Antihypertensive Therapy with Calcium-Channel Blockers: Comparison with Beta 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 es- sential hypertension. Worldwide, @ blockers and va- sodliators, especially the caicium-channei blockers, are the meet commonly used aitemative agents. Sev- eral 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 pa- tients’ 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 individuai- Led, based upon accompanying illnesses, adverse- effect profile and demographic factors.

(Am J Cardioi 1985;58:97H-1 OOH)

Although the Joint National Committee on the Detec- tion, Evaluation and Treatment of High Blood Pres- sure 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 Mul- tiple Risk Factor Intervention Trial that diuretic ther- apy may be associated with an excessive incidence of sudden death2 and the difficulty of demonstrating a decrease in coronary mortality despite successful anti- hypertensive therapy in several large trials using diur- etics have accentuated these doubts.

A second reason for modifying the stepped-care ap- proach is that patients with mild or moderate hyper- tension who are not controlled by diuretics alone may be controlled by other agents and, therefore, alterna- tive drugs should be evaluated before resorting to combination therapy.3 A third factor to consider is individualization of therapy in patients with multisys- temic disease. Accordingly, a B blocker might be used

From the Cardiology Service, Veterans Administration Medical Cen- ter, 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 Francis- co, California 94121.

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 in- stances, reinfarction by /l blockers in secondary pre- vention trials4p5 has encouraged many physicians to use these agents in hypertension with the hope that they are similarly effective in primary prevention, al- though evidence for this is lacking.

In the United States, /3 blockers are the most popu- lar 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 Administra- tion, 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 ,13 blockers have been published. Leon- etti et al6 evaluated 31 patients with mild to moderate hypertension who were withdrawn from previous ther- apy, and randomized to either propranolol, 60 to 80

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 peri- od, 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 verapa- mil (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-

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** P<O.Ol

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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 exercise- induced rise in SBP. NS = difference not significant. Reprinted with permission from Am J Cardiol.13

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 pre- sent at rest and during exercise. In addition, no differ- ences in the 24-hour blood pressure profiles were not- ed. The frequency and severity of adverse effects were similar, with constipation predominating on verapa- mil and fatigue on propranolol.

Doyle8 reported 2 studies-one comparing verapa- mil with pindolol in patients maintained on thiazide diuretics and the second comparing verapamil with labetalol in patients with coexisting chronic obstruc- tive pulmonary disease. Both trials indicated that the 2 classes of drugs caused equivalent antihypertensive responses.

Nifedipine

Ekelund et al9 performed an open-label trial in which 12 patients received placebo, nifedipine alone, nifedi- pine plus metoprolol and metoprolol alone for consecu- tive 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 meto- pro101 (differences not significant). During exercise, however, systolic blood pressure fell further with meto- pro101 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 low- ered 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 proprano- 101 were alternatively withdrawn for 2- to 4-week peri- ods, separated by a similar period in which the combi- nation was reinstituted. The addition of nifedipine (mean dosage 60 mg/day) was highly efficacious, re- sulting 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 nifedi- pine 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 6, 1985 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 56 SSH

tension. Nonetheless, there are 2 published trials, and preliminary findings from an ongoing multicenter study comparing this agent with /3 blockers are avail- able. 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 de- gree, but propranolol decreased systolic pressure some- what more than diltiazem and caused a greater reduc- tion 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 compa- rable antihypertensive effects, although metoprolol was more effective in preventing an increase in exer- cise 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 com- pleted the study are available. The study design in- cludes a 4-week, single-blind, placebo washout period, after which the patients are randomly assigned to dou- ble-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 in- creased 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, ultimate- ly required the addition of diuretic. With this therapy, 59% of the diltiazem patients and 40% of the proprano- 101 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 <O.OOOl); in the propranolol group, a com- parable reduction occurred from 154 f 221104 f 6 to 146 f 23/91 f 11 mm Hg. Heart rate fell from 81 f 24 to 74 f 11 beats/min (p <O.Ol) with diltiazem and from 77 f 8 to 64 f 11 beats/min (p <O.OOOl) with propranolol; this was the only significant difference between treatments. The addition of hydrochlorothia- zide produced a further decrease of 8 to 12 mm Hg in systolic and diastolic pressures in both treatment

groups. Adverse effects and adverse reactions were generally mild and were slightly more common on pro- pranolol(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 pecto- ris, positive treadmill exercise test results and diastol- ic 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 pres- sure, 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 find- ings 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 ob- servations 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 corrobo- rates 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, fur- ther 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; calci- um-channel blockers have not. Nonetheless, it would be informative to examine these measurements in a prospective comparative trial involving the same pa- tient population and laboratory.

The greatest differences between the responses to calcium-channel blockers and /3 blockers in the pub- lished trials were in exercise heart rate and systolic

IOOH A SYMPOSIUM: ROLE OF CALCIUM ENTRY-BLOCKING DRUGS IN

Age in years <40 40-60 >60

n= 82 118 43

% Responders to c 95 mmHg diastolic on betablocker

0

20

40

60

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Responders to < 95 mmHg 40 diastolic on calcium- antagonist 60

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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 deter- mine whether this is associated with actual differences in exercise performance. None of the published stud- ies addressed this issue by measuring oxygen utiliza- tion, and several did not use the appropriate protocols to examine this question.

Clinical Implications

The studies reviewed herein indicate that the calci- um-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 ac- companying 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 con- sidered. Blacks may be more responsive to calcium- channel blockers than to P blockers, although this re- mains 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

cardiac output, although the latter point has not been investigated at the high dosages used in antihyperten- sive therapy or in competitive athletes. Patients with bronchospastic conditions, peripheral vascular dis- ease, insulin-dependent diabetes and left ventricular dysfunction may be appropriate candidates for calci- um-channel blockers, while those predisposed to pos- tural 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 hyper- tension 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 calcium- channel blockers are cardioprotective will enormously influence their ultimate popularity.

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Tsuklyama H, Dtsuka K. Effect of pindolol and nifedipine alone and in combination on haemodynamic parameters/variables in essential hyper- tension. J Int Med Res 1984;12:154-182. Yamakado 1, Donishl N, Kondo S, Nozlrl A, Nakano 1, Takezawa H. Effects of diltiazem on cardiovascular responses during exercise in sys- temic hypertension and comparison with propranolol. Am J Cardiol 1983;52:1023-1027. Trlmarco B, DeLuca N, Ricclardelll B, Voipe M, Venlero A, Cucocolo A, Clcala M. Diltiazem in the treatment of mild or moderate essential hyper- tension. Comparison with metoprolol in a crossover double-blind trial. J Clin Pharmacol 1984;24:218-227. 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. 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.