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A Randomised, Placebo-Controlled, Double- Blind, Crossover Study of Losartan and Enalapril in Patients with Essential Hypertension

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A Randomised, Placebo-Controlled, Double- Blind, Crossover Study of Losartan and Enalapril in Patients with Essential Hypertension Journal of Human Hypertension (2001) 15, 161–167 2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh ORIGINAL ARTICLE A randomised, placebo-controlled, double- blind, crossover study of losartan and enalapril in patients with essential hypertension R Fagard, P Lijnen, K Pardaens, L Thijs and W Vinck Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, Faculty of Medicine, University of Leuven KU Leuven, Leuven, Belgium The primary objective of this randomised, placebo- enalapril (142/91 mm Hg) than during losartan treatment controlled, double-blind, crossover study, was to evalu- (147/95 mm Hg). Clinic BP, measured 2 to 4 hours after ate and compare the longer term effects of the angioten- drug intake, was reduced to the same extent by both sin II type 1 receptor antagonist losartan and the con- drugs. The losartan-induced BP changes were signifi- verting enzyme inhibitor enalapril on 24-h ambulatory cantly related to those obtained with enalapril (0.63 Ͻ r blood pressure (BP). After a 4-week placebo run-in per- Ͻ 0.93). Ambulatory BP monitoring was repeated after iod, nine patients with essential hypertension entered 4 weeks of combined therapy in six patients. The BP the double-blind phase of the study, which consisted of lowering effect of the combination was not significantly three 6-week periods during which patients were treated better than that achieved with enalapril alone. In con- with placebo, enalapril 20 mg o.d. or losartan 50 mg o.d. clusion, losartan 50 mg o.d. and enalapril 20 mg o.d. Losartan and enalapril, taken between 07.00 and 08.00, lower BP to approximately the same extent, except for reduced ambulatory BP throughout the 24-h period. a more pronounced effect of enalapril on daytime ambu- Average night time BP was reduced from 133/85 mm Hg latory BP. The current study does not provide convinc- on placebo to 124/78 mm Hg on enalapril and to 126/77 ing evidence that addition of losartan to enalapril in the mm Hg on losartan. Daytime BP averaged 157/101 doses used further reduces BP. mm Hg on placebo, and was significantly lower during Journal of Human Hypertension (2001) 15, 161–167 Keywords: ambulatory blood pressure; angiotensin II receptor antagonist; converting enzyme inhibitor; enalapril; losartan Introduction the angiotensin II receptor antagonist losartan, the two approaches led to similar clinic BP reductions Interference with the renin-angiotensin-aldosterone at trough,1–4 though enalapril appeared to be more system is one of several modalities to lower blood effective at peak.1,2 Ambulatory BP was, however, pressure (BP) in patients with hypertension. Inhibi- not monitored to compare the diurnal profile of the tors of the angiotensin converting enzyme (ACE) two drugs. In addition, such parallel studies cannot partially counteract the formation of angiotensin II answer the question whether the response to the two whereas the more recently developed nonpeptide drug classes would be similar in the individual orally active angiotensin II receptor antagonists patient. We have previously demonstrated a tight block the octapeptide’s binding to the type 1 recep- correlation between BP changes when hypertensive tor. Most of the cardiovascular effects of angiotensin patients were consecutively treated with the peptide II in adults, such as vasoconstriction, stimulation of angiotensin II antagonist saralasin and the ACE aldosterone release and cellular growth, are attribu- inhibitor captopril;5 on average, the captopril- table to the angiotensine II type 1 receptor. When induced BP change was more pronounced than the hypertensive patients were allocated at random to response to saralasin, which could either be attri- treatment with the ACE inhibitor enalapril, or with buted to additional antihypertensive actions of cap- topril or to the agonistic effect of saralasin, or to both. This issue of the relative potency of angioten- Correspondence: Dr R Fagard, U.Z. Gasthuisberg-Hypertensie, Herestraat 49, B-3000 Leuven, Belgium sin II antagonists vs ACE inhibitors in the same E-mail: Ͻrobert.fagardȰuz.kuleuven.ac.beϾ patient is particularly relevant when side effects Received 26 May 2000; revised 11 September 2000; accepted 29 develop to one of the drugs, in which case the phys- September 2000 ician may want to switch to a drug from the other Losartan and enalapril in hypertension R Fagard et al 162 class. It has also been argued that more complete Clinical measurements blockade of the renin-angiotensin system by combi- A clinical examination including assessment of nation of both drug classes might lower BP to a body height was performed initially. Blood pressure, greater extent.6–8 heart rate and body weight were measured at each The primary aim of the present study was to com- clinic visit. All visits during the double-blind period pare, using a randomised, placebo-controlled, were scheduled in the morning in the laboratory. double-blind, crossover design, the effects of 6-week Conventional BP was measured by the same investi- treatment with losartan and enalapril on ambulatory gator using a mercury sphygmomanometer and conventional BP in patients with essential (Korotkoff phase V for diastolic BP), three times in hypertension. A secondary aim was to repeat ambu- the supine position and three times in the sitting latory BP monitoring after 1 month of open com- position, after 15 and 5 min rest, respectively; the bined therapy in patients with insufficient BP con- three pressures were averaged for later analysis. trol on monotherapy. Pulse rate was determined during 30 s in each pos- ition. Materials and methods Ambulatory BP monitoring Patients Ambulatory BP monitoring was performed during the 24 hours preceding the clinic visit, using the White patients with essential hypertension, aged Spacelabs 90207 device (Redmond, Washington, у 18 years, in World Health Organization stages I or USA). The BP was measured every 15 min from II, were eligible for the study. Patients with any dis- 08.00 to 22.00 and every 30 min between 22.00 and ease that could interfere with the study protocol 08.00. The ambulatory BP recordings were not were excluded, as were women when pregnant or edited, that is, readings were only excluded if they receiving oral contraceptives. The protocol was had not been completed successfully by the monitor approved by the Ethics Committee of the Faculty of or if they fell outside the preset boundaries for BP Medicine of the KU Leuven and participants gave and heart rate (systolic BP Ͻ70 or Ͼ260 mm Hg, written witnessed informed consent to participate in diastolic BP Ͻ40 or Ͼ150 mm Hg, pulse pressure the study. Ͻ20 or Ͼ150 mm Hg, heart rate Ͻ20 or Ͼ200 beats/min). The following average BPs were derived: the average 24-h BP, daytime BP or the average BP Treatment protocol between 10.00 and 20.00, and night time BP as the pressure between 24.00 and 06.00. Patients were Eligible patients were invited for an initial visit after asked to go to bed between 20.00 and 24.00, and to they had not been administered antihypertensive get up between 06.00 and 10.00. In these conditions treatment for at least 2 weeks. They entered a 4-week the narrow clock-time dependent daytime and night run-in period during which they received two pla- time pressures have been shown to be similar to the 10 cebo capsules each day. Patients were instructed to actual awake and asleep pressures. ingest the study medication in the morning with their breakfast, between 07.00 and 08.00, including Biochemical measurements on visit days; they were asked to keep general life- style, diet and physical activity constant. Patients Routine biochemical variables, including blood glu- who satisfied the BP criteria on the final day of pla- cose and serum creatinine, sodium and potassium cebo treatment (mean sitting diastolic BP у95 concentrations, were determined on venous blood, mm Hg and р105 mm Hg) were allocated randomly as were plasma renin activity11 and circulating to be administered either placebo, the converting ACE.12 enzyme inhibitor enalapril (20 mg o.d.) or the angi- otensin II receptor antagonist losartan (50 mg o.d.). Statistical analysis However, the placebo period was always scheduled between the two active treatment periods, which Database management and statistical analyses were was not known to the investigators who performed performed using SAS software (SAS Institute Inc., the measurements. Each treatment period lasted 6 Cary, North Carolina, USA). Group data are reported weeks. Capsules containing placebo, enalapril or as means ± standard deviation (s.d.). Positively losartan had the same shape and colour. skewed data were transformed logarithmically for At the end of the double-blind study, patients the statistical analyses. The effects of treatment were whose clinic BP remained higher than 130/85 assessed by use of repeated measures analysis of mm Hg9 in all double-blind periods, were proposed variance. For the double-blind study, we compared to be treated with the combination of enalapril the data obtained with placebo, enalapril and losar- 20 mg and losartan 50 mg per day for the next 4 tan; the data during combined therapy were com- weeks. pared to those on monotherapy with, respectively, Journal of Human Hypertension Losartan and enalapril in hypertension R Fagard et al 163 enalapril and losartan. Relationships between treat- Ambulatory and conventional BP ment-induced changes were analysed using single regression analysis. Two-tailed P р 0.05 was con- Table 1 summarises the results on BP. The systolic sidered statistically significant. and diastolic daytime, night time and 24-h ambulat- ory blood pressures during the double-blind placebo period were similar to those during the baseline Results investigations (0.48 р P р 0.97).
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