Efficacy Of Trimetazidine For Chronic Heart Failure: A Systemic Review

BackgroundThe 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.ObjectivesSystemic 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 methodsSeveral 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.