Antihypertensive Therapy with Diltiazem and Comparison with Hydrochlorothiazide

ISA0 K. INOUYE, MD, BARRY M. MASSIE, MD, NEAL BENOWITZ, MD,

PAUL SIMPSON, MD, and DEBRA LOGE, BS

Fourteen hypertensive patients with a mean sitting systolic and diastolic blood pressure (BP) of 153 f 16/100 f 4 mm Hg were treated successively with hydrochlorothiazide and diltiazem for 8 weeks each. The BP response and changes in heart rate, left ventricular size and function, and plasma cate- cholamine concentrations and renin activity were monitored. The 2 drugs had comparable antihy- pertensive effects, with mean decreases of 14,9 and 11 mm Hg for the sitting, standing and supine dia- stolic BP, respectively, during hydrochlorothiazide treatment and mean decreases of 16,18 and 12 mm

Hg during diltiazem treatment. Heart rate was un- changed, although plasma norepinephrine con- centrations increased significantly during diltiazem treatment. Plasma renin activity increased slightly, from 0.6 to 0.9 ng/ml/hour during diltiazem treat- ment, but the change was not significant (p <O.lO). Left ventricular ejection fraction and end-diastolic volume were not affected by either agent. In con- clusion, diltiazem is an effective antihypertensive agent, which because of its benign side effect pro- file, may be useful as a step 1 agent.

(Am J Cardiol 1984:53:X88-1592)

An increase in peripheral vascular resistance is the most common hemodynamic derangement in chronic es- sential hypertension’; therefore, vasodilator drugs are theoretically ideal antihypertensive agents. However, the use of vasodilators as initial therapy or even in conjunction with diuretics is frequently limited by side effects and the development of tolerance, often resulting from the reflex activation of the sympathetic nervous and renin-angiotensin systems.2 The development of the calcium channel blockers has provided a new pharmacologic avenue to produce vasodilation, and the use of 2 of these agents, verapamil and nifedipine, as antihypertensive agents was recently reviewed.3,4 The antihypertensive efficacy of diltiazem has been less well investigated, but its benign side effect profile and lack of associated reflex tachycardia suggest that it is a

From the Cardiology Section of the Veterans Administration Medical Center, the Clinical Pharmacology Section, and the Department of Medicine and Cardiovascular Research Institute of the University of California, San Francisco, California. This study was supported in part by the Veterans Administration Research Service and by Grants HL 28146 and HL 11046, National Heart, Lung, and Blood Institute, Be- thesda, Maryland. Manuscript received December 27, 1983; revised manuscript received February 21, 1984, accepted February 23, 1984.

Address for reprints: Barry M. Massie, MD, Veterans Administration Medical Center, Department of Cardiology (11 lC), 4150 Clement Street, San Francisco, California 94143.

promising agent. Therefore, we examined the blood pressure (BP) responses, effects on resting left ven- tricular (LV) function, and changes in plasma renin activity and plasma catecholamine concentrations during 2 months of antihypertensive therapy with dil- tiazem. To better characterize the potential therapeutic role of diltiazem, we compared these results with the findings during diuretic therapy in the same subjects.

Methods

Patients: Fourteen subjects (13 men and 1 woman) with mild to moderate essential hypertension, defined as a sitting diastolic BP of 95 to 115 mm Hg on 2 consecutive visits at least 4 weeks without drug therapy, were studied. Their mean age was 59 f 8 years (f standard deviation). Ten were white and 4 were black. All patients had previously taken antihyper- tensive drugs. Patients with any other clinically apparent cardiovascular disease or other significant medical illnesses were excluded.

Study protocol: All patients initially went through a 4- to 6-week withdrawal phase in which antihypertensive drug therapy was discontinued. After qualification, baseline blood pool scintigraphy was performed and plasma renin and cate- cholamine levels were measured. Hydrochlorothiazide, 50 mglday, was then initiated and the dosage was increased after 2 to 4 weeks to 100 mg/day if a target of both a sitting diastolic BP of 190 mm Hg and a 210 mm Hg reduction were not achieved. A rash developed in 1 patient and disappeared after

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June 1, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53 1589

TABLE I Antihypertensive Effects of Hydrochlorothiazide and Diltiazem

Baseline Hydrochloro- Baseline 1 thiazide 2 Diltiazem

Sitting* Systolic pressure 153 f 16 153 f 11 Diastolic pressure 100 f 4

1:: : $’ 102 f 6

1;: $1:$x

Heart rate 75-f 11 73f 11 75& 11 724 IO Standing*

Diastolic pressure 99 f 6 Heart rate 79f 12 78f 11 77 + 13 77 f 12

Supine” Systolic pressure 153 IL 14 Diastolic 95 f 7 1;; : $? 152 f 12 99 f 9 1;; z $r

pressure Heart rate 67f 11 66f 11 68f 11 64f 11

’ Pressures are in mm Hg; heart rate is in beats/min. f p < 0.02 vs preceding baseline: T p <.OOl or below vs preceding

baseline; 5 p <O.Ol diltiazem vs hydrochlorothiazide; other measure- ments not significantly different between drugs.

No significant differences were present between baseline 1 and baseline 2.

Values are mean rt standard deviation for 13 patients.

he switched to metolazone treatment. After 8 weeks of diuret- ic therapy, including at least 4 weeks with the maximal dos- age, the radionuclide and hormonal values were again measured.

Subsequently, a second ii-week washout period was begun, at the end of which patients were required to achieve the same entry BP criteria. One subject did not qualify and was there- fore eliminated from the study. His data are not included in the results. A second set of baseline measurements was ob- tained and diltiazem therapy was then initiated at a dosage of 60 mg 3 times daily. Subjects who did not attain the target BP criteria had their dosage increased to 120 mg 3 times daily after 2 to 4 weeks. A final set of measurements was then ob- tained after a total of 8 weeks of diltiazem therapy, including at least 4 weeks at the highest dosage. Patients were instructed to maintain a 2-g sodium diet throughout the study.

Measurements: BP was measured by sphygmomanometry in triplicate in the sitting, standing and supine positions. Repeat measurements were made at the same time of day and by a single observer. The baseline and treatment BP levels on 2 successive visits were averaged to minimize the effect of random conditions. Equilibrium blood pool scintigraphy was performed by our previously described techniques.j LV ejection fraction was determined from the time-activity curve and end-diastolic volume by a counts-based method.

At the end of each baseline and treatment period, blood samples were drawn to measure plasma norepinephrine and epinephrine levels after 60 minutes in the supine position and 10 minutes of standing erect. All measurements were made in the fasting state at the same time of day in each subject. Blood was collected in chilled tubes, and the plasma was separated in a refrigerated centrifuge and stored at -70°C until assayed. Norepinephrine and epinephrine concentra- tions were determined by radioenzymatic techniques.6 Plasma renin activity was measured at the same time as the cate- cholamines, after 1 hour in the supine position. Samples were collected into chilled tubes, and the plasma was separated using a refrigerated centrifuge and stored at - 20°C until the time of assay. Renin activity was estimated from the amount of angiotensin I generated, as measured by radioimmuno- assay.Y

Statistical analysis: Data were analyzed by repeated measures analyses of variance and Newman-Keuls multiple- range tests to examine the significance of changes over time

chaseline 1 vs baseline 2) of drug effects (treatment vs pre- ceding baseline) and between treatments (hydrochlorothiazide vs diltiazem). All data are expressed as means f standard deviations.

Results

Effect on blood pressure (Table I): Baseline 1 and baseline 2 values were not significantly different. Both drugs decreased systolic and diastolic BP significantly and comparably (p <O.OOl) in the sitting position. Values for the individual patients are shown in Figure 1. During diltiazem treatment, 12 of 13 patients achieved the goal BP. One patient had a paradoxical increase in BP. In contrast, the diastolic BP was not reduced below 90 mm Hg in 4 of 13 patients receiving hydrochlorothiazide. The mean decrease in standing systolic BP was also significant and similar to that during diuretic therapy. The decrease in standing dia- stolic BP during diltiazem therapy (mean 18 mm Hg) was significantly greater (p <O.Ol) than that during hydrochlorothiazide therapy (mean 9 mm Hg). In the supine position, BP decreased significantly with both drugs, but the decrease in systolic BP was somewhat more impressive with diuretic treatment. Neither drug affected the heart rate in any position.

Figure 2 illustrates the effect of diltiazem dosage on BP response. The dosage of 60 mg 3 times daily de- creased both sitting systolic and diastolic BP, from 153 f 11/102 f 5 to 143 f 18/91 f 6 mm Hg (p (0.05 and p <O.OOl for systolic and diastolic BP, respectively). However, only 1 patient achieved the predetermined BP goal with the 60-mg dosage, and the further decrease to 135 f 15/86 f 8 mm Hg with 120 mg was significant compared with both baseline and the lower dosage.

Effects of therapy on left ventricular function: The radionuclide findings are shown in Table II. Nei- ther drug altered the mean ejection fraction for the

Systolic

BP

I Diastolic

BP

70 ’ ---pc OOI---v L-p< no,-- , 1 I 1 Base 1 HCTZ Base 2 tliltiazem

FIGURE 1. The effects of hydrochlorothiazide (HCTZ) and diltiazem on sitting systolic and diastolic blood pressure (BP) in individual subjects. The means for the 2 baselines are almost identical and both drugs significantly lowered systolic and diastolic BP by similar amounts. Four patients receiving HCTZ did not achieve the therapeutic goal of a diastolic pressure below 90 mm Hg (indicated by interrupted line), compared with 1 treatment failure with diltiazem therapy. The pa- tient in whom diltiazem therapy failed had a paradoxical increase in pressure.

1590 DILTIAZEM IN HYPERTENSION

TABLE II Scintigraphic and Hormonal Data

Ejection fraction (n = 12)

End-diastolic volume (ml)(n = 9)

Norepinephrine

Baseline 1

0.71 f .I3

120 f 31

Hydrochloro- thiazide

0.71 f .11

120 f 28

Baseline 2 Diltiazem

0.71 f .09 0.70 f .09

131 f 37 124 f 26

(pg/mlj(n = 13) Supine 383 f 216 % ; id:: 375 f 158 523 f 146*+ Standing 570 f 163 592 f 185 756 f 225’+

Epinephrine S(pp$l)(n = 13)

35f 15 Z : ::

24f 10 40f 19 Standing 42f 16 45 f 12 60 f 25

Plasma renin activity (ng/ml/hr)(n = 12) . 0.6 f 0.3 0.9 f 0.8

l p SO.05 or below vs preceding baseline; + p 10.05, hydrochlorothiazide vs diltiazem. No significant differences were present between baseline measurements. Values are mean f standard deviation.

group; in addition, there were no individual changes of greater than 0.05, the upper limit for interstudy vari- ability in our laboratory. Furthermore, there were no significant changes in LV end-diastolic volume.

Hormonal changes during therapy: Plasma cate- cholamine and plasma renin activity values are listed in Table II. Plasma norepinephrine concentration was not significantly altered either in the supine or standing position by hydrochlorothiazide. Norepinephrine con- centrations increased significantly with diltiazem treatment, from 375 f 158 to 523 f 146 pg/ml in the supine and 592 f 185 to 756 -f 225 pg/ml in the standing position, Plasma epinephrine levels did not change significantly.

P<.Oj

190

1

~p<.o5------- -NS-

170

150

130

Systolic

BP

Diastolic

BP

Baseline 60mg tid 120mg tid

Diltiazem Dosage (mg)

FIGURE 2. The blood pressure (BP) changes during low-dose (60 mg 3 times daily) and highdose (120 mg 3 times daily) diltiazem. The lower dosage significantly decreased sitting BP, but not to the treatment goal in 12 of 13 subjects, The higher dosage produced a significant further decrease in diastolic BP.

Plasma renin activity tended to increase slightly with diltiazem, from 0.6 f 0.3 to 0.9 f 0.8 ng/ml hour; 9 of 13 subjects had a higher value during diltiazem ther- apy, but this change was not statistically significant (p <O.lO).

Side effects: Two patients had drug-related side effects with hydrochlorothiazide therapy. In 1 patient, a rash developed but cleared when the drug was with- drawn, and did not recur during metolazone treatment. The second patient complained of muscle cramps, which resolved with potassium supplements, although his serum potassium level was in the low normal range. The only untoward event with diltiazem therapy was transient soft stools in 1 patient; this condition resolved despite continued therapy at higher dosages. No symptomatic arrythmias and no evidence of fluid re- tention, as evidenced by edema or weight gain, were noted.

Discussion

Drugs such as hydralazine, minoxidil and diazoxide, which act directly on vascular smooth muscle to reduce arteriolar tone, specifically reverse the primary hemo- dynamic abnormality in essential hypertension.172 However, during chronic therapy they evoke reflex sympathetic hyperactivity and stimulate the renin- angiotensin-aldosterone system, so that their antihy- pertensive efficacy is limited and side effects such as tachycardia and fluid retention are common.2 As a re- sult, drugs that lower peripheral resistance indirectly or not at all, such as diuretics and sympatholytic agents, have become the initial antihypertensive drugs of choice. Vasodilators have largely been relegated to the role of adjunctive agents. Nonetheless, an effective and well tolerated vasodilator might be advantageous be- cause of its more specific action. The use of the calcium channel blockers as vasodilators is particularly attrac- tive because of the potential involvement of calcium in the genesis of the increased peripheral resistance in hypertension.3,4’

All available calcium channel blockers relax vascular smooth muscle, although magnitude of this action rel-

J”“!? 1, ‘gr?r YE AVEPICAN JOIJRNAL 0’ CAPD’OLOGV ‘Volume 53 1591

ative to other effects and the precise mechanism by which this occurs may vary among drugs.gmll There is a growing literature concerning the use of these agents in essential hypertension.3,4 Several studies have shown the acute and short-term antihypertensive efficacy of nifedipine and verapamil. 12m17 In general, these have reported mean reductions in supine diastolic BP of 10 to 20 mm Hg, with a somewhat greater reduction in the upright position. Nifedipine produces an increase in heart rate acutely, whereas verapamil has little effect on heart rate. Plasma norepinephrine concentrations increase during nifedipine therapy, but this change is not always significant during sustained therapy. Plasma renin activity tends to increase with both drugs, al- though there has been only limited evidence of conse- quent fluid retention or diminution of antihypertensive effect over time. Although the data base is limited, side effects appear to occur with similar frequency in pa- tients with hypertension as in those with angina and tend to be more common with nifedipine.18,1g

Diltiazem has not been extensively studied in hy- pertension, although a European study and preliminary reports from Japan suggest that it is effective in essen- tial hypertension.20-22 The low incidence of side effects and the lack of reflex tachycardia and fluid retention with diltiazem suggest that it may be the most useful of the available calcium channel blockers for long-term antihypertensive therapy.2”

Effect of diltiazem on blood pressure and cardiac function: After 2 months of continuous therapy, dilti- azem lowered diastolic BP significantly, by 16, 18 and 12 mm Hg in the sitting, standing and supine positions, respectively. Systolic BP decreased comparably, and, as has been the case during diltiazem therapy for angina pectoris, heart rate was unaffected. In 12 of 13 patients the BP was decreased to the predetermined goal of a diastolic BP I 90 mm Hg together with a reduction of 110 mm Hg. These changes were dose-related, with the dose of 60 mg 3 times daily causing smaller changes than the dose of 120 mg 3 times daily. The higher dosage was required to achieve control in 11 of 12 successfully treated subjects. One patient showed a paradoxical in- crease in BP on diltiazem.

The magnitude of changes in BP is comparable to those changes previously reported with other calcium channel blockers, and similar or greater than those produced by hydrochlorothiazide in this group. Neither drug produced measurable changes in LV function or size.

Hormonal changes during diltiazem therapy: Diltiazem produced significant increases in plasma norepinephrine levels, similar to those described with nifedipine. However, unlike many reports with nifedi- pine, heart rate was not affected. This may reflect the negative chronotropic effect of diltiazem.24 One po- tential mechanism for the increase in norepinephrine levels is the inhibitory effect, of diltiazem on the post- synaptic cu2-adrenergic receptor.25 The patient whose BP increased with diltiazem therapy had a substantial increase in plasma norepinephrine levels (from 248 to 491 pg/ml supine and from 473 to 732 pg/ml standing),

but these increases were ot’a magnit,ude similar to that seen in other subjects.

Plasma renin activity also (ended to increase with diltiazem therapy, although this change was not sta- tistically significant (p = 0.10) with the few patients studied. Similar findings have been reported with ni- fedipine and during a previous short-term study with diltiazem.:‘,1”-‘4.2G No evidence of tolerance to the an- tihypertensive effect or of fluid ret,ention were observed. The increase in plasma renin levels may well be me- diated by the increased level of sympathetic nervous system activity.“7.g8

Implications: These preliminary findings confirm that diltiazem is an effective agent in essential hyper- tension, with an antihypertensive potency similar to that of diuretic drugs and to the findings with other calcium channel blockers. However, these results re- quire confirmation by more rigorous and more long- term controlled studies. Because of the minimal side effects usually encountered with diltiazem and its in- trinsic negative chronotropic action, it is likely to be useful as a single drug treatment of hypertension. The necessity of using thrice-daily dosing is likely to be ob- viated by the availability of a sustained-release prepa- ration. The higher cost of diltiazem and other calcium channel blockers compared with diuretic drugs and other antihypertensive agents may limit their use to groups of patients in whom advantages in efficacy, side-effect profiles or compliance are shown.

Acknowledgment: We thank Morris Schambelin, MD, for performing the plasma renin activity measurements and his helpful review of the manuscript, Steve Walker and Marion Laboratories for providing the diltiazem, and Sheila Hol- derness for preparing the manuscript.

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