Reference: Diabetes Care. 2024 Mar 1;47(3):467-470 and Front Cardiovasc Med. 2023 Oct 6:10:1244529
Practice Point: Colchicine is useful for secondary prevention of CVD and we think it should make its way into standard care. The AHA does too.
EBM Pearl: When benefits are shown in large trials, look at the effects in notable subgroups rather than assuming that the benefit is evenly distributed amongst all participants.
Inflammation plays a key role in cardiovascular disease, from the development of plaques to their disruption that causes a myocardial infarction. Elevation of CRP, a biomarker of inflammation, is associated with increased cardiovascular risk. In addition, the anti-inflammatory effects of statins are thought to be one of the reasons they are effective in cardiovascular disease prevention. Along those lines, in 2023 the AHA recommended considering colchicine for secondary prevention of cardiovascular disease because of its anti-inflammatory benefits. Somehow we’re just hearing about this now, and we wondered what evidence they had to support this recommendation. Turns out, this recommendation was influenced by the results of two trials: the COLCOT and the LODOCO2.
The COLCOT trial randomized 4,745 patients within 30 days of a myocardial infarction to colchicine 0.5 mg daily or placebo. Both groups received standard care. Median follow up was 22.6 months. The primary outcome was a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization. This occurred in 5.5% of the patients in the colchicine group, compared with 7.1% in the placebo group (HR 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The subsequent LODOCO2 trial, which had over 5,000 participants with chronic cardiovascular disease showed that adding colchicine to usual care similarly decreased cardiovascular events with an NNT of 36. There were no differences in harms between groups in either trial.
Because patients with diabetes are known to be at higher risk of both primary and secondary cardiovascular events, one of the key questions was the extent to which these results apply to patients with diabetes. Recently, subgroup analyses of each trial consisting of patients who had type 2 diabetes at time of randomization were published. The COLCOT trial included 959 patients with type 2 diabetes and found that the primary end point occurred in 8.7% of the patients in the colchicine group and in 13.1% of those in the placebo group (HR 0.65; 95% CI 0.44–0.96; P = 0.03). A subgroup analysis of the LODOCO2 trial with 1,007 patients with type 2 diabetes at the start of the trial found results consistent with the larger LODOCO2 cohort but for this subset, the difference was not statistically significant (HR 0.87, 95% CI 0.61-1.25).
If we go back to the primary (composite) results of LODOCO2, an NNT of 36 to prevent one additional secondary event over 2.5 years is pretty impressive, and is on par with the NNT for statins for secondary prevention over 5 years. And while the subgroup analyses focusing on patients with diabetes are helpful in answering the all-important question "do these results apply to my patient?,” the results leave us wondering if the impact of colchicine is really more or less in patients with diabetes. If we extrapolate, the magnitude of the reduction from the subgroup analysis of the COLCOT trial suggests an NNT of less than 25, which is even more clinically significant. However, if we were to combine those data with the nonsignificant subgroup results from LODOCO2, it's hard to know how great the magnitude of benefit in patients with diabetes really shakes out to be. Regardless, the overall effect of colchicine on secondary prevention seems important. One thing that’s even more certain is that it takes a long time for evidence to reach clinical practice: the COLCOT and LOCOCO2 trials were published in 2019 and 2020 respectively; the AHA/ACC updated the guidance in 2023. And yet, almost no one (in primary care anyway) has heard of this. Let’s hope colchicine becomes part of usual care for secondary prevention faster than the reported time lag of 17 years for evidence to reach clinical practice. By the way, we did notice that the dosing of colchicine was unusual for the United States market - 0.5 versus the standard 0.6 mg. Despite what colchicine manufacturers will undoubtedly tell you, we don’t think that matters.
For more information, see the topic Secondary Prevention of Coronary Artery Disease in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School. Edited by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, MPH, FACP, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Associate Editor at DynaMed.