© Current Medical Opinion and Research 1994,1995.
Although the combined administration of atenolol and nifedipine has been shown to be effective in the treatment of angina pectoris the optimum dosage level of the combination has not yet been established. A double-blind, randomly assigned three period cross-over study was carried out therefore to investigate the effects of different daily doses of a fixed combination of 50 mg atenolol and 20 mg sustained-release nifedipine per capsule. Twenty-one patients with stable angina pectoris were randomized, after a 2-week run-in period, to receive treatment for 4 weeks with either 1 capsule twice daily (A), 2 capsules in the morning and 1 in the evening (B), or 2 capsules twice daily (C). A treadmill exercise tolerance test was performed together with a clinical evaluation after the run-in and each of the three treatment periods. Analysis of the results from the 19 patients who completed the study revealed there were no significant differences between the three treatment periods with respect to the general exercise test parameters, number of angina attacks per week or nitrate consumption. Few side-effects were reported and were only mild in nature. On these findings, therefore, there would appear to be little justification for increasing the dose of the combination above the equivalent of treatment A.
Keywords: Atenolol, nifedipine, drugs combinations, angina pectoris
Both beta-blockers and dihydropyridine calcium antagonists are effective anti-anginal agents, either alone or in combination [1,2,4,9]. Whilst monotherapy is frequently effective in ameliorating symptoms, it is sometimes necessary to resort to combination therapy, for example, using atenolol and nifedipine. Such a combination may have particular advantages for certain patients [1,2,4,9]. Additionally, it may also have the advantage of improving the side-effect profile of the individual drugs, thereby improving patient acceptability and compliance [2,9]. Although concomitant administration of atenolol and nifedipine is one of the commonest regimens used, the optimum dosage of the combination has yet to be established. Obviously, there has to be a balance between patient tolerance and clinical efficacy.
In order to investigate this matter further, we studied varying dose levels of a fixed combination of these agents with respect to their side-effect profile, amelioration of symptoms and treadmill exercise capacity.
For inclusion into the study, patients had to be between 18 to 69 years of age, to have stable angina pectoris for at least 3 months with at least 2 attacks per week, to have a positive Bruce protocol exercise test on either monotherapy with nifedipine or atenolol and to have a normal haematological and biochemical profile. Patients were excluded if they had a history of prior myocardial infarction within the preceding 3 months, a history suggestive of unstable angina, an erect systolic blood pressure of less than 100 mgHg at the time of randomization or any prior history of other significant cardiovascular or respiratory disease.
The study was designed as a randomized, double-blind, three period cross-over investigation of the effects of different daily doses of a fixed combination of 50 mg atenolol and 20 mg sustained-release nifedipine per capsule (Tenif). Once patients satisfied the entry criteria they started on a 2-week run-in period during which they were given 1 capsule twice daily before randomization. Each randomized study period was 4 weeks in duration and patients received treatment for the period with one or other of three dose levels: (A) 1 capsule twice daily (100 mg atenolol plus 40 mg nifedipine per day), (B) 2 capsules in the morning and 1 at night (150 mg atenolol plus 60 mg nifedipine per day) and (C) 2 capsules twice daily (200 mg atenolol plus 80 mg nifedipine per day). No other anti-anginal drugs were allowed during the study except free use of sublingual nitrates. Compliance was checked by a blinded residual capsule count after each study period.
At each visit, patients underwent a physical examination, a diary card was issued to record episodes of angina and sublingual nitrate consumption, an assessment made of tolerance of the medication, and an exercise test carried out. Symptom limited exercise testing was performed using the standard Bruce protocol and was scheduled to be within 5 to 10 hours of the last dose of treatment and at least 2 hours after any sublingual nitrate consumption. Two run-in exercise tests were performed within the run-in phase to allow the patients to become accustomed to the exercise protocol.
All patients who completed the study were included in the statistical analysis. Prior to statistical analysis the time to 1 millimetre of exercise-induced ST depression and the time to normalization of the ST segments underwent log transformation in order to normalize the data. Similarly, the weekly number of angina attacks and nitrate consumption underwent square root transformation. General statistical analysis was undertaken using a cross-over analysis of variance, which allowed for patient and period effects in addition to treatment effects.
+
Of the 2 withdrawals, 1 patient was given the chance of early elective bypass surgery and thus withdrew from the study, whilst the other patient developed unstable angina and was withdrawn at day 6 during the first treatment period. This patient subsequently underwent emergency bypass surgery.
Table I. Assessments of the main variables investigated on entry and at the end of each 4-week treatment period during the study: mean (+ S.D.) and range of values for the 19 patients completing the study
Table I shows the major results of this study. With few exceptions there were no statistically significant differences with respect to the major variables. There was, however, an indication that treatments B and C prolonged the duration of exercise, to 1 millimetre of ST segment depression, compared to treatment A, by approximately 17% (p<0.04). The difference between treatments A and B was 36 seconds (95% confidence intervals 7 to 0.1; p="0.6)," the difference between treatments A and C was 40 seconds (95% confidence intervals 8 to 0; p="0.04)" and between treatments B and C was 4 seconds (95% confidence intervals 4 to 3; p="0.82)." There was also a borderline statistically significant difference between treatments A and B (p<0.05) for maximal heart rate.
In addition, there were no significant changes in the patients' weight between the different treatment periods. The mean compliance was 98.3% (range 92.2% to 100%) for all treatment periods. The number of reported side-effects with respect to the different treatment periods were small and those reported were of a minor nature only. The expected complaints of tiredness and vasodilation were similar in all groups and no patients with withdrawn due to adverse reactions.
The use of beta-blockers and dihydropyridine calcium antagonists in the treatment of stable angina pectoris is firmly established, for good reason [1,2,4,8--10]. Beta-blockers are useful because they limit heart rate and blood pressure, particularly during exercise, thus reducing myocardial oxygen consumption. Calcium antagonists also improve myocardial oxygen utilization by causing peripheral vasodilation and possibly coronary vasodilation. Beta-blocking agents, however, tend to cause cold extremities and calcium antagonists adverse features such as ankle oedema, flushing and headaches due to vasodilation. Combined administration of these two types of drugs has been reported to be better tolerated than the use of either drug alone, possibly by balancing out the side-effect profile for each drug [2,9].
One advantage of the vasodilatory properties of calcium antagonists is to offset the beta-blocker-induced coldness of the extremities. Studies have also shown that this combination, unlike atenolol monotherapy, does not adversely affect resting heart rate, cardiac output, resting ejection fraction or ejection fraction at peak exercise [4]. This combination has also been shown to reduce both the number of symptomatic and `silent' anginal attacks [2,4]. The effects upon exercise capacity are more variable, however; some studies show a definite benefit from the combination [2,4] whilst others do not [9,10].
Dihydropyridines such as nifedipine, nicardipine or felodipine tend to trigger a reflex tachycardia in response to their vasodilatory properties [3,6] and this effect can be ameliorated by concomitant beta-blockade [9]. The use of dihydropyridines, without concomitant beta-blockade, especially in patients with prior myocardial infarction, may also be associated with an excess mortality [5,7,11]. The mechanism for this is not fully understood but may be due to a drop in coronary perfusion pressure, secondary to the peripheral vasodilating properties of the drug, together with a reflex increase in heart rate.
For patients with ischaemic heart disease, there was considered previously to be a linear relationship between heart rate and mortality but this observation was not demonstrated in the recent TIBET study [10]. Therefore, although the maximum dose combination used in out study had the greatest effects upon regulating the heart rate, this would no longer appear per se to be a major advantage.
With the exception of a small improvement in time to 1 mm of ST depression for the higher therapeutic doses, out data essentially demonstrate a flat dose response curve for the different combinations used in this study. This is an interesting finding, as previous studies with both nifedipine and atenolol have shown advantages with doses of nifedipine higher than 40 mg per day and atenolol 100 mg per day, as used in the lowest combination in our study [8,10]. This result, therefore, suggests that not only is there an additive effect from the combination of atenolol and nifedipine but that the effect may be synergistic. If this is so, then a ceiling effect might be expected at a relatively small combination dosage as noted in this study. This is obviously an advantage because, if maximum anti-anginal effects can be obtained with modest doses of atenolol and nifedipine, the propensity for adverse reactions will be reduced. The higher dose combinations, however, were remarkably well tolerated, substantiating the potential advantages of concomitant administration of atenolol with nifedipine.
The one patient who developed unstable angina was quite unfortunate as he had by far the longest history of stable angina of 240 months with near average number of anginal attacks per week (15 attacks). He was subsequently randomized and during the run-in phase improved with the number of anginal attacks decreasing to 2 per week. His subsequent deterioration was totally unexpected and unlikely to be related to the medication.
In summary, although all combinations of atenolol and slow-release nifedipine were well tolerated, there would appear to be few advantages in increasing the combined dose above 50 mg of atenolol and 20 mg of slow-release nifedipine twice daily.
We are grateful to Stuart Pharmaceuticals, especially to Mr Ian Oliver, and to the Department of Applied Statistics at Reading University for their kind assistance with this study.
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Variable At End
of Initial
TreatmentA B C No. angina attacks per week
Mean 12.2+ 10.4 7.3+ 8.9 8.9+ 9.9 9.5+ 12.8
Range 2 to 40 0 to 34 0 to 37 0 to 45
Nitrate consumption (units)
Mean 10.1+ 11.7 4.4+ 8.3 5.4+ 8.7 (n=18) 6.1+ 12.0
Range 0 to 40 0 to 34 0 to 34 0 to 39
Total exercise duration (sec)
Mean 387+ 95 466+ 107 465+ 103 460+ 89
Range 341 to 433 414 to 517 416 to 514 418 to 503
Exercise duration to 1 mm ST depression (sec)
Mean 192+ 72 264+ 108 288+ 114 (n=18) 294+ 120* (n=18)
Range 120 to 360 120 to 540 120 to 540 120 to 600
Maximum ST depression at peak exercise (mm)
Mean 2.46+ 1.00 2.15+ 0.99 1.96+ 0.91 1.93+ 1.09
Range 1.5 to 5.0 1.0 to 4.0 0.8 to 4.0 0 to 5.0
Peak heart rate (beats/min)
Mean 117+ 21 110+ 15 105+ 10* 105+ 13*
Range 84 to 156 87 to 141 84 to 120 82 to 130
Peak systolic blood pressure (mmHg)
Mean 149+ 22 142+ 23 139+ 24 138+ 16
Range 114 to 202 114 to 216 104 to 180 108 to 164
Double product (x1000)
Mean 17.4+ 4.4 15.5+ 3.3 14.6+ 3.1 14.5+ 2.8
Range 11.6 to 25.5 10.9 to 21.6 10.2 to 20.3 10.0 to 18.8
Discussion
Acknowledgements
References
