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Calcium channel blocking drugs for chronic, stable angina Nifedipine
International Journal of Cardmlogv, Elsevier Biomedical Press
2 ( 1982) 13- 17
Editorial
13
Review
Calcium channel blocking drugs for chronic, stable angina Nifedipine Lars-Giiran Karolinska
Ekelund
Hospital, S-104 01 Stoc!;holm. Svvden
Nifedipine, one of the well-established blockers of slob calcium channels, belongs to a new class of substances, the dihydropyridines, and was first synthesized, described and investigated pharmacologically in 1971 by researchers at the Bayer AG laboratories in Germany. Mechanism of action The basic mechanism of action of nifedipine was elucidated by Fleckenstein and his group [l] to be due to a block of the influx of calcium through the slow channels in myocardial and smooth muscle cells. Nifedipine thus belongs to the group of calcium blockers or calcium antagonists [2.3] and will induce vasodilation in the peripheral vessels and, especially, in the coronary vessels. It also tends to diminish the contractility of the heart muscle and to decrease the consumption of ATP. Thus the action of nifedipine in angina pectoris is due to several mechanisms. One is the well-described and easily recorded reduction of afterload by decreasing systemic vascular resistance. Hemodynamic studies have also shown that nifedipine reduces left ventricular end-diastolic pressure and gives more pronounced diastolic relaxation. Nifeciipine also has a direct central action dilating the coronary vessels, especially if there is an increased tone, and the coronary collaterals. This increases flow through normally underperfused areas. Another central action is the direct effect on the working muscular cells with a decrease in the oxygen consumption [4]. Pharmacology and dosage Nifedipine is rapidly absorbed and effective plasma levels are seen within 2-3 min of sublingual administration. After oral administration the plasma peak is seen at 45-60 min. Its half-life is between 3-6 hours. 90% of nifedipine is absorbed in the
Reprint requests to: Lars-Giiran S-104 01 Stockholm. Sweden.
0167-5273/82/0000-0000/$02.75
Ekelund,
M.D., Department
0 1982 Elsevier Biomedical
of Clinical
Press
Physir,‘ogy.
Karolinska
Hospital.
14
intestine and its two main pharmacologically inactive metabolites are excreted in the urine [5]. The usual dose of nifedipine in treatment of fixed lesion angina is lo-20 mg 3-4 times daily. The S-hour dosing schedule is effective in most patients, but patients with pain at rest or during the night, which could be due to coronary artery spasm, often need a 6-hour dosing schedule or a further increase in dose. Since nifedipine in clinical doses does not influence atrio-ventricular condution, one can combine nifedipine with a beta-blocking agent [6]. The administration of a beta-blocker inhibits the sympathetic reflex increase in heart rate induced by a drop in blood pressure. Thus, the combination is much more effective in the treatment of angina than either drug alone. Side effects Practically all side effects of nifedipine are pharmacologically induced vasodilatation effects, the most frequent being headache, facial flush and feelings of warmth. However, the side effects diminish in most patients with time. An interesting observation is that there are fewer side effects reported when nifedipine is combined with a beta-blocker. Other rather infrequent side effects are slight gastrointestinal problems. Edema of the ankles and lower legs has been reported in from l-2% up to 5- 10% of the cases. The edema is not due to any cardiac insufficiency but is a result of the uneven dilatation of the pre- and postcapillary sphincters. The frequency of this side effect seems to increase if the dosage of nifedipine is 20 mg or more 3-4 times daily. Clinical studies in chronic stable angina Nifedipine has been extensively studied in the treatment of classical angina. Several randomized, double-blind studies using a single sublingual dose of 10 mg nifedipine have been performed [7-121. In one of the studies [7] 10 patients with stable angina pectoris performed two separate bicycle exercise tests, one with a stepwise increase in load and the other with a continuously increasing load. Nifedipine raised the heart rate at rest with a mean value of 8 beats/min both in supine and standing position compared to placebo. The systolic blood pressure decreased by 15 mmHg at rest and 1 1- 12 mmHg during exercise. Work time was prolonged, and higher work loads were achieved with a total work performance increase of 50% in one of the tests and 23% in the other. The rate pressure product achieved at the break point was the same with placebo and with nifedipine treatment. The same observation has been reported in several other studies using either bicycle tests or treadmill tests [S-12]. Repeated exercise tests in patients with angina pectoris showed an increase in exercise tolerance 6 hours after administration of 10 mg of nifedipine [lo]. Several double-blind subacute or chronic studies with nifedipine treatment have 3 times daily the been reported [ 13- 161. In one study [ 131 with 10 mg nifedipine exercise tolerance increased by a mean value of 20% expressed as total work
performed. In another study [14] with 20 mg 3 times daily the exercise time on a treadmill increased significantly. In that study there was a slightly higher increase in duration of exercise with 20 mg compared to 10 mg of nifedipine. In another double-blind study nifedipine was tested against placebo both at the dose level of 10 mg 3 times daily and 20 mg 3 times daily [15]. In this study the higher dose seemed to be more effective with a highly significant reduction in the number of angina1 attacks and consumption of nitrates. There was also a significant decrease in the amount of ST-depression registrated during exercise with a precordial mapping technique. Prolonged treatment of 4-6 months with nifedipine showed the same antianginal efficacy as 3-week treatment [6]. Since nifedipine induces an increase in sympathetic tone with a reflex increase in heart rate, it is logical to combine nifedipine treatment with beta-blockade. Such combinations are reported in several studies [6,7,13,15,18,19] using nifedipine doses of both 10 mg 3 times daily and 20 mg 3 times daily. The beta-blockers used were propranolol, metoprolol, alprenolol and acebutolol. In all these combination studies the addition of beta-blockers markedly increased the efficiency of nifedipine with a decrease in the number of angina1 attacks. decreased consumption of nitrates and a marked increase in exercise tolerance. In one study [ 131 the exercise tolerance increased by 41% with the combination and 20% with nifedipine alone, 10 mg 3 times daily. Also in the dose comparison study using nifedipine, 10 mg 3 times daily and 20 mg 3 times daily [ 151, the addition of a beta-blocker markedly increased the efficacy with a marked decrease in incidence of pain and consumption of nitrates. There was also a decrease in the amount of ST-depression during exercise compared to treatment with nifedipine alone. Comparison
with other calcium channel blockers
Verapamil, another established calcium blocker, has been shown in several double-blind controlled clinical trials [20,21] to be effective in stable angina in doses of 120- 160 mg 3 times daily. The effectiveness expressed as increase in exercise capacity and decrease in number of angina1 attacks seems to be the same as with nifedipine lo-20 mg 3 times daily. A few studies have directly compared nifedipine with verapamil and found them to be of about the same effectiveness [21]. A third calcium blocker, diltiazem, seems to be somewhat less effective in stable angina. Comparison
of calcium channel blockers with other anti-angina1 agents
The calcium blockers generally have been found to be as effective as long-acting nitrates and beta-blockers in the treatment of stable angina pectoris. There are several investigations comparing nifedipine with nitrates, and in most of them nifedipine was found to be of the same potency or to be more effective than nitrates. Also, comparison with beta-blockers showed that nifedipine in one study was as effective as a beta-blocker [13], but in another study the beta-blocker seemed to be
16
slightly more effective than nifedipine [ 151. However, the combination of nifedipine with a beta-blocker has always given the best results [6] with marked reduction in the number of angina1 attacks, decreased nitrate consumption and marked increase in exercise capacity. The combination treatment induced no further side effects; in fact there seemed to be less flush and headache. Calcium channel blockers versus beta-blockers The basic treatment of patients with fixed lesion angina should still be nitrates, both short- and long-acting. In the past, the next drug of choice was a beta-blocker which was used extensively with good climcal and experimental results. Now, however, we can, as the next step in therapy after nitrates, use calcium blockers such as nifedipine. As a single drug nifedipine has in some studies been as effective as beta-blockers though in other studies beta-blockers were slightly more effective than nifedipine. The choice between nifedipine and beta-blockers is open. but several groups of patients are more suitable for treatment with nifedipine. especially those with chronic bronchitis and a risk of bronchoconstriction. Other suitable groups are patients with peripheral vascular disease, patients who develop side effects with beta-blockade and those patients who do not respond to beta-blockade. A single, optimal dose of nifepidine in the treatment of stable angina pectoris has not yet been clearly established, nor may such a single dose exist. In several studies. however, the higher lose of nifedipine, 20 mg 3 times daily, seems to be more effective than 10 mg 3 times daily. In Sweden 10 mg 3 times daily is the most common dose, and an additional fourth dose is used if the patient has rest or nocturnal angina. As an increase in the dose of nifedipine will induce more side effects, it is advisable to use a combination of a low dose of nifedipine, 10 mg 3 times daily in combination with one of the ordinary beta-blockers. Such a combination gives a marked increase in exercise tolerance and a decrease in the number of Most of the combination studies angina1 attacks and nitroglycerine consumption. call for a rather low nifedipine dose, 10 mg 3 times daily, in combination with a low to moderate dose of beta-blocker. One should be aware of the possibility of inducing heart failure when combining high doses of nifedipine and beta-blockers. There are case reports of such reactions. Another possible negative effect of combined high doses could be marked lowering of the arterial pressure with an increase in angina. References 1 Fleckenstein A. Specific pharmacology of calcium in myocardium. cardiac pacemakers, and vascular smooth muscle. Ann Rev Pharmacol Toxicoi 1977: 17: 149-66. 2 Xndersson KE, Ekelund L-C, Johansson BW, Landmark K. Calciumantagonists (CA-blockers). Pharmacological. physiological and clinical aspects; Acta Pharmacol Toxic01 1978; 43: l-55. 3 Stone PH. Antman EM, Miller JE, Braunwald E. Calcium chazmel blocking agents in the treatment of cardiovascular disorder. Part II. Hemodynamic effects and clinical applications. Ann Intern Med 1980; 93: 886-904.
17
4 Schulz W, Kaltenbach M. Antianginal effect of nifedipine after intracoronary and intravenous administration judged by reduction of ischemic ST-segment depression in exercise tests. Cardiology 1981; 68: 200-8. 5 Kroneberg G. Krebs R. Pharmacology of nifedipine. In: Puech P. Krebs R, eds. Proceedings 4th International Adalat Symposium. New therapy of ischemic heart disease. Excerpta Medica, Amsterdam-Oxford-Princeton 1980; 14-24. 6 Ekelund L-G. Betablockers and calciumantagonists: synergistic effects. In: Delius W, Gerlach E, Grobecker H. Ktibler W, eds. Catecholamines and the heart. Berlin-Heidelberg-New York, Springer-Verlag. 1981; 363-70. 7 Atterhbg J-H. Ekelund L-G, Melin A-L. Effect of nifedipine on exercise tolerance in patients with angina pectoris. Eur J Clin Pharmacol 1975; 8: 125-30. 8 Stein G. Antianginal efficacy of different doses of Adalat in angina pectoris patients in a double-blind trial. Proceedings 3rd International Adalat Symposium. Rio de Janeiro: Excerpta Medica 1976; 233. 9 Prempree A, Tabatznik B. Influence of different doses of nifedipine on angina pectoris induced by exercise. In: Lochner W. Braasch W, Kroneberg G, eds. Proceedings. 2nd Adalat Symposium, Amsterdam. Berlin-Heidelberg-New York: Springer-Verlag 1974; 267-73. 10 McIlwraith GR, Kidner PH. Oram S. Effect of nifedipine on exercise tolerance in angina pectoris. Br Heart J 1980; 44: 335-41.
11 Vuori I, Kallio V, Hamllainen 12
13 14 15 16 17 18
19 20 21
H, Pietila J. Effects of nifedipine and glyceryltrinitrate on the ergometric performance of patients after myocardial infarction. Curr Ther Res 1977; 20: 435-48. Corbalan R, Gonzales R, Chamorro G, Munoz M, Rodriguez JA, Casanegra P. Effect of a calcium inhibitor, nifedipine, on exercise tolerance in patients with angina pectoris. A double-blind study. Chest 1981; 79: 302-5. Ekelund L-G, Ore L. Antianginal efficiency of nifedipine with and without a betablocker, studied with exercise test. A double-blind randomized subacute study. Clin Cardiol 1979; 2: 203-l 1. Mueller HS, Chahine RA. Interim report of multicenter double-blind, placebo-controlled studies of nifedipine in chronic stable angina. Am J Med 1981; 71: 645-57. Lynch P. Dargie H, Krikler S, Krikler D. Objective assessment of antianginal treatment; a double-blind comparison of propranolol, nifedipine, and their combination. Br Med J 1980; 1: 184-7. Jaiprakash SS, Sahay JN, Chatterjee SS, Macdonald G. Efficacy of nifedipine in the treatment of angina pectoris and chronic airways obstruction. Postgrad Med J 1980; 56: 624-8. Tweddel AC, Beattie JM, Murray RG. Hutton I. The combination of nifedipine and propranolol in the management of patients with angina pectoris. Br J Clin Pharmacol 1981; 12: 229-33. Schmutzler H, Dorow P. The combined use of acebutolol and nifedipine in patients with coronary heart disease. In: Roskamm H, Graefe K-H eds. Advances in /3-blocker therapy. Excerpta Medica, Amsterdam-Oxford-Princeton 1980; 120-7. Fox KM, Jonathan A, Selwyn AP. The use of propranol and nifedipine in the medical management of angina pectoris. Clin Cardiol 1981; 4: 125-9. Bala Subramanian V, Bowles M, Lahiri A, Davies AB, Raftery EB. Long-term antianginal action of verapamil assessed with quantitated serial treadmill stress testing. Am J Cardiol 1981; 48: 529-35. Dawson JR, Whitaker NHG, Sutton GC. Calcium antagonist drugs in chronic stable angina. Comparison of verapamil and nifedipine. Br Heart J 1981; 46: 508-12.
2 ( 1982) 13- 17
Editorial
13
Review
Calcium channel blocking drugs for chronic, stable angina Nifedipine Lars-Giiran Karolinska
Ekelund
Hospital, S-104 01 Stoc!;holm. Svvden
Nifedipine, one of the well-established blockers of slob calcium channels, belongs to a new class of substances, the dihydropyridines, and was first synthesized, described and investigated pharmacologically in 1971 by researchers at the Bayer AG laboratories in Germany. Mechanism of action The basic mechanism of action of nifedipine was elucidated by Fleckenstein and his group [l] to be due to a block of the influx of calcium through the slow channels in myocardial and smooth muscle cells. Nifedipine thus belongs to the group of calcium blockers or calcium antagonists [2.3] and will induce vasodilation in the peripheral vessels and, especially, in the coronary vessels. It also tends to diminish the contractility of the heart muscle and to decrease the consumption of ATP. Thus the action of nifedipine in angina pectoris is due to several mechanisms. One is the well-described and easily recorded reduction of afterload by decreasing systemic vascular resistance. Hemodynamic studies have also shown that nifedipine reduces left ventricular end-diastolic pressure and gives more pronounced diastolic relaxation. Nifeciipine also has a direct central action dilating the coronary vessels, especially if there is an increased tone, and the coronary collaterals. This increases flow through normally underperfused areas. Another central action is the direct effect on the working muscular cells with a decrease in the oxygen consumption [4]. Pharmacology and dosage Nifedipine is rapidly absorbed and effective plasma levels are seen within 2-3 min of sublingual administration. After oral administration the plasma peak is seen at 45-60 min. Its half-life is between 3-6 hours. 90% of nifedipine is absorbed in the
Reprint requests to: Lars-Giiran S-104 01 Stockholm. Sweden.
0167-5273/82/0000-0000/$02.75
Ekelund,
M.D., Department
0 1982 Elsevier Biomedical
of Clinical
Press
Physir,‘ogy.
Karolinska
Hospital.
14
intestine and its two main pharmacologically inactive metabolites are excreted in the urine [5]. The usual dose of nifedipine in treatment of fixed lesion angina is lo-20 mg 3-4 times daily. The S-hour dosing schedule is effective in most patients, but patients with pain at rest or during the night, which could be due to coronary artery spasm, often need a 6-hour dosing schedule or a further increase in dose. Since nifedipine in clinical doses does not influence atrio-ventricular condution, one can combine nifedipine with a beta-blocking agent [6]. The administration of a beta-blocker inhibits the sympathetic reflex increase in heart rate induced by a drop in blood pressure. Thus, the combination is much more effective in the treatment of angina than either drug alone. Side effects Practically all side effects of nifedipine are pharmacologically induced vasodilatation effects, the most frequent being headache, facial flush and feelings of warmth. However, the side effects diminish in most patients with time. An interesting observation is that there are fewer side effects reported when nifedipine is combined with a beta-blocker. Other rather infrequent side effects are slight gastrointestinal problems. Edema of the ankles and lower legs has been reported in from l-2% up to 5- 10% of the cases. The edema is not due to any cardiac insufficiency but is a result of the uneven dilatation of the pre- and postcapillary sphincters. The frequency of this side effect seems to increase if the dosage of nifedipine is 20 mg or more 3-4 times daily. Clinical studies in chronic stable angina Nifedipine has been extensively studied in the treatment of classical angina. Several randomized, double-blind studies using a single sublingual dose of 10 mg nifedipine have been performed [7-121. In one of the studies [7] 10 patients with stable angina pectoris performed two separate bicycle exercise tests, one with a stepwise increase in load and the other with a continuously increasing load. Nifedipine raised the heart rate at rest with a mean value of 8 beats/min both in supine and standing position compared to placebo. The systolic blood pressure decreased by 15 mmHg at rest and 1 1- 12 mmHg during exercise. Work time was prolonged, and higher work loads were achieved with a total work performance increase of 50% in one of the tests and 23% in the other. The rate pressure product achieved at the break point was the same with placebo and with nifedipine treatment. The same observation has been reported in several other studies using either bicycle tests or treadmill tests [S-12]. Repeated exercise tests in patients with angina pectoris showed an increase in exercise tolerance 6 hours after administration of 10 mg of nifedipine [lo]. Several double-blind subacute or chronic studies with nifedipine treatment have 3 times daily the been reported [ 13- 161. In one study [ 131 with 10 mg nifedipine exercise tolerance increased by a mean value of 20% expressed as total work
performed. In another study [14] with 20 mg 3 times daily the exercise time on a treadmill increased significantly. In that study there was a slightly higher increase in duration of exercise with 20 mg compared to 10 mg of nifedipine. In another double-blind study nifedipine was tested against placebo both at the dose level of 10 mg 3 times daily and 20 mg 3 times daily [15]. In this study the higher dose seemed to be more effective with a highly significant reduction in the number of angina1 attacks and consumption of nitrates. There was also a significant decrease in the amount of ST-depression registrated during exercise with a precordial mapping technique. Prolonged treatment of 4-6 months with nifedipine showed the same antianginal efficacy as 3-week treatment [6]. Since nifedipine induces an increase in sympathetic tone with a reflex increase in heart rate, it is logical to combine nifedipine treatment with beta-blockade. Such combinations are reported in several studies [6,7,13,15,18,19] using nifedipine doses of both 10 mg 3 times daily and 20 mg 3 times daily. The beta-blockers used were propranolol, metoprolol, alprenolol and acebutolol. In all these combination studies the addition of beta-blockers markedly increased the efficiency of nifedipine with a decrease in the number of angina1 attacks. decreased consumption of nitrates and a marked increase in exercise tolerance. In one study [ 131 the exercise tolerance increased by 41% with the combination and 20% with nifedipine alone, 10 mg 3 times daily. Also in the dose comparison study using nifedipine, 10 mg 3 times daily and 20 mg 3 times daily [ 151, the addition of a beta-blocker markedly increased the efficacy with a marked decrease in incidence of pain and consumption of nitrates. There was also a decrease in the amount of ST-depression during exercise compared to treatment with nifedipine alone. Comparison
with other calcium channel blockers
Verapamil, another established calcium blocker, has been shown in several double-blind controlled clinical trials [20,21] to be effective in stable angina in doses of 120- 160 mg 3 times daily. The effectiveness expressed as increase in exercise capacity and decrease in number of angina1 attacks seems to be the same as with nifedipine lo-20 mg 3 times daily. A few studies have directly compared nifedipine with verapamil and found them to be of about the same effectiveness [21]. A third calcium blocker, diltiazem, seems to be somewhat less effective in stable angina. Comparison
of calcium channel blockers with other anti-angina1 agents
The calcium blockers generally have been found to be as effective as long-acting nitrates and beta-blockers in the treatment of stable angina pectoris. There are several investigations comparing nifedipine with nitrates, and in most of them nifedipine was found to be of the same potency or to be more effective than nitrates. Also, comparison with beta-blockers showed that nifedipine in one study was as effective as a beta-blocker [13], but in another study the beta-blocker seemed to be
16
slightly more effective than nifedipine [ 151. However, the combination of nifedipine with a beta-blocker has always given the best results [6] with marked reduction in the number of angina1 attacks, decreased nitrate consumption and marked increase in exercise capacity. The combination treatment induced no further side effects; in fact there seemed to be less flush and headache. Calcium channel blockers versus beta-blockers The basic treatment of patients with fixed lesion angina should still be nitrates, both short- and long-acting. In the past, the next drug of choice was a beta-blocker which was used extensively with good climcal and experimental results. Now, however, we can, as the next step in therapy after nitrates, use calcium blockers such as nifedipine. As a single drug nifedipine has in some studies been as effective as beta-blockers though in other studies beta-blockers were slightly more effective than nifedipine. The choice between nifedipine and beta-blockers is open. but several groups of patients are more suitable for treatment with nifedipine. especially those with chronic bronchitis and a risk of bronchoconstriction. Other suitable groups are patients with peripheral vascular disease, patients who develop side effects with beta-blockade and those patients who do not respond to beta-blockade. A single, optimal dose of nifepidine in the treatment of stable angina pectoris has not yet been clearly established, nor may such a single dose exist. In several studies. however, the higher lose of nifedipine, 20 mg 3 times daily, seems to be more effective than 10 mg 3 times daily. In Sweden 10 mg 3 times daily is the most common dose, and an additional fourth dose is used if the patient has rest or nocturnal angina. As an increase in the dose of nifedipine will induce more side effects, it is advisable to use a combination of a low dose of nifedipine, 10 mg 3 times daily in combination with one of the ordinary beta-blockers. Such a combination gives a marked increase in exercise tolerance and a decrease in the number of Most of the combination studies angina1 attacks and nitroglycerine consumption. call for a rather low nifedipine dose, 10 mg 3 times daily, in combination with a low to moderate dose of beta-blocker. One should be aware of the possibility of inducing heart failure when combining high doses of nifedipine and beta-blockers. There are case reports of such reactions. Another possible negative effect of combined high doses could be marked lowering of the arterial pressure with an increase in angina. References 1 Fleckenstein A. Specific pharmacology of calcium in myocardium. cardiac pacemakers, and vascular smooth muscle. Ann Rev Pharmacol Toxicoi 1977: 17: 149-66. 2 Xndersson KE, Ekelund L-C, Johansson BW, Landmark K. Calciumantagonists (CA-blockers). Pharmacological. physiological and clinical aspects; Acta Pharmacol Toxic01 1978; 43: l-55. 3 Stone PH. Antman EM, Miller JE, Braunwald E. Calcium chazmel blocking agents in the treatment of cardiovascular disorder. Part II. Hemodynamic effects and clinical applications. Ann Intern Med 1980; 93: 886-904.
17
4 Schulz W, Kaltenbach M. Antianginal effect of nifedipine after intracoronary and intravenous administration judged by reduction of ischemic ST-segment depression in exercise tests. Cardiology 1981; 68: 200-8. 5 Kroneberg G. Krebs R. Pharmacology of nifedipine. In: Puech P. Krebs R, eds. Proceedings 4th International Adalat Symposium. New therapy of ischemic heart disease. Excerpta Medica, Amsterdam-Oxford-Princeton 1980; 14-24. 6 Ekelund L-G. Betablockers and calciumantagonists: synergistic effects. In: Delius W, Gerlach E, Grobecker H. Ktibler W, eds. Catecholamines and the heart. Berlin-Heidelberg-New York, Springer-Verlag. 1981; 363-70. 7 Atterhbg J-H. Ekelund L-G, Melin A-L. Effect of nifedipine on exercise tolerance in patients with angina pectoris. Eur J Clin Pharmacol 1975; 8: 125-30. 8 Stein G. Antianginal efficacy of different doses of Adalat in angina pectoris patients in a double-blind trial. Proceedings 3rd International Adalat Symposium. Rio de Janeiro: Excerpta Medica 1976; 233. 9 Prempree A, Tabatznik B. Influence of different doses of nifedipine on angina pectoris induced by exercise. In: Lochner W. Braasch W, Kroneberg G, eds. Proceedings. 2nd Adalat Symposium, Amsterdam. Berlin-Heidelberg-New York: Springer-Verlag 1974; 267-73. 10 McIlwraith GR, Kidner PH. Oram S. Effect of nifedipine on exercise tolerance in angina pectoris. Br Heart J 1980; 44: 335-41.
11 Vuori I, Kallio V, Hamllainen 12
13 14 15 16 17 18
19 20 21
H, Pietila J. Effects of nifedipine and glyceryltrinitrate on the ergometric performance of patients after myocardial infarction. Curr Ther Res 1977; 20: 435-48. Corbalan R, Gonzales R, Chamorro G, Munoz M, Rodriguez JA, Casanegra P. Effect of a calcium inhibitor, nifedipine, on exercise tolerance in patients with angina pectoris. A double-blind study. Chest 1981; 79: 302-5. Ekelund L-G, Ore L. Antianginal efficiency of nifedipine with and without a betablocker, studied with exercise test. A double-blind randomized subacute study. Clin Cardiol 1979; 2: 203-l 1. Mueller HS, Chahine RA. Interim report of multicenter double-blind, placebo-controlled studies of nifedipine in chronic stable angina. Am J Med 1981; 71: 645-57. Lynch P. Dargie H, Krikler S, Krikler D. Objective assessment of antianginal treatment; a double-blind comparison of propranolol, nifedipine, and their combination. Br Med J 1980; 1: 184-7. Jaiprakash SS, Sahay JN, Chatterjee SS, Macdonald G. Efficacy of nifedipine in the treatment of angina pectoris and chronic airways obstruction. Postgrad Med J 1980; 56: 624-8. Tweddel AC, Beattie JM, Murray RG. Hutton I. The combination of nifedipine and propranolol in the management of patients with angina pectoris. Br J Clin Pharmacol 1981; 12: 229-33. Schmutzler H, Dorow P. The combined use of acebutolol and nifedipine in patients with coronary heart disease. In: Roskamm H, Graefe K-H eds. Advances in /3-blocker therapy. Excerpta Medica, Amsterdam-Oxford-Princeton 1980; 120-7. Fox KM, Jonathan A, Selwyn AP. The use of propranol and nifedipine in the medical management of angina pectoris. Clin Cardiol 1981; 4: 125-9. Bala Subramanian V, Bowles M, Lahiri A, Davies AB, Raftery EB. Long-term antianginal action of verapamil assessed with quantitated serial treadmill stress testing. Am J Cardiol 1981; 48: 529-35. Dawson JR, Whitaker NHG, Sutton GC. Calcium antagonist drugs in chronic stable angina. Comparison of verapamil and nifedipine. Br Heart J 1981; 46: 508-12.