The VASCO-Angina Study☆

IJCA-15500; No of Pages 4 International Journal of Cardiology xxx (2012) xxx–xxx

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International Journal of Cardiology

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Efﬁcacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina — The VASCO-angina study☆

Cristiana Vitale a, Ilaria Spoletini a, Walter Malorni b,c, Pasquale Perrone-Filardi d, Maurizio Volterrani a, Giuseppe M.C. Rosano a,⁎ a Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy b Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy c San Raffaele Institute, Sulmona, L'Aquila; Italy d Department of Cardiology, Università Federico II, Napoli, Italy article info abstract

Article history: Background/objectives: Trimetazidine (TMZ) is a metabolic agent of proven efficacy in improving myocardial Received 12 July 2012 ischemia and angina. VASCO, a randomised double-blinded, placebo-controlled trial, assessed anti-anginal ef- Received in revised form 29 October 2012 ficacy and safety of standard and high dose of modified-release TMZ (70 mg/d and 140 mg/d) in symptom- Accepted 1 November 2012 atic and asymptomatic patients with chronic ischemic heart disease receiving background atenolol 50 mg/d Available online xxxx on exercise test parameters. The VASCO-angina study assessed the efficacy of the two doses of TMZ on total exercise duration (TED) and Keywords: time to 1-mm ST segment depression (T1), in symptomatic patients with chronic stable angina receiving Trimetazidine Myocardial ischemia background atenolol treatment. Angina Methods and results: In the all cohort of chronic stable angina patients TMZ significantly improved TED com- Exercise performance pared to baseline and to placebo. Both doses of TMZ significantly increased TED (p=0.0044 and p=0.0338 Heart disease for TMZ 140 mg/d and TMZ 70 mg/d, respectively). A greater TED improvement was observed in TMZ Exercise testing 140 mg/d than in TMZ 70 mg/d, although the difference was not significant. Amongst patients with limiting angina during exercise test, both doses of TMZ significantly improved both T1 and TED. No difference in se- rious adverse events was noted between TMZ and placebo. Conclusions: The VASCO-angina gives evidence for the efficacy and tolerability of standard and high dose of TMZ in improving effort-induced myocardial ischemia and functional capacity in patients with chronic stable angina receiving background beta-blockers. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction 35 mg modified release (MR) bid either in monotherapy or in combination with common anti-anginal drugs [5,9–16]. Previous meta-analyses Trimetazidine (TMZ) is an inhibitor of free fatty acids (FFA) oxida- [4,17–19] have confirmed that the effect of TMZ is comparable to that of tion that shifts cardiac and muscle metabolism from FFA to glucose common anti-anginal drugs both in monotherapy and in combination utilisation resulting into a greater production of high-energy phos- with heart rate reducing agents. phates and into an anti-ischemic effect [1–3]. Earlier studies have Despite the wealth of data on the anti-anginal and anti-ischemic ef- shown that TMZ improves myocardial ischemia, exercise performance fect of TMZ 20 mg, evidence on the efficacy of TMZ 35 mg MR in pa- and symptoms in patients with coronary artery disease and in those tients with effort-induced myocardial ischemia receiving beta-blockers with peripheral arterial disease [4–8]. Placebo-controlled studies have is still lacking. Furthermore, it is not clear whether higher doses of proven the anti-ischemic effect of TMZ at the dose of 20 mg tid or TMZ may exert a greater anti-ischemic effect than those currently ap- proved for the treatment of angina, based on bioequivalence with the doses of 20 mg. The VASCO study was a 12-week randomised double-blind, placebo- controlled trial aimed at assessing the anti-anginal efficacy and safety of ☆ Authors take responsibility for all aspects of the reliability and freedom from bias of 2 doses of TMZ MR (TMZ 70 mg/d, TMZ 140 mg/d) in 1962 coronary the data presented and their discussed interpretation. patients with and without angina receiving atenolol 50 mg/d [19].The ⁎ Corresponding author at: Centre for Clinical & Basic Research, IRCCS San Raffaele VASCO-angina study assessed the efficacy of the two doses of TMZ in Pisana, via della Pisana, 235, 00163 Rome, Italy. Tel.: +39 06 52252409; fax: +39 06 52252465. the patients reporting effort-induced angina despite treatment with E-mail address: [email protected] (G.M.C. Rosano). atenolol.

Please cite this article as: Vitale C, et al, Efﬁcacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina — The VASCO-angina study, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.11.001 2 C. Vitale et al. / International Journal of Cardiology xxx (2012) xxx–xxx

Table 1 Baseline clinical features of patients from the VASCO-angina study and the VASCO trial.

VASCO-angina study VASCO trial

TMZ MR 70 mg/day TMZ MR 140 mg/day Placebo All patients All patients (n=249) (n=260) (n=136) (n=645) (n=1962)

Age (years) 59.9±8.2 59.7±8.2 59.6±8.2 59.7±8.2 60.4±8.2 Gender (male) 225 (90.4%) 218 (83.9%) 120 (88.2%) 563 (87.3%) 1685 (85.9%) Body mass index 27.3±3.4 28.0±3.5 27.9±3.8 27.7±3.5 27.5±3.4 Physical activity (regular/occasional) 221 (88.8%) 239 (91.9%) 117 (86.0%) 577 (89.5%) 1701 (86.7%) Smoking habit 50 (20.1%) 60 (23.1%) 23 (16.9%) 133 (20.6%) 354 (18.0%) Diabetes mellitus 37 (14.9%) 36 (13.9%) 24 (17.7%) 97 (15.0%) 303 (15.4%) Duration of angina pectoris (months) 68.8±74.5 59.7±67.2 58.2±56.3 62.9±68.1 57.9±61.6 Mean number of angina attacks/week 5.3±4.8 6.2±6.4 5.8±6.8 5.8±6.0 5.2±6.6 Mean number of SAN/week 3.1±4.4 3.6±5.3 3.4±6.5 3.4±5.3 3.2±5.7 Time to angina onset during ETT (s) 295.2±103.3 271.9±97.8 318.4±111.3 290.7±104.3 305.0±107.4 HR at rest 67.9±12.0 67.7±11.1 67.8±11.6 67.8±11.5 68.1±11.3 HR at peak of exercise (bpm) 119.8±17.6 117.7±15.6 122.2±16.6 119.5±16.7 122.4±16.7 RPP at rest (bpm.mm Hg) 8506.2±1665.4 8553.2±1617.3 8653.3±1836.3 8556.2±1682.2 8640±1685 RPP at peak exercise(bpm.mm Hg) 19293.1±3824.3 18947.8±3695.0 20345.0±4156.8 19376.4±3875.8 20126±4098 Maximum ST depression (mm) −1.56±0.42 −1.55±0.39 −1.53±0.43 −1.55±0.41 −1.61±0.47 Total exercise duration (s) 402.1±113.2 375.0±109.5 420.3±107.1 395.0±111.7 420.1±114.3 Time to 1-mm ST segment depression (s) 337.7±113.1 313.0±103.7 354.4±108.8 331.3±109.5 343.5±112.1

Bpm, beats per minute; ETT, exercise test; HR, heart rate; RPP, rate pressure product; SAN, short-acting nitrates. Results are expressed as mean±standard deviation.

2. Methods included in the analysis. Comparisons amongst the three groups (placebo, TMZ 70 mg/d and TMZ 140 mg/d) for baseline values in TED and T1 were performed by The methods of the VASCO trial are described in detail elsewhere [19]. Briefly, 203 using a series of ANOVAs. Differences in TED and T1 between the pooled group of pa- active centres located in 13 countries participated in the study. Of the 4755 patients tients allocated to TMZ (i.e. both 70 mg/day or 140 mg/day) and the placebo group that attended the selection visit, 4705 were enrolled into the run-in period during were assessed by using t-tests. Between groups comparisons on the variation from which they were treated with atenolol 50 mg/d, and 1962 patients were randomised baseline values in TED and T1 were performed by using a series of ANCOVAs, adjusting to the active treatment phase during which they were treated with add-on TMZ MR for time to angina onset. The latter was chosen as covariate as highly correlated with 70 mg (35 mg/d), TMZ MR 140 mg (70 mg/d), or placebo b.i.d. the dependent variables. A total of 1907 patients completed the study (633 in the TMZ MR 70 mg group, 641 in the TMZ MR 140 mg group, and 633 in the placebo group). A central randomisation procedure was utilised, a stochastic minimisation following the Pocock 3. Results method [20,21] was also used. The randomisation was balanced between groups and stratified on the following factors: country, documentation of the coronary artery dis- A total of 645 patients fulfilled the inclusion criteria for this study ease or not, age (≤ or >65 years), presence of diabetes or not, and ventricular dysfunction (LVEF b or ≥40% or not available). Reasons for withdrawal were similar among and were analysed. Patients were distributed in the 3 treatment treatment groups: adverse event (n=25), non-medical reason (n=23) and protocol groups as follows: 249 patients in the TMZ MR 70 mg/day group, deviation (n=7). No difference in the occurrence of adverse events was observed 260 in the 140 mg/day group and 136 in the placebo group. Demo- amongst groups. graphic and baseline clinical characteristics of patients from the The VASCO-angina study – coordinated by the IRCCS San Raffaele and by the De- partment of Pharmacology of the Istituto Superiore di Sanità – was aimed at assessing VASCO-angina study and those of the main VASCO trial as reported the effect of TMZ 70 and 140 mg/d in the pre-specified patients fulfilling the current in Table 1. Baseline clinical features of patients allocated to TMZ therapeutic indication for TMZ, i.e. patients with chronic stable angina pectoris and, groups and placebo group were similar. Trimetazidine treatment in a further analysis, patients in which the reason for stopping the exercise test (ETT) was well tolerated throughout the study and there was no significant was angina (group with “limiting angina”). Since in VASCO study there was no require- difference between groups in the occurrence of adverse events. ment of a minimal number of angina attacks as inclusion criterion, for this study chronic stable angina was defined as that with a mean anginal attacks/week≥1. Separate ANOVAs showed significant differences in baseline Informed consent was obtained from each patient. The study protocol conforms to values of TED and T1 amongst groups (TED: F=8362; df=2642, the ethical guidelines of the 1975 Declaration of Helsinki as reflected in an a priori ap- p-value=0.0003; T1: F=7189; df=2642, p-value=0.0008). proval by the San Raffaele human research committee. The authors of this manuscript fi fi fi Fisher's Protected Least Signi cant Difference (PLSD) further clari ed have certi ed that they comply with the Principles of Ethical Publishing in the Interna- fi tional Journal of Cardiology [22]. that the group allocated to TMZ 140 mg/day signi cantly differed from the placebo group (TED: p=0.0001; T1: p=0.0003) and from

2.1. Assessment of efficacy the group allocated to TMZ 70 mg/day (TED: p=0.0057; T1: p= 0.0105). Therefore, in order to eliminate the confounding of different Efficacy was assessed by ETT using the Bruce protocol as reported in detail else- baseline values we analysed the variation after treatment, i.e. the per- where [19]. The assessment of efficacy of the VASCO-angina complies with the Guide- centage of change from baseline for both TED and T1. line for the clinical investigation of anti-anginal medicinal products in stable angina pectoris of the European Medicines Agency (CPMP/EWP/234/95 1996) that recom- mends exercise capacity, measured by total exercise duration (TED), as main evalua- 3.1. Effect of trimetazidine in patients with chronic stable angina tion criterion. Total exercise duration was therefore chosen as primary efficacy criterion, and expressed as the change between last value and baseline. Time to fi Compared to baseline, in the overall cohort of patients with chronic 1-mm ST segment depression (T1) was chosen as secondary ef cacy criterion. Time fi to angina was defined as the time to onset of angina during ETT and time to limiting stable angina TMZ signi cantly improved both TED (TMZ: 6%±23%; angina was defined as the time to angina of such a severity that the patient wished placebo: 0.7%±5%; t-value: −2.689; p-value: 0.0074) and T1 (TMZ: to stop exercising. 9.6%±33%; placebo: 3%±16.8%; t-value: −2.265; p-value: 0.0239). Similar results were observed in the pooled TMZ (70 and 140 mg; 2.2. Statistical analyses n=509) and in each of the two TMZ groups but not in the placebo group. The overall VASCO data-base was transferred to the two coordinating centres of Comparisons between the two TMZ groups and placebo group are the VASCO-angina study. Data were independently analysed by expert investigators, fi blinded on treatment allocation. Only patients with evidence of angina in the shown in Table 2. Trimetazidine signi cantly improved TED and T1 4 weeks prior the inclusion and/or limiting angina during the exercise test were compared to placebo. Time to angina onset highly correlated with

Please cite this article as: Vitale C, et al, Efﬁcacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina — The VASCO-angina study, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.11.001 C. Vitale et al. / International Journal of Cardiology xxx (2012) xxx–xxx 3

Table 2 Comparisons among TMZ 70 mg/day; TMZ 140 mg/day and placebo groups for post-treatment variation in total exercise duration and time to 1 mm ST segment depression, ad- justed for time to angina onset (ANCOVAs).

Characteristic TMZ 70 mg/day (n=249) TMZ 140 mg/day (n=260) Placebo (n=136) F-value(df=2642) p-value

Total exercise duration (s) 0.053±0.207 0.068±0.251 0.007±0.055 5.392 0.0048 Time to 1 mm ST depression (s) 0.085±0.308 0.107±0.351 0.030±0.168 2.898 0.0536

Bold=p-value b0.05; Italics=p-value b0.1. Results are expressed as mean±standard deviation.

TED and T1 baseline values (respectively: r=0.835, pb0.001; r= Trimetazidine significantly improved T1 compared to placebo. 0.799; pb0.001) and was therefore chosen as covariate. Both TMZ groups (140 mg/day and 70 mg/day) significantly differed The improvement in TED was significantly different amongst the in the improvement in T1 from the placebo group (F=4.776; df= three treatment groups, with mean values progressively increasing 1381, p-value=0.0295, and F=4.155; df=1381, p-value=0.0423, fromplacebotothegroupallocatedtoTMZ70mg/day,andtothe respectively) while no significant difference between the two doses group allocated to TMZ 140 mg/day. The group allocated to TMZ of TMZ was found (F=0.108; df=1381, p-value=0.7422). 140 mg/day significantly differed from the placebo group (p=0.0044), and that the group allocated to TMZ 70 mg/day significantly differed 4. Discussion from the placebo group (p=0.0338). The improvement in TED was greater but not significantly different between TMZ 70 mg/day and The present study shows that, in patients with effort induced an- TMZ 140 mg/day. However, a significant trend towards a greater effect gina receiving background therapy with atenolol, TMZ improves of TMZ 140 was found. both TED and T1. The study confirms the efficacy of MR TMZ com- Similarly to what observed for TED, TMZ significantly improved T1 pared to placebo in addition to beta-blocker treatment, in improving compared to placebo. Both groups allocated to TMZ 140 mg/day and functional capacity, measured by TED at ETT. These results mirror 70 mg/d significantly differed from the placebo group (F=5.453; those obtained in earlier smaller studies with TMZ 20 mg. Neverthe- df=1381, p-value=0.0200; and F=5.479; df=1381, p-value= less, while in the pooled symptomatic and asymptomatic patients 0.0198, respectively). Although a trend towards a greater effect of with coronary artery disease the VASCO trial reported a significant TMZ 140 mg was observed, no statistically significant difference be- improvement in TED only with the high doses of TMZ, the tween TMZ 70 mg/day and TMZ 140 mg/day was found (F=0.064; VASCO-angina study provides the first evidence of such efficacy of df=1381, p-value=0.7999). TMZ at both standard and higher dose. The clinical experience with TMZ dates back to the early 70s. The evidence on the anti-ischemic and anti-anginal effect of TMZ consists of 3.2. Effect of trimetazidine in patients with limiting angina studies conducted both in monotherapy and in combination with con- ventional anti-anginal therapy. Although the earlier studies on the effi- In order to further clarify the efficacy of TMZ in patients with se- cacy of anti-anginals have enrolled predominantly male patients, the vere effort angina, 574 patients with limiting angina (crescendo angi- more recent and larger size trials have included larger but still inade- na as main reason for stopping the exercise test) were analysed (n= quate numbers of female and elderly patients. Similarly, the percentage 217 receiving TMZ 70 mg/day; n=233 receiving TMZ 140 mg/day; of female patients included was also low in the VASCO study. The stud- n=124 placebo group). Compared to baseline, TMZ significantly im- ies conducted with TMZ in patients with coronary artery disease span proved both TED and T1 and significant differences were observed more than 30 years and for this reason the criteria used to assess effica- between the placebo and the pooled TMZ groups: TED (TMZ, 4.9%± cy differ between the oldest and the more recent studies. The 5.2%; placebo, 0.6%±0.3%; F=9.935, df=1570, p-value=0.0017) VASCO-angina has used TED as primary criterion for assessing the effi- and T1 (TMZ, 8.4%±32.9%; placebo, 2.8%±16.6%; F=4.875, df= cacy of an anti-anginal drug as add-on to beta-blockers. 1570, p-value=0.0276) (Figs. 1 and 2). Trimetazidine at both standard and high doses significantly im- Comparisons between the three groups show that the treatment proved both TED and T1 compared to placebo both in symptomatic pa- effect progressively increased from placebo to the group receiving tients with coronary artery disease and in those with more severe, TMZ 70 mg/day, and to that receiving TMZ 140 mg/day (Table 3). limiting angina. These improvements are dose-related with greater im- The comparison between the groups allocated to TMZ and placebo provements observed in patients receiving the higher doses of TMZ. was statistically significant (pb0.02).

Fig. 1. Percentages of post-treatment variations in total exercise duration in patients Fig. 2. Percentages of post-treatment variations in time to 1 mm ST segment depression with limiting angina allocated to the pooled TMZ (n=450) or placebo (n=124) in patients with limiting angina allocated to the pooled TMZ (n=450) or placebo (n= groups. *The value indicates standard error. 124) groups. *The value indicates standard error.

Please cite this article as: Vitale C, et al, Efﬁcacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina — The VASCO-angina study, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.11.001 4 C. Vitale et al. / International Journal of Cardiology xxx (2012) xxx–xxx

Table 3 Comparisons among TMZ 70 mg/day; TMZ 140 mg/day and placebo groups for post-treatment variation in total exercise duration and time to 1 mm ST segment depression, ad- justed for time to angina onset (ANCOVAs) in patients with angina as main reason for stopping ETT.

Characteristic TMZ 70 mg/day (n=217) TMZ 140 mg/day (n=233) Placebo (n=124) F-value p-value (df=2571)

Total exercise duration (s) 0.038±0.204 0.059±0.249 0.006±0.057 4.943 0.0074 Time to 1 mm st dep (s) 0.068±0.309 0.098±0.346 0.028±0.166 2.449 0.0873

Bold=p-value b0.05; Italics=p-value b0.1. Results are expressed as mean±standard deviation.

The VASCO-angina study extends further the well-known efficacy [4] Marzilli M, Klein WW. Efficacy and tolerability of trimetazidine in stable angina: a meta-analysis of randomized, double-blind, controlled trials. Coron Artery Dis of TMZ to the dose of 70 and 140 mg/d. Since a greater improvement 2003;14:171-9. in TED was observed in patients with limiting angina with higher [5] Szwed H, Sadowski Z, Elikowski W, et al. Combination treatment in stable effort doses of TMZ, this suggests that higher doses may be more appropri- angina using trimetazidine and metoprolol: results of a randomized, double- blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. Eur Heart J ate for those patients with more severe angina. 2001;22:2267-74. The observed improvements in exercise parameters observed in [6] Vitale C, Marazzi G, Pelliccia F, et al. Trimetazidine improves exercise performance the VASCO-angina study are to be related to the well-known meta- in patients with peripheral arterial disease. Pharmacol Res 2011;63:278-83. fi bolic mechanism of action of TMZ [23,24]. Trimetazidine optimises [7] Rosano GM, Marazzi G, Patrizi R, et al. Comparison of trimetazidine plus sildena l to chronic nitrates in the control of myocardial ischemia during sexual activity in cardiac metabolism, leading to an increase in cellular tolerance to is- patients with coronary artery disease. Am J Cardiol 2005;95:327-31. chemia and a change in the oxygen supply-to-demand-ratio. Thus, [8] Rosano GM, Vitale C, Sposato B, Mercuro G, Fini M. Trimetazidine improves left the benefits of TMZ here reported may be related to the mechanism ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study. Cardiovasc Diabetol 2003;2:16. of the drug, as modulator of skeletal muscle FFA metabolism, and [9] Chaitman BR. Efficacy and safety of a metabolic modulator drug in chronic stable are dose-dependent. Furthermore, we cannot rule out the possibility angina: review of evidence from clinical trials. J Cardiovasc Pharmacol Ther that the protective activity of TMZ could be due to the complex 2004;9(Suppl. 1):S47-64. [10] Dalla-Volta S, Maraglino G, Della-Valentina P, Viena P, Desideri A. Comparison of framework of intracellular events associated with cytoprotective anti- trimetazidine with nifedipine in effort angina: a double-blind, crossover study. oxidant properties of the drug together with the activation of p38 Cardiovasc Drugs Ther 1990;4(Suppl. 4):853-9. mitogen-activated protein kinase and Akt signalling hindering cell [11] Detry JM, Sellier P, Pennaforte S, Cokkinos D, Dargie H, Mathes P. Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients death [25]. with stable angina. Trimetazidine European Multicenter Study Group. Br J Clin A limitation of the study is that VASCO-angina is a pre-specified Pharmacol 1994;37:279-88. sub-analysis of the main VASCO trial. The VASCO trial was the largest [12] Levy S. Combination therapy of trimetazidine with diltiazem in patients with coronary artery disease. Group of South of France Investigators. Am J Cardiol study assessing the anti-ischemic effect of any anti-ischemic agent 1995;76:12B-6B. and the VASCO-angina study was of a similar size of the more recent [13] Manchanda SC, Krishnaswami S. Combination treatment with trimetazidine and studies conducted with Ranolazine. The difference between the diltiazem in stable angina pectoris. Heart 1997;78:353-7. VASCO-angina study and the CARISA study with Ranolazine lies in [14] Michaelides AP, Spiropoulos K, Dimopoulos K, Athanasiades D, Toutouzas P. Antianginal efficacy of the combination of trimetazidine–propranolol compared that in the VASCO-angina all patients were receiving background with isosorbide dinitrate–propranolol in patients with stable angina. Clin Drug treatment with atenolol while in the CARISA study only a subset of Investig 1997;13:8–14. patients received atenolol. In the VASCO-angina, as in all previous [15] Passeron J. Effectiveness of trimetazidine in stable effort angina due to chronic coronary insufficiency. A double-blind versus placebo study. Presse Med studies conducted with TMZ there was no gender difference in the 1986;15:1775-8. anti-ischemic effect. [16] Sellier P, Broustet JP. Assessment of anti-ischemic and antianginal effect at trough In conclusion, the VASCO-angina study suggests that metabolic plasma concentration and safety of trimetazidine MR 35 mg in patients with stable angina pectoris: a multicenter, double-blind, placebo-controlled study. Am J modulation exerted by TMZ may represent a new therapeutic option Cardiovasc Drugs 2003;3:361-9. in stable exertional angina patients to improve TED. Whether the [17] Abu-Amara M, Gurusamy KS, Hori S, Glantzounis G, Fuller B, Davidson BR. Phar- beneficial effects of TMZ translate into decreased morbidity and macological interventions versus no pharmacological intervention for ischaemia reperfusion injury in liver resection surgery performed under vascular control. mortality in the long term in stable angina patients, as it has been ob- Cochrane Database Syst Rev 2009:CD007472. served in patients with heart failure [26], requires further investiga- [18] Ciapponi A, Pizarro R, Harrison J. Trimetazidine for stable angina. Cochrane Data- tion and it is currently being tested in a large multinational study. base Syst Rev 2005:CD003614. [19] Danchin N, Marzilli M, Parkhomenko A, Ribeiro JP. Efficacy comparison of trimetazidine with therapeutic alternatives in stable angina pectoris: a network meta-analysis. Cardiology 2011;120:59-72. Acknowledgement of grant support [20] Freedman L, White S. On the use of Pocock and Simon's method for balancing treatment number over prognostic factors in the controlled clinical trials. Biomet- The VASCO study was funded by the Institut de Recherches rics 1976;32:691-4. [21] Pocock S, Simon R. Sequential assignment with balancing for prognostic factors in Internationales SERVIER. the controlled clinical trials. Biometrics 1975;31:103-15. The independent VASCO-angina study was supported by a grant [22] Coats AJ, Shewan LG. Statement on authorship and publishing ethics in the inter- from the IRCCS San Raffaele Pisana (Ricerca Corrente, Ministero national journal of cardiology. Int J Cardiol 2011;153:239-40. – [23] Fragasso G, Palloshi A, Puccetti P, et al. 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