title: Multicentre double-blind randomized controlled trial of perhexiline as a metabolic modulator to augment myocardial protection in patients with left ventricular hypertrophy undergoing cardiac surgery.
abstract: OBJECTIVE
  Patients undergoing cardiac surgery require adequate myocardial protection. Manipulating myocardial metabolism may improve the extent of myocardial protection. Perhexiline has been shown to be an effective anti-anginal agent due to its metabolic modulation properties by inhibiting the uptake of free fatty acids into the mitochondrion, and thereby promoting a more efficient carbohydrate-driven myocardial metabolism. Metabolic modulation may augment myocardial protection, particularly in patients with left ventricular hypertrophy (LVH) known to have a deranged metabolic state and are at risk of poor postoperative outcomes. This study aimed to evaluate the role of perhexiline as an adjunct in myocardial protection in patients with LVH secondary to aortic stenosis (AS), undergoing an aortic valve replacement (AVR).
  
  
  METHODS
  In a multicentre double-blind randomized controlled trial of patients with AS undergoing AVR ± coronary artery bypass graft surgery, patients were randomized to preoperative oral therapy with either perhexiline or placebo. The primary end point was incidence of inotrope use to improve haemodynamic performance due to a low cardiac output state during the first 6 h of reperfusion, judged by a blinded end points committee. Secondary outcome measures included haemodynamic measurements, electrocardiographic and biochemical markers of new myocardial injury and clinical safety outcome measures.
  
  
  RESULTS
  The trial was halted early on the advice of the Data Safety and Monitoring Board. Sixty-two patients were randomized to perhexiline and 65 to placebo. Of these, 112 (54 perhexiline and 48 placebo) patients received the intervention, remained in the trial at the time of the operation and were analysed. Of 110 patients who achieved the primary end point, 30 patients (16 perhexiline and 14 placebo) had inotropes started appropriately; there was no difference in the incidence of inotrope usage OR of 1.65 [confidence interval (CI): 0.67-4.06] P = 0.28. There was no difference in myocardial injury as evidenced by electrocardiogram odds ratio (OR) of 0.36 (CI: 0.07-1.97) P = 0.24 or postoperative troponin release. Gross secondary outcome measures were comparable between the groups.
  
  
  CONCLUSIONS
  Perhexiline as a metabolic modulator to enhance standard myocardial protection does not provide an additional benefit in haemodynamic performance or attenuate myocardial injury in the hypertrophied heart secondary to AS. The role of perhexiline in cardiac surgery is limited.
authors.affiliation: Department of Cardiothoracic Surgery, University Hospitals Birmingham NHS FT, Birmingham, UK School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Eshan L
authors.initials: EL
authors.lastname: Senanayake
authors.affiliation: Department of Cardiothoracic Surgery, University Hospitals Birmingham NHS FT, Birmingham, UK School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Howell
authors.affiliation: Department of Cardiothoracic Surgery, University Hospitals Birmingham NHS FT, Birmingham, UK School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Ranasinghe
authors.affiliation: Department of Cardiothoracic Surgery, University Hospitals Birmingham NHS FT, Birmingham, UK.
authors.forename: Nigel E
authors.initials: NE
authors.lastname: Drury
authors.affiliation: Department of Primary Care and Population Health, University College London, London, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Freemantle
authors.affiliation: School of Medicine, University of Aberdeen, Aberdeen, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Frenneaux
authors.affiliation: Department of Cardiothoracic Anaesthesia, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
authors.forename: Tessa
authors.initials: T
authors.lastname: Oelofse
authors.affiliation: Department of Cardiothoracic Anaesthesia, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
authors.forename: David
authors.initials: D
authors.lastname: Green
authors.affiliation: Department of Cardiothoracic Surgery, University Hospitals Birmingham NHS FT, Birmingham, UK.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Wilson
authors.affiliation: Department of Cardiothoracic Surgery, University Hospitals Birmingham NHS FT, Birmingham, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Rooney
authors.affiliation: Department of Cardiothoracic Surgery, University Hospitals Birmingham NHS FT, Birmingham, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Mascaro
authors.affiliation: Department of Cardiothoracic Surgery, University Hospitals Birmingham NHS FT, Birmingham, UK.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Graham
authors.affiliation: Department of Cardiothoracic Surgery, University Hospital Coventry and Warwickshire, Coventry, UK.
authors.forename: Sunil
authors.initials: S
authors.lastname: Bhudia
authors.affiliation: Department of Cardiothoracic Surgery, Royal Sussex County Hospital, Brighton, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Lewis
authors.affiliation: Department of Cardiothoracic Surgery, University Hospitals Birmingham NHS FT, Birmingham, UK domenico.pagano@uhb.nhs.uk.
authors.forename: Domenico
authors.initials: D
authors.lastname: Pagano
mesh_terms: D000368:Aged; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D001026:Coronary Artery Bypass / Q000379:methods; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000601:surgery / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010480:Perhexiline / Q000627:therapeutic use*
chemical_list: D002316:Cardiotonic Agents; D010480:Perhexiline
keywords: Aortic stenosis; Cardiac surgery; Left ventricular hypertrophy; Metabolic modulation; Myocardial protection; Perhexiline