Colchicine Effective Regardless of ACS History, Timing: LoDoCo2

Patrice Wendling

August 23, 2021

The benefits of low-dose colchicine (Colcrys) are consistent if started months or years after acute coronary syndrome (ACS) in patients with stable coronary artery disease, a new LoDoCo2 subanalysis suggests.

As previously reported, the parent trial showed that adding colchicine 0.5 mg daily to standard care reduced the risk of the primary endpoint — a composite of cardiovascular (CV) death, myocardial infarction (MI), ischemic stroke, or ischemia-driven coronary revascularization — by 31% compared with placebo.

In the new analysis, led by Tjerk S.J. Opstal, MD, the anti-inflammatory agent was equally effective in reducing the risk of the primary endpoint in patients with no prior ACS, a recent ACS (6-24 months), remote ACS (2-7 years), or very remote ACS (>7 years), with no interaction found between groups (P = .59).

The incidence of the primary endpoint per 100 person-years and hazard ratios (HR) for the four groups with colchicine and placebo are as follows:

  • No prior ACS: 2.8 vs 3.4; HR, 0.81 (95% CI, 0.52 - 1.27)

  • Recent ACS: 2.4 vs 3.3; HR, 0.75 (95% CI, 0.51 - 1.10)

  • Remote ACS: 1.8 vs 3.2; HR, 0.55 (95% CI, 0.37 - 0.82)

  • Very remote ACS: 3.0 vs 4.3; HR, 0.70 (95% CI, 0.51 - 0.96).

The results were reported today in the Journal of the American College of Cardiology.

In contrast, however, a recent subgroup analysis from the COLCOT trial reported an even greater reduction in its primary composite CV endpoint when colchicine was started within 3 days of an MI.

"The result of COLCOT could imply that initiation of colchicine treatment would be best suited directly after myocardial infarction," Opstal, from Radboud University Medical Center, Nijmegen, the Netherlands, told | Medscape Cardiology. "Our subanalysis shows that later initiation of colchicine therapy in patients visiting outpatient clinics years after their ACS events is equally effective. As such, colchicine therapy should not be limited to patients with recent ACS, and should be considered in all patients with coronary artery disease."

Opstal pointed out that the two trials targeted different populations. COLCOT enrolled 4765 patients within a month of MI, whereas LoDoCo2 enrolled 5522 patients who were clinically stable for at least 6 months after an ACS or coronary revascularization.

Overall, 864 LoDoCo2 patients had no prior ACS and 86% had a history of ACS, of which 1479 were recent, 1582 remote, and 1597 very remote.

Patients with a history of very remote ACS had a numerically higher event rate for the primary outcome, but the difference was not statistically significant and could be attributed to a play of chance, noted Opstal.

The team presumed patients with more recent prior ACS would remain at higher risk of ACS recurrence than those with a more remote ACS that had proven to be clinically stable under standard medical therapy. But, he said, the data show they were at equal risk of the primary outcome.

"This implies that current optimal medical therapy does not result in an attenuation of residual risk over time regardless of whether patients are clinically stable, and that the ongoing process of atherosclerosis results in continuously elevated risk, which warrants new avenues of therapy, such as anti-inflammatory medication," Opstal said.

In a binary analysis, there was no difference in composite cardiovascular events between patients with and without prior ACS (HR, 0.67 vs HR, 0.81; P value for interaction, 0.43).

Opstal observed that a lack of statistical power precludes any definitive conclusions and that a large randomized controlled trial in patients with established coronary artery disease (CAD) but no prior ACS would elucidate whether early initiation of colchicine is "warranted at the moment CAD is established but before a first ACS event, as is common practice with acetylsalicylic acid and statins."

In addition, the ongoing OASIS 9 trial will answer the question of whether patients with an estimated glomerular filtration rate of 30 to 60 mL/min can safely use low-dose colchicine. The gout medication is contraindicated in patients with severe renal or hepatic impairment and in patients on drugs that inhibit both CYP3A4 or the P-glycoprotein.

In an accompanying editorial, colchicine researchers Jean-Claude Tardif, MD, and Guillaume Marquis-Gravel, MD, both from the Montreal Heart Institute, Quebec, Canada, suggest that study design features likely explain the discord between the LoDoCo2 and COLCOT subgroup analyses and the lack of difference in CV event rates between patients with and without prior ACS.

The editorialists say lingering questions remain, including the value of colchicine in patients with diabetes or peripheral artery disease without known CAD, but they also point out that three 2021 meta-analyses confirmed large reductions in the risk of CV events, MI, and coronary revascularization with low-dose colchicine.

"In light of the positive results from LoDoCo2, COLCOT, and meta-analyses; its good tolerability profile; and cost-effectiveness, inflammation reduction with low-dose colchicine should be considered to treat patients with coronary disease in the absence of severe renal dysfunction," Tardif and Marquis-Gravel conclude.

The study was supported by the National Health Medical Research Council of Australia; a grant from the Sir Charles Gairdner Research Advisory Committee; the Withering Foundation; the Netherlands Heart Foundation; the Netherlands Organization for Health Research and Development; and a consortium of Teva, Disphar, and Tiofarma in the Netherlands. The funders had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript. Opstal reports no relevant financial relationships. Co-author disclosures are listed in the original article.

Tardif has received grant support from Amarin, AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Novartis, Pfizer, RegenXBio, and Sanofi; has received honoraria from AstraZeneca, DalCor Pharmaceuticals, HLS Pharmaceuticals, Pendopharm, and Sanofi; has minor equity interest in DalCor Pharmaceuticals; and is mentioned as an author on submitted patents on pharmacogenomics-guided CETP inhibition, use of colchicine after myocardial infarction, and use of colchicine in COVID-19 (he has waived his rights in the colchicine patents and does not stand to gain financially). Marquis-Gravel has received research grants from Bayer; has received speaker honoraria from Novartis; and has served on national advisory boards for Servier, JAMP, and Bayer.

J Am Coll Cardiol. Published online August 23, 2021. Abstract, Editorial

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