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
Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
School of Health and Population Sciences, University of Birmingham, Birmingham, UK.
Eur J Cardiothorac Surg. 2015 Mar;47(3):464-72. doi: 10.1093/ejcts/ezu238. Epub 2014 Jun 19.
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.
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.
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.
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.
NCT00845364.
哌克昔林被认为可通过抑制线粒体肉碱棕榈酰转移酶-1来调节代谢，减少脂肪酸摄取并增加碳水化合物利用。本研究评估术前使用哌克昔林是否能改善冠状动脉搭桥手术患者的心肌保护指标，并分析其对心肌代谢组的影响。
在一项前瞻性、随机、双盲、安慰剂对照试验中，两个中心的患者在手术前至少5天被随机分配接受口服哌克昔林或安慰剂。主要结局是术后6小时内出现低心排血量事件。所有预先指定的分析均按照意向性分析原则进行，统计效能为90%，以检测相对风险为0.5，传统单侧α值为0.025。对一部分缺血前左心室活检组织进行基于质谱的代谢组学分析。
在3年期间，286例患者被随机分组、接受干预并纳入分析。哌克昔林组低心排血量事件的发生率为36.7%（51/139），而对照组为34.7%（51/147）[优势比（OR）0.92，95%置信区间（CI）0.56 - 1.50，P = 0.74]。哌克昔林与术后6小时心脏指数降低相关[均值差异0.19，95% CI 0.07 - 0.31，P = 0.001]，且与术后12小时内强心支持增加相关（OR 0.55，95% CI 0.34 - 0.89，P = 0.015）。在心肌损伤标志物肌钙蛋白-T或心电图、再次手术、肾功能不全或住院时间方面无显著差异。代谢组学分析显示两组间缺血前左心室代谢无差异。
术前使用哌克昔林并不能改善冠状动脉手术患者的心肌保护，实际上还降低了围手术期心排血量，增加了对强心支持的需求。哌克昔林对人体体内质谱可见的极性心肌代谢组无显著影响，这支持了其通过独立于抑制心肌肉碱棕榈酰转移酶的途径发挥作用的观点，并可能解释了术后未观察到临床获益的原因。
NCT00845364。
