Abstract
Background:
The objective of this meta‐analysis was to evaluate the efficacy of the metabolic agent trimetazidine (TMZ) as monotherapy in the treatment of stable angina pectoris, from echocardiography and radionuclide angiography data.
Hypothesis:
Treatment with TMZ proved to be as effective as other first‐line antianginal agents for coronary patients, and it provided additional efficacy in combination with hemodynamic agents.
Methods:
A search of the literature published between 1965 and 2008 was performed on the MEDLINE and EMBASE databases. Only randomized, controlled trials were included in this meta‐analysis. Patients had to be treated for at least 2 weeks with data on the following 4 parameters at baseline and at the end of the treatment period: left ventricular ejection fraction (LVEF), LV end‐diastolic volume (LVEDV), LV end‐systolic volume (LVESV), and wall motion score index (WMSI). The quality of the trials was assessed by the Jadad score.
Results:
Eleven clinical studies meeting our criteria were analyzed. Results showed that TMZ significantly improved LVEF, with a mean increase of 6.88% (95% confidence interval [CI]: 5.50–8.25), and significantly reduced LVESV by 11.58 mL (95% CI: 5.79–17.37) and WMSI by 0.23 (95% CI: 0.07–0.38). Changes in LVEDV were variable. In both the long term and the short term, TMZ can improve LV function. The efficacy was unchanged in patients with diabetes mellitus.
Conclusions:
This meta‐analysis confirmed the efficacy of TMZ monotherapy in improving LV function compared with placebo. © 2011 Wiley Periodicals, Inc.
The authors have no funding, financial relationships, or conflicts of interest to disclose.
Introduction
Cardiovascular disease is the primary cause of death and disability in the industrialized world.1, 2 Angina pectoris, commonly known as angina, is severe chest pain resulting from ischemia of the heart muscle, generally arising from obstruction or spasm of the coronary arteries. The prevalence of angina is 24 000 per million and the incidence 800 per million in the population ≥30 years of age. The annual death rate is 1.6% to 3.7%, and the myocardial infarction (MI) rate is 1.2% to 3.1% in patients with stable angina.3, 4, 5 The most important determinants of prognosis are left ventricular (LV) systolic function, comorbid conditions, and the severity of coronary artery disease.5 Following MI, LV dysfunction and age remain the strongest predictors of cardiac death.6
In addition to relieving symptoms, medical treatments of stable angina pectoris aim to improve prognosis by reducing the risk of death and nonfatal MI. Drugs that adjust hemodynamic mechanisms are often used to improve myocardial ischemia in conventional antianginal therapy. In the elderly, hemodynamic combination therapy is often associated with a higher risk of drug interactions7 and a higher incidence of significant adverse effects that arise not only from their hemodynamic action, but also from altered pharmacokinetics and renal and hepatic function.7 On the other hand, treatment with coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) is effective, but most surgical patients still require medical treatment similar to patients who are managed medically from the start.8 Not only are CABG and PTCA more expensive treatments, but they require long periods of hospitalization. Emerging evidence suggests that LV dysfunction in patients with ischemic cardiomyopathy is caused by alterations in substrate metabolism.9 New agents that beneficially affect cardiac metabolism may play an important role in the treatment of patients with ischemic cardiomyopathy.
Trimetazidine (1‐[2, 3, 4‐trimethoxybenzyl] piperazine dihydrochloride; TMZ) is a well‐known metabolic anti‐ischemic agent, used both alone and in combination with hemodynamic antianginal drugs in the treatment of stable angina. Its cytoprotective effect is obtained by direct inhibition of mitochondrial long‐chain 3‐ketoacyl coenzyme A thiolase (KAT).10 Through selective inhibition of long‐chain KAT, TMZ optimizes cardiac metabolism by switching energy substrate preference from fatty‐acid oxidation to glucose oxidation. The preferential use of glucose, which requires less oxygen to produce the same amount of adenosine triphosphate (ATP), allows the production of the energy required by the heart in ischemic conditions. This specific mechanism of action protects the heart from the deleterious consequences of ischemia.10
Echocardiography (ECHO) and radionuclide angiography (RA) can reflect LV dysfunction directly, and results of many previous clinical trials include ECHO or RA. However, previous reviews11, 12 consistently reported the benefits of TMZ in terms of improvement in exercise tests, rather than the outcomes measured by ECHO and RA. This meta‐analysis therefore assessed the effectiveness of TMZ on cardiac function through its effects on ECHO and RA.
Methods
Data Collection
Relevant publications were identified separately by 2 professional researchers. Electronic database searching and selective hand searching were used to consult the MEDLINE and EMBASE databases covering the period from 1965 to December 2008. The search terms were “trimetazidine,” “echocardiography,” and “radionuclide angiography,” with publication types “randomized controlled trial” and “clinical trial.” Additionally, published reports were in English, on humans. In accordance with the search terms, 43 articles were identified. Abstracts of the 43 articles were reviewed for the objectives of the trials and their randomization and blinding methods, and 26 articles were selected according to our criteria. The full texts of the 26 articles were read, and finally we selected 11 articles reporting TMZ monotherapy with sufficient information for inclusion in the meta‐analysis, as detailed below.
Study Inclusion and Validity Assessment
Randomized controlled trials and parallel or crossover studies were eligible for inclusion. The trials evaluated the efficacy and tolerability of TMZ in the treatment of angina pectoris and had to report a minimum treatment duration of 2 weeks, a TMZ dose of 20 mg 3× daily, and the results of ECHO or RA. Studies were deemed eligible if sampling was clearly described, participant information fully described, stable angina pectoris clearly diagnosed, and more than 80% of included patients analyzed after treatment. Data were collected independently by 2 researchers and 2 clinicians. Consensus had to be reached by the 2 researchers; however, there was no case where all reviewers disagreed.
The Jadad score13 method was used to assess the quality of the clinical trials. Individual criteria for this scoring system were randomization, double‐blinding, the sample size, blinded outcome assessment, baseline equality of treatment, and basis for analysis. Data were extracted and checked for accuracy in a second review.
Outcomes of Interest
From the selected trials, data on LV ejection fraction (LVEF,%), LV end‐diastolic volume (LVEDV, mL), LV end‐systolic volume (LVESV, mL), and wall motion score index (WMSI) were extracted. All were measured in the TMZ‐treated and control groups, at baseline and at the end of the treatment period.
Data Analysis
All 4 analyzed variables were assumed to be normally distributed, and classical standard statistical methods for normally distributed data were used. A test of homogeneity was performed by calculating the sum of the squared distance of each study effect from the combined effect, weighing each value and according more weight to more precise studies. The percentage of variance explained by sampling error was also determined to evaluate the heterogeneity of the data: a low percentage of the variance explained by sampling error indicates that the residual variation is a result of systematic variation and that the data are heterogeneous; therefore, moderator variables should be investigated. In the case of heterogeneity, studies accounting for heterogeneity were determined and study features that might account for the unexplained variation were determined. If homogeneity of treatment effect was accessed, a fixed‐effect model was used; otherwise, a random‐effect model was used. Sensitivity analyses were performed by studying the influence on the meta‐analysis of each study. Evaluation of publication bias was performed by funnel plot analysis.
Subgroup analysis was performed on data of patients with diabetes and heart failure or on the long‐term results of TMZ, long‐term being defined as >6 months. Sensitivity analyses were performed in summarizing each indicator of the results of ECHO or RA.
Results
Description of Studies
The sample size of the 11 studies varied from a minimum of 16 patients14 to a maximum of 200 patients15 (median, 38). The total number of patients was 545. The age range was 50–78 years (median, 60) and 81% of patients were male. The duration of treatment was between 2 weeks and 2 years (median, 6 mo). All studies compared TMZ monotherapy with placebo. Three studies focused on patients with type 2 diabetes and heart failure.14, 16, 17 One study focused on elderly patients.18 Two studies used a crossover design17, 19; of these, the washout period of a French study17 was 2 weeks, but the authors of the Italian study19 considered that a washout period was not necessary in the trials of TMZ. The largest study had 200 patients,15 and although it was recognized that its large size would influence the meta‐analysis outcome, the quality and rigor of its methodology were considered to be a strong asset. The 11 studies are described in Table 1.
Table 1.
Main Features of Included Studies
| Study | Study Design | Age (y) | N (Male, %) | Treatment Duration (mo) | Method of Assessment |
|---|---|---|---|---|---|
| 2006 Fragasso | Crossover | 66.0 ± 5.0 | 12 (11, 91.7) | 3.0 | ECHO |
| 2004 Thrainsdottir | Crossover | 66.4 ± 8.0 | 20 (17, 85.0) | 1.0 | ECHO |
| 2001 Belardinelli | Parallel group | TMZ: 50.0 ± 7.0 | TMZ: 19 (15, 78.9) | 2.0 | ECHO |
| Pbo: 54.0 ± 7.0 | Pbo: 19 (16, 84.2) | ||||
| 2003 Rosano | Parallel group | TMZ: 65.6 ± 5.7 | TMZ: 16 (11, 68.8) | 6.0 | ECHO |
| Pbo: 65.2 ± 7.0 | Pbo: 16 (13, 81.2) | ||||
| 2005 Kady | Parallel group | TMZ: 52.8 ± 8.7 | TMZ: 100 (86, 86.0) | 24.0 | RA |
| Pbo: 53.1 ± 8.7 | Pbo: 100 (78, 78.0) | ||||
| 2006 Fragassoa | Parallel group | TMZ: 64.0 ± 7.0 | TMZ: 28 (25, 89.3) | 12.0 | ECHO |
| Pbo: 66.0 ± 7.0 | Pbo: 27 (25, 92.6) | ||||
| 2004 Vitale | Parallel group | TMZ: 77.0 ± 2.3 | TMZ: 23 (18, 78.3) | 6.0 | ECHO |
| Pbo: 78.0 ± 4.3 | Pbo: 24 (22, 91.7) | ||||
| 1990 Brottier | Parallel group | TMZ: 57.0 ± 3.2 | TMZ: 9 | 0.5 | RA |
| Pbo: 61.9 ± 0.9 | Pbo: 11 | ||||
| 2003 Fragasso | Parallel group | 64.0 ± 7.0 | TMZ: 8 (8, 100) | 6.0 | ECHO |
| Pbo: 8 (8, 100) | |||||
| 2007 Napoli | Parallel group | TMZ: 64.0 ± 6.0 | TMZ: 25 (15, 60.0) | 6.0 | ECHO |
| Pbo: 63.0 ± 7.0 | Pbo: 25 (18, 72.0) | ||||
| 2008 Belardinelli | Parallel group | TMZ: 59.0 ± 8.0 | TMZ: 30 (25, 83.3) | 2.0 | ECHO |
| Pbo: 58.0 ± 9.0 | Pbo: 26 (22, 4.6) |
Abbreviations: ECHO, echocardiography; Pbo, placebo; RA, radionuclide angiography; TMZ, trimetazidine.
Another study by Fragasso in 2006.
The criteria of quality and the Jadad score of each individual study are shown in Table 2. All 11 studies were randomized. Five of them14, 16, 17, 19, 20 were designed using blinded methods. Losses to follow‐up varied from 0% to a maximum of 34% (median, 15%). The validity of the studies was rated as acceptable for randomization, blinding, and losses to follow‐up, and 3 studies16, 19, 21 achieved a Jadad score of 5. Another 2 studies were rated as moderate methodological quality and had a Jadad score of 4.17, 20 The remaining 6 studies were considered to be of moderate to poor quality,14, 15, 18, 22, 23, 24 but no study was considered to be of low quality.
Table 2.
Quality Assessment of Included Studies
| Study | Randomization | Blinding | Losses (N, %) | Jadad Score |
|---|---|---|---|---|
| 2006 Fragasso | Y | Y | 0, 0.0 | 5 |
| 2004 Thrainsdottir | Y | Y | 3, 15.8 | 4 |
| 2001 Belardinelli | Y | Y | 6, 13.6 | 5 |
| 2003 Rosano | Y | Y | 11, 34.4 | 5 |
| 2005 Kady | Y | N | 46, 23.0 | 3 |
| 2006 Fragassoa | Y | N | 7, 11.3 | 3 |
| 2004 Vitale | Y | N | 9, 19.1 | 3 |
| 1990 Brottier | Y | N | 3, 13.0 | 3 |
| 2003 Fragasso | Y | N | 3, 18.8 | 3 |
| 2007 Napoli | Y | Y | 10, 16.7 | 4 |
| 2008 Belardinelli | Y | N | 1, 0.8 | 3 |
Abbreviations: N, no; Y, yes.
Another study by Fragasso in 2006.
Data on LVEF from all 11 articles are shown in Figure 1. Heterogeneity was observed when analyzing all studies and a random‐effect model was used. Overall, TMZ improved LVEF when all studies were taken into the analysis, with a mean improvement of 6.88% (95% confidence interval [CI]: 5.50–8.25). The WMSI was significantly reduced with TMZ compared with placebo (P = 0.004) in the meta‐analysis of 6 articles (Figure 2). Heterogeneity was observed and the reduction in WMSI was 0.23 (95% CI: 0.07–0.38). Data from 6 articles were used in the meta‐analysis of LVESV (Figure 3). Heterogeneity was observed, and LVESV was significantly reduced in the TMZ group (P<0.001), with a mean reduction of 11.58 mL (95% CI: 5.79–17.37). However, in the meta‐analysis of 6 articles, the effect of TMZ on LVEDV was not superior to placebo (Figure 4). Heterogeneity was observed, and the mean change in LVEDV was −2.24 mL (95% CI: –12.36–7.88). Sensitivity analysis showed that effect was not statistically significant (P≥0.39). When 1 study16 was withdrawn from the meta‐analysis, because it was negative with 98.63% weight (Figure 5), the result changed to −2.91 (95% CI: –3.68–9.50). Funnel plots showed no asymmetry of the data.
Figure 1.
Left ventricular ejection fraction (LVEF).
Figure 2.
Wall motion score index (WMSI).
Figure 3.
Left ventricular end‐systolic volume (LVESV).
Figure 4.
Left ventricular end‐diastolic volume (LVEDV; random‐effect model).
Figure 5.
Left ventricular end‐diastolic volume (LVEDV; fixed‐effect model).
In subgroup analysis of LVEF, 6 studies were long term (treatment duration ≥6.0 mo), and the other 5 studies were short term (treatment duration <6.0 mo). In both groups, TMZ improved LVEF significantly, with mean increases of 7.44% (95% CI: 6.40–8.47) and 6.26% (95% CI: 2.46–10.05), respectively. There were 6 studies, 3 long term and 3 short term, used for subgroup analysis of WMSI, LVEDV, and LVESV. In both subgroups, LVESV was significantly reduced by TMZ compared with placebo. The mean reductions were by 17.00 mL (95% CI: 13.72–20.27) and 8.10 mL (95% CI: 3.84–12.37), respectively. Wall motion score index was significantly reduced in the long‐term group by 0.26 (95% CI: 0.11–0.40), but the change in WMSI of −0.16 (95% CI: –0.54–0.22) was not statistically significant in the short‐term group. Left ventricular end‐diastolic volume significantly increased in the short‐term group, by 7.18 mL (95% CI: 0.36–13.99); LVEDV was significantly decreased, by 12.18 mL (95% CI: 9.20–15.16), in the long‐term group, which included the study with 98.63% weight.18
Three articles were included in the diabetes and heart failure subgroup; TMZ also improved LVEF significantly in these patients, by 7.24% (95% CI: 5.33–9.15).
Discussion
Exhibiting a metabolic mechanism of action,10 TMZ optimizes cardiac metabolism, leading to an increase in cellular tolerance to ischemia and a change in the oxygen supply‐to‐demand‐ratio.25 Other anti‐ischemic agents act essentially via different hemodynamic effects (peripheral and coronary vasodilation, reduction in heart rate and myocardial contractility). The anti‐ischemic effect of TMZ is obtained at a cellular level by shifting the energy substrate preference from fatty‐acid oxidation to glucose oxidation, secondary to selective inhibition of 3‐KAT.10 As more ATP is produced per oxygen consumed when glycogen is a substrate compared with fatty acids, less oxygen is required for a given amount of work.26 Because of the preferential promotion of glucose and pyruvate oxidation, TMZ improves the activity of the sodium‐potassium ATPase and the calcium uptake pump of the sarcoplasmic reticulum, which are responsible for LV systolic depolarization and diastolic relaxation, respectively.
The effects of TMZ on energy metabolism may contribute to the improvement in myocardial contractile function seen in patients with ischemic cardiomyopathy, especially when myocardial ischemia is responsible, at least in part, for the LV dysfunction. Some studies have confirmed this hypothesis using ECHO or RA techniques. Brottier and colleagues first addressed this hypothesis.24 They reported an absolute increase of 9.3% in radionuclide LVEF after a 6‐month period of treatment with TMZ compared with placebo. El‐Kady and associates observed an increase in LV function (increase of 23% with TMZ compared with 0.5% with placebo, P<0.001) and a decrease in LV volume, as assessed by gated single‐photon emission computed tomography.15 Another study confirmed these observations and demonstrated an increase in LVEF after treatment with TMZ, the effects being apparent at 6 months and maintained for 18 months.27 Left ventricular volume was also significantly reduced. These results have been consistently confirmed in other studies specifically addressing the treatment outcome in subgroups of patients. The effects of TMZ in patients with diabetes have been evaluated in 3 randomized trials. Increases in LVEF were observed after >2 months in patients receiving TMZ.14, 16, 17 In the elderly, Vitale and colleagues described similar effects of TMZ on LV function and volume.18 In the studies analyzed above, an improvement in WMSI was also observed. Thus, these beneficial effects explain how TMZ can improve symptoms and ventricular function in these patients. In the presence of reduced myocardial oxygen supply, TMZ appears to be able to facilitate energy production, which may result in improved LV contractile function.
Treatment with TMZ was able to ameliorate LV systolic and diastolic function, also improving quality of life in patients with angina. Many studies have shown that TMZ may also be beneficial in patients with heart failure, in terms of LV function preservation and symptom control.14, 18, 24, 27 Studies of Di Napoli20 and El‐Kady15 showed that TMZ can reduce all‐cause mortality and heart failure hospitalization, and improve New York Heart Association functional class and exercise tolerance in the long term. Other studies28, 29, 30 have assessed heart rate, systolic blood pressure, or rate‐pressure product and found that TMZ exerts its metabolic effect without changing any of these parameters.
Now, the data of long‐term prognosis for patients with angina pectoris is not enough to evaluate the efficacy of TMZ. On the other hand, there was insufficient data to pool the results of studies making direct comparisons between TMZ and established antianginal therapy such as beta‐blockers, calcium channel blockers, or nitrates. The efficacy of TMZ needs to be evaluated extensively and thoroughly in the future.
There are 3 limitations in the data available on TMZ. The main one is that the study follow‐up periods were too short to observe the endpoint of mortality and/or major adverse cardiovascular events. The second is that the majority of participants in the studies included in this analysis were male. Only 16% of participants were female, limiting the applicability of our findings to the general population. Additional research is needed to further investigate the effects of TMZ. The final limitation is that the origin of most of the studies was in Italy, and the results cannot be directly applied to other populations.
Conclusion
From the results of ECHO and RA, we found that TMZ could increase LVEF and reduce LVESV significantly compared with placebo. This favorable effect translated into improvements in left ventricular function and functional capacity. This evidence supports the concept that TMZ represents an effective treatment for improving LV function in patients with angina pectoris. Although the study suggests that metabolic modulation could represent a new therapeutic option, whether the observed beneficial effects translate into decreased morbidity and mortality in the long term requires further investigation.
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