Slow release nifedipine plus atenolol in chronic stable angina pectoris

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1 Br. J. clin. Pharmac. (1989), 28, Slow release nifedipine plus atenolol in chronic stable angina pectoris V. F. CHALLENOR, D. G. WALLER, A. G. RENWICK & C. F. GEORGE Clinical Pharmacology, Centre Block, Southampton General Hospital, Southampton S09 4XY 1 The effects of adding slow release nifedipine in doses of 20 mg and 40 mg twice daily to atenolol therapy (50 mg twice daily) were assessed in 18 patients with chronic stable angina. 2 The addition of the lower dose of nifedipine to atenolol did not significantly alter the weekly consumption of glyceryl trinitrate or the mean number of anginal attacks as assessed by diary cards. However, 2 h after dosing there was a significant prolongation during stress testing in the time to onset of both 1 mm ST depression on the ECG (by 28%) and to angina (by 37%) compared with atenolol alone, but no benefit was apparent by 12 h after dosing. 3 At a dose of 40 mg twice daily, nifedipine significantly reduced glyceryl trinitrate consumption by 25% and the number of anginal attacks by 36%. The times to onset of ST depression and angina were increased by 37% and 55% respectively at 2 h and by 24% and 26% respectively 12 h after dosing. 4 Analysis of the frequency distribution of anginal attacks showed decreasing efficacy with time after administration of nifedipine. The overall results also suggest a relationship between efficacy and the plasma nifedipine concentration, with a mean 20% improvement in time to development of angina occurring at a nifedipine plasma concentration of approximately ng mi In conclusion, the reduction of effort-related angina by nifedipine is related to its plasma concentration and the effective duration of action of the 20 mg slow release formulation is less than 12 h. Keywords slow release nifedipine atenolol chronic stable angina pectoris Introduction The value of P-adrenoceptor antagonists in the management of angina pectoris (Braun et al., treatment of angina pectoris is well established 1985; Fox et al., 1980; Tweddel et al., 1981). (Kostis et al., 1985; Alderman et al., 1975; However, following oral administration nifedipine Jackson et al., 1980). Their action to reduce undergoes extensive and variable first pass myocardial oxygen demand may be sufficient to metabolism (Waller et al., 1984), resulting in control symptoms, but a proportion of patients wide inter-individual variation in plasma nifediwill need additional treatment. The dihydro- pine concentrations and the need for individual pyridine derivative nifedipine, a slow-channel dose titration (Deanfield et al., 1983). When calcium blocker, has become widely accepted as given in the standard capsule preparation, an adjunct to,b-adrenoceptor blockade in the nifedipine improved exercise tolerance in patients Correspondence: Dr V. F. Challenor, Clinical Pharmacology, Centre Block, Southampton General Hospital, Southampton S09 4XY 509

2 510 V. F. Challenor et al. Atenolol 50 mg + Atenolol 50 mg + nifedipine 20 mg nifedipine 40 mg Atenolol 50 mg + Atenolol 50 mg + nifedipine 20 mg nifedipine 40 mg Group 1 Weeks 0 5 Group2 Atenolol 50 mg Atenolol 50 mg + placebo + placebo All medication administered twice daily Figure 1 Study design. Atenolol 50 mg Atenolol 50 mg + placebo + placebo with stable angina pectoris for up to 6 h after dosing (Ardissano et al., 1983). However, about 19% of patients treated with the capsule formulation can be expected to experience adverse effects, which are severe enough to cause withdrawal from treatment in up to 6% (Ebner & Donath, 1980). Side effects are not only doserelated (Covinsky & Hamburger, 1983) but also due to high peak plasma concentrations of the drug (Zylber-Katz et al., 1984). The slow release formulation of nifedipine gives lower peak plasma concentrations (Challenor et al., 1986) and a longer 'elimination' half-life than the capsule formulation. This formulation is of proven efficacy in the management of hypertension (Banzet et al., 1983) but its use in the management of angina pectoris has not been established. The present study has assessed the effect of forced-titration of a slow release formulation of nifedipine in patients with stable angina pectoris who were incompletely controlled by atenolol. Methods Approval for this study was obtained from the local ethics committee. Twenty patients (17 males, three females, aged years) were entered after giving written informed consent. Patient selection Patients were selected on the basis of a classical history of stable angina of at least 12 weeks duration. All were treated with,b-adrenoceptor antagonists alone and continued to experience more than three attacks of exercise-induced angina per week. The diagnosis of angina was substantiated by horizontal ST depression of at least 1 mm from the 'J' point on a standard 12 lead electrocardiogram during treadmill exercise using a modified Bruce protocol (The Committee on Exercise, 1972). Patients were excluded from the study if there was a history of cardiac failure, valvular heart disease, chronic obstructive pulmonary disease or intermittent claudication. Two patients had hypertension. Six patients had evidence of previous myocardial infarction, four anterior, two inferior. Concomitant therapy other than 3-adrenoceptor blockers and nifedipine consisted of frusemide (2), amiloride (1), isosorbide (2), sustac (1), cimetidine (1) and fybogel (1). Study design (Figure 1) The study was conducted using a double-blind, double-dummy cross-over design. Four types of tablets were used: a) Atenolol 50 mg combined with slow release nifedipine 20 mg; b) Atenolol 50 mg combined with placebo to slow release nifedipine; c) Slow release nifedipine 20 mg; d) Placebo to slow release nifedipine. During an initial 2 week run-in phase patients were stabilized on atenolol 50 mg twice daily with placebo to nifedipine (tablets b + d). Each patient undertook two treadmill exercise tests to obtain baseline exercise tolerance and to reduce any training effect. Provided that each patient was still experiencing more than three attacks of

3 Nifedipine plus atenolol in angina 511 Table 1 Number of anginal attacks and glyceryl trinitrate consumption from patient diary cards during treatment with atenolol alone and atenolol combined with nifedipine Atenolol + Atenolol + Atenolol nifedipine 20 mg nifedipine 40nmg Anginal attacks (number per week) 10.2 ± ± ± 5.3** Glyceryl consumption (number per week) 8.1 ± ± ± 5.4* * P < 0.02, ** P < 0.01 compared with atenolol Results are mean ± s.d. exercise-induced angina per week and the last exercise test was positive, they were then randomised to receive either atenolol 50 mg plus nifedipine 20 mg twice daily (tablets a + d) or to continue on atenolol 50 mg plus placebo to nifedipine twice daily (tablets b + d). After 3 weeks the dose of nifedipine was increased to 40 mg twice daily (tablets a + c). After 6 weeks patients were crossed over to the alternate form of therapy. Methods of assessment (a) Assessments of anginal frequency and glyceryl trinitrate consumption were made on daily diary cards. (b) Maximal treadmill exercise test tolerance was assessed using a modified Bruce protocol. The same physician supervised each exercise test throughout the study. Patients were studied on the final day of 3 weeks treatment approximately 12 h after the last tablets, and then 2 h after the morning tablets were taken. The times to the development of chest pain and significant ST depression were recorded. The test was terminated by the supervisor if the patient developed serious cardiac arrhythmias, falling systolic blood pressure, serious fatigue, unsteady gait or ST segment depression > 4 mm. (c) 20 ml blood samples were collected prior to each exercise test for estimation of plasma nifedipine and atenolol concentrations (Waller et al., 1984; McAinsh, 1985). Precautions were taken to avoid photodegradation of nifedipine. (d) Side-effects were elicited by completion of a symptom related questionnaire at each visit. Withdrawal Patients were withdrawn from the study if their angina frequency increased markedly during the study. Statistics Results obtained during randomised treatment with atenolol alone were compared by the Wilcoxon signed rank test and since no significant differences were observed, subsequently were analysed as the mean of the two periods. Results obtained with atenolol alone were then compared individually with those after addition of nifedipine by the Wilcoxon signed rank test. Results are expressed as the mean ± standard deviation. Data were analysed for the presence of order effects by the method of Hills & Armitage (1979). Results Two patients did not complete the study; one underwent coronary artery by-pass surgery, the other was killed in an accident at work. Eleven patients underwent coronary angiography. Seven had triple vessel disease, three had double vessel disease and one single vessel disease. Diary records The addition of slow release nifedipine 20 mg twice daily to atenolol resulted in a small, but non-significant, fall in both weekly glyceryl trinitrate consumption and number of anginal attacks. By contrast, on increasing the dose of nifedipine to 40 mg twice daily there were statistically significant reductions of 25% in weekly glyceryl trinitrate consumption (P < 0.02) and 36% in the number of anginal attacks (P < 0.01) (Table 1). Detailed analysis of the overall incidence of anginal attacks at given time intervals throughout the day revealed that the addition of nifedipine 20 mg to atenolol resulted in a reduction in the number of attacks for about 6-8 h post dosing.

4 512 V. F. Challenor et al. a 80 U, -C. _ CU._, Q.0 m E C h h h h h h h h h h 0 L M-.-.- Li h h h h h h h h h h h h Figure 2 The relationship of time of day to total number of anginal attacks in.18 patients during each treatment phase. 7 atenolol, 2 atenolol + nifedipine 20 mg, E atenolol + nifedipine 40 mg. When the dose of nifedipine was increased to 40 mg a reduction in the number of attacks was noted for 8-10 h post dosing (Figure 2). Plasma nifedipine concentrations Mean nifedipine plasma concentrations at 2 h following 20 mg and 40 mg doses were 62.2 ± 24.8 ng ml-' and ± 41.7 ng ml-' respectively. Twelve hours post dosing these had fallen to 13.9 ± 8.8 ng ml-' and 35.1 ± 19.3 ng ml-' respectively. Plasma atenolol concentrations Mean plasma atenolol concentrations did not differ significantly betwen the study days either at 2 h or 12 h post dosing. Mean plasma atenolol levels were ng ml-' (range ) following atenolol alone, ng ml-' (range ) following atenolol plus nifedipine 20 mg, ng ml-' (range ) following atenolol plus nifedipine 40 mg 2 h post dosing, and ng ml-' (range ) following atenolol alone, ng ml-1 (range

5 Nifedipine plus atenolol in angina 513 Table 2 Results of exercise testing 2 h post dosing with either atenolol alone or atenolol combined with nifedipine Atenolol Atenolol 50 mg + AtenololSO mg + 50 mg nifedipine 20 mg nifedipine 40 mg Exercise tolerance (min) 13.0 ± ± 2.7* 15.0 ± 2.5** Time to onset of angina (min) 8.3 ± ± 3.3** 12.7 ± 3.6** Time to onset of 1 mm ST depression (min) 9.4 ± ± 3.9** 13.1 ± 3.3** ST segment depression at minimum workload (mm) 1.9 ± ± 0.6*** 0.7 ± 0.6** Rate-pressure product a) Initial 7121 ± ± ± 947 b) Peak exercise ± ± ± 3510 c) Time to pain ± ± ± 3706 d) Time to 1 mm ST depression ± ± ± 2838 * P < 0.01 compared with atenolol alone ** P < compared with atenolol alone P < compared with atenolol alone P < 0.05 compared with atenolol + nifedipine 20 mg Results expressed as mean ± s.d ) following atenolol plus nifedipine 20 mg and ng ml-' (range ) following atenolol plus nifedipine 40 mg 12 h post dosing. The average resting heart rate prior to nifedipine therapy was 58 beats min- 1 2 h post dosing with atenolol. Exercise testing The absence of any period or order effects suggest that the training effect did not significantly influence the exercise test results. Two hours after nifedipine, exercise duration was increased significantly by 10.6% following the 20 mg dose and by 15.5% following the 40 mg dose compared to atenolol alone. There was a 37% improvement in time to development of angina and a 29% increase in time to 1 mm ST depression 2 h following the 20 mg dose, and improvements of 55% and 39% for these measurements 2 h following the 40 mg dose compared with atenolol alone (Table 2). Maximal ST depression on atenolol was significantly reduced at equivalent work-loads 2 h after both nifedipine 20 mg (P < 0.005) and nifedipine 40 mg (P < 0.001). By contrast, 12 h after nifedipine 20 mg, no significant differences were observed in any of the exercise measurements when compared to atenolol alone (Table 3). Twelve hours after nifedipine 40 mg the time to development of angina was increased by 26% and to 1 mm ST depression by 24% when compared with atenolol alone. Maximal ST depression after nifedipine 40 mg was also significantly reduced at equivalent work-loads (P < 0.01). However, no significant increase in exercise tolerance was observed (Table 3). When nifedipine 40 mg was compared with nifedipine 20 mg, the times to development of angina and 1 mm ST depression were significantly increased at 12 h post-dosing (P < 0.01), whilst at 2 h post-dosing only time to development of angina was significantly prolonged (P < 0.05). The percentage improvement in the mean times to significant ST depression, onset of anginal chest pain and exercise duration were closely correlated with the log mean plasma nifedipine concentration (Figure 3). The rate x pressure product was not significantly different between groups at either 2 h or 12 h post-dosing, at rest, peak exercise, onset of angina or 1 mm ST depression (Tables 2 and 3). No differences in exercise test results were noted between patients with one, two or three vessel disease. A higher incidence of some unwanted effects were reported after the addition of nifedipine to atenolol, with increased complaints of swollen ankles, tachycardia, flushing and dry mouth (Table 4). Although thirteen of 18 patients experienced such effects, none was severe enough to warrant withdrawal from the trial.

6 514 V. F. Challenor et al. Table 3 Results of exercise testing 12 h post dosing with either atenolol alone or atenolol combined with nifedipine Atenolol Atenolol 50 mg + Atenolol 50 mg + 50 mg nifedipine 20 mg nifedipine 40 mg Exercise tolerance (min) 11.5 ± ± ± 3.5 Time to onset of angina (min) 6.8 ± ± ± 3.0** Time to onset of 1 mm ST depression (min) 7.0 ± ± ± 4.3* ST segment depression at minimum workload (mm) 1.9 ± ± ± 0.9** Rate-pressure product a) Initial 8595 ± ± ± 1144 b) Peak exercise ± ± ± 2057 c) Time to pain ± ± ± 2501 d) Time to 1 mm ST depression ± ± ± 2000 * P < 0.01 compared with atenolol alone ** P < compared with atenolol alone P < 0.01 compared with atenolol + nifedipine 20 mg Results expressed as mean ± s.d. c 0 E 0. 0 E /zz.,r=0.97 r=0.93 r=0.97 I --A 0 U Nifedipine (ng ml-') Figure 3 The relationship between mean plasma nifedipine concentrations and % improvement in the results of exercise testing. e-* time to pain, 0.0 time to 1 mm ST depression, A--A maximal exercise tolerance. Discussion The addition of slow release nifedipine at a dose of 20 mg twice daily to atenolol therapy did not improve anginal control as measured by frequency of pain or glyceryl trinitrate consumption. Formal exercise testing demonstrated a clear cut improvement at 2 h post-dosing, whereas this was not evident at 12 h post-dosing. A study by Brugmann et al. (1983) suggested a limited duration of action of 20 mg of slow release nifedipine given as monotherapy for angina. The time to both onset of 1 mm ST depression and maximum ST depression was prolonged by 59% and 60% respectively at 2 h post-dosing, but by only 26% and 27% respectively at 8 h. In the current study, the distribution of anginal attacks during the hours following the morning daily dose of nifedipine support the gradual reduction of effectiveness with time, and suggest an effective duration of action of up to about 8 h. Table 4 Numbers of patients reporting unwanted effects with increased frequency after addition of nifedipine to atenolol Atenolol + Atenolol + Atenolol nifedipine 20 mg nifedipine 40 mg Ankle swelling Tachycardia Flushing Dry mouth 2 4 5

7 By contrast, a study by Crake et al. (1988) reported no difference in anginal control as assessed by angina diaries and treadmill exercise testing when a combination of atenolol and either slow release nifedipine or capsules were compared with atenolol monotherapy. However treatment periods were for 2 weeks only which may not be long enough to take into account the improvement with time of anginal control following nifedipine. Again no mention was made of the time post-dosing at which exercise testing was undertaken, and plasma nifedipine concentrations were not measured. Furthermore, although no statistically significant differences were obtained a trend towards improved anginal control in six out of 10 subjects was seen following the combination of slow release nifedipine with atenolol. Increasing the nifedipine dosage to 40 mg twice daily resulted in a statistically significant reduction in both the number of anginal attacks and glyceryl trinitrate consumption. The improvement in anti-anginal control appears to be related to the higher mean plasma nifedipine concentrations. Again, however, the anti-anginal action was considerably diminished 12 h post-dosing. Despite a significant reduction in ischaemia on treadmill exercise at 12 h after this dose, there was no significant improvement in exercise tolerance. The distribution of anginal attacks following the addition of nifedipine 40 mg suggests that a significant anti-anginal effect lasts only up to 10 h after the dose. The addition of nifedipine to atenolol did not alter myocardial oxygen consumption as measured by the double product at peak exercise, at the onset of angina or at the onset of 1 mm ST depression, consistent with results previously reported by Sherman & Liang (1983). Clinical benefit in angina is unlikely to be discernible if the time to onset of symptoms is increased by less than 20%. The present study showed a mean 20% improvement in both time to pain and 1 mm ST depression occurred at nifedipine concentrations over 35 ng ml-l. Previous workers have suggested that a minimum Nifedipine plus atenolol in angina 515 plasma concentration of nifedipine must be maintained for improvement in exercise tolerance and frequency of anginal attacks (Chaitman et al., 1984; Stern et al., 1984). The current results suggest that the low plasma concentrations of nifedipine 12 h after a 20 mg slow release tablet have little anti-ischaemic effect. Pharmacokinetic studies with 20 mg slow release nifedipine have shown plasma concentrations 8 h post-dosing between 10 and 20 ng ml-' (Banzet et al., 1983) consistent with the short duration of action in the current study. However, in accord with previous studies (Stern et al., 1984; Reves et al., 1983), marked inter-individual variation was found in the response to nifedipine. Eight patients achieved a greater than 20% improvement in time to onset of angina at plasma nifedipine concentrations of less than 30 ng mlv-l. However only three patients with a nifedipine plasma concentration greater than 35 ng ml- l did not achieve a 20% improvement in time to onset of angina. Futhermore, one paient deteriorated with high plasma concentrations of nifedipine suggestive of a 'steal' phenomenon. Individual dose titration is therefore essential to optimise the anti-anginal effect. The addition of nifedipine to atenolol caused only minor unwanted effects in 13 out of 18 patients. However, one patient felt markedly worse on addition of nifedipine 40 mg twice daily despite improved anginal control. We conclude that nifedipine is an effective adjunct to 3-adrenoceptor blockade with atenolol for stable angina pectoris. Reduction of effort-related angina is related to the plasma concentration of nifedipine, and dose titration of nifedipine is necessary to optimise the response. Used in slow release form, the average duration of action of a 20 mg dose is approximately 8 h, increasing to about 10 h when a 40 mg dose is given. The authors are grateful to Dr Neville Conway for allowing us to study his patients, Beryl Gruchy for technical assistance, Eve Allen and Sue Ellery for nursing assistance, Dianne Wilson for typing our manuscript and Bayer UK for financial support. References Alderman, E. L., Davies, R. O., Crowley, J. J., Lopes, M. G., Brooker, J. Z., Friedman, J. P., Graham, A. G., Matlof, H. M. & Harrison, D. C. (1975). Dose response effectiveness of propranolol for the treatment of angina pectoris. Circuilationi, 51, Ardissano, D., DeServi, S., Salerno, J. A., Specchia, G., Previtali, M. et al. (1983). 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