Treatment with metformin to limit cardiac injury during bypass surgery

INTERVENTION: Trade Name: metformin Product Name: Metformin Pharmaceutical Form: Capsule INN or Proposed INN: METFORMIN CAS Number: 657‐24‐9 Current Sponsor code: metformin Other descriptive name: metformin Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 850‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use CONDITION: coronary artery bypass grafting (CABG) ; MedDRA version: 13.1 Level: LLT Classification code 10006894 Term: CABG System Organ Class: 10042613 ‐ Surgical and medical procedures Therapeutic area: Diseases [C] ‐ Cardiovascular Diseases [C14] PRIMARY OUTCOME: Main Objective: To study the effect of oral pretreatment with metformin (850 mg bid for at least 3 days) on troponin‐I release after CABG in patients without diabetes mellitus. Primary end point(s): High‐sensitive troponin I levels measured 6, 12, 24, 48, and 72 hours after CABG. The primary endpoint is the calculated area under the curve of these values. Secondary Objective: Secondary endpoints will include the post‐operative occurrence of arrhythmias, the need for inotropic support, time to detubation, and time to discharge from the intensive care unit. Moreover, renal injury and function will be secondary endpoints of the study. Renal ischemia‐reperfusion will be assessed by measuring urinary excretion of the markers of tubular damage Kidney Injury Molecule (KIM)‐1 and neutrophil gelatinase‐associated lipocalin (NGAL), and renal function will be assessed by plasma and urine concentrations of creatinine. Finally, the right auricle will be harvested during surgery to determine whether metformin augments recovery of contractile function of isolated atrial trabeculae after ex vivo simulated ischemia‐reperfusion (vide infra) and to determine the effect of metformin on the expression and activation of protein kinases involved in ischemia‐reperfusion injury (Western blotting). Timepoint(s) of evaluation of this end point: 6, 12, 24, 48, and 72 hours after CABG SECONDARY OUTCOME: Secondary end point(s): ‐ postoperative occurence of arrhythmias; ‐ need for inortropic support; ‐ duration of ventilation; ‐ renal injury (measured with plasma creatinine concentration, and urinary excretion of NGAL and KIM‐1) Timepoint(s) of evaluation of this end point: during the first three days after surgery INCLUSION CRITERIA: ‐ Acceptation for CABG ‐ Informed consent ‐ Age = 18 years Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 110 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 110