Effectiveness and Safety of Valsartan in Children Aged 6 to 16 Years With Hypertension

ORIGINAL PAPER

Effectiveness and Safety of Valsartan in Children Aged 6 to 16 YearsWith Hypertension

Thomas Wells, MD;1 Jeffrey Blumer, MD, PhD;2 Kevin E.C. Meyers, MD;3 Jose P.R. Neto, MD;4 Rejane Meneses, MD;5

Mieczysław Litwin, MD;6 Johan Vande Walle, MD;7 Susan Solar-Yohay, MS, MBA;8 Victor Shi, MD;8 Guangyang Han, MS;8 andThe Valsartan Pediatric Hypertension Study Group

From the University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, AR;1 the Case Western Reserve University,

Rainbow Babies and Children’s Hospital, Cleveland, OH;2 The Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia,

PA;3 the Instituto Materno Infantil Professor Fernando Figueira, Rua dos Coelhos, Recife ⁄ PE, Brazil;4 the Centro de Nefrologia Pediatrica do

Parana, Hospital Pequeno Prıncipe, Agua Verde, Curitiba ⁄ PR, Brazil;5 the Children’s Memorial Health Institute, Warsaw, Poland;6 the UZ Gent

De Pintelaan 185, Gent, Belgium;7 and Novartis Pharmaceuticals Corporation, East Hanover, NJ8

The effectiveness and safety of valsartan have not beenassessed in hypertensive children. Therefore, hypertensivepatients aged 6 to 16 years (n=261) were randomized toreceive weight-stratified low- (10 ⁄ 20 mg), medium-(40 ⁄ 80 mg), or high-dose (80 ⁄ 160 mg) valsartan for2 weeks. After 2 weeks, patients were randomized to a 2-week placebo-controlled withdrawal phase. Dose-depen-dent reductions in sitting systolic blood pressure (SSBP)and sitting diastolic blood pressure (SDBP) were observedafter 2 weeks (low dose, )7.9 ⁄ )4.6 mm Hg; medium dose,

)9.6 ⁄ )5.8 mm Hg; high dose, )11.5 ⁄ )7.4 mm Hg [P<.0001for all groups]). During the withdrawal phase, SSBP andSDBP were both lower in the pooled valsartan group than inthe pooled placebo group (SSBP, )2.7 mm Hg [P=.0368];SDBP, )3.0 mm Hg [P=.0047]). Similar efficacy wasobserved in all subgroups. Valsartan was well tolerated andheadache was the most commonly observed adverse eventduring both the double-blind and 52-week open-labelphases. J Clin Hypertens (Greenwich). 2011;13:357–365.�2011 Wiley Periodicals, Inc.

Hypertension is a significant health concern in thepediatric population. Children with hypertension maynot manifest any overt signs; however, target organdamage similar to that seen in adults has beenreported widely.1–5 Prevention of target organ damageis preferable, and in children with persistent hyperten-sion despite aggressive nonpharmacologic therapy,antihypertensive agents are recommended.6,7 Inpatients with end-organ damage at the time of presen-tation, drug treatment to lower blood pressure (BP) isindicated.6–8

The safe and effective use of antihypertensive agentsin children and adolescents has emerged as an impor-tant unmet medical need recognized by primary carephysicians who treat these patients, academic subspe-cialists to whom these patients are referred frequently,and the US Food and Drug Administration (FDA) thathas issued a number of written requests calling forstudy of marketed agents in this vulnerable patientpopulation.6,9 The resulting studies have yielded mixedresults. While all have shown some effect on eithersystolic or diastolic BP compared with placebo orbaseline measurements, when evaluation is limited tomarketed agents using the same experimental design,

some have been shown to meet regulatory require-ments for effectiveness while others have not.10 At theheart of this ambiguity are issues of incorrect dosingand, often, an inability to demonstrate clearly anexposure-response relationship. For these reasons, eachagent with the potential for use in pediatric patientsmust be studied in this target population to ensure thateffectiveness and safety can be demonstrated.

The angiotensin-converting enzyme (ACE) inhibitorshave been among those most extensively evaluated inchildren and adolescents.11,12 Angiotensin II (A-II)receptor inhibition is perceived to have a physiologicadvantage over inhibition of the converting enzymealone since the latter does not inhibit tissue and serumenzymes that convert A-I to A-II, thus circumventingthe ACE inhibitor–induced blockade of the renin-angiotensin-aldosterone system.13–15 Blocking thereceptor mitigates the effects of A-II–induced vasocon-striction and aldosterone-dependent and aldosterone-independent sodium reabsorption.16

This study was designed to evaluate the efficacy andsafety of valsartan, an angiotensin receptor blocker(ARB), in hypertensive children and adolescents usinga randomized, dose-ranging, controlled-withdrawaldesign. The drug has recently been reported to be safeand effective in children aged 1 to 5 years with nonegative effects on growth and development.17 In thistrial, the age range is extended to patients aged 6 to16 years.

METHODSChildren with documented hypertension were studiedin a prospective 4-week, double-blind, randomized,

Address for correspondence: Jeffrey Blumer, MD, PhD, Department ofPediatrics, Pediatric Pharmacology and Pediatric Administration, CaseWestern Reserve University, Rainbow Babies and Children’s Hospital,11100 Euclid Avenue, Cleveland, OH 44106E-mail: [email protected]

Manuscript received: June 18, 2010; Revised: November 5, 2010;Accepted: November 8, 2010DOI: 10.1111/j.1751-7176.2011.00432.x

Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 13 | No 5 | May 2011 357

multicenter study followed by a 52-week, open-labelphase conducted at 55 centers in 9 countries (seeAppendix for a list of the principal investigators). Thestudy was conducted in response to a written requestfrom the FDA.

Study PopulationChildren aged 6 to 16 years old with a mean sittingsystolic BP (SSBP) �95th percentile for age, sex, andheight were eligible for participation in the study.7,18

Children who had not previously received antihyper-tensive therapy or, in the opinion of their treating phy-sician, could be withdrawn from antihypertensivetherapy, were considered for inclusion in the study.Potential patients who met the age and BP criteriawere excluded if any of the following were present:severe hypertension (BP �5% above the 99th percen-tile); hypertensive neurologic injury; estimated creati-nine clearance of <40 mL ⁄ min ⁄ 1.73 m2; severearrhythmias; coarctation of the aorta; bilateral renalartery stenosis (unilateral for children with a singlekidney); pregnancy or lactation; human immunodefi-ciency virus or hepatitis; clinically significant gastroin-testinal or hepato-biliary disease; pertinent electrolytedisorders and other significant systemic diseases; prioradverse reaction to an ARB; or concurrent treatmentwith antipsychotics, tricyclic antidepressants, mono-amine oxidase inhibitors, lithium, anticonvulsants, ordrugs known to have a significant effect on BP. Chil-dren who had functioning renal allografts for morethan 1 year and who met the other entry criteria werepermitted to enroll. As per FDA requirements, theintended demographic profile for the study was that�50% of the patients must be aged between 6 and11 years and 40% to 60% must be black.

Study DesignThe study design is shown in Figure 1. Before ran-domization, all eligible patients underwent a placebo-controlled washout period lasting up to 7 days. At theend of the washout period, patients entered phase 1, adouble-blind, dose-response phase in which they wererandomly assigned to low-, medium-, or high-dosevalsartan using a 2:1:2 randomization scheme. Patientscompleting phase 1 entered a placebo-controlledwithdrawal phase (phase 2). In phase 2, patients wererandomly assigned in a 1:1 ratio to either continue onthe same dose of valsartan that they had received inphase 1 or to receive placebo. Phases 1 and 2 wereeach 2 weeks in duration. Patients who completedphase 2 or who discontinued from the study dueto uncontrolled hypertension (>95th percentile)were given the option of continuing in a 52-week,open-label extension phase that assessed long-termsafety.

Valsartan DosingDuring phase 1, children were treated with valsartan10 mg (low dose), 40 mg (medium dose), or 80 mg(high dose) if their body weight was <35 kg at base-line, whereas children weighing �35 kg were treatedwith valsartan 20 mg (low dose), 80 mg (mediumdose), or 160 mg (high dose). During the 52-weekopen-label extension, all patients initially received val-sartan 40 mg daily. For those whose mean troughSSBP remained �95th percentile, the valsartan dosewas increased in a stepwise fashion from 40 mg to 80mg to 160 mg at 2-week intervals. Hydrochlorothia-zide 12.5 mg daily was added if BP remained �95thpercentile following 2 weeks’ treatment with valsartan160 mg.

FIGURE 1. Study design: a placebo-controlled washout preceded a 2-week, randomized, dose-ranging phase (phase 1), followed by a 2-week,randomized, placebo-controlled, withdrawal phase (phase 2). Patients were then permitted to roll over into a 52-week, open-label extension phaseto assess long-term valsartan safety. Valsartan dosing began at 40 mg ⁄ d and could be increased every 2 weeks incrementally to 160 mg ⁄ d. Hydro-chlorothiazide 12.5 mg daily could be added if the blood pressure (BP) remained �95th percentile with the highest dose of valsartan (160 mg ⁄ d).

358 The Journal of Clinical Hypertension Vol 13 | No 5 | May 2011 Official Journal of the American Society of Hypertension, Inc.

Effectiveness and Safety of Valsartan in Hypertensive Children | Wells et al.

Assessments and Outcome MeasurementsThree individual measurements of BP were taken inthe sitting position according to accepted standards ateach study visit.7 The mean of the 3 measurementswas used for analysis. All measurements were made attrough, 24 hours after the previous dose of valsartanor placebo. Mean SSBP and mean sitting diastolic BP(SDBP) were the primary and secondary outcome mea-sures, respectively. In both phases 1 and 2, a responderwas defined as a patient achieving an SSBP <95th per-centile for age, sex, and height, a cut-off derived fromthe definition of hypertension in the Fourth Report ofthe National High Blood Pressure Education ProgramWorking Group on High Blood Pressure in Childrenand Adolescents7 (average SBP or DBP �95th percen-tile for sex, age, and height on at least 3 occasions).Each patient was provided with an oscillometric moni-toring device to measure their home BP. Home BPmeasurements were used for monitoring safety only,these measurements were not used in the analysis.

The entire study lasted a total of 56 weeks. Patientswere seen 6 times during the double-blind phase andhad an additional 6 visits during the open-label por-tion of the study. Safety assessments were performedat each visit, including vital signs, physical examina-tions, developmental assessments, laboratory tests,pregnancy testing, and electrocardiography (ECG).Developmental evaluation included a neurocognitiveevaluation covering attention, processing speed, work-ing memory, cognitive flexibility, memory, and motorspeed. Standard laboratory evaluations were per-formed at a central location. ECG results were inter-preted by the investigators for diagnostic purposes andcentrally for data analysis. Adverse events (AEs) werereported according to their duration, severity, possiblerelationship to the study drug, and outcome.

Ethics ReviewThis study was conducted according to Good ClinicalPractice standards established by the InternationalConference on Harmonization. The study protocoland informed consent were reviewed by the institu-tional review board or ethics committee at each site.Informed consent and, where applicable, assent wereobtained from all participants and their parents orlegal guardians according to local standards.

Statistical MethodsFor phase 1, the slope of the dose-response curve forthe change from baseline in mean SSBP was analyzedusing an analysis of covariance (ANCOVA) model,with region strata, race strata, and weight strata asfactors, and centered baseline SSBP and dose ratio ascovariates. All pair-wise comparisons for the changesfrom baseline were made based on ANCOVA models,with treatment, region strata, race strata, and weightstrata as factors, and centered baseline SSBP as the co-variate. For phase 2, the change from end of phase 1in mean SSBP was analyzed using an ANCOVA model

with treatment (pooled valsartan group and pooledplacebo group), region strata, race strata, and weightstrata as factors, and centered visit 4 SSBP as the co-variate. All pair-wise treatment comparisons by doselevel for the changes from end of phase 1 were madebased on ANCOVA models, with treatment (3 doselevels and 3 placebo groups), region strata, race strata,and weight strata as factors, and centered visit 4 SSBPas the covariate. Descriptive statistics were employedin the open-label phase. No other statistical analyseswere conducted.

Both intent-to-treat and per-protocol analyses wereconducted. Unless specifically stated, data presentedare from the intent-to-treat analysis. All statistical testswere conducted against a 2-sided alternative hypothe-sis unless otherwise stated. The level of significanceaccepted was .05 for all analyses.

RESULTS

Patient Characteristics and DemographicsDemographic characteristics for patients enrolled inthe study are shown in Table I. Baseline characteristicswere similar across the 3 groups. By design, childrenaged 6 to 11 and 12 to 16 years were equally repre-sented in the study population. Approximately onehalf (50.6%) of randomized patients were prepubertalor had immature secondary sexual characteristics(Tanner stage <3) and 49.4% were in more advancedstages of pubertal development (Tanner stage �3).Black patients made up 48.7% of the randomizedpatient population, and 46.0% of patients were Cau-casian. A diagnosis of diabetes was present in 8(3.1%) patients (3 Caucasian, 4 black, and 1 of‘‘other’’ race). Of those enrolled, 37.9% had at least 1abnormality that was renal or urinary in nature (mostcommonly nephrotic syndrome [5.0%], refluxnephropathy [6.1%], chronic renal failure [7.7%], andvesicoureteric reflux [5.7%]); 8.0% had a history ofrenal transplant; and 54% had a body mass index thatwas �95th percentile for sex and age. Overall, 151patients (57.9%) had been treated with at least 1 anti-hypertensive drug before being enrolled in the study.

Phase 1: Dose ResponseA total of 261 children and adolescents were random-ized in phase 1. Two patients did not take study medi-cation following randomization. Sixteen patients(6.1%) did not complete phase 1: 3 patients wereremoved from the study due to protocol violations, 4patients were dropped because of a perceived lack oftherapeutic effect, 4 patients withdrew consent, 2patients withdrew because of AEs, 2 patients weredropped due to administrative problems, and 1 patientwas lost to follow-up.

Patients in phase 1 of the study received daily dosesof valsartan ranging from 0.1 mg ⁄ kg to 4.6 mg ⁄ kg(10-160 mg absolute dose range). The mean weight-adjusted doses administered in the low-, medium-, and



high-dose groups were 0.4 mg ⁄ kg, 1.3 mg ⁄ kg, and2.7 mg ⁄ kg, respectively. As shown in Table II, admin-istration of valsartan resulted in significant reductionsfrom baseline in mean SSBP and SDBP at all 3 doses.Larger doses resulted in greater reductions in meanSSBP and SDBP (Figure 2). The changes from baselinein mean SSBP in phase 1 were )7.9 mm Hg, )9.6 mmHg, and )11.5 mm Hg for the low-, medium-, andhigh-dose groups, respectively. Corresponding changesin mean SDBP were )4.6 mm Hg, )5.8 mm Hg, and)7.4 mm Hg, respectively. Regression modeling of thedose-response curve revealed a slope estimate of)0.43 mm Hg per unit increase in dose ratio (doseratio=1:4:8 for low-, medium-, and high-dose valsar-tan, respectively).

Subgroup analyses (Figure 3) demonstrated that theeffect of valsartan was consistent across the followingimportant demographic subgroups: weight (<35,�35 kg), sex (male, female), age (6–11 years, 12–16 years), Tanner stage (<3, �3), race (black, non-black), and region (United States, non–United States).Slightly steeper slopes were observed for patientsweighing <35 kg, females, and black patients; how-ever, these were not statistically significant.

Phase 2: Placebo WithdrawalA total of 245 patients completed phase 1 and enteredphase 2. Thirteen patients (5.3%) were withdrawnfrom phase 2: two patients were removed due to

TABLE I. Baseline Patient Characteristics by Treatment (Low-, Medium- and High-Dose Valsartan [RandomizedPopulation]) in Children Aged 6 to 16 Years

Variable

Valsartan

Total (N=261)Low Dose (n=103) Medium Dose (n=53) High Dose (n=105)

Age, mean (SD), y 11.4 (2.69) 11.4 (2.97) 11.4 (3.01) 11.4 (2.87)

Age group, No. (%), y

6–11 50 (48.5) 27 (50.9) 54 (51.4) 131 (50.2)

12–16 53 (51.5) 26 (49.1) 51 (48.6) 130 (49.8)

Sex, No. (%)

Female 40 (38.8) 24 (45.3) 39 (37.1) 103 (39.5)

Male 63 (61.2) 29 (54.7) 66 (62.9) 158 (60.5)

Race strata, No., (%)

Black 48 (46.6) 27 (50.9) 52 (49.5) 127 (48.7)

Non-black 55 (53.4) 26 (49.1) 53 (50.5) 134 (51.3)

Region strata, No. (%)

United States 50 (48.5) 26 (49.1) 54 (51.4) 130 (49.8)

Latin America 27 (26.2) 15 (28.3) 28 (26.7) 70 (26.8)

Europe 26 (25.2) 12 (22.6) 23 (21.9) 61 (23.4)

Weight, mean (SD), kg 66.1 (33.80) 64.9 (33.26) 65.8 (35.92) 65.8 (34.43)

Weight group, No. (%), kg

<35 17 (16.5) 9 (17.0) 19 (18.1) 45 (17.2)

�35 86 (83.5) 44 (83.0) 86 (81.9) 216 (82.8)

Tanner stage,a No. (%)

<3 56 (54.4) 25 (47.2) 51 (48.6) 132 (50.6)

�3 47 (45.6) 28 (52.8) 54 (51.4) 129 (49.4)

Weight-adjusted dose, mean (SD), mg ⁄ kgb 0.4 (0.32) 1.3 (0.48) 2.7 (0.96) 1.5 (1.23)

Abbreviations: SD, standard deviation. aScale of the stages of pubertal maturation: one denotes prepuberty and 5 indicates presence of mature ⁄adult-like secondary sexual characteristics. bWeight-adjusted dose at baseline is calculated by individual dose ⁄ weight (mg ⁄ kg).

TABLE II. Changes From Baseline to End of Phase 1in MSSBP and MSDBP According to ValsartanTreatment Group in Children Aged 6 to 16 Years

Variable

Valsartan

Low Dose

(n=102)

Medium Dose

(n=52)

High Dose

(n=105)

Blood pressure, mean (SD), mm Hg

Baseline

MSSBP 131.4 (10.54) 133.3 (9.91) 133.2 (9.70)

MSDBP 77.0 (13.04) 77.2 (9.31) 78.4 (11.25)

End of phase 1

MSSBP 123.4 (11.43) 123.7 (11.92) 121.7 (12.53)

MSDBP 72.4 (12.05) 71.4 (10.52) 71.0 (9.79)

Change from baseline to end of phase 1

Mean (SD), mm Hg

MSSBP )7.9 (10.41) )9.6 (9.12) )11.5 (11.16)

MSDBP )4.6 (10.98) )5.8 (8.87) )7.4 (9.51)

95% CIa

MSSBP )9.98 to )5.89 )12.16 to )7.08 )13.66 to )9.34

MSDBP )6.75 to )2.44 )8.26 to )3.33 )9.19 to )5.51

P valuea

MSSBP <.0001a <.0001a <.0001a

MSDBP .0001a <.0001a <.0001a

Abbreviations: CI, confidence interval; MSDBP, mean sitting diastolicblood pressure; MSSBP, mean sitting systolic blood pressure; SD,standard deviation. aP values and 95% CIs are based on the paired ttest of the null hypothesis of no change from baseline within eachtreatment group. aStatistical significance at the .05 level.



protocol violations, 8 patients were dropped from thestudy because of a perceived lack of therapeutic effect,1 patient withdrew consent, and 2 patients withdrewbecause of AEs.

Figure 4 depicts the changes in SSBP and SDBP fromthe end of phase 1 to the end of phase 2. At the endof phase 1, mean SSBP and SDBP were similar in thepooled valsartan and pooled placebo groups. At theend of phase 2, mean SSBP and SDBP in the pooledvalsartan group increased by 1.2 mm Hg and0.5 mm Hg, respectively, while in the pooled placebogroup, corresponding increases were 3.9 mm Hg and3.5 mm Hg, respectively. Both changes were highlysignificant (Table III). Significant differences wereobserved in both the intent-to-treat and the per-proto-col analyses.

Additional between-group comparisons were per-formed in patients who were re-randomized to con-tinue receiving low-, medium-, or high-dose valsartanand those who were re-randomized to receive placebo.These between-group comparisons, based on meanchanges in SSBP from the end of phase 1 to the end ofphase 2, showed a statistically significant differencebetween the high-dose valsartan group and placebo infavor of treatment with valsartan (least-squares meandifference=)5.4 mm Hg; P=.0034). There was anumeric difference (least-squares mean differ-ence=)3.5 mm Hg) between medium-dose valsartanand placebo, although this was not statistically signifi-cant. No difference was observed between the low-dose valsartan and placebo groups. Similar relation-ships were observed for mean SDBP. The subgroups(female patients, black patients, and non–US patients)with a greater BP reduction during phase 1, tended tohave a more significant rebound after withdrawal toplacebo in phase 2.

Safety ResultsThe mean and median durations of exposure to valsar-tan were both 14 days during each of the double-blind

phases. Corresponding values for the open-label phasewere 315 and 365 days, respectively. Headache wasthe most commonly observed AE, which was reportedin 11.6% of patients during phase 1, 9.8% of patientsduring phase 2, and 33.2% of patients during theopen-label phase. Headaches did not appear to bedose-dependent. All other AEs were reported in <5%of the study population during phases 1 and 2. Dizzi-ness was reported in 7 patients during phase 1, five ofwhom were randomized to the high-dose valsartangroup. Five patients reported dizziness during phase 2,one of whom was assigned to the placebo group.Orthostatic hypotension was reported by 1 patient inthe high-dose valsartan group during phase 1, and by1 valsartan-treated and 1 placebo-treated patient dur-ing phase 2. Diabetes was reported by 1 Caucasianfemale patient in the low-dose valsartan group duringphase 2. Insulin was used to manage the conditionuntil the patient was withdrawn from the study due toswelling of the left hand during open-label valsartantreatment (discontinuation was not related to diabe-tes). In general, during the double-blind phase, theincidence of AEs in patients treated with valsartancontinuously for 4 weeks (Val ⁄ Val) was similar to thatobserved in patients treated with valsartan for 2 weeksfollowed by placebo for 2 weeks (Val ⁄ Pbo). Asexpected, the reported frequency of all AEs during theopen-label phase was considerably higher than that inthe double-blind phase. During the open-label phase,the most frequent AEs were nasopharyngitis, pyrexia,cough, upper respiratory tract infection, and headache.Diabetes was reported in 1 black female patient duringopen-label treatment. Metformin was initiated to man-age the condition and was continued for the remainderof the study. There were no unanticipated changes inthe neurocognitive evaluations conducted at baselineand at the end of the open-label phase. There were noAEs on growth or annual weight gain.

One patient experienced a serious AE (SAE; acutegastroenteritis), which was judged to be unrelated tovalsartan, during the double-blind phase of the study.During the 52-week, open-label phase, 18 patients(7.7%) experienced a total of 34 SAEs. Of these, only2 were considered to be drug-related: 1 case of gastro-enteritis (valsartan 40 mg) and 1 case of hyperkalemia(valsartan 80 mg). Diarrhea, pyrexia, and gastroenteri-tis were the only SAEs reported by more than 1patient (2 occurrences each). Increased serum creati-nine and hyperkalemia were observed in 1 patienteach. Both patients were renal transplant recipientsand neither case was judged to be related to valsartan.In the patient with hyperkalemia, serum potassiumreturned to normal within 2 days after valsartan wasdiscontinued.

No deaths occurred during the study. A total of 4patients withdrew from the study due to AEs duringphases 1 and 2. During the open-label phase, 7patients (3.6%) withdrew from the study following anAE.

FIGURE 2. Mean changes in trough sitting systolic blood pressure(SSBP) and sitting diastolic blood pressure (SDBP) in children (aged 6–16 years) randomized to receive 1 of 3 dose levels of valsartan (phase1) for 2 weeks (low dose=10 ⁄ 20 mg; medium dose=40 ⁄ 80 mg; highdose=80 ⁄ 160 mg). The size of the circles is proportional to the numberof patients in each group.



There were no significant changes in the mean val-ues of any of the laboratory assessments between base-line and the end of the study. Liver enzymes, totalcholesterol, triglycerides, and glucose levels were unaf-fected by treatment with valsartan. Similarly, therewere no significant changes in the levels of hemoglobinand hematocrit.

Twenty-two patients (10%) had elevated creatinineconcentrations and 9 patients (4%) had elevated

potassium concentrations at some point during thestudy. Mean serum creatinine increased from62.7 mmol ⁄ L to 69.0 mmol ⁄ L in the study population.Mean serum potassium was essentially unchangedfrom baseline (4.18 mmol ⁄ L) to the end of the study(4.19 mmol ⁄ L). The frequency of AEs experienced byVal ⁄ Val patients during the double-blind phases of thestudy were compared with Val ⁄ Pbo patients. Patientsexperiencing an increase of >50% in serum creatinine

FIGURE 3. (A) Plot of the slope analysis for the change in mean sitting systolic blood pressure (SSBP) from baseline to the end of phase 1according to subgroup (intent-to-treat population). Estimates of the slope with 95% confidential intervals (CIs) are shown. (B) Plot of between-groupdifference in the mean change in SSBP (mm Hg) from the end of phase 1 to the end of phase 2 for patients treated with valsartan. Data arepresented according to subgroup. Estimates of the mean change difference with 95% CI are shown. The size of the circles is proportional to thenumber of patients in each group.



were more frequent in the Val ⁄ Pbo-treated groups atall 3 doses. In contrast, patients who experienced anincrease in serum potassium of >20% were observedmore frequently in the medium- and high-dose Val ⁄ Valgroups. Finally, uric acid was noted to increase bymore than 50% more frequently in the Val ⁄ Valgroups.

DISCUSSIONThe FDA Modernization Act, enacted in 1997, hasresulted in a significant increase in pediatric trials ofhypertensive medications in recent years. As a result,many commonly prescribed antihypertensive medica-tions, such as ACE inhibitors, ARBs, and calciumchannel blockers, have been evaluated in hypertensivechildren aged 6 to 16 years in well-controlled, pro-spective, multicenter studies.11,12,17,19,20 The resultsfrom most of these studies have demonstrated thatthese agents were effective in lowering BP and werewell tolerated in children. The safety profiles observedin children were not different from those observed inadult patients. Results from the current study demon-strated that a dose-dependent SSBP reduction wasobserved with valsartan in hypertensive children aged6 to 16 years. The efficacy of valsartan in reducing BPwas further confirmed in a randomized 2-week, pla-cebo-withdrawal period. The antihypertensive effect ofvalsartan was not influenced by the demographicmake-up of the patient population. Valsartan was welltolerated, and no unexpected AEs were reported dur-ing the study.

The mean daily dose of valsartan administered topatients in phases 1 and 2 of the study ranged from0.4 mg ⁄ kg to 2.7 mg ⁄ kg. Valsartan was shown toreduce SSBP and SDBP in a dose-dependent fashion inchildren aged 6 to 16 years. The reduction in BPappeared to be maximal within 2 weeks after startingtherapy. No further reduction in mean SSBP or SDBPwas observed in patients who continued on valsartanduring phase 2. Randomized withdrawal to activedrug or placebo confirmed the antihypertensive effec-tiveness of valsartan, especially in the medium- andhigh-dose groups.

It has been reported that black patients with hyper-tension respond poorly to certain classes of antihyper-tensive medications.21 To assess the impact ofdemographic make-up of the patient population on theefficacy and safety of valsartan in hypertensive chil-dren, an adequate number of patients from predefinedsubgroups were enrolled, including school children(50% older than 12 years), black children (46.8%),female patients (39.5%), and children from the UnitedStates and outside the United States (50% each).Approximately one half (54%) of the children wereobese (body mass index �95th percentile for sex andage), a finding not surprising considering the acceptedrelationship between obesity and hypertension. (Previ-ous reports have demonstrated hypertension preva-lence of up to 30% in obese adolescents.22) Subgroupanalyses revealed few differences between groups. Themagnitude of the response to valsartan increased withdose in all subgroups. Weight group, race, sex, andmaturation did not appear to influence response tovalsartan. There were no differences in response basedon age group (6–11 years vs 12–16 years) in phase 1.However, the younger children appeared to havelower placebo-corrected SDBP (but not SSBP) than the

FIGURE 4. Changes in sitting systolic blood pressure (SSBP) and sit-ting diastolic blood pressure (SDBP) from the end of phase 1 to theend of phase 2.

TABLE III. Changes From End of Phase 1 to End ofPhase 2 in MSSBP and MSDBP

Variable

Valsartan

(n=123)

Placebo

(n=122)

BP, mean (SD), mm Hg

End of phase 1 ⁄ visit 4

MSSBP 122.2 (12.07) 122.2 (11.51)

MSDBP 70.7 (11.26) 71.8 (10.04)

End of phase 2

MSSBP 123.3 (13.05) 126.1 (12.09)

MSDBP 71.2 (11.30) 75.3 (10.83)

Change in BP from end of phase 1 to end of phase 2, mean (SD),

mm Hg

MSSBP 1.2 (9.42) 3.9 (9.66)

MSDBP 0.5 (8.47) 3.5 (9.37)

95% CIa

MSSBP )0.52 to 2.84 2.15 to 5.61

MSDBP )1.05 to 1.98 1.87 to 5.23

P valuea

MSSBP .1758 <.0001a

MSDBP .5451 .0001a

P valueb

MSSBP .0368a

MSDBP .0047a

Abbreviations: BP, blood pressure; CI, confidence interval; MSDBP,mean sitting diastolic blood pressure; MSSBP, mean sitting systolicblood pressure; SD, standard deviation. aWithin-treatment P valuesand 95% CIs are based on the paired t test of the null hypothesis ofno change from end of phase 1 within each treatment group.bBetween-treatment P values are from the analysis of covariancemodel with treatment, region strata, weight strata, and race strataas factors, and centered visit 4 systolic blood pressure as acovariate. aStatistical significance at the .05 level.



older patients. This observation might be explained bythe greater likelihood that hypertension is caused byrenal diseases in younger children.23,24 Renal diseasesare a common cause of resistant hypertension inadults.25,26 Less is known about the impact of renaldisease on hypertension treatment in children; how-ever, in the recent multicenter observational ChronicKidney Disease in Children study,27 antihypertensivetreatment failed to control hypertension in nearly half(48.5%) of children (mean age, 11 years) with hyper-tension and chronic kidney disease.

Plasma renin and A-II activities were not measuredin this study. No assertions can be made regardingcorrelation of response to baseline activity of theRAAS. Since there were relatively few patients in thesubgroups, caution is indicated when generalizingfrom these results.

Although direct comparisons cannot be made, theresponse observed in children is comparable with thatseen in the adult population.28–30 Valsartan treatmentin adults resulted in a dose-dependent reduction inboth SSBP and SDBP when compared with placeboover a dose range of 10 mg to 320 mg.31 In this study,the valsartan 20-mg dose was not different from pla-cebo. The magnitude of response was similar to thatseen after 4 weeks of therapy using comparable dosesin adults.28 AEs in adults were similar to thoseobserved in children. Dizziness was significantly morecommon in adult patients who received 320 mg of val-sartan than in those who received lower doses (9.3%vs 2.1%–3.4% at doses of 20–160 mg).29

BP reductions were also comparable with those seenin children aged 6 to 16 years treated with losartan.19

Comparable reductions in mean SSBP and SDBP wereobserved in adults treated with either valsartan (80–160 mg) or losartan (50–100 mg) for up to 8 weeks.32

Overall, valsartan was well tolerated. Short-termdata from phase 2 suggests that the AEs observed invalsartan-treated patients are similar to those observedwith placebo, although the number of patients studiedwas relatively small and AEs in the placebo groupmight still be attributable to valsartan during the firstfew days of phase 2. Headaches were observed in>5% of patients. Headaches are a relatively commoncomplaint in children with and without hypertension.It is difficult to know whether the headaches observedin the patients in this study were due to valsartan orother causes. Dose-related dizziness seen in adults29

was also observed in a small number of children.New-onset diabetes was uncommon in this study, andno patient discontinued the study prematurely as aresult of diabetes development. Other AEs were rela-tively uncommon, generally mild to moderate in sever-ity, and rarely resulted in discontinuation of therapy.AEs that occur with a very low frequency may nothave been detected in this study.

Only two AEs were both serious and deemed to berelated to therapy. Of these AEs, hyperkalemiahas been described in the adult population and is a

predictable effect of A-II receptor blockade. In patientswith renal or renovascular disease, serum potassiumlevels should be monitored, especially in patients whoare concurrently treated with ACE inhibitors or potas-sium-sparing diuretics.

CONCLUSIONSValsartan appeared to provide dose-dependent reduc-tions in SSBP and SDBP in children with hypertensionover a dose range of 0.1 mg ⁄ kg to 4.6 mg ⁄ kg (10 mg–160 mg). Doses >160 mg or 4.6 mg ⁄ kg were nottested. Overall, valsartan was safe and well tolerated.Headaches and dose-dependent dizziness may occur.Renal function and serum potassium should be moni-tored in at-risk patients. Based on data from phases 1and 2 of the study, an initial once-daily dose of valsar-tan 40 mg is recommended for children aged 6 to16 years. Doses <0.4 mg ⁄ kg may not be effective. IfBP response is inadequate, the valsartan dose may betitrated to a maximum of 160 mg (maximum weight-adjusted dose up to 4.6 mg ⁄ kg for children <35 kg).An extemporaneously formulated solution can beprepared for children who are unable to swallow com-mercially available tablets.17 Valsartan should be con-sidered when use of an ARB is clinically appropriate.

Acknowledgments and disclosures: The authors acknowledge all investiga-tors and study coordinators at the participating centers and all patients fortheir commitment to the study, which was sponsored by Novartis Pharma-ceuticals Corporation. Editorial assistance was provided on the final draft ofthis manuscript by a professional medical writer, Joanne Bentley (ACUMED,Tytherington, UK); this support was funded by Novartis PharmaceuticalsCorporation. Thomas Wells, Jeffrey Blumer, Kevin E.C. Meyers, Jose Pach-eco Ribeiro Neto, Rejane Meneses, and Mieczysław Litwin have no conflictsof interest to disclose and all have participated or are participating in othertrials sponsored by Novartis. Johan Vande Walle has acted as a consultantfor Novartis and has participated in other trials sponsored by Novartis.Guangyang Han, Susan Solar-Yohay, and Victor Shi are employees ofNovartis Pharmaceuticals Corporation.

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Supporting Information

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Appendix. Valsartan Pediatric Hypertension StudyGroup principal Investigators.

Please note: Wiley-Blackwell are not responsible forthe content or functionality of any supporting materi-als supplied by the authors. Any queries (other thanmissing material) should be directed to the correspond-ing author for the article.



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Effectiveness and Safety of Valsartan in Children Aged 6 to 16 Years With Hypertension