Сlinical efficacy and tolerability of Тhiotriazolin in patients with unstable angina

Ye.P. SVISHCHENKO, L.V. BEZRODNAYA
National Research Center “M.D. Strazhesko Institute of Cardiology” of the National Academy of Medical Sciences of Ukraine
V.P. SHPAK, A.H. DUBCHAK
“Kyiv Regional Cardiology Dispensary”, Municipal Institution of the Kyiv Regional Council

The feasibility and effectiveness of metabolic therapy in coronary heart disease (CHD) remain a matter of debate. However, there is a continuing search for therapeutic agents targeted at optimizing metabolic processes in the myocardium in patients with stable or unstable angina. This is explained by the fact that the pathologic processes in the heart during ischemia and reperfusion, such as increased free radical production, lipid peroxidation, calcium overload, inflammation, cellular acidosis and antioxidant system suppression, are involved in damaging membrane structures of heart muscle cells. Agents with membrane protection properties, however, help protect membrane systems by reducing the extent of damage and preventing a transition from reversible to irreversible changes [8, 10]. Currently, the experience of successful use of metabolic agents in CHD treatment is recorded in the European Society of Cardiology Guidelines [17] and is based, on the one hand, on the proven anti-ischemic and anti-anginal effects of metabolic drugs (trimetazidine, ranolazine) [11-13, 16, 18] and, on the other hand, on insufficient evidence of a combination of several hemodynamically active drugs being superior to each of them used alone in terms of effects on the patient’s quality of life and disease prognosis [20]. Although the conventional anti-anginal and anti-ischemic treatment rests upon hemodynamic approach which is based on reducing the myocardial oxygen demand or increasing the oxygen supply, the concept of metabolic therapy has become widely accepted [6, 16-18]. The use of drugs with cardioprotective mechanism of action in acute coronary syndrome is aimed at improving the processes of energy production and consumption in the myocardium, as well as restoring the balance between free-radical oxidation and antioxidant protection [3, 6] to reduce progressive damage to the heart muscle cells.

Efficacy of a number of metabolic drugs with antioxidant and membrane protection properties for the treatment of coronary heart disease has been documented [9, 18, 19]. For instance, the anti-ischemic effect of trimetazidine was shown to be equivalent to that of β-blockers and calcium channel blockers, which constitute a standard background treatment for CHD [14, 15]. L-carnitine helps reduce the extent of ischemic injury to heart muscle cells [19]. C.J. Pepine and M.A. Welsch (1995) have shown that L-carnitine is an effective anti-anginal agent reducing the ST segment depression and left ventricular end-diastolic pressure in the stress test in patients with CHD. Quercetin, an antioxidant and metabolically active agent, was demonstrated to reduce dilatation of the left ventricular cavity and improve ventricular pumping ability in patients with myocardial infarction and acute heart failure [7].

The experience of the use of original domestic product Thiotriazolin for the treatment of cardiovascular disease suggests its high efficacy as a cardioprotective drug [4, 5, 9, 18]. The antioxidant and anti-ischemic effects of Thiotriazolin are based on its ability to reduce inhibition of oxidation processes in the citric acid cycle, enhance compensatory activation of anaerobic glycolysis and increase the intracellular ATP pool [4]. Thiotriazolin considerably increases the RNA level and activates protein synthesis in ischemic tissues, which indicates the initiation of adaptive processes aimed at cell metabolism rearrangement in the setting of hypoxia without increasing the oxygen demand and free radical production. Marked antioxidant properties of the product have been established [5].

The purpose of this study was to evaluate the efficacy and tolerability of medicinal product Thiotriazolin manufactured by Arterium (Ukraine) in patients with unstable angina associated with CHD.

Materials and methods

Eighty patients 46 to 68 years of age (with a mean age of 53.4 ± 0.9 years) diagnosed with CHD: unstable angina; stage I, class II heart failure were enrolled in the study. The diagnosis was based on clinical assessment, ECG and laboratory findings according to generally accepted criteria.  Electrocardiogram was recorded, general clinical assessments were made, lipid profile and the activity of creatine phosphokinase (CPK) and blood transaminases – aspartate aminotransferase (AST) and alanine aminotransferase (ALT) – were determined, blood levels of troponin (to exclude recurrent Q-wave myocardial infarction) and C-reactive protein (CRP) were measured, and 24-hour Holter ECG monitoring and echocardiography (Echo-CG) were performed in all patients at initial examination. The Holter monitoring was carried out using EC-GO monitor (Meditech, Hungary).

The number of painful (PMI) and painless (PLMI) episodes of myocardial ischemia, mean duration of each episode and their total daily duration were recorded. The following parameters were recorded at echocardiographic examination: end-systolic and end-diastolic volumes, ejection fraction (EF), left ventricular wall thickness (LVWT) and interventricular septum thickness (IVST), end-systolic volume index (ESVI), end-diastolic volume index (EDVI) and left ventricular myocardial mass index (LVMMI). The assessment of changes in the tolerance to physical exercise was based on 6-minute walk test results. The number of angina attacks and nitroglycerin tablets taken per week at the beginning and at the end of the observation period and mean daily number of angina attacks and nitroglycerin tablets in the respective periods were determined according to patient’s diary data.

Table 1. Clinical efficacy of Thiotriazolin in patients with unstable angina associated with CHD

Notes: 1 – the change from baseline is significant (P < 0.05); 2 – Р < 0.01; 3 – Р < 0.001; 4 – the difference in parameters between the intervention group and the control group is significant (Р < 0.05)

Table 2. Results of a 6-minute walk test at baseline and after 12 weeks of treatment by study group

Notes: 1 – Р < 0.001 for the change from baseline; 2 – the difference in parameters between the intervention group and the control group is significant (Р < 0.05)

The CRP concentration was measured by the turbidimetric method using the Biosystems kit (Spain) and Biosystems A-25 automatic analyzer (Spain). The normal range for CRP in this method is 0 to 6 mg/L.

The participants were randomized in two groups of 40 patients each (intervention and control groups). In addition to background treatment with β-blockers, ACE inhibitors, nitrates, statins, antiplatelet and antithrombin agents, the patients in the intervention group received Thiotriazolin 4 mL of 2.5% solution administered as an intramuscular injection twice daily for 4 days, followed by Thiotriazolin 100 mg tablets 3 times daily. The patients in the control group received background treatment without any metabolic drugs. Analgesics and anti-arrhythmic drugs were prescribed as indicated, and the frequency of their use did not differ significantly between groups.

The duration of study treatment was 12 weeks. Re-examination comprising the battery of baseline tests was carried out at the end of treatment.

The intervention and control groups were comparable with respect to age, sex, severity of the disease, background treatment dosage and comorbidity (diabetes mellitus, hypertension).

The statistical analysis was carried out on a personal computer using the SPSS software package for statistical analysis. To estimate the significance of differences, a paired Wilcoxon test was used for related samples and a Mann-Whitney test was used for independent samples.

Results

A significant improvement in the patients’ clinical condition attributable to the combination treatment of unstable angina was reported in both groups over the observation period. However, unstable angina developed into non-Q-wave myocardial infarction in two patients in the intervention group and three patients in the control group in the observation period, while another patient in the control group was readmitted to the hospital with acute coronary syndrome after 10 weeks of observation; all these patients were withdrawn from the study for the above reasons.

There were no significant baseline differences between groups in the daily and weekly frequency of angina attacks and their duration, the number of nitroglycerin tablets to relieve one attack and the number of nitroglycerin tablets taken daily. A significant reduction over time in the mean daily number of angina attacks was observed throughout the treatment period: from 3.41 ± 0.32 to 1.03 ± 0.15 in the intervention group (Р < 0.01) and from 3.52 ± 0.35 to 1.54 ± 0.12 (Р < 0.05) in the control group. 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 both study groups. 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 (1.03 ± 0.15 vs. 1.54 ± 0.12; Р < 0.05), their duration (7.52 ± 0.21 min vs. 9.94 ± 0.24 min; Р < 0.001), and the daily number of nitroglycerin tablets (1.02 ± 0.24 vs. 1.65 ± 0.19; Р < 0.05). No significant differences were detected between the groups in the number of nitroglycerin tablets required to relieve an angina attack.

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 12 weeks of treatment indicate anti-anginal activity of Thiotriazolin and its favorable effect on the course of unstable angina.

Results of the 6-minute walk test at the end of treatment have shown a significant increase from baseline in the 6-minute walk distance in both groups (Table 2), suggesting an improvement in the tolerance to physical exercise throughout the study treatment.

The 6-minute walk distance increased by 53.3 ± 2.1% (Р < 0.001) in the intervention group treated with Thiotriazolin and by 39.8 ± 2.4% (Р < 0.01) in the control group, which implies an increase in the myocardial coronary flow reserve in the course of treatment in both study groups.

The walk distance in the Thiotriazolin group increased to a higher extent compared to the control group (P < 0.05), confirming the anti-ischemic effect of Thiotriazolin.

The analysis of the Holter ECG monitoring results (Table 3) detected a clear improvement expressed as a reduction in the number of PMI episodes from 3.22 ± 0.11 to 0.92 ± 0.12 (Р < 0.001) and from 3.31 ± 0.14 to 1.28 ± 0.11 (Р < 0.001) in the intervention group and in the control group, respectively, and a reduction in the number of PLMI in both intervention and control groups (P < 0.01). The mean and total duration of painful and painless ischemia episodes were also significantly decreased in both groups (P < 0.01 and P < 0.001, respectively). The frequency (P < 0.05), the mean duration (P < 0.05) and the total duration (P < 0.001) of clinically relevant ischemia episodes at the end of the observation period were significantly lower in the Thiotriazolin group. There were no significant differences between study groups in the number of painless ischemia episodes at the end of week 12 of treatment (P < 0.05); however, the mean and total duration of PLMI episodes in the Thiotriazolin group were significantly lower (P < 0.05), suggesting anti-ischemic properties of Thiotriazolin and supporting experimental data [1, 2].

The Echo-CG findings (Table 4) showed no baseline differences between the intervention group and the control group in morphofunctional status of the left ventricular myocardium.

Table 3. Changes in the Holter ECG monitoring parameters in patients with unstable angina in the course of treatment including Thiotriazolin (intervention group) or without Thiotriazolin (control group)

Notes: 1 – Р < 0.01; 2 – Р < 0.001 for the change from baseline; 3 – Р < 0.05 compared to the intervention group values; 4 – Р < 0.001 compared to the intervention group values.

Table 4. Changes in the morphofunctional status of the left ventricle in patients with unstable angina after 12 weeks of treatment in the intervention and control groups

Note: 1 – Р < 0.05 for changes from baseline after 12 weeks of treatment.

According to echocardiography data, both study groups demonstrated improvements in terms of EDVI and ESVI reductions in the course of treatment (P < 0.05). However, no significant change in the EF value was observed (P > 0.05). A lower LVMMI value (P < 0.05) after 12 weeks of treatment was attributable to reductions in both the left ventricular wall thickness and the size of the left ventricle; the EDVI decreased from 70.4 ± 1.48 to 64.24 ± 1.25 L/m2 (Р < 0.05) in the intervention group and from 69.86 ± 0.78 to 63.35 ± 0.92 L/m2 (Р < 0.05) in the control group. There were no significant differences between groups in any of the Echo-CG parameters at the end of the observation period.

Positive shifts in the morphofunctional status of the left ventricle in the course of the 12-week study treatment were apparently caused by the anti-ischemic effect of the comprehensive background treatment and the ability of β-blockers and ACE inhibitors to act on the left ventricular remodeling processes. Some authors suggest that the use of drugs with metabolic and antioxidant effects in the treatment of acute coronary syndrome may improve the left ventricular pumping ability [2, 7]. Our study, however, included patients with preserved left ventricular systolic function at baseline, which obviously explains the absence of significant effect of Thiotriazolin on the EF parameter.

CRP is one of the inflammation markers in atherosclerosis, and its level in patients with unstable angina is of high prognostic value for the immediate and long-term prognosis of the disease and its complications.

The CRP level at baseline was similar in both groups and significantly exceeded the normal range (P < 0.05): 9.20 ± 0.13 mg/dL in the intervention group and 9.08 ± 0.15 mg/dL in the control group. A significant reduction in the CRP level to 6.22 ± 0.12 mg/dL (Р < 0.05) in the Thiotriazolin group and to 6.97 ± 0.13 mg/dL (Р < 0.05) in the control group was observed after 12 weeks of treatment. It should be noted that the reduction in the CRP level throughout the observation period was significantly greater in the intervention group (P < 0.05), which indicates a more favorable effect of the combination treatment including Thiotriazolin on the course of atherosclerosis in patients with unstable angina. This can be explained by a corrective effect of Thiotriazolin on energy metabolism, as well as its antioxidant activity and protective properties with regard to autoimmune inflammatory process [1, 2].

The analysis of biochemistry parameters over the treatment period did not reveal any significant changes, except for a trend towards reduction in total cholesterol and low-density lipoprotein levels in the Thiotriazolin group.

In summary, the data obtained in this study demonstrate that:

• • Thiotriazolin improves the clinical course of unstable angina by reducing the frequency and duration of angina attacks and the daily number of nitroglycerin tablets taken by patients;
  • Thiotriazolin significantly increases the distance in the 6-minute walk test and reduces the number and the mean and total duration of painful and painless myocardial ischemia episodes at Holter ECG monitoring, which suggests an anti-ischemic effect of the product;
  • Thiotriazolin helps reduce the level of CRP, a systemic inflammatory marker in CHD.

Therefore, adding Thiotriazolin to the treatment regimen in patients with unstable angina helps optimize the management of this disease.

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