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

Eshan L Senanayake, Neil J Howell, Aaron M Ranasinghe, Nigel E Drury, Nick Freemantle, Michael Frenneaux, Tessa Oelofse, David Green, Ian C Wilson, Stephen J Rooney, Jorge Mascaro, Timothy R Graham, Sunil Bhudia, Michael Lewis, Domenico Pagano

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

OBJECTIVES: 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.

Original languageEnglish
Pages (from-to)354-362
Number of pages9
JournalEuropean journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery
Volume48
Issue number3
Early online date23 Dec 2014
DOIs
Publication statusPublished - Sep 2015

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Perhexiline
Left Ventricular Hypertrophy
Thoracic Surgery
Randomized Controlled Trials
Aortic Valve Stenosis
Placebos
Hemodynamics
Outcome Assessment (Health Care)
Aortic Valve
Wounds and Injuries
Clinical Trials Data Monitoring Committees
Odds Ratio
Confidence Intervals
Low Cardiac Output
Troponin
Incidence
Nonesterified Fatty Acids
Coronary Artery Bypass
Reperfusion
Mitochondria

Keywords

  • myocardial protection
  • left ventricular hypertrophy
  • perhexiline
  • metabolic modulation
  • aortic stenosis
  • cardiac surgery

Cite this

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. / Senanayake, Eshan L; Howell, Neil J; Ranasinghe, Aaron M; Drury, Nigel E; Freemantle, Nick; Frenneaux, Michael; Oelofse, Tessa; Green, David; Wilson, Ian C; Rooney, Stephen J; Mascaro, Jorge; Graham, Timothy R; Bhudia, Sunil; Lewis, Michael; Pagano, Domenico.

In: European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, Vol. 48, No. 3, 09.2015, p. 354-362.

Research output: Contribution to journalArticle

Senanayake, Eshan L ; Howell, Neil J ; Ranasinghe, Aaron M ; Drury, Nigel E ; Freemantle, Nick ; Frenneaux, Michael ; Oelofse, Tessa ; Green, David ; Wilson, Ian C ; Rooney, Stephen J ; Mascaro, Jorge ; Graham, Timothy R ; Bhudia, Sunil ; Lewis, Michael ; Pagano, Domenico. / 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. In: European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2015 ; Vol. 48, No. 3. pp. 354-362.
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abstract = "OBJECTIVES: 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.",
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TY - JOUR

T1 - 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

AU - Senanayake, Eshan L

AU - Howell, Neil J

AU - Ranasinghe, Aaron M

AU - Drury, Nigel E

AU - Freemantle, Nick

AU - Frenneaux, Michael

AU - Oelofse, Tessa

AU - Green, David

AU - Wilson, Ian C

AU - Rooney, Stephen J

AU - Mascaro, Jorge

AU - Graham, Timothy R

AU - Bhudia, Sunil

AU - Lewis, Michael

AU - Pagano, Domenico

N1 - Date of Acceptance: 06/10/2014 © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

PY - 2015/9

Y1 - 2015/9

N2 - OBJECTIVES: 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.

AB - OBJECTIVES: 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.

KW - myocardial protection

KW - left ventricular hypertrophy

KW - perhexiline

KW - metabolic modulation

KW - aortic stenosis

KW - cardiac surgery

U2 - 10.1093/ejcts/ezu452

DO - 10.1093/ejcts/ezu452

M3 - Article

VL - 48

SP - 354

EP - 362

JO - European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery

JF - European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery

SN - 1873-734X

IS - 3

ER -