Comparison of the efficacy of nicardipine and nifedipine in patients with chronic stable angina

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1 Br. J. clin. Pharmac. (1986), 22, 325S33S Comparison of the efficacy of nicardipine and nifedipine in patients with chronic stable angina C. ARMSTROG, J.GARHAM & R. BLACKWOOD Wexham Park Hospital, Slough and Chiltern International Limited 1 This parallel, randomised singleblind study examined the antianginal efficacy of 9 mg/day nicardipine compared with that of 6 mg/day nifedipine in 4 patients with chronic stable angina pectoris. 2 Treadmill exercise test results showed both drugs to be effective in improving exercise time. Both the number of anginal attacks per week and glyceryl trinitrate consumption were reduced. o significant difference was shown between nicardipine and nifedipine in the efficacy parameters. 3 icardipine was associated with fewer sideeffects and in fewer patients than nifedipine. Keywords nicardipine nifedipine angina Introduction Calcium antagonists have been shown to be an effective treatment in patients with chronic stable angina pectoris (Theroux et al., 1983). They appear to act in patients with angina by dilating coronary arteries, thus improving oxygen supply to the myocardium, and by dilating peripheral vessels. The overall effect is to improve the ratio between cardiac oxygen supply and demand leading to improved myocardial performance. icardipine is a new calcium antagonist which has been reported in several studies to be an effective treatment in patients with chronic stable angina pectoris (Visser et al., 1984; Rousseau et al., 1984; Bowles et al., 1982). ifedipine has also been shown to be an effective drug in angina pectoris (Moskowitz et al., 1979; Sherman et al., 1983; De Ponti et al., 1979). Two previous studies comparing nicardipine and nifedipine have shown similar efficacy and sideeffects (Di Pasquale et al., 1984; Bowles et al., 1985). This study further investigates the comparative efficacy and safety of these two calcium entry blockers. Methods Prior to the study, 46 patients with a history of stable exertional angina were selected for evaluation for a 2 week period during which no prophylactic antianginal medication was taken, but unlimited GT was allowed for treatment of anginal attacks. For inclusion in the study it was necessary that patients showed exerciseinduced myocardial ischaemia diagnosed by a sustained ST segment depression of 1 mm or more in the V5 chest lead. Two exercise tests were performed in the 2 week runin period to demonstrate consistent changes. Patients who suffered from other conditions which may have caused a false positive stress test were excluded, as were patients with unstable angina pectoris, congestive cardiac failure, clinically significant valvular heart disease or cardiac septal defects, second or third degree atrioventricular block, myocardial infarction or cerebrovascular accident in the preceding two months. Patients were also excluded if the results of a prestudy blood test showed they had clinically significant renal, hepatic or thyroid function abnormalities, anaemia or abnormal 325S

2 326S C. Armstrong, J. Garnham & R. Blackwood potassium levels. Any coexisting serious mental or physical illness including insulintreated diabetes mellitus, hypotension and moderate hypertension also excluded patients from the study. Six patients were excluded from the study prior to receiving active medication; three because of nonreproducible exercise tests and three who declined to take further part in the study. All patients gave informed consent to their participation and approval for the study was granted by the hospital ethics committee. This was a singleblind parallel group study comparing the efficacy of 3 mg nicardipine hydrochloride three times a day with that of 2 mg nifedipine three times a day for 8 weeks. Treatments were allocated using a predetermined randomisation schedule. o other prophylactic antianginal therapy was taken by the patients, either during the 2 week baseline period or during the 8 weeks of study. Sublingual glyceryl trinitrate was permitted only as a treatment for anginal attacks during the study. Treadmill exercise tests were performed by patients before they received study medication and after 4 and 8 weeks of treatment. All these tests were performed according to a modified Bruce protocol (Bruce & Hornsten, 1969; Ellestad et al., 1979) and were stopped when signs or symptoms became too severe, e.g. progressive chest pain, shortness of breath, fatigue. Heart rate, systolic blood pressure and lead V5 on the electrocardiogram were monitored during the exercise test. Heart rate and systolic blood pressure were recorded at rest prior to the exercise test and at the end of each exercise test stage. The time taken for the heart rate to return to normal after the exercise test was noted, as were time to 1 mm ST segnent depression and the overall duration of the exercise test. (9D IC 1111' 1 Patients maintained a diary of frequency of anginal attacks and of the number of sublingual glyceryl trinitrate taken to treat chest pain. The investigator assessed the patients' responses to treatment at the 4 and 8 week followup visits on a scale of excellent, very good, good, fair and poor. Patients were questioned indirectly to assess the incidence and severity of adverse experiences at the 4 week and 8 week followup visits. Resting 12 lead electrocardiogram and laboratory tests were performed before commencement of active treatment and at the end of the treatment period. Results Twelve patients (five in the nicardipine group and seven in the nifedipine group) withdrew from the study because of adverse experiences (Figure 1). ine of these patients were lost at a very early stage and thus 31 patients, 23 males and eight females, were included in the efficacy analyses. The median age of these patients was 57 years (range 4269) and the median history of stable angina of.9 years (range.1 to 14.3). ineteen of the 31 patients had a concomitant disease or condition on entry to the study. These included diabetes, heart failure, duodenal ulcer, arthritis, asthma and bronchitis. Twelve patients in the nicardipine treatment group and 13 patients in the nifedipine group had exercise tests conducted at baseline and after receiving 4 weeks and 8 weeks of study medication. Table 1 shows the exercise test results. o statistically significant differences between treatments were found. Statistically significantly increased exercise times compared with baseline 1. Giddiness, 11 days 2. Constipation, depression, dizzy headache, 7 days 3. Flushing, palpitations, 1 day 4. Fatigue, disturbance of thinking, 4 days (t3 IF 3 nonreproducible exercise tests 3 refused to continue Figure 1 Dropouts Headache, palpitations, 1 days 2. Flushing, nausea, palpitations, headache, 1 day 3. Headache, 1 day 4. Flushing, headache, ankle swelling, 4 days 5. ausea, palpitations, 2 days

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4 328S C. Armstrong, J. Garnham & R. Blackwood were found for nicardipine at 4 weeks (P =.2) and 8 weeks (P =.3) and for nifedipine at 8 weeks (P =.4). Time to 1 mm ST segment depression was significantly increased in the nifedipine treatment group at week 4. At other time points all times were increased, although not statistically significantly. There were no significant differences between treatments for times to 1 mm ST segment depression. Heart rate increase at the last stage of exercise was reduced on both treatments compared with the pretreatment runin period. For nicardipinetreated patients this was significant at week 4 (P =.3). The systolic blood pressure change at the last stage of exercise increased slightly, but not significantly, in both treatment groups compared with the baseline exercise test. The ratepressure product was reduced in both treatment groups at weeks 4 and 8 compared with baseline. At week 4, the nifedipine treatment group ratepressure product result was statistically significantly decreased from baseline. The time for heart rate to return to normal after the exercise test was slightly increased in patients on nicardipine, whereas there was a slight decrease in nifedipinetreated patients. There were no statistically significant differences between treatments and no statistically significant changes from baseline. The number of angina attacks per week and the consumption of glyceryl trinitrate tablets per week are shown in Table 2. icardipinetreated patients had a statistically significantly reduced number of angina attacks per week after 4 weeks (P =.1) and 8 weeks (P =.3) of medication. ifedipinetreated patients had a statistically significantly reduced number of angina attacks after 4 weeks (P =.5) of treatment but the reduction after 8 weeks was not statistically significant. Consumption of glyceryl trinitrate tablets was reduced by both treatments, statistically significantly so at week 4 (P =.3 for both treatments.) o statistically significant differences were found between the treatment groups when the investigator's assessment of global response was analysed. At the end of the study, 11 of 15 (73%) nicardipinetreated patients and 9 of 16 (56%) nifedipinetreated patients were rated as having good to excellent response to treatment. Adverse experiences Adverse experiences in both treatment groups appeared to be consistent with the vasodilatory activity of these drugs. Eleven of 19 (58%) patients receiving nicardipilie reported 27 adverse effects and 16 of 21 (76%) patients receiving nifedipine reported 43 adverse effects. Five patients were withdrawn from the nicardipine treatment group for adverse effects and seven patients were withdrawn from the nifedipine treatment group. There were no serious adverse effects during the study and all adverse effects causing withdrawal of the patient from the study quickly resolved on termination of the study medication. One other patient in the nicardipine treatment group was withdrawn due to increased angina. Results of laboratory tests did not show any clinically significant changes from baseline. There were statistically significant decreases in thyroid stimulating hormone (.65 mu 1 1, P <.5) and uric acid (.1 mmol 1 ', P =.5) for nifedipinetreated patients. There were no statistically significant differences between the treatment groups for any of the laboratory result changes from baseline. Three nicardipinetreated patients and five nifedipinetreated patients had new abnormalities found on their resting electrocardiograms compared with baseline. These were all consistent with progression of the patient's ischaemic heart disease. Two nifedipinetreated patients and one nicardipinetreated patient had ST Table 2 umber of angina attacks and glyceryl trinitrate consumption Baseline Week 4 Week 8 icardipine ifedipine icardipine ifedipine icardipine ifedipine Median number of ** 2.68* 1.8* 2.25 angina attacks per week Median glyceryl * 1.17* trinitrate tablet consumption per week * P <.5, ** P <.1 Wilcoxon signed rank test for change from baseline.

5 depression at rest and one nifedipinetreated patient had developed left bundle branch block. Two nicardipinetreated patients and one nifedipinetreated patient had new intraventricular conduction defects and one nifedipinetreated patient had occasional ectopic ventricular extrasystoles. Discussion icardipine is a new calcium antagonist which is reported to have no effect on the conduction system and no negative inotropic effects at therapeutic doses. The antianginal effectiveness of nicardipine seems to be achieved mainly by reduced systemic vascular resistance which in turn leads to reduced myocardial oxygen demand. ifedipine appears to have a similar mode of action. Two previous studies (Di Pasquale et al., 1984; Bowles et al., 1985) compared nicardipine and nifedipine in patients with stable effort angina and found both treatments to be safe and effective with no significant differences between them. However, it has been shown (Pouleur et al., 1984) that at equipotent vasodilator dosage the additive effects of nicardipine after propranolol were greater than those of nifedipine after propranolol in terms of improving left ventricular pump function. A beneficial effect of nicardipine in increasing left ventricular pump activity in chronic heart failure has also been reported (Lahiri et al., 1984). In contrast, nifedipine can impair myocardial contractibility and only reduces left ventricular fillingpressure to a modest degree (Roberts, 1985). This study icardipine and nifedipine in chronic stable angina 329S was set up to compare the efficacy and safety of nicardipine and nifedipine in patients with chronic stable angina. The results have shown both nicardipine and nifedipine are effective antianginal agents when administered for up to 8 weeks. Objective parameters such as duration of exercise were significantly improved by both treatments and subjective evidence in terms of reduction of number of angina attacks and consumption of glyceryl trinitrate tablets showed that the patients obtained significant benefit from their treatment. More adverse events were seen in the nifedipine treatment group than in the nicardipine treatment group. The majority of these sideeffects appeared to be related to the vasodilatory properties of the two calcium entry antagonists, e.g. headache, flushing and peripheral oedema. However, it was noticed that of those patients who continued on treatment for more than 4 weeks only one patient on nicardipine complained of adverse events while six patients on nifedipine reported adverse experiences. This shows that the adverse experiences seen initially on nicardipine are well tolerated. Patients in this study were receiving 6 mg nifedipine per day and previous papers have suggested that the dose of nifedipine should be titrated (Deanfield et al., 1983; Fox et al., 1983). The fact that this was not done in this study may account for the number of adverse events experienced on nifedipine without further clinical benefit to the condition treated. In conclusion, this study has shown, both objectively and subjectively, that nicardipine and nifedipine are effective treatments in patients with angina pectoris. References Bowles, M. J., Bala Subramanian, V., Khurmi,. S., Davies, A. B. & Raftery, E. B. (1982). Efficacy of a new calcium channel blocking agent, nicardipine, in chronic stable angina. Br. J. clin. Pharmac., 13, 59P. Bowles, M. J., Khurmi,. S., O'Hara, M. J. & Raftery, E. B. (1985). icardipine in chronic stable angina: objective assessment with computerassisted exercise testing and ambulatory ST segment monitoring. Br. J. clin. Pharmac., 2, 177S. Bruce, R. A. & Hornsten, T. R. (1969). Exercise stress testing in evaluation of patients with ischemic heart disease. Prog. cardiovasc. Dis., 11, Deanfield, J., Wright, C. & Fox, K. (1983). Treatment of angina pectoris with nifedipine: importance of dose titration. Br. med. J., 286, De Ponti, C., Mauri, F., Ciliberto, G. R. & Caru, B. (1979). Comparative effects of nifedipine, verapamil, isosorbide dinitrate and propranolol on exerciseinduced angina pectoris. Eur. J. Cardiol., 1, Di Pasquale, G., Lusa, A. M., Manini, G. L., Coluccini, M., Bassein, L. & Pinelli, G. (1984). Comparative efficacy of nicardipine, a new calcium antagonist, versus nifedipine in stable effort angina. Int. J. Cardiol., 6, Ellestad, M. H., Blomqvist, C. G. & aughton, J. P. (1979). Standards for adult exercise testing laboratories. Circulation, 59, 421A43A. Fox, K. M., Deanfield, J., Selwyn, A., Krikler, S. & Wright, C. (1983). Factors influencing the treatment of chronic stable angina pectoris with nifedipine. Postgrad. med. J., 59 (Suppl. 2), Lahiri, A., Robinson, C. W., Tovey, J., Caruana,

6 33S C. Armstrong, J. Garnham & R. Blackwood M. P., Kohli, R. S., Harlow, B. J. & Raftery, E. B. (1984). Intravenous nicardipine in patients with chronic heart failure: a nuclear stethoscope study. Postgrad. med. J., 6 (Suppl. 4), Moskowitz, R. M., Piccini, P. A., acarelli, G. V. & Zelis, R. (1979). ifedipine therapy for stable angina pectoris: preliminary results of effects on angina frequency and treadmill exercise response. Am. J. Cardiol., 44, Pouleur, H., Etienne, J., Van Mechelen, H., Van Eyll, C., Charlier, A. A., Brasseur, L. A. & Rousseau, M. F. (1984). Effects of nicardipine or nifedipine added to propranolol in patients with coronary artery disease. Postgrad. med. J., 6 (Suppl. 4), Roberts, C. J. C. (1985). Drug treatment of cardiac failure. In Drugs in the management of heart disease, ed. Breckenridge, A., pp Lancaster: MTP Press. Rousseau, M. F., Vincent, M. F., Van Hoof, F., Van Den Berghe, G., Charlier, A. A. & Pouleur, H. (1984). Effects of nicardipine and nisoldipine on myocardial metabolism, coronary blood flow and oxygen supply in angina pectoris. Am. J. Cardiol., 54, Sherman, L. G. & Liang, C. S. (1983). ifedipine in chronic stable angina: a doubleblind placebocontrolled crossover trial. Am. J. Cardiol., 51, Theroux, P., Taeymans, Y. & Waters, D. D. (1983). Calcium antagonists. Clinical use in the treatment of angina. Drugs, 25, Visser, C. A., Jaarsma, W., Kan, G. & Lie, K. I. (1984). Immediate and longerterm effects of nicardipine, at rest and during exercise, in patients with coronary artery disease. Postgrad. med. J., 6 (Suppl. 4), 172.