Clinical Acceptability Of Trimetazidine Modified-Release 80mg Once Daily Versus Trimetazidine Modified-Release 35mg Twice Daily In Stable Angina Pectoris

Clinical Acceptability Of Trimetazidine Modified-Release 80mg Once Daily Versus Trimetazidine... Cardiol Ther (2018) 7:61–70 https://doi.org/10.1007/s40119-018-0110-5 ORIGINAL RESEARCH Clinical Acceptability Of Trimetazidine Modified- Release 80 mg Once Daily Versus Trimetazidine Modified-Release 35 mg Twice Daily In Stable Angina Pectoris Yuri M. Pozdnyakov On behalf of the study investigators Received: March 28, 2018 / Published online: May 19, 2018 The Author(s) 2018 12-lead resting ECG (electrocardiogram) and ABSTRACT Canadian Cardiovascular Society (CCS) classifi- cation were recorded. Introduction: Trimetazidine (TMZ) is an anti- Results: One-hundred and sixty-five patients ischemic metabolic agent that has been shown previously diagnosed with stable angina pec- to be efficacious in angina treatment, both in toris on treatment were randomized to receive monotherapy and in combination. A new for- either TMZ MR 80 mg od or TMZ MR 35 mg bid. mulation of TMZ modified-release (MR) 80 mg In the TMZ MR 80 mg group, fewer patients had was developed, which is to be taken once daily C 1 EAE (17.1 vs. 22.9% in the TMZ MR 35 mg (od), instead of twice daily (bid) for the cur- group). Serious EAEs were reported by three rently available TMZ MR 35 mg, with the aim of patients in each group. No EAE required dose simplifying the medication regimen. modification, withdrawal, or temporary inter- Methods: The present study was an interna- ruption of study treatments. Vital signs, 12-lead tional, multicenter, randomized, double-blind, ECG, and laboratory parameters did not change. parallel-group phase III study with a 12-week No worsening in CCS classes was observed with treatment period. The safety of TMZ MR 80 mg either treatment. once daily was assessed compared to TMZ MR Conclusions: TMZ MR 80 mg od and TMZ MR 35 mg twice daily, in patients previously treated 35 mg bid have similar safety profiles. This new successfully by the latter. Emergent adverse once-daily formulation could improve patient events (EAEs), biological parameters, vital signs, compliance with therapy, thereby enhancing The members of the study investigators are listed in clinical benefit. acknowledgements. Trial Registration: ISRCTN registry, ISRCTN Enhanced Digital Features To view enhanced digital Funding: Institut de Recherches Interna- features for this article go to https://doi.org/10.6084/ m9.figshare.6165716. tionales Servier and Servier, Moscow, Russian Federation. Electronic supplementary material The online Plain Language Summary: Plain language version of this article (https://doi.org/10.1007/s40119- 018-0110-5) contains supplementary material, which is summary available for this article. available to authorized users. Keywords: Formulation; Randomized clinical Y. M. Pozdnyakov (&) trial; Safety; Stable angina; Trimetazidine Moscow Regional Cardiology Centre, Zhukovsky, Russia e-mail: pozdn@progtech.ru 62 Cardiol Ther (2018) 7:61–70 ion pump function, ultimately resulting in PLAIN LANGUAGE SUMMARY improved cardiac efficiency [7]. The efficacy of TMZ in treating stable angina, both as Angina is a condition affecting more than a 100 monotherapy and in combination, has been million patients worldwide. The drug trimeta- reported and summarized in a meta-analysis of zidine has previously been shown to be effica- randomized clinical trials [8]. cious for treating angina. Trimetazidine is Non-adherence to treatment is frequently currently available as 20- and 35-mg pills, which observed in outpatient care and can be observed have to be taken two or three times daily, even in symptomatic conditions like angina [9]. respectively. In the present study, a new for- Decreasing the number of treatment doses mulation of 80 mg trimetazidine, for which one taken per day could help to improve adherence dose daily is sufficient, was compared to the [9–11] and thus potentially translate into clini- existing 35 mg trimetazidine in terms of safety cal benefit. With this aim of simplification of and was found to be similarly safe. Increased the medication regimen, a once-daily (od) oral number of medications to be taken has previ- formulation of TMZ 80 mg was developed, with ously been shown to decrease the probability of an equivalent systemic exposure to TMZ 35 mg patients taking their treatment as prescribed. twice daily (bid) demonstrated. The fact that this new trimetazidine formula- In the present 12-week study, the safety of tion reduces the number of pills taken daily TMZ modified-release (MR) 80 mg formulation could thus be a step towards helping patients to was compared with the already-marketed TMZ follow their treatment. MR 35-mg formulation, in patients with chronic stable angina. INTRODUCTION METHODS The prevalence of angina pectoris (AP) is con- siderable, as it affects nearly 112 million people The present study was an international, multi- worldwide [1]. Despite available treatments, center, randomized, double-blind, parallel- studies have reported that there is marked group phase III study with a treatment period of variability in achieving angina control [2, 3]. 12 weeks. The study was conducted in Russia Although the extent of its impact is often and in Serbia, from January 2013 to August underestimated by physicians [2, 4], angina can 2013. In total, 15 centers were selected and adversely affect patients’ quality of life and included at least one patient: 12 in Russia and result in increased healthcare costs [5]. three in Serbia. Beta-blockers, dihydropyridine calcium Patients were both male and female, aged channel blockers, and nitrates, which are widely C 21 years old, with chronic stable angina pec- used as antianginal medications, affect cardio- toris, where the symptoms were classified as vascular hemodynamics, reducing oxygen being class 1, 2, or 3 according to the Canadian demand and/or increasing oxygen supply. For Cardiovascular Society (CCS) classification. patients remaining symptomatic despite Patient treatment had to include at least one monotherapy, European guidelines [6] recom- regular antianginal medication such as beta- mend a combination of different antianginal blockers, calcium channel blockers, long-acting agents. The addition of trimetazidine (TMZ) can nitrates, nicorandil, ivabradine, or mol- provide an opportunity to optimize antianginal sidomine. Short-acting nitrates were adminis- treatment, as it does not have any hemody- tered on demand. At the time of selection, the namic effect but acts directly at the myocardial patient had to be already treated by his/her cell level instead. By inhibiting an enzyme physician for angina pectoris with TMZ MR involved in fatty acid oxidation, TMZ leads to 35 mg bid for at least 1 month, with satisfactory increased creatine phosphate/ATP (adenosine clinical effect and good tolerance. Coronary triphosphate) ratio and preservation of heart disease should have been documented by myocardial high-energy phosphate levels and Cardiol Ther (2018) 7:61–70 63 either previous MI (myocardial infarction) or the ethical standards of the institutional and/or previous coronary revascularization national research committee and with the 1964 C 3 months, or angiographic evidence of C 50% Helsinki Declaration and its later amendments narrowing of C 1 major epicardial coronary or comparable ethical standards. Informed artery, or in male patients only documented consent was obtained from all individual par- evidence of myocardial ischemia. The main ticipants included in the study. exclusion criteria were current or previous Parkinsonian symptoms and abnormal renal Statistical Analysis function with estimated creatinine clearance (eCrCl) \60 ml/min. Descriptive statistics were provided by treat- With respect to blinding, a double-dummy ment group (and all groups pooled for study design was used, with placebo tablets matching outcome criteria and adverse events) depending TMZ MR 35-mg tablets and placebo capsules on the nature of the criteria. For quantitative matching TMZ MR 80-mg capsules. The study criteria, the number of observed values, mean, consisted of a run-in period of 2 weeks, during standard deviation, minimum and maximum, which patients received TMZ MR 35 mg bid and median, first and third quartiles were used. For one capsule of placebo twice daily, followed by qualitative criteria, the number of observed a double-blind treatment period of 12 weeks, values, number, and percentage of patients per during which patients were randomized to class were used. receive either (A) one tablet of TMZ MR 35 mg and one capsule of placebo twice daily or (B) one capsule of TMZ MR 80 mg and one RESULTS tablet of placebo in the morning and one cap- sule of placebo and one tablet of placebo in the A total of 180 patients were screened and 177 evening. Randomization was not centralized. were selected for the study. Among them, 165 The treatments were allocated at the inclusion patients (130 in Russia and 35 in Serbia) were visit (week 0) by a balanced (non-adaptive) included and randomly assigned to one of the randomization (ratio 1:1) with stratification by two treatment groups: either the TMZ MR center. 80 mg od group (n = 82 patients) or the TMZ The main objective of the study was to assess MR 35 mg bid group (n = 83 patients). Reasons safety of TMZ MR 80 mg od compared to TMZ for exclusion of selected patients were: non- MR 35 mg bid. compliance with inclusion/non-inclusion crite- All of the 165 patients included in the study ria in nine patients and adverse events in three attended week 0 (W0), week 4 (W4), week 8 patients. No patient was withdrawn from the (W8), and week 12 (W12) visits for safety study, nor lost to follow-up. assessment. Safety evaluation was based on the The main characteristics at baseline are following: (1) adverse events, (2) laboratory summarized in Table 1. The two groups were parameters (biochemical and hematological, well balanced regarding demographic charac- only at inclusion/W0 and W12), (3) vital signs teristics at baseline (64 years old, 69% male, including weight (only at inclusion/W0 and 100% Caucasian) and duration of stable angina W12), supine and standing blood pressure and pectoris (mean duration, 6.3 ± 5.4 years). In pulse rate, (4) 12-lead electrocardiogram, and addition to angina pectoris, the most frequent (5) CCS classification of symptoms of angina medical histories related to CAD (coronary pectoris. artery disease) were myocardial infarction (73%) and unstable angina (15%). Forty-two percent of the patients had previous coronary angio- Compliance with Ethics Guidelines plasty and 26% previous coronary artery bypass. Before the treatment period, all of them were All procedures performed in studies involving receiving specific treatment for angina, mainly human participants were in accordance with beta-blocking agents (88%), calcium channel 64 Cardiol Ther (2018) 7:61–70 Table 1 Main baseline characteristics and therapies in the randomized patients Trimetazidine Trimetazidine All MR 80 mg od MR 35 mg bid (N 5 165) (N 5 82) (N 5 83) Age (years) 63.3 ± 6.9 64.3 ± 8.3 63.8 ± 7.6 Proportion of men 56 (68.3) 57 (68.7) 113 (68.5) Blood pressure SBP (mmHg) 129.7 ± 14.4 132.0 ± 13.7 130.9 ± 14.1 DBP (mmHg) 78.0 ± 7.5 78.7 ± 7.7 78.3 ± 7.6 Heart rate (bpm) 64.7 ± 9.8 63.3 ± 9.4 64.0 ± 9.6 Stable angina pectoris duration (years) 5.8 ± 5.4 6.9 ± 5.3 6.3 ± 5.4 CCS classification Class I 22 (26.8) 14 (16.9) 36 (21.8) Class II 49 (59.8) 63 (75.9) 112 (67.9) Class III 11 (13.4) 6 (7.2) 17 (10.3) Medical history of CAD 82 (100) 83 (100) 165 (100) Myocardial infarction 61 (74.4) 60 (72.3) 121 (73.3) Unstable angina 13 (15.9) 12 (14.5) 25 (15.2) Surgical/medical procedures history 50 (61.0) 53 (63.9) 103 (62.4) Coronary angioplasty 35 (42.7) 35 (42.2) 70 (42.4) Coronary artery bypass 19 (23.2) 24 (28.9) 43 (26.1) Baseline cardiovascular therapies Antithrombotic agents 78 (95.1) 79 (95.2) 157 (95.2) Statins 75 (91.5) 75 (90.4) 150 (90.9) ACEi and ARB 68 (82.9) 76 (91.6) 144 (87.3) CCB 27 (32.9) 29 (34.9) 56 (33.9) BB 74 (92.2) 71 (85.5) 145 (87.9) LAN 27 (32.9) 26 (31.3) 53 (32.1) Data presented are mean (±SD) or n (%) ACEi angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, BB beta-blocker, CAD coronary artery disease, CCB calcium channel blocker, CCS Canadian Cardiovascular Society, DBP diastolic blood pressure, LAN long- acting nitrates, SBP systolic blood pressure, SD standard deviation blockers (34%), and/or long-acting nitrates treatment period with no relevant difference (32%), which was maintained during the study. between groups. They were mainly diuretics Overall, 47.9% of the patients received addi- (20% of the patients) and drugs used in diabetes tional concomitant treatment before the (18% of the patients). No major difference Cardiol Ther (2018) 7:61–70 65 Table 2 Emergent adverse events by system organ classes reported during the treatment period with preferred term when more than a single patient is considered System organ class Trimetazidine Trimetazidine Preferred term MR 80 mg od MR 35 mg bid (N 5 83) (N 5 82) NEAE n % NEAE n % Infections and infestations 6 5 6.1 1 1 1.2 Influenza 2 2 2.4 – – – Investigations 4 4 4.9 5 5 6.0 Hyperbilirubinemia 1 1 1.2 2 2 2.4 Hyperglycemia – – – 4 4 4.8 Cardiac disorders 5 3 3.7 5 5 6.0 Atrial fibrillation – – – 2 2 2.4 Renal and urinary disorders 2 2 2.4 – – – Metabolism and nutrition disorders 2 1 1.2 7 6 7.2 Hepatobiliary disorders 1 1 1.2 2 2 2.4 Respiratory, thoracic, and mediastinal disorders 1 1 1.2 2 1 1.2 Blood and lymphatic system disorders 1 1 1.2 – – – Gastrointestinal disorders 1 1 1.2 – – – Musculoskeletal and connective tissue disorders 1 1 1.2 – – – Injury, poisoning, and procedural complications – – – 1 1 1.2 Nervous system disorders – – – 1 1 1.2 Vascular disorders – – – 1 1 1.2 ALL 24 14 17.1 25 19 22.9 N number of patients by group, NEAE number of emergent adverse events, n number of patients with at least one emergent adverse event, % =(n/N) 9 100 between the two groups was observed regarding (EAE) during the double-blind treatment period blood pressure and heart rate, ECG (electrocar- (Table 2) was slightly lower in the TMZ MR diogram), and laboratory parameters. There was 80-mg group (14 patients, 17.1%) than in the a slightly higher proportion of patients with TMZ MR 35-mg group (19 patients, 22.9%). In class I and class III CCS in the TMZ MR 80-mg the TMZ MR 80-mg group, the most frequently group than in the TMZ MR 35-mg group. No reported EAE (at least two patients) was influ- major changes were reported regarding con- enza (two patients), whereas in the TMZ MR comitant treatments during the study. 35-mg group it was hyperglycemia (four In the Safety Set (which consisted of all the patients), hyperbilirubinemia (two patients), randomized and treated patients, i.e., 165 and atrial fibrillation (two patients). No EAE led patients), the proportion of patients who expe- to dose modification, withdrawal, or temporary rienced at least one emergent adverse event interruption of the study treatments. 66 Cardiol Ther (2018) 7:61–70 Table 3 Emergent serious adverse events reported during the treatment period Preferred term Trimetazidine Trimetazidine MR 80 mg od MR 35 mg bid (N 5 82) (N 5 83) NEAE n % NEAE n % Cardiac failure acute 11 1.2 – – – Myocardial infarction 11 1.2 – – – Ventricular fibrillation 11 1.2 – – – Atrial fibrillation – – – 2 2 2.4 Blood pressure 11 1.2 – – – increased Renal colic 1 1 1.2 – – – Pulmonary edema 11 1.2 – – – Ischemic stroke – – – 1 1 1.2 ALL 6 3 3.7 3 3 3.6 N number of patients by group, NEAE number of emergent adverse events, n number of patients with at least one emergent serious adverse event, % =(n/N) 9 100 These events all occurred in the same patient on the same day and recovered In terms of intensity, most of the EAEs were No clinically significant changes were rated as mild (14 vs. 18 events, in the TMZ MR observed during the study regarding vital signs 80-mg and MR 35-mg group, respectively) or (weight, blood pressure, and pulse rate), ECG, moderate (seven events in each group). Three and laboratory parameters. Based on local lab- patients in each group experienced serious oratory tests, very few biological values reached adverse events (Table 3). None was considered a potentially clinically significant level (PCSA), to be related to treatment and all recovered. each of them affecting only one patient, with In addition, only one event (polyuria, which the exception of high triglycerides in the TMZ recovered fully) in the TMZ MR 80-mg group MR 35-mg group, which affected three patients: was considered to be related to the study treat- • 4 PCSA values in the TMZ MR 80-mg group: ment by the investigator. high GGT, low clearance creatinine, high Most emergent adverse events recovered in triglycerides, and low platelets, both treatment groups: 75.0% of events in the • 6 PCSA values in the TMZ MR 35-mg group: TMZ MR 80-mg group and 56.0% in the TMZ high glucose, low HDL cholesterol, high MR 35-mg group. Events not recovered at the triglycerides, and high white blood cell end of the study were mostly related to chronic count. diseases (i.e., diabetes, dyslipidemia) or were reported at the last visit (W12). None of them DISCUSSION was serious or of severe intensity. There was no study treatment interruption This is the first study to assess the clinical due to lack of efficacy. Regarding CCS classifi- acceptability of TMZ MR 80 mg, a new formu- cation of symptoms of angina, no worsening lation of trimetazidine allowing a single dose was reported with either treatment. daily. Previous pharmacokinetic studies Cardiol Ther (2018) 7:61–70 67 performed with the 80-mg MR formulation prescribed, since many of the patients have (data on file) showed that: multiple comorbidities, such as diabetes melli- • This formulation presents plasma profiles of tus or hypertension. Adherence has been shown an MR once-daily formulation, to be related not only to the number of medi- • This formulation leads to AUC24, C , and cations but also to the number of doses to be max C equivalent to the ones obtained with taken per day [12] and it is inversely related to min the MR 35 mg bid after repeated dosing in the latter [13]. Hence, simplifying a medication fed conditions in healthy volunteers, regimen might be expected to be associated • There is no food effect on pharmacokinetic with improved adherence and so with potential parameters. increased clinical benefits in patients with ang- In the present study, TMZ MR 80 mg once ina. A study showed that converting patients daily compared to TMZ MR 35 mg bid for a with chronic, stable angina to long-acting 12-week treatment period were found to have antianginal medications led to substantial similar safety profiles in patients with docu- improvement in symptom control [10]. mented coronary artery disease and Improved adherence with once-daily treatment stable chronic angina pectoris. Study treatment compared with twice-daily treatment was was given on top of both routine antianginal shown for both beta-blocker and nitrate regi- therapies and secondary prevention therapy. men [9, 11]. Health-related quality of life was Patients were treated with TMZ MR 35 mg bid also improved according to one study [11]. during the run-in period, therefore only a mar- In light of this evidence, the availability of a ginal additional benefit was expected on angina once-daily formulation of TMZ, with similar symptoms during the double-blind treatment safety to the twice-daily formulation, could period. According to the summary of product offer an opportunity for improving patient characteristics and minimization measure adherence to treatment. implemented to reduce the risk of overexposure to TMZ in patients with renal insufficiency, Study Limitations patients with moderate-to-severe renal impair- ment (creatinine clearance below 60 ml/min Despite its randomized, double-blind design, during the run-in period) were excluded, since the study has limitations related to the small no adaptation of the dose could be done with size of the patient population (n = 165 patients) the capsules containing 80 mg of TMZ. and to the protocol selection criteria. TMZ is a well-established therapy for angina control, with a mechanism of action that is distinct from that of other antianginal agents, CONCLUSIONS as it acts directly at the level of myocardial cells. Since it is devoid of any major hemodynamic TMZ MR 80 mg od was shown to have a similar properties, it can be combined with other clas- safety profile to TMZ MR 35 mg bid. This once- ses of antianginal therapy. The MR 80-mg for- daily formulation could possibly help increase mulation taken od simplifies the treatment treatment adherence and thus lead to clinical regimen and would thereby be expected to benefit in real life. improve adherence to treatment in real-life settings. Non-adherence to treatment is known to be ACKNOWLEDGEMENTS a problem in asymptomatic diseases, with the notable example of hypertension, but can also The author would like to thank the investiga- concern symptomatic diseases, and has been tors of the study. reported in patients with stable angina treated Arkhangelsk: Uskov V.L. Barnaul: Gon-char- with symptom-releasing nitrates [9]. Amongst enko I.I., Prasolova T.P. Belgorod: Guseva V.G., patients with angina, adherence could be Shinkar A.S. Bryansk: Samsonova S.M. Veliky hampered by the total number of medications 68 Cardiol Ther (2018) 7:61–70 Novgorod: Vikhrova I.V., Kuz’kina S.A. Vladi- Guryanova I.R., Zheltova V.L. Rostov-on-Don: mir: Mitina L.V., Timofeeva I.V. Vol-gograd: Bulygina E.D., Gorskaya E.V., Kosenko L.V., Archakova T.M., Kovaleva N.Y., Romanova E.A., Musaeva F.K., Fedorchenko M.Y., Harish V.I. Tivon Y.V. Vologda: Antonova Y.N., Kurganova Ryazan Region: Serbarinova O.M. Ryazan: Yat- O.B. Voronezh: Davydova N.N., Klyuchantseva senya Y.A. Sa-mara: Golubev M.N., Kopaev D.E., O.V., Popovskaya Y.V., Kharitonova E.I. Evpa- Miludina L.A., Polischuk L.V., Shilintseva O.A., toria: Kuzmina T.N. Ekaterinburg: Buzmakova Krylova, L.M. St. Petersburg: Vasilik M.V., Zotov K.V., Kaplenko L.I., Pospelova N.V., Stepanova D.D., Kalishevich N.B., Kachmazova L.I., Kon- A.Y. Ivanovo: Kol-basheva N.A. Irkutsk: Kras- torikova S.G., Mamoshko T.A., Osnovin S.A., nova G.M., Pal’vin-skaya A.Y., Toloknova V.A. Timosh-enko (Schmalz) I.O., Kashina A.N., Kir- Kazan: Bikmullina R.F., Gainullina A.A., yanova O.G. Saratov: Kotova L.E., Kuvshinova Kedrina E.V., Mikhailova S.A., Nabiullina T.A., L.E., Ulyanova I.M., Shevelo O.F. Simferopol: Nizamova A.F. Kaluga: Uskova A.A., Yushkova Kir-eeva I.B., Korohova L.V., Smolensk: Lisu- A.E. Kemerovo: Andreeva O.V., Fedotova G.V. nova T.I., Medvedeva E.V. Stavropol: Matvienko Kirov: Besser-geneva O.L., Gavrilyuk D.D., T.E., Shovgaryan S.L. Stary Oskol: Nebolsina T.F. Ehalo N.V., Zlo-bina M.V. Krasnodar: Zhemart- Syktyvkar: Mikusheva M.A., Misharin N.N. Tver seva E.Y., Markushina I.A., Pavlovets V.P., Region: Kutaliya T.O. Tolyatti: Chernova V.N., Sobolenko A.A. Krasnoyarsk: Apanovich I.E., Yanina Y.A. Tomsk: Permyakova O.V., Skur- Kireeva N.V., Maksimova I.V. Kursk: Butz T.V., ikhina N.N. Tula: Goldinova L.M., Pri-khodko Pavlova I.A. Lipetsk: Bachurina S.N., Orly- T.N. Tyumen: Myshyakova A.G. Ufa: Akhmer- achenko S.V. LR Sertolovo: Zaitseva T.V., LR ova E.Z., Zaitseva K.V., Ozerchuk A.A., Poly- Lomonosov: Beznogova V.F. LR-South: Litsis akova I.M., Rodionova, Safiullina I.D. N.N., Novozhenina A.Y. Moscow: Abramyan Cheboksary: Arsentieva I.N., Volkova O.O. L.L., Adamyan M.M., Askerko S.N., Bolmosov Chelyabinsk: Kondrina I.N., Kharlova T.E. Yalta: A.N., Vasilieva I.N., Volodova S.I., Grishko P.V., Grigorieva T.L. Yaroslavl: Kurtmulaeva K.V., Zherebetskaya E.S., Zemlyanaya N.S., Klysh- Rogozina O.M. nikova L.N., Kononchik E.I., Kuznetsova N.A., Kuz’minova I.A., Marmurova I.V., Mikhailova Funding. Sponsorship for this study was R.Y., Mordovina I.P., Nazarkina O.V., Per- provided by the Institut de Recherches Inter- epechko A.P., Pivovarova N.G., Potapova T.P., nationales Servier and Servier, Moscow, Russian Prokofiev D.A., Proniushkina N.E., Savelieva Federation. Article processing charges for this E.V., Semovskikh N.A, Timonenkova L.D., study were funded by Servier. All authors had Fomin V.V., Furman O.A., Tsutsieva R.M., full access to all of the data in this study and Chibrikina M.V., Shoshina I.N., Yashchenko.P. take complete responsibility for the integrity of Moscow region: Bocharova T.I., Demya-nenko the data and accuracy of the data analysis. O.L., Zhukova L.B., Melnikov A.Y., Mer-kulieva I.A., Tyasina E.I., Pakholkova N.S., Rogozina Medical Writing. Writing assistance was S.V., Chugunova I.V. Murmansk: Brazhnik M.L., provided by Diana Toli, PhD (Servier). Writing Guseva Y.V. Naberezhnye Chelny: Anisimova assistance was funded by Servier. A.N., Kuzeyina S.S., Kulakhmetova R.G., Petrova I.S. Nizhny Nov-gorod: Ignatyeva I.A., Moro- Authorship. All named authors meet the International Committee of Medical Journal zova T.A., Ryb-nikova N.V., Gritsenko I.I. Novokuznetsk: Kondratskaya O.V., Shishkin Editors (ICMJE) criteria for authorship for this A.V. Novosibirsk: Gogleva N.N., Kulipanova manuscript, take responsibility for the integrity V.M., Mitrofanova S.V., Parada E.V., Svistunova of the work as a whole and have given final S.Y., Sergeeva T.M. Omsk: Kryukova V.V., approval for the version to be published. Suprun T.N., Fedorova E.M., Shnor O.F. Orel: Authorship Contributions. The author Mitroshina T.N., Shemetova T.S., Orenburg: would like to thank all participating investiga- Val’kevich L.P., Varnikova S.N. Penza: Ivanova tors for their contribution to the study. E.A. Perm: Shlykova O.N. Pyatigorsk: Cardiol Ther (2018) 7:61–70 69 analysis for the Global Burden of Disease Study Prior Presentation. The data presented in 2010. Lancet. 2012;380:2163–96. this manuscript were previously presented in 2016 at the 38th Congress of the European 2. Beltrame JF, Weekes AJ, Morgan C, Tavella R, Society of Cardiology (ESC) as a poster entitled: Spertus JA. The prevalence of weekly angina among patients with chronic stable angina in primary care Clinical acceptability of trimetazidine 80 mg practices: the Coronary Artery Disease in General once daily versus trimetazidine modified-release Practice (CADENCE) Study. Arch Intern Med. 35 mg twice daily in chronic stable angina 2009;169:1491–9. pectoris. Eur Heart J 2016 Vol. 37 (suppl. 1): 388 3. Kureshi F, Shafiq A, Arnold SV, et al. The prevalence (P1857). Y. Pozdnyakov. Moscow Regional Car- and management of angina among patients with diology Center, Cardiology, Zhukovsky, Russian chronic coronary artery disease across US outpa- Federation. tient cardiology practices: insights from the Angina Prevalence and Provider Evaluation of Angina Relief Disclosures. Yuri M. Pozdnyakov, scientific (APPEAR) study. Clin Cardiol. 2017;40:6–10. coordinator of this study, received grants and 4. Qintar M, Spertus JA, Gosch KL, et al. Effect of honoraria for conducting research and hono- angina under-recognition on treatment in outpa- raria for lectures from Servier, Moscow, Russian tients with stable ischaemic heart disease. Eur Heart Federation. J Qual Care Clin Outcomes. 2016;2:208–14. 5. Arnold SV, Morrow DA, Lei Y, et al. Economic Compliance with Ethics Guidelines. All impact of angina after an acute coronary syndrome: procedures performed in studies involving insights from the MERLIN-TIMI 36 trial. Circ Car- human participants were in accordance with diovasc Qual Outcomes. 2009;2:344–53. the ethical standards of the institutional and/or 6. Montalescot G, Sechtem U, Achenbach S, et al. national research committee and with the 1964 2013 ESC guidelines on the management of Helsinki Declaration and its later amendments stable coronary artery disease: the Task Force on the or comparable ethical standards. Informed management of stable coronary artery disease of the European Society of Cardiology. 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Vasc with disability (YLDs) for 1160 sequelae of 289 Health Risk Manag. 2007;3:235–42. diseases and injuries 1990–2010: a systematic 70 Cardiol Ther (2018) 7:61–70 12. Cramer JA. Effect of partial compliance on cardio- 13. Claxton AJ, Cramer J, Pierce C. A systematic review of vascular medication effectiveness. Heart. the associations between dose regimens and medi- 2002;88:203–6. cation compliance. Clin Ther. 2001;23:1296–310. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cardiology and Therapy Springer Journals

Clinical Acceptability Of Trimetazidine Modified-Release 80mg Once Daily Versus Trimetazidine Modified-Release 35mg Twice Daily In Stable Angina Pectoris

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Medicine & Public Health; Internal Medicine; Cardiology
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Abstract

Cardiol Ther (2018) 7:61–70 https://doi.org/10.1007/s40119-018-0110-5 ORIGINAL RESEARCH Clinical Acceptability Of Trimetazidine Modified- Release 80 mg Once Daily Versus Trimetazidine Modified-Release 35 mg Twice Daily In Stable Angina Pectoris Yuri M. Pozdnyakov On behalf of the study investigators Received: March 28, 2018 / Published online: May 19, 2018 The Author(s) 2018 12-lead resting ECG (electrocardiogram) and ABSTRACT Canadian Cardiovascular Society (CCS) classifi- cation were recorded. Introduction: Trimetazidine (TMZ) is an anti- Results: One-hundred and sixty-five patients ischemic metabolic agent that has been shown previously diagnosed with stable angina pec- to be efficacious in angina treatment, both in toris on treatment were randomized to receive monotherapy and in combination. A new for- either TMZ MR 80 mg od or TMZ MR 35 mg bid. mulation of TMZ modified-release (MR) 80 mg In the TMZ MR 80 mg group, fewer patients had was developed, which is to be taken once daily C 1 EAE (17.1 vs. 22.9% in the TMZ MR 35 mg (od), instead of twice daily (bid) for the cur- group). Serious EAEs were reported by three rently available TMZ MR 35 mg, with the aim of patients in each group. No EAE required dose simplifying the medication regimen. modification, withdrawal, or temporary inter- Methods: The present study was an interna- ruption of study treatments. Vital signs, 12-lead tional, multicenter, randomized, double-blind, ECG, and laboratory parameters did not change. parallel-group phase III study with a 12-week No worsening in CCS classes was observed with treatment period. The safety of TMZ MR 80 mg either treatment. once daily was assessed compared to TMZ MR Conclusions: TMZ MR 80 mg od and TMZ MR 35 mg twice daily, in patients previously treated 35 mg bid have similar safety profiles. This new successfully by the latter. Emergent adverse once-daily formulation could improve patient events (EAEs), biological parameters, vital signs, compliance with therapy, thereby enhancing The members of the study investigators are listed in clinical benefit. acknowledgements. Trial Registration: ISRCTN registry, ISRCTN Enhanced Digital Features To view enhanced digital Funding: Institut de Recherches Interna- features for this article go to https://doi.org/10.6084/ m9.figshare.6165716. tionales Servier and Servier, Moscow, Russian Federation. Electronic supplementary material The online Plain Language Summary: Plain language version of this article (https://doi.org/10.1007/s40119- 018-0110-5) contains supplementary material, which is summary available for this article. available to authorized users. Keywords: Formulation; Randomized clinical Y. M. Pozdnyakov (&) trial; Safety; Stable angina; Trimetazidine Moscow Regional Cardiology Centre, Zhukovsky, Russia e-mail: pozdn@progtech.ru 62 Cardiol Ther (2018) 7:61–70 ion pump function, ultimately resulting in PLAIN LANGUAGE SUMMARY improved cardiac efficiency [7]. The efficacy of TMZ in treating stable angina, both as Angina is a condition affecting more than a 100 monotherapy and in combination, has been million patients worldwide. The drug trimeta- reported and summarized in a meta-analysis of zidine has previously been shown to be effica- randomized clinical trials [8]. cious for treating angina. Trimetazidine is Non-adherence to treatment is frequently currently available as 20- and 35-mg pills, which observed in outpatient care and can be observed have to be taken two or three times daily, even in symptomatic conditions like angina [9]. respectively. In the present study, a new for- Decreasing the number of treatment doses mulation of 80 mg trimetazidine, for which one taken per day could help to improve adherence dose daily is sufficient, was compared to the [9–11] and thus potentially translate into clini- existing 35 mg trimetazidine in terms of safety cal benefit. With this aim of simplification of and was found to be similarly safe. Increased the medication regimen, a once-daily (od) oral number of medications to be taken has previ- formulation of TMZ 80 mg was developed, with ously been shown to decrease the probability of an equivalent systemic exposure to TMZ 35 mg patients taking their treatment as prescribed. twice daily (bid) demonstrated. The fact that this new trimetazidine formula- In the present 12-week study, the safety of tion reduces the number of pills taken daily TMZ modified-release (MR) 80 mg formulation could thus be a step towards helping patients to was compared with the already-marketed TMZ follow their treatment. MR 35-mg formulation, in patients with chronic stable angina. INTRODUCTION METHODS The prevalence of angina pectoris (AP) is con- siderable, as it affects nearly 112 million people The present study was an international, multi- worldwide [1]. Despite available treatments, center, randomized, double-blind, parallel- studies have reported that there is marked group phase III study with a treatment period of variability in achieving angina control [2, 3]. 12 weeks. The study was conducted in Russia Although the extent of its impact is often and in Serbia, from January 2013 to August underestimated by physicians [2, 4], angina can 2013. In total, 15 centers were selected and adversely affect patients’ quality of life and included at least one patient: 12 in Russia and result in increased healthcare costs [5]. three in Serbia. Beta-blockers, dihydropyridine calcium Patients were both male and female, aged channel blockers, and nitrates, which are widely C 21 years old, with chronic stable angina pec- used as antianginal medications, affect cardio- toris, where the symptoms were classified as vascular hemodynamics, reducing oxygen being class 1, 2, or 3 according to the Canadian demand and/or increasing oxygen supply. For Cardiovascular Society (CCS) classification. patients remaining symptomatic despite Patient treatment had to include at least one monotherapy, European guidelines [6] recom- regular antianginal medication such as beta- mend a combination of different antianginal blockers, calcium channel blockers, long-acting agents. The addition of trimetazidine (TMZ) can nitrates, nicorandil, ivabradine, or mol- provide an opportunity to optimize antianginal sidomine. Short-acting nitrates were adminis- treatment, as it does not have any hemody- tered on demand. At the time of selection, the namic effect but acts directly at the myocardial patient had to be already treated by his/her cell level instead. By inhibiting an enzyme physician for angina pectoris with TMZ MR involved in fatty acid oxidation, TMZ leads to 35 mg bid for at least 1 month, with satisfactory increased creatine phosphate/ATP (adenosine clinical effect and good tolerance. Coronary triphosphate) ratio and preservation of heart disease should have been documented by myocardial high-energy phosphate levels and Cardiol Ther (2018) 7:61–70 63 either previous MI (myocardial infarction) or the ethical standards of the institutional and/or previous coronary revascularization national research committee and with the 1964 C 3 months, or angiographic evidence of C 50% Helsinki Declaration and its later amendments narrowing of C 1 major epicardial coronary or comparable ethical standards. Informed artery, or in male patients only documented consent was obtained from all individual par- evidence of myocardial ischemia. The main ticipants included in the study. exclusion criteria were current or previous Parkinsonian symptoms and abnormal renal Statistical Analysis function with estimated creatinine clearance (eCrCl) \60 ml/min. Descriptive statistics were provided by treat- With respect to blinding, a double-dummy ment group (and all groups pooled for study design was used, with placebo tablets matching outcome criteria and adverse events) depending TMZ MR 35-mg tablets and placebo capsules on the nature of the criteria. For quantitative matching TMZ MR 80-mg capsules. The study criteria, the number of observed values, mean, consisted of a run-in period of 2 weeks, during standard deviation, minimum and maximum, which patients received TMZ MR 35 mg bid and median, first and third quartiles were used. For one capsule of placebo twice daily, followed by qualitative criteria, the number of observed a double-blind treatment period of 12 weeks, values, number, and percentage of patients per during which patients were randomized to class were used. receive either (A) one tablet of TMZ MR 35 mg and one capsule of placebo twice daily or (B) one capsule of TMZ MR 80 mg and one RESULTS tablet of placebo in the morning and one cap- sule of placebo and one tablet of placebo in the A total of 180 patients were screened and 177 evening. Randomization was not centralized. were selected for the study. Among them, 165 The treatments were allocated at the inclusion patients (130 in Russia and 35 in Serbia) were visit (week 0) by a balanced (non-adaptive) included and randomly assigned to one of the randomization (ratio 1:1) with stratification by two treatment groups: either the TMZ MR center. 80 mg od group (n = 82 patients) or the TMZ The main objective of the study was to assess MR 35 mg bid group (n = 83 patients). Reasons safety of TMZ MR 80 mg od compared to TMZ for exclusion of selected patients were: non- MR 35 mg bid. compliance with inclusion/non-inclusion crite- All of the 165 patients included in the study ria in nine patients and adverse events in three attended week 0 (W0), week 4 (W4), week 8 patients. No patient was withdrawn from the (W8), and week 12 (W12) visits for safety study, nor lost to follow-up. assessment. Safety evaluation was based on the The main characteristics at baseline are following: (1) adverse events, (2) laboratory summarized in Table 1. The two groups were parameters (biochemical and hematological, well balanced regarding demographic charac- only at inclusion/W0 and W12), (3) vital signs teristics at baseline (64 years old, 69% male, including weight (only at inclusion/W0 and 100% Caucasian) and duration of stable angina W12), supine and standing blood pressure and pectoris (mean duration, 6.3 ± 5.4 years). In pulse rate, (4) 12-lead electrocardiogram, and addition to angina pectoris, the most frequent (5) CCS classification of symptoms of angina medical histories related to CAD (coronary pectoris. artery disease) were myocardial infarction (73%) and unstable angina (15%). Forty-two percent of the patients had previous coronary angio- Compliance with Ethics Guidelines plasty and 26% previous coronary artery bypass. Before the treatment period, all of them were All procedures performed in studies involving receiving specific treatment for angina, mainly human participants were in accordance with beta-blocking agents (88%), calcium channel 64 Cardiol Ther (2018) 7:61–70 Table 1 Main baseline characteristics and therapies in the randomized patients Trimetazidine Trimetazidine All MR 80 mg od MR 35 mg bid (N 5 165) (N 5 82) (N 5 83) Age (years) 63.3 ± 6.9 64.3 ± 8.3 63.8 ± 7.6 Proportion of men 56 (68.3) 57 (68.7) 113 (68.5) Blood pressure SBP (mmHg) 129.7 ± 14.4 132.0 ± 13.7 130.9 ± 14.1 DBP (mmHg) 78.0 ± 7.5 78.7 ± 7.7 78.3 ± 7.6 Heart rate (bpm) 64.7 ± 9.8 63.3 ± 9.4 64.0 ± 9.6 Stable angina pectoris duration (years) 5.8 ± 5.4 6.9 ± 5.3 6.3 ± 5.4 CCS classification Class I 22 (26.8) 14 (16.9) 36 (21.8) Class II 49 (59.8) 63 (75.9) 112 (67.9) Class III 11 (13.4) 6 (7.2) 17 (10.3) Medical history of CAD 82 (100) 83 (100) 165 (100) Myocardial infarction 61 (74.4) 60 (72.3) 121 (73.3) Unstable angina 13 (15.9) 12 (14.5) 25 (15.2) Surgical/medical procedures history 50 (61.0) 53 (63.9) 103 (62.4) Coronary angioplasty 35 (42.7) 35 (42.2) 70 (42.4) Coronary artery bypass 19 (23.2) 24 (28.9) 43 (26.1) Baseline cardiovascular therapies Antithrombotic agents 78 (95.1) 79 (95.2) 157 (95.2) Statins 75 (91.5) 75 (90.4) 150 (90.9) ACEi and ARB 68 (82.9) 76 (91.6) 144 (87.3) CCB 27 (32.9) 29 (34.9) 56 (33.9) BB 74 (92.2) 71 (85.5) 145 (87.9) LAN 27 (32.9) 26 (31.3) 53 (32.1) Data presented are mean (±SD) or n (%) ACEi angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, BB beta-blocker, CAD coronary artery disease, CCB calcium channel blocker, CCS Canadian Cardiovascular Society, DBP diastolic blood pressure, LAN long- acting nitrates, SBP systolic blood pressure, SD standard deviation blockers (34%), and/or long-acting nitrates treatment period with no relevant difference (32%), which was maintained during the study. between groups. They were mainly diuretics Overall, 47.9% of the patients received addi- (20% of the patients) and drugs used in diabetes tional concomitant treatment before the (18% of the patients). No major difference Cardiol Ther (2018) 7:61–70 65 Table 2 Emergent adverse events by system organ classes reported during the treatment period with preferred term when more than a single patient is considered System organ class Trimetazidine Trimetazidine Preferred term MR 80 mg od MR 35 mg bid (N 5 83) (N 5 82) NEAE n % NEAE n % Infections and infestations 6 5 6.1 1 1 1.2 Influenza 2 2 2.4 – – – Investigations 4 4 4.9 5 5 6.0 Hyperbilirubinemia 1 1 1.2 2 2 2.4 Hyperglycemia – – – 4 4 4.8 Cardiac disorders 5 3 3.7 5 5 6.0 Atrial fibrillation – – – 2 2 2.4 Renal and urinary disorders 2 2 2.4 – – – Metabolism and nutrition disorders 2 1 1.2 7 6 7.2 Hepatobiliary disorders 1 1 1.2 2 2 2.4 Respiratory, thoracic, and mediastinal disorders 1 1 1.2 2 1 1.2 Blood and lymphatic system disorders 1 1 1.2 – – – Gastrointestinal disorders 1 1 1.2 – – – Musculoskeletal and connective tissue disorders 1 1 1.2 – – – Injury, poisoning, and procedural complications – – – 1 1 1.2 Nervous system disorders – – – 1 1 1.2 Vascular disorders – – – 1 1 1.2 ALL 24 14 17.1 25 19 22.9 N number of patients by group, NEAE number of emergent adverse events, n number of patients with at least one emergent adverse event, % =(n/N) 9 100 between the two groups was observed regarding (EAE) during the double-blind treatment period blood pressure and heart rate, ECG (electrocar- (Table 2) was slightly lower in the TMZ MR diogram), and laboratory parameters. There was 80-mg group (14 patients, 17.1%) than in the a slightly higher proportion of patients with TMZ MR 35-mg group (19 patients, 22.9%). In class I and class III CCS in the TMZ MR 80-mg the TMZ MR 80-mg group, the most frequently group than in the TMZ MR 35-mg group. No reported EAE (at least two patients) was influ- major changes were reported regarding con- enza (two patients), whereas in the TMZ MR comitant treatments during the study. 35-mg group it was hyperglycemia (four In the Safety Set (which consisted of all the patients), hyperbilirubinemia (two patients), randomized and treated patients, i.e., 165 and atrial fibrillation (two patients). No EAE led patients), the proportion of patients who expe- to dose modification, withdrawal, or temporary rienced at least one emergent adverse event interruption of the study treatments. 66 Cardiol Ther (2018) 7:61–70 Table 3 Emergent serious adverse events reported during the treatment period Preferred term Trimetazidine Trimetazidine MR 80 mg od MR 35 mg bid (N 5 82) (N 5 83) NEAE n % NEAE n % Cardiac failure acute 11 1.2 – – – Myocardial infarction 11 1.2 – – – Ventricular fibrillation 11 1.2 – – – Atrial fibrillation – – – 2 2 2.4 Blood pressure 11 1.2 – – – increased Renal colic 1 1 1.2 – – – Pulmonary edema 11 1.2 – – – Ischemic stroke – – – 1 1 1.2 ALL 6 3 3.7 3 3 3.6 N number of patients by group, NEAE number of emergent adverse events, n number of patients with at least one emergent serious adverse event, % =(n/N) 9 100 These events all occurred in the same patient on the same day and recovered In terms of intensity, most of the EAEs were No clinically significant changes were rated as mild (14 vs. 18 events, in the TMZ MR observed during the study regarding vital signs 80-mg and MR 35-mg group, respectively) or (weight, blood pressure, and pulse rate), ECG, moderate (seven events in each group). Three and laboratory parameters. Based on local lab- patients in each group experienced serious oratory tests, very few biological values reached adverse events (Table 3). None was considered a potentially clinically significant level (PCSA), to be related to treatment and all recovered. each of them affecting only one patient, with In addition, only one event (polyuria, which the exception of high triglycerides in the TMZ recovered fully) in the TMZ MR 80-mg group MR 35-mg group, which affected three patients: was considered to be related to the study treat- • 4 PCSA values in the TMZ MR 80-mg group: ment by the investigator. high GGT, low clearance creatinine, high Most emergent adverse events recovered in triglycerides, and low platelets, both treatment groups: 75.0% of events in the • 6 PCSA values in the TMZ MR 35-mg group: TMZ MR 80-mg group and 56.0% in the TMZ high glucose, low HDL cholesterol, high MR 35-mg group. Events not recovered at the triglycerides, and high white blood cell end of the study were mostly related to chronic count. diseases (i.e., diabetes, dyslipidemia) or were reported at the last visit (W12). None of them DISCUSSION was serious or of severe intensity. There was no study treatment interruption This is the first study to assess the clinical due to lack of efficacy. Regarding CCS classifi- acceptability of TMZ MR 80 mg, a new formu- cation of symptoms of angina, no worsening lation of trimetazidine allowing a single dose was reported with either treatment. daily. Previous pharmacokinetic studies Cardiol Ther (2018) 7:61–70 67 performed with the 80-mg MR formulation prescribed, since many of the patients have (data on file) showed that: multiple comorbidities, such as diabetes melli- • This formulation presents plasma profiles of tus or hypertension. Adherence has been shown an MR once-daily formulation, to be related not only to the number of medi- • This formulation leads to AUC24, C , and cations but also to the number of doses to be max C equivalent to the ones obtained with taken per day [12] and it is inversely related to min the MR 35 mg bid after repeated dosing in the latter [13]. Hence, simplifying a medication fed conditions in healthy volunteers, regimen might be expected to be associated • There is no food effect on pharmacokinetic with improved adherence and so with potential parameters. increased clinical benefits in patients with ang- In the present study, TMZ MR 80 mg once ina. A study showed that converting patients daily compared to TMZ MR 35 mg bid for a with chronic, stable angina to long-acting 12-week treatment period were found to have antianginal medications led to substantial similar safety profiles in patients with docu- improvement in symptom control [10]. mented coronary artery disease and Improved adherence with once-daily treatment stable chronic angina pectoris. Study treatment compared with twice-daily treatment was was given on top of both routine antianginal shown for both beta-blocker and nitrate regi- therapies and secondary prevention therapy. men [9, 11]. Health-related quality of life was Patients were treated with TMZ MR 35 mg bid also improved according to one study [11]. during the run-in period, therefore only a mar- In light of this evidence, the availability of a ginal additional benefit was expected on angina once-daily formulation of TMZ, with similar symptoms during the double-blind treatment safety to the twice-daily formulation, could period. According to the summary of product offer an opportunity for improving patient characteristics and minimization measure adherence to treatment. implemented to reduce the risk of overexposure to TMZ in patients with renal insufficiency, Study Limitations patients with moderate-to-severe renal impair- ment (creatinine clearance below 60 ml/min Despite its randomized, double-blind design, during the run-in period) were excluded, since the study has limitations related to the small no adaptation of the dose could be done with size of the patient population (n = 165 patients) the capsules containing 80 mg of TMZ. and to the protocol selection criteria. TMZ is a well-established therapy for angina control, with a mechanism of action that is distinct from that of other antianginal agents, CONCLUSIONS as it acts directly at the level of myocardial cells. Since it is devoid of any major hemodynamic TMZ MR 80 mg od was shown to have a similar properties, it can be combined with other clas- safety profile to TMZ MR 35 mg bid. This once- ses of antianginal therapy. The MR 80-mg for- daily formulation could possibly help increase mulation taken od simplifies the treatment treatment adherence and thus lead to clinical regimen and would thereby be expected to benefit in real life. improve adherence to treatment in real-life settings. Non-adherence to treatment is known to be ACKNOWLEDGEMENTS a problem in asymptomatic diseases, with the notable example of hypertension, but can also The author would like to thank the investiga- concern symptomatic diseases, and has been tors of the study. reported in patients with stable angina treated Arkhangelsk: Uskov V.L. Barnaul: Gon-char- with symptom-releasing nitrates [9]. Amongst enko I.I., Prasolova T.P. Belgorod: Guseva V.G., patients with angina, adherence could be Shinkar A.S. Bryansk: Samsonova S.M. Veliky hampered by the total number of medications 68 Cardiol Ther (2018) 7:61–70 Novgorod: Vikhrova I.V., Kuz’kina S.A. Vladi- Guryanova I.R., Zheltova V.L. Rostov-on-Don: mir: Mitina L.V., Timofeeva I.V. Vol-gograd: Bulygina E.D., Gorskaya E.V., Kosenko L.V., Archakova T.M., Kovaleva N.Y., Romanova E.A., Musaeva F.K., Fedorchenko M.Y., Harish V.I. Tivon Y.V. Vologda: Antonova Y.N., Kurganova Ryazan Region: Serbarinova O.M. Ryazan: Yat- O.B. Voronezh: Davydova N.N., Klyuchantseva senya Y.A. Sa-mara: Golubev M.N., Kopaev D.E., O.V., Popovskaya Y.V., Kharitonova E.I. Evpa- Miludina L.A., Polischuk L.V., Shilintseva O.A., toria: Kuzmina T.N. Ekaterinburg: Buzmakova Krylova, L.M. St. Petersburg: Vasilik M.V., Zotov K.V., Kaplenko L.I., Pospelova N.V., Stepanova D.D., Kalishevich N.B., Kachmazova L.I., Kon- A.Y. Ivanovo: Kol-basheva N.A. Irkutsk: Kras- torikova S.G., Mamoshko T.A., Osnovin S.A., nova G.M., Pal’vin-skaya A.Y., Toloknova V.A. Timosh-enko (Schmalz) I.O., Kashina A.N., Kir- Kazan: Bikmullina R.F., Gainullina A.A., yanova O.G. Saratov: Kotova L.E., Kuvshinova Kedrina E.V., Mikhailova S.A., Nabiullina T.A., L.E., Ulyanova I.M., Shevelo O.F. Simferopol: Nizamova A.F. Kaluga: Uskova A.A., Yushkova Kir-eeva I.B., Korohova L.V., Smolensk: Lisu- A.E. Kemerovo: Andreeva O.V., Fedotova G.V. nova T.I., Medvedeva E.V. Stavropol: Matvienko Kirov: Besser-geneva O.L., Gavrilyuk D.D., T.E., Shovgaryan S.L. Stary Oskol: Nebolsina T.F. Ehalo N.V., Zlo-bina M.V. Krasnodar: Zhemart- Syktyvkar: Mikusheva M.A., Misharin N.N. Tver seva E.Y., Markushina I.A., Pavlovets V.P., Region: Kutaliya T.O. Tolyatti: Chernova V.N., Sobolenko A.A. Krasnoyarsk: Apanovich I.E., Yanina Y.A. Tomsk: Permyakova O.V., Skur- Kireeva N.V., Maksimova I.V. Kursk: Butz T.V., ikhina N.N. Tula: Goldinova L.M., Pri-khodko Pavlova I.A. Lipetsk: Bachurina S.N., Orly- T.N. Tyumen: Myshyakova A.G. Ufa: Akhmer- achenko S.V. LR Sertolovo: Zaitseva T.V., LR ova E.Z., Zaitseva K.V., Ozerchuk A.A., Poly- Lomonosov: Beznogova V.F. LR-South: Litsis akova I.M., Rodionova, Safiullina I.D. N.N., Novozhenina A.Y. Moscow: Abramyan Cheboksary: Arsentieva I.N., Volkova O.O. L.L., Adamyan M.M., Askerko S.N., Bolmosov Chelyabinsk: Kondrina I.N., Kharlova T.E. Yalta: A.N., Vasilieva I.N., Volodova S.I., Grishko P.V., Grigorieva T.L. Yaroslavl: Kurtmulaeva K.V., Zherebetskaya E.S., Zemlyanaya N.S., Klysh- Rogozina O.M. nikova L.N., Kononchik E.I., Kuznetsova N.A., Kuz’minova I.A., Marmurova I.V., Mikhailova Funding. Sponsorship for this study was R.Y., Mordovina I.P., Nazarkina O.V., Per- provided by the Institut de Recherches Inter- epechko A.P., Pivovarova N.G., Potapova T.P., nationales Servier and Servier, Moscow, Russian Prokofiev D.A., Proniushkina N.E., Savelieva Federation. Article processing charges for this E.V., Semovskikh N.A, Timonenkova L.D., study were funded by Servier. All authors had Fomin V.V., Furman O.A., Tsutsieva R.M., full access to all of the data in this study and Chibrikina M.V., Shoshina I.N., Yashchenko.P. take complete responsibility for the integrity of Moscow region: Bocharova T.I., Demya-nenko the data and accuracy of the data analysis. O.L., Zhukova L.B., Melnikov A.Y., Mer-kulieva I.A., Tyasina E.I., Pakholkova N.S., Rogozina Medical Writing. Writing assistance was S.V., Chugunova I.V. Murmansk: Brazhnik M.L., provided by Diana Toli, PhD (Servier). Writing Guseva Y.V. Naberezhnye Chelny: Anisimova assistance was funded by Servier. A.N., Kuzeyina S.S., Kulakhmetova R.G., Petrova I.S. Nizhny Nov-gorod: Ignatyeva I.A., Moro- Authorship. All named authors meet the International Committee of Medical Journal zova T.A., Ryb-nikova N.V., Gritsenko I.I. Novokuznetsk: Kondratskaya O.V., Shishkin Editors (ICMJE) criteria for authorship for this A.V. Novosibirsk: Gogleva N.N., Kulipanova manuscript, take responsibility for the integrity V.M., Mitrofanova S.V., Parada E.V., Svistunova of the work as a whole and have given final S.Y., Sergeeva T.M. Omsk: Kryukova V.V., approval for the version to be published. Suprun T.N., Fedorova E.M., Shnor O.F. Orel: Authorship Contributions. The author Mitroshina T.N., Shemetova T.S., Orenburg: would like to thank all participating investiga- Val’kevich L.P., Varnikova S.N. Penza: Ivanova tors for their contribution to the study. E.A. Perm: Shlykova O.N. Pyatigorsk: Cardiol Ther (2018) 7:61–70 69 analysis for the Global Burden of Disease Study Prior Presentation. The data presented in 2010. Lancet. 2012;380:2163–96. this manuscript were previously presented in 2016 at the 38th Congress of the European 2. Beltrame JF, Weekes AJ, Morgan C, Tavella R, Society of Cardiology (ESC) as a poster entitled: Spertus JA. The prevalence of weekly angina among patients with chronic stable angina in primary care Clinical acceptability of trimetazidine 80 mg practices: the Coronary Artery Disease in General once daily versus trimetazidine modified-release Practice (CADENCE) Study. Arch Intern Med. 35 mg twice daily in chronic stable angina 2009;169:1491–9. pectoris. Eur Heart J 2016 Vol. 37 (suppl. 1): 388 3. Kureshi F, Shafiq A, Arnold SV, et al. The prevalence (P1857). Y. Pozdnyakov. Moscow Regional Car- and management of angina among patients with diology Center, Cardiology, Zhukovsky, Russian chronic coronary artery disease across US outpa- Federation. tient cardiology practices: insights from the Angina Prevalence and Provider Evaluation of Angina Relief Disclosures. Yuri M. Pozdnyakov, scientific (APPEAR) study. Clin Cardiol. 2017;40:6–10. coordinator of this study, received grants and 4. Qintar M, Spertus JA, Gosch KL, et al. Effect of honoraria for conducting research and hono- angina under-recognition on treatment in outpa- raria for lectures from Servier, Moscow, Russian tients with stable ischaemic heart disease. Eur Heart Federation. J Qual Care Clin Outcomes. 2016;2:208–14. 5. Arnold SV, Morrow DA, Lei Y, et al. Economic Compliance with Ethics Guidelines. All impact of angina after an acute coronary syndrome: procedures performed in studies involving insights from the MERLIN-TIMI 36 trial. Circ Car- human participants were in accordance with diovasc Qual Outcomes. 2009;2:344–53. the ethical standards of the institutional and/or 6. Montalescot G, Sechtem U, Achenbach S, et al. national research committee and with the 1964 2013 ESC guidelines on the management of Helsinki Declaration and its later amendments stable coronary artery disease: the Task Force on the or comparable ethical standards. Informed management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. consent was obtained from all individual par- 2013;34:2949–3003. ticipants included in the study. 7. Fragasso G, Perseghin G, De Cobelli F, et al. Effects Data Availability. The datasets analyzed of metabolic modulation by trimetazidine on left during the current study are available from the ventricular function and phosphocreatine/adeno- sine triphosphate ratio in patients with heart fail- corresponding author on reasonable request. ure. Eur Heart J. 2006;27:942–8. Open Access. This article is distributed 8. Danchin N, Marzilli M, Parkhomenko A, Ribeiro JP. under the terms of the Creative Commons Efficacy comparison of trimetazidine with thera- Attribution-NonCommercial 4.0 International peutic alternatives in stable angina pectoris: a net- work meta-analysis. Cardiology. 2011;120:59–72. License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits any non- 9. Kardas P, On behalf of COMPASS investigators. commercial use, distribution, and reproduction Comparison of once daily versus twice daily oral in any medium, provided you give appropriate nitrates in stable angina pectoris. Am J Cardiol. 2004;94:213–6. credit to the original author(s) and the source, provide a link to the Creative Commons license, 10. Spertus JA, Dewhurst T, Dougherty CM, Nichol P. and indicate if changes were made. Testing the effectiveness of converting patients to long-acting antianginal medications: the Quality of Life in Angina Research Trial (QUART). Am Heart J. 2001;141:550–8. REFERENCES 11. Kardas P. Compliance, clinical outcome, and qual- ity of life of patients with stable angina pectoris receiving once-daily betaxolol versus twice daily 1. Vos T, Flaxman AD, Naghavi M, et al. Years lived metoprolol: a randomized controlled trial. Vasc with disability (YLDs) for 1160 sequelae of 289 Health Risk Manag. 2007;3:235–42. diseases and injuries 1990–2010: a systematic 70 Cardiol Ther (2018) 7:61–70 12. Cramer JA. Effect of partial compliance on cardio- 13. Claxton AJ, Cramer J, Pierce C. A systematic review of vascular medication effectiveness. Heart. the associations between dose regimens and medi- 2002;88:203–6. cation compliance. Clin Ther. 2001;23:1296–310.

Journal

Cardiology and TherapySpringer Journals

Published: May 19, 2018

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