曲美他嗪对慢性心力衰竭疗效的系统评价
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摘要
研究背景
心脏的代谢治疗是指应用代谢相关药物以提高心肌细胞功能。曲美他嗪(Trimetazidine, TMZ)是该类药物中应用较多的一种,经常被单独或与其他药物联合应用,来治疗急性冠脉综合征或稳定型心绞痛。新近研究显示,该类药物对改善心力衰竭患者的局部以及整体心脏功能亦有益处。对于心力衰竭患者,从1939年即有假说认为衰竭的心肌存在着相对的能量欠缺,心肌处于一种对ATP需求的状态。慢性心力衰竭患者存在慢性代谢障碍,可以直接引起血流减少和静息状态下氧供减少,并且在运动负荷等情况下,无法保证心肌糖摄入以确使心肌的机械功能有效施行。另有研究显示扩张型心肌病患者存在糖代谢紊乱,在缺血心肌动物模型上也发现存在心肌的胰岛素抵抗。因此,对于衰竭心肌代谢治疗的第一步是通过增加心肌糖的供给和利用来直接增强葡萄糖的氧化。研究显示TMZ通过抑制氧化磷酸化和转移能量底物从脂肪酸到葡萄糖氧化,以增强葡萄糖代谢,从而发挥改善心肌代谢的作用；该作用是通过选择性抑制长链3-酮酰基辅酶A硫解酶(3-KAT)完成的。TMZ尚可发挥直接的细胞保护作用以及维持细胞内高能磷酸盐水平等作用。然而,有关TMZ对慢性心力衰竭患者的临床作用尚有争议,目前国内外对该领域已有临床和基础研究,但单个研究病例数较少,观察指标多样,并且结论尚存争议。
研究目的
我们通过采用国际循证医学通用的系统评价方法,对目前TMZ治疗慢性心功能衰竭的国内外相关临床实验分别进行系统评价,用以系统阐明以下问题：
①评价在传统治疗方案基础上加用TMZ对西方人群中在心脏基础疾病(缺血性心肌病以及非缺血性心肌病)合并慢性心力衰竭患者的临床获益,并评估TMZ在这部分患者临床和预后方面的作用。
②对于中国非缺血性心肌病合并慢性心衰患者,基础治疗加TMZ能否使患者进一步获益,以及对患者临床终点即再入院率和死亡率的影响。研究方法
遵循循证医学的原则,系统检索1966年-2010年12月Cochrane图书馆临床对照试验资料库、Pubmed以及EMbase数据库,对治疗策略的检索,检索词为"trimetazidine" OR "vasorel";对纳入疾病的检索,检索词为"dysfunctional myocardium" OR "heart failure" OR "left ventricular dysfunction" OR "dilated cardiomyopathy" OR "ischemic cardiomyopathy";对随机对照试验的检索,检索词为："randomized controlled trials" OR "trial" OR "clinical trial" OR "random allocation" OR "double-blind method" OR "single-blind method"。检索目标论著均为英文论著,纳入随机、盲法、对照研究；同时检索1979年-2010年12月中国知网、中国国家数字图书馆、万方数据库,检索词‘曲美他嗪’或‘万爽力’和‘慢性心功能不全’或‘慢性心力衰竭’,剔除包含冠心病或缺血性心肌病的研究,纳入随机对照研究；并联系施维雅公司检索相关文集报道。纳入文章的参考文献均以手工方式进行进一步文献检索。研究目标为在常规抗心衰治疗基础上联合应用TMZ对慢性心力衰竭观察其治疗获益。排除重复发表的研究、未设立对照组的研究和动物实验,并排除药物组和对照组基础治疗有明显差别的文献；英文文献选用纽约心脏协会(New York Heart Association,NYHA)心功能分级、左室射血分数(left ventricular ejection fraction, LVEF)、左室缩短率(fractional shortening,FS)、E/A比、左室舒张末容积(left ventricularend-dialation volume,LVEDV)、左室收缩末容积(left ventricular end-systolic volume, LVESV)、左室舒张末直径(left ventricular end-dialation diameter, LVEDD)、左室收缩末直径(left ventricular end-systolic diameter, LVESD)和室壁运动积分指数(wall motion score index,WMSI)来评价TMZ对慢性衰竭心肌的临床和实验室检查指标等方面的作用；选取空腹血糖以及糖化血红蛋白(HbAC1)以评价TMZ对血糖代谢的影响；选取运动时间(exercise time,ET)和生活质量评价指数(quanlity of life,QOL)评价TMZ对生存质量的影响；以C反应蛋白(C reactive protein,CRP)反应TMZ对炎症情况的影响；以血压心率等指标评价TMZ对患者基础血液动力学的影响。中文文献则选用临床治疗效果(总有效率)、LVEF、心输出量(cardiac output, CO)、心脏指数(cardiac index, CI)、LVEDD、LVESD、NYHA心功能分级、6分钟运动试验(6 minutes walk test,6MWT)和利钠肽(brain natriuretic peptide,BNP)来评价TMZ对慢性衰竭心肌的临床以及实验室检查指标的作用；以血压心率等指标评价TMZ对患者血液动力学的影响,并以死亡率和心血管疾病再入院率等联合预测对其远期预后的影响。应用STATA11.0软件进行统计分析。异质性分析计算Z评分和卡方检验,以P<0.1为具有异质性,根据异质性结果选用进一步的系统评价方法。如果P>0.1,显示数据之间不存在异质性,采用固定效应模型进行进一步分析。如P<0.1,显示数据之间存在异质性,则采用随机效应模型进行进一步分析。病例数、均数以及标准差均来自文献原始数据。以P<0.05表示具有显著的统计学意义,以P<0.01表示具有非常显著的统计学意义。
结果：
共检索到122篇英文文献和1873篇中文文献,经过筛选,共纳入17篇英文文献和32篇中文文献,均为随机对照研究。英文文献一共901名患者入选,患者病因不限,包括缺血性心肌病和非缺血性心肌病患者,均合并慢性心力衰竭,部分研究对象合并糖尿病；纳入的中文文献均为非缺血性心肌病合并慢性心衰患者,共纳入1789名患者,基础疾病包括扩张型心肌病、肥厚型心肌病、酒精性心肌病、风湿性心脏病、心肌炎和老年退行性心瓣膜病。各研究纳入病例组和对照组的基线条件和基础治疗一致。
[TMZ治疗西方慢性心衰患者临床试验的荟萃分析]
①纳入文献研究质量：4个为A级,10个为B级,3个为C级。
②在心衰传统治疗方案中加入TMZ,对各种原因所致的慢性心衰,均可显著降低患者的NYHA心功能分级(pooled RR:-1.28,95%CI:-1.89,-0.67),提高LVEF(SMD:1.07,95%CI:0.77,1.37)和LVFS(SMD:1.34,95%CI：0.12,2.56),缩小LVEDD(SMD:-0.88,95%CI:-1.76,-0.01)和LVESD(SMD:-1.74,95%CI:-3.01,-0.47),降低WMSI(SMD:-0.70,95%CI:-1.01,-0.38),改善患者E/A比(SMD:1.66,95%CI：0.55,2.76),并显著提高患者运动时间(SMD:0.91,95%CI:0.25,1.57),对患者生活质量(QOL)的影响处于统计学边缘(SMD:1.38,95%CI:-0.03,2.75)；而对LVEDV的作用未见统计学差异(SMD：-0.25,95%CI：-0.59,0.10)。
③患者的血糖代谢显示明显受益,与传统治疗比较,空腹血糖(SMD：-0.72,95%CI：-1.01,-0.42)和HbAC1水平(SMD：-0.44,95%CI：-0.74,-0.10)在TMZ治疗组与常规治疗组相比较均可获下降。
④TMZ组表现出对炎症因子CRP水平明显下降(SMD：-1.14,95%CI：-1.58,-0.71)
⑤对于非缺血性心肌病心衰患者,TMZ并未表现出对LVEF的临床益处(SMD：0.81,95%CI：-0.32,1.93)。但文献少(2篇),存在偏倚。
⑥TMZ对血液动力学无明显影响,基础血压心率未见变化(P>0.05)。
⑦TMZ的副作用包括胃肠道反应和头痛等,共有2例患者因为药物副作用反应退出试验。
⑧2篇文献描述了TMZ组和对照组再入院和死亡病例情况。受文献具体指标和数据所限,未对临床试验金终点即再入院率或死亡率等指标做出评价。
⑨纳入文献在基础指标之外,大多描述性表述了TMZ对血脂等基础情况的影响。大部分研究发现TMZ对患者的血脂各项指标无明显影响,其中1篇针对扩张型心肌病心衰治疗的报道观察到TMZ尚具有升高HDL-L的作用。因为血脂水平变化仅1篇给出具体数值,未行进一步系统分析。
[TMZ治疗中国非缺血性心肌病慢性心衰患者的荟萃分析]
①纳入文献研究质量：0个为A级,11个为B级,21个为C级。
②在规范心衰治疗的基础上加用TMZ,可显著提高中国非缺血性心肌病合并慢性心衰患者的临床治疗效果,治疗总有效率升高(pooled RR：4.59,95%CI：3.26,6.47),具体表现在可以显著升高LVEF(SMD：0.86,95%CI：0.56,1.16),并使CO(SMD：0.85,95%CI：0.41,1.28)和CI(SMD：0.80,95%CI：0.56,1.05)增加,缩小扩大的左室腔,LVEDD(SMD：-0.73,95%CI：-1.05,-0.40)和LVESD(SMD：-0.97,95%CI：-1.59,-0.36)均显著缩小；降低BNP(SMD：-1.09,95%CI：-1.52,-0.66),并能够明显改善患者心功能状态(NYHA心功能分级：SMD：-0.69,95%CI：-0.90,-0.47)和运动能力(6MWT:SMD:0.89,95%CI:0.71,1.06)。
③在基础治疗方案中增加TMZ的慢性心衰患者,随访期间因为心血管事件的再入院率(pooled RR:0.21,95%CI:0.11,0.41)和死亡率((pooledRR：0.18,95%CI：0.07,0.46)显著下降。
④基础治疗加TMZ对基础心率并无影响(SMD：0.18,95%CI：0.07,0.46),患者的血压亦未受影响(收缩压SMD：0.05,95%CI：-0.36,0.46；舒张压：SMD：-0.09,95%CI：-0.49,0.32)。
⑤2篇文献对血糖进行治疗前后比较,认为基础治疗加以TMZ对血糖代谢有益。6篇文献描述性表述了TMZ对血脂等基础情况的影响,认为TMZ对患者的血脂各项指标无明显影响,但对血脂水平的变化并未给出具体数值,故未行进一步系统分析。
⑥TMZ组的不良反应包括头晕以及恶心等胃肠道反应,但未见患者因药物不良反应退出试验。
结论
[TMZ治疗西方慢性心衰患者临床试验的荟萃分析]
①TMZ联合常规系统治疗对于慢性心衰可以有效地提高左室收缩功能,并且舒张功能亦可受益,并改善患者生活质量。
②TMZ联合常规系统治疗可以进一步减少增大的左室直径,在伴或不伴糖尿病的心衰患者中均得到类似结论。
③TMZ组血糖代谢明确改善,空腹血糖和HbAC1均受益。
④TMZ联合常规系统治疗可以降低慢性心衰患者的炎症因子水平。
⑤TMZ应用于慢性心衰患者,对血液动力学并无影响,不影响患者的基础血压和心率,副作用大多局限于胃肠道反应,临床应用禁忌症少,相对安全。
⑥对于慢性心衰的入院率和死亡率,尚未得到TMZ作用的明确证据。有meta分析认为LVEF、LVESD和LVEDD的提高可以改善心衰患者的预后,那么或许可以推测,在心衰的基础治疗中加入TMZ,可以减低患者再入院和死亡发生。
[TMZ治疗中国非缺血性心肌病慢性心衰患者的荟萃分析]
①对于中国非缺血性心肌病慢性心衰患者,TMZ联合心衰常规系统治疗可以显著提高临床治疗有效率；具体而言,TMZ能够提高左室功能,缩小扩大的左室,改善患者运动耐量,在中国非缺血性心肌病心力衰竭患者中无论源于何种原发病均可以受益。
②在基础治疗中加入TMZ,可以有效减低中国非缺血性心肌病心衰患者再入院和死亡发生。
③TMZ应用于非缺血性心肌病慢性心衰患者,对血液动力学影响小,而且不影响患者的心率,副作用轻微且可耐受,临床应用相对安全。局限性及展望
本系统评价中纳入的临床试验样本量均较小,而且观察时间大多为3-6个月,很难得到有关TMZ与临床硬终点诸如死亡率或住院率的确切结论,而这些指标才是评价药物疗效的金标准；TMZ已经被证实可以改善缺血性心肌病患者的临床症状及预后。针对英文文献的研究所纳入的临床试验中研究对象基础心脏病大多数是冠心病,这样就会出现偏倚：冠心病患者缺血改善,也可以改善心功能状态。研究对象中未完全排除糖尿病,也就是未能排除TMZ由于对血糖代谢的益处而发挥的对临床症状等方面的作用,产生部分偏倚。大规模的相关临床试验,特别是对于排除上述混杂因素的心衰患者进行TMZ治疗的随机对照研究,观察时间相对延长,有望得到在常规治疗基础上加用TMZ是否能够确实较少慢性心衰患者死亡率的确凿资料。
Background
The term metabolic treatment has been used to describe the use of drugs that improve the function of cardiomyocytes. Trimetazidine(TMZ) is the most investigated of these drugs. It is commonly used both alone and in combination with hemodynamic antianginal in the treatment of acute coronary syndrome or stable angina. More recent evidence suggests the potential benefit of this agent on regional and global myocardial dysfunction. There has been a consistent hypothesis that the failing heart exists in a relatively energy-starving mode in which substrate preferene may switch in response to greater demands of ATP since 1939. Chronic metabolic abnormalities in patients with heart failure have been directly associated with reduced flow and oxygen consumption at rest and the lack of stress-induced increase in myocardial glucose uptake necessary to maintain cardiac mechanical efficiency. Patients with idiopathic dilated cardiomyopathy have demonstrated impaired glucose metabolism upon careful metabolic evaluation, and myocardial insulin resistance has been demonstrated in animal models of cardiomyopathy. Therefore, the first approach for myocardial dysfunction is to directly enhance the glucose oxidation pathways via promoting the capacity for glucose uptake and utilization in the myocardium.TMZ has been shown to affect myocardial substrate utilization by inhibiting oxidative phosphorylation and by shifting energy production from FFA to glucose oxidation. Experimental evidence indicates that this effect is predominantly caused by a selective block of long chain 3-ketaacyl coenzyme A thiolase (3-KAT); Additionally, TMZ can protect cellular function directly and maintain intracellular energyphosphate level. However, these issues are still under debate. This sustained the rationale for evaluating the efficacy of TMZ in combination on a large number of patients with chronic cardiac dysfunction.This meta-analysis was exclusively performed on RCT studies of TMZ.
Objectives
Systemic analyse methods were adopted to analyze RCT studies within China and the world, to clarify questions below:
1 To evaluate clinical efficacy and safety of TMZ for chronic heart failure patients with sorts of primary diseases on the baisis of traditional treatment, and assess its action on prognosis of chronic heart failure.
2 To evaluate clinical efficacy and safety of adding TMZ on the baisis of traditional treatment to Chinese chronic heart failure patients with primary heart diseases but not ischemic coronary diseases, and assess its action on rehospitality and motality of Chinese chronic heart failure.
Materials and methods
Several search strategies were undertaken to identify relevant publications. A systematic review, including electronic databases and selective hand searching, was used. The MEDLINE database of the National Library of Medicine and EMbase, converting the period from 1990 to August 2010, were consulted. We also searched Cochrane Central Register of Controlled Trials(CENTRAL) and database of ongoing trials:cuSMDent controlled trials at the same duration. The term 'trimetazidine' OR 'vasorel' and 'dysfunctional myocardium' OR 'heart failure' OR 'left ventricular dysfunction' OR 'dilated cardiomathy' OR 'ischemic cardiomyopathy' and publication types 'randomized controlled trials' OR 'trial' OR 'clinical trial' OR 'double-blind method' OR 'single-blind method' were used in the text search. A manual research of reference lists from identified studies and from review articles to find additional sources or unpublished abstracts (presented at major scientific meetings) was also performed. Published reports in English were identified and assessed for inclusion in this meta-analysis.Only randomized, parallel-group, blind, reference drug-controlled clinical trials evaluating the efficacy of TMZ in the treatment of heart failure with EF≤45% were selected. Meanwhile we searched 'Chinese Zhi net','Chinese National Digit Library' and 'Wanfang Data Liarary' from 1979 to December,2010. The term 'trimetazidine' OR 'vasorel' and 'chronic heart failure' were used in the text search. Ischemic coronary disease was rejected. A manual research of reference lists from identified studies and from review articles to find additional sources or unpublished abstracts (presented at major scientific meetings) was also performed. Drug-controlled clinical trials evaluating the efficacy of TMZ in the treatment of chronic heart failure with primary heary diseases but not ischemic cardiomyopathy were selected.Data were collected independently by two reviewers.left ventricular ejection fracture(LVEF), end-diastolic volume(EDV) and end-systolic volume(ESV) are predictors of mortality in patients with cardiac dysfunction. Overall, in the present analysis, for English documents,these three ergometric parameters, which were LVEF(%), LVEDV(ml) and LVESV(ml) and their SD were selected, together with New York heart Association(NYHA) heart function classification, left ventricular ejectional fraction(LVEF), E/A ratio, left ventricular end-dialation volume(LVEDV),left ventricular end-systolic volume(LVESV), fractional shortening(FS), left ventricular end-systolic(LVEDD), left ventricular end-dialation diameter(LVESD),and wall motion score index (WMSI) to assess clinical efficacy of TMZ, and indexes 'obesity glucose' and "HbACl" were selected to assess the action of TMZ for glucose metaboliam, exercise time(ET) and quality of life(QOL). And for Chinese documents, total effective rate and left ventricular ejectional fraction(LVEF), left ventricular end-systolic(LVEDD), left ventricular end-dialation diameter(LVESD), c reactive protein(CRP), cardiac output(CO), cardiac index(CI), wall motion score index(WMSI) and Brain natriuretic peptide(BNP) were selected to assess clinical efficacy of TMZ, New York heart Association(NYHA) heart function classification and 6 minute walk test(6MWT) were used to eveluate effection of TMZ foe patients'life status, blood pressure and heart rate were adopted to analyse the influence of TMZ for hemodynamics, most importantly, mortality and rehospitality were the vital indexes to estimate effection of TMZ for prognosis of Chinese chronic heart dysfundtion. All were measured in the TMZ-treated and controlled groups, at baseline and at the end of the trial period. All analyzed variables were assumed to be normally distributed. Classical standard statistical methods for normally distributed data were used. A test of heteogeneity was performed by calculating the sum of the squared distance of each study effect from the combined effect and weighting each value and according more weight to more precise studies.Data analysis was performed with STATA11.0. Data of sufficient quality and sufficient similarity were included in a meta-analysis. Results from dichotomous data were presented as relative risks, and results from continuous data were presented as weighted mean differences. Overall results were calculated based on the random-effects model as heterogeneity was observed. A fixed-effects model was used if no heterogeneity existed, otherwise a random-effect model was selected. Heterogeneity was tested withχ2 test, with statistical significance considered as P< 0.1. Mean and dispersion parameters presented in the stable come directly from results reported in the articles. SDs were calculated from SEMs, when appropriated. Z score shows stastically differences, P<0.05 means there exits stastically differences, and P<0.01 means there exits significant stastically differences.
Results
122 English documents and 1873 Chinese documents were selected totally and according to roll-in criteria,17 English randomized, blind, controlled studies including 901 patients and 32 Chinese Case-control studies including 1789 patinets were included and the relevant data was extracted. Baseline diseases were ischemic and non-ischemic cardiomyopathy in Englishi trials and in Chinese trials, we ejected ischemic heart dysfunction. The baseline situation and treatment were matched within TMZ groups and control groups in all trials.
[meta-analysis in English documents]
1 Quantity of enrolled documents:4 of A class,10 of B class and 3 of C class.
2 TMZ can significantly redused NYHA classification of patients with chronic heart failure(pooled RR:-1.28,95%CI:-1.89,-0.67),and increased LVEF(SMD:1.07, 95%CI:0.77,1.37) and LVFS(SMD:1.34,95%CI:0.12,2.56), lessened LVEDD(SMD:-0.88,95%CI:-1.76,-0.01) and LVESD(SMD:-1.74,95%CI:-3.01,-0.47), decreased WMSI(SMD:-0.70,95%CI:-1.01,-0.38), improved E/A ratio((SMD:1.66,95%CI: 0.55,2.76), and markedly prolonged ET (SMD:0.91,95%CI:0.25,1.57). Its effect for QOL was at the STATAstical margine(SMD:1.38,95%CI:-0.03,2.75) and seemed have no action on LVEDV(SMD:-0.25,95%CI:-0.59,0.10).
3 Glucose metabolism was modified markedly, including obesity glucose (SMD:-0.72,95%CI:-1.01,-0.42) and HbAC1(SMD:-0.44,95%CI:-0.74,-0.10).
4 CRP level decreased markedly in TMZ group((SMD:-1.14,95%CI:-1.58,-0.71).
5 For non-ischemic cardimyopathy patients, TMZ seems have no effection on LVEF((SMD:0.81,95%CI:-0.32,1.93). There would be bias exsisting because there were only two documents enrolled in the meta-analysis.
6 TMZ had no affection on hemodynamics. There were no change on baseline blood pressure and heart rate (P>0.05).
7 Side action were gastric reaction and headache, and two patients were dropped out from trials because of side actions.
8 Rehospitaly and mortality were not been analysed because of the limited data provided.
9 Most documens described TMZ exerted no effection on blood lipid levels but did not provide concrete data. One document found that HDL-C level increased after treatment of TMZ.
[meta-analysis in Chinese documents]
1 Quantity of enrolled documents:none of A class,11 of B class and 21 of C class.
2 TMZ can significantly increase total curative effective rates of Chinese patients with chronic heart failure (pooled RR:4.59,95%CI:3.26,6.47), increased LVEF(SMD:0.86,95%CI:0.56,1.16), lessened LVEDD(SMD:-0.73, 95%CI:-1.05,-0.40) and LVESD(SMD:-0.97,95%CI:-1.59,-0.36), aggrandized CO(SMD:0.85,95%CI:0.41,1.28) and CI(SMD:0.80,95%CI:0.56,1.05), and markedly decreased BNP(SMD:-1.09,95%CI:-1.52,-0.66). In addition,TMZ had benefit for patients'cardiac function(NYHA:SMD:-0.69,95%CI:-0.90,-0.47) and motive ability (6MWT:SMD:0.89,95%CI:0.71,1.06)。
3 Rehospitaly and mortality were significantly decreased during follow-up periods (SMD:0.21,95%CI:0.11,0.41) and(SMD:0.18,95%CI:0.07,0.46).
4 TMZ had no affection on hemodynamics. There were no change on baseline blood pressure and heart rate (P>0.05).
5 Side action were gastric reaction and headache, and no patients were dropped out from trials because of side actions.
6 Glucose and lipid metabolism were described well-enfluenced in some documents.
Cinclusion
[meta-analysis in English documents]
1 TMZ, together with systemic treatment, could effectively increase left ventricular function, including constractive and diastolic function and improved quality of life of patients with chronic heart failure.
2 TMZ could reduced enlarged left ventricular. And the impaction was same on patients with or without diabetes.
3 TMZ exerted beneficial action on glucose metabolism.
4 CRP levels were decreased in TMZ group, which means TMZ's useful function on inflmmatary factors.
5 TMZ exerted slight action on hemodynamics and had limited reversible side action, which shows applying safety of this medicine.
6 No definite conclusion can be drawn on rehospitality and mortality for TMZ. Since it was reported that LVEF, LVEDD and LVESD could act as predictors for prognosis of chronic heart failure patients, maybe we can say that TMZ could reduce rehospitality and mortality because of its action on these three indexes.
[meta-analysis in Chinese documents]
1For Chinese non-ischemic heart failure patients, TMZ together with systemic treatment could effectively increase tatal curativeeffective rates, increased heart function and improved exercising tolerance and reduced enlarged left ventricular, no metter what primary diseases they suffered from.
2 TMZ markedly decreased rehospitality and mortality of Chinese non-ischemic heart failure patients.
3 TMZ exerted slight action on hemodynamics and had limited reversible side action, which shows applying safety of this medicine.
Limitation
This meta-analysis has drawn a positive conclusion of the effect of TMZ on human left ventricular dysfunction, but it has many limitations. Firstly, the enrolled trials are all small-scaled studies with observing period of only three to six months. So they can not have results about TMZ and mortality or hospitality, which is the golden indicator for evaluating therapeutic effects. Secondly, TMZ has proved to be effective in the treatment of chronic stable angina via metabolic pathways, and primary diseases of HF patients of most of the enrolled trials are ischeamic cardiomyopathy. So the benefit for ischeamic heart may also have positive effect on heart function. The outstanding challenge is now to undertake a serious study of the effect of TMZ on human heart failure, including the non-ischaemic variety, making the study large enough and observing duration long enough to test the effect that metabolic therapy by TMZ could reduce death rates in other-wise fully treated patients.
心脏的代谢治疗是指应用代谢相关药物以提高心肌细胞功能。曲美他嗪(Trimetazidine, TMZ)是该类药物中应用较多的一种,经常被单独或与其他药物联合应用,来治疗急性冠脉综合征或稳定型心绞痛。新近研究显示,该类药物对改善心力衰竭患者的局部以及整体心脏功能亦有益处。对于心力衰竭患者,从1939年即有假说认为衰竭的心肌存在着相对的能量欠缺,心肌处于一种对ATP需求的状态。慢性心力衰竭患者存在慢性代谢障碍,可以直接引起血流减少和静息状态下氧供减少,并且在运动负荷等情况下,无法保证心肌糖摄入以确使心肌的机械功能有效施行。另有研究显示扩张型心肌病患者存在糖代谢紊乱,在缺血心肌动物模型上也发现存在心肌的胰岛素抵抗。因此,对于衰竭心肌代谢治疗的第一步是通过增加心肌糖的供给和利用来直接增强葡萄糖的氧化。研究显示TMZ通过抑制氧化磷酸化和转移能量底物从脂肪酸到葡萄糖氧化,以增强葡萄糖代谢,从而发挥改善心肌代谢的作用；该作用是通过选择性抑制长链3-酮酰基辅酶A硫解酶(3-KAT)完成的。TMZ尚可发挥直接的细胞保护作用以及维持细胞内高能磷酸盐水平等作用。然而,有关TMZ对慢性心力衰竭患者的临床作用尚有争议,目前国内外对该领域已有临床和基础研究,但单个研究病例数较少,观察指标多样,并且结论尚存争议。
研究目的
我们通过采用国际循证医学通用的系统评价方法,对目前TMZ治疗慢性心功能衰竭的国内外相关临床实验分别进行系统评价,用以系统阐明以下问题：
①评价在传统治疗方案基础上加用TMZ对西方人群中在心脏基础疾病(缺血性心肌病以及非缺血性心肌病)合并慢性心力衰竭患者的临床获益,并评估TMZ在这部分患者临床和预后方面的作用。
②对于中国非缺血性心肌病合并慢性心衰患者,基础治疗加TMZ能否使患者进一步获益,以及对患者临床终点即再入院率和死亡率的影响。研究方法
遵循循证医学的原则,系统检索1966年-2010年12月Cochrane图书馆临床对照试验资料库、Pubmed以及EMbase数据库,对治疗策略的检索,检索词为"trimetazidine" OR "vasorel";对纳入疾病的检索,检索词为"dysfunctional myocardium" OR "heart failure" OR "left ventricular dysfunction" OR "dilated cardiomyopathy" OR "ischemic cardiomyopathy";对随机对照试验的检索,检索词为："randomized controlled trials" OR "trial" OR "clinical trial" OR "random allocation" OR "double-blind method" OR "single-blind method"。检索目标论著均为英文论著,纳入随机、盲法、对照研究；同时检索1979年-2010年12月中国知网、中国国家数字图书馆、万方数据库,检索词‘曲美他嗪’或‘万爽力’和‘慢性心功能不全’或‘慢性心力衰竭’,剔除包含冠心病或缺血性心肌病的研究,纳入随机对照研究；并联系施维雅公司检索相关文集报道。纳入文章的参考文献均以手工方式进行进一步文献检索。研究目标为在常规抗心衰治疗基础上联合应用TMZ对慢性心力衰竭观察其治疗获益。排除重复发表的研究、未设立对照组的研究和动物实验,并排除药物组和对照组基础治疗有明显差别的文献；英文文献选用纽约心脏协会(New York Heart Association,NYHA)心功能分级、左室射血分数(left ventricular ejection fraction, LVEF)、左室缩短率(fractional shortening,FS)、E/A比、左室舒张末容积(left ventricularend-dialation volume,LVEDV)、左室收缩末容积(left ventricular end-systolic volume, LVESV)、左室舒张末直径(left ventricular end-dialation diameter, LVEDD)、左室收缩末直径(left ventricular end-systolic diameter, LVESD)和室壁运动积分指数(wall motion score index,WMSI)来评价TMZ对慢性衰竭心肌的临床和实验室检查指标等方面的作用；选取空腹血糖以及糖化血红蛋白(HbAC1)以评价TMZ对血糖代谢的影响；选取运动时间(exercise time,ET)和生活质量评价指数(quanlity of life,QOL)评价TMZ对生存质量的影响；以C反应蛋白(C reactive protein,CRP)反应TMZ对炎症情况的影响；以血压心率等指标评价TMZ对患者基础血液动力学的影响。中文文献则选用临床治疗效果(总有效率)、LVEF、心输出量(cardiac output, CO)、心脏指数(cardiac index, CI)、LVEDD、LVESD、NYHA心功能分级、6分钟运动试验(6 minutes walk test,6MWT)和利钠肽(brain natriuretic peptide,BNP)来评价TMZ对慢性衰竭心肌的临床以及实验室检查指标的作用；以血压心率等指标评价TMZ对患者血液动力学的影响,并以死亡率和心血管疾病再入院率等联合预测对其远期预后的影响。应用STATA11.0软件进行统计分析。异质性分析计算Z评分和卡方检验,以P<0.1为具有异质性,根据异质性结果选用进一步的系统评价方法。如果P>0.1,显示数据之间不存在异质性,采用固定效应模型进行进一步分析。如P<0.1,显示数据之间存在异质性,则采用随机效应模型进行进一步分析。病例数、均数以及标准差均来自文献原始数据。以P<0.05表示具有显著的统计学意义,以P<0.01表示具有非常显著的统计学意义。
结果：
共检索到122篇英文文献和1873篇中文文献,经过筛选,共纳入17篇英文文献和32篇中文文献,均为随机对照研究。英文文献一共901名患者入选,患者病因不限,包括缺血性心肌病和非缺血性心肌病患者,均合并慢性心力衰竭,部分研究对象合并糖尿病；纳入的中文文献均为非缺血性心肌病合并慢性心衰患者,共纳入1789名患者,基础疾病包括扩张型心肌病、肥厚型心肌病、酒精性心肌病、风湿性心脏病、心肌炎和老年退行性心瓣膜病。各研究纳入病例组和对照组的基线条件和基础治疗一致。
[TMZ治疗西方慢性心衰患者临床试验的荟萃分析]
①纳入文献研究质量：4个为A级,10个为B级,3个为C级。
②在心衰传统治疗方案中加入TMZ,对各种原因所致的慢性心衰,均可显著降低患者的NYHA心功能分级(pooled RR:-1.28,95%CI:-1.89,-0.67),提高LVEF(SMD:1.07,95%CI:0.77,1.37)和LVFS(SMD:1.34,95%CI：0.12,2.56),缩小LVEDD(SMD:-0.88,95%CI:-1.76,-0.01)和LVESD(SMD:-1.74,95%CI:-3.01,-0.47),降低WMSI(SMD:-0.70,95%CI:-1.01,-0.38),改善患者E/A比(SMD:1.66,95%CI：0.55,2.76),并显著提高患者运动时间(SMD:0.91,95%CI:0.25,1.57),对患者生活质量(QOL)的影响处于统计学边缘(SMD:1.38,95%CI:-0.03,2.75)；而对LVEDV的作用未见统计学差异(SMD：-0.25,95%CI：-0.59,0.10)。
③患者的血糖代谢显示明显受益,与传统治疗比较,空腹血糖(SMD：-0.72,95%CI：-1.01,-0.42)和HbAC1水平(SMD：-0.44,95%CI：-0.74,-0.10)在TMZ治疗组与常规治疗组相比较均可获下降。
④TMZ组表现出对炎症因子CRP水平明显下降(SMD：-1.14,95%CI：-1.58,-0.71)
⑤对于非缺血性心肌病心衰患者,TMZ并未表现出对LVEF的临床益处(SMD：0.81,95%CI：-0.32,1.93)。但文献少(2篇),存在偏倚。
⑥TMZ对血液动力学无明显影响,基础血压心率未见变化(P>0.05)。
⑦TMZ的副作用包括胃肠道反应和头痛等,共有2例患者因为药物副作用反应退出试验。
⑧2篇文献描述了TMZ组和对照组再入院和死亡病例情况。受文献具体指标和数据所限,未对临床试验金终点即再入院率或死亡率等指标做出评价。
⑨纳入文献在基础指标之外,大多描述性表述了TMZ对血脂等基础情况的影响。大部分研究发现TMZ对患者的血脂各项指标无明显影响,其中1篇针对扩张型心肌病心衰治疗的报道观察到TMZ尚具有升高HDL-L的作用。因为血脂水平变化仅1篇给出具体数值,未行进一步系统分析。
[TMZ治疗中国非缺血性心肌病慢性心衰患者的荟萃分析]
①纳入文献研究质量：0个为A级,11个为B级,21个为C级。
②在规范心衰治疗的基础上加用TMZ,可显著提高中国非缺血性心肌病合并慢性心衰患者的临床治疗效果,治疗总有效率升高(pooled RR：4.59,95%CI：3.26,6.47),具体表现在可以显著升高LVEF(SMD：0.86,95%CI：0.56,1.16),并使CO(SMD：0.85,95%CI：0.41,1.28)和CI(SMD：0.80,95%CI：0.56,1.05)增加,缩小扩大的左室腔,LVEDD(SMD：-0.73,95%CI：-1.05,-0.40)和LVESD(SMD：-0.97,95%CI：-1.59,-0.36)均显著缩小；降低BNP(SMD：-1.09,95%CI：-1.52,-0.66),并能够明显改善患者心功能状态(NYHA心功能分级：SMD：-0.69,95%CI：-0.90,-0.47)和运动能力(6MWT:SMD:0.89,95%CI:0.71,1.06)。
③在基础治疗方案中增加TMZ的慢性心衰患者,随访期间因为心血管事件的再入院率(pooled RR:0.21,95%CI:0.11,0.41)和死亡率((pooledRR：0.18,95%CI：0.07,0.46)显著下降。
④基础治疗加TMZ对基础心率并无影响(SMD：0.18,95%CI：0.07,0.46),患者的血压亦未受影响(收缩压SMD：0.05,95%CI：-0.36,0.46；舒张压：SMD：-0.09,95%CI：-0.49,0.32)。
⑤2篇文献对血糖进行治疗前后比较,认为基础治疗加以TMZ对血糖代谢有益。6篇文献描述性表述了TMZ对血脂等基础情况的影响,认为TMZ对患者的血脂各项指标无明显影响,但对血脂水平的变化并未给出具体数值,故未行进一步系统分析。
⑥TMZ组的不良反应包括头晕以及恶心等胃肠道反应,但未见患者因药物不良反应退出试验。
结论
[TMZ治疗西方慢性心衰患者临床试验的荟萃分析]
①TMZ联合常规系统治疗对于慢性心衰可以有效地提高左室收缩功能,并且舒张功能亦可受益,并改善患者生活质量。
②TMZ联合常规系统治疗可以进一步减少增大的左室直径,在伴或不伴糖尿病的心衰患者中均得到类似结论。
③TMZ组血糖代谢明确改善,空腹血糖和HbAC1均受益。
④TMZ联合常规系统治疗可以降低慢性心衰患者的炎症因子水平。
⑤TMZ应用于慢性心衰患者,对血液动力学并无影响,不影响患者的基础血压和心率,副作用大多局限于胃肠道反应,临床应用禁忌症少,相对安全。
⑥对于慢性心衰的入院率和死亡率,尚未得到TMZ作用的明确证据。有meta分析认为LVEF、LVESD和LVEDD的提高可以改善心衰患者的预后,那么或许可以推测,在心衰的基础治疗中加入TMZ,可以减低患者再入院和死亡发生。
[TMZ治疗中国非缺血性心肌病慢性心衰患者的荟萃分析]
①对于中国非缺血性心肌病慢性心衰患者,TMZ联合心衰常规系统治疗可以显著提高临床治疗有效率；具体而言,TMZ能够提高左室功能,缩小扩大的左室,改善患者运动耐量,在中国非缺血性心肌病心力衰竭患者中无论源于何种原发病均可以受益。
②在基础治疗中加入TMZ,可以有效减低中国非缺血性心肌病心衰患者再入院和死亡发生。
③TMZ应用于非缺血性心肌病慢性心衰患者,对血液动力学影响小,而且不影响患者的心率,副作用轻微且可耐受,临床应用相对安全。局限性及展望
本系统评价中纳入的临床试验样本量均较小,而且观察时间大多为3-6个月,很难得到有关TMZ与临床硬终点诸如死亡率或住院率的确切结论,而这些指标才是评价药物疗效的金标准；TMZ已经被证实可以改善缺血性心肌病患者的临床症状及预后。针对英文文献的研究所纳入的临床试验中研究对象基础心脏病大多数是冠心病,这样就会出现偏倚：冠心病患者缺血改善,也可以改善心功能状态。研究对象中未完全排除糖尿病,也就是未能排除TMZ由于对血糖代谢的益处而发挥的对临床症状等方面的作用,产生部分偏倚。大规模的相关临床试验,特别是对于排除上述混杂因素的心衰患者进行TMZ治疗的随机对照研究,观察时间相对延长,有望得到在常规治疗基础上加用TMZ是否能够确实较少慢性心衰患者死亡率的确凿资料。
Background
The term metabolic treatment has been used to describe the use of drugs that improve the function of cardiomyocytes. Trimetazidine(TMZ) is the most investigated of these drugs. It is commonly used both alone and in combination with hemodynamic antianginal in the treatment of acute coronary syndrome or stable angina. More recent evidence suggests the potential benefit of this agent on regional and global myocardial dysfunction. There has been a consistent hypothesis that the failing heart exists in a relatively energy-starving mode in which substrate preferene may switch in response to greater demands of ATP since 1939. Chronic metabolic abnormalities in patients with heart failure have been directly associated with reduced flow and oxygen consumption at rest and the lack of stress-induced increase in myocardial glucose uptake necessary to maintain cardiac mechanical efficiency. Patients with idiopathic dilated cardiomyopathy have demonstrated impaired glucose metabolism upon careful metabolic evaluation, and myocardial insulin resistance has been demonstrated in animal models of cardiomyopathy. Therefore, the first approach for myocardial dysfunction is to directly enhance the glucose oxidation pathways via promoting the capacity for glucose uptake and utilization in the myocardium.TMZ has been shown to affect myocardial substrate utilization by inhibiting oxidative phosphorylation and by shifting energy production from FFA to glucose oxidation. Experimental evidence indicates that this effect is predominantly caused by a selective block of long chain 3-ketaacyl coenzyme A thiolase (3-KAT); Additionally, TMZ can protect cellular function directly and maintain intracellular energyphosphate level. However, these issues are still under debate. This sustained the rationale for evaluating the efficacy of TMZ in combination on a large number of patients with chronic cardiac dysfunction.This meta-analysis was exclusively performed on RCT studies of TMZ.
Objectives
Systemic analyse methods were adopted to analyze RCT studies within China and the world, to clarify questions below:
1 To evaluate clinical efficacy and safety of TMZ for chronic heart failure patients with sorts of primary diseases on the baisis of traditional treatment, and assess its action on prognosis of chronic heart failure.
2 To evaluate clinical efficacy and safety of adding TMZ on the baisis of traditional treatment to Chinese chronic heart failure patients with primary heart diseases but not ischemic coronary diseases, and assess its action on rehospitality and motality of Chinese chronic heart failure.
Materials and methods
Several search strategies were undertaken to identify relevant publications. A systematic review, including electronic databases and selective hand searching, was used. The MEDLINE database of the National Library of Medicine and EMbase, converting the period from 1990 to August 2010, were consulted. We also searched Cochrane Central Register of Controlled Trials(CENTRAL) and database of ongoing trials:cuSMDent controlled trials at the same duration. The term 'trimetazidine' OR 'vasorel' and 'dysfunctional myocardium' OR 'heart failure' OR 'left ventricular dysfunction' OR 'dilated cardiomathy' OR 'ischemic cardiomyopathy' and publication types 'randomized controlled trials' OR 'trial' OR 'clinical trial' OR 'double-blind method' OR 'single-blind method' were used in the text search. A manual research of reference lists from identified studies and from review articles to find additional sources or unpublished abstracts (presented at major scientific meetings) was also performed. Published reports in English were identified and assessed for inclusion in this meta-analysis.Only randomized, parallel-group, blind, reference drug-controlled clinical trials evaluating the efficacy of TMZ in the treatment of heart failure with EF≤45% were selected. Meanwhile we searched 'Chinese Zhi net','Chinese National Digit Library' and 'Wanfang Data Liarary' from 1979 to December,2010. The term 'trimetazidine' OR 'vasorel' and 'chronic heart failure' were used in the text search. Ischemic coronary disease was rejected. A manual research of reference lists from identified studies and from review articles to find additional sources or unpublished abstracts (presented at major scientific meetings) was also performed. Drug-controlled clinical trials evaluating the efficacy of TMZ in the treatment of chronic heart failure with primary heary diseases but not ischemic cardiomyopathy were selected.Data were collected independently by two reviewers.left ventricular ejection fracture(LVEF), end-diastolic volume(EDV) and end-systolic volume(ESV) are predictors of mortality in patients with cardiac dysfunction. Overall, in the present analysis, for English documents,these three ergometric parameters, which were LVEF(%), LVEDV(ml) and LVESV(ml) and their SD were selected, together with New York heart Association(NYHA) heart function classification, left ventricular ejectional fraction(LVEF), E/A ratio, left ventricular end-dialation volume(LVEDV),left ventricular end-systolic volume(LVESV), fractional shortening(FS), left ventricular end-systolic(LVEDD), left ventricular end-dialation diameter(LVESD),and wall motion score index (WMSI) to assess clinical efficacy of TMZ, and indexes 'obesity glucose' and "HbACl" were selected to assess the action of TMZ for glucose metaboliam, exercise time(ET) and quality of life(QOL). And for Chinese documents, total effective rate and left ventricular ejectional fraction(LVEF), left ventricular end-systolic(LVEDD), left ventricular end-dialation diameter(LVESD), c reactive protein(CRP), cardiac output(CO), cardiac index(CI), wall motion score index(WMSI) and Brain natriuretic peptide(BNP) were selected to assess clinical efficacy of TMZ, New York heart Association(NYHA) heart function classification and 6 minute walk test(6MWT) were used to eveluate effection of TMZ foe patients'life status, blood pressure and heart rate were adopted to analyse the influence of TMZ for hemodynamics, most importantly, mortality and rehospitality were the vital indexes to estimate effection of TMZ for prognosis of Chinese chronic heart dysfundtion. All were measured in the TMZ-treated and controlled groups, at baseline and at the end of the trial period. All analyzed variables were assumed to be normally distributed. Classical standard statistical methods for normally distributed data were used. A test of heteogeneity was performed by calculating the sum of the squared distance of each study effect from the combined effect and weighting each value and according more weight to more precise studies.Data analysis was performed with STATA11.0. Data of sufficient quality and sufficient similarity were included in a meta-analysis. Results from dichotomous data were presented as relative risks, and results from continuous data were presented as weighted mean differences. Overall results were calculated based on the random-effects model as heterogeneity was observed. A fixed-effects model was used if no heterogeneity existed, otherwise a random-effect model was selected. Heterogeneity was tested withχ2 test, with statistical significance considered as P< 0.1. Mean and dispersion parameters presented in the stable come directly from results reported in the articles. SDs were calculated from SEMs, when appropriated. Z score shows stastically differences, P<0.05 means there exits stastically differences, and P<0.01 means there exits significant stastically differences.
Results
122 English documents and 1873 Chinese documents were selected totally and according to roll-in criteria,17 English randomized, blind, controlled studies including 901 patients and 32 Chinese Case-control studies including 1789 patinets were included and the relevant data was extracted. Baseline diseases were ischemic and non-ischemic cardiomyopathy in Englishi trials and in Chinese trials, we ejected ischemic heart dysfunction. The baseline situation and treatment were matched within TMZ groups and control groups in all trials.
[meta-analysis in English documents]
1 Quantity of enrolled documents:4 of A class,10 of B class and 3 of C class.
2 TMZ can significantly redused NYHA classification of patients with chronic heart failure(pooled RR:-1.28,95%CI:-1.89,-0.67),and increased LVEF(SMD:1.07, 95%CI:0.77,1.37) and LVFS(SMD:1.34,95%CI:0.12,2.56), lessened LVEDD(SMD:-0.88,95%CI:-1.76,-0.01) and LVESD(SMD:-1.74,95%CI:-3.01,-0.47), decreased WMSI(SMD:-0.70,95%CI:-1.01,-0.38), improved E/A ratio((SMD:1.66,95%CI: 0.55,2.76), and markedly prolonged ET (SMD:0.91,95%CI:0.25,1.57). Its effect for QOL was at the STATAstical margine(SMD:1.38,95%CI:-0.03,2.75) and seemed have no action on LVEDV(SMD:-0.25,95%CI:-0.59,0.10).
3 Glucose metabolism was modified markedly, including obesity glucose (SMD:-0.72,95%CI:-1.01,-0.42) and HbAC1(SMD:-0.44,95%CI:-0.74,-0.10).
4 CRP level decreased markedly in TMZ group((SMD:-1.14,95%CI:-1.58,-0.71).
5 For non-ischemic cardimyopathy patients, TMZ seems have no effection on LVEF((SMD:0.81,95%CI:-0.32,1.93). There would be bias exsisting because there were only two documents enrolled in the meta-analysis.
6 TMZ had no affection on hemodynamics. There were no change on baseline blood pressure and heart rate (P>0.05).
7 Side action were gastric reaction and headache, and two patients were dropped out from trials because of side actions.
8 Rehospitaly and mortality were not been analysed because of the limited data provided.
9 Most documens described TMZ exerted no effection on blood lipid levels but did not provide concrete data. One document found that HDL-C level increased after treatment of TMZ.
[meta-analysis in Chinese documents]
1 Quantity of enrolled documents:none of A class,11 of B class and 21 of C class.
2 TMZ can significantly increase total curative effective rates of Chinese patients with chronic heart failure (pooled RR:4.59,95%CI:3.26,6.47), increased LVEF(SMD:0.86,95%CI:0.56,1.16), lessened LVEDD(SMD:-0.73, 95%CI:-1.05,-0.40) and LVESD(SMD:-0.97,95%CI:-1.59,-0.36), aggrandized CO(SMD:0.85,95%CI:0.41,1.28) and CI(SMD:0.80,95%CI:0.56,1.05), and markedly decreased BNP(SMD:-1.09,95%CI:-1.52,-0.66). In addition,TMZ had benefit for patients'cardiac function(NYHA:SMD:-0.69,95%CI:-0.90,-0.47) and motive ability (6MWT:SMD:0.89,95%CI:0.71,1.06)。
3 Rehospitaly and mortality were significantly decreased during follow-up periods (SMD:0.21,95%CI:0.11,0.41) and(SMD:0.18,95%CI:0.07,0.46).
4 TMZ had no affection on hemodynamics. There were no change on baseline blood pressure and heart rate (P>0.05).
5 Side action were gastric reaction and headache, and no patients were dropped out from trials because of side actions.
6 Glucose and lipid metabolism were described well-enfluenced in some documents.
Cinclusion
[meta-analysis in English documents]
1 TMZ, together with systemic treatment, could effectively increase left ventricular function, including constractive and diastolic function and improved quality of life of patients with chronic heart failure.
2 TMZ could reduced enlarged left ventricular. And the impaction was same on patients with or without diabetes.
3 TMZ exerted beneficial action on glucose metabolism.
4 CRP levels were decreased in TMZ group, which means TMZ's useful function on inflmmatary factors.
5 TMZ exerted slight action on hemodynamics and had limited reversible side action, which shows applying safety of this medicine.
6 No definite conclusion can be drawn on rehospitality and mortality for TMZ. Since it was reported that LVEF, LVEDD and LVESD could act as predictors for prognosis of chronic heart failure patients, maybe we can say that TMZ could reduce rehospitality and mortality because of its action on these three indexes.
[meta-analysis in Chinese documents]
1For Chinese non-ischemic heart failure patients, TMZ together with systemic treatment could effectively increase tatal curativeeffective rates, increased heart function and improved exercising tolerance and reduced enlarged left ventricular, no metter what primary diseases they suffered from.
2 TMZ markedly decreased rehospitality and mortality of Chinese non-ischemic heart failure patients.
3 TMZ exerted slight action on hemodynamics and had limited reversible side action, which shows applying safety of this medicine.
Limitation
This meta-analysis has drawn a positive conclusion of the effect of TMZ on human left ventricular dysfunction, but it has many limitations. Firstly, the enrolled trials are all small-scaled studies with observing period of only three to six months. So they can not have results about TMZ and mortality or hospitality, which is the golden indicator for evaluating therapeutic effects. Secondly, TMZ has proved to be effective in the treatment of chronic stable angina via metabolic pathways, and primary diseases of HF patients of most of the enrolled trials are ischeamic cardiomyopathy. So the benefit for ischeamic heart may also have positive effect on heart function. The outstanding challenge is now to undertake a serious study of the effect of TMZ on human heart failure, including the non-ischaemic variety, making the study large enough and observing duration long enough to test the effect that metabolic therapy by TMZ could reduce death rates in other-wise fully treated patients.
引文
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