Short- and Long-Term Effects of Molsidomine Retard and Molsidomine Nonretard on Exercise Capacity and Clinical Status in Patients with Stable Angina

A Multicenter Randomized Double-Blind Crossover Placebo-Controlled Trial

Abstract

A multicenter, randomized, double-blind, crossover, placebo-controlled study was conducted in 90 isosorbide dinitrate responders showing stable angina to compare the efficacy of molsidomine retard, 8 mg b.i.d., with that of molsidomine, 4 mg t.i.d., for 6 weeks. Total work performance (workload × min) was significantly improved, compared with baseline and placebo until 8 and 12 h after molsidomine and molsidomine retard administration, respectively. ST-segment depression decreased significantly under the two treatments at 60 W as well as at maximal exercise. The rate-pressure product (heart rate × systolic blood pressure) decreased and increased significantly at submaximal and maximal exercise level, respectively. All these effects remained significant after 6-week treatment, with only the ST segment showing a nonsignificant tendency to improvement at maximal work. The frequency of anginal attacks and of sublingual nitroderivative-tablets consumption decreased significantly with molsidomine, 4 mg, and molsidomine retard, 8 mg. However, overall results showed that the latter form reduces myocardial ischemia more efficiently at submaximal exercise level, has a more prolonged effect on exercise tolerance, and maintains it at a somewhat higher level after 6-week treatment.

Molsidomine, a direct nitric oxide (NO) donor and thus vasodilator belonging to the group of sydnonimines, is metabolized in the liver to SIN-1 (linsidomine), which spontaneously hydrolyzes to SIN-1A, the active metabolite setting NO free ^(1,2). SIN-1A incorporated into γ-cyclodextrin has been shown to be active per os and ∼6 times more potent than SIN-1 ⁽³⁾. Molsidomine, 2 and 4 mg, administered 3 times a day, relieves symptoms of ischemic heart disease. The 8-mg extended-release form shows antianginal efficacy when administered twice a day ⁽⁴⁾.

Our study sought to determine the effect on angina and myocardial ischemia of molsidomine retard, 8 mg, and molsidomine nonretard, 4 mg, versus placebo, administered for 6 weeks on a b.i.d. and a t.i.d. regimen, respectively. End points were efficacy on exercise capacity and ST-segment depression during stress testing, as well as influence of therapy on the quality of life of patients with angina evaluated by the daily numbers of attacks and of nitroderivative tablets consumed.

METHODS

Study population

Ninety patients, 89 men and one woman aged 42-65 years (mean ± SD, 55.2 ± 5.2) were investigated. All had stable angina pectoris without increase of the frequency or severity of crises during the last 30 days. Ischemic heart disease was proven by a positive exercise test [ST-segment depression of ≥1 mm (i.e., 0.1 mV below resting level), upward-sloping ST-segment depression being measured 0.08 s after the J point] and an anamnesis of myocardial infarction >3 months before entering the study or a positive coronary angiography or thallium scintigraphy. All showed a positive response to isosorbide dinitrate (ISDN) shown by an increase of total exercise duration of ≥20% (mean, 34.8%) during a second test made 1 h later, after 5 mg ISDN administered sublingually.

Study design and medications

A multicenter randomized, double-dummy, double-blind, crossover placebo-controlled protocol was designed (Fig. 1) in accordance with the guidelines for clinical investigation of antianginal drugs provided by the European Agency for the Evaluation of Medicinal Products ⁽⁵⁾. Antianginal medications were discontinued during a 2-week run-in period, except for sublingual nitrates.

FIG. 1: Double-blind crossover placebo-controlled study design. ◊, baseline exercise test; ✦, exercise test 2, 4, 6, 8, 10 and 12 h after treatment intake.

Study medications (molsidomine, 8 mg b.i.d.; molsidomine, 4 mg t.i.d.; and placebo) were of identical appearance and odor.

To reduce the number of exercise tests in patients, they were divided into six equal groups managed by each of the six participating centers. Patients of each group performed a baseline test before medication intake and a second test at 2, 4, 6, 8, 10, or 12 h after medication intake, respectively. The patients performing the test 10 and 12 h after intake of medication were hospitalized for 2 days; they received the medication at 22.00 h and performed the exercise test at 8.00 or 10.00 the next morning. The timing of the exercise test was the same for all the patients belonging to a given group but was the free choice of each center, which could account for some heterogeneity in baseline measurements.

Patients were also randomized into three sequences of treatment: sequence 1 (molsidomine, 4 mg t.i.d.; placebo; molsidomine, 8 mg b.i.d.), sequence 2 (placebo; molsidomine, 8 mg b.i.d.; molsidomine, 4 mg t.i.d.), and sequence 3 (molsidomine, 8 mg b.i.d.; molsidomine, 4 mg t.i.d.; placebo; Table 1). Each sequence consisted of three 6-week periods separated by 2-week washout periods and two crossovers. Maximal graded exercise tests were performed with patients sitting on the bicycle ergometer; the workload was started at 30 W and was increased by 30 W every 3 min. An electrocardiogram (ECG) with one peripheral and three precordial leads was monitored continuously and registered every minute during exercise and for ≥5 min if the ST-segment depression had not disappeared, in the recovery period. The lead showing the most important ST-segment depression was selected for analysis. Heart rate (HR) was registered every minute, and blood pressure, every 3 min, by using the Korotkoff auscultation method. The test was stopped when exhaustion or manifestation of coronary insufficiency occurred.

TABLE 1: Drug-administration design

Episodes of angina, number of nitroderivate tablets used, and adverse effects were recorded by the patient on diary cards during the placebo periods and the treatment periods.

The study was performed in accordance with the guidelines of good clinical practice, and its design was approved by the ad hoc Ethical Committees. Informed consent was obtained from the patients.

Study variables

The following exercise parameters were analyzed: maximal working capacity quantified by total amount of work performed, HR at 60 W and at maximal workload, systolic blood pressure (SBP) at 60 W and at maximal workload, rate-pressure product (RPP = HR × SBP) at 60 W and at maximal workload, and ST-segment depression at 60 W and at maximal workload.

To evaluate the antianginal effects of the drugs, we also considered the number of anginal attacks and the sublingual nitroderivate-tablet consumption, both expressed as mean values per day during treatment with active drugs and placebo.

Statistical analysis

The homogeneity between the different treatment groups at baseline, the absence of carryover, and the lack of habituation to the drugs were assessed by analysis of variance (ANOVA). When homogeneity was achieved and in the absence of any carryover effect, the effect of treatment for all the parameters was evaluated by ANOVA. When the effect of treatment was significant (p < 0.05), all possible differences between active medications, placebo, and baseline were tested by Bonferroni's adjusted paired t tests.

RESULTS

Exercise test

Maximal working capacity. Sixty patients performed a baseline test followed by a second test 2, 4, 6, 8, 10, or 12 h after medication intake at the beginning of the 6-week placebo, molsidomine (4 mg), and molsidomine (8 mg) periods. No statistically significant effect was observed between the baseline values recorded before placebo, molsidomine (4 mg), or molsidomine retard (8 mg) intake, nor any sequence effect.

Maximal working capacity increased significantly, compared with baseline or placebo values or both, until 8 h after molsidomine (4 mg) administration and until 12 h after molsidomine retard (8 mg) administration (Fig. 2).

FIG. 2: Influence of molsidomine, 4 mg, and molsidomine retard, 8 mg, on maximal working capacity. Results are given as means ± SD. ***p < 0.001; **p < 0.01;*p < 0.05; NS, p > 0.05. Three levels of comparison: between molsidomine or placebo and baseline, between molsidomine treatments and placebo, and between molsidomine treatments. Top: open, shaded, and solid squares, 2, 4, and 6 h after administration, respectively; bottom: open, shaded, and solid squares, 8, 10, and 12 h after administration, respectively.

No tolerance to molsidomine(4 mg) or to molsidomine retard (8 mg) appeared after 6-week treatment (45 patients), maximal working capacity being not significantly different at the beginning and at the end of the period for both drugs and remaining, on the contrary, highly significantly more elevated under active treatment than under placebo or baseline conditions (Fig. 3).

FIG. 3: Influence of molsidomine, 4 mg, and molsidomine retard, 8 mg, on maximal working capacity after 6-weeks of treatment. Results are given as means ± SD. ***p < 0.001; *p< 0.05; NS, p > 0.05. Three levels of comparison: between molsidomine or placebo and baseline, between molsidomine treatments and placebo, and between molsidomine treatments.

ST-segment depression at 60-W level and at maximal exercise. There was a significant reduction of ST-segment depression compared with baseline and placebo values after molsidomine (4 mg) and molsidomine retard(8 mg) administrations at 60-W level as well as at the exercise arrest (Fig. 4).

FIG. 4: Influence of molsidomine, 4 mg, and molsidomine retard, 8 mg, on ST-segment depression. Results are given as means± SD. ***p < 0.001; *p < 0.05; NS, p > 0.05. Three levels of comparison: between molsidomine or placebo and baseline, between molsidomine treatments and placebo, and between molsidomine treatments.

Moreover, for both drugs, ST-segment depression was not significantly different at the beginning and at the end of the 6-week treatment period at submaximal and at maximal exercise. The reduction of ST-segment depression at 60-W level remained significant compared with placebo and baseline conditions after the 6-week treatment. At maximal exercise, however, that reduction did not reach a significant level (Fig. 5).

FIG. 5: Influence of molsidomine, 4 mg, and molsidomine retard, 8 mg, on ST-segment depression after 6-weeks of treatment. Results are given as means± SD. ***p < 0.001; **p < 0.01; *p < 0.05; NS, p > 0.05. Three levels of comparison: between molsidomine or placebo and baseline, between molsidomine treatments and placebo, and between molsidomine treatments.

RPP at 60-W level and at maximal exercise. RPP decreased significantly compared with baseline and placebo values after molsidomine (4 mg) and after molsidomine retard(8 mg) administration at 60-W level (because of a significant average decrease in HR of five to six beats and in systolic blood pressure of 14-17 mm Hg) and increased significantly at exercise arrest (because of a significant average increase in HR of nine to 13 beats and in systolic blood pressure of 7 mm Hg; Fig. 6).

FIG. 6: Influence of molsidomine, 4 mg, and molsidomine retard, 8 mg, on rate-pressure product (RPP). Results are given as means ± SD. ***p < 0.001; *p < 0.05; NS, p > 0.05. Three levels of comparison: between molsidomine or placebo and baseline, between molsidomine treatments and placebo, and between molsidomine treatments.

For both drugs, RPP was not significantly different at the beginning and at the end of the 6-week treatment period at submaximal and at maximal exercise. After 6-weeks of treatment, the reduction of RPP at 60-W level and its increase at maximal exercise remained highly significant compared with placebo and baseline (because of a significant average decrease in HR of five to eight beats and in systolic blood pressure of 10-13 mm Hg at 60 W and an increase in HR of seven to 10 beats and in systolic blood pressure of 5-9 mm Hg at maximal exercise; Fig. 7).

FIG. 7: Influence of molsidomine, 4 mg, and molsidomine retard, 8 mg, on rate-pressure product (RPP) after 6-weeks of treatment. Results are given as means ± SD.***p < 0.001; NS, p > 0.05. Three levels of comparison: between molsidomine or placebo and baseline, between molsidomine treatments and placebo, and between molsidomine treatments.

Antianginal effect

Forty-five patients filled in their diary cards completely during the 24-week duration of the study. There was a highly significant reduction compared with placebo in the frequency of angina attacks and of sublingual nitroderivate-tablet consumption with molsidomine(4 mg) and molsidomine retard (8 mg), 43 and 35% with molsidomine (4 mg), 47 and 30% with molsidomine retard (8 mg), respectively (Fig. 8).

FIG. 8: Influence of molsidomine, 4 mg, and molsidomine retard, 8 mg, on the occurrence of anginal attacks (mean number per day) and on sublingual nitroderivative consumption (mean number per day). Results are given as means ± SD. ***p < 0.001; NS, p > 0.05. Two levels of comparison: between molsidomine treatments and placebo and between molsidomine treatments.

Adverse events

Adverse events occurred in 10 (11%) of 90 patients with placebo as well as with molsidomine (4 mg) and molsidomine retard (8 mg). Headache represented 50% of side effects with placebo and 90% with molsidomine (4 mg) and molsidomine retard(8 mg). There was one case of unstable angina with placebo and one sudden death 1 week after the beginning of the last 2-week washout period. Autopsy revealed local hemorrhage into coronary atherosclerotic plaque fragmentation foci with myocardial damage. The other adverse events (palpitations or arterial hypertension with placebo as well as acute respiratory diseases) were not related to the study drugs.

DISCUSSION

Molsidomine is now routinely used in the treatment of angina pectoris, ischemic heart disease, and congestive heart failure. It is clinically active at the dosage of 4 mg, 3 times a day ^(6-8). The aim of this study was to compare that efficacy with that of extended-release molsidomine (8 mg) and to determine whether the latter could control angina pectoris in daily life when administered twice a day.

Results show that an increase in maximal working capacity is maintained 8 h after molsidomine (4 mg) and 12 h after molsidomine retard (8 mg) administration. These data largely corroborate the pharmacokinetic study conducted in healthy volunteers, demonstrating that a therapeutic plasma concentration of molsidomine was maintained 6-8 h after 5 days (steady-state) of administration of molsidomine, 4 mg t.i.d., and 12 h after 5 days of administration of molsidomine retard, 8 mg b.i.d (unpublished results). No tolerance to treatment appeared after 6-weeks of treatment, the effect of molsidomine retard (8 mg), however, was significantly more marked than that of molsidomine (4 mg). The absence of tolerance to molsidomine, contrary to that classically observed with nitrates, has been studied and recognized ⁽⁹⁾.

Similarly, highly significant improvement in ST-segment depression is observed at the 60-W level, more marked with molsidomine retard (8 mg) than with molsidomine (4 mg), and is concomitant to a highly significant reduction of the RPP, the latter suggesting reduced myocardial oxygen requirements at submaximal exercise levels.

At maximal exercise, a similar highly significant improvement in ST-segment depression is observed with molsidomine(4 mg) and molsidomine retard (8 mg), concomitant with a highly significant increase in RPP, suggesting that improvement in myocardial perfusion adds to a reduced need for myocardial oxygenation.

After 6-week treatment, the highly significant reduction of the RPP persists at submaximal and the highly significant increase at maximal exercise levels, with a somewhat less significant reduction in ST-segment depression with treatment at the 60-W level and the persistence of a tendency to ST-segment improvement at maximal work level, although it does not reach the statistical significance level, perhaps because of some outpouring of the coronary vasodilating effect.

The quality of life is significantly improved during the 6-week period of treatment with molsidomine, 4 mg t.i.d., or molsidomine retard, 8 mg b.i.d., as shown from the highly significant decrease in anginal attacks and sublingual nitroderivates consumption.

Moreover, our results show that molsidomine retard, 8 mg b.i.d., besides potentially improving patient compliance with treatment compared with molsidomine(4 mg), reduces myocardial ischemia more efficiently than does molsidomine (4 mg) at submaximal exercise level, perhaps owing to a more efficient improvement in myocardial perfusion, the reduction of the RPP being not significantly more marked compared with molsidomine (4 mg), increases working capacity for 12 h after intake and maintains it at a slightly higher level than molsidomine (4 mg) does after 6-week treatment.

Acknowledgment: We are grateful to Prof. J. M. Detry for his collaboration and advisory role in the design of the study protocol, to Dr. Gototsev and Dr. Baikova(Clinical Trial Organization) for the organization and monitoring of the trial, as well as to the six centers (directed by Prof. Lyakishev, Prof. Sidorenko, Prof. Karpov, Prof. Lazebnik, Prof. Glezer, and Prof. Ivashkin) that participated in the study.