Effect of Colchicine on Myocardial Injury in Acute Myocardial Infarction

Abstract

Background: Inflammation is a key factor of myocardial damage in reperfused ST-segment-elevation myocardial infarction. We hypothesized that colchicine, a potent anti-inflammatory agent, may reduce infarct size (IS) and left ventricular (LV) remodeling at the acute phase of ST-segment-elevation myocardial infarction.

Methods: In this double-blind multicenter trial, we randomly assigned patients admitted for a first episode of ST-segment-elevation myocardial infarction referred for primary percutaneous coronary intervention to receive oral colchicine (2-mg loading dose followed by 0.5 mg twice a day) or matching placebo from admission to day 5. The primary efficacy outcome was IS determined by cardiac magnetic resonance imaging at 5 days. The relative LV end-diastolic volume change at 3 months and IS at 3 months assessed by cardiac magnetic resonance imaging were among the secondary outcomes.

Results: We enrolled 192 patients, 101 in the colchicine group and 91 in the control group. At 5 days, the gadolinium enhancement-defined IS did not differ between the colchicine and placebo groups with a mean of 26 interquartile range (IQR) [16-44] versus 28.4 IQR [14-40] g of LV mass, respectively (P=0.87). At 3 months follow-up, there was no significant difference in LV remodeling between the colchicine and placebo groups with a +2.4% (IQR, -8.3% to 11.1%) versus -1.1% (IQR, -8.0% to 9.9%) change in LV end-diastolic volume (P=0.49). Infarct size at 3 months was also not significantly different between the colchicine and placebo groups (17 IQR [10-28] versus 18 IQR [10-27] g of LV mass, respectively; P=0.92). The incidence of gastrointestinal adverse events during the treatment period was greater with colchicine than with placebo (34% versus 11%, respectively; P=0.0002).

Conclusions: In this randomized, placebo-controlled trial, oral administration of high-dose colchicine at the time of reperfusion and for 5 days did not reduce IS assessed by cardiac magnetic resonance imaging. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03156816.

Keywords: clinical trial; colchicine; heart injuries; inflammation; myocardial infarction; thrombosis; ventricular remodeling.

Figure 1.

Enrollment and follow-up of the patients. CMR indicates cardiac magnetic resonance; and STEMI, ST-segment–elevation myocardial infarction.

Figure 2.

Assessment of infarct size by late gadolinium enhancement cardiac magnetic resonance and as a function of the area at risk (A). Infarct size (IS) was measured in a centralized core laboratory by quantification of the area of late gadolinium enhancement (LGE) by cardiac magnetic resonance at 5 days. IS Colchicine administration did not result in a significant reduction in IS in comparison with placebo (estimate: 0.99 [95% CI, –2.64 to 4.61]; P=0.59). The IS measured by LGE was expressed as a function of the APPROACH angiographic score, an estimate of the area at risk, as shown in B. To assess the relationship between the area at risk and IS, we performed a prespecified analysis of regression plots of IS by LGE at 5 days on angiographically estimated area at risk. There was a significant association between the 2 variables in the colchicine group (β=0.73; P<0.001) and the placebo group (β=0.35; P=0.003). There was a significant positive relationship between the 2 variables in both groups, and significantly larger in the colchicine group (P interaction=0.03). These data suggest that, for the largest areas at risk, colchicine administration was associated with an increase in the resulting infarct size as measured by LGE. This difference was confirmed to be significant by analysis of covariance (P for interaction= 0.03). APPROACH indicates Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease; and IQR, interquartile range.

Figure 3.

Subgroup analyses for the primary outcome at 5 days. CKD indicates chronic kidney disease; CKD-EPI, chronic kidney disease epidemiology collaboration; GFR, glomerular filtration rate; LAD, left anterior descending coronary artery; LM, left main coronary artery; and RANDO, randomization.