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Angina might persist or reoccur despite successful revascularisation with percutaneous coronary intervention (PCI) and antianginal therapy. Additionally, PCI in stable patients has not been shown to improve survival compared with optimal medical therapy. Trimetazidine is an antianginal agent that improves energy metabolism of the ischaemic myocardium and might improve outcomes and symptoms of patients who recently had a PCI. In this study, we aimed to assess the long-term potential benefits and safety of trimetazidine added to standard evidence-based medical treatment in patients who had a recent successful PCI. We did a randomised, double-blind, placebo-controlled, event-driven trial of trimetazidine added to standard background therapy in patients who had undergone successful PCI at 365 centres in 27 countries across Europe, South America, Asia, and north Africa. Eligible patients were aged 21–85 years and had had either elective PCI for stable angina or urgent PCI for unstable angina or non-ST segment elevation myocardial infarction less than 30 days before randomisation. Patients were randomly assigned by an interactive web response system to oral trimetazidine 35 mg modified-release twice daily or matching placebo. Participants, study investigators, and all study staff were masked to treatment allocation. The primary efficacy endpoint was a composite of cardiac death; hospital admission for a cardiac event; recurrence or persistence of angina requiring an addition, switch, or increase of the dose of at least one antianginal drug; or recurrence or persistence of angina requiring a coronary angiography. Efficacy analyses were done according to the intention-to-treat principle. Safety was assessed in all patients who had at least one dose of study drug. This study is registered with the EU Clinical Trials Register (EudraCT 2010-022134-89). From Sept 17, 2014, to June 15, 2016, 6007 patients were enrolled and randomly assigned to receive either trimetazidine (n=2998) or placebo (n=3009). After a median follow-up of 47·5 months (IQR 42·3–53·3), incidence of primary endpoint events was not significantly different between the trimetazidine group (700 [23·3%] patients) and the placebo group (714 [23·7%]; hazard ratio 0·98 [95% CI 0·88–1·09], p=0·73). When analysed individually, there were no significant differences in the incidence of the components of the primary endpoint between the treatment groups. Similar results were obtained when patients were categorised according to whether they had an elective or urgent PCI. 1219 (40·9%) of 2983 patients in the trimetazidine group and 1230 (41·1%) of 2990 patients in the placebo group had serious treatment-emergent adverse events. Frequencies of adverse events of interest were similar between the groups. Our results show that the routine use of oral trimetazidine 35 mg twice daily over several years in patients receiving optimal medical therapy, after successful PCI, does not influence the recurrence of angina or the outcome; these findings should be taken into account when considering the place of trimetazidine in clinical practice. However, the long-term prescription of this treatment does not appear to be associated with any statistically significant safety concerns in the population studied. Servier.

We investigated the impact of trimetazidine treatment on left ventricular (LV) functions and cardiac biomarkers in diabetic patients with diastolic dysfunction as an early stage of diabetic cardiomyopathy. Sixty-three patients were randomly assigned to receive either trimetazidine or a placebo for 3 months. At baseline and after 3-months of treatment, measurements of serum levels of glycemic control parameters, lipid profile, tumor necrosis factor alpha, transforming growth factor beta 1, n-terminal pro brain natriuretic peptide and assessment of modified Medical Research Council (mMRC) dyspnea score, echocardiographic indices of LV functions and LV global longitudinal strain (GLS) were performed. After 3-months, trimetazidine group exhibited a significant reduction in left atrial volume index by 6.99% versus an increase by 0.66% in placebo group, p = 0.034. Moreover, average e’ increased by a significantly higher percentage in trimetazidine versus placebo group (8.46 ± 18.64 vs. -2.49 ± 14.52, respectively. p  = 0.015). Trimetazidine treatment resulted in a significant increase in LVGLS by 6.66% versus LVGLS reduction by 2.79% in placebo group ( p  = 0.004). Trimetazidine group had a significantly lower median mMRC dyspnea score compared to placebo (0 vs. 1, respectively, p  = 0.015) and a significantly lower low-density lipoprotein (LDL-C) (103.43 ± 28.31 vs. 125.34 ± 45.27, respectively, p  = 0.032). There was no significant difference between both groups in levels of other biomarkers. Three-months treatment with trimetazidine improved diastolic function parameters, LVGLS, dyspnea severity and LDL-C levels in diabetic patients with diastolic dysfunction.

ObjectiveTrimetazidine may have beneficial effects on left ventricular (LV) function in patients with systolic heart failure. The authors assessed whether long-term addition of trimetazidine to conventional treatment could improve, along with LV function, resting whole body energy metabolism in patients with chronic systolic heart failure.DesignSingle blind randomised study.SettingUniversity Hospital.Patients44 patients with systolic heart failure receiving full medical treatment.InterventionsIndirect calorimetry and two-dimensional echocardiography at baseline and after 3 months.Main outcome measuresWhole body resting energy expenditure (REE), percentage of predicted REE, LV ejection fraction (EF), NYHA class, quality of life.ResultsTrimetazidine increased EF compared with conventional therapy alone (from 35±8% to 42±11% vs from 35±7% to 36±6%; p=0.02, analysis of variance for repeated measures). NYHA class and quality of life also improved compared with conventional therapy (p<0.0001). REE (from 1677±264 to 1580±263 kcal/day) and percentage of predicted REE (based on the Harris–Benedict equation: from 114±10% to 108±9%) decreased in the trimetazidine group, but not in the control group (REE from 1679±304 to 1690±337 kcal/day and percentage of predicted REE from 113±12% to 115±14%). The variation was different between groups (p=0.03 and 0.023, respectively).ConclusionsIn patients with systolic heart failure, improvement in functional class and LV function induced by middle-term trimetazidine therapy is paralleled by a reduction in whole body REE. The beneficial cardiac effects of trimetazidine may be also mediated by a peripheral metabolic effect.

Trimetazidine is an anti-ischemic agent with antioxidant activity. This study evaluated the effect of periprocedural administration of trimetazidine on the incidence of percutaneous coronary intervention (PCI)–induced myocardial injury and contrast-induced nephropathy (CIN) in diabetic patients with mild-to-moderate renal dysfunction. One hundred patients with a mean glomerular filtration rate of 48 ± 16 (ml/min/1.73 m2) were prospectively enrolled, then randomly assigned to receive (50 patients; trimetazidine group) or not receive (50 patients; control group) periprocedural trimetazidine (70 mg/day) for 72 hours. The serum creatinine level was measured pre-PCI, 72 hours, and 10 days thereafter. An increase in the serum creatinine level by >0.5 mg/dl or 0.25% of the baseline value is considered as CIN. Cardiac troponin I levels were measured before and 6, 12, and 24 hours after PCI. Mean age of the study cohort was 59 ± 6 years (men 68%). The serum creatinine level in the control group increased significantly 3 days after PCI and decreased on the tenth day. However, it showed no significant change in the trimetazidine group. Incidence of CIN was 12% in the trimetazidine group and 28% in the control group (p <0.05). Cardiac troponin I levels were significantly reduced in the trimetazidine group (6 hours: 8 ± 0.3 vs 16 ± 0.2 pg/ml, 12 hours: 13 ± 0.9 vs 24 ± 0.8 pg/ml, 24 hours: 7 ± 0.7 vs 14 ± 0.3 pg/ml, p <0.001). In conclusion, trimetazidine intake before elective PCI in diabetic patients with mild-to-moderate renal dysfunction is associated with decreased incidence of CIN and myocardial injury.

Abstract Aims Wild-type transthyretin cardiac amyloidosis (ATTRwt) is a cardiomyopathy causing myocardial hypoperfusion and impaired cardiac mitochondrial function. Trimetazidine is an antianginal agent used in patients with stable angina pectoris, which improves cardiac contractility and mitochondrial function. The aim of the study was to investigate the effect of trimetazidine on invasive haemodynamics and cardiac mitochondrial function in ATTRwt. Methods In a randomized, double-blind, placebo-controlled, crossover trial, 22 patients with ATTRwt received 4 weeks of trimetazidine and placebo in randomized order. After each treatment period followed examinations with endomyocardial biopsies taken for high-resolution respirometry and right heart catheterization at rest and during a cardiopulmonary exercise test. The primary endpoint was mean pulmonary artery wedge pressure (mPAWP) during peak exercise. The secondary endpoint was cardiac mitochondrial oxidative phosphorylation capacity. Exploratory endpoints were echocardiographic parameters, cardiac biomarker levels and quality of life. Results Trimetazidine did not significantly reduce mPAWP during peak exercise (31 ± 12 vs. 31 ± 13 mmHg, P = 0.61) or improve the cardiac mitochondrial oxidative phosphorylation capacity (73.4 ± 7.7 vs. 75.3 ± 7.7 pmol O2/(mg*s), P = 0.81) compared with placebo, nor did treatment with trimetazidine improve ejection fraction (P = 0.93), global longitudinal strain (P = 0.23), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P = 0.92) or the patients' quality of life (P = 0.98). Conclusions In ATTRwt, treatment with trimetazidine did not improve mPAWP or cardiac mitochondrial oxidative phosphorylation capacity compared with placebo.

Background Trimetazidine, as an anti-ischemic and antioxidant agent, has been demonstrated to have many cardioprotective effects. However, whether early administration of trimetazidine has an effect on diabetic cardiomyopathy and the mechanisms underlying the effect have not yet been elucidated. Methods We established a type 2 DCM rat model by high-fat diet and low-dose streptozotocin. Rats were separated into different groups: control, diabetes, and diabetes + trimetazidine (n = 6, each). Cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored. Results Rats with type 2 DCM showed severe insulin resistance, left ventricular dysfunction, increased cardiomyocyte apoptosis, and reduced cardiac autophagy. Collagen volume fraction (CVF) and perivascular collagen area/luminal area (PVCA/LA) ratio were significantly higher in the diabetic group than the control group. We found that trimetazidine treatment ameliorated metabolic disturbance and insulin resistance, reduced cardiomyocyte apoptosis, and restored cardiac autophagy. CVF and PVCA/LA ratio were also lower in the diabetes + trimetazidine group than the diabetic group (CVF, 4.75 ± 0.52 % vs. 11.04 ± 1.67 %, p  < 0.05; PVCA/LA, 8.37 ± 0.51 vs. 17.97 ± 2.66, p  < 0.05). Furthermore, trimetazidine inhibited phosphorylation of ERK and P38 MAPK to reduce myocardial fibrosis. Inhibited phosphorylation of AMPK was restored and the interaction between Bcl-2 and Beclin1 was enhanced in diabetes + trimetazidine group, resulting in the initiation of autophagy and alleviation of apoptosis. Conclusions Early administration of trimetazidine could ameliorate diabetic cardiomyopathy by inhibiting myocardial fibrosis and cardiomyocyte apoptosis and enhancing autophagy. Therefore, trimetazidine may be a good choice in the prevention of diabetic cardiomyopathy if applied at the early stage of diabetes.

Introduction: Coenzyme Q10 (CoQ10) is considered to be beneficial for patients with acute viral myocarditis (AVM). In addition, trimetazidine may be also beneficial to patients with AVM by promoting cardiac energy metabolism. This systematic review and meta-analysis examined the efficacy and safety of combining trimetazidine and CoQ10 with respect to CoQ10 alone in patients suffering from AVM. Methodology: PubMed, Embase, the Cochrane Library, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were searched for relevant randomized controlled trials (RCTs). An analysis of random effects was employed to combine the results.  Results: Sixteen RCTs that included 1,364 patients with AVM contributed to the meta-analysis. Overall, 687 patients received the combined treatment, while 677 received the CoQ10 alone for a duration of 2-12 weeks (mean: 5.2 weeks). In contrast to monotherapy with CoQ10, combined treatment with trimetazidine and CoQ10 significantly improved overall therapy effectiveness (risk ratio [RR]: 1.19, 95% confidence interval [CI]: 1.13 to 1.24, p < 0.001; I2 = 0%). Differences in study parameters such as the incidence of heart failure upon admission, dosage of CoQ10, or length of treatment did not significantly alter the outcomes (p for all subgroup analyses > 0.05). The combined treatment was associated with improved myocardial enzyme levels and recovery of cardiac systolic function as compared to CoQ10 alone (p all < 0.05). In addition, trimetazidine combined with CoQ10 caused no greater increase in adverse events than CoQ10 alone.  Conclusions: Trimetazidine combined with CoQ10 is an effective and safe treatment for AVM.

In nondiabetic patients with stable angina, combined treatment with hemodynamic agents and trimetazidine is well-tolerated and effective in controlling ischemia. This study aims to evaluate the antiischemic and metabolic effects of trimetazidine in patients with type 2 diabetes mellitus, not eligible for revascularization, who remained symptomatic despite the use of at least 2 antianginal agents. A randomized, double-blind, crossover clinical trial was used. Ten patients were randomized to receive trimetazidine (20 mg, 3 times a day) or placebo for 6-week periods. At baseline and at the end of each 6-week intervention period, clinical and biochemical evaluations, exercise testing, 24-hour ambulatory blood pressure, and Holter monitoring were performed. During trimetazidine therapy, patients had significant improvement on angina functional class ( P < .05), with decrease in the number of weekly angina episodes (1.5 ± 0.8 vs 0.4 ± 0.7, P < .01), and in sublingual nitrate doses (1.4 ± 0.7 mg vs 0.1 ± 0.3 mg, P < .001). Time to 1-mm ST-segment depression during exercise test was increased after trimetazidine use (229 ± 126 seconds at baseline, 276 ± 101 seconds after placebo, and 348 ± 145 seconds after trimetazidine, P < .001). No differences were observed between treatment periods on mean 24-hour blood pressure, heart rate, and rate-pressure product evaluated concomitantly with ambulatory blood pressure and Holter monitoring. Glycemic and lipid profiles were similar after trimetazidine and placebo use. In patients with diabetes who remain symptomatic, the addition of trimetazidine improves symptoms and exercise responses without hemodynamic or metabolic changes. The present data suggest that trimetazidine may be an effective adjunct therapy for these patients, but further investigation is needed to confirm these findings.

SUMMARY Objectives: The revascularization procedures become more and more popular to treat coronary artery disease, in many countries. Some patients are free of angina after revascularization, without any documented re-stenosis present with recurrent angina symptoms after a period of time. The aim of this work was to assess the efficacy of trimetazidine in the subpopulation of patients with a history of PTCA or CABG, who were included in the TRIMPOL II study. Methodology: A subgroup of 94 patients was retrospectively analysed from the Trimpol II study, a multicentre, double-blind randomised placebo-controlled trial in 426 patients with stable effort angina. These patients have a history of revascularization for coronary artery disease, and they are still symptomatic after 6 months despite a treatment with metoprolol (50 mg twice daily). They were randomly allocated to receive either trimetazidine (20 mg 3 times daily) or placebo for 12 weeks, on top of the β-blocker. Exercise test parameters, clinical efficacy and safety were assessed. Results were analysed using the Student test, the Mann-Whitney test or the Shapiro-Wilk test. Results: Compared to placebo, the 12-week treatment with trimetazidine significantly improved: time to 1 mm ST segment depression (385.1 s ± 144.6 s versus 465.0 s ± 143.8 s [p < 0.01]); exercise test duration (466.9 s ± 144.8 s versus 524.4 s ± 131.5 s [p = 0.048]), total workload (9.0 m.e. ± 2.4 m.e versus 10.1 m.e. ± 2.4 m.e [p = 0.035]) as well as time to onset of angina (433.6 s ± 164 s versus 508.1 s ± 132.4 s [p = 0.031]). Weekly number of angina attacks and nitrate consumption were significantly reduced in the trimetazidine group when compared to placebo. Three mild gastro-intestinal side-effects were reported in the trimetazidine group. Conclusion: These results show that trimetazidine provides anti-anginal efficacy in post-revascularized patients with recurrent angina despite a monotherapy with metoprolol. The treatment was well accepted.

Clinical studies have demonstrated that trimetazidine (TMZ) possesses a synergistic hypolipidemic effect together with statins, but the underlying mechanism remains to be elucidated. The present study aimed to investigate the role of TMZ in non-alcoholic fatty liver disease (NAFLD). By investigating the TMZ treatment of NAFLD, it was identified that high-fat diet (HFD) mice exhibit significant changes in several physiologic indices, including body weight, plasma lipids and glucose tolerance. Notably, hepatocyte bullous steatosis and fibrosis in HFD mice are greatly attenuated by 8 weeks of TMZ treatments. The results of the present study also indicated that the expression of carbohydrate-responsive element-binding protein (ChREBP), fatty acid synthase and acetyl-CoA carboxylase were all significantly reduced in the HFD + TMZ group compared with the HFD group. In order to confirm the hypothesis in vitro, the palmitate-treated liver cancer cell line (HepG2) was employed and similar results were obtained in TMZ-treated HepG2 cells. Furthermore, TMZ markedly upregulated the AMP-activated protein kinase (AMPK) signaling pathway and reduced the expression of forkhead box O1 (FOXO1) in the cells, while these effects controlled by TMZ were abolished by the AMPK inhibitor Compound C. The present study reported that knockdown of FOXO1 expression by FOXO1 small interfering RNA resulted in a reduction of ChREBP protein expression and post-transcriptional activity. In summary, for the first time, to the best of the authors' knowledge, the present study revealed a novel role of TMZ in hepatic steatosis; TMZ ameliorated ChREBP-induced de novo lipogenesis by activating the AMPK-FOXO1 pathway.