Journal of Clinical and Basic Cardiology An Independent International Scientific Journal Journal of Clinical and Basic Cardiology 2005; 8 (1-4), 43-46 Efficacy and Tolerability of Losartan in Patients with Essential Hypertension: a Multicentre, Double-Blind Comparison of Losartan with Metoprolol Dobovisek J, Kanic V, Niegowska J, Rekic S, Soucek M Spinar J Homepage: www.kup.at/jcbc Online Data Base Search for Authors and Keywords Indexed in Chemical Abstracts EMBASE/Excerpta Medica Krause & Pachernegg GmbH · VERLAG für MEDIZIN und WIRTSCHAFT · A-3003 Gablitz/Austria ORIGINAL PAPERS, CLINICAL CARDIOLOGY Efficacy and Tolerability of Losartan Versus Metoprolol J Clin Basic Cardiol 2005; 8: 43 Efficacy and Tolerability of Losartan in Patients with Essential Hypertension: a Multicentre, Double-Blind Comparison of Losartan with Metoprolol J. Dobovisv ek1, J. Špinar2, J. Niegowska3, M. Soucv ek4, V. Kanicv 5, S. Rekicv 6 A multicentre, randomised, double-blind, comparative study of antihypertensive efficacy and safety of losartan and metoprolol was carried out in 77 patients with mild to moderate essential hypertension. Normalisation of sitting diastolic blood pressure (siDBP) and sitting systolic blood pressure (siSBP) at the end of the study was considered as the primary criterion for evaluation. A decrease of siDBP for at least 10 % and that of siSBP for at least 15 % was considered as response to treatment. After 2 weeks of single placebo run-in period the patients were randomised to either losartan 50 to 100 mg od or metoprolol 50 to 100 mg bid. After 3 weeks of the treatment the initial dose of both drugs was doubled if target siDBP was not achieved. After 6 weeks of monotherapy hydrochlorothiazide 12.5 mg was added for the last 3 weeks if necessary. Losartan and metoprolol significantly reduced siSBP and siDBP versus baseline: –20.8/15.9 mmHg and –16.2/16.6 mmHg, respectively (all p < 0.001). There was no significant difference between the treatment regimens found during the study in regard to siSBP and siDBP decrease. In the losartan arm the primary criterion for efficacy was achieved in 72.3 % for both siSBP and siDBP. In patients treated with metoprolol these results were 63.0 and 85.2 %, respectively (n.s.). No significant differences between treatment regimens were observed in regard to complete normalisation of blood pressure (< 140/90 mmHg in single patient) and overall blood pressure response. In both groups heart rate decreased significantly and similarly. Both treatments were well tolerated. Adverse events were reported by 16.3 % of patients treated with losartan and 21.4 % of patients treated with metoprolol (n.s.). There were no serious adverse events. Conclusion: In this study in patients with mild to moderate essential hypertension, losartan in comparison with metoprolol exerted substantial and comparable antihypertensive efficacy, as well as a similar safety profile. J Clin Basic Cardiol 2005; 8: 43–6. Key words: essential hypertension, losartan, metoprolol. rterial hypertension is widely recognised as the most valsartan [12], and irbesartan [13, 14] already suggested that A common cardiovascular disease in countries with western in this respect angiotensin II receptor antagonists will not life-style. Hypertension is a potent risk factor for all major differ from proven drug classes. In hypertension, they have cardiovascular events, but the most for cerebrovascular acci- been compared more often with atenolol than with other dents particularly in the elderly [1]. Cardiovascular morbid- beta-blockers. Angiotensin II receptor antagonists exerted ity and mortality may be reduced by the control of blood similar antihypertensive efficacy but the incidence of adverse pressure but the extent of reduction depends on the magni- events was much lower than with atenolol [15–19]. tude of blood pressure lowering [2]. Blood pressure reduc- The aim of this study was first to prove the antihypertensive tion achieved with beta-blockers and diuretics was the best- efficacy of losartan in a double-blind study, and secondly, to recorded intervention to date for prevention of cardiovascu- compare the efficacy and safety of losartan with the cardio- lar morbidity and death in patients with hypertension. A sig- selective beta-blocker metoprolol that has not been exten- nificant reduction of the incidence of stroke (38 %), coronary sively compared with angiotensin II receptor antagonists in artery disease (16 %), and cardiovascular mortality (21 %) patients with non-complicated mild to moderate essential was achieved with blood pressure lowering of average 9–10/ hypertension. 5–6 mmHg over 5 years by use of diuretics and beta-blockers [3]. Later, comparable but not better results were obtained in trials with calcium antagonists and/or angiotensin-convert- Methods ing enzyme (ACE) inhibitors [2, 4–8]. It was a multicentre, prospective, randomised, double-blind, In numerous comparative studies the recently introduced class parallel-group, clinical study, carried out at four medical cen- of antihypertensive agents, angiotensin II receptor antago- tres in the Czech Republic (one), Poland (one), and Slovenia nists, has proven a comparable antihypertensive efficacy with (two). 77 outpatients, male and female in the age of 18 to 75 other classes of antihypertensive drugs but much better years with essential hypertension were eligible. The main in- safety profile. Until now, in patients with high risk only clusion criteria were a sitting diastolic blood pressure losartan demonstrated better efficacy in reducing the com- (siDBP) of 95–114 mmHg and a sitting systolic blood pres- posite cardiovascular endpoints and stroke [9]. So, LIFE sure (siSBP) < 180 mmHg. The patients had to be angio- study was the first comparative trial in which a newer anti- tensin II receptor antagonist- or beta-blocker-naive. In pa- hypertensive drug exerted significantly better protection tients who were already treated with other antihypertensive against overall cardiovascular morbidity and stroke than an drugs in monotherapy, the control of blood pressure had to older drug [9]. Earlier some studies with losartan [10, 11], be under satisfactory. These drugs were withdrawn at the in- Received: November 5th, 2002; accepted: June 5th, 2003. From the 1University Medical Centre Ljubljana, Dept. of Internal Medicine, Div. of Hypertension, Ljubljana, Slovenia, 2 the 2nd Dept. of Medicine, University Hospital Brno, Czech Republic, 3National Institute of Cardiology – Foundation Warsaw, Poland, 4 the 1st Dept. of Medicine, University Hospital Brno, Czech Republic, 5Teaching Hospital Maribor, Dept. of Internal Medicine, Div. of Cardiology and Angiology, Maribor, Slovenia, 6KRKA d. d. Medical Research Department, Novo Mesto, Slovenia Correspondence to: Dr. Jurij Dobovišek, MD, ScD, University Medical Centre Ljubljana, Dept. of Internal Medicine, Div. of Hypertension, Vodnikova 62, 1000 Ljubljana, Slovenia; e-mail: [email protected] For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. ORIGINAL PAPERS, CLINICAL CARDIOLOGY J Clin Basic Cardiol 2005; 8: 44 Efficacy and Tolerability of Losartan Versus Metoprolol clusion. By decision of the National Ethics Committee in A personal computer with SAS software was used for double Slovene centres only untreated patients at the time of inclu- data entry, data management, and statistical analysis. The sion were allowed to enter the study. Common exclusion cri- quantitative variables are described by their mean and stand- teria were in force for this study, among them women in ard deviation values. For the quantitative variables the Stu- childbearing period, secondary hypertension, malignant hy- dent’s t-test taking into account the possible inequality of the pertension, bradycardia < 50 beats/min–1, all stages of atrio- variance and Wilcoxon rank test were performed. The com- ventricular block, stroke or transient cerebral ischaemia parison between the two groups for the qualitative variables within the last 12 months, myocardial infarction within the was done by Chi square test and Cochran-Mantel-Haenszel last 6 months, heart failure, angina pectoris, diabetes mellitus test. Analysis of efficacy was per protocol. Safety analysis in- (with the exception of stable type 2 controlled with peroral cluded all patients from the time of randomisation to the end agents) etc. of the study, or to the point at which the study drug was per- manently stopped, whichever came first. The study was approved by local ethics committees and au- thorities. The patients had to sign the written informed con- sent prior to inclusion. Results All patients underwent basic cardiological examination, in- Study Sample cluding routine ECG and laboratory examinations. At the A total of 77 patients were enrolled. 74 patients completed visits after 3 and 6 weeks of active treatment serum concen- the study according to the protocol. Three patients left the tration of creatinine and potassium and proteinuria were de- study prematurely. Two of them, who discontinued the study termined. At the final visit all examinations performed at the after few days of active treatment were excluded form the sta- inclusion were repeated. tistical analysis. The data of one patient who left the study after 6 weeks of active treatment were included into analysis All patients underwent the controlled single-placebo run-in up to the time of withdrawal. (wash-out) period of 14 days of duration. Patients were ex- cluded from the study in the case