Impact of Trimetazidine on the Incident Heart Failure After Coronary Artery Revascularization.

ABSTRACT: Abnormal myocardial metabolism is a common pathophysiological process underlying ischemic heart disease and heart failure (HF). Trimetazidine is an antianginal agent with a unique mechanism of action that regulates myocardial energy metabolism and might have a beneficial effect in preventing HF in patients undergoing myocardial revascularization. We aimed to evaluate the potential benefit of trimetazidine in preventing incident hospitalization for HF after myocardial revascularization. Using the common data model, we identified patients without prior HF undergoing myocardial revascularization from 8 hospital databases in Korea. To compare clinical outcomes using trimetazidine, database-level hazard ratios (HRs) were estimated using large-scale propensity score matching for each database and pooled using a random-effects model. The primary outcome was incident hospitalization for HF. The secondary outcome of interest was major adverse cardiac events (MACEs). After propensity score matching, 6724 and 11,211 patients were allocated to trimetazidine new-users and nonusers, respectively. There was no significant difference in the incidence of hospitalization for HF between the 2 groups (HR: 1.08, 95% confidence interval [CI], 0.88-1.31; P = 0.46). The risk of MACE also did not differ between the 2 groups (HR: 1.07, 95% CI, 0.98-1.16; P = 0.15). In conclusion, the use of trimetazidine did not reduce the risk of hospitalization for HF or MACE in patients undergoing myocardial revascularization. Therefore, the role of trimetazidine in contemporary clinical practice cannot be expanded beyond its current role as an add-on treatment for symptomatic angina.

Trimetazidine alleviates paclitaxel-induced peripheral neuropathy through modulation of TLR4/p38/NF-κB and klotho protein expression.

Chemotherapy-induced peripheral neuropathy is a common adverse effect associated with a number of chemotherapeutic agents including paclitaxel (PTX) which is used in a wide range of solid tumors. Development of PTX-induced peripheral neuropathy (PIPN) during cancer treatment requires dose reduction which limits its clinical benefits. This study is conducted to investigate the role of toll like receptor-4 (TLR4) /p38 signaling and Klotho protein expression in PIPN and the role of trimetazidine (TMZ) in this pathway. Sixty-four male Swiss albino mice were divided into 4 groups (n = 16); Group (1) injected intraperitoneally (IP) with ethanol/tween 80/saline for 8 successive days. Group (2) received TMZ (5 mg/kg, IP, day) for 8 successive days. Group (3) treated with 4 doses of PTX (4.5 mg/kg, IP) every other day over a period of 7 days. Group (4) received a combination of TMZ as group 2 and PTX as group 3. The Effect of TMZ on the antitumor activity of PTX was studied in another set of solid Ehrlich carcinoma (SEC)-bearing mice that was similarly divided as the above-mentioned set. TMZ mitigated tactile allodynia, thermal hypoalgesia, numbness and fine motor discoordination associated with PTX in Swiss mice. The results of the current study show that the neuroprotective effect of TMZ can be attributed to inhibition of TLR4/p38 signaling which also includes a reduction in matrix metalloproteinase-9 (MMP9) protein levels as well as the proinflammatory interleukin-1ß (IL-1ß) and preserving the levels of the anti-inflammatory IL-10. Moreover, the current study is the first to demonstrate that PTX reduces the neuronal levels of klotho protein and showed its modulation via cotreatment with TMZ. In addition, this study showed that TMZ neither alter the growth of SEC nor the antitumor activity of PTX. In conclusion, we suggest that (1) Inhibition of Klotho protein and upregulation of TLR4/p38 signals in nerve tissues may contribute to PIPN. (2) TMZ attenuates PIPN by modulating TLR4/p38 and Klotho protein expression without interfering with its antitumor activity.

Fatty acid oxidation fuels agonist-induced platelet activation and thrombus formation: Targeting ß-oxidation of fatty acids as an effective anti-platelet strategy.

Platelet mitochondria possess remarkable plasticity for oxidation of energy substrates, where metabolic dependency on glucose or fatty acids is higher than glutamine. Since platelets metabolize nearly the entire pool of glucose to lactate rather than fluxing through mitochondrial tricarboxylic acid cycle, we posit that majority of mitochondrial ATP, which is essential for platelet granule secretion and thrombus formation, is sourced from oxidation of fatty acids. We performed a comprehensive analysis of bioenergetics and function of stimulated platelets in the presence of etomoxir, trimetazidine and oxfenicine, three pharmacologically distinct inhibitors of ß-oxidation. Each of them significantly impaired oxidative phosphorylation in unstimulated as well as thrombin-stimulated platelets leading to a small but consistent drop in ATP level in activated cells due to a lack of compensation from glycolytic ATP. Trimetazidine and oxfenicine attenuated platelet aggregation, P-selectin externalization and integrin αIIb ß3 activation. Both etomoxir and trimetazidine impeded agonist-induced dense granule release and platelet thrombus formation on collagen under arterial shear. The effect of inhibitors on platelet aggregation and dense granule release was dose- and incubation time- dependent with significant inhibition at higher doses and prolonged incubation times. Neither of the inhibitors could protect mice from collagen-epinephrine-induced pulmonary embolism or prolong mouse tail bleeding times. However, mice pre-administered with etomoxir, trimetazidine and oxfenicine were protected from ferric chloride-induced mesenteric thrombosis. In conclusion, ß-oxidation of fatty acids sustains ATP level in stimulated platelets and is therefore essential for energy-intensive agonist-induced platelet responses. Thus, fatty acid oxidation may constitute an attractive therapeutic target for novel antiplatelet agents.

Early Trimetazidine Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST Segment Elevation Myocardial Infarction Reduces Myocardial Infarction Size.

PURPOSE: Trimetazidine, a metabolic agent with anti-ischemic effects, was reported to reduce reperfusion injury in animal models. In this randomized double-blind placebo-controlled trial, we investigated the effects of trimetazidine on the reduction of infarction size in patients undergoing revascularization for ST segment elevation myocardial infarction (STEMI). METHODS: Patients with STEMI randomly received trimetazidine (n = 87) or placebo (n = 86) before primary percutaneous coronary intervention (PCI), and subsequently received oral trimetazidine or placebo for 12 months after reperfusion. The predefined primary endpoint was infarction size on cardiac magnetic resonance (CMR) performed at 7 days after primary PCI. The trial was registered on www. CLINICALTRIALS: gov (registration number: NCT02826616). RESULTS: The clinical characteristics of the patients in both groups were well-matched at baseline. At 7 days after primary PCI, the percentage and absolute infarction size in the trimetazidine group were significantly smaller than those in the control group (22% ± 12% [n = 74] vs. 27% ± 13% [n = 74], p = 0.011 and 28 ± 18 g [n = 74] vs. 35 ± 19 g [n = 74], p = 0.022, respectively), and the incidence of myocardial microvascular obstruction (MVO) measured by CMR was significantly reduced in the trimetazidine group (29.7% [22/74] vs. 52.7% [39/74], p = 0.005). The myocardial salvage index (MSI) measured by CMR was significantly higher in the trimetazidine group (48% ± 20% vs. 39% ± 20%, p = 0.008). The incidence of readmission due to aggravated heart failure did not differ significantly between the trimetazidine group and the control group (8.0% vs. 14.0%, p = 0.234). CONCLUSIONS: In patients with STEMI undergoing primary PCI, early trimetazidine before reperfusion reduced myocardial infarction size and MVO, and improved MSI.

The Impact of Trimetazidine on Cardiac Fibrosis, Inflammation, and Function in Ischemic Cardiomyopathy Patients.

BACKGROUND: Previous studies have shown that Trimetazidine (TMZ) improves vascular endothelial function and reduces the inflammatory process progression. However, limited data have been available regarding its effects on myocardial fibrosis following ischemia and causing left ventricular dysfunction. PURPOSE: To investigate the impact of TMZ adjuvant therapy for ischemic cardiomyopathy (ICM) on cardiac fibrosis, vascular endothelial function, inflammation, and myocardial functions. METHODS: This randomized, double-blind controlled clinical trial included 48 patients (aged 59.4 ± 9 years) with ICM who were randomly assigned to two groups: TMZ 35 mg twice daily and placebo in addition to conventional ICM medications. All patients received the tablets for 3 months. Both groups were then compared in terms of connective tissue growth factor (CTGF), endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-α), and some echocardiographic indices, weekly angina attacks and nitrate consumption before and after treatment. RESULTS: No significant differences between CTGF, ET-1, and TNF-α levels, in addition to some echocardiographic indices, were observed between both groups before treatment. After treatment, the TMZ group had significantly lower ET-1 than the placebo group, with both groups exhibiting a substantial decrease in TNF-α and CTGF. The TMZ group had lower mean ± SD levels for TNF-α and CTGF and showed significant improvement in echocardiographic indices and weekly angina attacks after treatment. CONCLUSION: Adjunctive TMZ therapy for ICM effectively improved vascular endothelial function and reduced inflammation. Furthermore, our exploratory findings may be used to provide new information on the potential effects of TMZ on myocardial fibrosis by downregulating CTGF.

Bioequivalence and Pharmacokinetic Profiles of 2 Trimetazidine Modified-release Tablets Under Fasting and Fed Conditions in Chinese Healthy Subjects.

This study aims to assess the bioequivalence of test and reference formulations of trimetazidine dihydrochloride in healthy Chinese volunteers under fasting and fed conditions, and to determine the effect of food on the pharmacokinetic profiles of both formulations. A randomized, open-label, crossover, four-period study with a 7-day washout period was conducted in 24 healthy Chinese subjects. The subjects fasted for at least 10 hours before being given a single 35-mg dose of the test and reference tablets. Venous blood samples were taken from predose at 0 hours to postdose at 36 hours at scheduled time points. The main pharmacokinetic parameters were calculated with a noncompartmental model. The nonparametric test of Tmax under both conditions showed no significant difference between the two formulations (P > .05). The 90% confidence intervals of geometric mean ratio of lnCmax and lnAUC0→∞ (the logarithmic values of area under the plasma concentration-time curve [AUC] and mean maximum plasma concentration [Cmax ]) all fell within 80%-125%. Cmax in the fed state was slightly higher than that in the fasting state (P < .05), while other pharmacokinetic parameters were comparable. No severe adverse events occurred. The test and reference formulations were bioequivalent under both fasting and fed conditions. Food did not affect the pharmacokinetic profiles of trimetazidine in Chinese healthy volunteers, therefore trimetazidine is suitable for administration under fasting or fed conditions.

Trimetazidine improves left ventricular global longitudinal strain value in patients with heart failure with reduced ejection fraction due to ischemic heart disease.

Heart failure with reduced ejection fraction (HFrEF) due to ischemic heart disease (IHD) showed a progressive decline in left ventricular contractile function. However, no previous study has examined the left ventricular global longitudinal strain (LV GLS) parameter that represents LV contractile function. We investigated whether trimetazidine could improve the LV GLS value in patients with HFrEF due to IHD. We performed a double-blind, randomized controlled trial (RCT) including 26 patients with HFrEF due to stable IHD who were given modified-release trimetazidine 35 mg twice per day (n = 13) or placebo (n = 13) for 3 months in addition to standard medication. Left ventricular systolic function including GLS values was assessed at baseline and after 3 months using echocardiography. A total of 25 participants (13 control and 12 trimetazidine groups) were recruited with a baseline average age of 57.1 ± 10 years, and LV ejection fraction (LVEF) value of 34.6% ± 4.4%, and a GLS value of 7.4% ± 2.1%. Baseline clinical characteristics and echocardiogram were similar between the two groups. There was significant GLS improvement in the trimetazidine group (-6.9% ± 2.4% to -8.4% ± 2.6%, p = 0.000), but no significant differences were noted in the control group. The GLS improvement was significantly higher in the trimetazidine group than the control (1.5% + 0.9% vs. -0.7% + 1.7%, p = 0.001). No adverse drug reactions from the administration of trimetazidine in this study. Trimetazidine may improve GLS values in patients with HFrEF due to IHD.

Trimetazidine inhibits liver fibrosis and hepatic stellate cell proliferation and blocks transforming growth factor-ß (TGFß)/Smad signaling in vitro and in vivo.

Trimetazidine (TMZ) has been used extensively to treat coronary artery disease and to reduce fibrosis. Liver fibrosis is a reversible process. However, the impacts of TMZ on liver fibrosis triggered by CCl4 and on hepatic stellate cells in liver fibrosis remain to be elaborated. In the current study, the liver fibrosis models were constructed by using CCl4-induced mice and TGF-ß-induced hepatic stellate cells. The involvement of TMZ in liver fibrosis was subsequently investigated. In the CCl4-induced hepatic fibrosis mouse model, it was shown that the expression levels of alanine aminotransferase and aspartate aminotransferase were reduced after TMZ treatment; the expression levels of the extracellular matrix proteins colla1 and α-SMA were down-regulated; furthermore, the expression levels of TGFß/Smad signaling proteins were inhibited. In TGF-ß-induced hepatic stellate cells, compared to the TGF-ß-induced group, cell proliferation and migration were inhibited after TMZ treatment; meanwhile, extracellular matrix protein and TGFß/Smad signaling protein expression levels followed the same trend as in the hepatic fibrosis model. In conclusion, TMZ could block the TGFß/Smad signaling in liver fibrosis model, with inhibiting liver fibrosis and hepatic stellate cell proliferation. This may broaden the application sphere of TMZ in liver fibrosis therapy.

Clinical Implications of Nicorandil Combined with Trimetazidine in Patients with Coronary Heart Disease: A Real-World Observational Study.

INTRODUCTION: Coronary heart disease (CHD) remains the leading cause of mortality in China. The treatment strategies, especially for patients with ischemic angina pectoris, are still far from satisfactory. Hence, this study was carried out to evaluate the long-term potential of nicorandil in Chinese patients with CHD. METHODS: Adult patients with CHD were reviewed retrospectively from three hospitals in Central China to obtain relevant data. The primary outcome was the rate of major adverse cardiovascular events (MACE) which is the composite outcome of stroke, myocardial infarction (MI), and mortality at 3 years while the secondary outcomes included rates of MACE, stroke, MI, and mortality at 1 and 2 years. The rates of MACE were estimated using Kaplan-Meir survival curves and compared by log-rank test. The association between various treatment regimens and hazards of MACE was estimated using Cox proportional hazards model. All analyses were carried out using SAS 9.4. RESULTS: A total of 5504, 1674, and 3923 patients treated with the nicorandil-trimetazidine combination, nicorandil, and trimetazidine were included in the study, respectively. At 3-year follow-up, the rate of MACE [hazard ratio (HR) 0.85; 95% CI 0.74-0.97; P = 0.017] and stroke (HR 0.58, 95% CI 0.48-0.71; P < 0.0001) was lower in the combination group compared to trimetazidine group. Similarly, the rate of stroke was significantly lower (HR 0.69; 95% CI 0.52-0.93; P = 0.0146) at 3 years in the nicorandil group compared to the trimetazidine group. The rate of stroke (HR 0.65; 95% CI 0.52-0.83; P = 0.0004) was significantly lower among the combination group compared with the trimetazidine group at 1-year follow-up. Similarly, the rate of stroke was significantly lower at 1 year (HR 0.70; 95% CI 0.50-0.97; P = 0.03) but not at 2 years (HR 0.70; 95% CI 0.52-0.94; P = 0.0177), while the rate of other outcomes, though lower in the nicorandil group than the trimetazidine group, was not statistically significant at 1 and 2 years respectively. CONCLUSION: Nicorandil in combination with trimetazidine can be considered as an effective and potential treatment strategy in reducing the rate of MACE in patients with CHD in the Chinese population.

Effects of trimetazidine in patients with severe chronic heart failure with reduced left ventricular ejection fraction: A prospective, randomized, open-label, cross-over study.

BACKGROUND: Trimetazidine (TMZ) modulates cardiac metabolism, but its use in heart failure remains controversial. The aim of the study was to evaluate the effects of TMZ on exercise capacity, left ventricular ejection fraction (LVEF), mortality, and quality of life in stable patients with heart failure with reduced left ventricular ejection fraction (HFrEF). METHODS: Forty-five patients with stable advanced HFrEF treated with optimal medical therapy were randomized in a prospective, single-center, open-label, cross-over study of trimetazidine (35 mg b.i.d.) on top of standard medical therapy or standard pharmacotherapy for two periods of 30 days and one period of 6 months. Initially and at the end of each period all patients underwent the following: exercise testing, six-minute walk test (6MWT), two-dimensional-echocardiography, and quality of life assessment. RESULTS: The mean age of patients was 58.2 ± 10.6 years. Etiology of HFrEF was ischemic in 66.6% of patients. After 6 months no significant changes were observed in either group with regards to peak VO2 uptake, 6MWT, LVEF, or quality of life. TMZ had no effect on mortality or cardiovascular events. CONCLUSIONS: The additional use of TMZ on top of standard medical therapy in stable advanced HFrEF patients was not associated with significant changes in mortality, exercise capacity, LVEF, or quality of life.

The efficacy of trimetazidine in non-ischemic heart failure patients: a meta-analysis of randomized controlled trials.

Trimetazidine has been reported to benefit patients with heart failure (HF) and angina. The impact of trimetazidine on non-ischemic HF remains unclear. We reviewed clinical trials to investigate whether trimetazidine could improve exercise endurance, life quality, and heart function in non-ischemic HF patients. We searched the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, and Web of science for randomized clinical trials published before April 30th, 2020; Studies limited to patients with non-ischemic HF, aged ≥18 years, comparing trimetazidine with conventional therapy with/without placebo. Outcome measurements included primary outcomes (6 minutes walking test (6-MWT)) and secondary outcomes (life quality scores, echocardiography parameters, biomarker, peak oxygen consumption). The follow-up period was longer than three months. This study was registered with international prospective register of systematic reviews (PROSPERO) (CRD42020182982). Six studies with 310 cases were included in this research. Trimetazidine significantly improved 6-MWT (weighted mean difference (WMD) = 48.51 m, 95% confidence interval (CI) [29.41, 67.61], p < 0.0001, I2 = 0%), left ventricle ejection fraction (LVEF) (WMD = 3.09%, 95% CI [1.09, 5.01], p = 0.002, I2 = 0%) at 3 months, and LVEF (WMD = 6.09%, 95% CI [3.76, 8.42], p < 0.0001, I2 = 12%) at 6 months. Furthermore, it reduced peak oxygen consumption (WMD = -2.24 mL/kg per minute, 95% CI [-4.09, -0.93], p = 0.02). This meta-analysis suggested that trimetazidine might be an effective strategy for improving exercise endurance and cardiac function in patients with non-ischemic HF.

Trimetazidine offers myocardial protection in elderly coronary artery disease patients undergoing non-cardiac surgery: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Trimetazidine (TMZ) pretreatment protects cardiomyocytes during cardiac surgery. TMZ may protect elderly patients with ischaemic heart disease (IHD) undergoing non-cardiac surgery. METHODS: This was a randomized, double-blind, placebo-controlled trial (registration #ChiCTR1900025018) of patients with IHD scheduled to undergo non-cardiac surgery at Shenzhen People's Hospital (Shenzhen, Guangdong Province, China) between June 2014 and September 2015, randomized to 60 mg TMZ or placebo 12 h before surgery. The primary endpoint was the occurrence of in-hospital cardiovascular events. The secondary endpoints were myocardial ischaemia on five-lead electrocardiogram (cECG), cardiac troponin I (cTnI) elevation, cardiac death, acute coronary events, heart failure, and arrhythmia requiring treatments. RESULTS: Compared with the placebo group, the TMZ group showed a lower occurrence of in-hospital cardiovascular events (primary endpoint, 20.0% vs. 37.5%, P = 0.02), myocardial ischaemia (15.0% vs. 32.5%, P < 0.01), cTnI elevation (2.5% vs. 10%, P < 0.01), acute coronary events (10.0% vs. 20.0%, P < 0.05), heart failure (0% vs. 2.5%, P < 0.05), and arrhythmia requiring treatment (17.5% vs. 35.0%, P < 0.05). There was no acute myocardial infarction during the 30-day postoperative period. CONCLUSIONS: In elderly patients with IHD undergoing non-cardiac surgery, TMZ pretreatment was associated with myocardial protective effects. Trial registration The trial was prospectively registered at http://www.chictr.org.cn/showproj.aspx?proj=41909 with registration number [ChiCTR1900025018] (7/8/2019).

Efficacy of Trimetazidine in Limiting Periprocedural Myocardial Injury in Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis.

We systematically searched the literature to assess the efficacy of trimetazidine in reducing periprocedural myocardial injury and improving postoperative left ventricular ejection fraction (LVEF) in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). An electronic search was conducted based on the PubMed, Ovid, Scopus, Springer, CENTRAL, and Google Scholar databases; 14 randomized controlled trials (RCTs) were included. Our meta-analysis showed a significant reduction in cardiac troponin I (cTnI) levels with trimetazidine compared with controls (P < .00001) but not in serum creatine kinase-myocardial band levels (P = .49). There were significantly reduced odds of ischemic ST-T segment changes with trimetazidine (P = .0.03) but lack of significant difference in the incidence of anginal attacks between the 2 groups (P = .10). Results also suggest significantly higher LVEF with trimetazidine compared with controls (P < .00001). Meta-regression analysis indicated no influence of duration of trimetazidine therapy on cTnI levels. The administration of preprocedure trimetazidine may have a role in reducing periprocedural myocardial injury in patients with CAD undergoing PCI. Evidence also suggests that postoperative trimetazidine may improve LVEF in the short term. Lack of high-quality trials and the heterogeneity of studies limit the ability of our analysis to draw strong conclusions. Further well-designed RCTs are required to supplement current evidence.

Trimetazidine Use and the Risk of Parkinsonism: A Nationwide Population-Based Study.

An association between trimetazidine (TMZ), an anti-anginal drug, and parkinsonism has been reported in a number of studies. However, evidence from studies with long-term follow-up and better validity is lacking. We investigated the risk of TMZ-associated parkinsonism, specifically the incidence rate, cumulative dose-response relationship, and combined effects with other parkinsonism-inducing medications. This propensity score-matched retrospective cohort study was conducted using 14-year health insurance claims data in South Korea. The risk of parkinsonism was evaluated using multivariate Cox proportional hazard regression analysis, adjusted for comorbidities and concurrent medications. A total of 9712 TMZ users and 29,116 matched non-TMZ users were included. TMZ users had a significantly higher incidence rate of parkinsonism than non-TMZ users (9.34 vs. 6.71 per 1000 person-years; p < 0.0001). TMZ use significantly increased the risk of parkinsonism (adjusted hazard ratio = 1.38; 95% confidence interval = 1.26-1.51). Increased risks were observed with accumulated doses of TMZ, as well as concurrent use of other parkinsonism-inducing medications. The findings indicate that TMZ use significantly increases the risk of parkinsonism in the South Korean population. Closer monitoring should be considered for TMZ users, especially for those who are older, using TMZ at high cumulative doses and other parkinsonism-inducing medications.

Single Ascending Dose Study to Assess Pharmacokinetic Linearity, Safety, and Tolerability of Trimetazidine - Modified Release in Healthy Human Subjects.

AIM: This study assessed the linearity of pharmacokinetics (PK) of trimetazidine (TMZ) modified-release tablets (indicated in adults as an add-on therapy for stable angina pectoris) and measured its renal elimination, safety, and tolerability in healthy subjects. METHODS: This was a randomized, open-label, single-ascending dose study in healthy subjects. Subjects were administered with a single dose of 35, 70, or 105 mg TMZ-modified release tablets (six subjects each). Pharmacokinetic evaluations and safety analysis were performed before the first dose and till 48 h post-first dose. RESULTS: Following administration of 35, 70, and 105 mg TMZ-modified release; the Cmax (mean±SD) was 79.32 (±23.08), 153.17 (±23.08), and 199.67 (±23.08) ng/mL, the Tmax was 5.42 (±0.49), 4.51 (±1.27), and 4.57 (±0.96) h, t1/2 was 7.75 (±1.62), 6.40 (±1.23), and 6.50 (±1.18) h, AUC(0-inf) was 1116.89 (±378.35), 1838.39 (±284.50), and 2504.84 (±348.35) ng.h/mL, CLR was 13.70 (±2.24), 14.80 (±5.91), and 19.58 (±6.24) L·h-1 and CL/F was 33.69 (±8.51), 38.85 (±6.15), and 42.74 (±7.10) L·h-1, respectively. Slope estimates for AUC(0-inf), AUC(0-t), and Cmax were less than 1. Corresponding 95% CI of the slope for the AUC parameters excluded 1, indicating that the deviation from dose-proportionality was statistically significant. Corresponding 95% CI of the slope for Cmax included 1, indicating that the less than dose-proportional increase in Cmax was not statistically significant. No significant adverse events were observed. CONCLUSION: Substantial deviation from a dose-proportional increase in AUC(0-inf) and AUC(0-t) suggested a non-linear PK for TMZ-modified release. Single dose of TMZ-modified release was well tolerated and safe.

Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: 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. METHODS: 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). FINDINGS: 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. INTERPRETATION: 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. FUNDING: Servier.

The Impact of Trimetazidine on Disease Severity and Quality of Life in Parkinson's Disease.

Trimetazidine is contraindicated in movement disorders, however, a not negligible part of trimetazidine users is still patients with Parkinson's disease (PD). The present study aimed to objectively determine the impact of trimetazidine on the severity of symptoms and the health-related quality of life of patients with PD by measuring changes after its withdrawal. A consecutive series of 42 patients with PD using trimetazidine underwent detailed neurological and neuropsychological assessments at baseline and three months after the discontinuation of trimetazidine. Clinically relevant improvements were achieved with discontinuation of trimetazidine according to changes in scores of each part of the Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (Part I: -25.7%, p < 0.001; Part II: -23.8%, p < 0.001; Part III: -28.5%, p < 0.001; Part IV: -30.1%, p = 0.004) and total scores of the Non-Motor Symptoms Scale (-25.6%, p = 0.004) and the Montgomery-Asberg-Depression Rating Scale (-20.1%, p = 0.001). Benefits resulting from the withdrawal of the drug also manifested in the improvement of the health-related quality of life based on changes in the summary index of the 39-item Parkinson's Disease Questionnaire (-18.2%, p = 0.031). Our results provide clinical rationale for strictly avoiding the use of trimetazidine in PD. Discontinuation of trimetazidin results in clinically relevant improvements in Parkinsonian symptoms.