Trimetazidine and stable angina a double-blind trial. [Effectiveness of trimetazidine in stable effort angina due to chronic coronary insufficiency. A double-blind versus placebo study]. Combination treatment with trimetazidine and diltiazem in stable angina pectoris. Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group. Anti-ischaemic efficacy and tolerability of trimetazidine administered to patients with angina pectoris: results of three studies. [The effects of trimetazidine on ergometric parameters in exercise-induced angina. Controlled multicenter double blind versus placebo study]. Treatment of stable angina with low dose diltiazem in combination with the metabolic agent trimetazidine. Combination therapy of trimetazidine with diltiazem in patients with coronary artery disease. Group of South of France Investigators. Comparison of trimetazidine with nifedipine in effort angina: a double-blind, crossover study.
The effect of trimetazidine was evaluated in patients with stable angina by adding it to the other antianginal regimen in a double blind crossover design each of 8 week's duration. The method of evaluation made use of symptom recall, daily dairy of the intake of sublingual nitrates or of anginal discomfort and in some, symptom limited treadmill exercise stress test (EST). Thirty-six patients completed the trial. Symptom-wise, 16 patients could not differentiate the effect of the true tablet from the placebo. Eight had less and 12 had more angina while on the drug. Of the 17 evaluable EST, 9 showed no change in the degree of ischemic changes while 4 performed with less and 4 with more ischemia while on the drug. Symptom-wise and taking into account the pre and post trial periods, a placebo effect was not found to be dominant. It is concluded that trimetazidine does not improve angina among those already being treated with conventional doses of nitrates, beta and calcium blockers. The antianginal activity of trimetazidine (Vastarel 20 mg) was evaluated in a double blind study versus placebo. The 54 subjects of the survey were males, of mean age 55.2 +/- 1.4 years in the trimetazidine group and 55.5 +/- 1.8 years in the placebo group, suffering from stable angina. The stability of angina was tested by two exercise tests carried out at the beginning and at the end of a two-week preselection period under placebo. Three tablets daily of either trimetazidine or placebo were given at random for two weeks. At the end of that time, a third exercise test was carried out. The clinical results showed a significant reduction (P less than 0.001) in the number of weekly attacks from 8.1 +/- 0.3 to 2.9 +/- 0.5 under trimetazidine and from 7.6 +/- 0.2 to 4.9 +/- 0.5 under placebo. Moreover, nitroglycerin consumption over a week decreased from 9.1 +/- 0.6 to 3.1 +/- 0.5 tablets under trimetazidine and from 7.9 +/- 0.3 to 5.4 +/- 0.6 tablets under placebo. The difference was significant (P less than 0.001). The global evaluation of the exercise tests showed a significant difference in favor of trimetazidine: 19 patients out of 27 improved under trimetazidine, as compared to 11 out of 27 under placebo. The total workload-capacity after treatment was increased by 62.1% under trimetazidine, and by 24.7% under placebo (P = 0.007). The rate-pressure product diminished by 12% with trimetazidine and by 4% with the placebo. Nevertheless, the interaction was not significant (P = 0.079). This study made it possible to evaluate the significant reduction of stress attacks frequency and nitroglycerin consumption under trimetazidine versus placebo. This clinical improvement was assessed by ergometric parameters. To assess antianginal efficacy and possible adverse haemodynamic effects of combination treatment with trimetazidine and diltiazem in patients with stable angina.
                Double blind, randomised, placebo controlled trial of four weeks duration.
                Outpatient department of two Indian hospitals.
                64 male patients with stable angina, uncontrolled on diltiazem alone.
                Diltiazem 180 mg and trimetazidine 60 mg, or diltiazem 180 mg and placebo daily.
                Change in exercise time to 1 mm ST segment depression.
                33 patients (55%) had no exercise induced angina at 3 mm ST segment depression at inclusion in the study (silent ischaemia). Intention to treat analysis showed that of 32 patients in each treatment group, the number (%) of patients responding to trimetazidine compared to placebo was: for anginal attacks, 28 (87.5) v 15 (46.9), p < 0.001; for exercise time to 1 mm ST segment depression, 21 (65.6) v 9 (28.1), p < 0.003; for exercise time to angina, 12 (37.5) v 5 (15.6), p < 0.05; and for maximum work at peak exercise, 17 (53.1) v 8 (25), p < 0.02. Compared to placebo, there was net improvement with trimetazidine in mean anginal attacks of 4.8/ week (95% confidence interval (CI) 7.5 to 2.1; p < 0.002); in mean exercise times at 1 mm ST segment depression of 94.2 seconds (95% CI 182.8 to 5.6; p < 0.05), and at onset of angina of 113.1 seconds (95% CI 181.6 to 44.6; p < 0.02); and in mean maximum work at peak exercise of 1.4 metabolic equivalents (95% CI 2.4 to 0.3; p < 0.05).
                Patients with stable angina uncontrolled with diltiazem had a clinically important improvement after combination treatment with trimetazidine, without adverse haemodynamic events or increased side effects. 1. Trimetazidine has a direct anti-ischaemic effect on the myocardium without altering the rate x pressure product or coronary blood flow. 2. The effects of trimetazidine (20 mg three times daily) were compared with those of propranolol (40 mg three times daily) in a double-blind parallel group multicentre study in 149 men with stable angina. 3. Reproducibility of exercise performance was verified during a 3 week run-in placebo washout period. All patients had > 1 mm ST-depression on exercise test. 4. After 3 months, similar anti-anginal efficacy was observed between the trimetazidine (n = 71) and propranolol (n = 78) groups. No significant differences were observed between trimetazidine and propranolol as regards anginal attack rate per week (mean difference P-TMZ: 2; 95% CI: -4.4, 0.5) and exercise duration (mean difference P-TMZ: 0 s; 95% CI: -33, 34) or time to 1 mm ST segment depression (mean difference P-TMZ: 13 s; 95% CI: -24, 51). Heart rate and rate x pressure product at rest and at peak exercise remained unchanged in the trimetazidine group but significantly decreased with propranolol (P < 0.001 in all cases). With both drugs there was a trend to decreased ischaemic episodes in the 46% patients who experienced ambulatory ischaemia on Holter monitoring. Six patients stopped trimetazidine and 12 propranolol. Of these, five in each group were withdrawn because of deterioration in cardiovascular status. 5. The results suggest that trimetazidine and propranolol at the doses studied have similar efficacy in patients with stable angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS) Several clinical studies have compared the anti-ischaemic properties of trimetazidine used as monotherapy with those of standard anti-anginal therapy. In the treatment of uncontrolled angina pectoris, the addition of a metabolic agent such as trimetazidine to existing therapy with a haemodynamic agent would appear to confer advantages over the addition of a second haemodynamic agent. Here we report the results of three studies conducted in Poland, the Czech Republic and Hungary that provide additional evidence for the beneficial effects of combining trimetazidine with a conventional haemodynamic agent such as beta-blockers, long-acting nitrate or calcium channel blockers. This combination provided significant benefits in terms of improved exercise capacity and decreased number of angina attacks along with a good tolerability profile. The antianginal effect of trimetazidine was assessed by a controlled multicentre double-blind versus placebo trial. The study included 32 males, average age 59.5 years, with stable angina of effort. The stability of angina was determined by two exercise stress tests performed at the beginning and at the end of a 15 day pre-selection period under placebo. The patients included in the trial were given 3 tablets a day of either trimetazidine (20 mg per tablet) or of placebo for one month. At the end of the treatment period the patients underwent a third exercise stress test. Comparing the results of exercise testing before and after treatment by a Mann and Whitney test, a statistically significant improvement with trimetazidine was demonstrated with respect to placebo for three parameters: total work increased from 4200 +/- 372 to 5620 +/- 387 Kpm in the trimetazidine group compared to 4191 +/- 399 to 4564 +/- 431 Kpm for placebo (p = 0.012); the duration of exercise increased from 10.2 +/- 0.5 to 12.1 +/- 0.5 minutes with trimetazidine compared to 10.2 +/- 0.5 to 10.7 +/- 0.5 with placebo (p = 0.016); the period to 1 mm ST depression increased from 8.3 +/- 0.6 to 9.8 +/- 0.5 minutes with trimetazidine compared to 8.4 +/- 0.5 to 9.0 +/- 0.7 minutes with placebo (p = 0.034). These results show that signs of ischaemia are delayed by trimetazidine. There were no significant changes in peripheral haemodynamics at rest or on effort. The antianginal action of trimetazidine seems therefore to be unrelated to a chronotropic or vasomotor effect and could be related to a mechanism of cellular regulation. The risk/benefit of moderate to high doses of calcium antagonists in stable angina is uncertain. This study investigates the efficacy and acceptability of low dose diltiazem in combination with trimetazidine for the treatment of stable angina.
                In a 28-day, randomized, double blind study, treatment with 90 mg diltiazem in combination with 60 mg trimetazidine or placebo per day was compared in 50 patients with stable angina. The primary outcomes were time to 1-mm ST segment depression and the Duke treadmill score.
                Of the 25 patients in each treatment group, the number (%) of patients responding to trimetazidine compared to placebo was, in time to 1-mm ST segment depression, 13 (52) versus 5 (20), P<0.05; in the Duke treadmill score, 18 (72) versus 8 (32), P<0.01; and in angina 17 (68) versus 3 (12), P<0.01. Compared to placebo there was an improvement with trimetazidine in mean exercise time to 1-mm ST segment depression of 128 s (95% confidence interval 45.0-208.5; P<0.01); in the mean Duke treadmill score of 57.4% (95% confidence interval 9.9-100; P<0.02); and in mean anginal attacks of 5.1 per week (95% confidence interval, 3.1-7.3, P<0.01).
                The combination of low dose diltiazem with trimetazidine is effective with few side-effects in the symptomatic control of patients with stable angina. The efficacy of trimetazidine, an antianginal agent with a direct effect on ischemic myocardium, has been tested alone or in combination with beta blockers or nifedipine. The combination with diltiazem, a widely used calcium antagonist, has not been studied. The aim of this study was to evaluate the potential benefit of oral trimetazidine (20 mg 3 times daily) in combination with oral diltiazem (60 mg three times daily). This was a multicenter, placebo-controlled study with a follow-up period of 6 months. Patients with stable angina and a positive exercise electrocardiogram before and after 15 days of diltiazem therapy were included. The 67 patients were randomized to diltiazem plus placebo (group I, 35 patients) and diltiazem plus trimetazidine (group II, 32 patients). Follow-up included a bicycle ergometer maximal exercise test and a physical examination at inclusion and at 3 and 6 months. The 2 groups were similar in terms of ergometric parameters, except for the ischemic threshold, defined as the time to 1-mm ST-segment depression. The latter was shorter in group II. Comparison of exercise tests performed at inclusion and after 6 months of therapy in both groups showed that the ischemic threshold was significantly prolonged (2 minutes 41 seconds; p < 0.001) in group II. This was not the case for group I, which showed a 41-second prolongation only (difference not significant). The work (kPM) produced at 1-mm ST-segment depression was also significantly increased in group II (1,445.9 kPM; p < 0.001) compared with group I (563.7 kPM; p = 0.012).(ABSTRACT TRUNCATED AT 250 WORDS) Trimetazidine has been shown to have an antianginal effect, increasing exercise capability without producing any significant change of heart rate or systolic blood pressure. The aim of this study was to compare trimetazidine efficiency to that of another classical antianginal drug. A double-blind crossover trimetazidine versus nifedipine trial was carried out in 39 male patients, mean age 58 years, with effort angina for 5 years on average, and a mean number of weekly attacks of 2.4. Thirteen patients had previous myocardial infarction. Nineteen patients received nifedipine (40 mg per day) then trimetazidine (60 mg per day), and 20 patients received the drugs in the opposite order. Each therapeutic period of 6 weeks was preceded by 1 week of washout with placebo. Drug efficacy was assessed by a bicycle exercise tolerance test, performed at the beginning and at the end of each therapeutic period, and by clinical symptoms observed with placebo or with treatment. The statistical analysis was performed according to a crossover design, with repeated measurements. The decrease of the number of weekly attacks was not significantly different with trimetazidine and nifedipine. Results on the exercise test showed no significant differences for maximum workload, the duration of exercise, ST-segment depression at peak exercise, and the time to 1-mm ST-segment depression. Heart rate and systolic blood pressure were not significantly different at rest and at peak exercise. However, the change in the rate-pressure product at the same workload differed significantly between the drugs: It decreased with nifedipine and remained unchanged with trimetazidine, indicating the difference to be in the mode of action of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
Trimetazidine is effective in the treatment of stable angina compared with placebo, alone or combined with conventional anti-anginal agents. Trimetazidine may result in fewer dropouts due to adverse events. Large, long term trials comparing trimetazidine with other anti-anginal drugs assessing clinically relevant important outcomes are required to establish its role in clinical management.