EFFICACY OF THIOTRIAZOLIN IN COMBINATION WITH THE STANDARD OF CARE FOR THE TREATMENT OF CORONARY HEART DISEASE (Results of a double-blind randomized placebo-controlled study)

V.Z. NETIAZHENKO, T.I. MALCHEVSKA
O.O. Bohomolets National Medical University

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 has 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 (MI) and improve early survival. Further studies have demonstrated that GIP, as well as nicotinic acid, reduces free fatty acid (FFA) release from adipocytes, which, in turn, leads to a 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 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 treatment is 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 cell apoptosis [7, 14, 15, 17, 18]. A non-exhaustive list of multiple ischemic cardiomyopathy manifestations includes microcirculatory disorders, endothelial dysfunction, activation of the mononuclear phagocyte system, T-lymphocytes and leukocytes, i.e. immune and systemic inflammation, with the activation of apoptosis inducers and subsequent left ventricular remodeling.

To understand the specifics of energy metabolism in the normal and ischemic myocardium, one should remember that in physiological conditions the myocardial synthesis of ATP as a major substrate of energy metabolism is driven by the dynamically balanced cycles of glucose and free fatty acid catabolism. Fatty acids (palmitic and stearic) account for 60 to 80% of ATP synthesis, while the glycolytic pathway of ATP synthesis provides 20 to 30% of total energy produced in the heart. For comparison: one molecule of palmitic acid or stearic acid generates 134 or 147 molecules of ATP, respectively, while one molecule of glucose generates 32 molecules of ATP. 

The healthy myocardium employs aerobic β-oxidation of FFAs with subsequent release of acetyl-coenzyme A (acetyl-CoA) for energy supply, which results in a higher oxygen demand. For instance, 17% more oxygen is needed to produce the same amount of ATP from FFA oxidation than from glucose oxidation. Both lipids and glucose are catabolized in the citric acid cycle by a conventional pathway, which leads to their competition for oxidation.

The ATP energy is consumed as follows:

• • 75 to 80% for myocardial contractility and transport of Na+, K+ and Ca2+ ions through sarcolemmas and mitochondrial membranes;
  • 20 to 25% for maintenance of mitochondrial volume, glycogen resynthesis and citric acid cycle activation.

Table 1. Results of the Mann-Whitney test application to compare pre-treatment treadmill test parameters between the study groups

Note: * – the conclusion is based on a 0.05 significance level.

 Glucose is certainly no less important energy substrate which can suppress the FFA oxidation in the setting of oxygen deficiency. Glucose is either supplied to the myocardium or derived from endogenous glycogen (i.e., its energy reserve in ischemia). The myocardial glycogen stores constitute at most 1% of the total cell volume.

Two pathways of glucose metabolism are known:  the aerobic and the anaerobic.

Aerobic glycolysis: in the event of oxidative phosphorylation in the mitochondrial pyruvate dehydrogenase citric acid cycle, glucose is oxidized to pyruvate at the expense of oxygen, leading to the synthesis of a small amount (less than 10%) of ATP, and pyruvate is further converted to acetyl-coenzyme A by pyruvate dehydrogenase. For example, oxidation of 2 moles of pyruvate is accompanied by the synthesis of 30 ATP molecules, and this reaction is inhibited by excess acetyl-coenzyme A and FFAs. Aerobic glycolysis is a more efficient glucose metabolism pathway in terms of the amount of energy produced.

Anaerobic glycolysis represents glucose metabolism in cardiomyocyte cytosol without the use of oxygen. The anaerobic pathway includes similar ways of glucose breakdown to pyruvate, but the latter is further converted to lactate. In the absence or lack of oxygen in the cell, pyruvate is reduced to lactate. This mechanism is energetically less favorable; however, it plays an outstanding role during the development of myocardial ischemia.

With regard to energy metabolism in the setting of myocardial ischemia, it is known that hypoperfusion leads to increased energy production and depletion of energy reserves.

When oxygen supply to cardiomyocytes decreases, mitochondria accumulate a large amount of incompletely oxidized fatty acids which cause deleterious effects on cell membranes.

The mechanisms of damage include:

• • inhibition of glucose utilization during ischemia and reperfusion;
  • uncoupling of oxidative phosphorylation in the mitochondrial electron transport chain;
  • alteration of membrane enzyme properties;
  • suppression of mitochondrial function and ATP production rate;
  • enhanced membrane permeability for Ca2+ ions accompanied by increased beta-adrenergic response of the myocardium. 

In the setting of ischemia, cardiomyocytes do not synthesize adequate amounts of creatine phosphate and ATP, which leads to a rapid and progressive decrease in ATP concentration and activation of anaerobic glycolysis resulting in the synthesis of lactate and only 2 molecules of ATP from pyruvate. Anaerobic glycolysis cannot meet the energy demand of the cardiomyocyte, as it provides at most 50% of the required ATP. Excess lactate entering the cell is a reliable sign of ischemia.

Activation of glycolytic pathways of ATP production becomes a matter of paramount importance in the ischemic conditions. When the energy supply is insufficient, cardiomyocytes start using glucose from endogenous glycogen as it is already phosphorylated (in contrast to exogenous glucose which is transported to the cell) and its utilization does not require ATP input for initial activation. However, glycogen stores in cardiomyocytes deplete rather quickly, raising the need for the activation of alternative ATP production pathways.

The energetic state of the heart in the setting of limited oxygen supply can be maintained for a short time by a breakdown of one glucose molecule to two molecules of pyruvate in the phosphoglycerate kinase and pyruvate kinase reactions resulting in ADP phosphorylation to ATP.

Therefore, cell metabolism during myocardial ischemia relies upon the use of endo- and exogenous pyruvate which is actively taken up from blood by the myocardium. Pyruvate is transferred to mitochondria where it is converted to acetyl-CoA in the presence of pyruvate dehydrogenase. Pyruvate dehydrogenase activity is considered to be the driving force of the glycolytic energy production pathway. One molecule of glucose produces 2 molecules of ATP upon conversion to pyruvate and 34 molecules of ATP upon subsequent oxidation of pyruvate in the citric acid cycle. In the ischemic conditions, the cardiomyocyte metabolism is switched to using fatty acids instead of oxidizing other substrates, such as glucose. However, this requires spending 15% more molecular oxygen, and the “oxygen cost” of glucose oxidation is somewhat lower compared to fatty acid oxidation, which is why the glucose oxidation pathway, which allows using residual oxygen more efficiently, is preferable in the setting of ischemia.

Thus, in the ischemic conditions, the respiratory chain function in the citric acid cycle is slowing down, acetyl-CoA production is gradually declining, and both glucose and fatty acid oxidation rates are decreasing. Accumulated incompletely oxidized fatty acids uncouple tissue respiration, promote the development of acidosis and intracellular calcium and sodium overload, inevitably leading to impaired relaxation and, subsequently, impaired contractility of the cardiomyocyte.

Previous studies have demonstrated that aerobic metabolism is arrested when the coronary flow slows down to less than 0.56 mL/min/kg myocardium weight. As ischemia worsens, anaerobic glycolysis producing ATP and lactate becomes the only possible mechanism for the synthesis of ATP. Lactate may be re-oxidized by lactate dehydrogenase to produce pyruvate which is subject to further conversion. Excess lactate causes tissue lactic acidosis which uncouples oxidative phosphorylation and leads to cardiomyocyte Ca2+ overload. Lactic acidosis activates phospholipase A2 causing damage to membrane structures and initiating lipid peroxidation processes. Excess lactate shifts the balance towards acidosis which activates peripheral pain receptors in the C7-T4 spinal cord segments and causes angina pain. Thus, hypoxic metabolism occurs. That is why, reducing the intracellular lactate level via its conversion to pyruvate is a key target of the metabolic therapy.

Therefore, one of the main tasks of metabolic therapy is to inhibit FFA oxidation and switch the cardiomyocyte metabolism to glucose oxidation which would allow using residual oxygen more efficiently.

In recent years, substantial progress have been made in understanding the role of cardiac energy metabolism in the pathogenesis of myocardial ischemia, which prompted the development of a new metabolic concept in the treatment of patients with CHD. The optimization of myocardial energy metabolism is based on increasing myocardial glucose oxidation which enhances the functional capacity of the heart and protects the myocardium against ischemic and reperfusion injury. The efficiency of glucose utilization by the myocardium in the setting of chronic hypoperfusion may be improved when FFA metabolism is modulated by medicinal products that inhibit the oxidation of FFAs. 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. By acting on myocardial energy metabolism, it reduces the myocardial demand for oxygen, a major pathophysiological determinant of myocardial ischemia. Moreover, the product stabilizes the cardiomyocyte membrane, exerts 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 effectively corrects alterations in the citric acid cycle in the setting of tissue hypoxia. Thiotriazolin is three times more effective than piracetam in reducing the level of lactate and increasing the levels of pyruvate and malate.

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 bioenergetic metabolism of the ischemic myocardium. This was accompanied by an increase in the endogenous glycogen level and a reduction in the FFA 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 efficacy in patients with various forms of CHD, including 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 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 metabolic therapy for the treatment of ischemic myocardium. Chronic hypoperfusion of myocardial tissues is associated with atherosclerotic coronary heart disease which is responsible for metabolic energy deficiency and is a target for the therapeutic action of Thiotriazolin as a metabolic agent.

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].

The clinical effect of Thiotriazolin was shown to be attributable to its anti-ischemic, antioxidant, membrane-stabilizing and immunomodulating properties. Thiotriazolin enhances the compensatory activation of anaerobic glycolysis and reduces the inhibition of oxidative processes in the citric acid cycle while preserving the intracellular ATP stores. The product was shown to activate the antioxidant system and suppress lipid peroxidation processes in ischemic areas of the myocardium, reduce myocardial sensitivity to catecholamines, prevent progressive suppression of the contractile function of the heart, stabilize and reduce myocardial ischemia and necrosis areas. The antioxidant effect of Thiotriazolin is exerted by increasing the level of catalase and reducing the levels of malonaldehyde, conjugated dienes and free radicals, which helps reduce the oxidative stress and the free-radical oxidation processes. Thiotriazolin is prescribed as add-on therapy in ischemic patients with acute MI, angina of effort and angina at rest, post-infarction cardiac sclerosis and arrhythmias. 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 restoring normal energy metabolism processes in the cardiomyocyte, and indirectly by exerting its antiplatelet and metabolic effects and thus reducing the load on the myocardium.

As mentioned above, positive characteristics of metabolic drugs include a total absence of adverse hemodynamic effects, targeted action on the underlying metabolic mechanisms of ischemia development and marked heart cell protection. By acting on the processes of energy production and consumption, metabolically acting drugs increase tissue tolerance to hypoxia and reperfusion consequences and are effective in the treatment of heart failure of ischemic origin. Similar to Thiotriazolin, trimetazidine, a metabolic drug commonly used in cardiological practice, also inhibits the oxidation of fatty acids. It acts by suppressing the myocardial metabolism of FFAs, which requires 17% more oxygen compared to glucose oxidation to produce the same amount of ATP, and its mechanism of action involves selective inhibition of CoA-thiolase, an enzyme responsible for β-oxidation of fatty acids. Unlike Thiotriazolin, trimetazidine exerts its action in the treatment of chronic CHD only and has no considerable effect in terms of acute MI treatment. The effect of trimetazidine is not immediate and requires some time for metabolism adjustment and stabilization. Trimetazidine enhances pyruvate oxidation and the glycolytic production of ATP and inhibits lactate accumulation and the development of acidosis by suppressing the free-radical oxidation. Like trimetazidine, the piperazine derivative ranolazine which has been included in the standard of care and the ECS Guidelines on the Management of Stable Angina Pectoris also inhibits fatty acid oxidation, but its biochemical target is yet to be determined and the product has not yet been approved for marketing in Ukraine. Ranolazine reduces the frequency of angina attacks and increases the tolerance to physical exercise. Its anti-ischemic effect is exerted by limiting the use of FFAs and increasing the use of glucose as energy substrates. This leads to higher ATP yield from each mole of oxygen consumed. However, ranolazine does not exert the anti-anginal effect when used alone, which is why it is administered in patients with CHD in combination with beta-blockers and calcium channel blockers.

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 stable 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 placebo in patients with CHD, class II or III stable angina and to assess their quality of life following the treatment.

Materials and methods

The study design involved the enrollment of 292 patients with CHD, class II or III stable angina aged 40 to 70 (mean age: 63.1 ± 2.0 years), with almost twice as many men as women included in the study. The diagnosis was established based on medical history data, physical examination and laboratory tests, and relevant changes on electrocardiograms (ECG), echocardiograms (Echo-CG) and in the treadmill test.

According to the ECS Guidelines on the Management of Stable Angina Pectoris (2006), all patients included in the study received background treatment with nitrates, beta-blockers, antiplatelet drugs (aspirin), statins and calcium channel blockers. The patients were prescribed sublingual nitroglycerin to relieve angina attacks. After 30 days of background treatment, the patients were examined and randomized into the intervention and the control treatment groups. In addition to background treatment, patients in the intervention group received Thiotriazolin and patients in the control group received placebo. The study groups were homogeneous in terms of hemodynamics and comparable as to the number of previous myocardial infarctions, interventions and coronary angiography procedures, the level of physical exercise tolerance and the presence of associated conditions, such as essential hypertension, type 2 diabetes mellitus and class II or III heart failure (Fig. 1).

Thiotriazolin or placebo were prescribed at a dose of 2 tablets 3 times a day for 30 days. 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 recorded: transaminase and creatine phosphokinase (CPK) MB fraction activity, bilirubin, lipids, total cholesterol, triglycerides, creatinine, blood glucose, potassium and sodium. The clinical course specifics of the primary disease were taken into account, including the assessment of the pain syndrome, the frequency of angina attacks, the nitroglycerin threshold and the tolerance to physical exercise as the integrated indicator of improvement in the quality of life. Basic ECG pattern and 24-hour ECG monitoring (ECGM) 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 treatment 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:

• • an increase in the physical exercise time to ≥ 1 mm ST segment depression in the treadmill test at the end of treatment;
  • a reduction in the frequency and severity of angina attacks;
  • an increase in the tolerance to physical exercise;
  • a reduction in the nitroglycerin threshold accompanied by a reduction in the number of ischemia episodes and nitroglycerin administrations per week at the end of treatment;
  • a reduction in the daily number of ischemia episodes and the total daily duration of ischemia episodes based on 24-hour ECG monitoring data;
  • an increase in patient survival rate.

Figure 1. Patient examination design in the intervention and control groups

 Figure 2. Reduction in the number of angina attacks per week in the Thiotriazolin and placebo groups 

Figure 3. Reduction in the number of nitroglycerin tablets taken per week in the Thiotriazolin and placebo groups

 Results and discussion

The analysis of the obtained results showed an improvement in terms of clinical course of CHD in the Thiotriazolin group. For instance, a faster regression of the pain syndrome was reported; at day 5 of inpatient treatment, pain syndrome was observed only in 9 patients in the first group and 43 patients in the second group. No patients receiving the study treatment with Thiotriazolin had pain syndrome at day 10.

There were no significant baseline differences between groups in the daily and weekly frequencies of angina attacks and their duration, the number of nitroglycerin tablets to relieve one attack and the number of nitroglycerin tablets taken daily. The analysis of the evolution of clinical symptoms over time revealed a reduction in the mean weekly number of typical angina attacks by 46.32% from 4.94 ± 0.22 (visit 2) to 2.65 ± 0.11 (р < 0.01) (at final visit) and the mean number of nitroglycerin tablets by 57.94% from 4.66 ± 0.31 (visit 2) to 1.96 ± 0.15 (р < 0.01) in the group of patients with class II or II stable angina treated with Thiotriazolin. The number of angina attacks in the placebo group decreased by only 33.24% from 5.01 ± 0.21 (visit 2) to 3.34 ± 0.12 (р < 0.01) (at final visit), and the mean number of nitroglycerin tablets in the placebo group was reduced to a lesser extent compared to the Thiotriazolin group: by 47.75% from 4.48 ± 0.13 (visit 2) to 2.34 ± 0.11 (р < 0.01) (at final visit). At the end of the observation period, there were significant differences between the intervention group and the control group in the frequency of angina attacks (2.65 ± 0.11 vs. 3.34 ± 0.12, respectively; p < 0.05), their duration (6.43 ± 0.21 min vs. 8.62 ± 0.24 min; p < 0.001), and the daily number of nitroglycerin tablets (1.96 ± 0.15 vs. 2.34 ± 0.11; p < 0.05). In addition, a decrease in the duration of angina attacks (p < 0.001), the number of nitroglycerin tablets to relieve an angina attack (p < 0.001) and the daily number of nitroglycerin tablets taken by patients (p < 0.001) was observed in the Thiotriazolin group (Fig. 2, 3).

Adding Thiotriazolin to background treatment significantly reduces the number of angina attacks and the number of nitroglycerin tablets taken by patients.

To conclude, the analysis of the clinical course of stable angina in patients treated with Thiotriazolin in addition to background therapy have demonstrated the favorable effect of the drug on clinical symptoms with the improvement in the quality of life of the study subjects.

The anti-anginal effect of treatment was apparently brought about by the combination therapy; however, significant differences between groups in the frequency and duration of angina attacks and the daily number of nitroglycerin tablets after 30 days of treatment indicate anti-anginal activity of Thiotriazolin and its beneficial effect on the course of stable angina.

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 24-hour ECG monitoring data showed significant reductions in the mean duration of ischemia episodes by 22.79% in the intervention group and by 15.05% in the control group.

The mean exercise time to ≥1 mm ST segment depression or onset of angina pain in the treadmill test in the intervention (Thiotriazolin) group increased on average by 1.87 min (27.48% from baseline) compared to 0.85 min (17.48% from baseline) in the control (placebo) group (Fig. 4).

This significant increase in the physical exercise time to persistent ST segment depression in the Thiotriazolin group compared to placebo indicates a marked anti-ischemic effect of the drug (Fig. 5 to 7).

The analysis of changes in laboratory findings did not show any adverse effects 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 drug.

Figure 4. One-minute increase in the physical exercise duration based on the treadmill test data

Figure 5. Reduction in the daily number of ischemic episodes in the Thiotriazolin and placebo groups

Figure 6. Reduction in the total daily duration of ischemic episodes in the Thiotriazolin and placebo groups

Comparative analysis of treatment tolerability and adverse events observed during the treatment with Thiotriazolin and placebo

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 ECGM 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 with Thiotriazolin, a significant increase in the duration of physical exercise to the onset of angina pain was observed. Moreover, the duration of physical exercise in the intervention group was significantly increased, which indicates an improvement in the quality of life and an intrinsic anti-ischemic effect of Thiotriazolin.

The clinical studies has demonstrated the safety of oral Thiotriazolin; its use is advisable in patients with class II or III stable angina in addition to current background treatment comprising nitrates, statins, β-blockers, calcium channel blockers, antiplatelets, ACE inhibitors.

To sum up, Thiotriazolin, an original product with cytoprotective and antioxidant properties supported by a high level of evidence, has passed a double-blind multicenter randomized trial evaluating its efficacy and tolerability in patients with CHD, class II or III stable angina.

Thiotriazolin significantly reduced the number and duration of ischemic episodes and angina attacks after a 30-day treatment course, which allowed to reduce the number of nitroglycerin tablets taken by patients. The treatment with Thiotriazolin allows to increase the duration of physical exercise taken by patients and thus improve the quality of life in patients with CHD.

Figure 7. Change in the maximum work capacity by study group, METs

Conclusions

1. A significant increase in the physical exercise duration to the onset of angina pain and physical exercise time to persistent ST segment depression confirms the previously observed anti-ischemic effect of Thiotriazolin.
2. Thiotriazolin improves clinical symptoms and the quality of life in patients with CHD, class II or III stable angina. Administration of Thiotriazolin in addition to the standard of care resulted in a reduction in the mean duration of ischemic episodes by 22.79% according to Holter ECG monitoring data and a significant increase in the physical exercise time to ≥1 mm ST segment depression or to onset of angina pain (27.48% from baseline; p=0.007) according to treadmill test data, while the said increase in the placebo group was less marked (17.48% from baseline).
3. A significantly higher reduction in the duration and frequency of angina attacks (by 46.3% from baseline) and the number of nitroglycerin tablets taken per week (by 57.9% from baseline) over 30 days of treatment with Thiotriazolin in addition to background therapy demonstrated the drug’s clinical efficacy in patients with CHD, class II or III stable angina.
4. Reductions in the number of angina attacks and the nitroglycerin threshold at the final visit compared to baseline values were significantly higher in the Thiotriazolin group versus the placebo group (p = 0.028). 
5. Thiotriazolin is an effective, well-tolerated and safe medicinal product for the treatment of patients with CHD, class II of III stable angina.

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