comparative study of the antihypertensive effect of verapamil and atenolol

Comparative Study of the Antihypertensive Effect of Verapamil and Atenolol

JORGE ESCUDERO, MD, HECTOR HERNANDEZ, MD, and FROYLAN MARTINEZ, MD

A clinical trial in 24 patients with essential arterial hypertension (14 women and 10 men; mean age 47.5) was conducted on a double-blind basis using a placebo, 240~mg verapamil and lOO-mg atenolol daily. The total duration of the trial was 12 weeks: a 2-week washout period on placebo, a 4-week period on one of the trial drugs,’ a second 2-week weaning period and’s further 4-week treatment period on the other trial drug. Stabilization of the hypertension was obtained in 80% of the patients on verapamil and 71’% ‘of the patients on atenolol both

in the supine and upright positions; there was no significant difference between the 2 drugs. A mod- erate decrease in heart rate was obtained. Sinus bradycardia was observed in 3 patients on verapamil and 4 patients on atenolol. No instances of atrioventricular block were observed on electrocardio- gram. No adverse effects were reported with verapamil and in ,only 1 patjent taking atenolol. Ade- quate stabilization of hypertension appears possible in most patients with both verapamil and atenolol;

(Am J Cardiol 1989;57i54D-58D)

I n 1964, Fleckensteinl reported the discovery of a new family of chemical compounds that he named the “calcium antagonists.” Verapamil (Lu-isopropyl-a-(N,- methyl-N-homoveratriI)-yTaminopropyl-3, +dimeth- oxyphenylacetonitrile hydrochloride] was the first of these compounds to undergo experimental trials. This drug inhibits the influx of calcium ions through the cell membrane; mainly in the myocardium, in the smooth muscle cells of the coronary arteries and peripheral blood vessels and in the atrioventricular’node? As a result of its biochemical and pharmacologic character- istics, verapamil has been widely used as an antian- ginal and antiarrhythmic agent. In recent years it has also been used as an antihypertensive, an effect ini- tially described’by Wette et al3 in 1966 and subse- quently by others. 4-10 Because arterial hypertension is a multifactorial disease that continues to be a serious public health problem, there is always room for new antihypertensive agents with different modes of action and properties, for administration on their own or in combination with other drugs. Like atenolol, a selec- tive blocking agent of the ,&adrenergic receptors, verapamil is an effective antihypertensive agent. We therefore undertook a comparative clinical trial of verapamil and the P-blocking agent atenolol.

From the Hospital de Cardiologia y Neumologia, Centro Medico National, I.M.S.S., Mexico City, Mexico.

Address for reprints: Jorge Escudero, MD, Fuego 618, 01900

Mexico DF, Mexico.

Methods Twenty-four hypertensive outpatients* (14 women

and 10 men, aged between 29 and 73 years, mean age of 47.5) entered the trial. Six of these patients were suffering from’stage I and Y8 patients from stage II hypertension according to the World Health Organiza- tion classification (160/95 mm Hg and 160/95 mm Hg plus left ventricular hypertrophy, respectively).

Patients with secondary or malignant arterial hypertension, advanced liver or kidney diseases, myocardial infarct or cerebrovascular accident within the past 3 months, cardiac insufficiency, pronounced bradycardia, atrioventricular block, pathologic mammary syn- drome, bronchial asthma, chronic bronchitis, bronchial spasm, pulmonary emphysema or respiratory insufficiency were excluded from the trial. Women who were pregnant, lactating or liable to become pregnant during the trial and patients requiring multiple therapy were also excluded. .’

The trial was carried out on a double-blind basis, using placebo, 240-mg verapamil (120 mg, 2 times a day) and 100-mg atenolol (50 mg, 2 times a day) in capsules of identical appearance. The total duration of the trial was 12 weeks, divided into 4 periods: an initial

*The patients were from the Cardiology and Pneumology Hospital of the IMSS National Medical Center, the 20th of No- vember Hospital of the ISSSTE and the Western Medical Cen- ter of Guadalajara, Jal.

54D

February 26, 1986 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 57 55D

Z-week weaning period from previous medications during which the patients received a placebo, a second 4-week period during which half the patients received verapamil and half received atenolol, a further weaning period on placebo and then administration of the other trial product for the remaining 4 weeks.

Each patient underwent 8 outpatient examinations; they were carried out weekly during the initial placebo period and fortnightly during the remainder of the trial. The arterial blood pressure was determined with a mercury sphygmomanometer by the same physician while the patient was in the supine and upright positions (3 times in each position); from these the mean reading was selected. The diastolic pressure was determined in phase 5 of the Korotkow sc&le. Any adverse effects were noted at each examination.

Laboratory analyses, electrocardiograms (ECGs) and Z-dimensional echocardiograms were performed on 3 occasions: at the end of the first weaning period, at the end of the 4-week period on the first drug and at the end of the 4-week period on the second drug.

The following laboratory analyses were performed: blood counts, urea, uric acid, creatinine, glucose, bili- rubin, pyruvic glutamic transaminase, alkaline phos- phatase, cholesterol, triglycerides, sodium, potassium, creatinine clearance and urine analysis.

110

FIGURE 1. Left, systolic arterial 100 pressure in the upright position (mean [x] f standard deviation 90

[SD]). Right, diastolic arterial pressure in the upright position. A 8a = atenolol; P = placebo; V = ,. verapamil.

60

The ventricular function and the ejection and contraction fractions were measured on the echocardiogram, in order to assess the pumping and muscular functions of the heart.

At the conclusion of the trial, the results were sub- jected to statistical analysis by the x2 test and analysis of variance.

Results Arterial blood pressure: A significant decrease in

both systolic and diastolic arterial pressures in comparison with the baseline values was observed both with verapamil and atenolol (Fig. 1 and 2). During verapamil treatment, the systolic pressure in the upright position fell from 154 f 19 to 135 f 19 mm Hg and in the supine position from 154 f 19 to 140 f 19 mm Hg; the diastolic pressure in the upright position fell from 105 f 9 to 87 f 10 mm Hg and in the supine position from 103 f 9 to 88 f 12 mm Hg (p <0.05). During atenolol treatment, the systolic pressure in the upright position fell from 154 f 16 to 134 f 16 mm Hg and in the supine position from 154 f 19 to 142 f 19 mm Hg, while the diastolic pressure in the upright position fell from 105 f 9 to 87 f 10 mm Hg and in the supine position from 103 f 9 to 90 f 14 mm Hg (p <0.05).

114.13

J 104.67

P-z 0.05

Systolic arterial pressure (in the upright position)

(X + SD)

Diastolic arterial pressure (in the upright position)

56D A SYMPOSIUM: CALCIUM ANTAGONISTS IN HYPERTENSION-FOCUS ON VERAPAMIL

No statistically significant difference could be found between the results obtained with the 2 drugs. Figures 3 to 6 show the antihypertensive effect of both drugs in the supine and upright positions in each of the patients treated.

Heart rate: The mean heart rate under baseline con- ditions was 71 f 9 beats/min. The heart rate fell to 67 f 7 beats/min during verapamil treatment and to 65 f 12 beats/min during atenolol; only the latter difference was statistically significant (p = 0.03).

A more pronounced decrease in heart rate was noted in 3 patients on verapamil and in 4 patients on atenolol but did not represent a serious problem; it was never necessary to interrupt the trial.

Adverse effects: Only 1 patient exhibited unwanted adverse effects [while on atenolol) in the form of nausea, asthenia and weakness of the lower limbs. The symptoms were sufficiently serious to necessitate sus- pension of treatment.

Electrocardiograms: The results of ECGs were normal in 10 patients. The most frequent abnormalities were a systolic overload of the left ventricle in 7 patients (29.1%), left ventricular hypertrophy in 6 patients (25%) and ventricular repolarization disorders

in 6 patients (25%). No significant changes occurred in the ECGs during the trial.

Echocardiograms: The ejection and contraction fractions and the circumferential contraction rate were normal both in the initial and subsequent examinations. The recorded changes were minimal and not statistically significant. The baseline ejection fraction was 69.06 f 7; it was 69.5 f 8 in the verapamil group and 69.05 f 8 in the atenolol group. The baseline contraction fraction was 32.79 f 6; it was 32.53 f 6 in the verapamil group and 32.98 f 6 in the atenolol group.

Laboratory indexes: No changes were observed in the laboratory indexes during the trial.

Discussion A reduction in the arterial blood pressure was ob-

tained as a result of the peripheral vasodilator effect of verapamil, which not only neutralizes a number of vasoconstrictor substances but also reduces the sensi- tivity of the systemic arteries and arterioles to mechan- ical stimuli, such as extension of the vascular wall, by increasing the intraluminal pressure (the Bayliss effect). This type of calcium antagonist can therefore suppress the automatic regulation of vasoconstriction

150-

WO-

130 -

120-

111.74 IlO-, T

103 ,oo- 100.4

94.26

OO- 66.13

oo- 75.66

IO-

60-

50-

‘to-

30-

20-

10. P<O.O5

Systolic arterial pressure

(X + SD)

Diastolic arterial pressure

FIGURE 2. Left, systolic arterial pressure in the supine position (mean [$ f standard deviation [SD]). Right, diastolic arterial pressure in the supine position. A = atenolol; P = placebo; V = verapamil.

February 26, 1986 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 57 578

based on calcium, reducing the increase in the secondary blood pressure accompanying an increase in the

atenolol was slightly greater (p = 0.03). No widening

peripheral resistance .ll By reducing the aortic resis- of the PR interval on the ECC was obtained in any of

tance and the peripheral vascular resistance in gener- the patients on verapamil, as described in other studies.2J2Js

al, it is possible to reduce the arterial blood pressure in proportion to the patient’s age, initial arterial pressure

In some hemodynamic and electrophysiological

and plasma renin levels9 without stimulating the sym- studies, verapamil has been found to decrease inotro-

pathetic nervous system responsible for the initial pism.5,6a7 It has also been reported that the oral admin-

tachycardia or the renin-angiotensin-aldosterone istration of a single large dose of verapamil caused

system.lO changes on the echocardiogram-e.g., decrease in the

In the present trial, satisfactory stabilization of the ejection time, in the diastolic diameter of the left ven-

hypertension was achieved in 19 patients with verapa- tricle, in the contraction rate of the circumferential

miI(80%) and in 17 patients with atenolol(71%), with fibers and of the rear wall, in the final diastolic volume

no statistically significant difference between the z of the left ventricle and in the ejection fraction and

drugs. In the 5 patients in whom arterial pressure val- heart output-accompanied by an increase in the

ues returned to normal, no correlation was found with preejection period, left ventricular ejection time ratio

age, although the ages varied from 41 to 61 years with a and in the final systolic volume.14 These findings could

mean age of 49.4. not be confirmed in the present trial; the changes in

A slight reduction in heart rate, which was not statis- the ejection and contraction fractions and in the cir-

tically significant, was obtained with verapamil; as cumferential contraction rate on the echocardiogram

was to be expected, the bradycardia obtained with were minimal and not statistically significant.

In previous clinical trials only 182 out of 4,352 patients have reported 1 or more adverse effects; bradycardia, hypotension, first-degree atrioventricular

00 1 B T 8 T

VERAPAMIL ATENOLOL

FIGURE 3. Systolic arterial pressure in the supine position. B = ‘$6 f8 T

basal; T = terminal. VERAPAMIL ATENOLOL

FIGURE 5. Systolic arterial pressure In the upright position. B= basal; T = terminal.

140 1 1 140

0-i 0 T B T c o “3 El T s T

VERAPAMIL ATENOLOL VERAPAMIL ATENOLOL

FIGURE 4. Diastolic arterial pressure in the supine position. B = FIGURE 6. Diastolic arterial pressure In the upright position. B = - basal; 1 = terminal. basal; T = terminal.

58D A SYMPOSIUM: CALCIUM ANTAGONISTS IN HYPERTENSION-FOCUS ON VERAPAMIL

block, cardiac insufficiency, constipation, nausea and vomiting were the most frequent. A feeling of sickness, headache, asthenia, pruritus and flushing in the facial area have also been reported. In the present trial mod- erate bradycardia was caused by verapamil in only 3 patients and by atenolol in 4 patients. One patient complained of nausea, asthenia and weakness of the lower limbs while taking atenolol.

References 1. Fleckenstein A. Die Bedeutung der energiereichen phosphate fur kon-

traktilitat und tonus des myokards. Verh Dtsch Ges Inn Med 1964;70: suppI:&91.

2. Nayler WG. Calcium antagonism: a new approach. Clin Exp Pharmacol PhysioJ 1382;suppI 6:~

3. Wette K, Heimsoth V, Jansen FK. lnfluencia del iproveratril sobre Jas modificaciones electrocardiograficas en 10s hipertensos con angina pectoris. Munch Med Wsch 1966;108:1238. (Spanish ed: 1967;109:44.) 4. Pichardo FA, Molina CA, Pedrero NL. Valoracion clinica de 10s efectos

antihipertensivos del clorhidrato de isoptin. Rev MBd ISSSTE M8x 1973;8:145-155. 5. Lewis BS, Mitha AS, Gotsman MS. Intermediate haemodynamic effects

of verapomil in man. Cardiology 1975;60:366-376.

6. Singh BN, Roche AHG. Effects of intravenous verapamil on hemody- namics in patients with heart disease. Am Heart J 1977;94:593-599.

7. Mangiardie LM. Hariman RJ. McAllister RG Jr, Bhargava V, Surawicz B, Shabetai R. Electrophysiologic and hemodynamic effects of verapamil. Cor- relation with plasma drug concentrations. Circulation 1978;57:366- 372.

8. Kabela E. Los antagonistas de1 calcio en la fisiologia deJ miocardio y de1 musculo Iiso. Relation con su utihdad terapeutica. Arch Inst Cardiol Mex 1980;50:533-534.

9. Biihler FR, Hulten UL, Kiowski W, Mtiller FB, Bolli P. The place of the calcium antagonist verapamil in antihypertensive therapy. J Cardiovasc Pharmacol 1982;4:suppf 3:350-357. 10. Leonetti G, Cuspidi C, Sampieri L, Terzoli L, Zanchetti A. Comparison of cardiovascular, renal and humoral effects of acute administration of two calcium channel blockers in normotensive and hypertensive subjects. J Car- diovosc Pharmacol 2982;4:suupJ 3:319-324. 11. Fleckenstein A, Fleckenstein-Grtin G, Frey M. Efecto antiespastico arterial, antihipertensivo y anticalcinotico de 10s antagonistas de1 calcio. Resu- menes del Simposio “Calcio-antagonistas en la hipertension: enfoque sobre verapamil” [abstr). Mexico D F 15-17 November 1984;l. 12. Midtbo K. Verapamil regular y de liberation prolongada en el trata- miento de la hipertension arterial esencial. In Ref 11: 12. 13. Dargie HJ, McInnes GT, Findlay IN, Cleland JGF. Respuestas cardiovas- culares al verapamil y propranolol en pacientes con hipertension esencial. In Ref 11: 16. 14. Ortiz J. Funcion de1 ventricuio izquierdo despues de una sola dosis alta de verapamil. In Ref 11: 6.

comparative study of the antihypertensive effect of verapamil and atenolol

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