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International Heart and Vascular Disease Journal • Volume 9, № 31, September 2021
Journal of the Cardioprogress Foundation
ORIGINAL ARTICLES
Early prescription of trimetazidine
in patients with acute coronary syndrome after incomplete myocardial revascularization: the assessment of the prognosis
1 Volgograd Clinical Cardiology Center, Volgograd, Russia.
2 Volgograd State Medical University of the Ministry of Healthcare of the Russian Federation, Volgograd, Russia.
Authors
Roman L. Shamraev*, M.D., Ph.D., researcher of the Department of Cardiology of the Volgograd Clinical Cardiology Center, Volgograd, Russia.
Oleg V. Ilyukhin, M.D., Ph.D., researcher of the Department of Cardiology of the Volgograd State Medical University of the Ministry of Healthcare of the Russian Federation, Volgograd, Russia. Vitaly V. Ivanenko, M.D., Ph.D., chief cardiologist of the Regional Health Committee of the Volgograd Region, chief physician of the Volgograd Clinical Cardiology Center, Volgograd, Russia.
Albert K. Prom, M.D., Ph.D., head of the Department of Functional Diagnostics of the Volgograd Clinical Cardiology Center, Volgograd, Russia.
Objective. To assess the effectiveness of the early prescription of trimetazidine in patients with acute coronary syndrome (ACS) and established muttivesset coronary artery disease syndrome after incomplete myocardial revascularization.
Materials and methods. This open-tabet randomized study included 100 patients with muttivesset coronary artery disease syndrome. The randomization was btind into two equat groups: the study group (received 70 mg/day trimetazidine during the entire observation period) and the controt group (did not receive trimetazidine). Echocardiography (EchoCG) was performed according to generatty accepted technique on the ACUSON 128XP 10 apparatus (USA) with the study of the fottowing characteristics: teft atrium and right ventricte anterior-posterior diameter, end-systotic and end-diastotic diameter of the teft ventricte (LV), interventricutar septat thickness, teft ventricutar (LV) posterior
Shamraev R.L.1, Ilyukhin O.V.2, Ivanenko V.V.12, Prom A.K.
2
Abstract
* Corresponding author. Tel. +7 960 871 12 30. E-mail: vip-hunter@mail.ru
wall thickness, end-systolic and end-diastotic volumes, as well as LV ejection fraction (EF) according to the Simpson method.
Results. According to the results of EchoCG, mean LV EF was 50.72±6.89 % in the modified-release trimetazidine (trimetazidine- MR) group and 52.69± 7.5%% in the comparison group. In addition, significant changes in the Echo CG linear dimensions were diagnosed, and in 100 % of cases there were LV diastolic dysfunction of varying severity. Patients with ACS with early prescription of trimetazidine, required significantly fewer repeat myocardial revascularizations. According to statistical analysis, the Kaplan — Meier curves significantly diverged at the 12th month of study. Thus, the survival coefficient in actively treated patients was 0.72, and 0.54 — in the control group, the differences between groups were 18 % in favor of the trimetazidine-MR use.
Conclusion. Early prescription of trimetazidine-MR in patients with ACS and incomplete myocardial revascularization is associated with the decrease of cardiovascular complications during the first year of treatment, which should be considered as an important component of rehabilitation after endovascular intervention. Keywords: trimetazidine-MR, acute coronary syndrome, incomplete myocardial revascularization.
Conflict of interest: None declared. Received: 25.02.2021 Introduction
Today cardiovascular complications (CVCs) are the main causes of death according to the statistics of the most countries including Russian Federation. Coronary heart disease (CHD) and many other atherosclerotic complications are still the leading causes of death and disability. Surgical treatment of coronary revascularization can improve the survival rate of patients with CHD and today are the primary treatment choice for patients with this pathology [1]. However, despite the improvement of the technology of invasive cardiology, there are still several unresolved issues in clinical practice, including the so-called incomplete revascularization. This approach is commonly observed in patients with acute coronary syndrome (ACS) and multivessel coronary artery disease, at the early stages of its onset, and is associated with the resumption of blood flow in the target artery. This type of revascularization has a number of advantages, but also has significant number of disadvantages, therefore, it has both supporters and opponents. The controversy about the effectiveness or ineffectiveness of incomplete revascularization can continue indefinitely, which will not make it easier for the clinical practitioners who will receive such patients for further treatment. Currently, these patients receive standard therapy, often independent of the degree of restoration of coronary blood flow. However, it should be noted that in this case, even in patients with pronounced positive clinical effect, areas of ischemic myocardial tissue still remain, therefore, additional pathogenetic medications should be considered. Pharmacological
Accepted: 08.06.2021
therapy prescribed for patients with CHD primary include symptomatic agents. For example, "metabolic" antianginal medication, the modified-release (MR) formulation of trimetazidine, that has been used for a long time in the complex therapy of CHD and showed its effectiveness [2]. Moreover, in recent years, the effect of trimetazidine-MR on cumulative survival rate and quality of life in patients with CHD has become the subject of separate study [3]. Therefore, studies evaluating the prognostic value of this medication in patients with CHD seem to be very relevant.
Objective
To assess the effectiveness of the early prescription of trimetazidine in patients with ACS, established multivessel coronary artery disease and incomplete revascularization.
Materials and methods
The study was conducted in accordance with Good Clinical Practice standards and Declaration of Helsinki principles. The study protocol was approved by the Ethics Committees of all participating clinical centers. Written informed consent was waived from all participants prior to the inclusion into the study.
This open randomized study included 100 patients with multivessel CHD that was defined as at least one hemodynamically significant stenosis (over 50 % in diameter) in at least two main arteries (anterior in-terventricular artery (AIA), right coronary artery, circumflex artery (CA) in patients with the right type of coronary circulation or AIA and CA — in patients with
the left type) and / or the presence of over 50 % stenosis of the main trunk of the left coronary artery. In all cases, ACS was identified, confirmed by the clinical picture, ECG data and/or significant increase of specific cardiac enzymes. Patients were divided into groups after percutaneous transluminal angioplasty (PTA) and stenting at least in 24 hours after the manifestation of symptoms.
The exclusion criteria were: the presence of concomitant diseases that could affect the final results, including decompensation of diabetes mellitus (DM), uncontrolled arterial hypertension (AH), kidney and liver diseases accompanied by the impaired function of these organs. The exclusion criterion was any planned surgical intervention (primarily cardiac surgery) within 4-6 months after the onset of ACS symptoms. The inclusion criterion was optimal pharmacological treatment.
Randomization was performed in blind manner into two equal groups: the study group (received 70 mg/day trimetazidine during the entire observation period) and the control group (did not receive trimetazidine). The follow-up period was 365 days. The clinical characteristics of the patients are presented in Table 1.
EchoCG was performed according to the generally accepted technique on the ACUSON 128 XP 10 apparatus (USA) and assessed the following parameters: anteroposterior dimension of the left atrium, right ventricle, end-systolic and end-diastolic dimensions of the left ventricle (LV), interventricular septal thickness, LV posterior wall, end-systolic and end-diastolic volumes and left ventricular ejection fraction (LV EF) according to Simpson's method.
Statistical analysis was performed using STATISTICA v.10.0, MS Excel 7.0 software. The normally distributed data were presented as M±m, where M is the mean, m is the standard error, the x2 criterion was used to assess the differences between the frequency of certain categorial variables between groups. The probability of adverse event was investigated using the Kaplan-Meier method; the differences between groups were assessed using the LogRank test, Breslow, and Taron-Ware tests. The following parameters were assessed in the long-term period: CVC frequency, death, myocardial infarction (MI), repeated interventions. The method of four-field table for case-control studies by Mantel — Haenzel was used to calculate the relative risk coefficient and 95 % confidence interval (CI).
Results
All study participants were divided into equal groups, 50 of them received 35 mg of trimetazidine-MR 2 times a day; 50 patients were included into the control group. The average age of patients from group 1 was 59.54±7.47 years, from group 2-60.36±7.05 years (p>0.05). The groups did not differ significantly by the main clinical data, including morphofunctional cardiac parameters (Tables 1, 2). According to the results of EchoCG, average LV EF was 50.72±6.89 0% in the trimetazidine-MR group and 52.69±7.5 in the comparison group. In addition, significant difference in the linear dimensions of the heart chambers were detected, and all the patients had LV diastolic dysfunction of various severity.
The groups included patients with unstable angina and acute myocardial infarction (AMI) with and with-
Table 2. The main clinical and instrumental parameters of patients with ACS included into the study
Table 1. Initial clinical characteristics of the studied groups
Parameter Trimetazidine, n=50 Control, n=50 P
Age 59.32±7.71 59.84±7.3 0.896
The duration of CHD, years 3.2±1.6 2.9± 1.9 0.224
Body mass index (kg/m2) 23.7±2.2 22.9±2.5 0.894
Female gender 17 34 % 15 30 % 0.668
Male gender 43 86 % LO 90 % 0.538
The history of MI 8 16 % 7 14 % 0.701
The history of AH 23 46 % 27 54 % 0.322
Diabetes mellitus 4 8 % 5 10 % 0.175
Smoking 11 22 % 10 10 % 0.788
Statins 18 36 % 23 46 % 0.118
Aspirin 31 62 % 34 68 % 0, 554
ACE inhibitors 22 44 % 24 48 % 0.721
Calcium antagonists 11 22 % 13 26 % 0.483
Parameter Trimetazidine, n=50 Control, n=50 X2 p
SBP (mmHg) 138.6± 7.4 141.7± 8.3 0.076 0.775
DBP (mmHg) 78.3± 9.0 77.4± 7.8 69 0.813
Average BP (mmHg) 104.5± 3.4 106.0± 2.7 0.048 0.917
HR (beats/min) 72.2± 4.9 76.1 ± 3.8 0.376 0.527
LV EF (%) 50.72± 6.89 52.69± 7.5 0.048 0.911
Unstable angina 11 22 % 10 20 % 0.060 0.806
Acute MI with ST-segment elevation 30 60 % 29 58 % 0.041 0.839
Acute MI without ST-segment elevation 9 18 % 11 22 % 0.250 0.617
Anterior MI 18 46.2 % 20 50 % 0.328 0.511
Posterior MI 21 53.9 % 20 50 % 0.367 0.532
Table 3. The severity of CHD in study participants
Parameter Trimetazidine-MR, n=50 Control, n=50 X2 P
Killip class I acute heart failure 32 64 % 30 60 % 0.170 0.680
Killip class II acute heart failure 7 14 % 10 20 % 0.638 0.424
Killip class III-IV acute heart failure 0 0 % 0 0 % - -
Hemodynamically significant stenoses (LCA trunk>50 %, other arteries>75%) of two vessels 26 52 % 20 40 % 1.449 0.229
Hemodynamically significant stenoses (LCA trunk>50 %, other arteries>75%) of three vessels 13 26 % 18 36 % 1.169 0.280
Hemodynamically significant stenoses (LCA trunk>50 %, other arteries>75%) of more than three vessels 11 22 % 12 24 % 0.056 0.812
out ST-segment elevation. The groups were comparable by the frequency the pathology, and its severity. Acute heart failure (AHF) severity class 1 prevailed in patients with AMI, which was diagnosed in over 60 % of patients in each group; the rest of the patients had AHF severity class II. LV EF in group I: min. — 28 %o, max. — 70 %, average — 50.72± 6.89 %. EF in group II: min. — 30 %, max. — 79 %, average — 53.62±7.51 %. According to coronary angiogram (CAG) data, hemo-dynamically significant stenoses (left coronary artery trunk> 50 %, other arteries>75 %) of two vessels were detected in most patients (Table 3).
Initially, 50 PTA with stenting and incomplete revascularization (mainly target coronary artery) were performed in both groups. During 1-year follow-up CAG was additionally required in 8 patients from in group I (16 %), in 18 (36 %) from group II (x2=5.19, p= 0.023). PTA was performed in 6 (12 %) patients from the main group and in 15 (30 %) —f rom the control group (x2= 4.88; p=0.027). As the result, patients with ACS with early prescription of trimetazidine, required significantly fewer repeat myocardial revascularizations. The use of sirolimus-eluting stents was comparable in both groups — in group I they were used in 3 (5.36 %) patients out of 56 (100 %), in group II — in 5 (7.69 %) out of 68 (100 %) (x2= 0.203, p= 0.653).
The surgical intervention with complete myocardial revascularization including coronary artery bypass grafting with cardiopulmonary bypass machine was required in 8 (16%) patients from the main group and in 7 (14%) patients from the control group (%2 = 0.460, p = 0.498). Repeated hospital admissions due
Trimetazidine-MR Control
57 r"^
Figure 1. The dynamics of LV EF in study participants
to CHD decompensation were required in 9 (18%) patients from the main group, and in 21 (42%) patients from the control group (%2 = 3.673, p = 0.055). During the 12-month follow-up period, the LV EF increased in both groups, mostly in patients receiving trimeta-zidine (2.9% and 1.5%), but without statistically significant difference (Figure 1). The survival rate during admission was 100% in both groups. The incidence of MI also did not differ between groups - 6 (12%) patients from the main group and 11 (22%) - from the control group (x2 = 1.772, p = 0.183).
During the 12-month follow-up, we assessed the survival rate of patients after ACS without adverse events. The analysis was carried out by the Kaplan — Meier method. The observation period was set as the period from the beginning to the end of the follow-up or until the endpoint for each individual patient. The endpoints were: all-cause death, nonfatal MI, acute cerebrovascular accident, decompensation of angina pectoris, the need for cardiac surgery, any admission due to CVD.
According to statistical analysis, the Kaplan — Meier curves significantly diverged at the 12th month of observation. Thus, the coefficient of survival in patients during active treatment was 0.72, and in the control group — 0.54, the difference between the groups was 18 % with the superiority of trimetazidine-MR group (Fig. 2). The probability of error was assessed by the Log-Rank test p= 0.048, with RR — 0.61; 95 % CI 0.360.98 (p<0.05). Therefore, in our study, there was significantly lower frequency of CVC in patients with ACS who were administered with "metabolic" antianginal medication after PTA and stenting with incomplete revascularization.
Figure 2. The probability of no adverse
Discussion
Anti-ischemic agent used in myocardial protection trimetazidine has been successfully used for a long time. Its high efficiency has been proven, but it is usually used as additional tool to enhance basic pharmacotherapy [4]. According to Russian guidelines for the diagnosis and treatment of stable CHD, trimeta-zidine-MR can be used at any stage of treatment to enhance the antianginal efficacy of hemodynamically active medications, as well as an alternative in case of their intolerance or the presence of contraindications for their use. Thus, the additional prescription of trimetazidine-MR to p-blockers leads to significantly more pronounced antianginal effect compared with the additional prescription of long-acting nitrate. Trimetazidin-MR increases the coronary flow reserve, prevents the consequences of ischemia, reduces the frequency of angina episodes, improves myocardial contractility and increases exercise tolerance in patients with CHD [5, 6]. The mechanism of trimetazidine-MR anti-ischemic effect is associated with the increase of glucose metabolism compared with the metabolism of fatty acids, with the suppression of fatty acid B-oxidation and the increase of pyruvate oxidation — a glucose metabolite during the ischemia, and, therefore, it maintains of the required level of adenosine triphosphate in cardiomyocytes, decreases intracellular acidosis and excessive accumulation of calcium ions [7].
The use of trimetazidine in patients with ACS is being actively investigated. It is known that this medication can limit cardiac reperfusion injury and, accordingly, reduce myocardial hibernation processes, as well as the frequency of reperfusion arrhythmias [8].
cardiovascular events in the study
In addition, the preventive use of this cytoprotector reduces the manifestations of transmural ischemia that develops during PTA, and can minimize ECG signs of reperfusion injury[9] and its severity, assessed by the levels of cardiac-specific biomarkers after coronary artery bypass graft surgery, and, therefore, positively affects the prognosis [10].
According to the " Consensus on the role and place of the myocardial cytoprotector Trimetazidine in the treatment of patients with chronic forms of CHD" [11], the use of this antianginal agent before surgical interventions (coronary artery bypass graft surgery, percutaneous coronary intervention) reduces the severity of myocardial injury, that is confirmed by the significant decrease of cardiac-specific biomarkers in the blood and the frequency of perioperative cardiac arrhythmias. Long-term therapy with trimetazidine after surgery has positive effect on the frequency of angina episodes and admissions due to ACS, significantly reduces the severity of myocardial ischemia, including silent myocardial ischemia, the rate of coronary artery restenosis, increases exercise tolerance, quality of life and, consequently, affects the survival rate of patients [12, 13].
Trimetazidine is the most studied "metabolic" antianginal medication. Several clinical studies have revealed the significant range its therapeutic mechanisms of action that are not limited only by its effect on cardiomyocytes. To this date, it is known that trimetazidine inhibits LV remodeling by the reduction of oxidative stress, apoptosis and inflammation, and affects the expression of endothelial nitric oxide synthase. It has been shown that trimetazidine can reduce inflammation in the arterial intima. At least two
clinical studies have shown the significant decrease of the serum C-reactive protein concentration during the therapy with this myocardial cytoprotector [14, 15].
Recently, very successful attempts have been made to study the effect of trimetazidine on the elastic properties of the large arteries. The preclinical trials have demonstrated positive effect of trimeta-zidine-MR on vascular endothelial cells in patients with arterial hypertension, including refractory hypertension, that reduces the severity of endothelial dysfunction. It has been shown that this effect is associated with intracellular signaling pathways, the intracellular calcium ions in particular, the activity of mitogen-activated protein kinases, the decrease of intracellular concentration of free radicals and the increase of the production of vascular endothelial growth factor [16]. Previously, we found that the use of 70 mg / day trimetazidine-MR for 4 months led to significant improvement of endothelium-dependent reactivity in the radial artery by over 32 %, compared with the initial parameters. Improvement of the endothelial function developed along with the increase of the myocardial metabolic equivalent of oxygen uptake and the increase of exercise tolerance [17, 18].
The evaluation of the effect of metabolic antianginal therapy on the survival rate and quality of life in patients with cardiac pathology has been performed in number of studies. It should be noted that only one medication from this group, trimetazidine, has an impressive evidence base on its impact on cumulative survival. The METRO study showed that the early prescription of trimetazidine as antianginal therapy in patients with stable angina pectoris (before the development of myocardial infarction) significantly reduces the 6-month risk of death from ACS by 64 %o compared with other antianginal agents [19]. The KAMIR study included approximately 10 thousand patients with stable CHD with the history of myocardial infarction, and showed that the additional prescription of trimetazidine-MR to basic therapy during one-year follow-up increased survival rate by 69 %o, due to the decrease of cardiovascular events and mortality [2]. P. Di Napoliet al., according to 2-year follow-up, noted the increase of cumulative survival in patients with ischemic cardiomyopathy after the additional prescription of this myocardial cytoprotector to traditional therapy [3].
According to the results of the meta-analysis by D. Gao et al., that analyzed results of 4 studies, trimetazidine therapy was associated with lower mortality compared with placebo (7.5 % of patients versus 27.5 %, respectively). The reduction in the risk of death due to chronic heart failure was 0.29 with 95 % CI 0.17-0.49 (p<0.01). Cardiovascular events and admissions significantly decreased — RR in the trimetazidine group was 0.42 with 95 % CI 0.30-0.58 (p<0.01) [20]. Previously, we estimated the 6-year survival rate of patients with CHD and heart failure (LV EF less than 40 %). The main endpoint in the active treatment group decreased by 15 % (p= 0.044) with the 0.51 RR and 95 % CI of 0.25-0.92 (p<0.05). The combined endpoint, that included all-cause mortality, the occurrence of nonfatal MI and stroke during entire observation period, decreased by 15.5 % (p= 0.025) with RR 0.61 and 95 % CI 0.97-0.35 (p<0.05) [4].
In this study we investigated the effect of early administration of the myocardial cytoprotector trimeta-zidine-MR in patients with ACS and incomplete revascularization after PTA and stenting. Currently, this method of blood flow partial restoration is used due to the number of reasons, including technical difficulties with complete revascularization (distal stenosis, the presence of extended occlusions, multivessel lesions in patients with ACS, etc.). Today, there are no clear recommendations for the management of patients after incomplete revascularization; in most cases, standard therapy is recommended after PTA and stenting that initially implies complete restoration of the blood flow. It should be noted that our study included patients with persistent myocardial ischemia. The additional prescription of trimetazidine to standard therapy led to the significant decrease of absolute risk of CVC by 18 %.
Conclusion
Thus, early prescription of trimetazidine-MR in patients with ACS and incomplete revascularization is associated with the decrease of CVC during the first year of treatment, which should be considered as an important component of rehabilitation after endovas-cular intervention.
Conflict of interest: None declared.
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