- Email: [email protected]
Antihypertensive therapy with calcium-channel blockers: Comparison with beta blockers
Antihypertensive Therapy with Calcium-Channel Comparison with Beta Blockers
Blockers:
BARRY M. MASSIE, MD
As a resuit of concern about the safety and long-term toxicity of diuretics, there is a growing trend toward the use of aitemative agents as initial therapy in essential hypertension. Worldwide, @ blockers and vasodliators, especially the caicium-channei blockers, are the meet commonly used aitemative agents. Several studies comparing these 2 classes of medications are reviewed. These studies indicate that verapamii, nifedipine and diitiazem are ail comparable in efficacy to @ blockers. When combined, calcium-channel blockers and /3 blockers produce additive responses.
These agents may differ in the relation between the magnitude of their antihypertensive effect and patients’ pretreatment plasma renin activity and age. Younger persons and those with high plasma renin activity tend to respond better to @ blockers; older subjects and those with iow plasma renin activity are more consistently responsive to calcium-channel blockers. The choice of agent should be individuaiLed, based upon accompanying illnesses, adverseeffect profile and demographic factors. (Am J Cardioi 1985;58:97H-1 OOH)
Although the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure continues to recommend diuretics as the initial therapy in essential hypertension,l there is a growing trend toward the use of alternative agents. The main impetus for this shift has been increasing concern about the safety and long-term toxicity of diuretics. The electrolyte and metabolic derangements induced by diuretics have been recognized for many years. The suggestion, albeit poorly substantiated, from the Multiple Risk Factor Intervention Trial that diuretic therapy may be associated with an excessive incidence of sudden death2 and the difficulty of demonstrating a decrease in coronary mortality despite successful antihypertensive therapy in several large trials using diuretics have accentuated these doubts. A second reason for modifying the stepped-care approach is that patients with mild or moderate hypertension who are not controlled by diuretics alone may be controlled by other agents and, therefore, alternative drugs should be evaluated before resorting to combination therapy.3 A third factor to consider is individualization of therapy in patients with multisystemic disease. Accordingly, a B blocker might be used
in patients with hypertension and angina and prazosin might be tried in competitive athletes, while diuretics would be avoided in patients with gout or diabetes. Finally, the reduction in mortality and, in some instances, reinfarction by /l blockers in secondary prevention trials4p5 has encouraged many physicians to use these agents in hypertension with the hope that they are similarly effective in primary prevention, although evidence for this is lacking. In the United States, /3 blockers are the most popular alternative to diuretics, and their use as initial therapy has been sanctioned by the Joint National Committee.l In Europe, the calcium-channel blockers are widely used as initial antihypertensive therapy. These agents have not yet been approved in the U.S. for this indication by the Food and Drug Administration, but marketing surveys suggest they are used widely in hypertension, nonetheless. This article will review studies in which these 2 classes of medications have been compared or used in combination therapy and it will attempt to place their use into a broader perspective. Verapamii Verapamil was the first calcium-channel blocker used in hypertension, and several trials comparing verapamil with ,13blockers have been published. Leonetti et al6 evaluated 31 patients with mild to moderate hypertension who were withdrawn from previous therapy, and randomized to either propranolol, 60 to 80
From the Cardiology Service, Veterans Administration Medical Center, and the Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, California. Address for reprints: Barry Massie, MD, Cardiology Division (11 lC), Veterans Administration Hospital, 4150 Clement Street, San Francisco, California 94121. 97H
99H
A SYMPOSIUM:
ROLE OF CALCIUM
ENTRY-BLOCKING
DRUGS
IN HYPERTENSION
mg, 3 times a day, or verapamil, 120 to 180 mg, 3 times a day, for 6 weeks. Then, after a 3-week washout period, patients were crossed over to the alternative drug. Verapamil produced a somewhat greater reduction in both systolic and diastolic pressures than propranblol (31/20 vs 17/17 mm Hg), but this difference was not statistically significant. Heart rate fell significantly (by 14 beats/min) on propranolol, but not on verapamil (insignificant decrease of 3 beats/min). Hornung et al7 evaluated the same 2 agents with interarterial pressure monitoring. Eighteen subjects completed an open-label, randomized crossover study in which pro-
* PCO.05 ** P
250
II II
Nifedipine
L
l-L
3 P
Rest (N=16)
Stage
1
(N=16)
Stage (N=ll)
:DP 2
* P
150
*‘* P
ri
NS
i
Rest (N= 16)
Stage 1 (N= 16)
Stage (N=ll)
pranolol and verapamil were titrated from 40 to 240 mg, 2 times a day, and 120 to 240 mg, 2 times a day, respectively, over 2 to 3 months. Both drugs produced similar antihypertensive responses, which were present at rest and during exercise. In addition, no differences in the 24-hour blood pressure profiles were noted. The frequency and severity of adverse effects were similar, with constipation predominating on verapamil and fatigue on propranolol. Doyle8 reported 2 studies-one comparing verapamil with pindolol in patients maintained on thiazide diuretics and the second comparing verapamil with labetalol in patients with coexisting chronic obstructive pulmonary disease. Both trials indicated that the 2 classes of drugs caused equivalent antihypertensive responses.
2
Max (N=16)
.*-s rII T-
Max (N=16) FIGURE 1. Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) during treatment with placebo (C), diltiazem (D) 60 mg, 3 times a day, and propranolol (P) 20 mg, 3 times a day. The findings at rest, during submaximal exercise at the same workload (stages 1 and 2) and during maximal exercise (Max) are shown. Both drugs produced comparable responses at rest and during exercise in DBP, but propranolol was more effective in blunting the exerciseinduced rise in SBP. NS = difference not significant. Reprinted with permission from Am J Cardiol.13
Ekelund et al9 performed an open-label trial in which 12 patients received placebo, nifedipine alone, nifedipine plus metoprolol and metoprolol alone for consecutive l-month periods. Blood pressure was measured at rest and during exercise. Nifedipine decreased supine systolic and diastolic pressures by 20 and 11 mm Hg, respectively, compared with 22 and 7 mm Hg with metopro101 (differences not significant). During exercise, however, systolic blood pressure fell further with metopro101 than with nifedipine (39 vs 14 mm Hg). Both at rest and during exercise, nifedipine produced a slight increase in heart rate, while metoprolol significantly lowered it. Combined therapy was significantly better than single therapy, both at rest and during exercise. Yagil et allo conducted a 2-phase study in which 26 severely hypertensive subjects (mean blood pressure 192/114 mm Hg on propranolol) were on a regimen consisting of nifedipine 10 to 30 mg, 3 times a day, added to propranolol. After a 14- to 30-week period of combined therapy (phase I), nifedipine and proprano101were alternatively withdrawn for 2- to 4-week periods, separated by a similar period in which the combination was reinstituted. The addition of nifedipine (mean dosage 60 mg/day) was highly efficacious, resulting in a sustained decrease in blood pressure from 189/112 to 136/84 mm Hg. During phase II, blood pressure was found to increase to pre-nifedipine levels when this drug was withdrawn. Propranolol withdrawal also resulted in a loss of control, but the blood pressure increase was significantly less than that during nifedipine withdrawal. It is noteworthy that adverse effects related to nifedipine occurred in 50% of the patients and necessitated discontinuation in 4 patients. Two additional studies11J2 evaluated acebutalol and nifedipine, alone and in combination, and pindolol and nifedipine, also in single and combined therapy. While both studies are limited by small numbers of patients, they each indicated equal antihypertensive efficacy for both classes of drugs, as well as added benefit from combination therapy. Ditiazem Diltiazem, because of its more recent development and availability, has been less widely studied in hyper-
December
tension. Nonetheless, there are 2 published trials, and preliminary findings from an ongoing multicenter study comparing this agent with /3 blockers are available. Yamakado et all3 treated 16 subjects with mild to moderate hypertension with placebo, propranolol 20 mg, 3 times a day, and diltiazem 60 mg, 3 times a day, for 4 weeks, using a Latin square design. Resting and treadmill exercise blood pressures were evaluated (Fig. 1). At rest, both agents lowered blood pressure comparably, from a mean of 171/106 to 148/95 mm Hg with diltiazem and to 150/98 mm Hg with propranolol. Heart rate fell from 76 to 70 beats/min with diltiazem and to 59 beats/min with propranolol. During exercise, both drugs lowered diastolic pressure to a similar degree, but propranolol decreased systolic pressure somewhat more than diltiazem and caused a greater reduction in maximal heart rate. No adverse effects were noted, but the dosages of both drugs were relatively low. Trimarco et all4 compared diltiazem 60 mg, 4 times a day, with metoprolol 100 mg, 2 times a day, in 20 patients using a randomized, double-blind crossover design with l-month treatment periods separated by a l-month placebo period. Both drugs produced comparable antihypertensive effects, although metoprolol was more effective in preventing an increase in exercise systolic pressure. Only metoprolol reduced heart rate. A multicenter trial comparing diltiazem with other agents is now in progress and will ultimately include 200 patients, thus permitting subgroup analysis based upon age and race. At present, only the findings from an interim analysis of the first 50 subjects who completed the study are available. The study design includes a 4-week, single-blind, placebo washout period, after which the patients are randomly assigned to double-blind treatment with diltiazem or propranolol. The first 3 months are a dose-titration phase in which the diltiazem dosage (in time-released form) is increased from 60 to 160 to 180 mg, 2 times a day, and propranolol is increased from 80 to 120 to 240 mg, 2 times a day, stepwise at monthly intervals. After 4 weeks at the titrated dosage, hydrochlorothiazide is added to the therapy of uncontrolled patients for an additional 8 weeks. Sixty percent of the diltiazem group and 44% of the propranolol group required the highest dose, and 32% and 40%, respectively, ultimately required the addition of diuretic. With this therapy, 59% of the diltiazem patients and 40% of the proprano101 patients achieved the predetermined treatment goal of a supine diastolic blood pressure <90 mm Hg, or, in those with initial diastolic pressure of 95 to 100 mm Hg, a minimum of a lo-mm Hg reduction. In the diltiazem group, the mean supine blood pressure fell from 148 f 17/101 f 5 pretreatment to 133 f 25/88 f 9 mm Hg (p
6, 1985
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
56
SSH
groups. Adverse effects and adverse reactions were generally mild and were slightly more common on propranolol(34%) than diltiazem (25%). Calcium-Channel Blockers and Beta Blockers in Patients with Angina and Hypertension In the U.S., calcium-channel blockers are currently used to treat hypertension primarily in patients with accompanying coronary artery disease. Frishman et all5 studied 12 such patients with stable angina pectoris, positive treadmill exercise test results and diastolic blood pressure >90 mm Hg. After a 2-week washout period, double-blind treatment was commenced with verapamil80 mg, 3 times a day, or propranolol20 mg, 3 times a day, with the dosage being increased at weekly intervals to 120 mg, 4 times a day, and 80 mg, 4 times a day, respectively. The two 3-week treatment periods were separated by a l-week placebo period. The 2 drugs produced comparable changes in blood pressure, but propranolol reduced heart rate significantly more. Both drugs reduced the frequency of anginal attacks, but exercise duration increased significantly on verapamil despite a lower rate-pressure product with propranolol. Factors Determining the Response to Calcium-Channel Blockers and Beta Blockers From these studies, it is apparent that both the calcium-channel blockers and /3 blockers are effective antihypertensive agents. Biihler et all6 have examined the response of a large number of patients in relation to the pretreatment plasma renin activity. Their findings confirm previous reports that /3 blockers are most effective in high renin hypertension. In contrast, they found that calcium-channel blockers are particularly potent in low renin hypertension. Clinically, these observations are most relevant in regard to age, because younger patients tend to have higher plasma renin activity; while older patients often have low plasma renin activity. Indeed, Biihler’s experience corroborates the greater efficacy of calcium-channel blockers in the elderly and p blockers in younger subjects (Fig. 2). Data are not yet available for the relative response rates of these 2 classes of agents in blacks, who usually have low plasma renin activity, and whites, who exhibit a wider spectrum of plasma renin activity. More Trials Needed Because of the small size of the reviewed trials, further information is needed on a number of important points. Definitive data concerning the relative efficacy of the 2 classes of agents in subgroups based on gender, race and age might help in the selection of therapy. Similar information concerning adverse effects may be equally valuable. Beta blockers have been associated with potentially adverse effects on serum lipids; calcium-channel blockers have not. Nonetheless, it would be informative to examine these measurements in a prospective comparative trial involving the same patient population and laboratory. The greatest differences between the responses to calcium-channel blockers and /3 blockers in the published trials were in exercise heart rate and systolic
A SYMPOSIUM:
IOOH
Age
ROLE
OF CALCIUM
<40
in years n=
ENTRY-BLOCKING
40-60
DRUGS
>60
82
118
43
25
69
47
0
20
% Responders to c 95 diastolic betablocker
mmHg on
40 60 r 80J n=
20
% Responders to < 95 diastolic calciumantagonist
mmHg on
40
60
80
FIGURE 2. Proportion (%) of patients responding with diastolic blood pressure reduction to 195 mm Hg during antihypertensive therapy with /3 blockers and calcium-channel blockers according to their age. Reprinted with permission from Am J Me&l6
blood pressure, which rose to a lesser extent on the latter agents. It would be interesting, then, to determine whether this is associated with actual differences in exercise performance. None of the published studies addressed this issue by measuring oxygen utilization, and several did not use the appropriate protocols to examine this question. Clinical Implications The studies reviewed herein indicate that the calcium-channel blockers are as effective in treating mild and moderate hypertension as /? blockers, and in the case of diltiazem, they are equally or better tolerated. Because of concerns about the safety of diuretics, both classes of agents are commonly used as initial therapy in Europe. The choice of which type of medication to use in individual patients should reflect demographic factors, the patient’s life-style and the nature of accompanying medical problems. Thus, in older patients calcium-channel blockers may be the most effective alternative to diuretics, whereas in young patients a fi blocker or converting enzyme inhibitor should be considered. Blacks may be more responsive to calciumchannel blockers than to P blockers, although this remains to be demonstrated. When mental activity or athletic performance is an issue, calcium-channel blockers may be preferable to /3 blockers, because they have few central nervous system effects and they are likely to have less of a depressant effect on maximal
IN
cardiac output, although the latter point has not been investigated at the high dosages used in antihypertensive therapy or in competitive athletes. Patients with bronchospastic conditions, peripheral vascular disease, insulin-dependent diabetes and left ventricular dysfunction may be appropriate candidates for calcium-channel blockers, while those predisposed to postural symptoms or edema are better candidates for ,6 blockers. Combination therapy with nifedipine and @ blockers is safe and effective, but more experience is needed with diltiazem. Beta blocker and verapamil combinations should not be used in this way for hypertension because of the potential for atrioventricular block, bradyarrhythmias or myocardial depression. Several additional factors will determine the future role of calcium-channel blockers in the treatment of hypertension, including their place relative to B blockers and diuretics. These include approval from the Food and Drug Administration for this indication, their relative cost, which is presently significantly higher than other antihypertensive agents, and the availability of twice-daily-or better still, once-daily -preparations. Finally, clarification of the safety of diuretics and determination of whether the calciumchannel blockers are cardioprotective will enormously influence their ultimate popularity.
References 1. The 1984 Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1984;144:1045-1057. 2. Multiple Risk Factor Intervention Trial Group. Multiple risk factor intet’vention trial: risk factor changes and mortality results. JAMA 1982; 248114851477. 3. inouye I, Massie EM, Benowftz N, Simpson P, Loge D, Topic N. Monotherapy in hypertension: comparison of hydrochlorothiazide, propranolol and prazosin. Am J Cardiol 1984;53:suppl:34A-38A. 4. The Norwegian Multicentar Study Grouo Timolol-Induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801-807. 5. The Beta Blocker Heari Attack Study Group. Beta blocker heart attack trial (BHAT). JAMA 1981;248:2073-2074. 6. Leonetti G, Pasotil C, Ferrarl 0, Zanchetti A. Verapamil and propranolol: ;g~4m8~;ra~3n_9’4~ anbhypertensive agents. Acta Med Stand [suppl] 7. Hornung R, Jones R, Gould B, Sonecha T, Raftery E. Propranolol versus verapamll for the treatment of essential hypertension. Am Heart J 1984;108:554-560. 6. Doyle A. Comparison of beta-adrenoceptor blockers and calcium antagonists in hypertension. Hvoertension 1983:5:suool ll:103-108. 9. Ekelund L, Ekeiund C,-Rossner S. Antihyper&nsive effects at rest and during exercise of a calcium blocker, nifediplne, alone and in combination with metoprolol. Acta Med Scand 1982;212:71-75. 10. Yagll Y, Kobrin I, Stessman J, Ghanem J, Lehbel B, Ben-lshay D. Effectiveness of combined nifedipine and propranolol treatment in hypertension. Hypertension 1983;5:suppl ll:ll-113-11-119. 11. deDlvitlls 0, Peiiito M, DlSomma S, Fazlo S, Gakierlsi M, Vlllarl B, Llguorl V, Santomauro M. Acebutolol and nifedlpine in the treatment of arterial hypertension: efficacy and acceptability. Arzneimittelforsch 1984;34:710-715. 12. Tsuklyama H, Dtsuka K. Effect of pindolol and nifedipine alone and in combination on haemodynamic parameters/variables in essential hypertension. J Int Med Res 1984;12:154-182. 13. Yamakado 1, Donishl N, Kondo S, Nozlrl A, Nakano 1, Takezawa H. Effects of diltiazem on cardiovascular responses during exercise in systemic hypertension and comparison with propranolol. Am J Cardiol 1983;52:1023-1027. 14. Trlmarco B, DeLuca N, Ricclardelll B, Voipe M, Venlero A, Cucocolo A, Clcala M. Diltiazem in the treatment of mild or moderate essential hypertension. Comparison with metoprolol in a crossover double-blind trial. J Clin Pharmacol 1984;24:218-227. 15. Frlshman W, Klein N, Klein P, Strom J, Tawii R, Slrair R, Wong B, Roth S, LeJemtel 1, Poiiack S, Sonnenbilck E. Comparison of oral propranolol and verapamil for combined systemic hypertension and angina pectoris. Am J Cardiol 1982;50:1164-1172. 16. Biihier F, Boiii P, Kiowskl W, Eme P, HuithanU, Block L. Renin profiling to select antihypartensive baseline drugs. Am J Mad 1984;77:suppl 2:36A-42A.
Blockers:
BARRY M. MASSIE, MD
As a resuit of concern about the safety and long-term toxicity of diuretics, there is a growing trend toward the use of aitemative agents as initial therapy in essential hypertension. Worldwide, @ blockers and vasodliators, especially the caicium-channei blockers, are the meet commonly used aitemative agents. Several studies comparing these 2 classes of medications are reviewed. These studies indicate that verapamii, nifedipine and diitiazem are ail comparable in efficacy to @ blockers. When combined, calcium-channel blockers and /3 blockers produce additive responses.
These agents may differ in the relation between the magnitude of their antihypertensive effect and patients’ pretreatment plasma renin activity and age. Younger persons and those with high plasma renin activity tend to respond better to @ blockers; older subjects and those with iow plasma renin activity are more consistently responsive to calcium-channel blockers. The choice of agent should be individuaiLed, based upon accompanying illnesses, adverseeffect profile and demographic factors. (Am J Cardioi 1985;58:97H-1 OOH)
Although the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure continues to recommend diuretics as the initial therapy in essential hypertension,l there is a growing trend toward the use of alternative agents. The main impetus for this shift has been increasing concern about the safety and long-term toxicity of diuretics. The electrolyte and metabolic derangements induced by diuretics have been recognized for many years. The suggestion, albeit poorly substantiated, from the Multiple Risk Factor Intervention Trial that diuretic therapy may be associated with an excessive incidence of sudden death2 and the difficulty of demonstrating a decrease in coronary mortality despite successful antihypertensive therapy in several large trials using diuretics have accentuated these doubts. A second reason for modifying the stepped-care approach is that patients with mild or moderate hypertension who are not controlled by diuretics alone may be controlled by other agents and, therefore, alternative drugs should be evaluated before resorting to combination therapy.3 A third factor to consider is individualization of therapy in patients with multisystemic disease. Accordingly, a B blocker might be used
in patients with hypertension and angina and prazosin might be tried in competitive athletes, while diuretics would be avoided in patients with gout or diabetes. Finally, the reduction in mortality and, in some instances, reinfarction by /l blockers in secondary prevention trials4p5 has encouraged many physicians to use these agents in hypertension with the hope that they are similarly effective in primary prevention, although evidence for this is lacking. In the United States, /3 blockers are the most popular alternative to diuretics, and their use as initial therapy has been sanctioned by the Joint National Committee.l In Europe, the calcium-channel blockers are widely used as initial antihypertensive therapy. These agents have not yet been approved in the U.S. for this indication by the Food and Drug Administration, but marketing surveys suggest they are used widely in hypertension, nonetheless. This article will review studies in which these 2 classes of medications have been compared or used in combination therapy and it will attempt to place their use into a broader perspective. Verapamii Verapamil was the first calcium-channel blocker used in hypertension, and several trials comparing verapamil with ,13blockers have been published. Leonetti et al6 evaluated 31 patients with mild to moderate hypertension who were withdrawn from previous therapy, and randomized to either propranolol, 60 to 80
From the Cardiology Service, Veterans Administration Medical Center, and the Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, California. Address for reprints: Barry Massie, MD, Cardiology Division (11 lC), Veterans Administration Hospital, 4150 Clement Street, San Francisco, California 94121. 97H
99H
A SYMPOSIUM:
ROLE OF CALCIUM
ENTRY-BLOCKING
DRUGS
IN HYPERTENSION
mg, 3 times a day, or verapamil, 120 to 180 mg, 3 times a day, for 6 weeks. Then, after a 3-week washout period, patients were crossed over to the alternative drug. Verapamil produced a somewhat greater reduction in both systolic and diastolic pressures than propranblol (31/20 vs 17/17 mm Hg), but this difference was not statistically significant. Heart rate fell significantly (by 14 beats/min) on propranolol, but not on verapamil (insignificant decrease of 3 beats/min). Hornung et al7 evaluated the same 2 agents with interarterial pressure monitoring. Eighteen subjects completed an open-label, randomized crossover study in which pro-
* PCO.05 ** P
250
II II
Nifedipine
L
l-L
3 P
Rest (N=16)
Stage
1
(N=16)
Stage (N=ll)
:DP 2
* P
150
*‘* P
ri
NS
i
Rest (N= 16)
Stage 1 (N= 16)
Stage (N=ll)
pranolol and verapamil were titrated from 40 to 240 mg, 2 times a day, and 120 to 240 mg, 2 times a day, respectively, over 2 to 3 months. Both drugs produced similar antihypertensive responses, which were present at rest and during exercise. In addition, no differences in the 24-hour blood pressure profiles were noted. The frequency and severity of adverse effects were similar, with constipation predominating on verapamil and fatigue on propranolol. Doyle8 reported 2 studies-one comparing verapamil with pindolol in patients maintained on thiazide diuretics and the second comparing verapamil with labetalol in patients with coexisting chronic obstructive pulmonary disease. Both trials indicated that the 2 classes of drugs caused equivalent antihypertensive responses.
2
Max (N=16)
.*-s rII T-
Max (N=16) FIGURE 1. Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) during treatment with placebo (C), diltiazem (D) 60 mg, 3 times a day, and propranolol (P) 20 mg, 3 times a day. The findings at rest, during submaximal exercise at the same workload (stages 1 and 2) and during maximal exercise (Max) are shown. Both drugs produced comparable responses at rest and during exercise in DBP, but propranolol was more effective in blunting the exerciseinduced rise in SBP. NS = difference not significant. Reprinted with permission from Am J Cardiol.13
Ekelund et al9 performed an open-label trial in which 12 patients received placebo, nifedipine alone, nifedipine plus metoprolol and metoprolol alone for consecutive l-month periods. Blood pressure was measured at rest and during exercise. Nifedipine decreased supine systolic and diastolic pressures by 20 and 11 mm Hg, respectively, compared with 22 and 7 mm Hg with metopro101 (differences not significant). During exercise, however, systolic blood pressure fell further with metopro101 than with nifedipine (39 vs 14 mm Hg). Both at rest and during exercise, nifedipine produced a slight increase in heart rate, while metoprolol significantly lowered it. Combined therapy was significantly better than single therapy, both at rest and during exercise. Yagil et allo conducted a 2-phase study in which 26 severely hypertensive subjects (mean blood pressure 192/114 mm Hg on propranolol) were on a regimen consisting of nifedipine 10 to 30 mg, 3 times a day, added to propranolol. After a 14- to 30-week period of combined therapy (phase I), nifedipine and proprano101were alternatively withdrawn for 2- to 4-week periods, separated by a similar period in which the combination was reinstituted. The addition of nifedipine (mean dosage 60 mg/day) was highly efficacious, resulting in a sustained decrease in blood pressure from 189/112 to 136/84 mm Hg. During phase II, blood pressure was found to increase to pre-nifedipine levels when this drug was withdrawn. Propranolol withdrawal also resulted in a loss of control, but the blood pressure increase was significantly less than that during nifedipine withdrawal. It is noteworthy that adverse effects related to nifedipine occurred in 50% of the patients and necessitated discontinuation in 4 patients. Two additional studies11J2 evaluated acebutalol and nifedipine, alone and in combination, and pindolol and nifedipine, also in single and combined therapy. While both studies are limited by small numbers of patients, they each indicated equal antihypertensive efficacy for both classes of drugs, as well as added benefit from combination therapy. Ditiazem Diltiazem, because of its more recent development and availability, has been less widely studied in hyper-
December
tension. Nonetheless, there are 2 published trials, and preliminary findings from an ongoing multicenter study comparing this agent with /3 blockers are available. Yamakado et all3 treated 16 subjects with mild to moderate hypertension with placebo, propranolol 20 mg, 3 times a day, and diltiazem 60 mg, 3 times a day, for 4 weeks, using a Latin square design. Resting and treadmill exercise blood pressures were evaluated (Fig. 1). At rest, both agents lowered blood pressure comparably, from a mean of 171/106 to 148/95 mm Hg with diltiazem and to 150/98 mm Hg with propranolol. Heart rate fell from 76 to 70 beats/min with diltiazem and to 59 beats/min with propranolol. During exercise, both drugs lowered diastolic pressure to a similar degree, but propranolol decreased systolic pressure somewhat more than diltiazem and caused a greater reduction in maximal heart rate. No adverse effects were noted, but the dosages of both drugs were relatively low. Trimarco et all4 compared diltiazem 60 mg, 4 times a day, with metoprolol 100 mg, 2 times a day, in 20 patients using a randomized, double-blind crossover design with l-month treatment periods separated by a l-month placebo period. Both drugs produced comparable antihypertensive effects, although metoprolol was more effective in preventing an increase in exercise systolic pressure. Only metoprolol reduced heart rate. A multicenter trial comparing diltiazem with other agents is now in progress and will ultimately include 200 patients, thus permitting subgroup analysis based upon age and race. At present, only the findings from an interim analysis of the first 50 subjects who completed the study are available. The study design includes a 4-week, single-blind, placebo washout period, after which the patients are randomly assigned to double-blind treatment with diltiazem or propranolol. The first 3 months are a dose-titration phase in which the diltiazem dosage (in time-released form) is increased from 60 to 160 to 180 mg, 2 times a day, and propranolol is increased from 80 to 120 to 240 mg, 2 times a day, stepwise at monthly intervals. After 4 weeks at the titrated dosage, hydrochlorothiazide is added to the therapy of uncontrolled patients for an additional 8 weeks. Sixty percent of the diltiazem group and 44% of the propranolol group required the highest dose, and 32% and 40%, respectively, ultimately required the addition of diuretic. With this therapy, 59% of the diltiazem patients and 40% of the proprano101 patients achieved the predetermined treatment goal of a supine diastolic blood pressure <90 mm Hg, or, in those with initial diastolic pressure of 95 to 100 mm Hg, a minimum of a lo-mm Hg reduction. In the diltiazem group, the mean supine blood pressure fell from 148 f 17/101 f 5 pretreatment to 133 f 25/88 f 9 mm Hg (p
6, 1985
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
56
SSH
groups. Adverse effects and adverse reactions were generally mild and were slightly more common on propranolol(34%) than diltiazem (25%). Calcium-Channel Blockers and Beta Blockers in Patients with Angina and Hypertension In the U.S., calcium-channel blockers are currently used to treat hypertension primarily in patients with accompanying coronary artery disease. Frishman et all5 studied 12 such patients with stable angina pectoris, positive treadmill exercise test results and diastolic blood pressure >90 mm Hg. After a 2-week washout period, double-blind treatment was commenced with verapamil80 mg, 3 times a day, or propranolol20 mg, 3 times a day, with the dosage being increased at weekly intervals to 120 mg, 4 times a day, and 80 mg, 4 times a day, respectively. The two 3-week treatment periods were separated by a l-week placebo period. The 2 drugs produced comparable changes in blood pressure, but propranolol reduced heart rate significantly more. Both drugs reduced the frequency of anginal attacks, but exercise duration increased significantly on verapamil despite a lower rate-pressure product with propranolol. Factors Determining the Response to Calcium-Channel Blockers and Beta Blockers From these studies, it is apparent that both the calcium-channel blockers and /3 blockers are effective antihypertensive agents. Biihler et all6 have examined the response of a large number of patients in relation to the pretreatment plasma renin activity. Their findings confirm previous reports that /3 blockers are most effective in high renin hypertension. In contrast, they found that calcium-channel blockers are particularly potent in low renin hypertension. Clinically, these observations are most relevant in regard to age, because younger patients tend to have higher plasma renin activity; while older patients often have low plasma renin activity. Indeed, Biihler’s experience corroborates the greater efficacy of calcium-channel blockers in the elderly and p blockers in younger subjects (Fig. 2). Data are not yet available for the relative response rates of these 2 classes of agents in blacks, who usually have low plasma renin activity, and whites, who exhibit a wider spectrum of plasma renin activity. More Trials Needed Because of the small size of the reviewed trials, further information is needed on a number of important points. Definitive data concerning the relative efficacy of the 2 classes of agents in subgroups based on gender, race and age might help in the selection of therapy. Similar information concerning adverse effects may be equally valuable. Beta blockers have been associated with potentially adverse effects on serum lipids; calcium-channel blockers have not. Nonetheless, it would be informative to examine these measurements in a prospective comparative trial involving the same patient population and laboratory. The greatest differences between the responses to calcium-channel blockers and /3 blockers in the published trials were in exercise heart rate and systolic
A SYMPOSIUM:
IOOH
Age
ROLE
OF CALCIUM
<40
in years n=
ENTRY-BLOCKING
40-60
DRUGS
>60
82
118
43
25
69
47
0
20
% Responders to c 95 diastolic betablocker
mmHg on
40 60 r 80J n=
20
% Responders to < 95 diastolic calciumantagonist
mmHg on
40
60
80
FIGURE 2. Proportion (%) of patients responding with diastolic blood pressure reduction to 195 mm Hg during antihypertensive therapy with /3 blockers and calcium-channel blockers according to their age. Reprinted with permission from Am J Me&l6
blood pressure, which rose to a lesser extent on the latter agents. It would be interesting, then, to determine whether this is associated with actual differences in exercise performance. None of the published studies addressed this issue by measuring oxygen utilization, and several did not use the appropriate protocols to examine this question. Clinical Implications The studies reviewed herein indicate that the calcium-channel blockers are as effective in treating mild and moderate hypertension as /? blockers, and in the case of diltiazem, they are equally or better tolerated. Because of concerns about the safety of diuretics, both classes of agents are commonly used as initial therapy in Europe. The choice of which type of medication to use in individual patients should reflect demographic factors, the patient’s life-style and the nature of accompanying medical problems. Thus, in older patients calcium-channel blockers may be the most effective alternative to diuretics, whereas in young patients a fi blocker or converting enzyme inhibitor should be considered. Blacks may be more responsive to calciumchannel blockers than to P blockers, although this remains to be demonstrated. When mental activity or athletic performance is an issue, calcium-channel blockers may be preferable to /3 blockers, because they have few central nervous system effects and they are likely to have less of a depressant effect on maximal
IN
cardiac output, although the latter point has not been investigated at the high dosages used in antihypertensive therapy or in competitive athletes. Patients with bronchospastic conditions, peripheral vascular disease, insulin-dependent diabetes and left ventricular dysfunction may be appropriate candidates for calcium-channel blockers, while those predisposed to postural symptoms or edema are better candidates for ,6 blockers. Combination therapy with nifedipine and @ blockers is safe and effective, but more experience is needed with diltiazem. Beta blocker and verapamil combinations should not be used in this way for hypertension because of the potential for atrioventricular block, bradyarrhythmias or myocardial depression. Several additional factors will determine the future role of calcium-channel blockers in the treatment of hypertension, including their place relative to B blockers and diuretics. These include approval from the Food and Drug Administration for this indication, their relative cost, which is presently significantly higher than other antihypertensive agents, and the availability of twice-daily-or better still, once-daily -preparations. Finally, clarification of the safety of diuretics and determination of whether the calciumchannel blockers are cardioprotective will enormously influence their ultimate popularity.
References 1. The 1984 Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1984;144:1045-1057. 2. Multiple Risk Factor Intervention Trial Group. Multiple risk factor intet’vention trial: risk factor changes and mortality results. JAMA 1982; 248114851477. 3. inouye I, Massie EM, Benowftz N, Simpson P, Loge D, Topic N. Monotherapy in hypertension: comparison of hydrochlorothiazide, propranolol and prazosin. Am J Cardiol 1984;53:suppl:34A-38A. 4. The Norwegian Multicentar Study Grouo Timolol-Induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801-807. 5. The Beta Blocker Heari Attack Study Group. Beta blocker heart attack trial (BHAT). JAMA 1981;248:2073-2074. 6. Leonetti G, Pasotil C, Ferrarl 0, Zanchetti A. Verapamil and propranolol: ;g~4m8~;ra~3n_9’4~ anbhypertensive agents. Acta Med Stand [suppl] 7. Hornung R, Jones R, Gould B, Sonecha T, Raftery E. Propranolol versus verapamll for the treatment of essential hypertension. Am Heart J 1984;108:554-560. 6. Doyle A. Comparison of beta-adrenoceptor blockers and calcium antagonists in hypertension. Hvoertension 1983:5:suool ll:103-108. 9. Ekelund L, Ekeiund C,-Rossner S. Antihyper&nsive effects at rest and during exercise of a calcium blocker, nifediplne, alone and in combination with metoprolol. Acta Med Scand 1982;212:71-75. 10. Yagll Y, Kobrin I, Stessman J, Ghanem J, Lehbel B, Ben-lshay D. Effectiveness of combined nifedipine and propranolol treatment in hypertension. Hypertension 1983;5:suppl ll:ll-113-11-119. 11. deDlvitlls 0, Peiiito M, DlSomma S, Fazlo S, Gakierlsi M, Vlllarl B, Llguorl V, Santomauro M. Acebutolol and nifedlpine in the treatment of arterial hypertension: efficacy and acceptability. Arzneimittelforsch 1984;34:710-715. 12. Tsuklyama H, Dtsuka K. Effect of pindolol and nifedipine alone and in combination on haemodynamic parameters/variables in essential hypertension. J Int Med Res 1984;12:154-182. 13. Yamakado 1, Donishl N, Kondo S, Nozlrl A, Nakano 1, Takezawa H. Effects of diltiazem on cardiovascular responses during exercise in systemic hypertension and comparison with propranolol. Am J Cardiol 1983;52:1023-1027. 14. Trlmarco B, DeLuca N, Ricclardelll B, Voipe M, Venlero A, Cucocolo A, Clcala M. Diltiazem in the treatment of mild or moderate essential hypertension. Comparison with metoprolol in a crossover double-blind trial. J Clin Pharmacol 1984;24:218-227. 15. Frlshman W, Klein N, Klein P, Strom J, Tawii R, Slrair R, Wong B, Roth S, LeJemtel 1, Poiiack S, Sonnenbilck E. Comparison of oral propranolol and verapamil for combined systemic hypertension and angina pectoris. Am J Cardiol 1982;50:1164-1172. 16. Biihier F, Boiii P, Kiowskl W, Eme P, HuithanU, Block L. Renin profiling to select antihypartensive baseline drugs. Am J Mad 1984;77:suppl 2:36A-42A.