Dose-Response Efficacy of Valsartan, a New Angiotensin II Receptor Blocker
Total Page：16
File Type：pdf, Size：1020Kb
Journal of Human Hypertension (1999) 13, 275–281 1999 Stockton Press. All rights reserved 0950-9240/99 $12.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE Dose-response efficacy of valsartan, a new angiotensin II receptor blocker JL Pool1, R Glazer2, Y-T Chiang2 and M Gatlin2 1Baylor College of Medicine, Houston, TX; 2Cardiovascular Clinical Development, Novartis, East Hanover, NJ, USA Objective: To study the efficacy and tolerability of a baseline in trough MSuDBP, indicated a positive dose range of valsartan doses in patients with mild-to-moder- response. Responder rates were 16%, 24%, 33%, 46%, ate hypertension. 54% for placebo, valsartan 10 mg, 40 mg, 80 mg, 160 mg Design: 122 adult out-patients were randomised in equal respectively, which also indicated a positive dose numbers to receive valsartan 10 mg, 40 mg, 80 mg, response in the dose range of 10 mg to 160 mg. Greater 160 mg or placebo once daily (OD) for 4 weeks in this than 50% of the antihypertensive effect measured at multicentre, double-blind, fixed-dose, parallel trial. peak persisted at trough for each of the four active treat- Patients were assessed at 0, 2 and 4 weeks. ment groups, confirming efficacy over a 24-h period. No Main outcome measures: The primary efficacy variable dose-related adverse experiences were observed, with was change from baseline in trough mean supine dias- overall incidence (regardless of relationship to trial tolic blood pressure (MSuDBP). Other variables medication) of 44% with placebo and 44%, 36%, 22%, included change from baseline in trough mean supine 21% for valsartan 10 mg, 40 mg, 80 mg, 160 mg respect- systolic blood pressure (MSuSBP), responder rates and ively. The most common adverse experience reported trough/peak ratio. was headache which occurred most frequently with pla- Results: All treatments significantly reduced MSuDBP cebo (12%). No trial drug-related cough was observed. and MSuSBP at 4-week end-point compared to baseline Treatment with valsartan did not produce clinically sig- (P Ͻ 0.001). The magnitude of blood pressure lowering nificant orthostatic changes in diastolic or systolic was greater with increasing doses of valsartan (least blood pressure. One case of symptomatic orthostatic square mean change from baseline for placebo, valsar- hypotension was observed on placebo. tan 10 mg, 40 mg, 80 mg, 160 mg respectively: MSuDBP Conclusions: The results of this trial show valsartan to −4.4 mm Hg, −4.9 mm Hg, −6.5 mm Hg, −8.2 mm Hg, −9.1 effectively lower blood pressure in patients with mild- mm Hg; MSuSBP −1.3 mm Hg, −3.6 mm Hg, −7.0 mm Hg, to-moderate hypertension, and demonstrate that the −11.1 mm Hg, −11.9 mm Hg). A fitted quadratic curve, to reduction in blood pressure increases with increasing predict relationship between dose and change from dose levels. Keywords: valsartan; angiotensin II receptor antagonist; hypertension Introduction level would be anticipated to result in effective anti- hypertensive agents devoid of these unwanted Effective blood pressure control in essential hyper- effects. Angiotensin II antagonists, also known as tension may be achieved through blockade of the angiotensin II receptor blockers, have a novel mech- renin-angiotensin system (RAS). Angiotensin-con- anism of action and have been reported to effec- verting enzyme (ACE) inhibitors effectively block tively lower blood pressure without cough as a side the cascade by suppressing angiotensin II levels effect.5–8 These agents effectively block the RAS by through inhibition of the converting enzyme, and competitive antagonism of the action of angiotensin have played a major role in the management of II at its cellular receptor site.5,6,7,9 The AT cellular hypertension during the past decade.1,2 However, 1 receptor site appears to mediate most of the known inhibition of the converting enzyme has effects actions of angiotensin II, although a second receptor beyond the RAS and results in well recognised side- site exists, AT ,10 which appears to play an effects associated with this class of agents including 2 important role in apoptosis11 and inhibition of cell cough and angioneurotic oedema. These side-effects 12 are thought to be due to the accumulation of other growth and fibrillar collagen metabolism. substrates of the converting enzyme such as bradyki- Valsartan is a new orally active angiotensin II nin and substance P.3,4 antagonist which inhibits the RAS by selectively Selective inhibition of the RAS at a more distal preventing the interaction of angiotensin II at its AT1 cellular receptor site9,13 Previous Phase I trials with valsartan have shown it to be well tolerated in single doses ranging from 10 to 400 mg once daily.14 Correspondence: Dr James Pool, Methodist Hospital Research, Adverse experiences reported in these trials were of 6535 Fannin Mail Station, F-504 Room 531, Houston, TX 77030, USA mild-to-moderate intensity, generally self-limiting Received 5 August 1998; revised and accepted 25 November 1998 and judged unlikely to be related to valsartan. The Dose-response efficacy of valsartan JL Pool et al 276 most common adverse experience observed was The primary efficacy variable was the change from headache. baseline in trough MSuDBP after 4 weeks of treat- The current placebo-controlled, dose-ranging ment. Secondary variables included change from study was undertaken to assess the efficacy, toler- baseline in mean supine systolic blood pressure ability and safety of valsartan 10 mg, 40 mg, 80 mg (MSuSBP), and trough/peak ratio, defined as the and 160 mg once daily, and to explore the dose- ratio of the difference in least squares MSuDBP of response relationship of valsartan in the reduction valsartan pre-dose to valsartan post-dose, after sub- of blood pressure over this dose range. The doses traction of the placebo effect. Responder rates were selected in this trial covered the potential thera- defined as MSuDBP Ͻ90 mm Hg or a у10 mm Hg peutic range for valsartan based on previous trials. decrease compared to baseline. The main criterion for tolerability and safety was Materials and methods the reporting of adverse experiences, orthostatic changes in blood pressure and symptomatic ortho- Patients static hypotension (defined as a postural decrease of Male and post-menopausal or surgically sterile blood pressure from supine to standing after 2 min у у female outpatients, aged 18–70 years, diagnosed 20 mm Hg in SBP and/or a decrease 10 mm Hg with uncomplicated mild-to-moderate essential in DBP accompanied by symptoms of cerebral hypertension, defined as mean supine diastolic hypoperfusion). blood pressure (MSuDBP) у95 mm Hg and р115 mm Hg, were eligible to participate in the trial. Statistical methodology Patients were required to have less than ±5mmHg variability in MSuDBP and no significant orthostatic The originally planned sample size of 100 evaluable blood pressure changes during a 4-week placebo patients was chosen to assess whether a dose run-in period. response exists in the dose range of 10 mg to 160 mg The most important exclusion criteria were a his- and was not based on a statistical calculation for tory of heart failure within the preceding 6 months; pairwise comparisons between doses. Comparability second or third degree heart block, concomitant among treatment groups for baseline demographics angina pectoris, or clinically relevant arrhythmias; was examined using the Mantel–Haenszel chi- clinically significant valvular heart disease; hyper- square test and the F-test. tensive retinopathy (Grade III or IV); history of For each efficacy variable, an analysis of covari- hypertensive encephalopathy or cerebrovascular ance was performed both as a within-treatment accident; confirmed evidence of hepatic disease analysis (post treatment end-point compared to and/or renal impairment; or insulin-dependent dia- baseline) and a between-treatment analysis betes mellitus. (compared to placebo) of covariance with treatment All patients gave written consent to participate in group and trial centres as factors and baseline as the study which was approved by the relevant Insti- covariate. tutional Review Board. The study was conducted A polynomial regression analysis was performed according to the revised Declaration of Helsinki and to investigate the dose-response relationship for Good Clinical Practice requirements. change from baseline in trough MSuDBP at end- point. The goodness of fit for a quadratic response curve was examined by a lack-of-fit test. The stan- Study design dardised unit for valsartan dose was used in the This was a multicentre (five centre), double-blind, regression analysis. randomised, placebo-controlled, fixed dose, parallel Two patient datasets were analysed, the intent-to- design trial of 4 weeks duration. After the placebo treat dataset including all randomised patients with run-in period, patients were randomised in equal a baseline measurement and at least one post-base- numbers to receive either valsartan 10 mg, valsartan line measurement carried forward in case of prema- 40 mg, valsartan 80 mg, valsartan 160 mg, or placebo ture discontinuation, and the Week 4 patient dataset once daily (OD) for 4 weeks. consisting of all randomised patients with both All trial drugs were presented as identical cap- baseline and Week 4 measurements. All patients sules to be taken once a day in the morning. The were included in the safety analysis, which was use of concomitant medications that could interfere descriptive. with the evaluation of efficacy or safety were not The trough/peak ratios for all valsartan treatment allowed throughout the duration of the trial. groups were assessed for change from baseline in Patients were assessed at baseline and at 2 and 4 diastolic blood pressure by means of a two-way weeks post treatment. On visit days, blood samples, repeated measures analysis of covariance, using all supine and standing blood pressure and pulse patients with available measurements at all three measurement were taken prior to that day’s intake post-dose time points.