IN THE TREATMENT OF HYPERTENSION

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1 Br. J. clin. Pharmac. (1981), 12, A MPARATIVE STUDY OF ATENOLOL AND METOPROLOL IN THE TREATMENT OF HYPERTENSION S. RASMUSSEN, K. ARNUNG, P.C. ESKILDSEN & P.E. NIELSEN Medical Department C, Diakonissestiftelsen, DK-2 Copenhagen F, Denmark 1 In an open, randomized cross-over investigation of thirteen patients (nine men and four women, aged years) with mild or moderate essential hypertension a mparison between atenolol and metoprolol was carried out in order to study the effects of 5, 1 and 2 mg given once daily on blood pressure and heart rate at rest and during exercise. 2 Before one 8-adrenoceptor blocking drug was replaced by the other in a patient an intervening drug-free interval of sufficient length was secured to allow an increase in the blood pressure to pretreatment levels. 3 A maximal fall in blood pressure was achieved with 5 mg atenolol once daily, with no further reduction when the dose was increased-to 1 mg or 2 mg. Maximal blood pressure reduction was achieved with 1 mg metoprolol daily, while the hypotensive effect of 5 mg once daily was not nsistent. Significant reductions in heart rate in all test situations were observed with 5 mg atenolol, while 2 mg metoprolol was necessary to reduce exercise-induced tachycardia. 4 Atenolol 5 mg and metoprolol 1 mg once daily are efficient in treating mild or moderate hypertension and doses beyond these may not reduce the blood pressure further. On the ntrary lower doses than generally remmended may be effective in the individual patient. Introduction The introduction of cardioselective /3-adrenoceptor blocking agents for the treatment of hypertensive patients has raised questions ncerning not only their relative hypotensive potency in relation to dose response, and the frequency of drug administration but also to the incidence of side-effects and the price differences. In Denmark two cardioselective /8-adrenoceptor blocking agents have been introduced recently, namely metoprolol in 1975 and atenolol in In the few clinical mparisons between these two drugs the smallest dose used has been 1 mg (Comerford & Besterman, 1977; Jeffers etal., 1978; Barber, 1978; Comerford & Besterman, 198; Lyngstam & Ryden, 1981), but an even smaller dose of either drug may be of clinical relevance. We, therefore, decided to mpare the effect of these two,8-adrenoceptor blocking agents on blood pressure (BP) and heart rate (HR) at rest and during exercise in hypertensive patients, in a cross-over investigation using once daily doses of 5, 1 and 2 mg and fixed treatment periods with intervening drug free intervals of sufficient length with the intention of avoiding a carry-over effect /81/ $1. Methods Thirteen patients with essential hypertension (WHO stage I-II), nine men and four women aged years (mean 5.5 years) mpleted this open randomized cross-over study. Two patients had a newly disvered hypertension, while the remaining patients had received antihypertensive treatment from 4 months to 18 years. The prerandomization period nsisted of at least 3 weeks without antihypertensive treatment. Patients with a systolic BP 2 16 mmhg and/or diastolic BP 2 15 mmhg at the end of this period were randomly allocated to start monotherapy with either metoprolol or atenolol. All patients had normal serum creatinine at entry to the study and none of them had obstructive airway disease, heart failure, diabetes or other nditions which precludes the use of f8-adrenoceptor blocking drugs. Both drugs were administered once daily in the morning starting with 5 mg and increased bi-weekly via 1 mg to 2 mg daily. When a patient had mpleted a treatment period with one j8-adrenoceptor blocker the drug was tapered off during the Macmillan Publishers Ltd 1981

2 888 S. RASMUSSEN, K. ARNUNG, P.C. ESKILDSEN & P.E. NIELSEN next week. BP and HR were measured bi-weekly and when pretreatment levels were attained the other /3-adrenoceptor blocking drug was mmenced in the same way as previously described. Three patients had severe symptoms of hypertension during the first drug free interval. These patients were therefore switched directly from the highest dose of the first used 3-adrenoceptor blocking agent to the lowest dose of the other. This dose was then maintained for 4-6 weeks before the planned increase. For reasons unrelated to the therapy three patients on metoprolol and four patients on atenolol were not investigated on maximum dose. All investigations were carried out at the same time for each patient in the morning in the out-patients hypertension clinic a least 24 h after the last ingestion of medicine. After a resting period of 1 min in the lying position measurements of supine and standing BP were performed with a random zero sphygmomanometer (Hawksley). Diastolic blood pressure was rerded at the disappearance of the Korotkoff sounds (phase V). Subsequently a bicycle exercise test was performed with 3 min on 3 and 6 kpm, respectively. BP during exercise was measured with a standard mercury sphygmomanometer during the last minute of each exercise load. Statistical analysis was performed using the Wilxon test for matched pairs. Values of P <.5 were nsidered statistically significant. c) U. cu ) C. 4- E bo._u E._ a) ) 4 Cu' la. Cu _. ** * * * * * * W) r- In c7n tl +l +l +l +l +l Cu * * * sc * * * m ) En 64o. o- or +l +1 'C +1 CD -o x ooooro tn o\c Rto) m \C _t '. 4 r \ q, rnio 1 +l oo. o½'2o +l +l+l +l1+1+l * * * t* * * t N r' oy o. * * * C* Results Both drugs caused significant reductions in BP and heart rates in the supine and standing position at rest as well as during exercise (Tables 1 and 2, Figure 1). Atenolol (5 mg) reduced BP and HR in all test situations. There was no further decrease in BP or HR by increasing the daily dose to 1 or 2 mg. Metoprolol in a once daily dose of 1 mg also reduced resting BP as well as the exercise induced BP on both 3 and 6 kpm. Metoprolol 5 mg daily failed to reduce supine systolic and standing diastolic resting BP as well as the exercise-induced diastolic BP on 3 and 6 kpm. The hypotensive effect was not further increased on 2 mg daily. Only resting HR was reduced significantly on 1 mg daily while 2 mg daily was necessary to lower the exercise HR on both work loads. Reductions in BP and HR were generally larger on atenolol than metoprolol. Comparing the effect of 5 mg of either drug showed that atenolol caused significantly lower levels of resting supine systolic as well as standing systolic and diastolic blood pressures. Also, statistical significant differences in heart rates were obtained in the resting standing position and during exercise on both workloads. The incidence of side-effects did not differ in the Cu =.3 _ c#: cn O ) o -uc. = CL Q ou - ou, ) CL ~C: -o = o'u Cut o -o +l re N N '. I-- _-4.h &N; +1 +l +l +o ma& ^ c oo 4 oo *- +l +l +l +l +l +l ) kcu NS'rf'.- -- 'I t- It * c9'-nt m N s C) X _ E -. C X Cu 6 VQ-. 6 VC.

ATENOLOL AND METOPROLOL IN HYPERTENSION 889 two drugs. Two patients mplained of diarrhoea and one patient had Raynaud's phenomenon on each drug. ' ' ' c C.) e C). co ). ' C) ' = > co.=._ *C4 C > ).

3 ATENOLOL AND METOPROLOL IN HYPERTENSION 889 two drugs. Two patients mplained of diarrhoea and one patient had Raynaud's phenomenon on each drug. ' ' ' c C.) e C). co ). ' C) ' = > co.=._ *C4 C > ).8r * * * +I +I +l * ** ^ _ N _e_ ** +I t+ +1 _.4 --I *-* N _, t o6 o6 wi C4 4 +l ~ _e q \~ 'It % * * * o6o % %CD r- -4 ** * en 'I*) % 4- lo N- o 'I C r~ Z S: -; -4 C4 T en N- - cn N- r-4 t ci -) en 7% Ci4 A4 en IC v I') v} V *, Discussion The aim of the present study was to mpare the antihypertensive effect of the two cardioselective,8- adrenoceptor blocking drugs metoprolol and atenolol given once daily to hypertensive subjects. The study was designed as a single blind cross-over investigation with a drug free interval of sufficient duration to secure a rise in blood pressure to pretreatment levels prior to the next treatment phase. This ndition is not fulfilled when patients are switched directly from one drug to another. It is well-documented that blood pressure may be reduced several weeks to months after withdrawal of antihypertensive therapy (VA study group, 1975). The few studies mparing the antihypertensive effect of atenolol and metoprolol have suggested that the two drugs are equipotent given once daily to patients with mild or moderate hypertension (Comerford & Besterman, 1977; Barber, 1978; Comerford & Besterman, 198; Lyngstam & Ryden, 1981). However, no previous studies have been presented mparing the effect of atenolol and metoprolol in doses of 5 mg given once daily. Our study showed that atenolol generally caused greater reductions in BP and HR mpared to metoprolol, reaching statistical significance in several instances. Atenolol in a dose of 5 mg daily was as effective as 1 and 2 mg (Tables 1 and 2). Although 5 mg metoprolol did cause reductions in blood pressure it was not significant in all situations investigated. However, 1 mg metoprolol daily uld reduce the blood pressure nsistently at rest as well as during exercise (Tables 1 and 2). Our study showed that 5 mg atenolol caused a significant reduction in resting as well as exerciseinduced tachycardia. For metoprolol this was first achieved in all situations with 2 mg daily. Several studies have shown that atenolol (Douglas- Jones & Cruickshank, 1976; Jeffers, Webster & Petrie, 1977; Nilsson et al., 1979) as well as metoprolol (Reybrouck et al., 1978; Karlberg et al., 1979) given once daily to hypertensive patients may cause significant reductions in blood pressure. For metoprolol the smallest dose used in this ntext as well as in the mparative studies with atenolol (Barber, 1978; Comerford & Besterman, 198; Lyngstam & Ryden, 1981) has been 1 mg/day. The doseresponse curve for atenolol is relatively flat (Dollery, 1977). Studies have shown that the hypotensive effect of 5 mg atenolol daily did not differ from 1 mg and 2 mg daily (Douglas-Jones & Cruickshank, 1976; Jeffers et al., 1977). It has been suggested by Marshall et al. (1979) that the dose-response curve for atenolol

4 89 S. RASMUSSEN, K. ARNUNG, P.C. ESKILDSEN & P.E. NIELSEN 22 Ateso * M.toprolol S E E Go *to. isn aoowo Supine S1aing 3 6 k km- Figure 1 Median changes in blood pressure (systolic,diastolic ---- ) and heart rate at rest and during exercise in 13 hypertensive patients before (-) and during treatment in random order with 5 mg (O), 1 mg ( A) and 2 mg ( O3) once daily of atenolol and metoprolol, respectively. lies between and 25 mg daily. They found that the fall in blood pressure with 25 mg was not significantly different than with 1 mg when the blood pressure was measured 6-8 h after the last tablet (Marshall et al., 1979). In nclusion, the present study showed that the maximal fall in blood pressure was achieved with 5 mg atenolol once daily, while no further reduction was observed when the dose was increased to 1 mg or 2 mg. Maximal blood pressure reduction was achieved with 1 mg metoprolol daily, while the hypotensive effect of 5 mg once daily was not nsistent. Significant reductions in heart rate in all test situations were observed with 5 mg atenolol, while 2 mg metoprolol was necessary to reduce exerciseinduced tachycardia. The clinical implications of References BARBER, J.H. (1978). Relative activity of atenolol and metoprolol. Br. med. J., 2,357. MERFORD, M.B. & BESTERMAN, E.M.M. (1977). Relative activity of atenolol and metoprolol. Br. med. J., 2, 26. MERFORD, M.B. & BESTERMAN, E. (198). Dosing intervals in f-blocker therapy. Lancet, U, 96. DOLLERY, C.T. (1977). Dose-response in hypertension. Proc. Roy. Soc. Med., 7 (suppl 5), 9-1. these observations may be that atenolol 5 mg or metoprolol 1 mg once daily should be sufficient in treating patients with mild or moderate hypertension. However, even smaller doses of either /8-adrenoceptor blocking agent may be effective on some of these patients. It is of interest to study further the relationship between dose and blood pressure response with smaller doses used on this study. This seems particularly relevant for atenolol in doses less than 5 mg daily (Marshall et al., 1979). Far reaching nclusions as to the relative potency of the two drugs cannot be deduced from this study in view of the small number of patients investigated. Further, prevailing price differences uld be decisive for the choice of drug. Correspondence should be addressed to Dr S. Rasmussen, Department of Clinical Physiology, Glostrup Hospital, DK- 26 Copenhagen, Denmark. DOUGLAS-JONES, A.P. & CRUICKSHANK, J.M. (1976). Once-daily dosing with atenolol in patients with mild or moderate hypertension Br. med. J., 1, JEFFERS, T.A., WEBSTER, J. & PETRIE, J.C. (1977). Atenolol once-daily in hypertension. Br. J. clin. Pharmac., 4, JEFFERS, T.A., WEBSTER, J., REID, B. & PETRIE, J.C. (1978). Atenolol and metoprolol in mild hypertension. Br. med. J., 2,1269.

ATENOLOL AND METOPROLOL IN HYPERTENSION 891 KARLBERG, B.E., NILSSON, O., TOLAGEN, K., NITELIUS, E. & WAERN, U. (1979). Once-daily metoprolol in primary hypertension. Clin. Pharmac. Ther., 25, 39947.

5 ATENOLOL AND METOPROLOL IN HYPERTENSION 891 KARLBERG, B.E., NILSSON, O., TOLAGEN, K., NITELIUS, E. & WAERN, U. (1979). Once-daily metoprolol in primary hypertension. Clin. Pharmac. Ther., 25, LYNGSTAM,. & RYDEN, L. (1981). Metoprolol and atenolol administered once daily in primary hypertension. Acta med. Scand., 29, MARSHALL, A.J., BARRIIT, D.W., HEATON, S. & HARRY, I.D. (1979). Dose response for blood pressure and degree of cardiac,8-blockade with atenolol. Postgrad. med. J., 55, NILSSON, O.R., KARLBERG, B.E., OHLSSON, O., THULIN, T. & TOLAGEN, K. (1979). Atenolol administered once daily in primary hypertdnsion. Acta med. Scand., 26, REYBROUCK, T., AMERY, A., FAGARD, R., JOUSTEN, P., LIJNEN, P. & MEULEPAS, E. (1978).,8-blockers: once or three times a day? Br. med. J., 1, VETERANS ADMINISTRATION OPERATIVE STUDY GROUP ON ANTIHYPERTENSIVE AGENTS (1975). Return of elevated blood pressure after withdrawal of antihypertensive drugs. Circulation, 51, (Received March 4, 1981)

OPEN EVALUATION OF LABETALOL IN THE TREATMENT OF ANGINA PECTORIS OCCURRING IN HYPERTENSIVE PATIENTS

OPEN EVALUATION OF LABETALOL IN THE TREATMENT OF ANGINA PECTORIS OCCURRING IN HYPERTENSIVE PATIENTS Br. J. clin. Pharmac. (1979), 8, 25S-29S OPN VALUATION OF LABTALOL IN TH TRATMNT OF ANGINA PTORIS ORRING IN HYPRTIV PATINTS.M.M. BSTRMAN & M. SPNR ardiological Department, St Mary's Hospital, Norfolk Place,