Author + information
- Received August 1, 2011
- Revision received October 18, 2011
- Accepted November 11, 2011
- Published online March 6, 2012.
- Lei Zhang, MD⁎,
- Yizhou Lu, MD†,
- Hong Jiang, MD⁎,
- Liming Zhang, MD†,
- Aijun Sun, MD⁎,
- Yunzeng Zou, MD⁎ and
- Junbo Ge, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Junbo Ge, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China
Objectives The aim of this meta-analysis was to evaluate the effects of additional trimetazidine (TMZ) treatment on patients with chronic heart failure (CHF).
Background Conflicting results currently exist on the clinical use of TMZ in CHF patients.
Methods PubMed, MEDLINE, EMBASE, and EBM Reviews databases were searched through November 2010 for randomized controlled trials (RCTs) assessing TMZ treatment in CHF patients. Data concerning the study design, patient characteristics, and outcomes were extracted. Risk ratio (RR) and weighted mean differences (WMD) were calculated using fixed or random effects models.
Results Sixteen RCTs involving 884 CHF patients were included. Hospitalization for cardiac causes (RR: 0.43, p = 0.03), but not all-cause mortality (RR: 0.47, p = 0.27), was reduced by TMZ treatment. Moreover, TMZ therapy was associated not only with the increase of left ventricular ejection fraction (WMD: 6.46%, p < 0.0001) and total exercise time (WMD: 63.75 seconds, p < 0.0001), but also with the decrease of New York Heart Association functional class (WMD: −0.57, p = 0.0003), left ventricular end-systolic diameter (WMD: −6.67 mm, p < 0.0001), left ventricular end-diastolic diameter (WMD: −6.05 mm, p < 0.0001), and B-type natriuretic peptide (WMD: −203.40 pg/ml, p = 0.0002).
Conclusions Additional use of TMZ in CHF patients may decrease hospitalization for cardiac causes, improve clinical symptoms and cardiac function, and simultaneously ameliorate left ventricular remodeling.
Despite therapeutic advances, chronic heart failure (CHF) remains a major cause of mortality in the worldwide. Evidence suggests that the alterations in energy metabolism, such as high rates of fatty acid oxidation, may lead to abnormal function of the failing heart (1,2).
Trimetazidine (1-[2,3,4-trimethoxybenzyl] piperazine dihydrochloride, TMZ), which shifts energy production from fatty acid oxidation to glucose oxidation (3), is effective in stable angina pectoris (4). Studies have shown that TMZ exerted cardioprotective effects by reducing oxidative damage, inhibiting inflammation and apoptosis, and improving endothelial function (5–7). TMZ was, therefore, considered a promising candidate for the treatment of CHF.
This meta-analysis of randomized controlled trials (RCTs) was performed to estimate the effects of TMZ treatment on CHF patients.
Search strategy and selection criteria
We performed an electronic literature search of PubMed, MEDLINE, EMBASE, and EBM Reviews databases through November 2010, using the terms “trimetazidine,” “Vastarel,” “Idaptan,” “heart failure,” “cardiac dysfunction,” “cardiac insufficiency,” “cardiac inadequacy,” “cardiomyopathy,” and “ventricular dysfunction.” The references of the studies were also searched for relevant titles.
RCTs in which CHF patients were assigned to TMZ or placebo were included. Exclusion criteria were: 1) treatment interval <4 weeks; 2) cross-over trials without washout period; and 3) no access to full text for quality assessment and data extraction.
Data extraction and quality assessment
Two investigators independently reviewed all potentially eligible studies and collected data on patient and study characteristics. Quality assessments were evaluated with Jadad quality scale.
Data synthesis and analysis
Dichotomous data were analyzed using risk ratio (RR) with 95% confidence intervals, whereas continuous variables (change from baseline to follow-up) were analyzed using weighted mean differences (WMD) or standardized mean differences (SMD). Pooled analyses were calculated using fixed-effect models, whereas random-effect models were applied in case of significant heterogeneity across studies. When no events were observed, 0.5 was added to both arms of the trial. Statistical heterogeneity were measured using the I2 statistic. Meta-regression analyses were conducted to estimate the extent to which other covariates might have influenced the treatment effects. Sensitivity analyses (exclusion of 1 study at a time) were performed to determine the stability of the overall treatment effects. Additionally, publication bias was assessed using the Begg adjusted rank correlation test and Egger regression asymmetry test. All p values were 2-tailed, and the statistical significance was set at 0.05. Statistical analyses were performed using RevMan 5.0 (The Cochrane Collaboration, Copenhagen, Denmark), STATA software 10.0 (StataCorp, College Station, Texas), and nlme package in R Language 2.12.1.
The flow of selecting studies for the meta-analysis is shown in Figure 1. Briefly, of the initial 499 hits, 84 articles were retrieved for detailed evaluation, and 16 RCTs (8–23) satisfying the inclusion criteria were finally analyzed.
Quality assessments of the RCTs are shown in Online Table 1. Table 1 summarizes the characteristics of the included trials. Specifically, 459 patients were assigned to TMZ, whereas 425 subjects were assigned to control. All studies have enrolled patients with reduced left ventricular ejection fraction (LVEF).
All-cause mortality and hospitalization for cardiac causes
On the whole, TMZ treatment was well tolerated in CHF patients. The results showed all-cause mortality in the TMZ group was not lower than control (RR: 0.47, p = 0.27). Nevertheless, 7 of 80 patients with TMZ treatment needed hospitalization for cardiac causes, which was significantly <17 of 76 patients assigned to control (RR: 0.43, p = 0.03) (Fig. 2). Sensitivity analyses suggested that this beneficial effect was concealed when the study by Fragasso et al. (16) (p = 0.08) or by Vitale et al. (22) (p = 0.07) was omitted.
Left ventricular structure and function
The results indicated that additional TMZ therapy was superior to standard therapy in terms of LVEF improvement (WMD: 6.46%, p < 0.0001). Furthermore, TMZ therapy was similarly found to reduce left ventricular end-systolic diameter (WMD: −6.67 mm, p < 0.0001), left ventricular end-diastolic diameter (WMD: −6.05 mm, p < 0.0001), and left ventricular end-systolic volume (SMD: −0.61, p = 0.02). Additionally, TMZ therapy tended to decrease left ventricular end-diastolic volume (SMD: −0.38, p = 0.10) (Fig. 3).
Sensitivity analyses confirmed in direction and magnitude of statistical significance the results regarding LVEF. According to the results of meta-regression analyses, no statistically significant association was found between: the benefits of TMZ therapy and year of publication, age of patients, etiology of CHF, baseline LVEF, baseline New York Heart Association (NYHA) functional class, and follow-up duration. Nevertheless, we found a statistically significant association between patients' sex and LVEF improvement (p = 0.03) (Fig. 4). Subgroup analyses showed the original form of TMZ significantly increased LVEF (p < 0.0001), whereas the modified form did not (Table 2). Moreover, the difference in LVEF improvement was not shown on etiology, as indicated by indirect comparison (p = 0.99). No publication bias was found, as shown by Egger's test (p = 0.16) and Begg's test (p = 0.83) (Online Fig. 1).
Benefits of TMZ treatment were shown on both NYHA functional class (WMD: −0.57, p = 0.0003) and total exercise time (WMD: 63.75 seconds, p < 0.0001) (Figs. 5A and 5B). Subgroup analyses indicated that ischemic CHF patients with baseline LVEF ≥30% were more likely to get such benefits from TMZ treatment (Table 2).
Blood pressure and heart rate
Resting heart rate in the TMZ group was slightly lower than that of the control group (WMD: −2.62 beats/min, p = 0.04), whereas no significant differences were observed in resting systolic blood pressure (WMD: −0.94 mm Hg, p = 0.42) or resting diastolic blood pressure (WMD: −1.86 mm Hg, p = 0.27) (Figs. 5C to 5E).
B-type natriuretic peptide (BNP) level was significantly down-regulated by TMZ treatment (WMD: −203.40 pg/ml, p = 0.0002), whereas high-sensitivity C-reactive protein (hsCRP) level was not (WMD: −2.45 mg/l, p = 0.10) (Figs. 6A and 6B).
Corrected QT interval
As shown in Figure 6C, TMZ therapy tended to be, albeit nonsignificantly, associated with corrected QT interval shortening (WMD: −31.32 ms, p = 0.07).
The main findings of this meta-analysis are that although the additional use of TMZ failed to reduce all-cause mortality in CHF patients, the beneficial effects have been demonstrated by the increase of LVEF and total exercise time, and by the decrease of hospitalization for cardiac causes, NYHA class and of left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular end-systolic volume, and serum BNP level. Moreover, as illustrated by the unchanged resting blood pressure and an average decrease of a mere 2.6 beats/min in resting heart rate, our study indicated that the aforementioned beneficial effects may be hemodynamically neutral.
The well-established anti-ischemic effects of TMZ are thought to be mediated by reducing fatty acid β-oxidation and increasing glucose oxidation, resulting in higher ATP production (3,24). Combining these findings with the “energy starvation” hypothesis, which suggests that inadequate ATP supply underlies the contractile dysfunction presenting in heart failure (25), it seems plausible that TMZ improves energy metabolism in cardiomyocytes, which may finally translate into mechanical efficiency and contribute to the improvement of cardiac function and clinical symptoms. Besides, it is noteworthy that TMZ exerts cardioprotective effects by restoring phosphorylation processes, inhibiting inflammatory response, oxidative damage, and apoptosis, as well as by improving endothelial function and coronary microcirculation (5-7,26,27), which may account for the amelioration of left ventricular remodeling. Furthermore, it seems reasonable that the BNP level could be down-regulated by TMZ treatment, considering that the BNP level is negatively related to the alteration of cardiac structure and function (28).
TMZ treatment may play beneficial roles, not only in cardiac structural remodeling, but in electrical remodeling (29). Moreover, inflammatory mediators are involved in the pathogenesis of CHF (e.g., hsCRP), whereas the anti-inflammatory effects of TMZ have been observed (6,30). Unexpectedly, we failed to show the beneficial effects of TMZ either on corrected QT interval or on hsCRP, which may be due to the insufficiently powered studies included.
Subgroup estimation indicated that clinical symptoms and left ventricular structure in ischemic CHF patients were more likely to be ameliorated with TMZ treatment, nevertheless, such superiority may not totally deny the utility of TMZ in nonischemic CHF, with respect to LVEF improvement. Furthermore, modified TMZ may yield less benefits than the original form in LVEF enhancement, which may be associated with the difference in pharmacokinetics (31). Additionally, it was shown that female patients were more likely to get benefits from TMZ therapy regarding LVEF, suggesting that the difference in the proportion of female patients might be an origin of the interstudy discrepancy.
Drawbacks pertinent to this meta-analysis were the differences in characteristics among included studies, encompassing patients' age, follow-up duration, and so on. Moreover, it is worth noticing that only 884 patients were involved in the 16 RCTs, which justifies the performance of more large-scale RCTs for evaluating the impact of TMZ treatment on CHF patients.
The additional use of TMZ in CHF patients may exert beneficial effects, not only in ameliorating clinical symptoms and left ventricular structure and function, but in reducing hospitalization for cardiac causes, indicating that it may be an additional therapeutic agent for CHF.
The authors thank Dr. Tiansong Zhang at Jing′an District Central Hospital of Shanghai, China, for kindly providing statistical assistance.
For a supplementary table and figure, please see the online version of this paper.
This study was supported by the Key Projects in the National Science & Technology Pillar Program in the Eleventh Five-year Plan Period (No. 2006BAI01A04) and National Natural Science Foundation of China (No. 30871073). The authors have stated that they have no relationships relevant to the contents of this paper to disclose. Drs. Lei Zhang and Y. Lu contributed equally to this work.
- Abbreviations and Acronyms
- B-type natriuretic peptide
- chronic heart failure
- high-sensitivity C-reactive protein
- left ventricular ejection fraction
- New York Heart Association
- randomized controlled trial
- risk ratio
- standardized mean differences
- weighted mean differences
- Received August 1, 2011.
- Revision received October 18, 2011.
- Accepted November 11, 2011.
- American College of Cardiology Foundation
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