European Journal of Clinical Pharmacology © by Springer-Verlag 1978
Europ. J. clin. Pharmacol. 14, 301-304 (1978)
Labetalol, a Cross-Over Double Blind Controlled Trial G. L. Sanders, P. A. Routledge, J. G. Rao, G. M. Gales, D. M. Davies, and M. D. Rawlins Department of Pharmacological Sciences(Clinical Pharmacology),The University, Newcastleupon Tyne and Department of Clinical Pharmacology. Shotley Bridge General Hospital, Co. Durham, England
Summary. 20 patients (12 female) with moderately severe essential hypertension [blood pressure during placebo treatment 181 + 6 (systolic), 107 _+ 3 (diastolic)] completed a double-blind, cross-over dosetitrated comparison of labetalol and methyldopa. Both drugs reduced lying and standing arterial blood pressure to a similar extent, although only labetalol reduced heart rate. Compliance was high ( > 95%) with both drugs, and the incidence of subjective adverse effects was similar. Key words: Labetalol, methyldopa, comparative trial, arterial hypertension,/3-blockade, a-blockade.
Beta-adrenoceptor antagonists are widely used as "first-line" treatment for hypertension because of their efficacy and the relatively low incidence of adverse effects. However, blood pressure control with beta-blockade may be inadequate even when used in conjunction wdth a diuretic, and the addition of a peripheral vasoditator or a centrally acting hypotensive drug may be required. Recently, there has also been interest in the benefits of combining beta-blockade with alpha blockade; and though treatment with propranolol and phenoxybenzamine  is associated with a high incidence of side-effects (particularly postural hypotension), the combination of oxprenolol and phentolamine [2, 3] has been better tolerated, and associated with a satisfactory hypotensive response. Labetolot is both an alpha-and beta-adrenoceptor antagonist, and has been shown to be an effective antihypertensive agent . The present study was undertaken in order to compare its efficacy and short-term toxicity with those of methyldopa.
Patients and Methods Patients with arterial hypertension were considered for inclusion in the study if they fulfilled the following criteria: (1) Untreated diastolic blood pressure > 95 and < 130 mmHg. (2) No clinical features or history of accelerated hypertension. (3) Absence of certain underlying causes of hypertension (phaeochromocytoma, Conn's syndrome, Cushing's syndrome, coarctation of the aorta). (4) Absence of heart block, cardiac failure, ischaemic heart disease, cerebrovascular disease, obstructive airways disease, or diabetes mellitus. Twenty-two patients (13 women; mean age 52.8 + 2.6 years) agreed to participate in the study which had received approval from the local ethical committee. Antihypertensive drug therapy was withdrawn for a three week "run-in" period from the patients who had previously received treatment, except for one female patient who continued to take hydrochlorothiazide throughout the study. Thereafter all patients were seen at fortnightly intervals between 0900 and 1100 h. At each visit, systolic and diastolic blood pressure (first and fourth phases of Korotkoff sounds) were measured in triplicate with a random zero sphygmomanometer  by an independent observer who was unaware of the patient's drug therapy. Heart rate was measured by palpation of radial artery. Both blood pressure and heart rate were measured after 15 min recumbency and 3 min standing. At the end of the "run-in" period patients were randomly allocated to treatment with either labetalol or methyldopa which were supplied in identical capsules. Both drugs were administered at an initial dose of 100 mg three times daily and increased every two weeks (200mg × 3; 300mg × 3; 4 0 0 m g × 3; 600mg × 3; 800mg × 3; 1000rag × 3) until the 0031-6970/78/0014/0301/$01.00
G.L. Sanders et al.: Labetalol, a Cross-Over Double Blind Controlled Trial
Table 1, Arterial blood pressure, pulse rate, body weight, daily dosage and compliance (Mean -+ 1 SEM)
Lying blood pressure
(mmHg) Systolic 181 -+6 Diastolic 107-+3 Standing blood pressure (mmHg) Systolic 173 -+5 Diastolic 104-+ 3 Systolic postural change (mmHg) -7_+3 Diastolic postural change (mmHg) -2-+1 Pulse rate (beats/min) Lying 81_+2 Standing 84-+3 Body Weight (kg) 70.6-+3.3 Drug dose (mg/day) Drug compliance % 91_+3
158-+5 *** 92-+2***
71.8-+2.4" 810-+166 95+1"
72.5-+2.4*** 1183-+201 96-+1"
* P < 0.05 (difference compared to placebo) ** P < 0.01 (difference compared to placebo) *** P < 0.001 (difference compared to placebo)
Table 2. Adverse Effects
5 0 0
20 5 10
15 0 0
10 0 0 0 0 5 0
10 0 0 0 10 0 0
35 0 0 0 5 0 0
50 15 20 30 25 30
62 29 24 24 33 29 29
68 37 26 32 37 16 21
0 0 0 5 5 20
0 5 5 5 5 20
25 0 0 0 0 20
25 20 15 35 30 18
19 14 19 33 38 18
53 16 16 21 26 18
Postural hypotension Ankle swelling Shortness of breath
32 11 -
Drowsiness/tiredness Headaches Depression Vivid dreams Muscle effects Blurred vision Dry eyes
Dry mouth Nausea Indigestion Constipation Diarrhoea Total number of patients
lying and standing diastolic pressures were below 90 mmHg, or a dose of 1000 mg three times daily had been reached, or presumed adverse effects precluded further dosage increments. Dosage adjustments were made by another independent observer who was
aware of the patients' blood pressures at that visit, but who was unaware of the therapy which the patients were receiving. This observer also recorded the patients' spontaneous reports of symptoms. Once a patient's optimum dose of labetalol or methyldopa had been defined, he was maintained at this dose for a further six weeks before transfering "blindly" to placebo treatment for six weeks. Then the dose of the other drug was titrated in similar incremental steps, and the trial ended after six weeks treatment at the optimum dose level. At each visit patients were given more capsules than were required for correct treatment and were instructed to return the surplus: the difference was used to calculate compliance. Venous blood was withdrawn at the end of each active treatment and placebo periods and the following tests carried out: full blood count, erythrocyte sedimentation rate, plasma urea and electrolytes, plasma proteins, liver function tests, direct antiglobulin test, and antinuclear antibodies (ANA). At the same time an adverse effects questionnaire  was given to each patient to complete at home and to return by post. Results are expressed as mean ___1 SEM. The significance of the differences between the means of the cardiovascular changes were determined using Student's t test, and for laboratory measurements by Wilcoxon's signed rank test. McNemar's test for paired data was used in the analysis of the questionnaires.
Two patients were withdrawn from the trial: one woman because of poor compliance, and one man because his diastolic blood pressure was less than 90 mmHg during the placebo period. Of the twenty patients who completed the study, two failed to complete the methyldopa maintenance dose period; one because of drug-induced lethargy and another because the maximum amount of methyldopa failed to control the blood pressure. In four patients the placebo period lasted only two weeks because of a rise in diastolic blood pressure to above 120 mmHg. Methyldopa and labetalol produce significant falls (p < 0.001) in blood pressure in both supine and standing positions compared with those during placebo period (Table 1). Mean falls in arterial pressures (systolic/diastolic) were 30/15, 23/ 14 mmHg for supine blood pressure, and 30/15, 29/ 16 mmHg for standing blood pressure for methyldopa and labetalol respectively (Table 1). There were no significant differences between the reduc-
G. L. Sanders et al.: Labetalol,a Cross-OverDouble Blind Controlled Trial tions in blood pressure produced by methyldopa and labetalol in both standing and lying positions. Labetalol therapy but not methyldopa was associated with a significant postural fall in systolic blood pressure compared with placebo (Table 1). Labetalol produced a significant fall in pulse rate during both lying and standing positions compared with placebo (p < 0.001) while methyldopa caused a significant fall in pulse rate in the supine position alone (p < 0.05). Pulse rates were significantly lower in both positions with labetalol treatment compared with methytdopa treatment (p < 0.01). The average time to reach optimal blood pressure control for labetalol was 5.7 weeks and methyldopa 6.2 weeks (p > 0.5). The blood pressures achieved at the end of the titration periods were not significantly different from those at the end of the maintenance period for either drug. Drug compliance was similar during labetalol (95 -+ 1%) and methyldopa (96 _+ 1%) periods. Although significant weight gain occurred during both treatment with methyldopa (1.4 _+ 0.4 kg, p < 0.001) and with labetalol (0.6 _+ 0.3 kg, p < 0.05) when compared with placebo, there was no significant difference between the weight gained during these treatment periods. No significant changes were observed in the results of the laboratory investigations, except for the changes in white blood cell count and the presence of antinuclear antibodies. Mean white blood cell counts were lower during treatment with both labetalol (5.3 +_ 0.4 × 103 mm -3, n = 17) and methyldopa (5.9 _+ 0.5 X 10 3 mm -3, n = 16) when compared to placebo (6.8 -t- 0.6 103 mm -3, n = 17). However, the difference was only statistically significant (p < 0.05) during labetalol therapy. The changes were not associated with any symptoms although one patient's white blood cell count fell to 3.0 × 103 mm -3 during treatment with labetalol. Before the study, antinuclear antibodies were not detected in any of the patients. During the study, antinuclear antibodies (1/16 dilution) were detected in two patients during labetalol treatment and in two other patients, antibodies were detected during placebo treatment and in one case these remained present during the methyldopa phase. Certain of the spontaneously reported adverse effects, shortness of breath, ankle oedema, nausea and indigestion, were apparently reported more frequently during labetalol treatment than either placebo or methyldopa therapy. Similarly, apparently more patients complained of a dry mouth and drowsiness during methyldopa treatment only. However, statistical analysis by McNemar's test for paired data failed to show any statistical differences in spontane-
ous or questionnaire reported adverse effects during any of the treatment periods.
Discussion Our results suggest that labetalol is as effective as methyldopa in lowering arterial blood pressure in patients with mild or moderate hypertension. In no patient did the hypertension prove resistant to labetalol, though in one patient blood pressure was not controlled by methyldopa. The time taken to achieve adequate control was similar for the two drugs. Labetalol and methyldopa reduced supine and standing blood pressure to the same extent. A significant postural effect on systolic blood pressure was observed amongst patients receiving labetalol (see Table 1) which we attribute to a-blockade. However, this was not dose-limiting and questionnaire analysis failed to demonstrate that this was a significant adverse effect. Previous studies  have indicated that in doses of more than 2 g daily labetalol is associated with an increased incidence of postural hypertension: in our study only one patient exceeded this dose and he remained asymptomatic. We have observed a significant reduction in white blood cell count during labetalol treatment compared with placebo. Although a small gain in weight was observed during labetalol treatment, the fall in white blood cell count was not due to a haemodilutional effect since no significant change occurred in the haemoglobin concentration. Larger populations will need to be studied for longer periods for this effect to be confirmed. In four other studies [3, 7, 8, 9] with a total of 80 patients, no changes in white blood cell count have been described although one reported a small decrease  from 7.1 to 6.5 x 103 mm -3 in 19 patients. There have been no reports of agranulocytosis. Our reports of positive A N A in so few patients are of doubtful significance since a positive A N A is found in 3% of untreated hypertensives . Moreover, treated patients show positive A N A tests more often with methyldopa (13%) than patients who have received other hypotensive agents (3.8%) . In our study of 20 patients, we were likely to detect only very large statistical differences in the incidence of side-effects, and it is not unexpected that none were found. Recording of spontaneous sideeffects also failed to identify any unusual drug reactions in our small population.
Acknowledgements. We are grateful to Sister S. Sparks, Staff Nurse E. Rainbow, Nurse D. Nattras
G.L. Sanders et al.: Labetalol, a Cross-Over Double Blind Controlled Trial
for their nursing assistance and to Drs. S. M. Bell and I. B. Porteous for undertaking routine laboratory investigations. Allen and Hanburys Ltd. provided medical supplies and financial support, and methyldopa was supplied by Merck Shark and Dohme.
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7. Prichard, B. N. C., Boakes, A. J.: Labetalol in long term treatment of hypertension. Br. J. clin. Pharmacol. Suppl. 3 (4) 743-750 (1976) 8. Pugsley, D. J., Armstrong, B. K., Nassim, M. A., Beilin, L. J.: Controlled comparison of labetalol and propranolol in the management of severe hypertension. Br. J. clin. Pharmacol. Suppl. 3 (4) 777-782 (1976) 9. Hansson, L., Hanel, B.: Labetalol, a new a- and/3-adrenoceptor blocking agent, in hypertension. Br. J. clin. Pharmacol. Suppl. 3 (4) 763-764 (1976) 10. Bolli, P., Waal-Manning, H.J., Wood, A.J., Simpson, F. O.: Experience with labetalol in hypertension. Br. J. clin. Pharmacol. Suppl. 3 (4) 765-771 (1976) 11. Wilson, J.D., Bullocke, J.Y., Sutherland, D.C., Main, C., O'Brien, K.P.: Antinuclear antibodies in patients receiving non-practolol beta-blockers. Br. Med. J. 1978/I, 14-16
Received: May 22, 1978, accepted." August 23, 1978
Dr. G. L. Sanders Senior Research Associate Department of Pharmacological Science Wolfson Unit of Clinical Pharmacology Claremont Place Newcastle upon Tyne, NE1, 7RU, U.K.