Comparative hypotensive effects of acebutolol and hydrochlorothiazide in patients with mild to moderate essential hypertension: A double-blind multicenter evaluation

Comparative hypotensive effects of acebutolol and hydrochlorothiazide in patients with mild to moderate essential hypertension: A double-blind multicenter evaluation A double-blind multicenter study compared oral acebutolol (n = 182) with hydrochlorothiaride (n = 178) in the treatment of mild to moderate essential hypertension (diastolic blood pressure 95 to 114 mm Hg). Both agents produced significant and comparable reductions in systolic, diastolic, and mean arterial blood pressures of 15.9, 14.9, and 15.3 mm Hg on acebutolol, and 15.2, 13.3, and 11.8 mm Hg on hydrochlorothiazide (p = 0.001). Acebutolol induced a significant reduction in resting heart rate of 9.3 bpm (p = 0.001) from baseline. The mean effective doses of acebutolol and hydrochlorothiazide were 757 and 68 mg, respectively. Significantly fewer patients on acebutolol experienced arrhythmia, anorexia, and flatulence, although an equal number of patients (14) in each group discontinued therapy prematurely due to side effects. More hydrochlorothiazide-treated patients developed abnormalities in the levels of serum glucose, uric acid, blood urea nitrogen (BUN), serum potassium, and chloride. No clinically significant trends in laboratory parameters were seen on acebutolol, although a small number of patients (11 on acebutolol and 3 on hydrochlorothiazide) developed asymptomatic positive antinuclear antibody (ANA) tests of low titer. The data show that acebutolol is as effective as hydrochlorothiazide in the treatment of hypertension, is as well tolerated, and produces fewer biochemical abnormalities. (AM HEART J 111:353, 1986.)

Janice Wahl, M.D., Bramah

N. Singh, M.D., D. Phil.,

and William

R. Thoden,

M.A.

Los Angeles, Calif.

During the last decade, diuretics and beta-adrenergic blocking agents have assumed increasingly important roles in the treatment of mild and moderate essential hypertension. Efficacy of both classes of agents has been clearly demonstrated, although their mechanisms of action differ. Recently there has been a growing interest in patient tolerance of hypotensive regimens and in metabolic changes resulting from chronic antihypertensive therapy. In addition, the responses of patient subgroups (race and age) to particular treatments have been exam-

From the Department of Medical Department of Cardiology, Veterans Los Angeles; and the Department cine.

Research, Ives Laboratories Inc.; the Administration Medical Center West of Medicine, UCLA School of Medi-

Supported in part by grants from the Medical Research Service of the Veterans Administration, and the American Heart Association, Greater Los Angeles Affiliate. The multicenter studies were also supported by grants-in-aid from Ives Laboratories Inc. Received accepted Reprint 691/111E, Angeles,

for publication Aug. 2, 1985.

Jan.

23, 1985;

requests: Bramah N. Singh, Wadsworth VA Hospital, CA 90073.

revision

received

July

8, 1985;

M.D., Ph.D., Section of Cardiology, Wilshire and SawteIIe Blvds., Los

ined in order to permit the selection of the most appropriate “step-one” antihypertensive treatment. Acebutolol is a new cardioselective, hydrophilic beta-antagonist which has weak partial agonist (intrinsic sympathomimetic) and membrane depressant properties’; the latter property, however, may not be manifest at therapeutic blood levels. Several clinical studies2e4 have demonstrated the effectiveness of acebutolol in the management of hypertension. Since acebutolol differs somewhat from other beta blockers in terms of its pharmacologic profile, and as the beta blocker-diuretic comparison has generated much interest, a 19.center (see Appendix) multiclinic, double-blind, parallel study was performed to compare the safety and efficacy of acebuto101 and hydrochlorothiazide in patients with mild to moderate essential hypertension. METHODS

Patient population. Male and female patients between the agesof 21 and 75years with mild to moderate essential hypertension (sitting diastolic blood pressure [DBP], phaseV, of 95 to 114mm Hg) were entered into the study.

353

354

Wahl, Singh,

and Thoden

Table

1. Profile of efficacy-analyzable patients

American

Acebutolol No. of patients

Age

134 50.5

(yr)

(25-74) 16 118 176.6 (106-276)

65 and over Under 65 Weight (Ibs) Sex Male Female Race White Black Other Duration of hypertension (yr) Baseline severityof hypertension Mild (DBP 95-104 mm Hg) Moderate (DBP 105-114 mm Hg) Smokers Diabetes DBP

= diastolic

blood

73 61

Hydrachlorothiazide 139

51.4 (27-74) 17 12% 179.3 (99-275) 87 52

112 15 7 6.6 (O-38)

3 7.7 (O-47)

101 33 35 0

102 37 44 0

125 11

pressure.

Mean baseline blood pressure was computed from the average of two seated blood pressure measurements recorded at three separate times during the baseline period. Patients with atrioventricular (AV) block of more than first-degree, angina pectoris, congestiveheart failure, significant peripheral vascular disease,bronchopulmonary disease,diabetesmellitus requiring insulin, any gastrointestinal disorder which might impair drug absorption, chronic conjunctivitis, hepatic failure, or marked renal insufficiency were excluded. Patients requiring medication which might interfere with the evaluation of clinical effectivenessand/or safety were also excluded. The protocol wasreviewed and approved by the appropriate institutional review committees at each participating center and all patients provided written informed consent prior to entering the study. Study design. The trial was conducted as a doubleblind, parallel, randomized study comparing acebutolol and hydrochlorothiazide. It consistedof three phasesas follows: 1. An initial 3-week placebo washout phase during which all antihypertensive medications were withdrawn and patients wereinstructed to take a placebocapsuleand a placebotablet twice daily. Patients were seenon the first day and at the end of 2 and 3 weeks to establish the presence of stable essential hypertension. During this phase,usually after 2 weeksof placebo treatment, history was taken and a physical examination was performed. A chest x-ray film (if not taken in the previous 3 months), ECG (12-lead),routine hematologicand biochemicallaboratory parameters,in addition to urinalysis and antinuclear antibody (ANA) titer determination were obtained.

February, 1986 Heart Journal

2. A 15-week, dose-titration phase during which patients with a DBP between 95 and 114 mm Hg were randomized (investigators used individual computer-generated randomization schedules)in a double-blind fashion to either acebutolol capsules (400 to 1200 mg/day) or hydrochlorothiazide tablets (50to 100mg/day), starting at the lowest dose level and adjusting at 2-week intervals according to the blood pressure response.Patients randomized to acebutolol also received placebo tablets and patients randomized to hydrochlorothiazide alsoreceived placebo capsules.Medications were administered on a twice-a-day schedule.Patients were seenat 3-week intervals for monitoring of vital signs (blood pressure,heart rate, and body weight) and side effects. Recorded side effects were either spontaneously volunteered by the patient or were solicited by the investigator. Laboratory determinations were obtained during the middle and at the end of the dose-titration phase. 3. A 12-week maintenance phase for those patients completing the dose-titration phase who achieved the therapeutic (DBP 590 mm Hg) or acceptable goal (DBP >90 mm Hg but L 10% reduction from baseline).Patients continued on the optimal dosage regimen established during dose-titration, and were seen at 4-week intervals for monitoring of vital signsand side effects. At the end of the study, medical history, physical examination, ECG, chest x-ray film, and laboratory determinations were repeated. At each patient visit, blood pressure was taken twice using a standard mercury sphygmomanometerwith the patient in both the sitting and standing positions. The DBP reading wasobtained at the disappearanceof Korotkoff sounds (phase V). Pulse rate was also measuredon two occasions,after the patient had restedfor 3 minutes in the sitting position. All measurementswere taken just prior to the morning doseof medication. Patients wereprohibited from taking concomitant medication which might influence the assessmentof efficacy or safety of the trial drug. Supplemental potassiumwas added during the study depending on the individual investigator’s assessmentof results of routine serum potassiummeasurement. Patients were withdrawn from the study if one or more of the following supervened: (1) seriousside effects; (2) bradycardia of <48 bpm; (3) orthostatic hypotension (standing systolic blood pressure124 mm Hg at any doselevel; (5) DBP <70 mm Hg at dose level 1; or (6) poor drug compliance, defined as a patient taking lessthan 80% or more than 120% of the medication on two or more consecutivevisits. In addition, patients were withdrawn at the end of the dose-titration phaseif the DBP was not reduced by at least 10% from baseline(acceptablegoal). If the DBP increasedabove the acceptable goal on two consecutive visits during the maintenance phase, treatment was also discontinued. Statistical analysis. For continuous efficacy parameters, the two treatments were statistically compared by both nonparametric (basedon ranks amongpooled data) and parametric (basedon actual measurements)two-way analysesof variance with treatment-by-center interaction.

Volume

111

Number

2

The within-treatment changes between two study phases were analyzed using a weighted Wilcoxon signed rank test and the paired t test. For categorical parameters, side effect, and laboratory parameters, Fisher’s exact test, McNemar’s test, and/or t test were used. A finding was considered to be statistically significant when the corresponding nonparametric analysis yielded a two-tailed p value of 0.05 or less. RESULTS Patient population. Of the 521 patients entering the study, 161 (30.9%) were withdrawn during the placebo phase before randomization: 136 for not meeting entry criteria, 24 for administrative reasons, and one due to a fatal myocardial infarction. Of the remaining 360 patients randomized, 182 received acebutolol and 178 received hydrochlorothiazide. Among these, 10 in the acebutolol group and seven in the hydrochorothiazide group were withdrawn at or before the first dose-titration visit for administrative reasons. From the remaining 172 and 171 patients in the acebutolol- and hydrochlorothiazidetreated groups, data from 38 and 32 patients were excluded from analysis of efhcacy because of unacceptable concomitant medications or poor drug compliance. Thus, data for efficacy were analyzed in 134 acebutolol- and 139 hydrochlorothiazide-treated patients (“efficacy” patients). Safety was evaluated in all randomized patients who received study medication (acebutolol, n = 182; hydrochlorothiazide, n = 178). The patients in whom the efficacy profile of the two regimens were analyzed were comparable with respect to general characteristics (Table I), reasons for withdrawal from the study (Table II), and drug compliance (94 % for acebutolol and 93 % for hydrochlorothiazide). One acebutolol-treated and two hydrochlorothiazide-treated patients had a past history of myocardial infarction. One patient, a 54-year-old man, suffered a fatal myocardial infarction on placebo treatment 1 day after discontinuing propranolol (20 mg per day), hydralazine, and triamterene/hydrochlorothiazide. Four acebutolol- and five hydrochlorothiazidetreated patients were withdrawn because of development of an intercurrent illness which was unrelated to study medication. One acebutolol patient developed angina, and one complained of palpitations. Among hydrochlorothiazide patients, two developed angina and one had a nonfatal myocardial infarction. The remaining intercurrent illnesses were noncardiovascular. Hypotensive effects. The mean daily dose of patients completing the entire study was 757.3 f 38.2 mg for acebutolol and 66.7 + 2.8 mg for hydrochlorothiazide. Both acebutolol and hydrochlorothi-

Acebutolol and hydrochlorothiazide

in hypertension

355

Table II. Reasonsfor premature drop-outs from the study

amongall (efficacy) patients Reason

Side effects Intercurrent illnesses Abnormal laboratory parameters Therapeutic failure* Administrative* Total

Acebutolol [N = 182 (134)]

Hydrochlorothiazide

[N = 178 (139)]

14 (6) 4 (2) 9 (8)

14 (9) 5 (1) 3 (3)

17 (15) 21 (12) 65 (43)

26 (24) 19 (12) 67 (49)

*Mean sitting DBP Xl0 mm Hg and not attaining acceptable goal (~10% reduction from baseline) at last visit during dose-titration phase or on two consecutive visits during the maintenance phase. Patients who were withdrawn by investigators as “therapeutic failures” but did not meet the above protocol definition were tabulated as drop-outs for administrative reasons.

azide significantly (p < 0.001) reduced sitting and standing blood pressures (Table III). Reduction in blood pressure was noted after 3 weeks of treatment in both groups and was maintained throughout the study. The blood pressure reduction from baseline induced by either acebutolol or hydrochlorothiazide at the end of dose-titration and maintenance phases was similar (Fig. 1). At the end of dose-titration, 96 of 134 acebutolol-treated (72%) and 88 of 139 hydrochlorothiazide-treated patients (63 %) were responders. There was no additional decrement in blood pressure during the maintenance phase. A comparable percentage of “efficacy” patients on acebutolol (91 of 134, 67.9%) and on hydrochlorothiazide (90 of 139, 64.7%) completed the study. Due to interest in the comparative efficacy of beta-blocking drugs and diuretics among black and the elderly hypertensive populations, the response of these subgroups was evaluated. Conclusions are limited, however, due to the small numbers of such patients. Among “efficacy” patients who received an adequate exposure to drug during the dose-titration phase, therapeutic response to acebutolol and hydrochlorothiazide was achieved in 93% (13 of 14) and 86% (12 of 14) of patients ~65 years, and in 60% (6 of 10) and 70% (7 of 10) of black patients, respectively. Among all patients 265 years of age regardless of the duration of exposure to either drug, only 4 of 20 acebutolol-treated (20%) and 7 of 19 hydrochlorothiazide-treated patients (37 %) were considered to be therapeutic failures. In all black patients receiving either drug, 11 of 22 acebutololtreated (50%) and five of 14 hydrochlorothiazidetreated patients were considered therapeutic failures. Both mildly and moderately hypertensive patients who completed the study responded well to treatment. Among patients who did not complete

356

Wahl, Singh,

and Thoden

American

February, 1966 Heart Journal

130

130

110

90

Rzion 0

Acebutokl

Mebtenence Hydrochiwothklde

1. Sitting meanblood pressureof “efficacy” patients who completed the study. Systolic and diastolic blood pressures(both sitting and standing) were significantly (p < 0.001) reduced by both acebutolol and hydrochlorothiazide at the end of the dose-titration and maintenancephases.Blood pressurewasreduced at 3 weeks of therapy and maintained throughout the study. Therapeutic goal was 90 mm Hg. Fig.

the study, 15 of 43 on acebutolol and 24 of 49 on hydrochlorothiazide were therapeutic failures. Among completing patients, 12 and 19 acebutololand hydrochlorothiazide-treated patients, respectively, failed to respond. Thus, the total number of therapeutic failures on acebutolol was 27 and 43 on hydrochlorothiazide; this difference was not statistically significant. Patients with higher baseline DBPs required higher doses. The mean total daily dose for patients with baseline DBP 95 to 104 mm Hg was 695.5 f 42.3 mg of acebutolol and 63.5 -t 2.9 mg of hydrochlorothiazide. Patients with baseline DBP of 105 to 114 mm Hg required 1019.9 + 53.1 mg of acebutolol or 79.0 f 6.9 mg of hydrochlorothiazide. A higher percentage of moderately hypertensive than mildly hypertensive patients were therapeutic failures. In the acebutolol treatment group, 16.8% of mildly hypertensive and 30.3% of moderately hypertensive patients were therapeutic failures; the comparable figures for the hydrochlorothiazide treatment group were 26.5 % and 40.5 % , respectively. Among all patients who were withdrawn from therapy (acebutolol, n = 65; hydrochlorothiazide, n = 67), mean baseline diastolic blood pressure was 102.6 f 0.7 mm Hg in acebutolol- and 102.4 1 0.7 mm Hg in hydrochlorothiazide-treated patients. These baseline blood pressures were significantly

(p = 0.01) higher than baseline diastolic blood pressure in patients who completed the study (acebuto101, n = 91, 100.2 + 0.4 mm Hg; hydrochlorothiazide, n = 90, 100.3 f 0.5 mm Hg). Age and sex were not significantly different between these two groups. Among all therapeutic failures, mean baseline diastolic blood pressure was 102.6 _+ 0.9 mm Hg in acebutolol-treated patients (n = 27) and 102.7 +- 0.7 mm Hg in hydrochlorothiazide-treated patients (n = 41). These blood pressures were significantly higher (p = 0.01) than in completing patients. Of the efficacy patients completing the study (91 on acebutolol and 90 on hydrochlorothiazide), distribution by ultimate dose level for acebutolol was 40.0%, 22.2%, and 37.870, receiving 400, 800, and 1200 mg per day, respectively. Within the hydrochlorothiazide treatment group, 58.9% and 41.1% received 50 and 100 mg per day, respectively. Thus, most patients responded to the lower dose levels; only about 40% of patients in either group required their dose to be increased beyond 800 mg per day of acebutolol or 50 mg per day of hydrochlorothiazide. Heart rate. Within 3 weeks of treatment, heart rate was decreased from baseline by 11.5% (8.9 bpm) while on acebutolol and was increased by 2.8% (2.3 bpm) during hydrochlorothiazide treatment. After this initial decrease, no further significant decrease

Volume Number

Table

111 2

Acebutolol

and

hydrochlorothiazide

III. Blood pressure (mm Hg) during the various phases of the multicenter

Sitting Systolic Diastolic Mean Standing Systolic Diastolic Mean

Dose titration* (n = 134)

hypertension

study

Maintenance* (n = 98)

Baseline (fl = 139)

Dose titration* (n = 139)

Maintenance* (n = 96)

f 1.4 f 0.4 + 0.6

138.1 + 1.7 88.6 Lk 0.9 105.1 f 1.0

137.0 +- 1.8 85.9 f 0.1 102.9 + 0.9

152.8 t 1.3 101.1 AZ 0.4 118.4 t 0.6

137.7 f 1.4 89.6 f 0.8 105.7 k 0.9

135.0 f 1.4 86.6 * 0.7 102.7 t 0.8

150.4 f 1.4 100.8 f 0.5 117.3 k 0.7

136.2 2 1.7 90.1 * 0.9 105.5 + 1.1

135.2 f 2.0 81.5 + 0.8 103.4 + 1.1

150.0 f 1.4 100.6 -t 0.6 117.0 k 0.8

135.3 +- 1.4 91.3 +- 0.8 106.0 -L 0.9

133.4 * 1.3 88.8 + 0.9 103.7 + 0.9

152.9 100.8 118.2

*Data from each “efficacy” titration and maintenance significant (p > 0.10).

357

Hydrochlorothiazide

Acebutolol Baseline (n = 134)

in

patient’s last visit in the dose-titration and maintenance phases were used. Values represent mean 2 SEM. All values for dose represent significant (p = 0.001) changes from baseline; comparison between acebutolol and hydrochlorothiazide was not

was observed on acebutolol. The mean heart rate in the hydrochlorothiazide group returned close to baseline value after 5 weeks of treatment. Only acebutolol treatment resulted in a significant (p = 0.001) change in heart rate from baseline; the difference between acebutolol and hydrochlorothiazide treatments was significant (p = 0.001) during dose-titration as well as maintenance phases. The decrease in heart rate from baseline induced by acebutolol was significant at each dose level (p < 0.001) but did not appear to be dose-dependent. Although the hydrochlorothiazide treatment group as a whole did not demonstrate a significant change in heart rate, when these patients were separated according to total daily dose, a significant (p < 0.01) increase in heart rate was observed among those treated with 100 mg daily of hydrochlorothiazide. Four patients treated with acebutolol developed heart rates less than 48 bpm. Side effects and laboratory abnormalities. From a listing of individual symptoms, only the differences in the following treatment-related side effects achieved statistical significance: arrhythmia (none on acebutolol, 2.8 % on hydrochlorothiazide; p = 0.03); anorexia (none on acebutolol, 3.4% on hydrochlorothiazide; p = 0.01); and flatulence (1.1% on acebutolol, 6.7 % on hydrochlorothiazide; p = 0.01). A marginally significant difference was noted for nocturia (6.6% on acebutolol, 13.5% on hydrochlorothiazide; p = 0.05). For both treatment groups, there were no dose-related trends in the frequency of side effects. A small and comparable number of patients on acebutolol and hydrochlorothiazide experienced the following treatment-related side effects: fatigue, impotence, micturition frequency or urgency, dys-

pnea, wheezing, congestive heart failure, peripheral edema, peripheral ischemia, dry eyes, blurred or abnormal vision, or rash. Fourteen patients in each treatment group were withdrawn prematurely from the study due to side effects. The most frequent body system affected was neurologic for the hydrochlorothiazide-treated patients and cardiovascular (predominantly asymptomatic bradycardia with termination required by protocol) for the acebutolol-treated patients. Side effects necessitating withdrawal of patients from the study are listed in Table IV for both drug regimens. Significant (p < 0.05) changes from baseline observed in the various laboratory parameters at the middle and end of dose-titration and during maintenance therapy are listed in Table V. Significantly more patients treated with hydrochlorothiazide than acebutolol had out-of-range laboratory tests for serum uric acid, sodium, and potassium on all three occasions and for serum glucose and blood urea nitrogen (BUN) on two occasions (p < 0.05). Hypokalemia (K+ <3.5 mmol/L) was observed on the final visit in 34 patients treated with hydrochlorothiazide and in no patient receiving acebutolol. Among the 34 patients on hydrochlorothiazide, 11 reported symptoms of fatigue, weakness, muscle cramps, myalgias, or rhythm disturbance; one patient with hypokalemia (K+ = 2.9 mmol/L) had ventricular fibrillation complicating an acute myocardial infarction. During the study, 20 of 178 and 4 of 182 patients treated with hydrochlorothiazide and acebutolol, respectively, received a potassium supplement as concomitant medication. Among the patients who had ANA tests prior to and during treatment, new and persistent positive (~1: 40) titers developed in 11 of 144 acebutololand in 3 of 151 hydrochlorothiazide-treated

358

Wahl, Singh,

Table

IV. Premature

and Thoden

American

drop-outs due to side effects

V. Statistically

Table

significant laboratory changes

No. of patients Body

system

Acebutolol

Change from baseline (range at 3 visits)

H\ldrochlorothiazide Laboratory

Neurologic Cardiovascular Respiratory Gastrointestinal Dermatologic Ophthalmologic Multiple body Total

4 .i

systems

0

I 2

1 1

2 2

1

0

4 14

-L 14

DISCUSSION

The results demonstrate acebutolol to be as effective as hydrochlorothiazide in the treatment of mild to moderate essential hypertension, while it produced fewer laboratory abnormalities and compared favorably in terms of treatment-related side effects. Average reductions in sitting blood pressures of l&9/14.9 mm Hg for acebutolol and 17.8/14.5 mm Hg for hydrochlorothiazide confirm earlier reports of their comparable antihypertensive efficacy.5,6 There is evidence, however, that a beta blocker might afford additional protection to the hypertensive patient during exercise and stress when adrenergic tone increases.l A marked reduction in blood pressure was seen within 3 weeks of therapy with both agents, and control was maintained throughout the 24-week trial, demonstrating the sustained efficacy of both drugs. The trend for a positive correlation between baseline severity of blood pressure and total daily dose of on

blood

pressure

test

ACB

HCTZ

6

patients. Titers were generally low, with 6 of the 11 acebutolol patients developing titers rl : 160 (n = 4) or ~1:320 (n = 2). One of three hydrochlorothiazide-treated patients developed an ANA titer I 1: 320. Most ANA patterns were reported as diffuse or speckled. New symptoms of arthralgias and myalgias not attributed to another etiology were reported by 1 of the 11 acebutolol patients with a persistent, newly positive ANA; her symptoms resolved spontaneously while continuing acebutolol. In addition to these patients, four patients on acebutolol and two on hydrochlorothiazide developed transiently positive (21: 40) ANA titers which reverted to negative during continued treatment, Nine patients (4.9%) on acebutolol and three (1.7 % ) on hydrochlorothiazide were dropped from the study due to laboratory abnormalities.

Effects

February, 1966 Heart Journal

and

heart

rate.

Serum chemistry Potassium (mmol/L) Glucose (mg/dl) BUN (mg/dl) Uric acid (mg/dl) Sodium (mmol/L) Chloride (mmol/L) Calcium (mg/dl) Phosphorus (mg/dl) Total protein (gm/dl) Albumin (gm/dl) Cholesterol (mg/dl) Hematology Hematocrit (“(a ) RBC (x10”) ESR (mm/hr) Urinalysis

t 0.2. -

-

t 0.; 0.9 1 0.; t 0.3 i 0.2-

f 1.0-1.4 tO.6-0.8 43.1-3.8 -

0.3

J 0.5

0.9

1 2.6-

3.0

to.1

to.4-0.8

= acebutolol;

mentation

0.2

10.4-0.5 t4.3-7.5

i 0.1 j16.3-16.7

PH ACB

0.3

HCTZ = hydrochlorothiazide; = red blood cell; BUN

rate; RBC

ESR = erythrocyte = blood urea nitrogen.

sedi-

these two agents is noteworthy. Compared to mild hypertensives (DBP 95 to 104 mm Hg), moderate hypertensives (DBP 105 to 114 mm Hg) required approximately a 1.4-fold greater total daily dose to control blood pressure. Although both agents lowered the blood pressure in these two subgroups, the percentage of therapeutic failures in the moderately hypertensive group was approximately 1.7-fold greater than in the mildly hypertensive group. As in the case of blood pressure reduction, acebutolol induced a modest reduction in heart rate within the first 3 weeks of drug administration, with no further reduction thereafter. This change did not appear to be dose-dependent, and acebutolol’s partial agonst activity may limit the degree of bradycardia.lv8 Patients receiving 100 mg hydrochlorothiazide per day had a modest but significant increase in heart rate. Effects in special patient populations. Experimental results have yielded conflicting data regarding agerelated changes in beta-adrenergic receptor function and response to beta blockade.‘+‘l In this study, elderly patients responded favorably to acebutolol. Although the geriatric (265 years) subgroup was small, thus limiting the conclusions which can be drawn, a similar number of patients with adequate exposure to drug responded to acebutolol (13 of 14; 93%) and to hydrochlorothiazide (12 of 14; 86%).

Volume Number

111 2

Similarly, among all patients 265 years of age, the number of therapeutic failures in the two groups (acebutolol n = 4, hydrochlorothiazide n = 7) was comparable. Black patients have been reported to be more responsive to diuretics than beta blockers,12-l4 although acebutolol has been shown to produce satisfactory blood pressure control in several studies Among the small number of of black populations. 15-17 black patients in this study, the number of patients responding to hydrochlorothiazide (7 of 10; 70%) and to acebutolol (6 of 10; 60% ) was similar; in all black patients, 11 of 22 (50% ) on acebutolol and 5 of 14 (36%) on hydrochlorothiazide were therapeutic failures. In this limited patient population, it appears that as a group blacks responded better to the diuretic. Due to the small number of black hypertensive patients, however, conclusions regarding the comparative efficacy of the two drugs in this patient population are limited. Side effects and metabolic disturbances. At equieffective antihypertensive doses, acebutolol was better tolerated than hydrochlorothiaxide. Although the relatively high dose of hydrochlorothiazide used (mean dose: 66.7 + 2.8 mg/day) may have increased the biochemical abnormalities in this treatment group, the study design provided for titration at 2-week intervals to an effective hypotensive dose. Both agents were well tolerated by patients 265 years and a similar number of patients were withdrawn due to side effects. Other studies? la however, have not shown any significant differences in side effects between beta blockers and diuretics. In this study, respiratory side effects were similar between acebutolol and hydrochlorothiaxide, possibly related to the cardioselective properties of acebutolol, although patients with preexisting bronchopulmonary diseases were excluded from the study. No patients developed congestive heart failure or symptoms of peripheral ischemia, nor was there a higher incidence of neurologic side effects and fatigue on acebutolol. Conversely, a higher incidence of micturition frequency and urgency on hydrochlorothiazide was not noted. The hydrophilic nature of acebutolol and especially of the metabolite (diaceto101) may result in less penetration of the blood-brain barrierlg and fewer neurologic side effects than observed with more lipophilic beta antagonists. As ischemic heart disease is the most frequent cause of death among hypertensive patients, it is important to consider the impact of antihypertensive therapy on the risk factors and complications of ischemic heart disease. Diuretic-treated patients

Acebutolol and hydrochlorothiazide

in hypertension

359

have been shown to have a relatively high incidence of death due to coronary artery disease,20 while beta blockers have been shown to be effective in improving survival following acute myocardial infarction.21-24 Although data are not available to permit a conclusion, it is interesting to speculate whether the use of beta blockers in hypertensive patients with other cardiovascular risks might decrease occurrences of initial myocardial infarctions and of sudden death. Although evidence generally supports the development of hyperglycemia or abnormalities of glucose tolerance tests on thiaxides,25-27 there are conflicting reports28 2gDiuretic-induced glucose intolerance is generally mild and reversible upon discontinuing treatment. However, an increased mortality rate due to coronary heart disease in patients with modest hyperglycemia has been noted.30,31 Pulsinelli et al.32 found a poorer neurologic outcome after ischemic stroke in diabetics vs nondiabetics, as well as in nondiabetics with serum glucose >120 mg/dl vs nondiabetics with serum glucose <120 mg/dl. The mechanism by which thiazides increase serum glucose has not been clearly established, although it has been suggested that hyperglycemia may be related to loss of potassium.“3 Beta blockers, particularly those which are nonselective and block fl,-receptors, might be expected to impair insulin release during hyperglycemia as well as glycogenolysis and gluconeogenesis, which occur as serum glucose falls. The evidence is conflicting, however, and differences have not always been observed between the effects of selective and nonselective beta blockers.34-36 In this study, acebuto101 had no effect on serum glucose, while hydrochlorothiazide produced a significant increase in serum glucose from baseline at all three testings, ranging from 4.27 to 7.53 mg/dl which, although modest, may assume clinical significance in certain patients (one obese patient with prior diureticinduced hyperglycemia discontinued hydrochlorothiaxide treatment because of symptomatic hyperglycemia and glycosuria). Generally, thiaxide-induced hypokalemia is mild and asymptomatic, not requiring intervention.6*24 For example, in the VA study:? 23% of patients treated with diuretics showed lowering of serum potassium, although only 1% had serum potassium <2.5 mEq/L. Although associated with an increased likelihood of spontaneous cardiac arrhythmias,38-40 arrhythmias complicating acute myocardial infarction,4*-43 and sudden death,” a causative relationship between diuretic-induced hypokalemia and rhythm

360

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disturbances is uncertain. 45*46We found a significant decrease (0.4 to 0.5 mmol/L) in serum potassium at all three testing visits in the hydrochlorothiaxide group, despite administration of potassium supplements to 11% of these patients. Myocardial irritability may have been enhanced by hypokalemia (2.9 mmol/L) in one patient who had ventricular fibrillation at the time of acute myocardial infarction. It is indeed possible that the beneficial hypotensive effects of diuretics in some patients may be negated by a propensity for cardiac arrhythmias.47 Diuretic-induced hyperuricemia has been found in numerous large studies,‘8*48 being statistically significant in patients with preexisting hyperuricemia. Although results of the current study demonstrated an increase from baseline in serum uric acid of 0.6 to 0.8 mg/dl among hydrochlorothiazidetreated patients, there were no reports of symptomatic hyperuricemia. It is known that diuretics increase plasma triglycerides and total cholesterol.49 Chlorthalidone has been shown to increase LDL-cholesterol with no change in HDL-cholestero150-52; the increase in LDLcholesterol could be prevented or reversed by the addition of propranolol or atenolol. These diureticinduced lipid alterations may offset their hypotensive benefit.53 In general, beta blockers also appear to increase plasma triglycerides without altering total cholestero1,4g although some beta blockers may reduce HDL-cholesterol.” The clinical significance of such alterations remains uncertain. A comparison of propranolol and acebutoloP5 showed that these two beta blockers produced no deleterious metabolic changes. In the study reported here, a significant decrease of 16.3 to 16.7 mg/dl in total serum cholesterol from baseline was noted at all three testing visits in the acebutolol group, although serum triglycerides were not significantly altered by either treatment (HDL cholesterol was not assayed). In a recent study of hypertensive patients receiving acebutolol for 6 months,55 no significant changes were seen in plasma levels of total, LDL, and VLDL cholesterol or triglycerides; a slight but nonsignificant decrease was seen in HDL cholesterol, and HDL:total cholesterol was not significantly changed. Conclusions. Both acebutolol and hydrochlorothiaside, when given on a chronic twice-daily dosage regimen, effectively reduced blood pressure in patients with mild and moderate essential hypertension. Side effects were minor and comparable. Hydrochlorothiazide produced more biochemical alterations, such as hyperglycemia and hypokalemia. This short-term study demonstrated a decrease

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in cholesterol during acebutolol treatment and no change while on hydrochlorothiazide. Further attention should be directed toward these metabolic effects as well as towards identifying specific subgroups of hypertensive patients, such as by race, age, or presence of other cardiovascular risk factors, who would respond optimally to one or the other form of therapy. REFERENCES

1. Basil B, Jordan R, Loveless AH, Maxwell DR: P-adrenoceptor blocking properties and cardioselectivity of M&B 17802A. Br J Pharmacol 48:198, 1973. 2. Dreslinski GR, Aristimuno GA, Messerli FZ, Suarez GR, Frohlich ED: Effects of beta blockade with acebutolol on hypertension, hemodynamics and fluid volume. Clin Pharmaco1 Ther 26:562, 1979. 3. Hansson L, Berglund G, Andersson 0, Holm M: Controlled trial of acebutolol in hypertension. Eur J Clin Pharmacol 12:89, 1977. 4. Martin MA, Phillips CA, Smith AJ: Acebutolol in hypertension: A double-blind trial against placebo. Br J Clin Pharmaco1 6351, 1978. 5. Wilcox RG: Randomized study of six beta-blockers and a thiazide diuretic in essential hypertension. Br Med J 5:383, 1978. 6. Nadeau J, Ogilvie RI, Ruedy J, Brossard J-J: Acebutolol and hydrochlorothiazide in essential hypertension. Clin Pharmaco1 Ther 28:296, 1980. 7. Franz IW: Differential antihypertensive effect of acebutolol and hvdrochlorothiazide/amiloride hvdrochloride combination on elevated exercise blood pressures in hypertensive patients. Am J Cardiol 46:301, 1980. 8. Dunlon D. Shanks RG: Selective blockade of adrenocentive beta receptors in the heart. Br J Pharmacol 32:201, 1968. 9. Buhler FR, Burkart F, Lutold BE, Kung M, Marbet G, Pfisterer M: Antihypertensive beta blocking action as related to renin and age: A pharmacologic tool to identify pathogenetic mechanisms in essential hypertension. Am J Cardiol 36:653, 1975. 10. Vestal RE, Alastair JJW, Shand DG: Reduced /3-adrenoceptor sensitivity in the elderly. Clin Pharmacol Ther 26:181, 1979. 11. Abrass IB, Scarpace PJ: Human lymphocyte beta-adrenergic receptors are unaltered with age. J Gerontol 36:298, 1981. 12. Hollifield JW, Sherman K, Slaton P: Age, race and sex as a determinant of successful antihypertensive therapy. Prev Med 7:88, 1978. 13. Woods JW, Pittman AW, Pulliam CC, Werk EE, Waider W, Allen CA: Renin profiling in hypertension and its use in treatment with propranolol and chlorthalidone. N Engl J Med 294:1137, 1976. 14. Humphries DG, Delvin DG: Ineffectiveness of propranolol in hypertensive Jamaicans. Br Med J 2:601, 1968. 15. Mabadeje AFB, Femi-Pearse 0: An open trial of acebutolol in the treatment of hypertension in Nigeria. Clin Res 25:273A, 1977. 16. Oli JM: Acebutolol in the management of hypertension in Nigerians. Curr Ther Res 30:477,1981. -17. Khalil SI. Elzein 0. Bella MEM: A double-blind. crossover study of acebutolol and hydrochlorothiazide amiloride diuretic in Sudanese patients with essential hypertension. Curr Med Res Opin 8:39, 1982. 18. The Medical Research Council Working Party on Mild to Moderate Hypertension: Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 2:539, 1981. 19. Zaman R, Jack DB, Kendall MJ: The penetration of acebuto-

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Lown B, Calvert AF, Armington R, Ryan M: Monitoring for serious arrhythmias and high risk of sudden death. Circulation 51 and 52(suppl 111):189, 1975. Medical Research Council Working Party on Mild to Moderate Hypertension: Ventricular extrasystoles during thiazide treatment: Substudy of MRC mild hypertension trial. Br Med J 287:1249, 1983. Poole-Wilson PA: Ventricular extrasystoles during thiazide treatment. Br Med J 287:1798, 1983. Poole-Wilson PA: Hypokalaemia induced by thiazide diuretics in the treatment of hypertension: A cause for concern, not nihilism. Postgrad Med J 59(suppl 3):137, 1983. Bulpitt CJ: Serum uric acid in hypertensive patients. Br Heart J 37:1210, 1975. Johnson BF: The emerging problem of plasma lipid changes during antihypertensive therapy. J Cardiovasc Pharmacol 4:S213, 1982. Goldman AI, Steele BW, Schnaper HW, Fitz AE, Frohlich ED, Perry M: Serum lipoprotein levels during chlorthalidone therapy. JAMA 244:1691, 1980. Grimm RH. Leon AS. Hunninehake DB. Lenz K. Hannan P. Blackburn H: Effects of thiazyde diuretics on plasma lipids’ and lipoproteins in mildly hypertensive patients. Ann Intern Med 94:7, 1981. Weidmann P, Schiffl H, Boehringer K, Meier A, Mordasini R, Riesen W: Effects of diuretics alone or in combination with @-adrenoreceptor blockers on serum lipoproteins. Br J Clin Pharmacol 1334498, 1982. Ames RP: Metabolic disturbances increasing the risk of coronary heart disease during diuretic-based antihypertensive therapy: Lipid alterations and glucose intolerance. AM HEART J 106:1207, 1983. Miettinen TA, Vanhanen H, Huttumen JK, et al: HDLcholesterol and @-adrenoceptor blocking agents in a 5-year multifactorial primary prevention trial. Br J Clin Pharmacol 13:4318, 1982. Lehtonen A: The effect of acebutolol on plasma lipids, blood glucose and serum insulin levels. Acta Med Stand 216:57, 1984.

APPENDIX MULTICENTER

STUDY-INVESTIGATOR

LISTING

Frank J Alvarez III, M.D. The Medical Clinic; Baton Rouge, LA Dale Anderson, M.D. Wayne Peitz, M.D. Wausau, WI James V. Barnes, M.D. The Elkhart Clinic; Elkhart, IN Albert Barnett, M.D. Friendly Hills Medical Group; La Hobra, CA Robert H. Brier, M.D. Smith-Hanna Medical Center; San Diego, CA Richard C. Combs, M.D. Welborn Clinic; Evansville, IN Hobart Edson, M.D. Ross Valley Medical Clinic, Greenbrae, CA James P. Hampsey, M.D. Mease Hospital & Clinic; Dunedin, FL George J. Hegstrom, M.D. The McFarland Clinic; Ames, IA

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Paul 0. Kretschmar, M.D. The Vancouver Clinic, Inc. P.S., Vancouver, WA Lawrence S. Larson, M.D. Milwaukee Medical Clinic, S.C.; Milwaukee, WI James Lewis, M.D. Sunnyvale Medical Clinic; Sunnyvale, CA Michael Mihalick, M.D. Kelsey-Seybold Clinic; Houston, TX Wayne R. Miller, M.D. The Medical Center Clinic; Pensacola, FL Jacob P. Neathawk, M.D. Lewis-Gale Clinic, Inc.; Salem, VA

American

Harlan Nevin, M.D. Houston, TX John Repaire, M.D. San Diego, CA Robert J. Sansom, M.D. Visalia Medical Clinic, Visalia, CA Robert Smith, M.D. Metropolitan Clinic; Portland, OR Frank Thomas, M.D. Corvallis Clinic; Corvallis, OR

February, 1986 Heart Journal