Effect of Colchicine on Myocardial Injury in Acute Myocardial Infarction.

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.

Colchicine for Left Ventricular Infarct Size Reduction in Acute Myocardial Infarction: A Phase II, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Study Protocol - The COVERT-MI Study.

Inflammatory processes have been identified as key mediators of ischemia-reperfusion injury in ST-segment elevation myocardial infarction (STEMI). They add damage to the myocardium and are associated with clinical adverse events (heart failure and cardiovascular death) and poor myocardial recovery. Colchicine is a well-known alkaloid with potent anti-inflammatory properties. In a proof-of-concept phase II trial, colchicine has been associated with a significant 50% reduction of infarct size (assessed by creatine kinase levels) in comparison to placebo in acute STEMI patients referred for primary percutaneous coronary intervention (PPCI). The Colchicine in STEMI Patients Study (COVERT-MI) is an ongoing confirmative prospective, multicenter, randomized, double-blind trial testing whether a short course oral treatment with colchicine versus placebo decreases myocardial injury in patients presenting with STEMI referred for PPCI. Adult patients, with a first STEMI episode and an initial TIMI flow ≤1, referred for PPCI, will be randomized (n = 194) in a 1:1 ratio to receive an oral bolus of colchicine of 2 mg followed by 0.5 mg b.i.d. treatment during 5 days or matching placebo. The primary endpoint will be the reduction in infarct size as assessed by cardiac magnetic resonance at 5 ± 2 days between both groups. The main secondary endpoints will be tested between groups in hierarchical order with left ventricular ejection fraction at 5 days, microvascular obstruction presence at 5 days, and absolute adverse left ventricular remodeling between 5 days and 3 months. This academic study is being financed by a grant from the French Ministry of Health (PHRCN-16-0357). Results from this study will contribute to a better understanding of the complex pathophysiology underlying myocardial injury after STEMI. The present study describes the rationale, design, and methods of the trial.

Colchicine in acute myocardial infarction: cardiovascular events at 1-year follow up.

OBJECTIVE: In the COVERT-MI randomised placebo-controlled trial, oral administration of high-dose colchicine at the time of reperfusion and for 5 days in acute ST-elevated myocardial infarction did not reduce infarct size but was associated with a significant increase in left ventricular thrombus (LVT) in comparison to placebo. We aimed to assess the 1-year clinical outcomes of the study population. METHODS: This study is a follow-up analysis of the COVERT-MI study on prespecified secondary clinical endpoints at 1 year. The primary endpoint of this study was a composite of major adverse cardiovascular events (MACEs), including all-cause death, acute coronary syndromes, heart failure events, ischaemic strokes, sustained ventricular arrhythmias and acute kidney injury at 1-year follow-up. The quality of life (QOL) and the drug therapy prescription were also assessed. RESULTS: At 1 year, 192 patients (101 patients in the colchicine group, 91 in the placebo group) were followed up. Seventy-six (39.6%) MACEs were reported in the study population. There was no significant difference regarding the number of MACEs between groups: 36 (35.6%) in the colchicine group and 40 (44.1%) in the placebo group (p=0.3). There were no differences in the occurrence of ischaemic strokes between the colchicine group and the control group (3 (3%) vs 2 (2.2%), respectively, p=0.99). There was a trend towards fewer heart failure events in the colchicine group compared with the placebo group (12 (11.9%) vs 18 (19.8%), p=0.20). There was no significant difference in QOL scores at 1 year (75.8±15.7 vs 72.7±16.2 respectively, p=0.18). CONCLUSIONS: There was no significant difference between the colchicine and placebo groups at 1 year regarding MACEs, especially concerning deaths or ischaemic strokes. No excess of ischaemic adverse events was observed despite the initial increase in LVT in the colchicine group. TRIAL REGISTRATION NUMBER: NCT0315681.