曲美他嗪在经皮冠脉介入术中心肌保护作用的Meta分析
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摘要
研究背景
经皮冠脉介入术(percutaneous coronary intervention, PCI)操作可损伤冠脉血管内皮功能、诱发冠脉痉挛、斑块或血栓碎片导致远端冠脉栓塞,从而导致心肌缺血或心肌损伤。如何预防和减轻PCI围手术期心肌损伤已成为研究热点之一。心肌代谢类药物——曲美他嗪在治疗缺血性心脏病中的有效性和安全性已得到充分证实,但对其在预防和减轻PCI围手术期心肌损伤中的有效性则研究报道较少。由于不同临床研究所纳入的患者样本较小,研究结果不尽相同,尚不能为曲美他嗪在PCI围手术期中是否具有心肌保护作用提供充分的循证医学证据。
研究目的
收集关于曲美他嗪在PCI围手术期心肌保护作用的随机对照试验,应用1neta分析评价曲美他嗪在PCI围手术期的心肌保护作用,以及对PCI术后30天左心室收缩功能的影响。
研究方法
系统检索PubMed数据库、Cochrane临床对照试验中心注册库、自1980年1月至2012年12月期间公开发表的关于曲美他嗪在PCI手术相关心肌损伤中保护作用的随机对照临床试验。检索词包括“trimetazidine"或“vasorel"和"percutaneous coronary intervention"或"reperfusion"或"myocardio damage",通过文献纳入和排除标准决定纳入文献,并进行文献质量评价,提取与本研究相关的数据。应用RevMan5.1软件对PCI术中心电图缺血性ST-T改变、术中心绞痛症状发作、术后24小时肌钙蛋白I(cardiac troponin I, cTnl)升高、以及PCI术后30天左室射血分数(left ventricular ejection fraction, LVEF)等参数进行meta分析,来评价曲美他嗪在PCI围手术中在对心肌损伤的心肌保护作用。
研究结果
1.本研究共检索文献458篇,其中随机对照临床试验183篇。最终纳入5项随机对照临床试验,共包括514例接受PCI的冠心病患者,其中曲美他嗪治疗组265例,对照组249例。
2.共有2项试验(曲美他嗪治疗组190例,对照组177例)对PCI术中心电图ST-T改变进行了评价。Meta分析结果显示,曲美他嗪治疗组在PCI术中出现缺血性ST-T改变的发生率显著低于对照组(32.1%比41.2%,OR：0.60,95%CI：0.37-0.95,P=0.03)。
3.共有2项试验(曲美他嗪治疗组76例,对照组69例)对PCI术中心绞痛症状进行了研究。Meta分析显示,曲美他嗪治疗组在PCI术中出现心绞痛症状的发生率显著低于对照组(15.8%比43.5%,OR：0.16,95%CI：0.67-0.38,P<0.0001)。
4.共有3项试验(曲美他嗪治疗组107例,对照组97例)评价了PCI术后30天LVEF测值的变化。Meta分析结果显示,曲美他嗪治疗组术后30天LVEF测值显著高于对照组(WMD：4.60,95%CI：2.68-6.53,P<0.00001)。
5.共有3项试验(曲美他嗪治疗组185例,对照组177例)分析了PCI术后cTnl测值及术后24小时cTnI升高超过2倍正常值上限的患者数。尽管meta分析显示,PCI术后cTnl超过2倍正常值上限的发生率在两组间无显著性差异(24.3%比28.8%,OR0.43,95%CI：0.28-1.45,P=0.28),但3项试验中PCI术后不同时间段cTnl测值均显著低于对照组(P<0.05)
结论
该meta分析表明,PCI围手术期应用曲美他嗪可以显著降低术中心肌缺血所导致的缺血性ST-T改变与心绞痛的发生率,改善术后左室收缩功能,降低PCI术后cTnl水平。但由于纳入的临床试验数量少,包括的患者样本量较小,未能显示出cTnl水平升高超过2倍正常值上限的发生率,有待于更大样本的临床试验结果为曲美他嗪在PCI围手术期的心肌保护作用提供更多循证证据。该meta分析结果支持在PCI围手术期应用曲美他嗪进行治疗。
Background and Objective:The operation of percutaneous coronary intervention (PCI) can induce coronary spasm, endothelial cell injury and the debris of atherosclerotic plaque or thrombus may cause coronary artery distal embolization, thereby resulting in myocardial ischemia or myocardial injury. The measures concerning cardioprotection during PCI procedure is of intriguing interest and has become one of the research hot topics in cardiology. The efficiency and safety of trimetazidine has been widely recognized in the treatment of patients with coronary artery disease (CAD). However, due to lack of sufficient evidence in clinical conditions, there is still doubt whether the administration of trimetazidine to patients undergoing PCI operation can minimize the myocardial ischemia or injure following successful PCI procedure. We aimed to performe a meta-analysis to evaluate the cardioprotective effect of trimetazidine on patients who underwent successful PCI.
Methods:We systematically searched the literatures through the PubMed and Cochrane Central Registry of Clinical Trials for the published randomized controlled clinical trials (published from Jan1980to Dec2012) concerning the administration of trimetazidine to patients before and after PCI operations. The search terms including 'trimetazidine' or 'vasorel' and 'percutaneous coronary intervention'or'reperfusion' or 'myocardio damage'. Data concerning the study design, patient characteristics, and outcomes were reviewed and extracted. The meta-analysis was performed using a software of RevMan5.1.7to evaluate the incidences of ischemic ST-T changes on electrocardiogram (ECG) and angina attacks during PCI, the incidence of elevated cardiac troponin I (cTnI) within24hours after PCI, and also the changes of left ventricular ejection fraction (LVEF)30days after PCI procedure.
Results:
1) We reviewed a total of458articles and183articles were randomized controlled clinical trials. Five trials which enrolled514patients with CAD were in accordance with the inclusion criteria and were included in this meta-analysis. Among of them,265subjects received trimetazidine (the trimetazidine group) and249subjects received placebos (the control group).
2) The incidence of ischemic ST-T changes on ECG during the PCI procedure was assessed in2trials (including514patients in all,265patients in the trimetazidine group and249patients in the control group). The meta-analysis showed that the incidence of ischemic ST-T changes in the trimetazidine group was significantly lower than that in the control group (32.1%vs41.2%, OR:0.60,95%CI:0.37-0.95, P=0.03).
3) The occurrence of angina attacks during the PCI procedure was evaluated in2trials (including145subjects,76subjects in the trimetazidine group and69patients in the control group). The results demonstrated that the incidence of angina attacks in the trimetazidine group was markedly lower than that in the control group (15.8%vs43.5%, OR:0.16,95%CI:0.67-0.38, P<0.0001).
4) Three trials (204patients in all,107patients in the trimetazidine group and97patients in the control group) measured the LVEF values30days after the PCI procedure. The meta-analysis found that the mean value of LVEF in the trimetazidine group was significantly higher than that in the control group (WMD:4.60,95%CI:2.68-6.53, P<0.00001).
5) A total of3trials (including362patients,185cases in the trimetazidine group and177cases in the control group) analysed the incidence of elevated cTnI≥2times the upper limit of normal, which was measured24hours after the PCI procedure. Although the meta-analysis demonstrated no significant difference between the trimetazidine group and the control group (24.3%vs28.8%, OR:0.43,95%CI:0.28-1.45, P=0.28), the cTnI measures tested on different time points following PCI precedures all showed much lower in the trimetazidine group than those in the control group in all the3trials (all P<0.05).
Conclusion:Administration of trimetazidine before and after PCI provides a significant benefit over placebo in reducing the incidence of ischemic ST-T changes and angina attacks during the procedure, and improving the left ventricular systolic function after the procedure. The lack of evidence for reducing the incidence of elevated cTnI≥2times the upper limit of normal might be partly attributed to the small amout of trials and patients enrolled in this study.
经皮冠脉介入术(percutaneous coronary intervention, PCI)操作可损伤冠脉血管内皮功能、诱发冠脉痉挛、斑块或血栓碎片导致远端冠脉栓塞,从而导致心肌缺血或心肌损伤。如何预防和减轻PCI围手术期心肌损伤已成为研究热点之一。心肌代谢类药物——曲美他嗪在治疗缺血性心脏病中的有效性和安全性已得到充分证实,但对其在预防和减轻PCI围手术期心肌损伤中的有效性则研究报道较少。由于不同临床研究所纳入的患者样本较小,研究结果不尽相同,尚不能为曲美他嗪在PCI围手术期中是否具有心肌保护作用提供充分的循证医学证据。
研究目的
收集关于曲美他嗪在PCI围手术期心肌保护作用的随机对照试验,应用1neta分析评价曲美他嗪在PCI围手术期的心肌保护作用,以及对PCI术后30天左心室收缩功能的影响。
研究方法
系统检索PubMed数据库、Cochrane临床对照试验中心注册库、自1980年1月至2012年12月期间公开发表的关于曲美他嗪在PCI手术相关心肌损伤中保护作用的随机对照临床试验。检索词包括“trimetazidine"或“vasorel"和"percutaneous coronary intervention"或"reperfusion"或"myocardio damage",通过文献纳入和排除标准决定纳入文献,并进行文献质量评价,提取与本研究相关的数据。应用RevMan5.1软件对PCI术中心电图缺血性ST-T改变、术中心绞痛症状发作、术后24小时肌钙蛋白I(cardiac troponin I, cTnl)升高、以及PCI术后30天左室射血分数(left ventricular ejection fraction, LVEF)等参数进行meta分析,来评价曲美他嗪在PCI围手术中在对心肌损伤的心肌保护作用。
研究结果
1.本研究共检索文献458篇,其中随机对照临床试验183篇。最终纳入5项随机对照临床试验,共包括514例接受PCI的冠心病患者,其中曲美他嗪治疗组265例,对照组249例。
2.共有2项试验(曲美他嗪治疗组190例,对照组177例)对PCI术中心电图ST-T改变进行了评价。Meta分析结果显示,曲美他嗪治疗组在PCI术中出现缺血性ST-T改变的发生率显著低于对照组(32.1%比41.2%,OR：0.60,95%CI：0.37-0.95,P=0.03)。
3.共有2项试验(曲美他嗪治疗组76例,对照组69例)对PCI术中心绞痛症状进行了研究。Meta分析显示,曲美他嗪治疗组在PCI术中出现心绞痛症状的发生率显著低于对照组(15.8%比43.5%,OR：0.16,95%CI：0.67-0.38,P<0.0001)。
4.共有3项试验(曲美他嗪治疗组107例,对照组97例)评价了PCI术后30天LVEF测值的变化。Meta分析结果显示,曲美他嗪治疗组术后30天LVEF测值显著高于对照组(WMD：4.60,95%CI：2.68-6.53,P<0.00001)。
5.共有3项试验(曲美他嗪治疗组185例,对照组177例)分析了PCI术后cTnl测值及术后24小时cTnI升高超过2倍正常值上限的患者数。尽管meta分析显示,PCI术后cTnl超过2倍正常值上限的发生率在两组间无显著性差异(24.3%比28.8%,OR0.43,95%CI：0.28-1.45,P=0.28),但3项试验中PCI术后不同时间段cTnl测值均显著低于对照组(P<0.05)
结论
该meta分析表明,PCI围手术期应用曲美他嗪可以显著降低术中心肌缺血所导致的缺血性ST-T改变与心绞痛的发生率,改善术后左室收缩功能,降低PCI术后cTnl水平。但由于纳入的临床试验数量少,包括的患者样本量较小,未能显示出cTnl水平升高超过2倍正常值上限的发生率,有待于更大样本的临床试验结果为曲美他嗪在PCI围手术期的心肌保护作用提供更多循证证据。该meta分析结果支持在PCI围手术期应用曲美他嗪进行治疗。
Background and Objective:The operation of percutaneous coronary intervention (PCI) can induce coronary spasm, endothelial cell injury and the debris of atherosclerotic plaque or thrombus may cause coronary artery distal embolization, thereby resulting in myocardial ischemia or myocardial injury. The measures concerning cardioprotection during PCI procedure is of intriguing interest and has become one of the research hot topics in cardiology. The efficiency and safety of trimetazidine has been widely recognized in the treatment of patients with coronary artery disease (CAD). However, due to lack of sufficient evidence in clinical conditions, there is still doubt whether the administration of trimetazidine to patients undergoing PCI operation can minimize the myocardial ischemia or injure following successful PCI procedure. We aimed to performe a meta-analysis to evaluate the cardioprotective effect of trimetazidine on patients who underwent successful PCI.
Methods:We systematically searched the literatures through the PubMed and Cochrane Central Registry of Clinical Trials for the published randomized controlled clinical trials (published from Jan1980to Dec2012) concerning the administration of trimetazidine to patients before and after PCI operations. The search terms including 'trimetazidine' or 'vasorel' and 'percutaneous coronary intervention'or'reperfusion' or 'myocardio damage'. Data concerning the study design, patient characteristics, and outcomes were reviewed and extracted. The meta-analysis was performed using a software of RevMan5.1.7to evaluate the incidences of ischemic ST-T changes on electrocardiogram (ECG) and angina attacks during PCI, the incidence of elevated cardiac troponin I (cTnI) within24hours after PCI, and also the changes of left ventricular ejection fraction (LVEF)30days after PCI procedure.
Results:
1) We reviewed a total of458articles and183articles were randomized controlled clinical trials. Five trials which enrolled514patients with CAD were in accordance with the inclusion criteria and were included in this meta-analysis. Among of them,265subjects received trimetazidine (the trimetazidine group) and249subjects received placebos (the control group).
2) The incidence of ischemic ST-T changes on ECG during the PCI procedure was assessed in2trials (including514patients in all,265patients in the trimetazidine group and249patients in the control group). The meta-analysis showed that the incidence of ischemic ST-T changes in the trimetazidine group was significantly lower than that in the control group (32.1%vs41.2%, OR:0.60,95%CI:0.37-0.95, P=0.03).
3) The occurrence of angina attacks during the PCI procedure was evaluated in2trials (including145subjects,76subjects in the trimetazidine group and69patients in the control group). The results demonstrated that the incidence of angina attacks in the trimetazidine group was markedly lower than that in the control group (15.8%vs43.5%, OR:0.16,95%CI:0.67-0.38, P<0.0001).
4) Three trials (204patients in all,107patients in the trimetazidine group and97patients in the control group) measured the LVEF values30days after the PCI procedure. The meta-analysis found that the mean value of LVEF in the trimetazidine group was significantly higher than that in the control group (WMD:4.60,95%CI:2.68-6.53, P<0.00001).
5) A total of3trials (including362patients,185cases in the trimetazidine group and177cases in the control group) analysed the incidence of elevated cTnI≥2times the upper limit of normal, which was measured24hours after the PCI procedure. Although the meta-analysis demonstrated no significant difference between the trimetazidine group and the control group (24.3%vs28.8%, OR:0.43,95%CI:0.28-1.45, P=0.28), the cTnI measures tested on different time points following PCI precedures all showed much lower in the trimetazidine group than those in the control group in all the3trials (all P<0.05).
Conclusion:Administration of trimetazidine before and after PCI provides a significant benefit over placebo in reducing the incidence of ischemic ST-T changes and angina attacks during the procedure, and improving the left ventricular systolic function after the procedure. The lack of evidence for reducing the incidence of elevated cTnI≥2times the upper limit of normal might be partly attributed to the small amout of trials and patients enrolled in this study.
引文
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43 Brottier L, Barat JL, Combe C, et al. Therapeutic value of a cardioprotective agent in patients with severe ischaemic cardiomyopathy. Eur Heart J.1990; 11:207-212.
44 El-Kady T, El-Sabban K, Gabaly M, et al. Effects of trimetazidine on myocardial perfusion and the contractile response of chronically dysfunctional myocardium in ischemic cardiomyopathy:a 24-month study. Am J Cardiovasc Drugs.2005;5: 271-278.
45 Kantor PF, Lucien A, Kozak R, et al. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000;86:580-588.
46 Lopaschuk GD, Barr R, Thomas PD, et al. Beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of glucose oxidation secondary to immbition of long-chain 3-ketoacyl coenzyme a thiolaso. Circ Res. 2003;93:e33-37.
47 Van Overschelde J-L, Wijns W, Depr'e C, et al. Mechanisms of chronic regional postischemia dysfunction in humans. Circulation 1993; 87 (5):1513-23
48 Ruiz-Meona M, Garcia-Dorado D, Julia M, et al. Pretreatment with trimetazidine increases sarcolemma mechanical resistance on reoxygenated myocytes. Cardiovasc Res 1996; 32 (3):587-92
49 Rossr R. Atherosclerosis:An inflammatory disease. N Engl J Med 1999;340:115-26.
50 Filiz Kuralay, Emel Altekin, Ayten Sayin Yazlar, et al. Suppression of angioplasty-related inflammation by pre-procedural treatment with trimetazidine. Tohoku J Exp Med 2006;208:203-212.
51 Kober G, Pennaforte S, Buck T, et al. Myocardial cytoprotection during percutaneous transluminal coronary angioplasty. Eur Heart J 1993;14(Suppl G):6-11
52 Steg PG, Grollier G, Gallay P, et al. for the LIST Study Group. A randomized double-blind trial of intravenous trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction. Int J Cardiol 2001;77(2-3):263-73
1 Lopaschuk GD, Belke DD, Gamble J, Itoi I, Schonekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1994; 1213:263-76.
2 Stanley WC, Lopaschuk GD, et al. Regulation of myocardial carbohydrate metabolism under normal and ischaemic condition. Potential for pharmacological interventions [J]. Cardiovasc Res,1997;33:243-57.
3 Lopaschuk GD, Stanley WC. Glucose metabolism in the ischemic heart. [J]. Circulation,1997;95:313-5.
4 Lopaschuk GD, Belke DD, Gamble J, Itoi I, Schonekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1994;1213:263-76.
5 Opie L. The mechanism of myocytes death in ischemia. Eur Heart J 1993;14(Suppl G]:31-3.
6 Stanley WC Partial fatty acid oxidation inhibitors for stable angina. Expert Opin Investig Drugs 2002; 11(5):615-29.
7 Kantor P, Lucien A, Kozak R, Lopaschuk G. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000;86(5):580-8.
8 Lopaschuk, GD, Barr R, Thomas PD, Dyck JR. Beneficial effects of trimetazidine in exvivo working ischemic hearts are due to astimulation of glucose oxidationse condary to inhibition of long-chain 3-ketoacylcoenzymea thiolase. Circ Res.2003;93(3):e33-37.
9 El Banani H, Bernard M, Baetz D, et al. Changes in intracellular sodium and pH during ischaemia-reperfusion are attenuated by trimetazidine. Comparison between lowand zero-flow ischaemia. Cardiovasc Res 2000;47:688-696.
10 Stanley WC, Marzilli M. Metabolic therapy in the treatment of ischaemic heart disease:the pharmacology of trimetazidine. Fundam Clin Pharmacol, 2003;17:133-145.
11 Morillas Blasco PJ, Hernandiz Martinez A, Azorin Villena I, et al. Mitochondrial changes induced by trimetazidine in the myocardium. Med Sci Monit 2005;11:162 -7.
12 Morin D, Elimadi A, SaPella R, et al. Evidence for the existence of [3H] trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore. Br J Pharmacol,1998;123(7):1385-1394.
13 Monteiro P, Duarte AI, Goncalves LM, et al. Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia. Eur J Pharmacol.2004;503:123-128.
14 Argaud L, Gomez L, Gateau-Roesch O, et al. Trimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia-reperfusion injury J Mol Cell Cardiol.2005;39(6):893-9.
15 Onay-Besikci A, Guner S, Arioglu E, et al. The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts. Can J Physiol Pharmacol 2007;85:527-535.
16 Lagadic-Gossman D, Le Prigent K, Feuvray D. Effects of trimetazidine on pHi, regulation in the rat isolated ventricular myocyte. Br J Pharmacol 1996;117:831-8.
17 Wisel S, Khan M, Kuppusamy ML, et al. Pharmacological preconditioning of mesenchymal stem cells with trimetazidine (1-[2,3,4-trimethoxybenzyl]piperazine) protects hypoxic cells against oxidative stress and enhances recovery of myocardial function in infracted heart through Bcl-2 expression. J Pharmacol Exp Ther.2009;329(2),543-550.
18 McClellan KJ, Plosker GL, Trimetazidine:A review of its use in stable angina pectoris and other coronary conditions. Drugs,1999;58:143-57.
19 Liu X, Gai Y,Liu F, et al. Trimetazidine inhibits pressure overload-induced cardiac fibrosis through NADPH oxidase-ROS-CTGF pathway. Cardiovasc Res. 2010;88(1):150-8.
20 Detry JM, Sellier P, Pennaforte S, et al. Trimetazidine:a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group. Br J Clin Pharmacol 1994;37(3):279-88.
21 Sellier P, Braustet JP Efficacy at trough and safety of trimetazidine MR 35 mg in patients with stable angina pectoris. Cardiovasc Drugs Ther 2001;15(Suppl):81
22 Marxilli M. Clinical benefits of a metabolic approach in the management of coronary patients. Rev Port Cardiol 2000;19(Suppl 5):V25-30.
23 Lei Zhang, Yizhou Lu, Hong Jiang, Additional Use of Trimetazidine in Patients With Chronic Heart Failure, A Meta-Analysis. J Am Coll Cardiol.2012;59:913-22.
24 Wenmeng W, Qizhu T. Early adminstration of trimetazidine may prevent or ameliorate diabttic cardiomyopathy. Med Hypotheses.2011;76:181-3.
25 Ioannidis JP, Karvouni E, Katritsis DG. Mortality risk conferred by small elevations of creatine kinase-MB isoenzyme after percutaneous coronary intervention. J Am Coll Cardiol 2003;42:1406-1411.
26 Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur Heart J 2007;28:2525-2538.
27 Testa L, Van Gaal WJ, Biondi Zoccai GG, et al. Myocardial infarction after percutaneous coronary intervention:a meta-analysis of troponin elevation applying the new universal definition. QJM 2009;102:369-378.
28 Khan TA, Bianchi C, Voisine P, et al. Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest. J Thorac Cardiovasc Surg 2004; 128:602-608.
29 Hayasaki T, Kaikita K, Okuma T, et al. CC chemokine receptor-2 deficiency attenuates oxidative stress and infarct size caused by myocardial ischemia-reperfusion in mice. Circ J 2006; 70:342-351.
30 Girish GB, Malcolm W, Derek MY, et al. Peri-procedural myocardial injury during percutaneous coronary intervention:an important target for cardioprotection. Eur Heart J 2011;32:23-32
31 Laurent Bonello, Pascal Sbragia, Nicolas Amabile, et al. Protective effect of an acute oral loading dose of trimetazidine on myocardial injury following percutaneous coronary Intervention. Heart 2007;93:703-707.
32 Labrou A et al.Trimetazidine Administration Minimizes Myocardial Damage and Improves Left Ventricular Function after Percutaneous Coronary Intervention. Am J Cardiovasc Drugs 2007; 7:143-150.
33 Filiz Kuralay, Emel Altekin, Ayten Sayin Yazlar, et al. Suppression of angioplasty-related inflammation by pre-procedural treatment with trimetazidine. Tohoku J Exp Med,2006;208:203-212.
34 Kober G, Pennaforte S, Buck T, et al. Myocardial cytoprotection during percutaneous transluminal coronary angioplasty. Eur Heart J 1993;14(Suppl G):6-11.
35 Polonski L, Dec I, Wojnar R, Wilczek K. Trimetazidine limits the effects of myocardial ischaemia during percutaneous coronary angioplasty. Curr Med Res Opin 2002;18(7):389-96.
36 Steg PG, Grollier G, Gallay P, et al. for the LIST Study Group. A randomized double-blind trial of intravenous trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction. Int J Cardiol 2001;77(2-3):263-73.
37 Tunerir B, Colak O, Alatas O, et al. Measurement of troponin T to detect cardioprotective effect of trimetazidine during coronary artery bypass grafting. Ann Thorac Surg 1999;68(6):2173-6.
38 Martins GF, Siqueira Filho AG, Santos JB, et al. Trimetazidine on Ischemic Injury and Reperfusion in Coronary Artery Bypass Grafting. Arq Bras Cardiol 2011; 97(3):209-216.
39 Iskesen I, Kurdal AT, Eserdag M, et al. Trimetazidine May Protect the Myocardium during Cardiac Surgery. Heart Surg Forum.2009;12:E175-9.
40 Martins GF, Siqueira Filho AG, Santos JB, et al. Trimetazidine and Inflammatory Response in Coronary Artery Bypass Grafting. Arq Bras Cardiol 2012;99(2):688-696.
41 Ihsan Iskesen, Osman Saribulbul, Mustafa Cerrahoglu, et al. Trimetazidine Reduces Oxidative Stress in Cardiac Surgery. Circ J 2006; 70:1169-73.
42 Barsotti A, Di Napoli P. Trimetazidine and cardioprotection during ischemia-reperfusion. Ital Heart J 2004; 5:29-36.
43 Vedrinne JM, Vedrinne C, Bompard D,et al. Myocardial protection during coronary artery bypass graft surgery:a randomized, double-blind, placebo-controlled study with trimetazidine. Anesth Analg 1996;82(4):712-18.
44 Pasquale PD, Verso PL, Bucca V, et al. Effects of Trimetazidine Administration Before Thrombolysis in Patients with Anterior Myocardial Infarction:Short-term and Long-term Results. Cardiovasc Drugs Ther 1999; 13:423-428.
45 The EMIP-FR Group. European Myocardial Infarction Project -Free Radicals. Effect of 48-h intravenous trimetazidine on short- and long-term outcomes of patients with acute myocardial infarction, with and without thrombolytic therapy; double-blind, placebo-controlled, randomized trial. Eur Heart J 2000;21(18):1537-46.
46 Rebrova TY, Lasukova TV, Afanas'ev SA, et al. Cardioprotective effect of trimetazidine during thrombolytic therapy in patients with acute myocardial infarction. Bull Exp Med.2002;134(6):559-61.
2苑飞,宋现涛,吕树铮.中国内地2008年经皮冠状动脉介入治疗调查注册研究分析.中华心血管杂志[J].2010；38(7)：629-632.
3 Schiano P, Gabriel Steg P. Measurement and prevention Of myocardial injury during percutaneoug coronary intervention.Heart 2007;93:656-657.
4 Garciarena CD, Fantinelli JC, Caldiz CI, et al. Myocardial reperfusion injury: reactive oxygen species vs NHE-1 reactivation[J]. Cell Physiol Biochem 2011; 27(1):13-22.
5 Braunersreuthe V, Jaquet V. Reactive oxyben species in myocardial repeffusion injury:from physiopathology to therapeutic approaches[J]. Curr Pharm Biotechnol 2011:13(1):97-114.
6 Yun KH, Shin IS, Shin SN, et at. Effect of previous statin therapy in patients with acute coronary syndrome and percutaneous coronary intervention[J]. Korean Circ J, 2011;41(8):458-463.
7 Lee JY, Kim CJ, Chung MY. Effect of high-dose vitamin C on oxygen free radical production and myocardial enzyme after tourniquet ischaemia-reperfusion injury during bilateral total knee replacement. J Int Med Res.2010;38:1519-29.
8 Doganci S, Yildirim V, Bolcal C, et al. Sodium nitrite and cardioprotective effect in pig regional myocardial ischemia-reperfusion injury model. Adv Clin Exp Med. 2012;21:713-26.
9 Briguori C, Colombo A, Airoldi F, et al. Statin administration before percutaneous coronary intervention:impact on periprocedural myocardial infcrction. Eur Heart J 2004; 25:1822-8.
10 Athyros VG, Kakafika AI, Tziomalos K, et al. Pleiotropic effects of statins— clinical evidence.Curr Pharm Des 2009; 15:479-89.
11 Levine GD, Bates ER, Blankenship JC, et al.2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention:a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol.2011;58(24):e44-122.
12 Marzilli M, Klein WW. Efficacy and tolerability of trimetazidine in stable angina: a meta-analysis of randomized,double-blind, controlled trials. Coronary Artery Dis.2003;14:171-9.
13 Di Napoli P, Taccardi AA, Barsotti A. Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy. Heart 2005;91:161-5.
14 Morin D, Sapena R, Elimadi A. [(3)H]-trimetazidine mitochondrial binding sites: regulation by cations, effect of trimetazidine derivatives and other agents and interaction with an endogenous substance. Br J Pharmacol.2000;130(3):655-663.
15 Kara AF, Demiryurek S, Celik A, et al. Effects of trimetazidine on myocardial preconditioning in anesthetized rats. Eur J Pharmacol.2004;503:135-45.
16 Haynes RB, McKibbon KA, Wilczynski NL, et al. Optimal search strategies for retrieving scientifically strong studies of treatment from Medline:analytical survey. BMJ 2005;330:1179.
17 Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials:is blinding necessary? Control Clin Trials 1996; 17: 1-12.
18 Birand A et al. Effects of Trimetazidine on Heart Rate Variability and Left Ventricular Systolic Performance in Patients with Coronary Artery Disease After Percutaneous Transluminal Angioplasty. Angiology 1997;48:413-422.
19 Bonello L et al. Protective effect of an acute oral loading dose of trimetazidine on myocardial injury following percutaneous coronary intervention. Heart 2007;93: 703-707.
20 CHEN YD et al. Evaluation of the myocardial protection of trimetazidine during percutaneous coronary intervention:a multicenter randomized and controlled clinical study.Chin J Intern Med,June 2010;49:473-476
21 Labrou A et al.Trimetazidine Administration Minimizes Myocardial Damage and Improves Left Ventricular Function after Percutaneous Coronary Intervention. Am J Cardiovasc Drugs 2007;7:143-150.
22 Polonski L et al.Trimetazidine Limits the Effects of Myocardial Ischaemia During Percutaneous Coronary Angioplasty. Curr Med Res Opin.2002;18(7):389-96.
23 Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analysis. BMJ 2003;327:557-60.
24 Maxwell SR, Lip GY. Reperfusion injury:A review of the pathophysiology, clinical manifestations and therapeutic options. Int J Cardiol 1997; 58:95-117.
25 Dhalla NS, Elmoselhi AB, Hata T, et al. Status of myocardial antioxidants in ischemia-reperfusion injury. Cardiovasc Res 2000;47:446-456.
26 Wattanapitayakul SK, Bauer JA. Oxidative pathways in cardiovascular disease: Roles, mechanisms, and therapeutic implications. Pharmacol Ther 2001; 89:187-206.
27 Chew DP, Bhatt DL, Lincoff AM, et al. Clinical end point definitions after percutaneous coronary intervention and their relationship to late mortality:an assessment by attributable risk. Heart 2006;92:945-50.
28 Chen WH, Lee P, Ng W, et al. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pre-treatment. J Am Coll Cardiol 2004;43:1122-6.
29 Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005;111:2099-106.
30 Anderson KM, Califf RM, Stone GW, et al. Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol 2001;37:2059-65.
31 Pasceri V, Patti G, Nusca A, on behalf of the ARMYDA investigators, et al. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention. Results from the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2004; 110:674-8.
32 Pan-Pan Hao,Yu-Guo Chen, Jia-LiWang, et al. Meta-analysis of the role of high-dose statins administered prior to percutaneous coronary intervention in reducing major adverse cardiac events in patients with coronary artery disease. Clin Exp Pharmaco Physiol 2010;37:496-500.
33 Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000;86:580-8.
34 Stanley WC, Lopaschuk GD, Hall JL, McCormack JG. Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions-Potential for pnarmacoiogicai interventions. Cardiovasc Res 1997;33:243-57.
35 Lopaschuk GD, Barr R, Thomas PD, et al. Beneficial effects of trimetazidine in exvivo working is chemic hearts are due to a stimulation of glucose oxidation secondary to inhibition of long-chain 3-ketoacylcoenzyme a thiolase. Circ Res.2003;93(3):e33-37.
36 Park KH et al. Effects of trimetazidine on endothelial dysfunction after sheath injury of radial artery. Am J Cardiol.2000; 105:1723-7
37 Ihsan Iskesen, Osman Saribulvul, et al. Trimetazidine Reduces Oxidative Stress in Cardiac Surgery. Circ J 2006;70:1169-73
38 Williams FM, Tanda K, Kus M, Williams TJ. Trimetazidine inhibits neutrophil accumulation after myocardial-ischemia and reperfusion in rabbits. J Cardiovasc Pharmacol 1993;22:828-33.
39 Mann DL. Inflammatory mediators and the failing heart:past, present, and the foreseeable future. Circ Res 2002;91:988-98.
40 Demaison L, Fantini E, Sentex E, et al. Trimetazidine:in vitro influence on heart mitochondrial functin. Am J Cardiol.1995;76:31B-37B.
41 Boueher FR. Hearse DJ. Opie LH. Effects of trimetazidine on ischaemic contracture in isolated perfused rat hearts. J Cantiovosc Pharmaeol. 1994;24:45-49.
42 Katz AM. Is the failing heart energy depleted? Cardiol Clin 1998; 16:633-44.
43 Brottier L, Barat JL, Combe C, et al. Therapeutic value of a cardioprotective agent in patients with severe ischaemic cardiomyopathy. Eur Heart J.1990; 11:207-212.
44 El-Kady T, El-Sabban K, Gabaly M, et al. Effects of trimetazidine on myocardial perfusion and the contractile response of chronically dysfunctional myocardium in ischemic cardiomyopathy:a 24-month study. Am J Cardiovasc Drugs.2005;5: 271-278.
45 Kantor PF, Lucien A, Kozak R, et al. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000;86:580-588.
46 Lopaschuk GD, Barr R, Thomas PD, et al. Beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of glucose oxidation secondary to immbition of long-chain 3-ketoacyl coenzyme a thiolaso. Circ Res. 2003;93:e33-37.
47 Van Overschelde J-L, Wijns W, Depr'e C, et al. Mechanisms of chronic regional postischemia dysfunction in humans. Circulation 1993; 87 (5):1513-23
48 Ruiz-Meona M, Garcia-Dorado D, Julia M, et al. Pretreatment with trimetazidine increases sarcolemma mechanical resistance on reoxygenated myocytes. Cardiovasc Res 1996; 32 (3):587-92
49 Rossr R. Atherosclerosis:An inflammatory disease. N Engl J Med 1999;340:115-26.
50 Filiz Kuralay, Emel Altekin, Ayten Sayin Yazlar, et al. Suppression of angioplasty-related inflammation by pre-procedural treatment with trimetazidine. Tohoku J Exp Med 2006;208:203-212.
51 Kober G, Pennaforte S, Buck T, et al. Myocardial cytoprotection during percutaneous transluminal coronary angioplasty. Eur Heart J 1993;14(Suppl G):6-11
52 Steg PG, Grollier G, Gallay P, et al. for the LIST Study Group. A randomized double-blind trial of intravenous trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction. Int J Cardiol 2001;77(2-3):263-73
1 Lopaschuk GD, Belke DD, Gamble J, Itoi I, Schonekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1994; 1213:263-76.
2 Stanley WC, Lopaschuk GD, et al. Regulation of myocardial carbohydrate metabolism under normal and ischaemic condition. Potential for pharmacological interventions [J]. Cardiovasc Res,1997;33:243-57.
3 Lopaschuk GD, Stanley WC. Glucose metabolism in the ischemic heart. [J]. Circulation,1997;95:313-5.
4 Lopaschuk GD, Belke DD, Gamble J, Itoi I, Schonekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1994;1213:263-76.
5 Opie L. The mechanism of myocytes death in ischemia. Eur Heart J 1993;14(Suppl G]:31-3.
6 Stanley WC Partial fatty acid oxidation inhibitors for stable angina. Expert Opin Investig Drugs 2002; 11(5):615-29.
7 Kantor P, Lucien A, Kozak R, Lopaschuk G. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000;86(5):580-8.
8 Lopaschuk, GD, Barr R, Thomas PD, Dyck JR. Beneficial effects of trimetazidine in exvivo working ischemic hearts are due to astimulation of glucose oxidationse condary to inhibition of long-chain 3-ketoacylcoenzymea thiolase. Circ Res.2003;93(3):e33-37.
9 El Banani H, Bernard M, Baetz D, et al. Changes in intracellular sodium and pH during ischaemia-reperfusion are attenuated by trimetazidine. Comparison between lowand zero-flow ischaemia. Cardiovasc Res 2000;47:688-696.
10 Stanley WC, Marzilli M. Metabolic therapy in the treatment of ischaemic heart disease:the pharmacology of trimetazidine. Fundam Clin Pharmacol, 2003;17:133-145.
11 Morillas Blasco PJ, Hernandiz Martinez A, Azorin Villena I, et al. Mitochondrial changes induced by trimetazidine in the myocardium. Med Sci Monit 2005;11:162 -7.
12 Morin D, Elimadi A, SaPella R, et al. Evidence for the existence of [3H] trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore. Br J Pharmacol,1998;123(7):1385-1394.
13 Monteiro P, Duarte AI, Goncalves LM, et al. Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia. Eur J Pharmacol.2004;503:123-128.
14 Argaud L, Gomez L, Gateau-Roesch O, et al. Trimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia-reperfusion injury J Mol Cell Cardiol.2005;39(6):893-9.
15 Onay-Besikci A, Guner S, Arioglu E, et al. The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts. Can J Physiol Pharmacol 2007;85:527-535.
16 Lagadic-Gossman D, Le Prigent K, Feuvray D. Effects of trimetazidine on pHi, regulation in the rat isolated ventricular myocyte. Br J Pharmacol 1996;117:831-8.
17 Wisel S, Khan M, Kuppusamy ML, et al. Pharmacological preconditioning of mesenchymal stem cells with trimetazidine (1-[2,3,4-trimethoxybenzyl]piperazine) protects hypoxic cells against oxidative stress and enhances recovery of myocardial function in infracted heart through Bcl-2 expression. J Pharmacol Exp Ther.2009;329(2),543-550.
18 McClellan KJ, Plosker GL, Trimetazidine:A review of its use in stable angina pectoris and other coronary conditions. Drugs,1999;58:143-57.
19 Liu X, Gai Y,Liu F, et al. Trimetazidine inhibits pressure overload-induced cardiac fibrosis through NADPH oxidase-ROS-CTGF pathway. Cardiovasc Res. 2010;88(1):150-8.
20 Detry JM, Sellier P, Pennaforte S, et al. Trimetazidine:a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group. Br J Clin Pharmacol 1994;37(3):279-88.
21 Sellier P, Braustet JP Efficacy at trough and safety of trimetazidine MR 35 mg in patients with stable angina pectoris. Cardiovasc Drugs Ther 2001;15(Suppl):81
22 Marxilli M. Clinical benefits of a metabolic approach in the management of coronary patients. Rev Port Cardiol 2000;19(Suppl 5):V25-30.
23 Lei Zhang, Yizhou Lu, Hong Jiang, Additional Use of Trimetazidine in Patients With Chronic Heart Failure, A Meta-Analysis. J Am Coll Cardiol.2012;59:913-22.
24 Wenmeng W, Qizhu T. Early adminstration of trimetazidine may prevent or ameliorate diabttic cardiomyopathy. Med Hypotheses.2011;76:181-3.
25 Ioannidis JP, Karvouni E, Katritsis DG. Mortality risk conferred by small elevations of creatine kinase-MB isoenzyme after percutaneous coronary intervention. J Am Coll Cardiol 2003;42:1406-1411.
26 Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur Heart J 2007;28:2525-2538.
27 Testa L, Van Gaal WJ, Biondi Zoccai GG, et al. Myocardial infarction after percutaneous coronary intervention:a meta-analysis of troponin elevation applying the new universal definition. QJM 2009;102:369-378.
28 Khan TA, Bianchi C, Voisine P, et al. Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest. J Thorac Cardiovasc Surg 2004; 128:602-608.
29 Hayasaki T, Kaikita K, Okuma T, et al. CC chemokine receptor-2 deficiency attenuates oxidative stress and infarct size caused by myocardial ischemia-reperfusion in mice. Circ J 2006; 70:342-351.
30 Girish GB, Malcolm W, Derek MY, et al. Peri-procedural myocardial injury during percutaneous coronary intervention:an important target for cardioprotection. Eur Heart J 2011;32:23-32
31 Laurent Bonello, Pascal Sbragia, Nicolas Amabile, et al. Protective effect of an acute oral loading dose of trimetazidine on myocardial injury following percutaneous coronary Intervention. Heart 2007;93:703-707.
32 Labrou A et al.Trimetazidine Administration Minimizes Myocardial Damage and Improves Left Ventricular Function after Percutaneous Coronary Intervention. Am J Cardiovasc Drugs 2007; 7:143-150.
33 Filiz Kuralay, Emel Altekin, Ayten Sayin Yazlar, et al. Suppression of angioplasty-related inflammation by pre-procedural treatment with trimetazidine. Tohoku J Exp Med,2006;208:203-212.
34 Kober G, Pennaforte S, Buck T, et al. Myocardial cytoprotection during percutaneous transluminal coronary angioplasty. Eur Heart J 1993;14(Suppl G):6-11.
35 Polonski L, Dec I, Wojnar R, Wilczek K. Trimetazidine limits the effects of myocardial ischaemia during percutaneous coronary angioplasty. Curr Med Res Opin 2002;18(7):389-96.
36 Steg PG, Grollier G, Gallay P, et al. for the LIST Study Group. A randomized double-blind trial of intravenous trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction. Int J Cardiol 2001;77(2-3):263-73.
37 Tunerir B, Colak O, Alatas O, et al. Measurement of troponin T to detect cardioprotective effect of trimetazidine during coronary artery bypass grafting. Ann Thorac Surg 1999;68(6):2173-6.
38 Martins GF, Siqueira Filho AG, Santos JB, et al. Trimetazidine on Ischemic Injury and Reperfusion in Coronary Artery Bypass Grafting. Arq Bras Cardiol 2011; 97(3):209-216.
39 Iskesen I, Kurdal AT, Eserdag M, et al. Trimetazidine May Protect the Myocardium during Cardiac Surgery. Heart Surg Forum.2009;12:E175-9.
40 Martins GF, Siqueira Filho AG, Santos JB, et al. Trimetazidine and Inflammatory Response in Coronary Artery Bypass Grafting. Arq Bras Cardiol 2012;99(2):688-696.
41 Ihsan Iskesen, Osman Saribulbul, Mustafa Cerrahoglu, et al. Trimetazidine Reduces Oxidative Stress in Cardiac Surgery. Circ J 2006; 70:1169-73.
42 Barsotti A, Di Napoli P. Trimetazidine and cardioprotection during ischemia-reperfusion. Ital Heart J 2004; 5:29-36.
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