© 1990 S. Kargcr AG, Basel 0008-6312/90/0776-0459S2.75/0
Cardiology 1990;77:459-465
Bopindolol for the Treatment of Chronic Stable Angina pectoris - A Clinical Study of the Relationship between Dose and Effect D. Holmesa, Z Fryda-Kaurimsky3-+, K. Kruegerb “Clinical Research Department, Sandoz Ltd., Basel, Switzerland; b Medical Director (retired), Clinic for Cardiac and Circulatory Diseases. Tegemsee, FRG
Key Words. Stable angina pectoris • Exercise testing • Beta-blockade • Bopindolol
Introduction Bopindolol is a new beta-adrenoceptor blocking drug with a long duration of action and mild intrinsic sympathomimetic activity (ISA) [1]. Experimental studies in healthy volunteers have shown that beta-blockade is almost maximal following single oral doses of 2 mg and that, with this dose, about 50% of the maximal achieved effect is still present 24 h after administration [2, 3]. It has also been shown [4] that the results of single-dose studies are predictive for the pharmacody namic response to exercise after multiple doses. Since the therapeutic effect of betaadrenoceptor blocking drugs in the treat
ment of angina pectoris is primarily due to the reduction of the heart rate and blood pressure response to stress, it seemed likely that the maximum clinical effect of bopindo lol would be achieved with once-daily doses of 2 mg in such patients. Of particular inter est was the effect of doses giving submaximal beta-blockade and the response to exercise at the end of the dosing interval since, with morning therapy, this coincides with the greatest incidence of myocardial ischemia [5, 6] and coronary incidents [7], The purpose of our study was to examine the effect of once-daily therapy with bopin dolol on exercise tolerance (bicycle ergome try) and on clinical symptoms (frequency of
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Abstract. Following a 4-week placebo period, 19 patients ( 12 male, average age 62.3 years) with chronic stable angina pectoris and a positive exercise test were treated with the betaadrenoceptor antagonist bopindolol at increasing doses of 0.5, 1 and 2 mg, each being given once daily for 4 weeks. For the final 4 weeks of the study, active treatment was replaced by placebo. Maximum tolerated exercise (bicycle ergometry, performed 24 h after drug admin istration) increased dose-dependently from 519 ± 59 s (baseline) to 758 ± 95 s with 2 mg (p < 0.001) and fell again to 508 ± 48 s (placebo). The frequency of anginal attacks also fell dose-dependently from an average of 5.4 per week (baseline) to 0.5 with 2 mg (p < 0.001) and rose again to 5.1 per week when active treatment was stopped.
Holmes/Fryda-Kaurimsky/Krueger
anginal attacks). We selected a dose range commencing with 0.5 mg once daily, which has been shown in volunteers to give submaximal beta-blockade [2] and increasing to 2 mg daily, a level at which almost maximal beta-blockade is achieved [2], Materials and Methods Patients Studied Nineteen patients (12 male, 7 female) aged be tween 56 and 66 (mean 62.3) years were studied. All had a history of typical angina pectoris and a positive exercise test defined as at least 1 mm of ST segment depression associated with anginal pain occurring within 12 min of exercise on a bicycle ergometer with steps of 25 W and 3 min per step. Not eligible for the study were patients with contraindications for betaadrenoceptor blocking drugs (e.g. heart failure, asth ma. bradycardia), those who had suffered a myocar dial infarction within the previous 3 months or un dergone cardiac surgery within the previous 6 months, those with clinically relevant disease of the liver, kidneys or gastrointestinal tract and those tak ing any medications considered to potentially in fluence the results of the study. Also excluded were patients who were unable or unwilling to co-operate with the foreseen study plan. All patients were fully informed of the details of the study and gave their consent to participate. One patient took the highest dosage (2 mg) for only 3 weeks and then developed a bradycardia (see later). The dosage was reduced and this patient was included only in the assessment of clinical effect (number of anginal attacks) but not in the exercise test results. Study Design A single-blind study design was used. Patients who were already receiving anti-anginal drugs had these gradually withdrawn over a period of at least 2 weeks, anginal attacks being treated with short-acting nitrates when they occurred but not prophylactically. Thereaf ter, all patients received 1 placebo capsule daily for 4 weeks. Active treatment was then begun with bopindolol 0.5 mg once daily in the morning. This was increased after 4 weeks in all cases to 1 mg daily and after a further 4 weeks to 2 mg daily for 4 weeks. After this 12-week active treatment period, the dosage was
reduced stepwise over 7 days and finally replaced by placebo for the last 4 weeks of the study. Placebo and active drug at all dose levels were given as identically appearing yellow capsules, the patients taking 1 cap sule daily in the morning with breakfast. Exercise testing was carried out before and after 2 and 4 weeks of the first placebo phase, at the end of each dose level and at the end of the second placebo phase (a total of 7 tests). Clinical assessment was also carried out as these times and, in addition, after 2 weeks at each dose level and weekly during the last placebo phase (a total of 13 examinations). Exercise Testing All tests were carried out in the same air-condi tioned laboratory by the same staff on every occasion. A bicycle ergometer was used, with an initial load of 25 W which was increased every 3 min in steps of 25 W to a maximum of 150 W if the test was not termi nated earlier. The test was terminated on the occur rence of moderately severe anginal pain, ST segment depression of more than 4 mm, hypotension or ven tricular arrhythmia or when the maximum load was reached. Time to onset of first anginal pain and to exercise termination was recorded together with the blood pressure, heart rate and ST segment deviation at each of these two time points. The degree of betablockade achieved was assessed by the change in the heart rate at a load of 75 W. This load was chosen as it was the highest load achieved by all patients on all occasions. The exercise tests were carried out in the morning before therapy for the day was taken, i.e. at the end of the 24-hour dosing interval. Clinical Assessment Patients were examined at each clinic visit and laboratory tests (hematology and biochemistry) were carried out before and after active treatment. The number and severity of anginal attacks and the num ber of nitroglycerine tablets taken were recorded on diary cards and compliance with medication was checked by pill counts carried out each time the patients attended the clinic. Statistical Analysis Conventional descriptive statistics were calcu lated and the effect of each dose of bopindolol on exercise tolerance and the average weekly frequency of anginal attacks was statistically tested using Wilcoxon’s signed rank test (two-sided, alpha = 0.05)
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with the values at the end of the first placebo phase as the baseline. Th effect of withdrawal of active treat ment was tested in a similar way.
Results The results of the exercise tests are taken from the 18 patients who adhered to the foreseen dosage scheme and took each dos age for 4 weeks. Pill-counting at each visit established that adherence to therapy had been satisfactory.
Exercise Duration The results of exercise testing are shown in table 1 and figure 2. Only 2 patients termi nated the exercise test after 8 and 12 weeks of treatment (1 and 2 mg daily) because of angina. Even the lowest dosage (0.5 mg dai ly) caused an increase in exercise tolerance but the highest dosage (2 mg daily) was only slightly more effective than the 1 mg dosage. The difference from baseline was significant (p < 0.001) with all doses. Exercise toler ance at the end of the second placebo period had returned to the baseline value. ST Segment Deviation The average ST segment deviation at the end of exercise was lower during active ther apy than during either of the placebo phases, both of which showed about the same aver age ST depression. This effect was also dose dependent (fig. 3).
Dosage, mg
Fig. 1. Heart rate (beats/min) at 75 W exercise during treatment with placebo (P) or bopindolol at doses of 0.5, 1 and 2 mg once daily (values are means and standard deviations of 18 patients).
Angina Attacks For the assessment of clinical effect, all 19 patients were used, including the patient who took the highest dosage for only 3 weeks. The number of anginal attacks was constant during the first placebo phase and fell from an average of 5.4 to 2.2 per week with the lowest dosage although none of the patients were free of attacks. A further re duction to an average of 1.2 per week was achieved with a dosage of 1 mg daily and 2 patients were free of attacks. With the high est dosage, 10 patients were free of attacks and the average had fallen to 0.5 per week. The difference from baseline was significant
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Degree o f Beta-Blockade Achieved The heart rate at a load of 75 W fell even with the lowest dosage given and the further fall seen with the two higher dose levels was much smaller (fig. 1). At the end of the sec ond placebo phase, it had returned to the baseline level.
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Table 1. Time (seconds) to end of exercise and number of patients terminating exercise because of angina before and during treatment with bopindolol
Mean Median SD 95% confidence limit Lower Upper Angina as end-point
Baseline
0.5 mg
1 mg
2 mg
Placebo II
519 495 59
670 690 99
732 750 108
758 765 95
508 510 48
489 548 18
621 719 11
678 785 2
711 805 2
485 532 18
Table 2. Average number of anginal attacks per week and number of patients with no attacks before and during treatment with bopindolol
Mean Median SD Minimum Maximum No angina
Baseline
0.5 mg
1 mg
2 mg
Placebo II
5.4 6.0
2.2 2.0 1.2 1 5 0
1.2
0.5 0 0.8 0 3 10
5.1 5.0 0.7 4 6 0
1.0
3 7 0
1.0
1.4 0 5 2
Table 3. Number of patients reporting adverse drug reactions during each phase of the study
Tiredness Sleep disturbances Bradycardia
Placebo I
0.5 mg
1 mg
2 mg
Placebo II
1 0 0
1 0 0
5 0 0
7 2 1
1 0 0
(p < 0.001) with all doses. The number of attacks increased again during the second placebo phase, at the end of which the aver age was 5.1 per week, and all patients were again experiencing anginal attacks (table 2).
Adverse Events Twelve patients reported adverse events but all were able to complete the study. Nine patients reported tiredness and 2 reported sleep disturbances. One patient was found to
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Note: patients reporting tiredness in more than one phase are counted in each phase in which the adverse event was reported.
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Fig. 2. Maximum exercise tolerance (seconds) during treatment with placebo (P) or bopindolol at doses of 0.5, I or 2 mg once daily (values are means and standard deviations of 18 patients).
Fig. 3. ST segment depression (mm) at different loads (W) during placebo and at different dose levels of bopindolol (values arc means of 18 patients).
have a heart rate of 48 beats/min after taking the highest dose for 3 weeks but reported no adverse events attributable to the bradycar dia. The heart rate increased to 56 beats/min when the dosage was reduced to 1 mg daily. The incidence was dose-related as shown in table 3.
whether maximum beta-blockade is needed to achieve a good clinical effect. The dosage of bopindolol used in our study has already been studied in healthy vol unteers [2]. The results have shown that, fol lowing single doses of 0.5 mg of bopindolol, beta-blockade is never maximal but 24 h after administration, is still evident. With single doses of 2 mg, maximum beta-blockade is achieved about 3 h after administration and about 50% of this is still present 24 h after administration. It has been shown [4] that the results of single-dose studies are predictive for the pharmacodynamic response to exer cise after multiple dosing. Thus, it can be con cluded that the dose/effect relationship re
Discussion Anti-anginal effects with bopindolol have been reported in several other studies [8-10] but none of these have attempted to relate the clinical effect seen to the degree of betablockade achieved or to address the question
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Load, W
ported persists after multiple dosing with no accumulation of beta-blocking effect. Since there is no reason to believe that our patients would respond differently from these volun teers, we can conclude that our patients were not maximally beta-blocked during most of the treatment period. This is further con firmed by the fact that, following treatment, the heart rate response to a load of 75 W showed the expected dose/effect relationship. Exercise testing in our patients with angina pectoris was also carried out 24 h after ad ministration and showed that the degree of beta-blockade present at this time even fol lowing doses of 0.5 mg of bopindolol is clearly clinically relevant as seen from the fact that exercise tolerance was increased by about 30% and the frequency of anginal at tacks reduced by about 50%. The highest dose used in our study (2 mg daily) increased exercise tolerance by about 50% and achieved complete freedom from anginal at tacks in 10 of 19 patients, none of the other 9 having more than 3 attacks per week. This clinically very good result was, therefore, achieved with a dosage which, in the experi mental studies referred to, gave maximal beta-blockade during only part of the 24-hour observation period following the highest dose and not at all following the lowest dose. Com parable effects on anginal attacks and exer cise tolerance have been reported for other beta-blockers, for example, atenolol [11]. Intuitively one tends to believe that the optimal treatment with beta-blockers of pa tients with angina pectoris requires that maximum beta-blockade should be achieved for as great a part of the dosing interval as possible. This may, however, be neither true nor desirable. It has been demonstrated that the incidence of myocardial ischemia follows a circadian variation [5, 6] and that this
Holmes/Fryda-Kaurimsky/Krueger
applies to both painful and ‘silent’ ischemic incidents [12]. All these reports confirm that the incidence is highest during the forenoon and lower in the afternoon and evening. Studies of the circadian variation in blood pressure and heart rate in hypertensive pa tients and healthy volunteers [13] have shown a pattern similar to that seen with myocardial ischemia, suggesting that these changes in blood pressure and heart rate may be one factor in the etiology of myocardial ischemia. Thus, it can be argued that maxi mal beta-blockade may only be needed when sympathetic tone is greatest, i.e. when the blood pressure and heart rate are highest, and that submaximal blockade may be suffi cient later in the day when sympathetic tone falls spontaneously. The fact that activity and thus changes in blood pressure and heart rate are limited not only by myocardial ischemia but also by tiredness is also a factor to be considered. In our study, even with the lowest dose used, 11 patients did not reach their new ‘angina threshold’ and terminated the exercise test because of tiredness. With the two higher doses, only 2 patients stopped the test be cause of anginal pain. Although 2 of the 19 patients showed slightly inconsistent results in that both reported angina at an exercise level which they had tolerated well in one of the earlier tests, most of the patients did not, during beta-blocker therapy, reach the level of activity at which anginal pain would occur although the maximum tolerated exercise was increased in all cases. This finding also supports the suggestion that the achievement of maximal beta-blockade may be unneces sary for many patients with angina pectoris and that a satisfactory clinical response may be achievable in many cases without increas ing the dosage of beta-blocking drugs to a
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Acknowledgements The authors are grateful to Mr. E. Hachmann of IDV, Gauting, FRG for data processing and statisti cal analysis and to Dr. W.H. Aellig for helpful criti cism of the manuscript.
References 1 Berthold R, Waite R, Weber H: Pharmacological studies with bopindolol: a new long-acting betaadrenoceptor antagonist. Br J Pharmacol 1981;74: 829P. 2 Aellig WH: Pharmacological experiments in healthy volunteers with bopindolol. a long-acting beta-adrenoceptor blocking drug with partial ago nist activity. Br J Clin Pharmacol 1985; 19:775781. 3 Aellig WH: Bopindolol - a new beta-adrenoceptor blocking drug. Curr Opin Cardiol 1988;3(suppl 2): S7-S12. 4 Platzer R. Galeazzi RL, Niedcrberger W, Rosenthaler J: Simultaneous modelling of bopindolol kinetics and dynamics. Clin Pharmacol Ther 1984;38:5-13.
5 Quyyumi A, Mockus L, Wright C, Fox K: Mor phology of ambulatory ST segment changes in patients with varying severity of coronary artery disease: Investigation of the frequency of noctur nal ischaemia and coronary spasm. Br Heart J 1985;53:186-193. 6 Rocco MB, Barry J, Campbell S, Nabel W, Cook EF. Goldman L, Selwyn AP: Circadian variation of transient myocardial ischaemia in patients with coronary artery disease. Circulation 1987;75:395400. 7 Muller JE, Stone PH. Turi ZG: Circadian varia tion in the frequency of onset of acute myocardial ischaemia. N Engl J Med 1985:313:1315-1322. 8 Vermeulen A: Efficacy of bopindolol. a new beta blocking agent in angina pectoris compared to metoprolol; in van Zwieten PA (ed): The Position of Bopindolol, a New Beta-Blocker. London, Royal Society of Medicine Services, 1987, pp 8790. 9 Cristal N, Cantor A, Hochberg Y: Bopindolol in the treatment of chronic stable angina: Compari son with the efficacy of nifedipine. Curr Opin Cardiol 1988;3(suppl 2):S109-S111. 10 Dorow P, Schiess W: The acute anti-anginal effi cacy of bopindolol. Curr Opin Cardiol 1988: 3(suppl 2):S113-SI 16. 11 Jackson G, Schwartz J, Kates RE, Winchester M. Harrison DC: Atenolol: Once-daily cardio-selective beta blockade for angina pectoris. Circula tion 1980:61:555-560. 12 Mulcahy D, Cunningham D, Crean P, Wright C, Keegan J, Quyyumi A, Park A, Fox K: Circadian variation of total ischaemic burden and its altera tion with anti-anginal agents. Lancet 1988:8614: 755-759. 13 Millar-Craig MW, Bishop CN, Raftery EB: Circa dian variation of blood pressure. Lancet 1978;i: 795-797. 14 Pepine CJ, Hill JA: Medical therapy for silent myocardial ischaemia. Circulation 1987;75(suppl II):II43—1144. Received: February 26. 1990 Accepted after revision: May 11, 1990 D. Holmes Clinical Research Department Sandoz Ltd. CH-4002 Basel (Switzerland)
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level at which full beta-blockade is present throughout the dosing interval. Whether, however, a satisfactory clinical response such as we achieved (minimal anginal at tacks and an increase in exercise tolerance of 30-50%) can be regarded as acceptable is at present subject to discussion. It has been suggested [14] that the aim of treatment for ischemic heart disease should be the elimina tion of all ischemic episodes (‘total ischemic burden’) - not just those associated with anginal pain. We did not carry out Holter ECG studies in our patients but, however, since 17 of the 19 patients reported no an gina even when exercised to their maximum capacity 24 h after drug administration, we can conclude that the ‘total ischemic burden’ was certainly very much reduced by the use of bopindolol in daily doses of 0.5-2 mg.
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Cardiology 1990;77:459-465
Bopindolol for the Treatment of Chronic Stable Angina pectoris - A Clinical Study of the Relationship between Dose and Effect D. Holmesa, Z Fryda-Kaurimsky3-+, K. Kruegerb “Clinical Research Department, Sandoz Ltd., Basel, Switzerland; b Medical Director (retired), Clinic for Cardiac and Circulatory Diseases. Tegemsee, FRG
Key Words. Stable angina pectoris • Exercise testing • Beta-blockade • Bopindolol
Introduction Bopindolol is a new beta-adrenoceptor blocking drug with a long duration of action and mild intrinsic sympathomimetic activity (ISA) [1]. Experimental studies in healthy volunteers have shown that beta-blockade is almost maximal following single oral doses of 2 mg and that, with this dose, about 50% of the maximal achieved effect is still present 24 h after administration [2, 3]. It has also been shown [4] that the results of single-dose studies are predictive for the pharmacody namic response to exercise after multiple doses. Since the therapeutic effect of betaadrenoceptor blocking drugs in the treat
ment of angina pectoris is primarily due to the reduction of the heart rate and blood pressure response to stress, it seemed likely that the maximum clinical effect of bopindo lol would be achieved with once-daily doses of 2 mg in such patients. Of particular inter est was the effect of doses giving submaximal beta-blockade and the response to exercise at the end of the dosing interval since, with morning therapy, this coincides with the greatest incidence of myocardial ischemia [5, 6] and coronary incidents [7], The purpose of our study was to examine the effect of once-daily therapy with bopin dolol on exercise tolerance (bicycle ergome try) and on clinical symptoms (frequency of
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Abstract. Following a 4-week placebo period, 19 patients ( 12 male, average age 62.3 years) with chronic stable angina pectoris and a positive exercise test were treated with the betaadrenoceptor antagonist bopindolol at increasing doses of 0.5, 1 and 2 mg, each being given once daily for 4 weeks. For the final 4 weeks of the study, active treatment was replaced by placebo. Maximum tolerated exercise (bicycle ergometry, performed 24 h after drug admin istration) increased dose-dependently from 519 ± 59 s (baseline) to 758 ± 95 s with 2 mg (p < 0.001) and fell again to 508 ± 48 s (placebo). The frequency of anginal attacks also fell dose-dependently from an average of 5.4 per week (baseline) to 0.5 with 2 mg (p < 0.001) and rose again to 5.1 per week when active treatment was stopped.
Holmes/Fryda-Kaurimsky/Krueger
anginal attacks). We selected a dose range commencing with 0.5 mg once daily, which has been shown in volunteers to give submaximal beta-blockade [2] and increasing to 2 mg daily, a level at which almost maximal beta-blockade is achieved [2], Materials and Methods Patients Studied Nineteen patients (12 male, 7 female) aged be tween 56 and 66 (mean 62.3) years were studied. All had a history of typical angina pectoris and a positive exercise test defined as at least 1 mm of ST segment depression associated with anginal pain occurring within 12 min of exercise on a bicycle ergometer with steps of 25 W and 3 min per step. Not eligible for the study were patients with contraindications for betaadrenoceptor blocking drugs (e.g. heart failure, asth ma. bradycardia), those who had suffered a myocar dial infarction within the previous 3 months or un dergone cardiac surgery within the previous 6 months, those with clinically relevant disease of the liver, kidneys or gastrointestinal tract and those tak ing any medications considered to potentially in fluence the results of the study. Also excluded were patients who were unable or unwilling to co-operate with the foreseen study plan. All patients were fully informed of the details of the study and gave their consent to participate. One patient took the highest dosage (2 mg) for only 3 weeks and then developed a bradycardia (see later). The dosage was reduced and this patient was included only in the assessment of clinical effect (number of anginal attacks) but not in the exercise test results. Study Design A single-blind study design was used. Patients who were already receiving anti-anginal drugs had these gradually withdrawn over a period of at least 2 weeks, anginal attacks being treated with short-acting nitrates when they occurred but not prophylactically. Thereaf ter, all patients received 1 placebo capsule daily for 4 weeks. Active treatment was then begun with bopindolol 0.5 mg once daily in the morning. This was increased after 4 weeks in all cases to 1 mg daily and after a further 4 weeks to 2 mg daily for 4 weeks. After this 12-week active treatment period, the dosage was
reduced stepwise over 7 days and finally replaced by placebo for the last 4 weeks of the study. Placebo and active drug at all dose levels were given as identically appearing yellow capsules, the patients taking 1 cap sule daily in the morning with breakfast. Exercise testing was carried out before and after 2 and 4 weeks of the first placebo phase, at the end of each dose level and at the end of the second placebo phase (a total of 7 tests). Clinical assessment was also carried out as these times and, in addition, after 2 weeks at each dose level and weekly during the last placebo phase (a total of 13 examinations). Exercise Testing All tests were carried out in the same air-condi tioned laboratory by the same staff on every occasion. A bicycle ergometer was used, with an initial load of 25 W which was increased every 3 min in steps of 25 W to a maximum of 150 W if the test was not termi nated earlier. The test was terminated on the occur rence of moderately severe anginal pain, ST segment depression of more than 4 mm, hypotension or ven tricular arrhythmia or when the maximum load was reached. Time to onset of first anginal pain and to exercise termination was recorded together with the blood pressure, heart rate and ST segment deviation at each of these two time points. The degree of betablockade achieved was assessed by the change in the heart rate at a load of 75 W. This load was chosen as it was the highest load achieved by all patients on all occasions. The exercise tests were carried out in the morning before therapy for the day was taken, i.e. at the end of the 24-hour dosing interval. Clinical Assessment Patients were examined at each clinic visit and laboratory tests (hematology and biochemistry) were carried out before and after active treatment. The number and severity of anginal attacks and the num ber of nitroglycerine tablets taken were recorded on diary cards and compliance with medication was checked by pill counts carried out each time the patients attended the clinic. Statistical Analysis Conventional descriptive statistics were calcu lated and the effect of each dose of bopindolol on exercise tolerance and the average weekly frequency of anginal attacks was statistically tested using Wilcoxon’s signed rank test (two-sided, alpha = 0.05)
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with the values at the end of the first placebo phase as the baseline. Th effect of withdrawal of active treat ment was tested in a similar way.
Results The results of the exercise tests are taken from the 18 patients who adhered to the foreseen dosage scheme and took each dos age for 4 weeks. Pill-counting at each visit established that adherence to therapy had been satisfactory.
Exercise Duration The results of exercise testing are shown in table 1 and figure 2. Only 2 patients termi nated the exercise test after 8 and 12 weeks of treatment (1 and 2 mg daily) because of angina. Even the lowest dosage (0.5 mg dai ly) caused an increase in exercise tolerance but the highest dosage (2 mg daily) was only slightly more effective than the 1 mg dosage. The difference from baseline was significant (p < 0.001) with all doses. Exercise toler ance at the end of the second placebo period had returned to the baseline value. ST Segment Deviation The average ST segment deviation at the end of exercise was lower during active ther apy than during either of the placebo phases, both of which showed about the same aver age ST depression. This effect was also dose dependent (fig. 3).
Dosage, mg
Fig. 1. Heart rate (beats/min) at 75 W exercise during treatment with placebo (P) or bopindolol at doses of 0.5, 1 and 2 mg once daily (values are means and standard deviations of 18 patients).
Angina Attacks For the assessment of clinical effect, all 19 patients were used, including the patient who took the highest dosage for only 3 weeks. The number of anginal attacks was constant during the first placebo phase and fell from an average of 5.4 to 2.2 per week with the lowest dosage although none of the patients were free of attacks. A further re duction to an average of 1.2 per week was achieved with a dosage of 1 mg daily and 2 patients were free of attacks. With the high est dosage, 10 patients were free of attacks and the average had fallen to 0.5 per week. The difference from baseline was significant
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Degree o f Beta-Blockade Achieved The heart rate at a load of 75 W fell even with the lowest dosage given and the further fall seen with the two higher dose levels was much smaller (fig. 1). At the end of the sec ond placebo phase, it had returned to the baseline level.
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Table 1. Time (seconds) to end of exercise and number of patients terminating exercise because of angina before and during treatment with bopindolol
Mean Median SD 95% confidence limit Lower Upper Angina as end-point
Baseline
0.5 mg
1 mg
2 mg
Placebo II
519 495 59
670 690 99
732 750 108
758 765 95
508 510 48
489 548 18
621 719 11
678 785 2
711 805 2
485 532 18
Table 2. Average number of anginal attacks per week and number of patients with no attacks before and during treatment with bopindolol
Mean Median SD Minimum Maximum No angina
Baseline
0.5 mg
1 mg
2 mg
Placebo II
5.4 6.0
2.2 2.0 1.2 1 5 0
1.2
0.5 0 0.8 0 3 10
5.1 5.0 0.7 4 6 0
1.0
3 7 0
1.0
1.4 0 5 2
Table 3. Number of patients reporting adverse drug reactions during each phase of the study
Tiredness Sleep disturbances Bradycardia
Placebo I
0.5 mg
1 mg
2 mg
Placebo II
1 0 0
1 0 0
5 0 0
7 2 1
1 0 0
(p < 0.001) with all doses. The number of attacks increased again during the second placebo phase, at the end of which the aver age was 5.1 per week, and all patients were again experiencing anginal attacks (table 2).
Adverse Events Twelve patients reported adverse events but all were able to complete the study. Nine patients reported tiredness and 2 reported sleep disturbances. One patient was found to
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Note: patients reporting tiredness in more than one phase are counted in each phase in which the adverse event was reported.
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Fig. 2. Maximum exercise tolerance (seconds) during treatment with placebo (P) or bopindolol at doses of 0.5, I or 2 mg once daily (values are means and standard deviations of 18 patients).
Fig. 3. ST segment depression (mm) at different loads (W) during placebo and at different dose levels of bopindolol (values arc means of 18 patients).
have a heart rate of 48 beats/min after taking the highest dose for 3 weeks but reported no adverse events attributable to the bradycar dia. The heart rate increased to 56 beats/min when the dosage was reduced to 1 mg daily. The incidence was dose-related as shown in table 3.
whether maximum beta-blockade is needed to achieve a good clinical effect. The dosage of bopindolol used in our study has already been studied in healthy vol unteers [2]. The results have shown that, fol lowing single doses of 0.5 mg of bopindolol, beta-blockade is never maximal but 24 h after administration, is still evident. With single doses of 2 mg, maximum beta-blockade is achieved about 3 h after administration and about 50% of this is still present 24 h after administration. It has been shown [4] that the results of single-dose studies are predictive for the pharmacodynamic response to exer cise after multiple dosing. Thus, it can be con cluded that the dose/effect relationship re
Discussion Anti-anginal effects with bopindolol have been reported in several other studies [8-10] but none of these have attempted to relate the clinical effect seen to the degree of betablockade achieved or to address the question
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Load, W
ported persists after multiple dosing with no accumulation of beta-blocking effect. Since there is no reason to believe that our patients would respond differently from these volun teers, we can conclude that our patients were not maximally beta-blocked during most of the treatment period. This is further con firmed by the fact that, following treatment, the heart rate response to a load of 75 W showed the expected dose/effect relationship. Exercise testing in our patients with angina pectoris was also carried out 24 h after ad ministration and showed that the degree of beta-blockade present at this time even fol lowing doses of 0.5 mg of bopindolol is clearly clinically relevant as seen from the fact that exercise tolerance was increased by about 30% and the frequency of anginal at tacks reduced by about 50%. The highest dose used in our study (2 mg daily) increased exercise tolerance by about 50% and achieved complete freedom from anginal at tacks in 10 of 19 patients, none of the other 9 having more than 3 attacks per week. This clinically very good result was, therefore, achieved with a dosage which, in the experi mental studies referred to, gave maximal beta-blockade during only part of the 24-hour observation period following the highest dose and not at all following the lowest dose. Com parable effects on anginal attacks and exer cise tolerance have been reported for other beta-blockers, for example, atenolol [11]. Intuitively one tends to believe that the optimal treatment with beta-blockers of pa tients with angina pectoris requires that maximum beta-blockade should be achieved for as great a part of the dosing interval as possible. This may, however, be neither true nor desirable. It has been demonstrated that the incidence of myocardial ischemia follows a circadian variation [5, 6] and that this
Holmes/Fryda-Kaurimsky/Krueger
applies to both painful and ‘silent’ ischemic incidents [12]. All these reports confirm that the incidence is highest during the forenoon and lower in the afternoon and evening. Studies of the circadian variation in blood pressure and heart rate in hypertensive pa tients and healthy volunteers [13] have shown a pattern similar to that seen with myocardial ischemia, suggesting that these changes in blood pressure and heart rate may be one factor in the etiology of myocardial ischemia. Thus, it can be argued that maxi mal beta-blockade may only be needed when sympathetic tone is greatest, i.e. when the blood pressure and heart rate are highest, and that submaximal blockade may be suffi cient later in the day when sympathetic tone falls spontaneously. The fact that activity and thus changes in blood pressure and heart rate are limited not only by myocardial ischemia but also by tiredness is also a factor to be considered. In our study, even with the lowest dose used, 11 patients did not reach their new ‘angina threshold’ and terminated the exercise test because of tiredness. With the two higher doses, only 2 patients stopped the test be cause of anginal pain. Although 2 of the 19 patients showed slightly inconsistent results in that both reported angina at an exercise level which they had tolerated well in one of the earlier tests, most of the patients did not, during beta-blocker therapy, reach the level of activity at which anginal pain would occur although the maximum tolerated exercise was increased in all cases. This finding also supports the suggestion that the achievement of maximal beta-blockade may be unneces sary for many patients with angina pectoris and that a satisfactory clinical response may be achievable in many cases without increas ing the dosage of beta-blocking drugs to a
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Bopindolol in Angina pectoris
Acknowledgements The authors are grateful to Mr. E. Hachmann of IDV, Gauting, FRG for data processing and statisti cal analysis and to Dr. W.H. Aellig for helpful criti cism of the manuscript.
References 1 Berthold R, Waite R, Weber H: Pharmacological studies with bopindolol: a new long-acting betaadrenoceptor antagonist. Br J Pharmacol 1981;74: 829P. 2 Aellig WH: Pharmacological experiments in healthy volunteers with bopindolol. a long-acting beta-adrenoceptor blocking drug with partial ago nist activity. Br J Clin Pharmacol 1985; 19:775781. 3 Aellig WH: Bopindolol - a new beta-adrenoceptor blocking drug. Curr Opin Cardiol 1988;3(suppl 2): S7-S12. 4 Platzer R. Galeazzi RL, Niedcrberger W, Rosenthaler J: Simultaneous modelling of bopindolol kinetics and dynamics. Clin Pharmacol Ther 1984;38:5-13.
5 Quyyumi A, Mockus L, Wright C, Fox K: Mor phology of ambulatory ST segment changes in patients with varying severity of coronary artery disease: Investigation of the frequency of noctur nal ischaemia and coronary spasm. Br Heart J 1985;53:186-193. 6 Rocco MB, Barry J, Campbell S, Nabel W, Cook EF. Goldman L, Selwyn AP: Circadian variation of transient myocardial ischaemia in patients with coronary artery disease. Circulation 1987;75:395400. 7 Muller JE, Stone PH. Turi ZG: Circadian varia tion in the frequency of onset of acute myocardial ischaemia. N Engl J Med 1985:313:1315-1322. 8 Vermeulen A: Efficacy of bopindolol. a new beta blocking agent in angina pectoris compared to metoprolol; in van Zwieten PA (ed): The Position of Bopindolol, a New Beta-Blocker. London, Royal Society of Medicine Services, 1987, pp 8790. 9 Cristal N, Cantor A, Hochberg Y: Bopindolol in the treatment of chronic stable angina: Compari son with the efficacy of nifedipine. Curr Opin Cardiol 1988;3(suppl 2):S109-S111. 10 Dorow P, Schiess W: The acute anti-anginal effi cacy of bopindolol. Curr Opin Cardiol 1988: 3(suppl 2):S113-SI 16. 11 Jackson G, Schwartz J, Kates RE, Winchester M. Harrison DC: Atenolol: Once-daily cardio-selective beta blockade for angina pectoris. Circula tion 1980:61:555-560. 12 Mulcahy D, Cunningham D, Crean P, Wright C, Keegan J, Quyyumi A, Park A, Fox K: Circadian variation of total ischaemic burden and its altera tion with anti-anginal agents. Lancet 1988:8614: 755-759. 13 Millar-Craig MW, Bishop CN, Raftery EB: Circa dian variation of blood pressure. Lancet 1978;i: 795-797. 14 Pepine CJ, Hill JA: Medical therapy for silent myocardial ischaemia. Circulation 1987;75(suppl II):II43—1144. Received: February 26. 1990 Accepted after revision: May 11, 1990 D. Holmes Clinical Research Department Sandoz Ltd. CH-4002 Basel (Switzerland)
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level at which full beta-blockade is present throughout the dosing interval. Whether, however, a satisfactory clinical response such as we achieved (minimal anginal at tacks and an increase in exercise tolerance of 30-50%) can be regarded as acceptable is at present subject to discussion. It has been suggested [14] that the aim of treatment for ischemic heart disease should be the elimina tion of all ischemic episodes (‘total ischemic burden’) - not just those associated with anginal pain. We did not carry out Holter ECG studies in our patients but, however, since 17 of the 19 patients reported no an gina even when exercised to their maximum capacity 24 h after drug administration, we can conclude that the ‘total ischemic burden’ was certainly very much reduced by the use of bopindolol in daily doses of 0.5-2 mg.
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