Journal of Human (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 II receptor blocker

JL Pool1, R Glazer2, Y-T Chiang2 and M Gatlin2 1Baylor College of Medicine, Houston, TX; 2Cardiovascular Clinical Development, , 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- 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- -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 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. The trough/peak ratio esti- of study medication (trough measurement). Patients mates were calculated based on the placebo-sub- then remained in the office for a 6-h observation per- tracted least squares means at trough and peak. iod during which supine and standing blood press- Three post-dose time points (hours 2, 4, and 6) were ure and pulse were measured at 2, 4 and 6 h post- included to investigate a peak effect. dosing. In addition, plasma renin activity, angioten- The pharmacokinetic assessment of plasma con- sin II, and valsartan plasma levels were centration and its relationship with pharmacodyn- measured pre-dose and at 2, 4 and 6 h post-dose. amic effect (diastolic blood pressure reduction) was Dose-response efficacy of valsartan JL Pool et al 277 explored by summary statistics. All patients with Mean supine diastolic blood pressure: Although both plasma concentration and diastolic blood the pre-specified analysis of covariance was perfor- pressure were included in this descriptive assess- med, an analysis of covariance using a reduced ment. model (deleting treatment-by-centre interaction from the original model) was also performed for Results change from baseline in diastolic blood pressure. The analysis of covariance using the reduced model Patients was added due to the statistical consideration of A total of 122 patients were randomised to receive relatively high variation in the distribution of sam- treatment, with 114 completing the trial as planned. ple sizes among the five study centres (ranged from The intention-to-treat (primary) analysis included 1–2 patients to 4–5 patients per group). Both analy- 120 patients as two randomised patients were ses produced relatively comparable least squares prematurely discontinued from the trial without a means and treatment differences. In fact, the pre- post-baseline blood pressure measurement. Of the specified analysis results were slightly more favour- patients who discontinued prematurely these were able to valsartan (ie, a slightly greater placebo-sub- due to either unsatisfactory therapeutic response tracted mean reduction in diastolic blood pressure). (three patients), adverse experiences (two patients), For simplicity, the more conservative (least or ‘other’ reasons (three patients). favourable) analysis results using the reduced model Table 1 shows the patient demographics and base- are reported in the manuscript. line characteristics. A significant difference between A significant reduction in trough MSuDBP from the treatment groups was found for sex (P = 0.041), baseline was observed in all treatment groups at 4- Ͻ height (P = 0.014) and significant past medical week end-point (P 0.001), with greater changes history/concomitant diagnosis (P = 0.011). observed for increasing doses of valsartan (least − Additional analyses were performed by incorpor- squares mean change from baseline: placebo, 4.4 − ation of these variables into an analysis of covari- mm Hg; valsartan 10 mg, 4.9 mm Hg; valsartan − − ance model for the primary efficacy variable. Similar 40 mg, 6.5 mm Hg; valsartan 80 mg, 8.2 mm Hg; least squares means were obtained indicating there valsartan 160 mg, −9.1 mm Hg) (Figure 1). The glo- was no major impact on the conclusion due to these bal test to assess the efficacy of four doses of valsar- imbalances. In all groups the majority of patients tan vs placebo was statistically significant (P Ͻ 0.05) had significant medical histories or concomitant with the Dunnett multiple comparison procedure diagnoses (range 76–100%). No other significant applied. The sample sizes were relatively small so baseline demographic differences were detected the power at the planning stage was somewhat low among the five treatment groups. to detect statistical significance between individual doses of valsartan and placebo. Nevertheless, both valsartan 80 mg and 160 mg reached statistical sig- Efficacy nificance at the nominal level of 0.05 (ie, no Results for the intention-to-treat dataset were similar adjustment). The results of the pairwise compari- to those for the Week 4 dataset; therefore, only the sons to placebo are given in Table 2. intention-to-treat data are reported. The regression analysis for the assessment of dose

Table 1 Patient baseline demographics

Placebo Valsartan Valsartan Valsartan Valsartan (n = 25) 10 mg 40 mg 80 mg 160 mg (n = 25) (n = 25) (n = 23) (n = 24)

Sex (% female) 52.0% 24.0% 32.0% 17.4% 50.0% Race Caucasian 80.0% 84.0% 72.0% 82.6% 83.3% Black 8.0% 4.0% 8.0% 13.0% 8.3% Other 12.0% 12.0% 20.0% 4.4% 8.3% Age in years (mean ± s.d.) 53.0 (±9.3) 54.3 (±10.1) 52.4 (±9.3) 52.3 (±12.9) 52.2 (+10.2) Weight in lbs (mean ± s.d.) 187.2 (±41.1) 200.5 (±29.3) 194.7 (±31.4) 217.4 (±46.5) 189.8 (±44.3) Height in inches (mean ± s.d.) 65.4 (±4.0) 68.4 (±3.3) 67.6 (±3.5) 69.1 (±3.4) 67.5 (±4.8) Duration of hypertension in years 10.2 8.4 9.2 12.5 12.3 (mean and range) (0.5–39.0) (0.2–21.0) (0.6–25.0) (0.1–33.0) (0.3–34.0) Antihypertensive treatment over previous 3 months 92.0% 92.0% 84.0% 87.0% 79.2% (%) Significant medical history (% yes) 96% 96% 76% 96% 100% Baseline trough supine blood pressure in mm Hg diastolic 101.7 (±4.9) 102.6 (±5.8) 101.8 (±5.3) 100.7 (±5.0) 101.0 (±5.2) systolic 156.4 (±17.6) 157.3 (±13.8) 150.7 (±13.5) 152.7 (±13.4) 155.1 (±15.7) Dose-response efficacy of valsartan JL Pool et al 278

Figure 1 Least squares mean change from baseline in trough mean supine blood pressure at 4 week end-point for placebo (n = 25), valsartan 10 mg (n = 25), 40 mg (n = 24), 80 mg (n = 22), 160 mg (n = 24).

Table 2 Between treatment comparisons of mean supine blood pressures

Comparison Diastolica Systolic vs placebo (mm Hg) (mm Hg) Estimate (P-value) Estimate (P-value)

Valsartan 10 mg −0.52 (P = 0.764) −2.32 (P = 0.581) Valsartan 40 mg −2.14 (P = 0.219) −5.66 (P = 0.194) Valsartan 80 mg −3.86 (P = 0.033) −9.75 (P = 0.039) Valsartan 160 mg −4.69 (P = 0.008) −10.53 (P = 0.014)

aA modified covariance model using without treatment-by-centre interaction was used for the calculation of P-values. The purpose was to minimise the effect of centres with small number of patients per treatment group. Figure 2 Valsartan dose vs trough diastolic blood pressure after 4 weeks with mean raw data (b), n = 22 to 25 per group and predicted curve (—), quadratic analysis. response yielded the following quadratic relation- ship between dose and trough mean supine diastolic Table 3 Response surface analyses (predicted and raw mean blood pressure at end-point: changes) in trough mean supine diastolic blood pressure y =−7.787 − 2.266 VAL + 0.730 VAL2, Treatment group Change from baseline in mm Hg where VAL = (valsartan dose − 80)/80 is the stan- dardised unit of the valsartan dose. End-point The lack-of-fit test result and predicted dose responses were precisely identical whether the stan- Predicted mean Raw mean dardised unit or the actual dose is used. The lack-of- fit test result was highly non-significant (P = 0.955) Placebo −4.8 −4.6 indicating that the goodness of fit was strong. The Valsartan 10 mg −5.3 −5.4 Valsartan 40 mg −6.5 −6.7 estimated slope of the linear term was highly sig- − − = Valsartan 80 mg 7.8 7.6 nificant (P 0.008), indicating that there was a posi- Valsartan 160 mg −9.3 −9.4 tive dose response: an increase in mean reduction in blood pressure with increasing doses (Figure 2). The goodness of fit of the model was also confirmed by the comparison between the predicted responses response for valsartan was evident. For simplicity, and the observed values in diastolic blood pressure only the results based on the pre-specified model are reduction in Table 3. Furthermore, the observed raw presented in this manuscript. mean reductions in all dose groups in Table 3 also descriptively indicated a positive dose response. Mean supine systolic blood pressure: For the For robustness purposes, both Emax model and analysis of MSuSBP, the original and modified log-linear model were subsequently assessed. The covariance model with/without the treatment-by- predicted mean diastolic blood pressure reductions centre interaction term was used. As the results of were all comparable among the three models, indi- both models were similar, only those calculated cating that the conclusion with a positive dose from the original model are reported. Dose-response efficacy of valsartan JL Pool et al 279 All treatments decreased trough MSuSBP com- 10 mg to 160 mg (Table 4). The mean valsartan con- pared to baseline (least squares mean change from centrations observed were consistent within a given baseline: placebo, −1.32 mm Hg; valsartan 10 mg, dose after 2 and 4 weeks. −3.64 mm Hg; valsartan 40 mg, −6.97 mm Hg; valsar- tan 80 mg, −11.07 mm Hg; valsartan 160 mg, −11.85 Neurohormones: The plasma concentration of mm Hg). Similarly, as with supine diastolic blood angiotensin II increased after all doses of valsartan pressure, the global test to assess the efficacy of four (Figure 4). Trough levels of angiotensin II rose to the doses of valsartan vs placebo was statistically sig- highest level after 2 weeks of treatment and then lev- nificant (P Ͻ 0.05) with the Dunnett multiple com- elled off after 4 weeks. No clear correlation was seen parison procedure applied. The results of the pair- between plasma levels and valsartan dose, although wise comparisons to placebo are given in Table 2. the maximum increase in the level of angiotensin II was seen after 160 mg (Figure 4). Responder rates: Responder rates were 16%, 24%, A correlation was observed between increasing 33%, 46% and 54% for placebo, valsartan 10 mg, doses of valsartan and plasma renin. As the dose of 40 mg, 80 mg and 160 mg, respectively. The results valsartan increased from 10 mg to 160 mg, plasma also demonstrated a positive dose response. renin activity increased (Figure 4). The maximum level of plasma renin for each dose was seen after 2 Pulse rate: No significant changes from baseline in weeks and then the levels stabilised after 4 weeks trough supine pulse or trough standing pulse were of treatment. Aldosterone concentrations decreased seen in any group. after 4 weeks of treatment with the greatest reductions seen 6 h post-dose, however, there was Trough/peak ratios: The trough/peak assessment no clear relationship with increasing doses of valsar- was based on all 115 patients who had available tan (data not shown). diastolic blood pressures at all three post-dose time points (hours 2, 4, and 6). The results are presented Tolerability and safety in Figure 3. All trough/peak ratio estimates were у50% for all A total of 41 (33.6%) of the 122 randomised patients valsartan dose group and consistently smallest at reported adverse experiences, regardless of relation- Hour 4 among the three post-dose time points, indi- ship to trial medication. Headache was the most fre- cating: (1) that at least 50% of the peak effect in dias- quently reported adverse experience, highest in pla- tolic blood pressure reduction was preserved at cebo (12%) and valsartan 10 mg (8%) groups. There trough; and (2) that the peak effect occurred between was no dose-related incidence of adverse experi- 2 to 6 hours (around 4 hours) post-dose. It appeared ences in the valsartan groups, with 44% of patients that two trough/peak ratio estimates (out of 12) were complaining of adverse experiences on placebo, greater than one at the early post-dose time point, 44% on valsartan 10 mg, 36% on valsartan 40 mg, Hour 2, which may be explained by random errors 22% on valsartan 80 mg and 21% on valsartan in the data, in particular a relatively large mean dia- 160 mg. stolic blood pressure reduction observed at Hour 2 Adverse experiences considered trial drug related in the placebo group. were of mild intensity (except for one patient with equilibrium dysfunction and headache, considered : Only 97 patients had available serious, in the placebo group) and were reported by plasma concentration to be included in the pharma- less patients on valsartan compared with placebo— cokinetic assessment. Peak valsartan concentrations total of four patients (16%) in the placebo group were reached at 2–4 h post-dose. Plasma levels of (postural hypotension; severe ataxia; headache; valsartan increased as the dose increased from nervousness), two patients (8%) in the valsartan 10 mg group (headache; rash), one patient (4%) in the valsartan 40 mg group (mild peripheral oedema), one patient (4.3%) in the valsartan 80 mg group () and one patient (4.2%) in the valsartan 160 mg group (libido decrease). No clinically sig- nificant trends for adverse experiences were observed in men or women or in patients of differ- ent race. No trial drug-related cough was reported. For rou- tine laboratory parameters, all mean and median values remained within the normal range with no clinically significant changes in any groups. There were no deaths during the trial. Patients experiencing significant orthostatic decreases in blood pressure (decrease у10 mm Hg in diastolic blood pressure or у20 mm Hg in systolic blood pressure from supine to standing) totalled two (8%) in the placebo group, four (16%) in the valsar- Figure 3 Trough-to-peak ratio at 4-week end-point for valsartan tan 10 mg group, three (12%) in the valsartan 40 mg 10 mg (n = 24), 40 mg (n = 22), 80 mg (n = 22), 160 mg (n = 23). group, three (13%) in the valsartan 80 mg group and Dose-response efficacy of valsartan JL Pool et al 280 Table 4 Average plasma valsartan concentration and net effect on days 1, 14 and 28, monitored for 6 hours post dose

Dose (mg) Average plasma valsartan concentration (ng/ml)/ net effect (mm Hg)a

Day Pre-dose 2 hours 4 hours 6 hours

10 1 0 440/0.9 269/−2 172/−1.8 14 0/0.08 351/−0.4 271/−3 180/−3.4 28 0/−1 393/−2.1 296/−2.4 199/−4.8

40 1 0 930/−1.3 802/−3.6 463/−4 14 80/−1.9 969/−1.5 709/−3.8 412/0.9 28 75/−2 950/−3.8 778/−4.2 452/−5

80 1 0 1334/−1 1258/−2.7 809/−4 14 156/−2.1 1395/−2.8 1382/−3.1 907/−2.9 28 148/−2.3 1488/−1.9 1358/−3.8 862/−3.6

160 1 0 1638/−1 1755/−2.8 1009/−4.2 14 215/−3.5 1831/−3.1 1995/−6.3 1140/−3.6 28 213/−4.5 2222/−5.2 2168/−5.4 1378/−7.6

aNet effect = mean change from baseline minus placebo effect for MSuDBP.

Figure 4 Angiotensin II concentrations and plasma renin activity at baseline and weeks 2 and 4 post treatment for placebo (n = 25), valsartan 10 mg (n = 25), 40 mg (n = 25), 80 mg (n = 23), 160 mg (n = 24). (··· ᭜ ··· placebo; —࡯— Val 10 mg; ··· ̆ ··· Val 40 mg; --„-- Val 80 mg; ··· b ··· Val 160 mg).

four (17%) in the valsartan 160 mg group. Almost all same trend, with increasing percentage with increas- changes were decreases in standing systolic blood ing doses of valsartan. pressures, in the range of −22 to −54 mm Hg. The The pharmacokinetic assessments showed that standing diastolic decreases were in the range of −10 plasma valsartan concentrations increased with to −13 mm Hg. These changes were not dose, in agreement with previous data seen in heal- accompanied by symptoms in any of the valsartan thy patients.9 Plasma concentrations of valsartan groups. There was one case of symptomatic ortho- were similar on Days 14 and 28, indicating that there static hypotension on placebo which resolved after was no significant accumulation of drug. This is as 10 minutes. expected since the half-life of valsartan is 6 h and the dosing interval was 24 h. Maximum pharmaco- Conclusions dynamic effect (measured by net effect on MSuDBP) was reached at 2–6 h post dose and, as expected, The results of this trial show valsartan to effectively was later than the maximum plasma concentration lower blood pressure in patients with mild-to-mod- of valsartan, which was observed at 2 h. The net erate hypertension, and demonstrate dose-related effect was consistent for Days 14 and 28 for all val- antihypertensive efficacy of valsartan. sartan doses, suggesting that patients reach pharma- As the dose of valsartan increased from 10 mg to codynamic steady state for diastolic blood pressure 160 mg, the magnitude of diastolic and systolic by 2–4 weeks of valsartan therapy. The trough/peak blood pressure lowering was greater. The data show results, showing at least 50% of the peak antihyper- doses of 80 mg OD and above to provide good anti- tensive effect observed at trough, are in keeping with hypertensive efficacy. Responder rates followed the current recommendations for once daily antihyper- Dose-response efficacy of valsartan JL Pool et al 281 tensive agents15 and support a once-daily dose regi- ulmonary airways of dogs. Am Physiol Soc 1980; 48: men for valsartan. 511–517. Valsartan was well tolerated by all patients during 5 Foote EF, Halstenson CE. New therapeutic agents in this trial. The overall incidence of adverse experi- the management of hypertension: angiotensin II recep- ences for the valsartan treatment groups were equal tor antagonists and renin inhibitors. Ann Pharm- acother 1993; 27: 1495–1503. to or less than the placebo group and showed no 6 Johnston CI. Angiotensin receptor antagonists: focus dose relationship. The good tolerability profile is in on . Lancet 1995; 346: 1403–1407. keeping with data reported for other angiotensin 7 Black HR et al. 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