Review

Cardiology 2011;120:59–72 Received: June 26, 2011 DOI: 10.1159/000332369 Accepted: June 29, 2011 Published online: November 25, 2011

Efficacy Comparison of Trimetazidine with Therapeutic Alternatives in Stable Pectoris: A Network Meta-Analysis

a b c d Nicolas Danchin Mario Marzilli Alexander Parkhomenko Jorge P. Ribeiro a Department of and Acute Cardiac Care, Hôpital Européen Georges Pompidou (HEGP), b c Paris , France; Cardiothoracic Department, Azienda Ospedaliero, Universitaria Pisana, Pisa , Italy; Department d of Resuscitation and Intensive Care, Strazhesko M.D. Institute of Cardiology, Kiev , Ukraine; Cardiology Division, Hospital de Clínicas de Porto Alegre, and Department of Internal Medicine, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre , Brazil

Key Words showed a mean improvement of +46 s (95% credibility inter- Angina pectoris ؒ Trimetazidine ؒ Meta-analysis ؒ val: 28; 66) for total exercise duration, +55 s (35; 77) for 1-mm Exercise testing ST segment depression (T1), and +54 s (24; 84) for time to onset of angina, in favor of trimetazidine. Differences be- tween trimetazidine and active comparators were not sig- Abstract nificant when exercise tolerance and clinical criteria were Aims: To compare the antianginal efficacy of trimetazidine analyzed, with +7 s (–12; 28) for total exercise duration, –1 s with that of other agents with no influence on heart rate. (–23; 22) for T1, +8 s (–22; 40) for time to onset of angina, and Methods and Results: Medline and Embase databases were –0.28 (–1.17; 0.64) attacks per week for trimetazidine com- searched for blinded, randomized, controlled trials assessing pared with antianginal agents as a group. Conclusions: the effects of non-heart-rate-lowering antianginal treat- Trimetazidine efficacy was comparable to that of other non- ments on exercise tolerance and/or clinical criteria in stable heart-rate-lowering antianginal treatments in patients with angina patients. All relevant trimetazidine trials including stable angina pectoris. Copyright © 2011 S. Karger AG, Basel the VASCO trial, the results of which are published herein, were included. A Bayesian network meta-analysis on the summary data was performed. Comparator antianginal agents were considered as a group and in agent/class sub- Introduction groups. Trials involving ␤ -blockers, non-dihydropyridine cal- cium channel blockers, and ivabradine were excluded. 218 The therapeutic aim of treatments for stable angina trials totaling 19,028 patients were included in at least 1 pectoris is the reduction in the frequency and severity of network analysis. Effects of trimetazidine were statistically stress-induced ischemic episodes and the prevention of significant compared with placebo for exercise tolerance myocardial infarction and death. According to European and clinical criteria. Transposition of results into seconds guidelines, heart-rate-lowering agents can be prescribed for clinical interpretation of exercise tolerance parameters as first-line therapy, with ␤ -blockers representing the

© 2011 S. Karger AG, Basel Prof. Nicolas Danchin 0008–6312/11/1202–0059$38.00/0 Department of Coronary Artery Disease and Acute Cardiac Care Fax +41 61 306 12 34 Hôpital Européen Georges Pompidou (HEGP) E-Mail [email protected] Accessible online at: 20 rue Leblanc, FR–75015 Paris (France) www.karger.com www.karger.com/crd Tel. +33 1 5609 2571, E-Mail nicolas.danchin @ egp.aphp.fr first option. Dihydropyridine calcium-channel blockers, ment comparisons) using data from comparator- and/or long-acting nitrates, nicorandil, and metabolic agents – placebo-controlled trials that evaluated the efficacy of such as trimetazidine or – are recommended these agents in stable angina. As network meta-analyses as second-line alternatives or as add-on therapies [1] . combine results from direct comparisons (A vs. B from Trimetazidine, which is indicated for the long-term head-to-head comparisons) and indirect comparisons (A treatment of stable angina pectoris, stands out as having vs. C is extrapolated from A vs. B and B vs. C), informa- a distinctive and complementary approach to that of tion about the relative efficacy of treatments that have not heart-rate-lowering agents because it reduces the fre- been compared in head-to-head trials can be acquired. quency of anginal episodes and improves exercise perfor- More specifically, such an approach allows the compari- mance without affecting hemodynamic parameters [2, 3] . son of trimetazidine efficacy with that of direct therapeu- Indeed, whereas most antianginal therapies aim to re- tic alternatives, i.e. non-heart-rate-lowering combination store the balance between myocardial oxygen supply and therapies. demand by acting hemodynamically, trimetazidine mod- ulates the metabolic changes induced in the myocardial cells under ischemic conditions thereby directly increas- Materials and Methods ing levels of ATP, a process which is essential for myocar- dial integrity and contractility [4, 5]. In a clinical evalua- Trial Selection Criteria The Medline and Embase databases were searched until May tion, for example, trimetazidine was shown to induce a 17, 2010. Publications were selected based on pre-defined criteria 33% increase in the myocardial phosphocreatine/ATP ra- and then reviewed by two different persons. Disagreements were tio [6] . resolved through consensus. In order to be included, trials had Data from a large panel of randomized, controlled tri- to be randomized, controlled, single- or double-blind, parallel- als and meta-analyses have shown that the anti-ischemic group or cross-over clinical trials assessing the treatment of stable angina pectoris or stable ischemic disease in adult patients. At and cardioprotective properties of trimetazidine de- least one treatment arm had to include a treatment of interest, scribed in vitro and in animal studies translate into clin- which was defined as a non-heart-rate-lowering antianginal agent ically significant antianginal benefits for patients with registered in France or Europe. ␤ -Blockers, non-dihydropyridine stable angina pectoris [2, 3, 7–10]. In the 2005 Cochrane calcium channel blockers, and ivabradine were not considered as meta-analysis, trimetazidine was shown to be effective treatments of interest based on their common action on heart rate. and well tolerated: compared with placebo, time to 1-mm Treatments could be given at any dosage, as a monotherapy or segment depression (T1) was significantly improved as a combination therapy, if the antianginal treatment of interest (standardized difference in means 0.32; 95% CI 0.15 to was considered insufficient as a monotherapy. Nifedipine imme- 0.48; p = 0.0002), the number of weekly angina attacks diate release (IR), which is indicated in stable angina patients al- ␤ was significantly reduced (–1.44 attacks; p ! 0.0001), and ready treated with a -blocker, was considered only when it was used in combination; trimetazidine 6 mg was not considered be- weekly short-acting nitrate consumption was significant- cause the dose is not marketed in Europe. Trials in which sublin- ly reduced (–1.47 intakes; p ! 0.0001) [9]. Furthermore, gual short-acting nitrates were prescribed for angina attacks were individual trials have shown that these effects occur allowed. The comparators could be any antianginal agent or pla- without affecting hemodynamic parameters such as the cebo. The minimum treatment follow-up period was 1 week. Tri- rate-pressure product [2] and are associated with im- als needed to assess exercise tolerance (total exercise duration, T1, and/or time to onset of angina) and/or clinical criteria (number provements in left ventricular ejection fraction [11] . A re- of angina attacks and/or number of short-acting nitrates per cent meta-analysis indicated that trimetazidine improves week). The abstract or the whole publication had to be in English, capacity and may even reduce mortality in patients with French, or Spanish. For trimetazidine, the literature search was [12] . Together, these data underscore the extended to other languages as well as to Servier’s internal files. benefits of add-on trimetazidine treatment, which pro- More specifically the unpublished VASCO trial, a large random- ized, double-blind, trial was also included. The main methods vides additional antianginal efficacy without having an and results of this trial are presented hereafter. effect on hemodynamic parameters, thus providing a complementary approach to the disease. D a t a A n a l y s i s In order to position the efficacy of trimetazidine Summary data obtained from the trial publications were ex- among its non-heart-rate-lowering alternatives and to tracted into Microsoft Excel (Microsoft, Seattle, Wash., USA) spreadsheets. When available, intention-to-treat (ITT) results update the results from the 2005 Cochrane meta-analy- were used. In trials in which study medication was titrated, only sis, which focused on head-to-head comparisons, sever- data for the longer duration and for the maximal dosage were in- al network meta-analyses were conducted (mixed treat- cluded.

60 Cardiology 2011;120:59–72 Danchin /Marzilli /Parkhomenko /Ribeiro Specific networks of studies were created in order to consider the efficacy criteria (mean exercise tolerance data [total exercise 628 publications 11 TMZ publications not in Medline of Embase duration, T1, and time to onset of angina] and clinical criteria from Medline or - 10 studies included in Cochrane 2005 [mean number of angina attacks per week and mean number of Embase - 1 unpublished study (VASCO) short-acting nitrates per week]), the different antianginal medica- tions (all antianginal agents pooled or by agent/class subgroup), 639 references and the type of prescription (monotherapy or combination ther- apy). The overall set included monotherapy, combination therapy, 426 references excluded and mixed monotherapy/combination therapy study designs. - 194: no useful data - 111: inappropriate design The network meta-analyses were performed based on a ran- - 86: inadequate population dom-effects model within a Bayesian framework using WinBUGS - 35: duplication/substudy version 1.4 [13] . Heterogeneity was assumed constant for the dif- ferent comparisons. In order for the observed results not to be 213 references (218 trials) influenced by the prior distribution, a non-informative prior dis- In overall set: 2 - 170 TED trials tribution was retained (distribution N(0,100 ) for the effect and - 126 T1 trials Gamma (10-3, 10-3) for the variance) [14] . - 111 TOA trials The results of the exercise tolerance tests are presented as an - 108 AA trials effect size and in seconds for clinical interpretation. The trans- - 79 SAN use position of the effect size into seconds, the original scale, was performed considering a 120-second standard deviation. All re- sults are reported as effect size and 95% credibility interval (CI). Fig. 1. Flow chart of trial selection. AA = Angina attacks; SAN = Due to the limited number of selected trials for ranolazine and to short-acting nitrates; T1 = time to 1-mm ST segment depression; the fact that network meta-analyses are more appropriate for TED = total exercise duration; TMZ = trimetazidine; TOA = time treatment classes which are documented by several studies, the to onset of angina. relative effect of ranolazine as compared to trimetazidine was evaluated using adjusted indirect comparisons based on the com- mon placebo comparator.

Validation and Sensitivity Analyses toris was confirmed by repeated positive exercise tests. The To verify that the results from the analyzed networks were co- data set included a total of 19,028 patients. The sample size herent and to visualize the accuracy of the estimates and the in- of the trials varied from 5 to 1,962 patients (median: 30 pa- fluence of direct and indirect evidence, a node splitting graph was tients). generated for each pairwise comparison using WinBUGS and R statistical software [15]. To investigate the possibility of statistical The trimetazidine (IR or modified release [MR]) treat- heterogeneity in pairwise meta-analyses, tests for study-by-treat- ment regimens ranged from 60 to 140 mg/day. Antiangi- ment interaction using the Cochran statistic (I2) and visual in- nal agent subgroups included in the analyses were dihy- spection of the forest plots were performed [16] . Sensitivity was dropyridines (amlodipine, felodipine IR and sustained assessed by performing comparisons in a trial set that excluded release [SR], isradipine, nicardipine, nifedipine IR and cross-over studies. These analyses were performed using SAS € software version 9.1 (SAS Institute Inc., Cary, N.C., USA). SR, nisoldipine IR and SR), long-acting nitrates (isosor- bide mononitrate IR and SR, isosorbide dinitrate IR and SR, nitroglycerin SR, nitroglycerin patches), nicorandil, and ranolazine SR. R e s u l t s Trimetazidine and Other Antianginal Agents versus Of the 639 references identified ( fig. 1 ), 213 references Placebo (218 trials) covering a period from 1966 to 2010 were in- In the overall set, trimetazidine significantly improved cluded in at least 1 network meta-analysis (for list of refer- exercise tolerance parameters and clinical criteria com- ences included in the network meta-analyses, see online pared with placebo ( fig. 2 ). Mean effect sizes of +0.38 suppl. material, www.karger.com/doi/10.1159/000332369). (95% CI 0.23; 0.55) corresponding to a 46-second increase Twenty-five trimetazidine studies were included. Most tri- in the total exercise duration, of +0.46 (95% CI 0.29; 0.64) als evaluated at least 1 exercise tolerance parameter (n = corresponding to a 55-second increase in T1, and of +0.45 191), monotherapies (n = 145), or the combination of sev- (95% CI 0.20; 0.70) corresponding to a 54-second increase eral antianginal drugs (n = 37). Over half of the trials had in the time to onset of angina were noted. A significant a cross-over design (128 trials; 3,233 patients). Treatment mean reduction in angina attacks per week of –1.95 (95% duration varied from 1 to 28 weeks with a median of 4 CI –2.88; –1.00) and in short-acting nitrate use per week weeks. In most of the recent trials, stability of angina pec- of –1.57 (95% CI –2.44; –0.70) was observed with trimeta-

Treatment of Stable Angina Pectoris with Cardiology 2011;120:59–72 61 Trimetazidine a Trials n Effect size Transposition into (95% CI) seconds (95% CI)

Trimetazidine TED 170 15,744 0.38 (0.23; 0.55) 46 (28; 66) Trimetazidine T1 126 13,598 0.46 (0.29; 0.64) 55 (35; 77) Trimetazidine TOA 111 11,652 0.45 (0.20; 0.70) 54 (24; 84)

Antianginal agents TED 158 13,791 0.32 (0.26; 0.38) 38 (31; 46) Antianginal agents T1 117 12,440 0.47 (0.39; 0.56) 56 (47; 67) Antianginal agents TOA 105 10,905 0.38 (0.29; 0.47) 46 (35; 56)

Dihydropyridines TED 170 15,744 0.34 (0.27; 0.41) 41 (32; 49) Dihydropyridines T1 126 13,598 0.52 (0.42; 0.62) 62 (50; 74) Dihydropyridines TOA 111 11,652 0.42 (0.32; 0.53) 50 (38; 64)

Long-acting nitrates TED 170 15,744 0.30 (0.22; 0.38) 36 (26; 46) Long-acting nitrates T1 126 13,598 0.40 (0.28; 0.53) 48 (34; 64) Long-acting nitrates TOA 111 11,652 0.31 (0.18; 0.44) 37 (22; 53)

Nicorandil TED 170 15,744 0.32 (0.04; 0.60) 38 (5; 72) Nicorandil T1 126 13,598 0.43 (0.10; 0.77) 52 (12; 92) Nicorandil TOA 111 11,652 0.45 (0.09; 0.81) 54 (11; 97)

Ranolazine TED 2 966 0.29 (0.09; 0.50) 35 (11; 60) Ranolazine T1 2 966 0.33 (–0.03; 0.69) 40 (–4; 83) Ranolazine TOA 2 966 0.31 (0.09; 0.53) 37 (11; 64) –0.2 0 0.3 0.8 Favors placebo Favors antianginal agent

b Trials n Effect size (95% CI)

Trimetazidine AA 108 9,936 –1.95 (–2.88; –1.00) Trimetazidine SAN 79 7,807 –1.57 (–2.44; –0.70)

Antianginal agents AA 100 9,417 –1.69 (–2.24; –1.16) Antianginal agents SAN 72 7,340 –1.16 (–1.60; –0.72)

Dihydropyridines AA 108 9,936 –1.94 (–2.68; –1.21) Dihydropyridines SAN 79 7,807 –1.57 (–2.33; –0.82)

Long-acting nitrates AA 108 9,936 –1.61 (–2.46; –0.78) Long-acting nitrates SAN 79 7,807 –0.85 (–1.68; –0.01)

Nicorandil AA 108 9,936 –2.86 (–5.12; –0.66) Nicorandil SAN 79 7,807 –1.75 (–4.05; 0.54)

Ranolazine AA 2 1,349 –0.83 (–1.34; –0.31) Ranolazine SAN 1 558 –0.85 (–2.15; 0.45) –6 –5 –4 –3 –2 –1 0 1 Favors antianginal agent Favors placebo

Fig. 2. Comparison of trimetazidine and other antianginal agents AA = Number of angina attacks per week; CI = credibility inter- with placebo: overall set. a Exercise tolerance parameters. b Clin- val; n = number of patients involved in the network; SAN = num- ical criteria. Antianginal agents included dihydropyridines, long- ber of short-acting nitrates per week; T1 = time to 1-mm ST seg- acting nitrates, nicorandil, and ranolazine. The overall set was ment depression; TED = total exercise duration; TOA = time to defined monotherapy and combined therapy. In a , transposition onset of angina; trials = number of trials involved in the network. into seconds was based on a 120-second standard deviation.

62 Cardiology 2011;120:59–72 Danchin /Marzilli /Parkhomenko /Ribeiro zidine compared with placebo. All other antianginal heterogeneity in the exercise tolerance criteria (I 2 1 70%) agents improved nearly all exercise tolerance test param- was noted in the direct comparison meta-analysis of eters and clinical symptoms significantly. trimetazidine versus placebo. However, no qualitative Analyses performed in the monotherapy set lead to study-by-treatment interaction was of concern, with all similar observations (fig. 3 ). The differences in total ex- treatment effect estimates being in favor of trimetazidine. ercise duration, T1, time to onset of angina, and clinical Forest plots summarizing all treatment effects among criteria observed between trimetazidine and placebo studies suggested that the VASCO study is the cause of were in favor of trimetazidine and statistically significant the heterogeneity (data not shown). When the VASCO for total exercise duration, T1, and clinical criteria. Dif- study was excluded, no significant changes were found ferences between other antianginal agents (pooled and by (data not shown) and the heterogeneity was no longer sta- subgroup) and placebo were statistically significant for all tistically significant (I2 ϳ 36%). This heterogeneity was criteria. The specific analysis of combination therapies taken into account using a random effect model provid- provided consistent results (data not shown). ing an estimate of the treatment effect less accurate, as compared to the fixed effect model. A description of the Trimetazidine versus Other Antianginal Agents results of VASCO is therefore given hereafter in order to In the overall set, the differences in total exercise du- investigate further the reasons of the observed heteroge- ration, T1, and time to onset of angina observed between neity. trimetazidine and other antianginal agents (pooled and The meta-analyses of direct comparisons of trimeta- by subgroup) were not statistically or clinically signifi- zidine versus nitrates (combining 2 studies) presented a cant ( fig. 4 a). When other antianginal agents were pooled, statistically significant heterogeneity between treatment mean effect sizes of +0.06 (95% CI –0.10; 0.23) corre- effects for the exercise tolerance criteria (I 2 ϳ 75%). How- sponding to a 7-second increase in the total exercise du- ever, no qualitative study-by-treatment interaction was ration, of –0.01 (95% CI –0.19; 0.18) corresponding to a of concern, with a treatment effect estimate in favor of –1-second decrease in the T1, and of +0.07 (95% CI –0.18; trimetazidine in one trial [17] and neutral in the other 0.33) corresponding to a 8-second increase in the time to [18]. This heterogeneity was taken into account using a onset of angina were noted for trimetazidine. Compari- random effect model. When the other network meta- son of the frequency of angina attacks and short-acting analyses were considered, no additional concerns were nitrate use between trimetazidine and other antianginal found regarding the homogeneity of the treatment effect agents (pooled and by subgroup) was not significant. A within direct evidence and the consistency between di- decrease of –0.28 angina attacks per week (95% CI –1.17; rect and indirect evidence (data not shown). 0.64) and –0.45 short-acting nitrate intakes per week Lastly, sensitivity analyses assessing the treatment ef- (95% CI –1.13; 0.22) was observed for trimetazidine com- fect of trimetazidine as compared to other antianginal pared with all other antianginal agents as a group agents in parallel-group studies (n = 90) confirmed the (fig. 4 b). main results of the overall set (data not shown). Similar results were observed when trials that only in- cluded monotherapy were considered. The differences in VASCO Trial total exercise duration, T1, time to onset of angina, and Study Design clinical criteria observed between trimetazidine and The VASCO trial was a phase III, international, other antianginal agents (pooled and by subgroup) were randomized, placebo-controlled, double-blind, parallel- small and not statistically significant ( fig. 5 ). Similar ob- group study, in which ambulatory patients with stable an- servations were also made in the combined therapy set gina pectoris entered a 2-week run-in period during which (data not shown). they were treated with atenolol 50 mg q.d. followed by a 12-week active treatment period during which they were Validation and Sensitivity Analyses treated with add-on trimetazidine MR 70 mg (35 mg The treatment effects combining direct evidence and b.i.d.), trimetazidine MR 140 mg (2 ~ 35 mg b.i.d.), or pla- indirect evidence were relatively consistent, though for cebo b.i.d. Short-acting nitrates were authorized through- time to onset of angina, the combined results from the out the study period. Inclusion and exclusion criteria were network meta-analysis were closer to the direct evidence designed to select patients with stable angina and to ex- than the indirect evidence due to the availability of more clude those with parameters liable to interfere with the direct data. In the overall set, a statistically significant interpretation of results (table 1 ). In addition, in order to

Treatment of Stable Angina Pectoris with Cardiology 2011;120:59–72 63 Trimetazidine a Trials n Effect size Transposition into (95% CI) seconds (95% CI)

Trimetazidine TED 112 8,350 0.58 (0.26; 0.90) 70 (31; 108) Trimetazidine T1 79 6,727 0.50 (0.12; 0.89) 60 (14; 107) Trimetazidine TOA 73 6,120 0.52 (–0.16; 1.23) 62 (–19; 148)

Antianginal agents TED 104 6,909 0.40 (0.31; 0.48) 48 (37; 58) Antianginal agents T1 73 6,064 0.60 (0.48; 0.73) 72 (58; 88) Antianginal agents TOA 70 5,690 0.44 (0.31; 0.57) 53 (37; 68)

Dihydropyridines TED 112 8,350 0.42 (0.32; 0.52) 50 (38; 62) Dihydropyridines T1 79 6,727 0.61 (0.48; 0.75) 73 (58; 90) Dihydropyridines TOA 73 6,120 0.46 (0.32; 0.61) 55 (38; 73)

Long-acting nitrates TED 112 8,350 0.36 (0.23; 0.48) 43 (28; 58) Long-acting nitrates T1 79 6,727 0.59 (0.38; 0.79) 71 (46; 95) Long-acting nitrates TOA 73 6,120 0.40 (0.21; 0.60) 48 (25; 72)

Nicorandil TED 112 8,350 0.50 (0.09; 0.91) 60 (11; 109) Nicorandil T1 79 6,727 0.84 (0.28; 1.41) 101 (34; 169) Nicorandil TOA 73 6,120 0.47 (0.02; 0.94) 56 (2; 113)

Ranolazine TED 1 175 0.40 (0.24; 0.55) 48 (29; 66) Ranolazine T1 1 175 0.52 (0.36; 0.67) 62 (43; 80) Ranolazine TOA – – – –

–0.2 0 0.3 0.8 Favors placebo Favors antianginal agent

b Trials n Effect size (95% CI)

Trimetazidine AA 67 4,647 –2.07 (–3.87; –0.23) Trimetazidine SAN 47 3,646 –2.28 (–3.30; –1.23)

Antianginal agents AA 62 4,280 –2.24 (–3.11; –1.40) Antianginal agents SAN 42 3,279 –1.37 (–1.99; –0.74)

Dihydropyridines AA 67 4,647 –2.37 (–3.57; –1.17) Dihydropyridines SAN 47 3,646 –1.43 (–2.16; –0.68)

Long-acting nitrates AA 67 4,647 –2.22 (–3.57; –0.91) Long-acting nitrates SAN 47 3,646 –1.32 (–2.10; –0.50)

Nicorandil AA 67 4,647 –3.72 (–6.79; –0.70) Nicorandil SAN 47 3,646 –1.93 (–4.12; 0.29)

Ranolazine AA – Ranolazine SAN – –6 –5 –4 –3 –2 –1 0 1 Favors antianginal agent Favors placebo

Fig. 3. Comparison of trimetazidine and other antianginal agents bility interval; n = number of patients involved in the network; with placebo: monotherapy set. a Exercise tolerance parameters. SAN = number of short-acting nitrates per week; T1 = time to b Clinical criteria. Antianginal agents included dihydropyri- 1-mm ST segment depression; TED = total exercise duration; dines, long-acting nitrates, nicorandil and ranolazine. In a , TOA = time to onset of angina; trials = number of trials involved transposition into seconds was based on a 120-second standard in the network. deviation. AA = Number of angina attacks per week; CI = credi-

64 Cardiology 2011;120:59–72 Danchin /Marzilli /Parkhomenko /Ribeiro a Trials Number Effect size (95% CI) Transposition into seconds

Antianginal agents TED 158 13,791 0.06 (–0.10; 0.23) 7 (–12; 28) Antianginal agents T1 117 12,440 –0.01 (–0.19; 0.18) –1 (–23; 22) Antianginal agents TOA 105 10,905 0.07 (–0.18; 0.33) 8 (–22; 40)

Dihydropyridines TED 170 15,744 0.05 (–0.12; 0.22) 6 (–14; 26) Dihydropyridines T1 126 13,598 –0.06 (–0.25; 0.13) –7 (–30; 16) Dihydropyridines TOA 111 11,652 0.03 (–0.23; 0.30) 4 (–28; 36)

Long-acting nitrates TED 170 15,744 0.09 (–0.09; 0.26) 11 (–11; 31) Long-acting nitrates T1 126 13,598 0.06 (–0.13; 0.26) 7 (–16; 31) Long-acting nitrates TOA 111 11,652 0.14 (–0.13; 0.42) 17 (–16; 50)

Nicorandil TED 170 15,744 0.07 (–0.25; 0.39) 8 (–30; 47) Nicorandil T1 126 13,598 0.03 (–0.35; 0.40) 4 (–42; 48) Nicorandil TOA 111 11,652 0.00 (–0.43; 0.43) 0 (–52; 52)

Ranolazine TED 11 3,791 0.06 (–0.24; 0.37) 7 (–29; 44) Ranolazine T1 13 3,861 0.17 (–0.27; 0.61) 20 (–32; 73) Ranolazine TOA 6 3,576 0.05 (–0.32; 0.42) 6 (–38; 50) –0.5 0 0.5 1.0 Favors comparator Favors trimetazidine

b Trials Number Effect size (95% CI)

Antianginal agents AA 62 4,280 –0.02 (–1.63; 1.62) Antianginal agents SAN 42 3,279 –0.90 (–2.05; 0.23)

Dihydropyridines AA 67 4,647 0.30 (–1.73; 2.34) Dihydropyridines SAN 47 3,646 –0.85 (–2.01; 0.32)

Long-acting nitrates AA 67 4,647 0.15 (–1.96; 2.29) Long-acting nitrates SAN 47 3,646 –0.97 (–2.18; 0.28)

Nicorandil AA 67 4,647 1.66 (–1.78; 5.14) Nicorandil SAN 47 3,646 –0.36 (–2.73; 2.06)

Ranolazine AA – Ranolazine SAN – –2 –1 0 123 Favors trimetazidine Favors comparator

Fig. 4. Comparison of trimetazidine with other antianginal ber of angina attacks per week; CI = credibility interval; n = num- agents: overall set. a Exercise tolerance parameters. b Clinical cri- ber of patients involved in the network; SAN = number of short- teria. Antianginal agents included dihydropyridines, long-acting acting nitrates per week; T1 = time to 1-mm ST segment depression; nitrates, nicorandil and ranolazine. In a , transposition into sec- TED = total exercise duration; TOA = time to onset of angina; tri- onds was based on a 120-second standard deviation. AA = Num- als = number of trials involved in the network.

Treatment of Stable Angina Pectoris with Cardiology 2011;120:59–72 65 Trimetazidine a Trials Number Effect size (95% CI) Transposition into seconds

Antianginal agents TED 104 6,909 0.17 (–0.14; 0.48) 20 (–17; 58) Antianginal agents T1 73 6,064 –0.11 (–0.50; 0.28) –13 (–60; 34) Antianginal agents TOA 70 5,690 0.08 (–0.60; 0.75) 10 (–72; 90)

Dihydropyridines TED 112 8,350 0.16 (–0.16; 0.48) 19 (–19; 58) Dihydropyridines T1 79 6,727 –0.11 (–0.49; 0.27) –13 (–59; 32) Dihydropyridines TOA 73 6,120 0.06 (–0.62; 0.76) 7 (–74; 91)

Long-acting nitrates TED 112 8,350 0.22 (–0.11; 0.55) 26 (–13; 66) Long-acting nitrates T1 79 6,727 –0.09 (–0.50; 0.33) –11 (–60; 40) Long-acting nitrates TOA 73 6,120 0.12 (–0.58; 0.83) 14 (–70; 100)

Nicorandil TED 112 8,350 0.08 (–0.42; 0.58) 10 (–50; 70) Nicorandil T1 79 6,727 –0.34 (–1.01; 0.32) –41 (–121; 38) Nicorandil TOA 73 6,120 0.06 (–0.76; 0.85) 7 (–91; 102)

Ranolazine TED 2 207 0.60 (–0.16; 1.35) 72 (–19; 162) Ranolazine T1 2 207 0.00 (–0.73; 0.72) 0 (–88; 86) Ranolazine TOA – – –1.5 –1.0 –0.5 0 0.5 1.0 1.5 Favors comparator Favors trimetazidine

b Trials Number Effect size (95% CI)

Antianginal agents AA 100 9,417 –0.28 (–1.17; 0.64) Antianginal agents SAN 72 7,340 –0.45 (–1.13; 0.22)

Dihydropyridines AA 108 9,936 0.00 (–1.15; 1.14) Dihydropyridines SAN 79 7,807 0.00 (–1.10; 1.08)

Long-acting nitrates AA 108 9,936 –0.34 (–1.51; 0.87) Long-acting nitrates SAN 79 7,807 –0.72 (–1.89; 0.38)

Nicorandil AA 108 9,936 0.90 (–1.42; 3.32) Nicorandil SAN 79 7,807 0.18 (–2.23; 2.62)

Ranolazine AA 20 4,439 –0.92 (–1.84; 0.00) Ranolazine SAN 16 3,561 –0.67 (–2.18; 084) –2 –1 0 123 Favors trimetazidine Favors comparator

Fig. 5. Comparison of trimetazidine with other antianginal Number of angina attacks per week; CI = credibility interval; n = agents: monotherapy set. a Exercise tolerance parameters. b Clin- number of patients involved in the network; SAN = number of ical criteria. Antianginal agents included dihydropyridines, long- short-acting nitrates per week; T1 = time to 1-mm ST segment acting nitrates, nicorandil and ranolazine. In a , transposition into depression; TED = total exercise duration; TOA = time to onset of seconds was based on a 120-second standard deviation. AA = angina; trials = number of trials involved in the network.

66 Cardiology 2011;120:59–72 Danchin /Marzilli /Parkhomenko /Ribeiro be eligible to enter the 12-week active treatment phase, Table 1. I nclusion and exclusion criteria in the VASCO trial patients had to have had 2 positive exercise tolerance tests: one at the start of the run-in period and one at random- Main inclusion criteria – Age between 30 and 80 years ization (week 0). Exercise tolerance tests, which were per- – Documented coronary artery diseasea or non-documented cor- formed at the trough of drug activity using a treadmill onary artery disease for male patients between 40 and 80 years with a 12-lead electrocardiogram and according to the of age and female patients between 60 and 80 years of age Bruce protocol, were read centrally at a Core Reading – ≥3-month history of chronic stable effort angina pectorisb Centre and needed to show stability defined according to – 2 positive exercise tests during the run-in period ^ – Stability criteria: ≤20% variation in total exercise duration and guidelines ( 20% variation in total exercise duration and T1 between the 2 run-in period exercise tests T1 with a week 0/run-in ratio between 0.80 and 1.20; the – Written informed consent European Agency for the Evaluation of Medicinal Prod- Main exclusion criteria ucts and Committee for Medicinal Products for Human – Incapacity to undergo exercise testing Use, 2006). – Myocardial infarction within the previous 3 months The primary objective was to evaluate the superiority – Coronary revascularization within the previous 6 months or of trimetazidine MR compared to placebo in terms of planned during the study period change in total exercise duration between week 0 and – Significant stenosis of the left main coronary artery (≥50%) – Pacemaker or cardioverter-defibrillator week 12 with a sample of size necessary to have 91% pow- – Electrocardiographic abnormalities or any condition that er to detect superiority of each trimetazidine group com- could interfere with the interpretation of an exercise test pared with placebo assuming a 35-second difference be- – Clinically significant heart disease (other than coronary artery tween trimetazidine and placebo for the change from disease) baseline in total exercise duration. All analyses were per- – Stroke or transient ischemic attack during the previous year – Poor short-term prognosis formed on the ITT population (all randomized patients – Liver function test abnormalities to whom study treatment was dispensed) using the last – Renal failure observation carried forward. Statistical analyses were € Run-in period exclusion criteria performed using SAS software, version 8.2. – Interruption of exercise testsc The VASCO trial was conducted in accordance with – Reaching the predicted maximum heart rate (220 minus the principles of Good Clinical Practice, conformed with patient’s age) during exercise testing the ethical principles outlined in the Declaration of Hel- – Insufficient compliance (70–130% compliance with atenolol sinki 1964 and revised in Washington in 2002, and re- treatment) – Poor tolerance to atenolol ceived approval from institutional review boards of each – Significant clinical deterioration participating center. T 1 = Time to 1-mm ST depression. Baseline Characteristics and Results a Proven myocardial infarction more than 3 months prior to Of the 4,755 patients who attended the selection visit, the study, and/or a previous coronary revascularization more than 6 months prior to the study, and/or a coronary angiography 4,705 were enrolled into the run-in period, and 1,962 pa- showing significant coronary artery stenosis in a major artery tients were randomized to the active treatment phase. other than the left main coronary artery. Reasons for exclusion from the active treatment period b Class II or III according to the Canadian Cardiovascular So- were driven by exercise test stability criteria being not ciety. Stable effort angina pectoris was defined as exertional an- met (n = 2,263), but also included exclusion criteria other gina with no resting angina or accelerated chest pain pattern for at least 3 months plus stable symptoms and nitrate consumption than exercise test criteria (n = 288), personal reasons (n = for at least two weeks prior to the study. 225), technical/organizational reasons (n = 15), and death c Due to dyspnea, exhaustion, fatigue, severe chest pain, ap- (n = 2). A total of 1,907 patients completed the study (633 pearance of ST segment depression greater than 4 mm in any lead, in the trimetazidine MR 70-mg group, 641 in the trimeta- sudden decrease in heart rate, major increase, cir- culatory failure during exercise, arrhythmia, conduction distur- zidine MR 140-mg group, and 633 in the placebo group). bances, appearance of ST segment elevation in leads not affected Reasons for withdrawal were similar among treatment by a previous myocardial infarction, or new Q wave. groups: adverse event (n = 25), non-medical reason (n = 23), and protocol deviation (n = 7). At week 0, no significant differences in demographics or baseline characteristics were noted among groups (table 2). Mean total exercise duration was 424.0 8

Treatment of Stable Angina Pectoris with Cardiology 2011;120:59–72 67 Trimetazidine Table 2. VASCO trial: demographic and baseline characteristics at week 0

Trimetazidine MR Trimetazidine MR Placebo All 70 mg (n = 654) 140 mg (n = 655) (n = 653) (n = 1,962)

Age, years 60.588.2 60.388.1 60.388.2 60.488.2 ≤65 454 (69.4) 454 (69.3) 453 (69.4) 1,361 (69.4) >65 200 (30.6) 201 (30.7) 200 (30.6) 601 (30.6) Gender, male 568 (86.9) 550 (84.0) 567 (86.8) 1,685 (85.9) Body mass index, kg/m2 27.583.3 27.583.5 27.683.4 27.583.4 Physical activity 558 (85.3) 577 (88.1) 566 (86.7) 1,701 (86.7) Smoking habit 117 (17.9) 120 (18.3) 117 (17.9) 354 (18.0) Diabetes mellitus 97 (14.8) 102 (15.6) 104 (15.9) 303 (15.4) Duration of angina pectoris, months 60.3866.1 58.5862.1 55.0856.2 57.9861.6 CCS classification II 517 (79.1) 494 (75.4) 500 (76.6) 1,511 (77.0) III 136 (20.8) 160 (24.4) 153 (23.4) 449 (22.9) Number of angina attacks/weeka 5.086.0 5.387.1 5.486.8 5.286.6 Number of SAN intakes/weeka 2.984.8 3.486.0 3.486.0 3.285.7 Previous myocardial infarction 288 (44.0) 285 (43.5) 296 (45.3) 869 (44.3) Previous coronary revascularization 151 (23.1) 145 (22.1) 146 (22.4) 442 (22.5) Coronary angiography 247 (37.8) 229 (35.0) 256 (39.2) 732 (37.3) Family history of angina pectoris 271 (41.4) 300 (45.8) 286 (43.8) 857 (43.7) Previous angina treatments 634 (96.9) 643 (98.2) 643 (98.5) 1,920 (97.9) Previous ␤-blockers 564 (86.2) 582 (88.9) 589 (90.2) 1,735 (88.4) Previous cardiac therapy 538 (82.3) 574 (87.6) 557 (85.3) 1,669 (85.1) Previous calcium channel blockers 73 (11.2) 76 (11.6) 77 (11.8) 226 (11.5) LVEF <40% 1 (0.2) 1 (0.2) 1 (0.2) 3 (0.2) LVEF ≥40% 549 (83.9) 544 (83.1) 533 (81.6) 1,626 (82.9) Total exercise duration, s 424.08113.9 417.78118.2 418.68110.9 420.18114.3 Time to 1-mm ST segment depression, s 348.08112.6 341.68115.6 340.88108.0 343.58112.1 Time to angina onset, s 305.78106.1 302.68111.1 306.68105.0 305.08107.4 Lowest ST segment depression, mm –1.6180.47 –1.6180.47 –1.6080.48 –1.6180.47 Heart rate at rest, bpm 67.8811.3 68.0811.0 68.4811.5 68.1811.3 Heart rate at peak of exercise, bpm 122.7816.7 122.7817.1 121.9816.2 122.4816.7 RPP at rest, bpmؒmm Hg 8,61781,701 8,63281,624 8,67081,731 8,64081,685 RPP at peak of exercise, bpmؒmm Hg 20,20284,122 20,16184,170 20,01484,005 20,12684,098 Number of angina attacks/weekb 2.883.9 3.284.9 3.384.9 3.184.6 0 150 (22.9) 120 (18.3) 118 (18.1) 388 (19.8) 1–3 296 (45.3) 320 (48.9) 318 (48.7) 934 (47.6) >3 208 (31.8) 215 (32.8) 41 (33.2) 640 (32.6) Number of SAN intakes/weekb 1.583.2 1.983.8 2.084.4 1.883.8 0 321 (49.1) 273 (41.7) 262 (40.1) 856 (43.6) 1–3 233 (35.6) 265 (40.5) 268 (41.0) 766 (39.0) >3 100 (15.3) 117 (17.9) 123 (18.8) 340 (17.3)

M ean 8 standard deviations are presented for continuous variables; n (%) are presented for categorical variables. a During the month preceding the selection visit. b During the run-in period. CCS = Canadian cardiovascular society; LVEF = left ventricular ejec- tion fraction; MR = modified release; SAN = short-acting nitrates; RPP = rate pressure product.

113.9 s in the trimetazidine MR 70-mg group, 417.7 8 After 12 weeks of treatment, total exercise duration, 118.2 s in the trimetazidine MR 140-mg group, and 418.6 T1, time to onset of angina, number of angina attacks per 8 110.9 s in the placebo group. Criteria for stability were week, and number of short-acting nitrate intakes per met by 99.8% of patients based on total exercise duration week were significantly improved in all treatment groups and 100% of patients based on T1. compared with week 0 (table 3 ). Differences between

68 Cardiology 2011;120:59–72 Danchin /Marzilli /Parkhomenko /Ribeiro Table 3. VASCO trial: changes from baseline in exercise tolerance and clinical parameters at week 12

Trimetazidine MR Trimetazidine MR Placebo 70 mg (n = 654) 140 mg (n = 655) (n = 653)

Intention-to-treat population Total exercise duration, s n 654 655 653 Change from baseline mean 8 SD 17.2865.2 21.9872.4 15.9867.6 Significance vs. baseline 95% CI 11.9; 22.4a 16.7; 27.2a 10.7; 21.2a Significance vs. placebo p value 0.319 0.056 Time to 1-mm ST segment depression, s n 641 640 644 Change from baseline mean 8 SD 25.2881.3 26.7889.7 22.3881.8 Significance vs. baseline 95% CI 18.7; 31.7a 20.2; 33.2a 15.7; 28.8a Significance vs. placebo p value 0.191 0.158 Time to angina, s n 639 636 642 Change from baseline mean 8 SD 37.9879.4 46.9891.0 34.0880.7 Significance vs. baseline 95% CI 31.4; 44.4a 40.4; 53.5a 27.5; 40.5a Significance vs. placebo p value 0.206 0.004 AA, number/week n 654 655 653 Change from baseline mean 8 SD –1.082.4 –1.183.3 –1.283.2 Significance vs. baseline 95% CI –1.3; –0.8a –1.3; –0.9a –1.5; –1.0a Significance vs. placebo p value n.s. n.s. Short-acting nitrates intake, number/week n 654 655 653 Change from baseline mean 8 SD –0.581.6 –0.583.4 –0.782.6 Significance vs. baseline 95% CI –0.7; –0.3a –0.7; –0.3a –0.9; –0.5a Significance vs. placebo p value n.s. n.s. Total exercise duration in symptomatic patients (AA >0), s AA >0 n 504 535 535 Change from baseline mean 8 SD 16.8868.1 23.8875.7 13.1865.6 Significance vs. placebo p value 0.191 0.01 AA >0 + hs-CRP ≥2 mg/l n 249 281 273 Change from baseline mean 8 SD 18.1869.4 25.2871.7 6.0865.8 Significance vs. placebo p value 0.02 <0.001 AA >0 + hs-CRP ≥2 mg/l + ACEI + statin n 82 88 84 Change from baseline mean 8 SD 19.9867.4 24.7862.4 1.5866.5 Significance vs. placebo p value 0.037 0.007 a Statistically significant vs. baseline. controlling the rate of false-positive conclusions. The statistical For total exercise duration, time to 1-mm ST segment depres- significance of the change from baseline in exercise tolerance cri- sion, and time to onset of angina, between group comparisons teria and clinical criteria was assessed using a two-sided 95% CI were made using an ANCOVA adjusting for baseline, diabetes that was calculated based on an ANOVA and on the Hodges- mellitus, and country. For the clinical criteria, the between group Lehmann’s estimator using Walsh averages. comparisons were based on an analysis of variance estimating AA = Angina attack; ACEI = angiotensin converting enzyme treatment effect or on Mann-Whitney Wilcoxon tests. The Hoch- inhibitor; CI = confidence interval; hs-CRP = high sensitivity C- berg’s stepwise procedure for multiple comparisons was used for reactive protein.

trimetazidine MR groups and placebo on exercise toler- These results should be considered in light of the fact ance parameters were in favor of trimetazidine; however, that at the end of the study 60% of the placebo patients did these results did not reach statistical superiority with the not meet stability criteria: 42.7% of placebo patients im- exception of time to onset of angina in the trimetazidine proved by more than 20% and 17.3% worsened by more MR 140 mg group (p = 0.004). No statistically significant than 20% on either total exercise duration or T1. In addi- difference was noted between the two groups on clinical tion, changes in total of exercise duration that were greater parameters. than the 35 s defined in the protocol occurred in 51.4% of placebo patients (34.2% improved and 17.2% worsened).

Treatment of Stable Angina Pectoris with Cardiology 2011;120:59–72 69 Trimetazidine Table 4. Patients reporting treatment emergent adverse events

Trimetazidine MR Trimetazidine MR Placebo 70 mg (n = 652) 140 mg (n = 655) (n = 653)

Patients reporting at least 1 adverse event 87 (13.3) 88 (13.4) 74 (11.3) AE occurring in >3 patients in any group Influenza 2 (0.3) 6 (0.9) 3 (0.5) Upper respiratory tract infection 3 (0.5) 5 (0.8) 2 (0.3) Nasopharyngitis 3 (0.5) 4 (0.6) 4 (0.6) Dyspepsia 1 (0.2) 4 (0.6) 3 (0.5) Angina pectoris 1 (0.2) 4 (0.6) 1 (0.2) Blood glucose increased 2 (0.3) 4 (0.6) – Viral upper respiratory tract infection 5 (0.8) 3 (0.5) 3 (0.5) Blood pressure inadequately controlled 4 (0.6) 2 (0.3) 4 (0.6) Gamma-glutamyl transferase increased 4 (0.6) 1 (0.2) 2 (0.3) Back pain 2 (0.3) 1 (0.2) 4 (0.6)

Data presented as n (%). The safety set was defined as all randomized patients who took at least one dose of study treatment. Two patients in the trimetazidine MR 70-mg group did not start study treatment after inclu- sion and were excluded from the safety set (n = 1,960).

When complementary analyses were performed on Discussion symptomatic patients (mean number of angina attacks/ week at baseline 1 0), on symptomatic patients with a Results of these network meta-analyses show that high-sensitivity C-reactive protein (hs-CRP) 6 2 mg/l, in the treatment of exercise-induced ischemic episodes, and on symptomatic patients with an hs-CRP 6 2 mg/l trimetazidine is as efficacious as its therapeutic alterna- taking an angiotensin-converting enzyme (ACE) inhibi- tives (non-heart-rate-lowering antianginal treatments). tor and a statin, differences in total exercise duration be- The antianginal agents that were evaluated presented tween trimetazidine groups and placebo group increased significant and comparable anti-ischemic efficacies, as with increasing severity ( table 3 ). In symptomatic pa- shown by the assessment of exercise tolerance and clini- tients with an hs-CRP 6 2 mg/l and in symptomatic pa- cal parameters. These results also confirmed the prophy- tients with an hs-CRP 6 2 mg/l taking ACE inhibitors lactic effect of trimetazidine on angina attacks in stable and statins, both trimetazidine groups showed superior- angina. ity to the placebo group. The placebo effect lessened when Differences between trimetazidine and alternative patients had more severe disease, whereas the trimetazi- treatments were small and non-significant. Compared dine effect persisted. with other antianginal agents, trimetazidine treatment Few adverse events were reported ( table 4 ). No rele- tended to increase total exercise duration by 7 s and time vant difference in frequency was observed between the to onset of angina by 8 s and decrease T1 by 1 s, the num- 70- and 140-mg doses of trimetazidine, indicating that ber of angina attacks by 0.28 per week, and short-acting there was no apparent dose-effect relationship with re- nitrate intakes by 0.45 per week. Furthermore, compared spect to adverse events. Emergent adverse events led to to placebo, significant differences were noted for all vari- treatment discontinuation in, 1.2, 0.9, and 0.8 of 70- ables tested with an increase in total exercise duration of mg trimetazidine, 140-mg trimetazidine, and placebo 46 s, an increase in T1 of 55 s, an increase in time to onset patients respectively. Fifty-two patients (2.7%) experi- of angina of 54 s, a decrease in angina attacks of 1.95 per enced serious adverse events including 5 deaths: 1 in week, and a decrease in short-acting nitrate intakes by each trimetazidine MR group (closed head injury, ven- 1.57 per week. tricular fibrillation), and 3 in the placebo group (myo- These data are consistent with data previously pub- cardial infarction, sudden cardiac death, coronary ar- lished in randomized controlled trials, meta-analyses, tery disease), none of which were considered related to and open-label studies conducted under real-life condi- treatment. tions that consistently show that trimetazidine is effective

70 Cardiology 2011;120:59–72 Danchin /Marzilli /Parkhomenko /Ribeiro in the treatment of stable angina pectoris [2, 3, 7–10, 17] . of combination treatments with multiple therapies that More specifically, they confirm the benefits of trimetazi- alter hemodynamic parameters [19] . Indeed, as a meta- dine on exercise tolerance and clinical parameters high- bolic agent that modulates the changes that take place in lighted in the meta-analysis conducted by the Cochrane ischemic myocytes, trimetazidine lends itself particular- collaboration [9] . Additionally, they also allow a compar- ly well to combination treatment; it provides antianginal ison of this efficacy with that of all trimetazidine direct benefits without having an effect on hemodynamic pa- therapeutic alternatives. By contrast, in the VASCO trial, rameters [2, 3] . In addition, safety data have shown con- which is presented herein, no significant differences be- sistently that trimetazidine is well tolerated in a wide tween treatment with trimetazidine MR and placebo range of patients both in clinical [10] and in everyday were observed. These data, which are not consistent with practice conditions [20] . Although the network meta- results reported in other trials, may be attributable to sev- analysis did not evaluate safety, in the VASCO trial pre- eral reasons. Specific population analysis showed that the sented herein, very few patients withdrew due to adverse population enrolled in the trial did not correspond to the events and few adverse events were treatment-related. population treated with trimetazidine MR in usual med- Lastly, unlike many other antianginal treatments, tri- ical practice. Indeed, although the target population was metazidine has not been shown to interact with other patients with stable angina pectoris, during the run-in drugs. period, 20% of patients had no angina attack and 44% Although the data presented above do not describe percent of patients did not take any short-acting nitrates. long-term efficacy and prognosis, in vitro and in vivo Furthermore, the placebo group displayed a large in- data suggest that treatment with trimetazidine may be dividual variability in exercise tolerance results, which cardioprotective in chronic ischemic heart disease. More- could not be explained by the clinical course of the dis- over, in clinical trials, treatment with trimetazidine sig- ease. However, when complementary analyses were per- nificantly improved left ventricular function in patients formed in more severe patients, the placebo effect less- with stable angina pectoris and in patients with chronic ened and the differences with placebo in total exercise coronary artery disease [21, 22]. In addition, long-term duration became statistically significant. Thus, although treatment of patients with ischemic cardiomyopathy in- the inclusion criteria followed guideline recommenda- creased left ventricular ejection fraction and reduced tions, the baseline results and the observed heterogeneity overall mortality and hospitalization for heart failure, a analyses in the meta-analysis suggest that the study pop- finding supported by a recent meta-analysis [11, 12, 23] . ulation does not represent the target population ade- Together these data suggest that trimetazidine may im- quately and that the ITT efficacy data in the overall pop- prove prognosis in patients with stable angina pectoris ulation of the VASCO study should be interpreted with and that additional long-term trials would be needed to caution. confirm this hypothesis and to evaluate further benefits Despite the results of the VASCO trial, the results of of trimetazidine in ischemic cardiomyopathy that could the network meta-analysis can be considered as robust as potentially extend beyond its effects on cardiac energet- they are supported by extensive validation and sensitivity ics. analyses: results were consistent among the 3 exercise tol- erance parameters; placebo comparisons were consistent with expected clinical effects; and treatment effects esti- Conclusions mated by direct evidence and indirect evidence were rel- atively consistent. Furthermore, when the VASCO study Results of these network meta-analyses show that was excluded from the analyses, overall results did not trimetazidine is effective as a monotherapy and as a com- change significantly, but heterogeneity disappeared with- bination therapy in patients with stable angina pectoris in the meta-analysis of direct comparisons of trimetazi- and that the antianginal efficacy of trimetazidine is sim- dine versus placebo. ilar to that of non-heart-rate-lowering alternatives. When The results of this network meta-analysis, which sup- considered in light of the previously demonstrated fea- port the use of trimetazidine as a monotherapy, and more tures of trimetazidine and of the fact that trimetazidine importantly and according to guidelines [1], as a combi- is the only drug to address directly cardiac energetics in nation therapy, need to be considered in the context of ischemic myocardium, these results support the use of trimetazidine’s mechanism of action and safety profile trimetazidine in clinical practice. and in the context of what is known about the limitations

Treatment of Stable Angina Pectoris with Cardiology 2011;120:59–72 71 Trimetazidine Acknowledgements N.D. reports having received consulting or speaking fees from Astra Zeneca, BMS, Boehringer-Ingelheim, Eli-Lilly, Glaxow We would like to thank Dr. Hélène Dassule for her editorial SmithKline, Menarini, Merck, Novo-Nordisk, Pfizer, Sanofi- help as well as Les Laboratoires Servier Industrie (Gidy, France) Aventis, Servier, Takeda, and The Medicines Company. He has for providing trimetazidine and placebo tablets of a similar form also received research grants from Astra Zeneca, Eli-Lilly, Glaxow to the VASCO trial. We are indebted to L. Feldmann, MD as well SmithKline, Merck, Novartis, Pfizer, Sanofi-Aventis, Servier, and as S. Guilleminot and A. Racaud of the statistical department of The Medicines Company. In addition, N.D. was the principal in- IRIS (Institut de Recherche International Servier), who per- vestigator of the VASCO trial. formed the statistical analysis. M.M. reports receiving an educational grant from Servier. J.P.R. reports having received consulting and speaking fees from AstraZeneca, Bioassist, Boehringer-Ingelheim, Merck- Sharp and Dohme, Sanofi-aventis, and Sevier. He has also re- C o n f l i c t o f I n t e r e s t ceived research grants from Abbott, Bristol-Myers Squibb, Merck-Sharp and Dohme, Servier, and Takeda. The VASCO study was funded by the Institut de Recherche SERVIER.

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