Efficacy of Thiotriazolin® versus Meldonium in patients with class II or class III stable angina. Results of a prospective, randomized, open-label, parallel-group, comparative study

Yu.M. Sirenko, MD, A.D. Radchenko, MD, K.V. Mikheieva, O.L. Rekovets,
National Research Center “M.D. Strazhesko Institute of Cardiology” of the NAMS of Ukraine, P.N. Babych, The State Expert Center, Kyiv

Notwithstanding the success achieved in the prevention and treatment of coronary heart disease (CHD), optimization of its treatment remains among the most relevant problems of contemporary medicine in general and cardiology in particular. The high relevance of this problem is associated with severe complications of CHD, such as myocardial infarction, heart failure and sudden coronary death, the incidence of which remains high and has decreased only slightly due to the implementation of contemporary medical treatment principles. In view of the above, there is a continuing search for the ways to increase CHD treatment efficacy, which, inter alia, focuses on influencing the metabolic processes in the myocardium [2, 10, 11, 14, 15].

The feasibility and effectiveness of metabolic therapy in CHD remain a matter of debate. Although a number of metabolic drugs (e.g., trimetazidine, ranolazine) have shown anti-ischemic and anti-anginal effects in multicenter studies, there is no strong evidence of their positive effect on disease prognosis; that is why, their use is limited to add-on therapy. Currently, the experience of successful use of the above metabolic agents in CHD treatment is documented in the Guidelines on Management of Stable Angina Pectoris issued by the European Society of Cardiology and the Ukrainian Association of Cardiology [10, 16].

It should be mentioned that ranolazine is less studied than trimetazidine. However, some metabolic drugs not included in the above Guidelines, such as Meldonium, remain popular in this country. Meldonium (trimethylhydrazinium propionate), an analogue of gamma-butyrobetaine, inhibits γ-butyrobetaine hydroxylase, thus decreasing carnitine biosynthesis and the transmembrane transport of long-chain fatty acids, preventing the accumulation of activated forms of unoxidized fatty acids – derivatives of acylcarnitine and acylcoenzyme A. In ischemic conditions, it restores the balance between cell oxygen supply and demand and prevents ATP transport impairment, along with the activation of glycolysis which is carried out without extra oxygen uptake [11, 17]. The anti-anginal, anti-ischemic and cardiotonic clinical effects of the drug are completely consistent with its mechanism of action [5, 6, 8, 12]. 

Another popular metabolic drug in this country is Thiotriazolin®, a new domestic medicinal product. Its mechanism of action is associated with its anti-ischemic, antioxidant and membrane-stabilizing effects. The product is thought to enhance the compensatory activation of anaerobic glycolysis and reduce 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, suppress the lipid peroxidation processes in the ischemic myocardium, reduce myocardial sensitivity to catecholamines, prevent progressive suppression of the contractile function of the heart, stabilize and, consequently, reduce myocardial ischemia and necrosis areas, as well as improve blood flow properties and activate the fibrinolytic system [1, 3, 4, 13]. The efficacy data regarding the use of this product in patients with CHD is currently limited to small clinical trials or the experience of isolated clinics. The purpose of this study was to assess the efficacy and tolerability of medicinal product Thiotriazolin®, solution for injection manufactured by Halychfarm JSC and tablets manufactured by Kyivmedpreparat OJSC, compared to medicinal product Meldonium (Mildronate) in patients with CHD, class II or III stable angina.

Materials and methods

The study was designed as a prospective, open-label, comparative, randomized study in two parallel groups. Clinical research phase: IV. A total of 80 patients diagnosed with CHD: class II or III stable angina and receiving background treatment for CHD in NRC “M.D. Strazhesko Institute of Cardiology” of the NAMSU have been enrolled in the study. Forty of these patients (intervention group) received Thiotriazolin® solution for infusion and tablets and another forty patients (control group) received Meldonium (Mildronate solution for infusion and capsules manufactured by Grindeks JSC) according to the treatment regimens described below. The patients were distributed to study groups using a simple randomization technique with sealed envelopes. The patients were randomized into study groups according to a table based on random numbers that were obtained using a built-in random number generator of MS Excel analysis package. The inclusion criteria were as follows:

• • men and women aged from 40 to 70 with established CHD (hemodynamically significant coronary artery stenosis at angiograms, previous myocardial infarction, positive results of a double stress test (on a cycle ergometer) – horizontal or downsloping ST segment depression of ≥1 mm, ≥0.08 sec after the J-point or ST segment elevation of ≥1 mm);
  • patients with stable angina corresponding to functional class II or III at the end of the background treatment administration period;
  • patients stable on their angina treatment for at least 30 days prior to inclusion or patients who had not received prior treatment for angina; the treatment regimen and/or patient condition had to be stable throughout the course of their participation in the study;
  • a signed patient informed consent to participate in the study;
  • participation in any other clinical trial within the 3 months prior to inclusion;

The exclusion criteria were as follows:

• • individual intolerance to the study drug;
  • occurrence of a severe and/or unexpected adverse reaction in the course of the study;
  • marked worsening of general health condition within the study period;
  • patient’s non-compliance with the study treatment regimen;
  • patient’s non-compliance with the study procedures;
  • patient’s unwillingness to participate in the study.

Early withdrawals from the study were excluded from the efficacy analysis but included in the tolerability analysis.

Clinical, instrumental and laboratory methods were used for patient examination. Physical examination included questioning, visual inspection, palpation, abdominal percussion, auscultation of the heart and lungs. The daily number of angina attacks and the number of nitroglycerin tablets taken were recorded by the investigator based on patient diaries.

Sitting blood pressure (BP) was measured using a mercury sphygmomanometer, with the mean of two measurements recorded. The heart rate (HR) was measured between the 1st and 2nd BP measurements. Standard resting 12-lead electrocardiograms (ECG) in a supine position were recoded using an ECG machine.

24-hour ECG monitoring was carried out according to the standard technique using EC-GO Holter monitor (Meditech, Hungary) with the following parameters analyzed: daily number of ischemic episodes, total daily duration of ischemic episodes.

The cycle ergometer test was performed according to R. Bruce protocol with a gradually increasing work rate (at 3-minute intervals between grades). The stress test was performed in the morning, in a fasted state, before taking any medicines. The following parameters were recorded: BP, HR, onset of anginal pain, ischemic changes on ECG (ST segment). The data were recorded throughout the testing and for 5 to 10 minutes after its end.

Standard laboratory tests were performed by the Clinical and Biochemical Laboratory of the Institute (Chief – H.V. Ponomariova), with the following parameters analyzed: complete blood count (RBC, hemoglobin, WBC, platelets, ESR), urine analysis (pH, specific gravity, protein, glucose, epithelial cells, WBC, RBC, casts, salts), blood serum biochemistry (alanine transaminase and aspartate transaminase activity, total bilirubin, creatinine, glucose, total cholesterol, low-density and high-density lipoprotein cholesterol, triglycerides, Na+, К+). If patients were not receiving anti-anginal treatment at screening (visit 1), background treatment for CHD was prescribed, including beta-blockers, antiplatelet drugs, statins and sublingual nitroglycerin to relieve angina attacks. After 30 days of treatment, the patients were examined (visit 2) and distributed to the intervention group or control group by a simple randomization technique. If patients were receiving anti-anginal treatment, they were randomized into the intervention group or control group immediately after screening (visit 1) and examination.

Patients in the intervention group received study drug Thiotriazolin® in addition to background treatment, according to the following regimen: 4 mL of 2.5% solution for injections intramuscularly twice daily for 10 days, followed by 200 mg tablets orally 3 times daily for 20 days, and patients in the control group received Meldonium (medicinal product Mildronate) according to the following regimen: 5 mL of 10% solution for injections intramuscularly twice daily for 10 days, followed by two 250 mg capsules once daily for 20 days. The total duration of treatment was 30 days.

Patients who had not previously received anti-anginal treatment were prescribed anti-anginal drugs for 30 days prior to inclusion in the study drug treatment period.

Preliminary examination according to the study protocol was held after the informed consent form was signed by the patient.

Efficacy endpoints

Primary:

• • an increase in the duration of physical exercise taken by the patient in the cycle ergometer test according to R. Bruce protocol at the end of treatment.

Secondary:

• • a 1-minute increase in the duration of physical exercise taken by the patient in the cycle ergometer test according to R. Bruce protocol at the end of treatment;
  • a 2-minute increase in the duration of physical exercise taken by the patient in the cycle ergometer test according to R. Bruce protocol at the end of treatment;
  • a reduction in the number of angina episodes per week at the end of treatment;
  • a 50% reduction in the number of angina episodes per week at the end of treatment;
  • a reduction in the number of nitroglycerin tablets taken per week at the end of treatment;
  • a 50% reduction in the number of nitroglycerin tablets taken per week at the end of treatment;
  • a reduction in the number of myocardial ischemia episodes based on 24-hour Holter ECG monitoring at the end of treatment; 
  • a reduction in the total duration of myocardial ischemia episodes based on 24-hour Holter ECG monitoring at the end of treatment;
  • a 50% reduction in the total duration of myocardial ischemia episodes based on 24-hour Holter ECG monitoring at the end of treatment; The tolerability of the medicinal product was assessed based on:

1. Objective data collected by the investigator in the course of the study. Physical examinations comprising questioning, visual inspection, palpation, percussion, auscultation or the heart and lungs, and measurements of HR and BP were performed for this purpose at study visits. 
2. Laboratory findings.
3. Adverse events/reactions reported by the patient.

The general tolerability of medicinal products was assessed by the investigator according to the categorical scale shown in Table 1 below. 

The data were analyzed using a built-in statistical analysis tool of the Microsoft Excel spreadsheets and the SPSS 13.1 software package.

 Table 1 General tolerability rating scale

The statistical analysis was performed using descriptive statistics (n, arithmetic mean, median, standard deviation, minimum and maximum for quantitative data; frequency and percentage for qualitative data), graphical methods, interval estimation (confidence intervals were calculated for arithmetic means or medians depending on data consistency with the normal distribution), two-way analysis of variance with contrasts. The Mann-Whitney test or the Student’s t-test for independent samples (depending on the normality of data distribution) was used to estimate the significance of differences between two groups, and the Wilcoxon signed-rank test or the Student’s t-test for paired samples was used to compare the pre-treatment and post-treatment values of the parameters. The analysis of covariance with contrasts was used to compare the initially heterogeneous quantitative parameters between groups [18, 19].

Results

Clinical characteristics of the groups

A total of 80 patients (41 men and 39 women) diagnosed with CHD, class II or III stable angina were included in the study, as scheduled.

There were no dropouts from the study. As no dropouts were recorded, all patients (100%) were included in the efficacy analysis and tolerability analysis.

Basic demographic characteristics of the patients are shown in Table 2.

Table 2 Demographic and clinical characteristics of the patients by study group (quantitative: M±s; qualitative: frequency (%)

Table 3 Assessment of the relative change in the frequency of angina attacks per week and the number of nitroglycerin tablets per week by study group, based on mean values

As seen from the table, the patients in both study groups met the inclusion criteria, and the difference between groups was not statistically or clinically significant for most parameters. However, it should be noted that patients in the Thiotriazolin® group had slightly more severe manifestations of the disease than those treated with Meldonium: they were significantly older (almost 4 years), had a 2.5 year longer duration of their CHD, and showed a trend toward a higher incidence of complications, with four cases of previous myocardial infarction and one revascularization procedure. Yet, hypertension in this group was 25% less common, which explains the lower rate of ACE inhibitor use.

Anti-anginal efficacy of the treatment

According to patient diaries, both medicinal products demonstrated anti-anginal efficacy: statistically and clinically significant reductions in the frequency of angina attacks and the number of nitroglycerin tablets per week were observed in both study groups after treatment. Changes in the number of angina attacks and the number of nitroglycerin tablets taken per week are shown in Fig. 1 and 2.

Comparison of the above changes (Table 3) shows that the number of attacks and the number of nitroglycerin tablets in the intervention group continued to decrease progressively starting from week 2 and reaching maximum reductions of 53% and 65%, respectively, at the end of treatment. In the control group, however, maximum reductions in the frequency of attacks and the number of tablets were observed at week 3 of treatment, and the effect was slightly reduced by week 4. Patients in the intervention group showed a significantly higher reduction in the number of angina attacks per week compared to the control group at week 2 (p=0.038) and week 4 (p=0.014) of study treatment. 

Patients in the intervention group showed a significantly higher reduction in the use of nitroglycerin tablets per week versus the control group at week 4 of the study treatment (p=0.012). 

The descriptive statistics (frequency and percentage) for treatment efficacy analysis in terms of a 50% reduction in the number of angina attacks and the number of nitroglycerin tablets taken per week, as well as the results of group comparison using the Pearson χ2 test with Yates’ correction are shown in Table 4.

Table 4 Frequencies of the 50% reduction in the number of angina attacks (per week) and number of nitroglycerin tablets taken (per week) by study group

Table 5 Changes in the tolerance to physical exercise in the cycle ergometer test by study group (M±s)

As seen from the table, the frequency of a 50% reduction in the number of nitroglycerin tablets per week was 30% higher (p=0.013) in the Thiotriazolin® group versus the Meldonium group at the end of treatment. These data are shown in Figure 3. No statistically significant differences were detected between the study groups in the frequency of a 50% reduction in the number of angina attacks per week; however, the percentage of patients with a 50% reduction in the number of angina attacks per week in the intervention group was higher than in the control group. These differences may have become statistically significant had the sample size been larger.

Evaluation of treatment efficacy in terms of tolerance to physical exercise

Changes in the exercise duration and work rate in the cycle ergometer test are presented in Table 5. As can be seen from the table, there were differences between the study groups at baseline, both in the duration of cycling and the work rate: patients in the intervention group had a significantly more severe condition compared to those in the control group. At the end of the observation period, the duration of cycling in the intervention group was significantly increased by 72%, and the work rate was significantly increased by 44%.

In the control group, both values were also significantly increased by 17% and 13%, respectively. Due to a greater increase in values in the intervention group, the levels of both the exercise duration and the work rate achieved at the end of the observation period did not differ between the two groups.

The increase in the duration of physical exercise taken by the patients in the intervention group was statistically and clinically significantly greater (by 2.45 min) compared to the control group (р=0.031). This demonstrates the superior treatment efficacy in the intervention group versus the control group with regard to the primary study endpoint. Comparison of the increases in exercise duration by study group is shown in Figure 4. The degree of increase in the work rate in the intervention group was not significantly different from that in the control group.

However, the observed trend suggests that this increase may become significant with a larger sample size.

As a ≥1-minute increase and a ≥2-minute increase in physical exercise duration in the cycle ergometer test were chosen as the pre-defined parameters of interest in this study, the degree of changes in these parameters across the study groups was analyzed. The descriptive statistics (frequency and percentage) for the analysis of the above parameters, as well as the results of group comparison using the Pearson χ2 test with Yates’ correction are shown in Table 6.

Table 6 Results of the analysis of 1- and 2-minute increases in exercise duration in the cycle ergometer test

As seen from the table, the percentage of patients who achieved 1- and 2-minute increases in physical exercise duration in the cycle ergometer test was greater in the intervention group versus the control group.

Evaluation of treatment efficacy based on Holter ECG monitoring results

Сhanges in the analyzed parameters of the 24-hour ECG monitoring across the study groups are presented in Table 7.

Table 7 Changes in the Holter monitoring parameters by study group (Ms)

It should be noted that, due to a strong deviation of the analyzed data distribution from the normal distribution, only certain trends can be documented based on the mean values; these trends suggest a decrease in the 24-hour ECG monitoring values across the study groups. As shown in the table, a statistically significant reduction both in the total daily number of ischemic episodes (69%) and the total duration of ischemic episodes (21%) was observed in the intervention group. 

Improvement in the above parameters was also observed in the control group, although it was not statistically significant.

The data obtained in the contrast analysis demonstrate statistically significant differences between groups with regard to changes in the 24-hour ECG monitoring parameters (changes from baseline to end of treatment), namely the total daily number of ischemic episodes and total daily duration of myocardial ischemia episodes (p=0.001 and p=0.003, respectively). These differences suggest the superior efficacy of treatment in the intervention group (Thiotriazolin®) compared to the control group (Meldonium).

Treatment tolerability and safety analysis

No side effects were observed for any of the study drugs; thus, no dose adjustment or discontinuation of treatment was required in the course of the study.

Discussion

The current standard of care in the treatment of patients with CHD is primarily focused on the use of neurohumoral modulation agents (beta-blockers, ACE inhibitors), hemodynamic support (nitrates, calcium channel blockers) and other therapies improving the patient’s prognosis (statins, antiplatelet drugs) [2, 10, 15, 16]. However, if the basic therapies have already fulfilled their potential and/or there are clinical limitations of their use (hypotension, bradycardia), substantial assistance in maintaining the viability of the ischemic organ can be provided by metabolic drugs increasing the efficiency of oxygen utilization, switching the metabolism to more sparing pathways and protecting tissues from the oxidative stress consequences during reperfusion. Metabolically active agents have an anti-ischemic effect by acting on metabolic processes in the myocardium [2, 10, 11, 14]. The mechanism of action of these drugs is directly related to myocardial energy supply.

The clinical trials with Meldonium were mostly dedicated to the evaluation of its anti-ischemic effect in stable angina and acute myocardial infarction.

Most patients receiving this medicinal product at daily doses from 0.5 to 1.0 g for 1 to 3 weeks demonstrated both a lower daily number of angina attacks and a higher tolerance to physical exercise expressed as an increase in total duration of the cycle ergometer test to the onset of anginal pain attack, a higher level of work rate and an increase in the anaerobic threshold value [5, 6, 9]. The efficacy results for Meldonium obtained in this study confirm the above-mentioned literature data.

In addition, the marked anti-ischemic effect of Thiotriazolin® observed in this study is consistent with the literature data [1, 3, 13]. For instance, according to the data obtained by V.A. Vizir et al. (2010) in a multicenter randomized clinical trial, the use of medicinal product Thiotriazolin® versus placebo in addition to background treatment in patients with class II or III stable angina resulted in significant reductions in the daily number of ischemic episodes by 53.9% and the total daily duration of ischemic episodes by 44% [4].

According to H.V. Dziak et al. (2010), treatment with Thiotriazolin® for 30 days in addition to background therapy in patients with CHD and class II or III stable angina resulted in a statistically significant reduction from baseline in the frequency of typical angina attacks and the number of nitroglycerin tablets taken by patients per week [7]. Reduction from baseline in the number of angina attacks and nitroglycerin tablets taken per week at the final visit was significantly greater in the Thiotriazolin® group compared to the placebo group.

In addition, treatment with Thiotriazolin® significantly increased the exercise time to 1 mm ST segment depression or the onset of anginal pain during treadmill test compared to baseline values. The increase in the exercise time to 1 mm ST segment depression or the onset of anginal pain in patients receiving Thiotriazolin® was significantly higher than in the placebo group. For instance, the mean exercise time to 1 mm ST segment depression or the onset of anginal pain in the Thiotriazolin® group increased on average by 1.9 min (27.5% from baseline) compared to 0.8 min (17.5% from baseline) in the control group. This study is different from the above in that the control group consisted of the patients taking an active metabolic drug instead of placebo: the data obtained were directly compared with the efficacy data for Meldonium. Such direct comparison showed that the frequency of angina attacks and the number and duration of ischemic attacks based on the 24-hour ECG monitoring results were reduced, and the tolerance to physical exercise was increased, to a greater extent in patients treated with Thiotriazolin® than in those receiving other active metabolic drugs.

Conclusions

1. The study has demonstrated a superior efficacy of treatment with Thiotriazolin® compared to Meldonium as per the protocol-defined regimens in increasing the duration of physical exercise in the cycle ergometer stress test according to R. Bruce protocol in patients with class II or III stable angina. For instance, the increase in exercise duration in the intervention group was significantly greater (2.45 min; p=0.031) than in the control group.
2. A highly significant (р<0.001) reduction in the 24-hour Holter ECG monitoring parameters (total daily number of myocardial ischemia episodes and total daily duration of myocardial ischemia episodes) was observed in the intervention (Thiotriazolin®) group, while the changes in these parameters in the control (Meldonium) group were not statistically significant.
3. Statistically significant differences favoring the use of Thiotriazolin® were observed between study groups with regard to the changes in 24-hour Holter ECG monitoring parameters, namely the total daily number of myocardial ischemia episodes and total daily duration of myocardial ischemia episodes, recorded over the treatment period (р=0.001 and р=0.003, respectively).
4. A statistically significant reduction in the frequency of angina attacks per week and the weekly number of nitroglycerin tablets at weeks 2, 3 and 4 compared to week 1 values was observed in the intervention (Thiotriazolin®) group demonstrating the efficacy of the administered treatment regimen including Thiotriazolin®.
5. The number of nitroglycerin tablets taken by the patients in the control (Meldonium) group at week 3 was significantly lower than at week 1. Changes in the number of nitroglycerin tablets at week 2 and week 4 compared to week 1 were not significant. Moreover, changes in the number of angina attacks at weeks 2, 3 and 4 compared to week 1 were also not significant. All of this indicates the insufficient effect of the treatment regimen including Meldonium on the analyzed parameters.
6. The reduction in the number of angina attacks in the intervention (Thiotriazolin®) group was significantly greater than in the control (Meldonium) group at week 2 (р=0.038) and week 4 (р=0.014) of treatment.
7. The reduction in the weekly use of nitroglycerin tablets was significantly higher in the intervention (Thiotriazolin®) group compared to the control (Meldonium) group at week 4 of treatment (р=0.012).
8. The percentage of patients who achieved a reduction in the number of nitroglycerin tablets taken per week was significantly higher (p=0.013) in the intervention (Thiotriazolin®) group compared to the control (Meldonium) group. The percentage of such patients was 67.5% (95% CI: 52.02-79.92%) in the intervention group and 37.5% (95% CI: 24.22-52.97%) in the control group.
9. The study drugs did not cause any adverse changes in the vital signs (HR and BP) or in the laboratory parameters of complete blood count, blood biochemistry or urinalysis. No adverse reactions / adverse events were recorded in the course of this study.