Is Treatment with Trimetazidine Beneficial in Patients with Chronic Heart Failure?

Background Whether additional benefit can be achieved with the use of trimetazidine (TMZ) in patients with chronic heart failure (CHF) remains controversial. We therefore performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of TMZ treatment in CHF patients. Methods We searched PubMed, EMBASE, and Cochrane databases through October 2013 and included 19 RCTs involving 994 CHF patients who underwent TMZ or placebo treatment. Risk ratio (RR) and weighted mean differences (WMD) were calculated using fixed or random effects models. Results TMZ therapy was associated with considerable improvement in left ventricular ejection fraction (WMD: 7.29%, 95% CI: 6.49 to 8.09, p<0.01) and New York Heart Association classification (WMD: −0.55, 95% CI: −0.81 to −0.28, p<0.01). Moreover, treatment with TMZ also resulted in significant decrease in left ventricular end-systolic volume (WMD: −17.09 ml, 95% CI: −20.15 to −14.04, p<0.01), left ventricular end-diastolic volume (WMD: −11.24 ml, 95% CI: −14.06 to −8.42, p<0.01), hospitalization for cardiac causes (RR: 0.43, 95% CI: 0.21 to 0.91, p = 0.03), B-type natriuretic peptide (BNP; WMD: −157.08 pg/ml, 95% CI: −176.55 to −137.62, p<0.01) and C-reactive protein (CRP; WMD: −1.86 mg/l, 95% CI: −2.81 to −0.90, p<0.01). However, there were no significant differences in exercise duration and all-cause mortality between patients treated with TMZ and placebo. Conclusions TMZ treatment in CHF patients may improve clinical symptoms and cardiac function, reduce hospitalization for cardiac causes, and decrease serum levels of BNP and CRP.


Introduction
Chronic heart failure (CHF) is a complex clinical syndrome characterized by decreased myocardial contractility, hemodynamic abnormality and neuroendocrine activation. There are multiple etiologies leading to this final common clinical pathway, which carries a 50% 5-year mortality rate and is responsible for over one third of all deaths in the United States from cardiovascular causes [1]. The past few decades have witnessed remarkable progress in the drug therapy for CHF. The clinical application of betaadrenergic receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and aldosterone receptor antagonists has significantly reduced cardiovascular events and mortality in patients with CHF [2]. However, CHF remains a leading cause of morbidity and mortality throughout the world.
Trimetazidine (TMZ), a piperazine derivative used as an antianginal agent, selectively inhibits mitochondrial long-chain 3ketoacyl coenzyme A thiolase. By decreasing fatty acid oxidation and stimulating glucose utilization, TMZ restores coupling between glycolysis and carbohydrate oxidation, and leads to ATP production with less oxygen consumption. Previous studies have reported that TMZ exerts cardioprotective effects by reducing oxidative damage, inhibiting inflammation and apoptosis, and improving endothelial function [3][4][5][6].
Over the past few years, several small randomised controlled trials (RCTs) have been conducted to evaluate the effects of TMZ treatment in patients with CHF. These trials investigated clinical symptoms, cardiac function, quality of life, hospitalization, mortality and cardiovascular events, comparing TMZ with placebo. In addition, two meta-analyses of RCTs have also been performed to assess the therapeutic effects of TMZ in CHF patients [7,8]. However, some conclusions drawn from these two meta-analyses are not consistent. We therefore performed an updated meta-analysis including a few recently published RCTs to provide more convincing evidence of TMZ therapy in patients with CHF.

Data extraction and quality assessment
Two investigators independently reviewed all potentially eligible studies using predefined eligibility criteria and collected data from the included trials. We extracted details on study characteristics, patient characteristics, inclusion criteria, ischemic etiology, intervention strategies, duration of follow-up, and clinical outcomes including LVEF, LVESV, LVEDV, NYHA classification, exercise duration, all-cause mortality, hospitalization, BNP and CRP. The quality of included RCTs was assessed by the Jadad scale [9], and a numerical score between 0 and 5 was assigned as a measure of study design.

Statistical analysis
Dichotomous data were analyzed using risk ratio (RR) with 95% confidence intervals (CI), while continuous variables were analyzed using weighted mean differences (WMD) and 95% CI. The heterogeneity of results across trials was assessed using the Chi-square based Q-test. A p value.0.10 for the Q-test indicated a lack of heterogeneity among the studies. Thus, the pooled effect was calculated using fixed effects model. Otherwise, random effects model was applied in case of significant heterogeneity across studies. Sensitivity analysis was also conducted to assess the influence of each individual study on overall estimates by sequential removal of individual studies. All statistical analyses were performed using RevMan 5.0 (Cochrane Collaboration, Oxford, UK) and STATA software 10.0 (Stata Corporation, College Station, Texas, USA). P,0.05 was considered statistically significant.

NYHA classification and exercise tolerance
Pooled analysis showed that TMZ therapy resulted in a significant improvement in NYHA functional class compared with placebo control (WMD: 20.55, 95% CI: 20.81 to 20.28, p,0.01) ( Figure 3A). However, there was no significant difference in exercise duration between patients treated with TMZ and placebo (WMD: 18.58 s; 95% CI: 26.88 to 44.05, p = 0.15) ( Figure 3B).

Sensitivity analysis
Since a significant heterogeneity across studies was observed for NYHA classification, we conducted a sensitivity analysis to assess the effect of each study on the pooled estimate under the random effects model. As shown in Table 4, removal of any individual study could not significantly reduce the heterogeneity.

All-cause mortality and hospitalization for cardiac causes
Our results suggested that there was no significant difference in all-cause mortality between patients treated with TMZ and placebo (RR: 0.47, 95% CI: 0.12 to 1.78, p = 0.27) ( Figure 4A). Nevertheless, 7 of 80 patients with TMZ therapy needed hospitalization for cardiac causes, which was significantly lower than 17 of 76 patients with placebo treatment (RR: 0.43, 95% CI: 0.21 to 0.91, p = 0.03) ( Figure 4B).

Discussion
There is growing evidence that impaired carbohydrate oxidation and high rates of fatty acid oxidation contribute to the progression of myocardial dysfunction in CHF patients. TMZ has an inhibitory effect on the mitochondrial long-chain 3-ketoacyl coenzyme A thiolase, which plays a critical role in the fatty acid beta-oxidation pathway in the myocardium. As a result, there is a switch of cardiac metabolism from free fatty acid to glucose oxidation, which represents a more efficient metabolic pathway in terms of oxygen consumption and energy generation [29].
In the past few years, the beneficial effects of TMZ treatment in patients with CHF were confirmed in several small RCTs. Brottier et al. showed that TMZ improved clinical symptoms and LVEF in patients with severe ischemic cardiomyopathy [10]. Vitale et al. reported that TMZ improved left ventricular function and quality of life in elderly patients with coronary artery disease [15]. In addition, the other 4 reports of RCT revealed the protective effects of TMZ against left ventricular dysfunction in diabetic patients with ischemic cardiomyopathy [12][13][14]22]. The cardioprotective effects of TMZ were also evaluated in patients with dilated cardiomyopathy. Tuunanen et al. reported that TMZ enhanced cardiac function and had both cardiac and extracardiac metabolic effects in idiopathic dilated cardiomyopathy with heart failure [23]. Zhao et al. indicated that TMZ treatment was associated with a considerable improvement of cardiac function and physical tolerance in diabetic patients with idiopathic dilated cardiomyopathy [28]. The pooled results of these studies suggested that TMZ therapy could significantly improve LVEF and NYHA classification in patients with CHF. The effects of TMZ on all-cause mortality and hospitalization in CHF patients are still controversial. Only 3 reports of RCT with small samples described all-cause mortality [16,17,19], and 4 described hospitalization for cardiac causes [13,15,17,23]. The pooled results of these studies demonstrated that TMZ treatment was associated with a significant decrease in hospitalization for cardiac causes. However, there was no significant difference in allcause mortality between patients treated with TMZ and placebo. In this meta-analysis, we also evaluated the effects of TMZ on serum levels of BNP and CRP in patients with CHF. The pooled results suggested that BNP and CRP levels were significantly decreased in patients with TMZ treatment.
There are some differences in the pooled results between our meta-analysis and two previous meta-analyses performed by Gao et al. and Zhang et al. [7,8]. The heterogeneities of LVEF, LVESV and LVEDV in our study were much smaller than those in the other two studies. In addition, our results showed no improvement in exercise duration and no decline in all-cause mortality in CHF patients treated with TMZ, which was not consistent with the other two meta-analyses. Furthermore, our pooled results also suggested that TMZ therapy could significantly decrease BNP and CRP levels in CHF patients.
Our study had several limitations. Firstly, the methodological quality of included studies was less than optimal, so we were not able to exclude the potential risk of bias in these trials. Secondly, the number of patients included in this meta-analysis was relatively    small, so the conclusions drawn from this study should be interpreted with caution. Thirdly, the follow-up duration in these studies varied widely, from 4 weeks to 24 months.
In conclusion, our meta-analysis demonstrates that TMZ treatment in CHF patients may improve clinical symptoms and cardiac function, reduce hospitalization for cardiac causes, and decrease serum levels of BNP and CRP.

Supporting Information
Checklist S1 PRISMA Checklist.