COlchicine for Left VEntricular Remodeling Treatment in Acute Myocardial Infarction

Hospices Civils de Lyon194 enrolled

Overview

Inflammatory processes have been identified as key mediators of ischemia/ reperfusion injury in ST-segment elevation myocardial infarction. They add additional damage to the myocardium and are associated with clinical adverse events (heart failure and cardiovascular death) and poor myocardial recovery. All the different anti-inflammatory approaches to reduce reperfusion injury have been disappointing. Colchicine is a well-known substance with potent anti-inflammatory properties. In a recent pilot study performed in 151 acute STEMI patients treated with primary percutaneous coronary intervention(PPCI) Deftereos et al. showed a 50% reduction of infarct size (creatine kinase release) with a short course treatment of colchicine in comparison to placebo. One mechanism to explain this effect could be the reduction of adverse left ventricular (LV) remodelling. LV remodelling is part of the healing process of myocardium after MI. It is defined as the end diastolic volume (EDV) increase in the first months after MI. Adverse LV remodelling is increased by inflammation and ultimately leads to heart failure. Our main hypothesis is that colchicine with its anti-inflammatory properties significantly reduces the initiation of adverse LV remodelling, together with a significant reduction of infarct size and microvascular obstruction in comparison to placebo in acute STEMI patients referred for PPCI. After inclusion and randomisation, patients will receive the first part of their experimental treatment: colchicine or placebo before PCI, then, the second part after PCI and during 5 days. They will be followed up during their hospitalization and until one year. In order to evaluate LV remodelling, two cardiac magnetic resonance studies will be performed during their participation: one during their hospitalization and a second at 3 months. At 1 year, adverse events will be collected by phone.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Interventions

Colchicine group (experimental arm)DRUG

In the experimental group, patients will receive colchicine, starting with a loading dose of 2 mg at the time of revascularization and continuing with 0.5 mg twice daily (b.i.d) for 5 days.

Placebo group (control arm)DRUG

In the placebo group, patients will receive placebo, starting with a loading dose of 2 mg at the time of revascularization and continuing with 0.5 mg twice daily for 5 days.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * All patients, aged over 18 and \<80 years, * Presenting within 12 hours of chest pain onset, * With ST segment elevation ≥ 0.2 mV in two contiguous leads or new onset of left bundle branch block, * Referral for primary percutaneous coronary intervention (PPCI). * Preliminary oral informed consent followed by signed informed consent as soon as possible * With an initially occluded coronary artery (TIMI angiographic flow of the culprit coronary artery ≤1) Exclusion Criteria: * Patients with any legal protection measure, * Patients without any health coverage, * Patients with loss of consciousness or confused * Patients with a history of prior myocardial infarction * Patients with cardiogenic shock as defined by a systolic blood pressure \<90 mmHg, despite 30 minutes of fluid challenge or requiring intravenous vasoactive agents (dobutamine, noradrenaline, adrenaline) * Patient with severe liver or known renal dysfunction (known GFR≤30 ml/min) * Patient with known history of severe drug intolerance to colchicine * Female patients currently pregnant or women of childbearing age not using contraception (oral diagnosis) * Patients with any obvious contraindication to magnetic resonance imaging (claustrophobia, pace maker, defibrillator….) * Patients treated by macrolides or pristinamycin * Chronic treatment with COLCHICINE (Mediterranean familial fever mainly) * Patient with lactose intolerance * Patient with swallowing disorders

Locations (8)

Centre Hospitalier Universitaire Angers

Angers, France

Hôpital Louis Pradel

Bron, France

Hôpital Saint Joseph

Lyon, France

CHU Arnaud de Villeneuve

Montpellier, France

CHU de Mulhouse

Mulhouse, France

CHU de Poitiers

Poitiers, France

CHU de Rangueil

Toulouse, France

CHRU de Tours

Tours, France

Outcomes

Primary Outcomes

infarct size (in % of LV mass) as estimated by CMR

The primary endpoint will be the infarct size as estimated by CMR at 5 days follow-up between both groups

Time frame: 5 days

Secondary Outcomes

LV ejection fraction

Time frame: At 5 days

Microvascular obstruction (in % of LV mass)

Time frame: At 5 days

Absolute adverse left ventricular remodeling (mL)

Time frame: at 3 months

Relative ventricular remodeling (%)

Time frame: at 3 months

Infarct size in % of LV mass

Infarct size in % of LV mass assessed by ce-CMR

Time frame: At 3 months

LVEDV

LVEDV (indexed to body surface area) as determined by CMR at the acute phase and 3 months follow-up respectively

Time frame: At 3 months

LVESV

LVEDV (indexed to body surface area) as determined by CMR at the acute phase and 3 months follow-up respectively

Time frame: at 3 months

Relative LV ejection fraction

Time frame: 5 days

Percent of thrombi in the LV

Time frame: At 5 days

Incidence of major adverse cardiovascular events

All cause death, cardiovascular death, heart failure worsening during initial hospitalization, hospitalization for heart failure, non-fatal myocardial infarction, life-threatening ventricular arrhythmias and atrial fibrillation.

Time frame: at 3 months

Incidence of major adverse cardiovascular events

Time frame: At 12 months

Quality of life assessed by the EuroQol-5D (EQ5D) questionnaire

Evaluation of quality of life by the EQ5D questionnaire ( scale on which the best state is marked 100 and the worst state is marked 0).

Time frame: At 12 months

Dosage of inflammation biomarkers

Dosage of inflammation biomarkers * For all centers: neutrophil count, C-reactive protein, hematology, Platelets, fibrinogen. * For the centers participating to the BioCollection: interleukin 6, interleukin 8, interleukin 1β and interleukin 18, complement system components.

Time frame: up to 3 months

number of treatment discontinuation

Time frame: 5 days

number of adverse events

(diarrhea, nausea/vomiting and myelotoxicity, renal function at 48H).

Time frame: up to 5 days

COlchicine for Left VEntricular Remodeling Treatment in Acute Myocardial Infarction

Overview

Conditions

Interventions

Eligibility

Locations (8)

Outcomes

Primary Outcomes

Secondary Outcomes