The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial.

Research output: Contribution to journalArticle

Authors

  • Michael E. Lewis
  • Jonathan A J Hyde
  • David H. Green
  • Jorge G. Mascaro
  • Ian C. Wilson
  • Timothy R. Graham
  • Stephen J. Rooney
  • Mark Viant
  • Nick Freemantle
  • Michael P. Frenneaux
  • Domenico Pagano

External organisations

  • Centre for Cardiovascular Sciences; School of Clinical and Experimental Medicine; University of Birmingham; Edgbaston Birmingham UK
  • Health Economics Unit, School of Health and Population Sciences, Public Health Building, University of Birmingham, Birmingham, B15 2TT.
  • Department of Cardiothoracic Surgery, Royal Sussex County Hospital
  • Department of Cardiac Anesthesia, Queen Elizabeth Hospital Birmingham
  • Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham
  • University College London
  • University of Aberdeen

Abstract

OBJECTIVES: Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome. METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometrybased metabolomics. RESULTS: Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56-1.50, P = 0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07-0.31, P = 0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34-0.89, P = 0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups onmetabolomics analysis. CONCLUSIONS: Preoperative perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry- visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery.

Details

Original languageEnglish
Pages (from-to)464-472
Number of pages9
JournalEuropean Journal of Cardio-Thoracic Surgery
Volume47
Issue number3
Early online date19 Jun 2014
Publication statusPublished - 2015

Keywords

  • Cardiac output, Metabolism, Metabolomics, Myocardial reperfusion injury, Myocardial stunning