Vasyl Zakharovych NETIAZHENKO
Editor-in-Chief, Associate Member of the AMS of Ukraine, MD, Head of the Internal Medicine Propedeutics Department No. 1 at O.O. Bohomolets National Medical University, Honored Science and Technology Worker of Ukraine
T.I. MALCHEVSKA, H.I. MISHANYCH, T.D. ZALEVSKA, A.H. MASHKEVYCH
O.O. Bohomolets National Medical University, Kyiv
Abstract. A positive effect of metabolic therapy as part of combination therapy in patients diagnosed with CHD: class II or III stable angina was demonstrated by a significant improvement in the patients’ quality of life and increased tolerance to physical exercise.
Key words: coronary heart disease, stable angina, metabolic therapy, Thiotriazolin.
The treatment of coronary heart disease (CHD) has long been addressed from the perspective of cardiac hemodynamics improvement. It is known that the pathogenetically targeted action of conventional medicines is aimed at reducing the myocardial oxygen demand or increasing the oxygen supply to heart muscle cells. Medicinal products that influence the hemodynamic parameters are effective in preventing angina attacks but provide virtually no protection against ischemic changes to the myocardial cells.
That is why, pharmacologists, pharmacists and clinicians have focused their research in the past decades on the synthesis, development and practical implementation of cardioprotective drugs which effectively correct impaired cell metabolism and ion homeostasis and restore cardiomyocyte membrane functions preventing the development of irreversible processes in the myocardium. Nowadays, metabolic therapy has rightfully taken its leading place among the treatment plans for cardiovascular disease and has been included in the international guidelines [1-4].
Emergence of the metabolic approach to the treatment of CHD is traditionally associated with the glucose-insulin-potassium (GIP) solution first used in a non-randomized clinical trial by D. Sodi-Pallaris et al. in 1962 and shown to have a positive effect on ECG changes in acute myocardial infarction and improve early survival. Further studies have demonstrated that GIP, as well as nicotinic acid, reduces free fatty acids (FFAs) release from adipocytes, which, in turn, promotes the reduction of FFA concentration in the ischemic myocardial area. These findings allowed to conclude that a marked activation of glucose oxidation can be achieved by blocking the oxidation of FFAs. This pharmacological approach has become the most common in the metabolic therapy of CHD and stable angina. That is why, improved efficiency of myocardial oxygen uptake in the ischemic conditions is considered to be the best effect of metabolic therapy [7, 14, 16, 18].
The range of medicinal products with known metabolic effects is growing every year. Metabolically active drugs are widely used in the medical practice, the most recognized of them being trimetazidine, ranolazine, Thiotriazolin, L-carnitine, Mildronate, Mexicor, quercetin and Cardonat in cardiology, and Actovegin, Mexidol, Nootropil, Instenon and Thiocetam in neurology, which intrinsically show the highest affinity for the myocardium or neural tissue. Most of these drugs have passed comparative studies and their clinical efficacy has been confirmed. Positive characteristics of metabolic drugs include a total absence of adverse hemodynamic effects, good tolerability in all age groups and targeted effects on the underlying metabolic mechanisms of ischemia development and heart cell protection. Efficient production and use of energy is a key moment in the development of heart disease, and metabolically targeted agents increase tissue tolerance to hypoxia and reperfusion consequences. Metabolic therapy has recently become one of the directions in the treatment of coronary heart failure [5, 6].
The conclusive evidence of myocardial pharmacological protection provided by metabolic therapy in ischemia-reperfusion syndrome has been reflected in the Guidelines of the European Cardiology Society (ECS) on the Management of Stable Angina Pectoris, 2006. In particular, the ECS recommended using metabolic agents (trimetazidine, ranolazine) where available as add-on therapy, or as substitution therapy when conventional drugs are not tolerated (class IIb recommendation), to improve the symptoms and reduce the manifestations of ischemia.
The ischemia and reperfusion syndromes frequently accompanying atherosclerotic coronary heart disease and myocardial ischemia per se are characterized by inadequate oxygen supply to the tissues, depletion of ATP and creatine phosphate stores in cardiomyocytes, switching from aerobic to anaerobic glycolysis pathways, exacerbation of intracellular acidosis, ion pump dysfunction, increased cytoplasmic levels of sodium and calcium and reduced cytoplasmic potassium in cardiomyocytes. Unbalanced redox processes in mitochondria lead to unlimited formation of free radicals and other aggressive factors, not only causing damage to cardiomyocyte membrane, but also initiating apoptosis [7, 14, 15, 17, 18]. A non-exhaustive list of multiple ischemic manifestations includes microcirculatory disorders, activation of the mononuclear phagocyte system, T-lymphocytes and leukocytes, and structural damage to the left ventricle.
Considering the versatility of pathogenetic mechanisms for the development and progression of coronary heart disease as the most prevalent heart condition and the wide range of myocardial protection mechanisms, the classification of medicinal products with cardioprotective effects is somewhat tentative. The two groups of commonly used drugs with cardioprotective effects comprise the direct-acting drugs which directly reduce the impact of pathogenic factors on cardiomyocytes and the indirect-acting drugs which alleviate the load on the myocardium. The effect of direct cardioprotective drugs is attributable to their immediate local action on cardiomyocytes, cell membrane stabilization, dilation of the coronary vessels and central effect on the neural centers controlling vasomotor tone [7]. One of the direct-acting cardioprotective drugs is Thiotriazolin, a domestic medicinal product with classical antioxidant properties. It reduces the myocardial oxygen demand acting on myocardial energy metabolism. Moreover, the product stabilizes the cardiomyocyte membrane, demonstrates an anti-arrhythmic effect and has marked anabolic capacity.
Thiotriazolin effectively corrects the imbalance in the ATP — ADP — AMP adenine nucleotide system in the setting of myocardial hypoperfusion, thus preventing rapid depletion of energy stores in the cells and their metabolic switch to energetically less favorable anaerobic pathway of glucose oxidation.
Low creatine phosphokinase levels during the treatment of patients with stable angina reflect the drug’s positive effect on energy metabolism and cardiomyocyte membrane stabilization. Thiotriazolin can reduce the level of lactate in the citric acid cycle and increase the levels of pyruvate and malate in the setting of tissue hypoxia.
Experiments have demonstrated that Thiotriazolin was capable of reducing the myocardial ischemia and necrosis area by 42%, which was significantly higher than the corresponding reduction observed with the use of carnitine chloride, a well-known antioxidant, and had a positive effect on myocardial ischemic injury parameters.
The cardioprotective effect of Thiotriazolin reproduced in animal models was exerted by influencing the ischemic changes in the myocardial bioenergetic metabolism. This was accompanied by an increase in the endogenous glycogen level and a reduction in the free fatty acid level.
Metabolic drugs, such as trimetazidine, ranolazine, L-carnitine and the domestic medicinal product Thiotriazolin, have recently been shown to possess intrinsic anti-anginal effects.
A large body of research is dedicated to studying Thiotriazolin in patients with stable angina. A review of the studies has shown that the product was included in metabolic therapy complexes for patients with class I to IV stable angina and marked ECG signs of ischemia, and for the treatment of post-infarction cardiac sclerosis in the elderly. While trimetazidine had no considerable effect on cardiac hemodynamics parameters and did not significantly change the systolic blood pressure level and heart rate, the Thiotriazolin treatment in patients with post-infarction cardiac sclerosis improved both the systolic and the diastolic function of the left ventricle [10, 11, 13, 15]. Combined treatment with Nitrosorbide, Phenihydine and Thiotriazolin in patients with post-infarction angina was shown to have a positive effect on intracardiac hemodynamics, not only reducing the preload (Nitrosorbide) and the afterload (Phenihydine), but also increasing the cardiac inotropic function due to a cardioprotective effect of Thiotriazolin as a metabolic therapy for the treatment of stunned myocardium.
Works concerning the use of Thiotriazolin in patients with both CHD and essential hypertension, irrespective of the functional class of angina, have demonstrated its favorable effect on the course of disease. A reduction in the pain syndrome severity and restoration of the heart rhythm were observed in this group of patients. Patients with angina experienced a smaller number of angina attacks, demonstrated better tolerance to physical exercise and saw an improvement in their hyperlipidemia [7, 9, 12].
We have found it interesting to extrapolate the mechanism of Thiotriazolin action to other cardioprotective drugs, one of them being trimetazidine which is considered to be a reference cardioprotective agent included in the ECS Guidelines on the Management of Stable Angina Pectoris, 2006. Thiotriazolin is known to reduce the necrotic area and destructive lesions in the myocardium in hypoxic conditions. Both Thiotriazolin and trimetazidine are metabolically active drugs which correct the impaired energy metabolism.
Thanks to its unique molecular structure, Thiotriazolin combines the properties of both direct- and indirect-acting cardioprotective drugs, i.e., it acts directly as a metabolic drug by normalizing the energy metabolism processes in the cardiomyocyte, and indirectly by exerting its antiplatelet and metabolic effects and thus reducing the load on the myocardium.
Despite a wide range of medicinal products available for the treatment of angina, two large-scale studies (TRIMPOL II, 2000; TRIKET, 2000) have shown that 66% of patients with angina rated their quality of life as unsatisfactory or poor, and only 17% of patients did not experience angina pain. Therefore, the scope of our research also included determining and evaluating the quality of life in patients with CHD.
Study purpose and objectives: the main objective of this study was to evaluate the efficacy and tolerability of Thiotriazolin tablets manufactured by pharmaceutical corporation Arterium versus trimetazidine in patients diagnosed with CHD: class II or III stable angina. The study was conducted as an open-label study according to the requirements to phase II clinical trials set by the State Pharmacological Center of the MoH of Ukraine.
56 men and 34 women aged 40 to 70 (mean age: 63.1 ± 2.0 years) – diagnosed with CHD: class II or III stable angina have been enrolled in this study. The diagnosis was established based on medical history data, physical examination and laboratory tests, and relevant changes on ECG, Echo-CG and in the treadmill test. The study subjects were randomized into 2 groups: patients in the first group received background treatment + Thiotriazolin 100 mg, 2 tablets 3 times a day for 30 days, and patients in the second group received original trimetazidine 20 mg, 3 times a day for 30 days as an add-on to their background treatment. The treatment period lasted for 5 weeks, and patients were followed up for 6 weeks. All patients were receiving in-patient treatment in the Cardiology Unit of Railway Hospital No. 2, Kyiv Railway Station.
All patients had general physical examination, and the following blood biochemistry parameters were measured: transaminase and CPK-MB fraction activity, bilirubin, lipids, creatinine, total cholesterol, triglycerides, blood glucose, potassium, sodium, and C-reactive protein. The specifics of the primary disease were taken into account, including the evaluation of the pain syndrome and the frequency of heart rhythm disorders.
Basic ECG pattern and 24-hour ECG monitoring parameters, namely the duration of PQ, QRS and QT intervals, were evaluated, and the treadmill test was performed unless contraindicated.
The statistical analysis was carried out using the Excel software package (data are presented as M ± m). The significance of differences between parameters was determined by paired Student’s t-test.
The evaluation of the efficacy criteria was based on the reduction in the number of painful and painless myocardial ischemia episodes according to 24-hour ECG monitoring data, increase in the tolerance to physical exercise based on the treadmill test data, and return of laboratory values to normal.
The metabolic therapy efficacy variables were as follows:
The clinical study has shown that Thiotriazolin improved the left ventricular function, which is an important determinant of improvements in the quality of life and the short-term and long-term prognosis of patients with class II or III stable angina. This improvement manifested itself as a trend towards a decrease in both systolic and diastolic dimensions of the left ventricle and an increase in the ejection fraction.
The clinical studies have demonstrated the safety of oral Thiotriazolin. Its use is advisable in patients with class II or III stable angina in addition to current standard of care comprising nitrates, β-blockers, calcium channel blockers, antiplatelets, ACE inhibitors, diuretics.
The evaluation of treatment efficacy was based on the results of 24-hour ECG monitoring and two-stage treadmill-tests taken before treatment and after 30 days of treatment.
The analysis of these results showed an improvement in the course of CHD in both groups. For instance, both groups reported faster regression of the pain syndrome; at day 5 of inpatient treatment, pain syndrome was observed only in 4 patients in the first and second groups. No patients receiving the study treatment had pain syndrome at day 10.
A significantly lower frequency of ventricular extrasystoles as a result of reduced myocardial electrical instability was recorded in both groups after treatment with Thiotriazolin and trimetazidine, respectively.
A reduction in the frequency of ventricular and supraventricular extrasystoles was observed in the Thiotriazolin group, which indicates a substantial improvement of myocardial electrophysiological characteristics.
According to treadmill test data at baseline and after 30 days of treatment, a marked significant increase in the duration of physical exercise to the onset of angina pain was observed (from 6.63 ± 1.20 min to 9.32 ± 0.15 min in the first group and from 6.4 ± 0.4 min to 10.71 ± 0.11 min in the second group). Moreover, the physical exercise time to persistent ST segment depression was significantly increased in both groups, which indicated improvements both in the electrophysiological properties of the myocardium and its ischemic resistance. No significant difference between groups was detected when comparing the efficacy of treatment with Thiotriazolin and trimetazidine. Both products had equally positive effects on the course of CHD: class II or III stable angina.
Table 1. Anti-ischemic and anti-arrhythmic activity of Thiotriazolin in patients diagnosed with CHD: class II or III stable angina (based on 24-hour ECG monitoring data)
Parameter | Thiotriazolin + background therapy (before treatment) | Thiotriazolin + background therapy (after treatment) | Trimetazidine + background therapy (before treatment) | Trimetazidine + background therapy (after treatment) |
Daily duration of ischemia, min | 19,80 ± 1,42 | 17,4 ± 1,6 | 18,2 ± 1,9 | 16,1 ± 2,4 |
Mean duration of ischemia episodes, min | 6,50 ± 0,05 | 5,3 ± 0,1 | 7,20 ± 0,63 | 6,0 ± 0,5 |
Number of ventricular extrasystoles | 215,0 ± 10,4 | 178,3 ± 9,4 | 190,3 ± 9,4 | 165,5 ± 8,7 |
Number of supraventricular extrasystoles | 176,2 ± 11,2 | 163,1 ± 10,9 | 185,0 ± 14,2 | 180,4 ± 15,3 |
Note: * — р < 0.05 for the comparison of parameters after treatment in each group.
Table 2. Effects of Thiotriazoline and trimetazidine on the physical exercise level in patients diagnosed with CHD: class II or III stable angina (based on treadmill test data)
Parameter | Thiotriazolin + background therapy (before treatment) | Trimetazidine + background therapy (before treatment) | Thiotriazolin + background therapy (after treatment) | Trimetazidine + background therapy (after treatment) |
Total exercise time to the onset of angina pain, min | 6,63 ± 1,20* | 6,4 ± 0,4* | 9,32 ± 0,15* | 10,71 ± 0,11* |
Physical exercise time to ≥1 mm ST segment depression, min | 5,32 ± 0,30* | 5,12 ± 0,10* | 7,87 ± 0,16* | 8,03 ± 0,10* |
Maximum heart rate achieved (% of the maximum value) | 61,3 ± 2,1* | 60,5 ± 2,3* | 85,6 ± 2,2* | 83,7 ± 3,1 |
Maximum systolic BP level, mm Hg | 161,3 ± 3,1 | 163,5 ± 2,9 | 154,6 ± 3,2* | 158,7 ± 4,8 |
Note: * — р < 0.05 for the comparison of baseline and post-treatment values in each group.
The analysis of changes in laboratory findings did not show any negative impact on complete blood count and urinalysis parameters in both study groups. No significant changes in transaminase levels and blood lipid profile were observed, suggesting no adverse effects on the liver and kidneys.
The absence of adverse changes in laboratory values indicates the safety of treatment with the study drugs.
The comparative evaluation of the study drug tolerability was based on the analysis of physical examination data and subjective sensations reported by the patients, ECG recordings and 24-hour ECG monitoring results. Throughout the treatment period, no patients developed allergic reactions, nausea, bronchial obstruction syndrome or other adverse events requiring study drug discontinuation. According to treadmill test data at baseline and at day 30 of treatment, a significant increase in the duration of physical exercise to the onset of angina pain was observed. Moreover, the duration of physical exercise was significantly increased in both groups, which indicated improvements both in the electrophysiological properties of the myocardium and its ischemic resistance. The tolerability of both drugs was rated as good.
1. The treatment with Thiotriazolin improves the clinical parameters and quality of life in patients diagnosed with CHD: class II or III stable angina.
2. A lower frequency and severity of angina attacks, a lower mean duration of ischemia and daily duration of ischemia, a decrease in the frequency of arrhythmia according to Holter ECG monitoring data, and an increase in the tolerance to physical exercise were clinically observed in 68% of patients in the Thiotriazolin group compared to those not treated with Thiotriazolin (Tables 1 and 2).
3. Thiotriazolin demonstrates an additive effect potentiating the effects of nitrates, β-blockers, calcium channel blockers, antiplatelets, ACE inhibitors and diuretics in the treatment of patients with stable angina.
4. Thiotriazolin is a well-tolerated, effective and safe product for the treatment of patients diagnosed with CHD: class II or III stable angina.
5. The myocardial ischemic resistance detected in both groups is confirmed by a significant increase in the physical exercise duration to the onset of angina pain and physical exercise time to persistent ST segment depression.
6. A reduction in the frequency of ventricular and supraventricular extrasystoles was observed in the Thiotriazolin group, which indicates a substantial improvement of myocardial electrophysiological characteristics.
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