Cardiovascular Drugs and Therapy 4: 451-456, 1990 9 Kluwer Academic Publishers, Boston. Printed in U.S.A.
Nisoldipine Tablets once Daily versus Nifedipine Capsules three times daily in Patients with Stable Effort Angina Pectoris Pretreated with Atenolol Terje R. Pedersen, ~ M i c h a e l K a n t o r 2 ~Cardioloyy Department, Aker Sykehus, Oslo, Norway; 2Bayer (Sverige) AB, Stockholm, Sweden
Summary. T r e a t m e n t with nisoldipine (2 • 10 m g tablets once daily) a n d nifedipine (2 • 10 m g c a p s u l e s t h r e e times daily) in p a t i e n t s with severe, b u t stable effort a n g i n a pret r e a t e d with a t e n o l o l (100 m g once daily in 19 p a t i e n t s and 50 m g once daily in one p a t i e n t ) were c o m p a r e d for t h e i r effects on bicycle e x e r c i s e t o l e r a n c e a n d t h e i r adverse effects in a r a n d o m i z e d 2 • 4 week, double-blind, d o u b l e - d u m m y crossover s t u d y . All p a t i e n t s had m u l t i v e s s e l disease, 16 p a t i e n t s had o c c l u s i o n o f at least one vessel, a n d eight p a t i e n t s had a h i s t o r y o f m y o c a r d i a l i n f a r c t i o n . Two p a t i e n t s left the s t u d y d u r i n g t h e initial n i s o l d i p i n e period, one b e c a u s e of a g g r a v a tion o f t h e a n g i n a a n d t h e o t h e r b e c a u s e o f s u s p e c t e d allergic reaction. Addition o f nifedipine to atenolol t r e a t m e n t s i g n i f i c a n t l y improved t h e v a r i a b l e s m e a s u r e d for severity of a n g i n a , s u c h as t i m e o f exercise until 1 m m a n d 2 m m STs e g m e n t d e p r e s s i o n , total exercise t i m e and total workload. In c o n t r a s t , no s u c h i m p r o v e m e n t w a s noted a f t e r t h e addition of n i s o l d i p i n e to atenolol. However, nisoldipine resulted in a s i g n i f i c a n t p r o l o n g a t i o n o f t h e t i m e to t h e i n i t i a t i o n of c h e s t d i s c o m f o r t , t h e m a x i m u m h e a r t rate, and t h e double product. In a t e n o l o l - t r e a t e d p a t i e n t s with severe effort a n g i n a pectoris, n i f e d i p i n e 20 m g tid improved exercise capacity, while n i s o l d i p i n e 20 m g once daily did not have a s i m i l a r effect.
Key Words. a n g i n a pectoris, nifedipine, nisoldipine, atenolol.
Nisoldipine is a calcium antagonist of the dihydropyridine family. In animal studies it has been shown to have a higher vascular specificity than nifedipine, the vasodilating effect being highest in the coronary and femoral arteries [1-3]. It has been shown to have a more prolonged effect than nifedipine [3]. The antiischemic effect in patients with angina pectoris has been reported to persist over at least 7 hours after administration of 20 mg of nisoldipine [4]. In the present study the antianginal effect of 20 mg nisoldipine once daily was compared with the effect of nifedipine 20 mg tid in patients with severe angina who were pretreated with atenolol. The effect was compared using a graded bicycle exercise test.
Methods Patients of both sexes, below 70 years of age, who were submitted to the hospital for coronary angiography because of severe effort angina pectoris were asked to participate in the study. Patients were eligible for entry if they had had angiographically confirmed severe coronary artery disease and a symptom-limited bicycle exercise test with at least 1 mm ST-segment depression in lead CF5. Patients were excluded fl'om entry if they had angina at rest, unstable angina, diastolic blood pressure of 100 m m H g or above, congestive heart failure, cardiac valvular disease, significant noncardiac disease, or if they required therapy with longlasting nitrates, digitalis, o1" other drugs that might influence the study results. Patients with previous adverse experience with dihydropyridine drugs were also excluded. After having given informed consent, 20 patients entered the study. Since the waiting time for coronary artery bypass surgery in patients with stable angina was 4-6 months or more in Oslo at the time of the study, no patient had to delay their operation because of study participation. Of the 20 patients, 17 had been treated with beta-adrenergic blocking agents, six of them in combination with long-acting nitrates, six with nifedipine, and five with both. The remaining three patients had received monotherapy with either nifedipine, isosorbide dinitrate, or sublingual nitroglycerin, respectively. Two patients had previously had aortocoronary bypass grafting. Other patient characteristics are listed in Table 1. The study was approved by the local ethical committee and by the National Bureau for Drug Control.
Address for correspondence and reprint requests: Terje R. Pedersen, M.D., Cardiology Department, Aker Sykehus, N 0514 Oslo 5, Norway.
451
452
Pedersenand Kantor
Table I. Characteristics of the 20 patie~ds randomized. Number Age (years) Sex male female Height (cm) Weight (kg) Smokers Duration of angina (years) NYHA class I I class Ill Previous iIffarction Ejection fraction (c/c) Coronary angiography Occlusions i artery 2 arteries 3 arteries > 70~ stenosis 1 artery 2 arteries > 3 arteries Collaterals Not visible Few/little Moderate Extensive
Study
Mean
Range
55
39-69
173 71
154-190 59-86
16 4 11 6.3
1-21
2 18 8 68
44-84
13 2 1 1 8 11 3 2 9 6
by 10 rag, to a maximum of 20 mg tid during the fourth week. An upright bicycle exercise test was performed 6-9 hours (mean 7.1 hours) after the morning intake of study medication and 1.5-2.5 hours (mean 2.1 hours) after the midday intake. This testing time was chosen since it represents a time of the day with heavy exercise demands for most patients, as well as an adequate time from the morning dose of nisoldipine to test this drug's long-acting capability. The patients were allowed to have a light meal a minimum of 2 hours before the exercise test. Smoking or consumption of coffee or tea was not allowed. All tests were performed with the same Elema-Sch6nander electrically braked bicycle, and measures were taken to keep the room temperature constant at each test for each individual patient. The starting level was 300 kpm/min (49.05 W); this was increased every 4 minutes in steps of 300 kpm/min, until the patient experienced symptoms that prevented him or her from further exercise. The variables analyzed included: resting and maximum heart rate and blood pressure, time until initiation of chest discomfort, total exercise time, total workload, time until 1 mm and 2 mm ST-segment depression and maximum ST-segment depression, double product (heart rate x systolic blood pressure) and heart rate, systolic blood pressure, and ST recovery of 2 and 4 minutes after termination of the test.
Design
After 2-4 weeks (mean, 2.95) of monotherapy with atenolol 100 mg once daily (50 mg in one patient), each patient performed an exercise tolerance test to confwm the presence of exercise-induced angina with ST-segment depression of at least 1 ram. Thereafter the patients were randomly allocated to adding either nifedipine or nisoldipine. After 4 weeks of therapy, a second exercise test was performed followed by crossover of the two treatments for another 4 weeks. At the end of this period, a third exercise test was performed. Sublingual nitroglycerin was taken whenever necessary. Double blindness of the study was ensured through a double-dummy technique. Nisoldipine/nisoldipineplacebo tablets was taken every morning along with nifedipine/nifedipine-placebo capsules three times daily. Atenolol and trial drugs were supplied in individually labeled drug dispensers, each for one week. Atenolol was given as two 50 mg tablets to be taken every morning. The dosage of nisoldipine was 10 mg daily the first week, thereafter 20 mg daily. Nifedipine was given as 10 mg capsules. The starting dose was one capsule three times daily, increased every week
S t a t i s t i c a l Methods Statistical analyses were performed with Student's t test for paired samples for normal variables such as heart rate, systolic and diastolic blood pressure, and double product. Time variables and total workload were compared using the Wilcoxon matched-pairs signed rank test. The Wilcoxon-Mann-Whitney test of the total exercise time, the total workload and the time until chest discomfort (the main variables of the study) did not show any difference attributable to the time of inclusion or the order of treatment. Twotailed tests were used and the differences were considered statistically significant when p < 0.05.
Results Of 20 patients randomized into the study, two patients were withdrawn during the initial period while taking nisoldipine. One patient experienced aggravation of angina necessitating hospitalization; this patient underwent aortocoronary bypass grafting earlier than originally planned. The other patient reported by phone the occurrence of rash or erythema the second
Nisoldipbte vs N(fedipb~e b~ At~gb~a Pectoris
j 9
p (0.01
453
p 40.01
-
[---p (0.01
{---p
Nisoldipine Tablets once Daily versus Nifedipine Capsules three times daily in Patients with Stable Effort Angina Pectoris Pretreated with Atenolol Terje R. Pedersen, ~ M i c h a e l K a n t o r 2 ~Cardioloyy Department, Aker Sykehus, Oslo, Norway; 2Bayer (Sverige) AB, Stockholm, Sweden
Summary. T r e a t m e n t with nisoldipine (2 • 10 m g tablets once daily) a n d nifedipine (2 • 10 m g c a p s u l e s t h r e e times daily) in p a t i e n t s with severe, b u t stable effort a n g i n a pret r e a t e d with a t e n o l o l (100 m g once daily in 19 p a t i e n t s and 50 m g once daily in one p a t i e n t ) were c o m p a r e d for t h e i r effects on bicycle e x e r c i s e t o l e r a n c e a n d t h e i r adverse effects in a r a n d o m i z e d 2 • 4 week, double-blind, d o u b l e - d u m m y crossover s t u d y . All p a t i e n t s had m u l t i v e s s e l disease, 16 p a t i e n t s had o c c l u s i o n o f at least one vessel, a n d eight p a t i e n t s had a h i s t o r y o f m y o c a r d i a l i n f a r c t i o n . Two p a t i e n t s left the s t u d y d u r i n g t h e initial n i s o l d i p i n e period, one b e c a u s e of a g g r a v a tion o f t h e a n g i n a a n d t h e o t h e r b e c a u s e o f s u s p e c t e d allergic reaction. Addition o f nifedipine to atenolol t r e a t m e n t s i g n i f i c a n t l y improved t h e v a r i a b l e s m e a s u r e d for severity of a n g i n a , s u c h as t i m e o f exercise until 1 m m a n d 2 m m STs e g m e n t d e p r e s s i o n , total exercise t i m e and total workload. In c o n t r a s t , no s u c h i m p r o v e m e n t w a s noted a f t e r t h e addition of n i s o l d i p i n e to atenolol. However, nisoldipine resulted in a s i g n i f i c a n t p r o l o n g a t i o n o f t h e t i m e to t h e i n i t i a t i o n of c h e s t d i s c o m f o r t , t h e m a x i m u m h e a r t rate, and t h e double product. In a t e n o l o l - t r e a t e d p a t i e n t s with severe effort a n g i n a pectoris, n i f e d i p i n e 20 m g tid improved exercise capacity, while n i s o l d i p i n e 20 m g once daily did not have a s i m i l a r effect.
Key Words. a n g i n a pectoris, nifedipine, nisoldipine, atenolol.
Nisoldipine is a calcium antagonist of the dihydropyridine family. In animal studies it has been shown to have a higher vascular specificity than nifedipine, the vasodilating effect being highest in the coronary and femoral arteries [1-3]. It has been shown to have a more prolonged effect than nifedipine [3]. The antiischemic effect in patients with angina pectoris has been reported to persist over at least 7 hours after administration of 20 mg of nisoldipine [4]. In the present study the antianginal effect of 20 mg nisoldipine once daily was compared with the effect of nifedipine 20 mg tid in patients with severe angina who were pretreated with atenolol. The effect was compared using a graded bicycle exercise test.
Methods Patients of both sexes, below 70 years of age, who were submitted to the hospital for coronary angiography because of severe effort angina pectoris were asked to participate in the study. Patients were eligible for entry if they had had angiographically confirmed severe coronary artery disease and a symptom-limited bicycle exercise test with at least 1 mm ST-segment depression in lead CF5. Patients were excluded fl'om entry if they had angina at rest, unstable angina, diastolic blood pressure of 100 m m H g or above, congestive heart failure, cardiac valvular disease, significant noncardiac disease, or if they required therapy with longlasting nitrates, digitalis, o1" other drugs that might influence the study results. Patients with previous adverse experience with dihydropyridine drugs were also excluded. After having given informed consent, 20 patients entered the study. Since the waiting time for coronary artery bypass surgery in patients with stable angina was 4-6 months or more in Oslo at the time of the study, no patient had to delay their operation because of study participation. Of the 20 patients, 17 had been treated with beta-adrenergic blocking agents, six of them in combination with long-acting nitrates, six with nifedipine, and five with both. The remaining three patients had received monotherapy with either nifedipine, isosorbide dinitrate, or sublingual nitroglycerin, respectively. Two patients had previously had aortocoronary bypass grafting. Other patient characteristics are listed in Table 1. The study was approved by the local ethical committee and by the National Bureau for Drug Control.
Address for correspondence and reprint requests: Terje R. Pedersen, M.D., Cardiology Department, Aker Sykehus, N 0514 Oslo 5, Norway.
451
452
Pedersenand Kantor
Table I. Characteristics of the 20 patie~ds randomized. Number Age (years) Sex male female Height (cm) Weight (kg) Smokers Duration of angina (years) NYHA class I I class Ill Previous iIffarction Ejection fraction (c/c) Coronary angiography Occlusions i artery 2 arteries 3 arteries > 70~ stenosis 1 artery 2 arteries > 3 arteries Collaterals Not visible Few/little Moderate Extensive
Study
Mean
Range
55
39-69
173 71
154-190 59-86
16 4 11 6.3
1-21
2 18 8 68
44-84
13 2 1 1 8 11 3 2 9 6
by 10 rag, to a maximum of 20 mg tid during the fourth week. An upright bicycle exercise test was performed 6-9 hours (mean 7.1 hours) after the morning intake of study medication and 1.5-2.5 hours (mean 2.1 hours) after the midday intake. This testing time was chosen since it represents a time of the day with heavy exercise demands for most patients, as well as an adequate time from the morning dose of nisoldipine to test this drug's long-acting capability. The patients were allowed to have a light meal a minimum of 2 hours before the exercise test. Smoking or consumption of coffee or tea was not allowed. All tests were performed with the same Elema-Sch6nander electrically braked bicycle, and measures were taken to keep the room temperature constant at each test for each individual patient. The starting level was 300 kpm/min (49.05 W); this was increased every 4 minutes in steps of 300 kpm/min, until the patient experienced symptoms that prevented him or her from further exercise. The variables analyzed included: resting and maximum heart rate and blood pressure, time until initiation of chest discomfort, total exercise time, total workload, time until 1 mm and 2 mm ST-segment depression and maximum ST-segment depression, double product (heart rate x systolic blood pressure) and heart rate, systolic blood pressure, and ST recovery of 2 and 4 minutes after termination of the test.
Design
After 2-4 weeks (mean, 2.95) of monotherapy with atenolol 100 mg once daily (50 mg in one patient), each patient performed an exercise tolerance test to confwm the presence of exercise-induced angina with ST-segment depression of at least 1 ram. Thereafter the patients were randomly allocated to adding either nifedipine or nisoldipine. After 4 weeks of therapy, a second exercise test was performed followed by crossover of the two treatments for another 4 weeks. At the end of this period, a third exercise test was performed. Sublingual nitroglycerin was taken whenever necessary. Double blindness of the study was ensured through a double-dummy technique. Nisoldipine/nisoldipineplacebo tablets was taken every morning along with nifedipine/nifedipine-placebo capsules three times daily. Atenolol and trial drugs were supplied in individually labeled drug dispensers, each for one week. Atenolol was given as two 50 mg tablets to be taken every morning. The dosage of nisoldipine was 10 mg daily the first week, thereafter 20 mg daily. Nifedipine was given as 10 mg capsules. The starting dose was one capsule three times daily, increased every week
S t a t i s t i c a l Methods Statistical analyses were performed with Student's t test for paired samples for normal variables such as heart rate, systolic and diastolic blood pressure, and double product. Time variables and total workload were compared using the Wilcoxon matched-pairs signed rank test. The Wilcoxon-Mann-Whitney test of the total exercise time, the total workload and the time until chest discomfort (the main variables of the study) did not show any difference attributable to the time of inclusion or the order of treatment. Twotailed tests were used and the differences were considered statistically significant when p < 0.05.
Results Of 20 patients randomized into the study, two patients were withdrawn during the initial period while taking nisoldipine. One patient experienced aggravation of angina necessitating hospitalization; this patient underwent aortocoronary bypass grafting earlier than originally planned. The other patient reported by phone the occurrence of rash or erythema the second
Nisoldipbte vs N(fedipb~e b~ At~gb~a Pectoris
j 9
p (0.01
453
p 40.01
-
[---p (0.01
{---p
