Acta Med Scand 1985; 217: 155-60

Long-term Effects of Captopril and Atenolol in Essential Hypertension

LENNART ANDREN, BENGT E. KARLBERG, ANDERS SVENSSON, PETER OHMAN, OVE R. NILSSON and LENNART HANSSON From the Hypertension Section. Department of Medicine, Ostra Hospital, University of Gbteborg, Goteborg. and the Department of Medicine, University Hospital, Linkoping, Sweden

ABSTRACT. AndrCn L, Karlberg BE, Svensson A, Ohman P, Nilsson OR, Hansson L. (Department of Medicine, Hypertension Section, Ostra Hospital, University of Goteborg, Goteborg, and Department of Medicine University Hospital, Linkoping, Sweden.) Long- term effects of captopril and atenolol in essential hypertension. Acta Med Scand 1985; 217: 155-60.

Fifty patients with mild or moderate essential hypertension were randomized (double- blindly) to treatment with either captopril (n=26) or atenolol (n=24). Their mean supine diastolic blood pressure after placebo was 100-125 mmHg. The study included an initial dose finding phase (12 weeks) during which the dosages of captopril and atenolol were increased stepwise every second week in order to obtain normotension (supine diastolic blood pressure <95 mmHg). Hydrochlorothiazide was added when necessary. During the second phase of the study the patients were followed on active treatment for 2 years. After the initial 12 weeks of active treatment, recumbent and standing blood pressures had fallen significantly both in the captopril group (by 31/20 and 33/19 mmHg, p<O.OOl) and in the atenolol group (by 24/18 and 30/20 mmHg, p<O.OI (systolic), p<O.OOI (diastolic)). The antihypertensive effect was maintained in both groups during long-term treatment. The antihypertensive effect of both agents was potentiated to the same extent by addition of hydrochlorothiazide. Side-effects were few and mild. It can be concluded that both captopril and atenolol are safe and effective antihypertensive drugs. Key words: essential hypertension, captopril, atenolol, hydrochlorothiazide.

Captopril is an orally active inhibitor of the angiotensin I- angiotensin 11-converting en- zyme (1). Inhibition of this enzyme may also prevent degradation of bradykinin (2). Captopril can reduce blood pressure both in renovascular and essential hypertension (3-6). Atenolol is a PI-selective adrenoceptor blocking drug. It is a safe and useful antihyperten- sive agent (7, 8) and has been used as the drug of first choice in the treatment of mild and moderate hypertension in Scandinavian countries for several years.

The purpose of this study was to compare the antihypertensive efficacy and safety of captopril and atenolol as single drugs and in combination with hydrochlorothiazide during long-term treatment in patients with mild and moderate essential hypertension.

PATIENTS AND METHODS Fifty patients with mild or moderate essential hypertension were recruited for the study. There were 29 males and 21 females. Their mean age was 49 years (range 31-69). Secondary hypertension was excluded by a standardized work-up procedure. Seventeen patients had newly detected hypertension and had not been treated previously, while 33 patients were on antihypertensive treatment. All medication was withdrawn at least 2 weeks before the study and all patients were given placebo for at least 2 weeks during the first phase of the trial. If the supine diastolic blood pressure at the end of the placebo period was 100-125 mmHg, the patients were included in the study and randomized (double- blindly) to treatment with either captopril, 25 mg three times daily, or atenolol. 50 mg once daily. The captopril group comprised 26 patients (13 males, 13 females, mean age 50 years, range 32-66). The atenolol group comprised 24 patients (16 males, 8 females, mean age 49 years, range 3149).

Blood pressure and heart rate were recorded every second week for 14 weeks and then every third month for 2 years.

156 L . AndrCn et al. Acta Med Scand 1985; 217

H 25 m g x l H 50 m g x l H 50 m g x l H 50 m g x l Placebo C 25 mgx3 C 50 mgx3 C 50 mgx3 C 50 mgx3 , C 100 mgx3 C 100 mgx3

I I I 1 I 1--- 4 0 2 4 6 8 10 12 14 104 Week

H 25 m g x l H 50 m g x l H 50 m g x l H 50 m g x l Placebo A 50 m g x l A 100 m g x l I A 100 m g x l I A 100 m g x l , A 200 m g x l I A 200 m g x l

1 1 I I I I -. 1 0 2 4 6 8 10 12 14 104 Week

Fig. I. Design of the dose finding part of the study. A = atenolol, C = captopril, H = hydrochloro- thiazide.

The therapeutic goal was to obtain normotension, defined as supine diastolic blood pressure <95 mmHg. If normotension was achieved, the dosages of captopril and atenolol were not changed. If supine diastolic blood pressure was 395 mmHg, the captopril dosage was increased to 50 mg three times daily and the atenolol dosage to 100 mg once daily (Fig. 1). If the patients were not normoten- sive after another 14 days, hydrochlorothiazide, 25 mg once daily, was added. This dosage was increased to 50 mg once daily in patients who did not become normotensive on the 25 mg dose. The final dose step was to increase the captopril dose to 100 mg three times daily and the atenolol dose to 200 mg once daily (Fig. 1).

The study went on for 2 years and the patients were controlled every third month. During this period reductions in dosage were attempted in patients with repeatedly well controlled blood pressure (diastolic recumbent S85 mmHg).

Blood pressure and heart rate were measured under strictly standardized conditions by specially trained nurses. The mean of three measurements was used for each registration and recumbent measurements were performed after 5 min of supine rest and standing measurements after 1-2 min. A mercury sphygmomanometer (cuff balloon 13x35 cm) was used and the disappearance of Korotkoff sounds (phase V) was taken as the diastolic blood pressure.

The study was approved by the Ethical Committees at the Universities of Goteborg and Linkoping.

Statistics Student's t-test (two-tailed) for paired observations was used for statistical observations. A p-value <0.05 was considered statistically significant.

RESULTS

Captopril group Twenty-four patients in the captopril group completed the first phase of active treatment (12 weeks). Their mean daily dose of captopril was 156273 mg. Eighteen patients required addition of hydrochlorothiazide (mean daily dose 38+ 13 mg). Both supine and standing blood pressures were significantly reduced (Table I). Thus, the recumbent blood pressure decreased from 162/107 to 131187 mmHg (p<O.OOl) and the standing blood pressure from 16311 13 to 130/94 mmHg (p<O.OOl). There was no significant change in heart rate (Table I). Nineteen patients completed two years of treatment with captopril. Their mean dosage of captopril was 132+75 mg, which is significantly lower than during the initial phase (p<0.05). Thirteen patients received hydrochlorothiazide during long-term treatment (mean daily dose 35+15 mg). The decrease in both supine and standing blood pressures was maintained during long-term treatment in spite of the significant reduction in the captopril dosage (Table I). Thus, recumbent blood pressure was reduced from 162/107 to 136/89 mmHg @<0.001) and standing from 163/113 to 132/96 mmHg (pc0.001).

Atenolol group Twenty-two patients completed 12 weeks of active therapy with atenolol. Their mean daily dosage of atenolol was 130+57 mg. Seventeen patients required addition of hydrochloro-

Acta Med Scand 1985; 217

thiazide (mean dose 44-t 1 1 mg). There was a significant reduction in both recumbent and standing blood pressures (Table I). Thus, supine blood pressure was reduced from 164/108 to 140/90 mmHg ( p < O . O l , p<O.OOl) and standing from 162/113 to 132/93 mmHg @<0.01, p<O.OOl). Both supine and standing heart rates were significantly reduced (Table I). Twelve patients in the atenolol group completed 2 years of treatment. Their mean daily dosage of atenolol was 104+48 mg. Nine patients required addition of hydrochlorothiazide (mean dose 36+13 mg). The blood pressure reduction was maintained during long-term treatment (Table I). Thus, recumbent blood pressure was reduced by 29/20 ( ~ ~ 0 . 0 0 1 ) and standing blood pressure by 29/23 mmHg ( p < O . O O I ) . The reduction in heart rate persisted also during long-term treatment (Table I).

Side-effects were observed in both treatment groups. Exanthema, taste disturbances, vertigo, sweating, reduced potency, itching, headache and palpitation were reported by patients in the captopril group. Vertigo, sick sinus syndrome, vasovagal syncope, cold fingers, bronchospastic problems, fluid retention, dizziness, chest pain and abdominal discomfort were observed in the atenolol group.

Three patients were excluded from the study during the first 12 weeks of active

Long-term effects of captopril and atenolol 157

Table I. Blood pressure and heart rate during placebo and active treatment with captopril and hydrochlorothiazide and with atenolol and hydrochlorothiazide

Blood pressure (rnmHg)

Supine Standing Supine Standing

Heart rate (beatdrnin)

Captopril group Placebo

Mean SD

12 weeks Mean SD

1 year Mean SD

2 years Mean SD

Atenolol group Placebo

Mean SD

12 weeks Mean SD

1 year Mean SD

2 years Mean SD

1621 107 1516

13 1 ***/87* ** 1417

133***/90*** 1716

136***/89*** 18/8

164/108 2116

140**190*** 1619

139**/90*** 2017

135***/88*** 1717

16311 13 1516

130***/94*** 1619

130***/94*** 19/10

132***/96*** 1819

162/113 2119

132**/93*** 19/12

133***/95*** 1 616

133***190*** 23/10

71 12

75 9

72 9

71 1 1

71 16

57** 13

56** 8

58** 8

79 10

84 12

81 14

78 13

77 15

62** 12

58** 8

61** 9

** p<O.Ol, *** p<O.oOl.

158 L. And& et al. Acta Med Scand 1985; 217

treatment in the captopril group (one due to exanthema, one due to taste disturbance, one was non-responder). Two patients were excluded from the atenolol group during the initial phase, one due to sick sinus syndrome and the other was considered non-responder.

During the long-term treatment, one patient was excluded from the captopril group due to exanthema and taste disturbances. No cases of significant proteinuria or leukopenia were observed. In the atenolol group, there were 8 patients who did not complete the long- term treatment. Five of these drop-outs were due to medical reasons (inadequate blood pressure control in three, bronchospastic problems in one, chest pain and abdominal discomfort in one) and three due to non-complicance.

In the captopril group there was a significant reduction in plasma sodium concentration (2.8 mmol/l, pC0.05). No such change was seen in the atenolol group.

There was a significant reduction in plasma potassium in the atenolol group (0.44 mmoyl, p<O.OS), while no such change was observed in the captopril group. Uric acid, cholesterol and triglycerides remained unchanged in both groups during long-term treat- ment.

The body weight was significantly reduced (3.0 kg, p<0.02) during captopril treatment, while a slight non-significant weight gain (0.8 kg) was observed in the atenolol group after 2 years of active treatment.

DISCUSSION

Both captopril and atenolol as single drugs and in combination with hydrochlorothiazide caused highly significant reductions in both recumbent and standing blood pressures in patients with essential hypertension. These findings confirm earlier observations of blood pressure lowering properties of both captopril and atenolol in hypertensive patients (3-8). Atenolol reduced both supine and standing heart rate, and this reduction persisted during long-term treatment. Since the drop-out rate was high in the atenolol group, the results should be interpreted with caution.

Our findings are, however, in agreement with earlier studies, which have shown that p- adrenoceptor blocking drugs without intrinsic sympathomimetic activity lower blood pressure mainly through a pulse rate dependent reduction in cardiac output (7, 8, 9).

The mechanisms by which captopril causes blood pressure reduction in patients with essential hypertension are still not fully known. The acute blood pressure lowering effect appears to be closely related to the plasma renin level. Several studies have shown a positive correlation between blood pressure reduction and plasma renin activity (10, 11). Captopril, however, also lowers blood pressure in anephric patients (12) indicating that other mechanisms may also be of importance. Thus, other renin-angiotensin systems, e.g. in the vascular walls and in the central nervous system, may be of importance for the long- term antihypertensive effect of captopril(l3-16). Furthermore, the drug can interfere with the degradation of bradykinin (2) and it can impair vascular smooth muscle contraction mediated by postsynaptic az-adrenoceptors (17). Thus, there are several possible mechan- isms by which captopril can lower blood pressure. Irrespective of which of these mechan- isms comes into play, it is obvious that captopril has a clinically useful antihypertensive effect and the present study confirms this.

This study has shown that the dosage of captopril can be reduced during long-term treatment without loss of its antihypertensive effect. We found that captopril in a daily dose of 75-150 mg was clinically useful in patients with mild and moderate essential hypertension. This dosage was accompanied by few side-effects, the most serious being taste disturbances and exanthema. These side-effect were always reversible and disap- peared within a few weeks after withdrawal of the drug.

Acta Med Scand 1985; 217 Long-term ejfects of captopril and atenolol 159

The antihypertensive effect of both captopril and atenolol was potentiated to the same magnitude by hydrochlorothiazide.

When captopril and hydrochlorothiazide were given together, there was no need for extra potassium supplementation. This was, however, often necessary when hydrochloro- thiazide was combined with atenolol in spite of the fact that atenolol also has a certain conserving effect on potassium when combined with saluretics (18).

It can be concluded that both captopril and atenolol are safe and effective antihyperten- sive agents. The drop-out rate in the atenolol group was considerable and it is therefore not possible to evaluate whether there is any difference in the antihypertensive effect between the two drugs. There is, however, no evidence that captopril should be less potent than atenolol. In spite of being more expensive than atenolol, captopril could be a useful alternative in the treatment of hypertensive patients who do not tolerate /3-adrenoceptor blocking drugs. Both drugs could be used in the long-term treatment of mild and moderate essential hypertension.

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Received April 25, 1984.

Correspondence: L. AndrCn, MD, Department of Medicine, Ostra Hospital, S-416 85 Goteborg, Sweden.