10 region and the risk of GI events in these was nearly four times higher with colchicine (47.1% vs 18.9%; HR, 3.98; 95% CI 2.24 – 7.07).
Functional genomic analyses of the identified regions were also performed and showed that the chromosome 9 locus overlaps with the SAXO1 gene, a stabilizer of axonemal microtubules 1.
“The leading variant at this locus (rs10811106 C allele) correlated with the expression of the HAUS6 gene, which is involved in microtubule generation from existing microtubules, and may interact with the effect of colchicine, which is known to inhibit microtubule formation,” observed Dubé.
Also, the chromosome 6 locus associated with gastrointestinal events was co-localizing with the Crohn’s disease locus, adding further support for this region.
“The results support potential personalized approaches to inflammation reduction for cardiovascular prevention,” Dubé said.
This is a post-hoc subgroup analysis, however, and replication is necessary, ideally in prospective randomized trials, she noted.
The substudy is important because it provides further insights into the link between colchicine and microtubule polymerization, affecting the activation of the inflammasome, session moderator Imazio said.
“Second, it is important because pharmacogenomics can help us to better understand the optimal responder to colchicine and colchicine resistance,” he said. “So it can be useful for personalized medicine, leading to the proper use of the drug for the proper patient.”
COLCOT was supported by the government of Quebec, the Canadian Institutes of Health Research, and philanthropic foundations. Bouabdallaoui has disclosed no relevant financial relationships. Dubé reported grants from the government of Quebec; personal fees from DalCor and GlaxoSmithKline; research support from AstraZeneca, Pfizer, Servier, Sanofi; and minor equity interest in DalCor. Dubé is also coauthor of patents on pharmacogenomics-guided CETP inhibition, and pharmacogenomics markers of response to colchicine.
European Society of Cardiology Congress 2020: Presented August 29, 2020.