sustained-release diltiazem compared with atenolol monotherapy for mild to moderate systemic...

Sustained-Release Diltiazem Compared with Atenolol Monotherapy for Mild to Moderate

Systemic Hypertension

MAllHEW R. WEIR, MD, JOHN JOSSELSON, MD, MARK J. GIARD, PharmD, J. BRYAN WARREN, MD, JEFFREY N. POSNER, MD,

Y. W. FRANCIS LAM, PharmD, DARWIN E. ZASKE, PharmD, and ELIJAH SAUNDERS, MD

The daily administration of 240 to 360 mg of diltiazem lowered blood pressure in a dose-related pat- tern similar to that seen in patients taking a daily dosage of 50 to 100 mg of atenolol. Sustained-release diltiazem was administered twice daily and atenolol once. Coal blood pressure was defined as <90 mm Hg or a reduction of L 10 mm Hg for patients with baseline pressures of 95 to 99 mm Hg In the supine position and was achieved In 60% of diltiazem-treated and 63% of atenolol-treated patients. The mean diltiazem dosage at the end of the study was 329 mg daily; for atenolol tt was 80 mg

daily. Adverse reactions considered possibly or probably drug related were reported by 26% of diltiazem patients and 38% of atenolol patients. Al- though both drugs were associated with a slower heart rate, atenolol patients showed a signlflcantly greater negative chronottopic effect. Diltiazem, in a sustalned-release form taken twice daily, is as effective as atenolol as a sole antihypertenslve agent. It has a favorable side-effect profile and may be a useful alternative antihypertensive medication compared with existing &blod<er therapy with atenolol.

(Am J Cardiol 1987;60:36 l-41 I)

E arly experience with calcium antagonists for angina pectoris and various tachyarrhythmias suggested that this class of drug produced a hypotensive effect that could have clinical application. Several studies have subsequently shown the safety and efficacy of calcium antagonists in acutely reducing blood pressure in patients with essential hypertension.‘-6 Further studies have increasingly led European investigators to use calcium antagonists as monotheraphy for patients with both angina and hypertension.7-12 The implications are that this class of drugs may be useful as initial monotherapy in patients with mild to moderate hypertension. Currently, there is limited published experience with calcium antagonists in the treatment of patients with chronic stable hypertension. The need for well-controlled trials to compare this class of drugs with currently available antihypertensive therapy re- mains. We conducted a randomized, double-blind study to compare a sustained-release preparation of diltiazem hydrochloride with atenolol as monotherapy in patients with stable, sustained mild to moderate hypertension.

Materials and Methods Patients: Of 97 patients with mild to moderate hy-

pertension (supine diastolic blood pressure 95 to 114 mm Hg) originally enrolled in this study after provid- ing informed consent, 78 entered the active treatment phase of the study (19 did not meet entry requirements). Patients with any of the following conditions were excluded: significant cardiovascular disease other than essential hypertension, impaired renal function [serum creatinine >2 mg/dl), greater than first- degree heart block, sick sinus syndrome, known abuse of alcohol or other drugs, pregnancy, known hypersen- sitivity to diltiazem or atenolol or inability to discontin- ue use of any drug known to affect blood pressure. Any

From the Ilniversity of Maryland Hospital, Baltimore, Mary- land, and the St. Paul-Ramsey Medical Center, St. Paul, Minn- esota.

Address for reprints: Matthew R. Weir, MD, University of Maryland Hospital, 22 South Greene Street, Baltimore, Mary- land 21201.

361

December ‘4, 1987 T&E AMERICAN JOlJR1\‘AL OF CARDIOLOGY Volume 60

other medications required by patients were continued throughout the study.

Study design: Placebo run-in: A single-blind, placebo run-in screening of up to 4 weeks was used to establish baseline blood pressures. Stable resting supine diastolic pressures (each recorded pressure being the average of 3 readings) within the previously defined pressure range and varying by 5 7 mm Hg had to occur on 2 consecutive weekly visits starting with day 7 to 10 of the placebo run-in. Any patient who required longer than 4 weeks to stabilize was considered labile and was excluded from further study participation.

Titration period: After the run-in period, eligible patients were randomized fo treatment with diltiazem or atenolol in a double-blind, double-dummy, parallel fashion and entered into an &week titration period during which they were given increasing doses of study medications. In the first 4 weeks patients were given 2 capsules twice daily and 1 tablet once daily (240 mg diltiazem daily plus placebo or 50 mg atenolol daily plus placebo]. During the second 4 weeks they received up to 360 mg diltiazem or 100 mg atenolol daily. Titration continued through week 8 or until a stable decrease in supine diastolic pressure to <9O mm Hg or a reduction of at least 10 mm Hg for patients with baseline pressures of 95 to 99 mm Hg was achieved. Upon reaching this optimal response, patients entered an evaluation period for 8 weeks during which they continued to take their titrated dosage. Patients were observed for side effects. If clinically significant adverse effects occurred, the patient was withdrawn from the study or the dosage was reduced to the great- est tolerated dose. A final 2-week period allowed for a tapering off from study medications.

Methods of observation: Supine and upright blood pressures and heart rates were measured every 2 weeks. These observations were made 10 to 14 hours after the most recent administration of study medication

Statistical analysis: Analysis of variance, Fisher’s exact test and x2 tests were used to determine the pretreatment comparability of the treatment groups. A repeated measures analysis of variance was performed for each efficacy parameter to determine (11 whether the change from baseline to a given evaluation was statistically significant for either treatment group and (2) whether significant differences existed between the 2 treatment groups. Goal pressure response was compared between the groups at each evaluation using the Mantel-Haenszel procedure.

Screening tests: Blood counts and chemistries were analyzed at baseline (beginning of titration), week 8 and week 16. A chest x-ray was performed at the beginning of the study, unless one had been performed within 6 months of beginning the study. An electrocardiogram was performed before and after the study,

Results Study population and demographics: Of the 97 pa-

tients enrolled in the study, 71 were evaluated for both safety and efficacy. Thirty-nine patients were treated

with diltiazem and 39 with atenolol. Data from 7 patients were analyzed for safety only; 4 were in the diltiazem group and 3 in the atenolol group. Two patients withdrew from the study with clinically significant side effects, 4 were withdrawn for protocol viola- tions and 1 was withdrawn at the patient’s request. Nineteen patients did not meet entrance requirements during the initial placebo phase. An additional ateno- 101 patient was withdrawn after completing the titration period because treatment effect was not demonstrated. Table I shows the demographic profile of the 2 treatment groups. Smoking status and age were the

TABLE I Patient Demographics

Diltiazem (n = 35)

Atenolol (n = 36)

Sex M F

Race Black White

Smoker’ Yes No

Family history of hypertension Yes No Uriknown

Duration of hypertension

(years) Age (years)* Height (inches)

M F

Weight (Ibs.) M F

22 13

6 10 29 26

13 21

22 22 9 11 4 3

6.5 f 6.4 7.0 f 5.2

47f 11 52% 10

70 f 2 70 f 3 63 f 3 63 * 3

196 f 24 200 f 40 182 f 48 175 f 40

28 a

5 30

* Significant intergroup difference (comparing estimated means).

Supine Blood Pressure

0 i\

Mean Change From Baseline

I I I 1

BaselIne End TitvAon WK 12 WK 16

- mtiarem --- *tend0 *p = OODOl

FlbURE 1. Decreases in both diastolic and systolic supine blood pressure with diltiazem and atenolol therapy during the study. The differences from baseline for both treatment groups at end titration, week 12 and week 16 were statistically significant (p = 0.0001).

381 A SYMPOSIUM: HYPERTENSION-THE HEART AND KIDNEY

only criteria that showed significant differences between groups. No clinically significant alterations in electrocardiographic or laboratory parameters were noted.

Efficacy: Diltiazem and atenolol produced significant decreases in blood pressures (supine, diastolic and mean arterial] throughout the study when compared with baseline. The magnitude of decrease was similar for both drugs (Fig. I]. Diltiazem decreased supine diastolic blood pressure to goal levels of <90 mm Hg or a reduction of 110 mm Hg for patients with

TABLE II Summary of Goal Reduction in Supine Diastolic Blood Pressure

Diltiazem Atenolol

Week 8 (end titration)

Week 12 Week 16 Maintenancet

57 % (20735) 64% (23/36)

57% (20/35) 60% (21/35)* 60% (21/35) 63% (22/35) 80% (16/20) 78% (18/23)

* One patient was withdrawn after titration because treatment effect was not demonstrated.

+ Percentage of patients who had achieved goal pressure reduction at week 16 as a percentage of those who originally achieved goal at week 8.

Difference was not significant for any comparison of therapies.

TABLE Ill Mean Dosage and Patients/Dose at End Evaluation Phase (week 16)

Drug Dosage

(mg daily) Pts

(N

Diltiazem 120 0 240 9

Mean dose

Atenolol 50 14

Mean dose

baseline pressures of 95 to 99 mm Hg in 60% (21/35) of the patients versus 63% (22/35) of the patients treated with atenolol.

Achievement of goal response: The ability of diltiazem and atenolol to produce goal reductions in supine diastolic blood pressure was compared at week 8 (end titration), week 12 and week 16. Diltiazem produced goal in 5770, 57% and 60% of patients, while atenolol produced goal in 6470, 60% and 63% of patients, respectively [Table IT). Diltiazem and atenolol were able to’maintain goal at the end of active treatment (week 161 in 80% and 78% of patients who had initially achieved goal at end of titration (week 8).

The titration regimen of 240 and 360 mg daily of diltiazem and 50 and 100 mg daily of atenolol was designed to allow for individually optimized dosages. The mean diltiazem dosage at end of week 16 was 329 mg daily and the mean atenolol dosage was 80 mg daily. Table III lists the number of patients receiving each dosage after the completion of the evaluation phase (week 16).

Mean decremental changes in systolic, diastolic and mean arterial pressures were similar in both groups in both the supine (Table IV] and standing positions (Table V) over the entire period of the study. Control of blood pressure was achieved equally well with both drugs, yet there were significantly different chronotropic effects on the heart.

Although both drugs reduced heart rate in both the ‘supine [Table IV] and standing positions (Table V) compared with baseline, the atenolol-treated patients had a significantly greater decrease compared with the diltiazem patients. Although not statistically significant, diastolic blood pressures in both groups showed a general decrease as dosages were increased.

Examination of vital signs revealed that except for slight increases in week 12 mean arterial pressure immediately on standing and week 16 systolic and diastolic blood pressures immediately on standing for diltiazem patients, changes in blood pressure and heart rate that normally occur immediately on standing were not altered significantly with diltiazem or ateno- 101 therapy.

TABLE IV Mean Blood Pressure (BP) Changes from Baseline in the Supine Position

Baseline (actual) Baseline Week 8 Baseline Week 12 Baseline Week 16 Overall p Value

Diltiazem Atenolol Diltiazem Atenolol Diltiazem Atenolol Diltiazem Atenolol

(n = 35) (n = 36) (n = 35) (n = 36) (n = 35) (n = 35) Comparing

(n = 35) (n = 35) Therapies

Systolic BP 153 f 3 153f3 -10.7 f 2.3t -11.1 f 2.4t -12.6 f 2.4% -11.9 f 2.5$ -11.7 f 2.2% -13.8 f 2.3t NS

(mm Iis) Diastolic BP 100f 1 100f 1 -12.5 f 1.ot -11.1 f l.li -13.7 & 1.3% -12.0 f 1.4$ -11.8 f 1.2t -12.3 f 1.2t NS

(mm Hg) Mean arterial pressure 118 f 1 117f 1 -11.9 f 1.2$ -11.1 f 1.3t -13.3 f 1.5t -12.9 f 1.6t -11.8 f 1.3t -12.8 f I.31 NS

(mm Hsj Heart rate 78 f 2 74f 2 -8.9 f 1.5? -9.5 f 1.6f -4.2 f 1.7’ -11.5 f 1.8t -4.5 f 1.4+ -9.8 f 1.5’ 0.0077

(beats/min)

* p <0.05 versus baseline. 7 p <0.005 versus baseline. i p = 0.0001 versus baseline. Data are mean f standard error of the mean. NS = difference not significant.

December 24, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 60 391

TABLE V Mean Blood Pressure (BP) Changes from Baseline in the Mlinute Standing Position

Baseline (actual) Baseline VVeek 8 Baseline Week 12 Baseline Week 16 Overall -- - p Value

Diltiazem Atenolol Diltiazem Atenolol Diltiazem Atenolol Diltiazem Atenolol Comparing

(n = 35) (n = 36) (n = 35) (n = 36) (n = 35) (n = 35) (n = 35) (n = 35) Therapies

Systolic BP 151 f 3 151 f 3 -9.3 f 2.3+ -12.5 f 2.5t -9.3 rt 2.7’ -12.3 f 2.8$ -7.3 i 2.3’ -11.8 f 2.51: NS

(mm Hg) Diastolic BP 105f 1 103f 1 -8.9 f l.lt -10.5 f I.21 -9.8 f 1.7$ -10.3 f 1.7$ -9.1 f 1.3$ -9.6 f 1.3t NS

(mm Hg) Mean arterial pressure 120% 1 119f 1 -9.0 f 1.4$ -11.1 f 1.5’ -9.6 f 1.9t -11.0 f 2.0t -8.5 f 1.5t -10.3 f I.@ NS

(mm Hg) Heart rate 85 f 2 81 f 2 -3.1 f 1.7t -10.9 f 1.7’ -2.5 f 1.9 -12.5 f 1.9t -2.8 f 1.7t -10.7 f 1.8t 0.0001

(beatslmin)

* p <0.05 versus baseline. + p <0.005 versus baseline. t p = 0.0001 versus baseline. Data are mean f standard error of the mean. NS = difference not significant.

Diltiazem was more effective in reducing upright blood pressures as age increased, while both drugs were more effective in reducing upright blood pressures in women than in men. Historically, atenolol might be expected to be less effective in blacks than diltiazem. However, a difference in response due to race was not detected with either atenolol or diltiazem.

Compliance: Overall compliance during the active portion of the study for diltiazem and atenolol was 95% and 97%, respectively. Two atenolol patients were withdrawn for poor compliance.

Safety/adverse reactions: Ten of 39 (26%] diltiazem patients and 15 of 39 (38%) atenolol patients reported adverse events that were considered to be possibly or probably drug related (Table VI]. Significant side effects were minimal for both diltiazem and aten- 0101 patients. One patient given each drug discontin- ued participation in the study due to an adverse reaction. The patient taking diltiazem withdrew because of insomnia and anxiety; the atenolol patient withdrew because of recurrent anxiety attacks associated with dosing. Only 1 diltiazem patient had symptomatic side effects associated with postural changes. This patient experienced an episode of syncope with a duration of 15 minutes, but it was determined to be only remotely drug related. No adverse reactions related to postural change were associated with atenolol.

Electrocardiograms: Electrocardiograms were as- sessed pre- and poststudy. The average PR, QRS and QT intervals for all patients are listed in Table VII, Atenolol patients showed greater average changes in QRS and QT intervals. All changes observed between pre- and poststudy were less than 4% with the following exceptions: diltiazem was associated wtih an 8.4% mean increase in QRS (80 f 20 vs 84 f 19); atenolol was associated with an 8.5% mean increase in QT (378 f 36 vs 410 f 39).

Discussion The hypotensive action of calcium antagonists has

been widely recognized since this class of drugs was introduced for the treatment of angina pectoris and

TABLE VI Frequency of Adverse Reactions: Events by Patient Count

Diltiazem Atenolol (n = 39) (n = 39)

Headache 4 Somnolence 4 Somnolence 1 Urinary frequency 3 Nocturia 1 Asthenia 3 Impotence 1 Decreased libido 2 Edema, peripheral 1 Nocturia 1 Dizziness 1 Impotence 1 Insomnia 1 Edema, peripheral 1 Flatulence 1 Dizziness 1 Dream, abnormal 1 Urinary urgency 1 Anxiety 1 Sweating 1 Alopecia 1 Malaise 1

Hyperlipidemia 1 Glossitis 1 Dry mouth 1 Depression 1 Bradycardia 1

certain cardiac tachyarrythmias.1-6 Oral and sublin- gual calcium antagonists are now an accepted form of initial therapy in syndromes of accelerated hypertension where ease and rapidity of administration are important considerations.1-6J3-17

Theroux et alI8 reported that diltiazem reduced mean arterial pressure by 6% in patients with acute myocardial infarction. Subsequently, Klein et al9 reported in 1983 that diltiazem effectively reduced systemic blood pressure in patients with sustained mild to moderate hypertension. Other investigators have shown that calcium antagonists reduce arterial blood pressure as a result of producing systemic arterial va- sodilation.gJ7Jg-22 Thus, a number of studies suggest that this class of drugs may be effective when used as monotherapy in the treatment of patients with essential hypertension.

Atenolol has enjoyed widespread acceptance as monotherapy for mild to moderate stable primary hypertension.23-2g Atenolol is currently one of the most widely prescribed single-daily-dose drug for the treat-

401 A SYMPOSIUM: HYPERTENSION-THE HEART AND KIDNEY

TABLE VII Electrocardiographic Intervals (ms)

Prestudy Poststudy Average Change from Baseline*

Diltiazem (n = 34)

Atenolol (n = 34)

Diltiazem (n = 34)

Atenolol (n = 34)

Diltiazem vs Baseline (n = 34)

Atenolol vs Baseline (n = 34) Diltiazem vs Atenolol

PR

QRS

QT

157 f 15 157 f 25 162 f 17 159 f 24 4.59 f 11.58 1.88 f 15.62 NS (p <0.05) (W

80 f 20 84f 13 85f 19 84f 12 4.76 f 13.38 0.18 f 8.58 p <O.lO (p <0.05) (N-3

366 f 33 378 f 36 380 f 40 410 f 39 13.94 f 26.07 31.29 f 27.32 p <O.Ol (p <O.Oi) (p <O.OOi)

* Paired ttests used for comparison with baseline. Two-sample t tests used for comparison between treatments. Data are mean f standard deviation. NS = difference not significant.

ment of essential hypertension, excluding thiazide diuretics. It is for this reason that we chose to compare a sustained-release preparation of diltiazem in a controlled, randomized, blinded study.

Diltiazem and atenolol both produced goal reduc- s tions in supine diastolic blood pressure during the

course of the study in 60% and 63% of the patients, ‘respectively. Also, they both caused significant reductions in upright blood pressures compared with baseline. Thus, diltiazem was as effective as atenolol in reducing and sustaining blood pressure to target levels, and did so with fewer side effects. The mild, negative chronotropic effect of diltiazem compared with atenolol suggests that diltiazem may be advantageous in elderly patients and in those patients with fixed cardiac outputs, where B blockade might be otherwise contraindicated.30-35 In addition, the package insert for atenolol cautions against the use of the drug in patients with bronchospasm; this caution does not apply to the use of diltiazem. Neither drug caused clinically rele- vant changes on the electrocardiogram, and significant side effects were minimal with only 1 diltiazem and 1 atenolol patient withdrawn from the study because of an adverse reaction.

Recent work with diltiazem has demonstrated that it can cause a decrease in blood pressure yet maintain renal perfusion or even improve perfusion by reducing renal vascular resistances3” Diltiazem also decreases arterial pressure in a physiologic sense without expansion of intravascular volume, reduction of cardiac index or alterations in circulating levels of renin or angiotensin II.37 The same cannot be said of atenolol, which although it does not decrease glomerular filtra- tion rate to the same extent that propranolol does,38 has effects on cardiac hemodynamics by reducing cardiac index and increasing total peripheral vascular resis- tance.39 Thus, diltiazem does have some physiologic advantages over atenolol in the way it reduces blood pressure.

Among the most important characteristics of the “ideal” antihypertensive agent are (1) the ability to reproducibly and effectively reduce blood pressure to “normal” levels with easily achieved sustained control that minimizes wide fluctuations above or below the therapeutic range desired, (2) a wide therapeutic index

without adverse reactions and side effects and (3) long dosing intervals to maximize patient compliance.

Diltiazem satisfies these 3 criteria, as shown in this short-term trial. As monotherapy, diltiazem is safe and effective for the treatment of mild to moderate sustained primary hypertension and, because of its lower side-effect profile, compares favorably with the widely used antihypertensive agent atenolol. It may also have selective advantages in controlling blood pressure in a physiologic way, especially in the low renin, salt-sensitive subset of hypertensive patients.

Acknowledgment: We gratefully acknowledge the following: Aqunetta Lancaster, RN, Pamela Sue Hall, RN, Bayinnah Shabazz, MD, B. Wayne Kong, PhD, Diane Brundage, PharmD, Kevin Kious, M. Lorie Skalland, MS, M. Bruce Morrill, MS, and Kendle Re- search Associates.

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