The effect of perhexiline on myocardial protection during coronary artery surgery

a two-centre, randomized, double-blind, placebo-controlled trial

Nigel E Drury, Neil J Howell, Melanie J Calvert, Ralf J M Weber, Eshan L Senanayake, Michael E Lewis, Jonathan A J Hyde, David H Green, Jorge G Mascaro, Ian C Wilson, Timothy R Graham, Stephen J Rooney, Mark R Viant, Nick Freemantle, Michael P Frenneaux, Domenico Pagano, on behalf of the investigators

Research output: Contribution to journalArticle

6 Citations (Scopus)
3 Downloads (Pure)

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 spectrometry-based 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 on metabolomics 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.

CLINICALTRIALSGOV ID: NCT00845364.

Original languageEnglish
Pages (from-to)464-472
Number of pages9
JournalEuropean journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery
Volume47
Issue number3
Early online date19 Jun 2014
DOIs
Publication statusPublished - Mar 2015

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Perhexiline
Coronary Vessels
Placebos
Carnitine O-Palmitoyltransferase
Low Cardiac Output
Metabolomics
Metabolome
Confidence Intervals
Mass Spectrometry
Arm
Odds Ratio
Troponin T
Reoperation
Coronary Artery Bypass
Cardiac Output
Length of Stay
Electrocardiography
Fatty Acids
Carbohydrates
Transplants

Keywords

  • cardiac output
  • metabolism
  • metabolomics
  • myocardial reperfusion injury
  • myocardial stunning

Cite this

The effect of perhexiline on myocardial protection during coronary artery surgery : a two-centre, randomized, double-blind, placebo-controlled trial. / Drury, Nigel E; Howell, Neil J; Calvert, Melanie J; Weber, Ralf J M; Senanayake, Eshan L; Lewis, Michael E; Hyde, Jonathan A J; Green, David H; Mascaro, Jorge G; Wilson, Ian C; Graham, Timothy R; Rooney, Stephen J; Viant, Mark R; Freemantle, Nick; Frenneaux, Michael P; Pagano, Domenico; on behalf of the investigators.

In: European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, Vol. 47, No. 3, 03.2015, p. 464-472.

Research output: Contribution to journalArticle

Drury, NE, Howell, NJ, Calvert, MJ, Weber, RJM, Senanayake, EL, Lewis, ME, Hyde, JAJ, Green, DH, Mascaro, JG, Wilson, IC, Graham, TR, Rooney, SJ, Viant, MR, Freemantle, N, Frenneaux, MP, Pagano, D & on behalf of the investigators 2015, 'The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial', European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, vol. 47, no. 3, pp. 464-472. https://doi.org/10.1093/ejcts/ezu238
Drury, Nigel E ; Howell, Neil J ; Calvert, Melanie J ; Weber, Ralf J M ; Senanayake, Eshan L ; Lewis, Michael E ; Hyde, Jonathan A J ; Green, David H ; Mascaro, Jorge G ; Wilson, Ian C ; Graham, Timothy R ; Rooney, Stephen J ; Viant, Mark R ; Freemantle, Nick ; Frenneaux, Michael P ; Pagano, Domenico ; on behalf of the investigators. / The effect of perhexiline on myocardial protection during coronary artery surgery : a two-centre, randomized, double-blind, placebo-controlled trial. In: European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2015 ; Vol. 47, No. 3. pp. 464-472.
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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 spectrometry-based 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 on metabolomics 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.CLINICALTRIALSGOV ID: NCT00845364.",
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TY - JOUR

T1 - The effect of perhexiline on myocardial protection during coronary artery surgery

T2 - a two-centre, randomized, double-blind, placebo-controlled trial

AU - Drury, Nigel E

AU - Howell, Neil J

AU - Calvert, Melanie J

AU - Weber, Ralf J M

AU - Senanayake, Eshan L

AU - Lewis, Michael E

AU - Hyde, Jonathan A J

AU - Green, David H

AU - Mascaro, Jorge G

AU - Wilson, Ian C

AU - Graham, Timothy R

AU - Rooney, Stephen J

AU - Viant, Mark R

AU - Freemantle, Nick

AU - Frenneaux, Michael P

AU - Pagano, Domenico

AU - on behalf of the investigators

N1 - © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.

PY - 2015/3

Y1 - 2015/3

N2 - 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 spectrometry-based 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 on metabolomics 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.CLINICALTRIALSGOV ID: NCT00845364.

AB - 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 spectrometry-based 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 on metabolomics 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.CLINICALTRIALSGOV ID: NCT00845364.

KW - cardiac output

KW - metabolism

KW - metabolomics

KW - myocardial reperfusion injury

KW - myocardial stunning

U2 - 10.1093/ejcts/ezu238

DO - 10.1093/ejcts/ezu238

M3 - Article

VL - 47

SP - 464

EP - 472

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 -