Effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre randomised double-blind placebo-controlled trial

Abstract

BackgroundPerhexiline is thought to modulate metabolism through the inhibition of mitochondrial carnitine palmitoyltransferase, reducing fatty acid uptake and increasing carbohydrate utilisation. Our group has shown that a glucose-insulin-potassium infusion enhances myocardial protection during coronary artery bypass graft (CABG) surgery through metabolic manipulation. This study assessed whether perhexiline improves clinical or biochemical markers of myocardial protection and analysed its effect on the myocardial metabolome. MethodsIn a prospective randomised double-blind placebo-controlled trial, patients undergoing CABG at two centres were randomised to receive oral perhexiline or placebo for at least 5 days before surgery. The primary outcome was a low cardiac output episode in the first 6 h after removal of the aortic cross-clamp. A low cardiac output episode was defined as a cardiac index of less than 2·2 L/min/m2 in the presence of adequate preload, afterload, and heart rate. All analyses were conducted according to the intention-to-treat principle with a 90% power to detect a relative risk of 0·5 with a one-sided α of 0·025. Left ventricular biopsy samples were taken before ischaemia, snap-frozen, and analysed with mass spectrometry-based (MS) metabolomics. This trial is registered with ClinicalTrials.gov, number NCT00845364. FindingsOver a 3-year period, 286 patients were randomised, received the intervention, and included in the analysis. There were no important baseline differences between groups. The incidence of a low cardiac output episode in the perhexiline arm was 36·7% (51/139) versus 34·7% (51/147) in the control arm (odds ratio 0·92 [95% CI 0·56–1·50]; p=0·74). There were no significant differences in inotrope usage, myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction, or length of hospital stay. No difference in pre-ischaemia left ventricular metabolism was identified between groups. InterpretationPreoperative perhexiline does not improve myocardial protection in patients undergoing CABG. That perhexiline has no significant effect on the MS-visible polar myocardial metabolome in vivo in human beings supports the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition. FundingBritish Heart Foundation and Sussex Heart Charity.