Comparative efficacy of nicardipine hydrochloride and atenolol

Transcription

1 Br. J. clin. Pharmac. (1986), 22, 345S-350S Comparative efficacy of nicardipine hydrochloride and atenolol in the treatment of chronic stable angina R. L. LOGAN,3 H. IKRAM,2 M. W. WEBSTER2 & W. GUPPY' 'Hutt Hospital, Lower Hutt, 2Princess Margaret Hospital, Christchurch and 3Wellington Clinical School, and Hutt Hospital, Wellington, New Zealand 1 The efficacy and safety of nicardipine, 30 mg three times a day, were compared with atenolol, 100 mg once daily in a randomised, double-blind, 11-week, crossover study of 46 patients with stable angina pectoris. 2 Both drugs significantly decreased the frequency of angina and improved total exercise time, time to angina, and time to 1 mm ST-segment depression. No statistically significant differences were observed between nicardipine and atenolol in clinical responses or treadmill performance. 3 At maximum workload, the double product decreased significantly in patients taking atenolol and did not change in those using nicardipine. 4 During treatment with atenolol, statistically significant decreases were observed in heart rate and QTc interval; these parameters increased minimally on nicardipine. 5 The incidence and severity of adverse experiences associated with each treatment were similar and did not interfere with the study. The two major adverse experiences, myocardial infarction and sudden death, occurred only in patients receiving atenolol. 6 Nicardipine therapy compared favourably with atenolol therapy in patients with angina pectoris. Keywords angina atenolol nicardipine Introduction 0-adrenoceptor blockers have been used widely in the management of patients with angina pectoris. However, their use is associated with a relatively high incidence of side-effects (Feely et al., 1983; Segal et al., 1982; Prichard, 1974). They also are contraindicated for patients with a number of not uncommon conditions, such as asthma and brittle diabetes. More recently, calcium channel blockers have been shown to be effective in the treatment of angina (Bala Subramanian et al., 1982; Pepine & Gelman, 1985; Scheidt et al., 1985). Their efficacy appears to be achieved by relaxation of arterial wall smooth muscle leading to vasodilatation, hence reducing cardiac work and myocardial oxygen demand (Braunwald, 1982; Fleckenstein, 1977; Grossman & Barry, 1980; McCredie et al., 1985; Singh, 1982; Stone et al., 1980; Visser et al., 1985). Whilst some calcium antagonists have been shown to have a negative inotropic effect, this is by no means as great as that associated with f-adrenoceptor blocker treatment (Silke et al., 1985). Nicardipine hydrochloride is a new calcium channel blocker, which has been used extensively in Japan since It is a potent vasodilator without any apparent negative inotropic effects (Campbell et al., 1985; Rousseau et al., 1985). Clinical trials have demonstrated its safety and efficacy in the treatment of angina at dosages of mg daily (Khurmi et al., 1984; Georghiade et al., 1985; Scheidt et al., 1985). In this study, we compared the efficacy and Correspondence Dr R. L. Logan, Hutt Hospital, High Street, Private Bag, Lower Hutt, New Zealand 345S

2 346S R. L. Logan et al. safety of nicardipine, 90 mg day 1, with that of atenolol, 100 mg day-', in patients with chronic stable angina pectoris. Methods Study design Two centres participated in a randomised, double-blind, crossover study comparing nicardipine, 90 mg day- 1, and atenolol, 100 mg day 1, for the treatment of stable angina pectoris. The study lasted 11 weeks and was conducted in four phases: a 2 week placebo run-in period followed by 4 weeks of active drug treatment (either nicardipine or atenolol); a 1 week placebo washout phase; and then the alternate drug for the last 4 weeks of the study. No concomitant cardiovascular or psychotropic medications were taken during the study; however, benzodiazepine, hypnotic, or diuretic therapy initiated prior to the study was continued. Patients were evaluated every 2 weeks during the active treatment periods and once at the end of the washout period. Patients All patients had classical stable angina pectoris with at least five angina attacks per week during the placebo run-in phase, and had resting ECG patterns that would not interfere with interpretations of ST-segment changes during exercise. Each patient demonstrated a reproducible pattern of angina during exercise testing associated with ST-segment depression of 1 mm or more at 80 ms after the J point. Treadmill entry criteria required that the onset of angina occur within 3-8 min after beginning the treadmill test. Patients with conditions that could interfere with clear intrepretations of data or cause undue risk to the patient were not included, nor were those with a known intolerance to,- adrenoceptor blockers or a history of bronchospasm. Informed consent was given by each patient. Drug adrministration Nicardipine was taken at a dose of 30 mg three times a day in a capsule and atenolol at a dose of 100 mg one daily as a tablet; throughout the study patients took three capsules and one tablet every day. Placebo was formulated to mimic active drugs. Glyceryl trinitrate (GTN) was supplied in 60 tg tablets to be taken in the event of angina attack, but was not to be used prophylactically. Evaluations ofefficacy and safety At entry a brief physical examination was performed, a medical history was taken, and the results of a chest X-ray taken within 12 months prior to the study was recorded. Clinical laboratory tests were performed at entry and at the end of each phase of the study. ECG measurements were recorded at the end of the placebo run-in (baseline) and thereafter at the end of each active treatment phase. Five exercise tolerance tests were performed using a standard Bruce protocol (Bruce & Hornsten, 1969), during the first week of placebo treatment and again at the beginning and end of each active treatment phase. Resting heart rates and blood pressures were monitored beginning 5 min before exercise testing and continuing until values returned to baseline postexercise. Among the treadmill variables measured were total exercise time, time to angina, time to 1 mm ST-segment depression, and peak double product (systolic blood pressure x heart rate at maximal workload). Throughout the study each patient recorded in a daily diary the number of angina attacks experienced and the amount of GTN taken. Diary data were evaluated by the investigator at each 2 week clinic visit, at which time patients were asked if any adverse experiences or unusual symptoms had occurred since their last visit. All such reports were recorded, and the investigators evaluated their relationship to the study drugs rating severity as mild, moderate, or severe. At the end of the study, both the patients and the investigators provided a subjective assessment of overall therapeutic response to each drug (rated as much better, better, or no difference between drugs). Statistical analysis Both descriptive and inferential statistics were applied to the resultant data. For the crossover analyses, an analysis of variance model appropriate for a multi-centred crossover was used for all numeric efficacy parameters. Baseline and first period change from baseline analyses were carried out using appropriate parallel trial methodology. Angina attacks were analysed using the non-parametric analogs. Results Patients Fifty patients enrolled in the study; three discontinued since they did not meet study criteria,

3 and one was lost to follow-up. Fo patients were included in the evaluati' safety. Six patients were excluded from t] cacy evaluations: one patient taking nicai discontinued the study prematurely beca lack of efficacy, one had a myocardial inft while taking atenolol and discontinue( four were excluded because of protoc( lations (failure to fulfil treadmill entry with regard to either the time of onset of or the development of ST-segment chang additional three patients discontinued the second active treatment period: durii nolol treatment, one patient died sudden one experienced severe chest pains; nicardipine treatment, one patient discor because of lack of efficacy. Efficacy and data for these three patients are included the time of discontinuation. Of the 40 patients evaluated for efficz were male and three were female. Their r age was 58 years, and the median hist angina was approximately 7 months. Ni patients were assigned to Groi (nicardipine --atenolol) and 21 to Gr4 (atenolol - nicardipine); demographic e teristics and medical history were comi for the two groups (Table 1). Response to treatment Analysis of patients' diaries showed that the first active treatment period, a stati significant decrease from baseline in fre of anginal attacks occurred in both tre groups (P < 0.01, Table 2). No statistica nificant difference between drugs was n( the first period analysis or in the crc analysis. As shown in Table 3, during the first I both treatment groups showed statistical nificant improvement from baseline in Table 1 Demographic characteristics and medical history for patients evaluated for efficacy Group I Group II nicardipine atenolol atenolol nicardipine Total Number of patients Median age (years) Sex (M/F) 18/1 19/2 37/3 Weight (kg) Smoker (%) Median history of angina (years) History of myocardial infarction (%) Nicardipine vs atenolol for chronic stable angina 347S Table 2 Angina attacks per week-first period analysis Angina attacks per week (Q1/Med/Q3) Nicardipine Atenolol Baseline' 1.1/5.0/ /5.5/10.5 Change from -6.6/-1.3/0.0* -7.2/-2.8/-0.2* baseline * P < Q1/Med/Q3 = First quartile-median-third quartile. Sign test was used to assess the significance of change from baseline. a End of (pretreatment) placebo run-in. exercise time (P < 0.01), time to angina (P < 0.05) and time to 1 mm ST-segment depression (P < 0.01), with no statistically significant difference between treatments. During the first period, double product at maximum workload decreased significantly from baseline among patients taking atenolol (mean decrease -5,497 mm Hg beats min-1, (P < 0.01) and increased slightly, but not statistically significantly (mean increase, 588 mm Hg beats min-1), among those taking nicardipine. The difference between treatments was statistically significant in both first period and crossover analysis (P < 0.01, Tables 3 and 4). The difference in double products between treatments primarily was due to a lower peak systolic pressure with atenolol. There was no statistically significant maximum absolute exercise ST segment change from rest for either treatment group, nor was the difference between treatments statistically significant in either the first period or the crossover analysis (Tables 3 and 4). There was no statistical difference between the two drugs as assessed by both investigator and patient preferences. Electrocardiogram assessments As expected, during treatment with atenolol, statistically significant decreases from baseline were observed in heart rate and QTc interval (P < 0.05), whereas the heart rate and QTc interval increased slightly while patients were taking nicardipine (Table 5). The differences between drugs in heart rate and QTc intervals were statistically significant (P < 0.01). Significantly more patients (P < 0.05) increased their PR interval while taking atenolol as compared with their nicardipine treatment period. Changes in QRS intervals were not statistically or clinically significant. Two patients taking atenolol developed sinus bradycardia (Table 5).

4 348S R. L. Logan et al. Table 3 Exercise tolerance test - first period analysis Mean difference between Variable Nicardipine Atenolol treatments Total exercise time (min) Baseline * Mean change 0.92** 1.19** Time to angina (min) Baseline * Mean change 1.07* 1.30** Time to 1 mm ST-segment depression (min) Baseline Mean change 1.51** 1.87** Double product (mmhg beats mi -1 at maximum workload Baseline 21,190 21, Mean change 588-5,497** 6,671** Maximum absolute exercise ST-segment change from rest (mm) Baseline Mean change Systolic blood pressure (mmhg) at maximum workload Baseline Mean change * 10.9 *P 0.05, **P Exercise variables: Change from baseline analyses used a paired t-test on raw values. Between treatment analyses used two-way ANOVA on raw values. Table 4 Exercise tolerance test - crossover analysis Nicardipine - atenolol treatment difference Variable (P value) Total exercise time (min) 0.99 Time to angina (min) 0.42 Time to 1 mm ST-segment 0.81 depression(min) Double product <0.01 (mmhg beats min') at maximum workload Maximum absolute exercise 0.99 ST-segment change from rest (mm) Systolic blood pressure <0.01 (mmhg) at maximum workload Exercise variables: between treatment comparisons used ANOVA with cross-over model (raw values). Adverse experiences Adverse experiences most commonly reported during the study were related to the central nervous system (dizziness, fatigue, headache, malaise and paresthesia), and these were equally distributed between the two treatment groups. Symptoms related to the cardiovascular system (chest pains, palpitations and vasodilation) were reported more frequently during nicardipine treatment (36%) than during treatment with atenolol (11%). Patients reported more digestive system complaints (constipation, gastrointestinal pain and nausea) while taking atenolol (25%) than while taking nicardipine (13%). Most of the adverse experiences reported by both groups were mild or moderate. However, during atenolol treatment, one patient discontinued because of severe chest pain, and two other patients on atenolol had serious adverse experiences: one had a myocardial infarction and another died suddenly. Discussion The results of our study indicate that the antianginal efficacies of nicardipine and atenolol are comparable. Both treatments reduced the frequency of angina attacks and improved total exercise time, time to angina and time to 1 mm

5 Table 5 Summary of resting electrocardiogram assessments Nicardipine vs atenolol for chronic stable angina Changes from baseline Assessment Baseline Nicardipine (n = 44) Atenolol (n = 42) Min. Med. Max. Min. Med. Max. P value Heart rate t ** (beats min- 1) QTc interval (s) t ** PR interval (s) * QRS interval (s) Number (%) of 0 2 (5) patients with new abnormalities$ Min. = minimum; Med. = median; Max. = maximum. * Statistically significant difference between treatments: P < ** Statistically significant difference between treatments: P < t Statistically significant within treatment change: P < On atenolol, there were significantly more increases from baseline in PR interval than decreases. Wilcoxon rank tests were used to ascertain significance. I Patients with new abnormalities (as compared to baseline) on active treatment. 349S ST-segment depression during exercise testing. While the drugs appear to be of equal efficacy clinically and by treadmill assessment, they differ in their effects on the peak double product. Statistically significant decreases in double product at maximum workload were observed during atenolol treatment, which is to be expected with,-adrenoceptor blockers, while minimal increases were observed during nicardipine treatment. The fact that nicardipine does not alter the double product suggests that its anti-anginal effect is mediated by other means, presumably vasodilatation (Braunwald, 1982; Fleckenstein, 1977; Grossman & Barry, 1980, McCredie et al., 1985; Singh, 1982; Stone et al., 1980; Visser et al., 1985), and perhaps by an augmentation of coronary blood flow, which is well known to result after nicardipine administration (McCredie et al., 1985; Rousseau et al., 1985; Visser et al., 1985). The data suggest that atenolol may prolong the PR interval and electrophysiological studies indicate that atenolol prolongs atrio-ventricular nodal impulse conduction time (Hombach et al., 1982; Hotvedt et al., 1984). These characteristics may be clinically significant for some patients. The lack of reduction of resting heart rate by nicardipine may be of benefit to patients whose heart rates already are slow or to those who develop symptoms as a result of bradycardia. The majority of adverse experiences reported during both treatment regimens were mild to moderate in severity and did not interfere with the study. Withdrawal from the study because of adverse experiences was relatively infrequent and similar for the two treatment groups. However, it was during atenolol treatment that the two serious adverse experiences occurred. Nicardipine is an effective and safe antianginal agent that compares favourably, both clinically and statistically, with atenolol for the treatment of chronic stable angina. In view of its vasodilating effect and lack of negative inotropic effect, nicardipine can be considered as an alternative to a j-adrenoceptor blocker in the treatment of patients with angina pectoris. References Bala Subramanian, V., Bowles, M. J., Khurmi, N. S. & Raftery, E. B. (1982). Comparative evaluation of four slow channel blockers with propranolol in stable angina pectoris. Circulation, 66 (Suppl. II), II-18. Braunwald, E. (1982). Mechanism of action of calcium-channel blocking-agents. New Engl. J. Med., 307, Bruce, R. A. & Hornsten, T. R. (1969). Exercise stress testing in evaluation of patients with ischemic heart disease. Prog. cardiovasc. Dis., 11, Campbell, B. C., Kelman, A. W. & Hillis, W. S. (1985). Noninvasive assessment of the haemodynamic effects of nicardipine in normotensive subjects. Br. J. clin. Pharmac., 20, 55S-6IS. Feely, J., de Vane, P. J. & Maclean, D. (1983). Betablockers and sympathomimetics. Br. med. J., 286, Fleckenstein, A. (1977). Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Ann. Rev. Pharmac. Tox., 17,

6 350S R. L. Logan et al. Georghiade, M, St Clair, C., St Clair, J, Freedman, D. & Schwemer, G. (1985). Short- and long-term treatment of stable effort angina with nicardipine, a new calcium channel blocker: a double-blind, placebocontrolled, randomised, repeated cross-over study. Br. J. clin. Pharmac., 20,195S-205S. Grossman, W. & Barry, W. H. (1980). Diastolic pressure-volume relations in the diseased heart. Fed. Proc., 39, Hombach, V., Braun, V., Hopp, H. W., Gil-Sanchez, D., Behrenbeck, D. W., Tauchert, M. & Hilger., H. H. (1982). Electrophysiological effects of cardioselective and non-cardioselective fi-adrenoceptor blockers with and without ISA at rest and during exercise. Br. J. clin. Pharmac., 13, 285S-293S. Hotvedt, R., Refsum, H. & Platou, E. S. (1984). Cardiac electrophysiological and hemodynamic effects of 3-adrenoceptor blockade and thoracic epidural analgesic in the dog. Anesth. Analg., 63, Khurmi N. S., Bowles, M. J., Bala Subramanian, V. & Raftery, E. B. (1984). Short- and long-term efficacy of nicardipine, assessed by placebo-controlled single- and double-blind crossover trials in patients with chronic stable angina. J. Am. Coll. Cardiol., 4, McCredie, R. M., McKenzie, W. B. & McGill, D. A. (1985). The acute haemodynamic effects of oral nicardipine. Br. J. clin. Pharmac., 20, 163S-168S. Pepine, C. J. & Gelman, J. S. (1985). Prevention of vasospastic angina with nicardipine. Br. J. clin. Pharmac., 20, 187S-194S. Prichard, B. N. C. (1974). Beta-adrenergic receptor blocking drugs in angina pectoris. Drugs, 7, Rousseau, M. F., Vincent, M. F., Cheron, P., Van Den Berghe, G., Charlier, A. A. & Pouleur, H. (1985). Effects of nicardipine on coronary blood flow, left ventricular inotropic state and myocardial metabolism in patients with angina pectoris. Br. J. clin. Pharmac., 20, 147S-157S. Scheidt, S., LeWinter, M. M., Hermanovich, J., Venkataraman, K. & Freedman, D. (1985). Nicardipine for stable angina pectoris. Br. J. clin. Pharmac., 20, 178S-186S. Segal, B. L., Kotler, M. N. & Iskandrian, A. S. (1982). Managing angina with beta blockers. Geriatrics, 37, Silke, B., Verma, S. P., Frais, M. A., Hafizullah, M. & Taylor, S. H. (1985). Effects of nicardipine on cardiac volume at rest and during exercise-induced angina. Br. J. clin. Pharmac., 20, 169S-176S. Singh, B. N. (1982). Pharmacological basis for the therapeutic applications of slow-channel blocking drugs. Angiology, 33, Stone, P. H., Antman, E. M., Muller, J. E. & Braunwald, E. (1980). Calcium channel blocking agents in the treatment of cardiovascular disorders. Part II: Hemodynamic effects and clinical applications. Ann. int. Med., 93, Visser, C. A., Jaarsma, W., Kan, G., Koolen, J. J. & Lie, K. I. (1985). Immediate and long-term effects of nicardipine, at rest and during exercise, in patients with coronary artery disease. Br. J. clin. Pharmac., 20, 158S-162S.