REVIEW

Niger J Paed 2015; 42 (3):180 –187

Nwaiwu O

Olayemi SO

Amao O

Use of angiotensin II receptor

blockers in children- a review of

evidence

DOI:http://dx.doi.org/10.4314/njp.v42i3.2

Accepted: 19th May 2015

in English language .

Abstract: Background: The inci-

dence of hypertension in the pedi-

atric population has been increas-

ing. Childhood blood pressure is

predictive of adult BP. The renin

angiotensin aldosterone system

pathway is important in the me-

diation of pediatric hypertension.

Results: A total of 120 publica-

tions were accessed from which

68 references were included in

the review. The design and out-

come of ten key randomised trials

are summarised. Randomised trials

have demonstrated the efficacy of

angiotensin receptor blockers in

the pediatric population aged 1–16

years. This class of drugs reduce

blood pressures in pediatric pa-

tients with hypertension and pro-

teinuria in renal disease. Safety

pharmacokinetic, dosage, and

palatability of adult formulations

for the paediatric age group are

highlighted

Conclusion: Angiotensin receptor

antagonists are useful effective

and safe alternatives to available

antihypertensive therapy in paedi-

atric population. Angiotensin re-

ceptor antagonists should however

be prescribed cautiously for sexu-

ally active adolescent females due

to concern about angiotensin

(

)

Nwaiwu O

Amao O

Department of Pharmacology,

Therapeutics & Toxicology, College of

Medicine , University of Lagos,

Nigeria.

Email: obiyo_nwaiwu@yahoo.com

New therapies approved

for

Olayemi SO

adults are often used off label

in children with little or no

efficacy and safety data in the

paediatric population The angio-

tensin receptor blockers has been

shown to be effective and safe in

the treatment of pediatric hyper-

tension.

Objective: The objective of this

review is to highlight available

clinical evidence on the efficacy,

safety tolerability and kinetics of

angiotensin receptor blockers in

childhood hypertension and its

antiproteinuric effect in renal

disease.

Method: The search strategy was

based on Pubmed, Medline data-

base, Cochrane Library, manual,

Google and Yahoo searches. We

summarized ten randomized con-

trolled trials (RCTs .The search

was done in June 2014 and up-

dated in January and May 2015

Department of Medicine,

Lagos University Teaching Hospital,

Idi-Araba, Lagos Nigeria

receptor blocker fetopathy.

Keywords: Angiotensin receptor

blockers, childhood hypertension,

drug safety, drug efficacy, pharma-

cokinetics and renal diseases.

5

Introduction

level of blood pressure into adulthood .

Hypertension is a common disease in adults, with a

prevalence which increases with age, ranging from 15%

in young adults to 60% in persons over the age of 65

Normal blood pressure values, definition of hyperten-

sion

1

years . Persistent hypertension in children is predomi-

In the criteria of the Fourth Report on the Diagnosis,

Evaluation, and Treatment of High Blood Pressure in

Children and Adolescents, normal BP in children is de-

fined as systolic blood pressure (SBP) and diastolic

blood pressure (DBP) less than 90th percentile for age,

sex and height, whereas hypertension is defined as SBP

and/or DBP persistently 95th percentile or more, meas-

ured on at leas₂t three separate occasions with the auscul-

tatory method .

nantly secondary and norms for blood pressure in chil-

dren and adolescents, definitions of hypertension ,

guidelines for the diagnosis and treatment of hyperten-

sion have been published for children aged 2 to 18

2

years .

Globally the₃prevalence of hypertension in children is on

the increase and varies between studies a study in

South East Nigeria reported the prevalence of hyperten-

sion in adolescents to be 4% with male and female

4

prevalence rates of 3.8% and 6.9% respectively . Chil-

The fourth report also provides criteria for staging the

severity of hypertension in children and adolescents, and

dren with elevated blood pressure tend to maintain that

1

81

this is useful c₂linically to guide evaluation and man-

agement(Table1)

drug labeling and includes where a total lack of infor-

mation in the label about pediatric use of the drug and

the use₁₄o_-₁f₇ a non-approved dose in relation to age or

Table 1: Definition and classification of hypertension in chil-

dren and adolescents

weight.

Concerns has been expressed by different

authors about the interpretation of safety data by the

18,19

pharmaceutical industry in relation to new products.

Class

SBP and/or DBP Percentile

th

Normal

High-normal

<90

This is because many physiologic differences between

children and adults may result in age-related changes in

p₂₀h_,₂a₁rmacokinetics and pharmacodynamics of drugs.

Therefore adjusting from adult dosages does not

always give correct doses for children .

Reports have highlighted safety concerns regarding

the use of angiotensin II receptor blockers in preschool

children. Although considered to be unrelated to the

investigational drug these reports highlighted the deaths

of three preschool children out of the 183 children with

hypertension who₂r₂eceived valsartan or candesartan in

two clinical trials.

th

> 90 to < 95

120/80 even if below 90 percentile in

adolescents

th

>

th

Stage1 hypertension 95 percentile to the 99 percentile plus

5

mmHg

th

Stage2 hypertension > 99 percentile plus 5mmHg

Modified fr₂om task force on high blood pressure in children &

adolescents .

The renin-angiotensin-aldosterone system (RAAS)

The primary objective of this review was to highlight

available clinical evidence on the efficacy, safety toler-

ability and kinetics of angiotensin receptor blockers in

childhood hypertension and its antiproteinuric effect

in renal disease .

The renin-angiotensin-aldosterone system (RAAS)

plays an important role in the pathogenesis of hyperten-

sion in patients of all ages. Angiotensin II, the principal

pressor agent of RAAS mediates the effects of an

over-active renin-angiotension system such as vaso-

constriction and retention of sodium and water which

6,7

leads to hypertension . Plasma concentrations of an-

giotensin II and aldosterone are largely determined by

8

Methods

the level of plasma rennin activity . Renin is secreted

by the juxtaglomerular apparatus in response to vari-

ous stimuli such as a decrease in arterial blood pressure

as detected by barareceptors a decrease in sodium lev-

els in the ultrfiltrate of the nephron, and lastly sympa-

thetic nervous system activity, which also controls

The search strategy was based on Pubmed, Medline da-

tabase, Cochrane Library, manual, Google and Ya-

hoo searches. The search was done in English language

in June 2014 and updated in January and may 2015.

There was no limitation to the year of publication.

Search was based on the following keywords : angio-

tensin receptor blockers, childhood hypertension, drug

safety, drug efficacy kinetics, tolerability, renal diseases.

randomised clinical trials in pediatric patients with hy-

pertension, and safety of antihypertensive drugs in

pregnancy .

blood p₉ressure, acting through the beta adrenergic re-

1

ceptors.

The angiotensin receptors are a class of G protein

10

coupled receptors with angiotensin II as their ligand .

The receptors are responsible for the signal transdu₁c₁tion

of the vasoconstricting effect of angiotensin II.

Angiotensin II is a very important mediator of pro-

gressive renal failure. It is responsible for proteinuria

which results from glomerular hyperfiltration due to

increased intraglomerular pressure and

structural

Results

changes to the glomeruli caused by proinflamatory

mediators, fibroblast pr₁o₂liferation and production of

superoxide free radicals.

A total of 120 publications were accessed from

which 68 references were included in the review .

Ten key randomised trials are summarised and pre-

sented in table 2. Randomised trials have demon-

strated the efficacy of angiotensin receptor blockers in

the pediatric population aged 1–16 years. This class of

drugs reduce blood pressures in pediatric patients with

hypertension and proteinuria in renal disease. Safety

pharmacokinetic, dosage, issues of paediatric formu-

lations and palatability for the child have been high-

lighted

Angiotensin II antagonists exerts their blood pres-

sure lowering effects by directly and selectively

blocking the activity of angiotensin II on the AT

1

receptor.Angiotensin-II antagonists have been shown to

be both well tolerated and effec₁₀tive in lowering blood

pressure in adult clinical trials.

Justification for this review

New medicines can result in significant improvements

13

in reducing morbidity and mortality . Drugs approved

for adults are often used in children because lim-

ited pediatric clinical trials, has led to limited or no pedi-

atric documentation with respect to many drugs ap-

proved for adults . This off label use of drugs in chil-

dren often implies that the dose, dosing frequency, or

the age/weight of the patient is not in agreement with

1

82

Table 2: Study design and treatment outcome of studies conducted with arbs in children

Study

Deisign

Outcome /Conclusion

4

0

Lubrano,R et al.

A randomized study of 10 children (mean

age: 12.3 _ 4.06 years) with proteinuria

resulting from chronic renal diseases of

various causes.

In the short term, the combination of

angiotensin-converting enzyme in-

hibitors and angiotensin II type 1

receptor antagonists for children with

proteinuria of renal origin reduced

proteinuria significantly

From the perspective of the neph-

ropathic child, the taste of pulverized

candesartan cilexetil is superior to

that of irbesartan,losartan, telmisartan

or valsartan

In children _6 years of age, valsartan

effectively lowered SBP and diastolic

blood pressure compared with pla-

cebo. Valsartan treatment had no

demonstrable negative effects on

growth and development

Pediatrics 2006;118;e833;

6

3

Meier, CM et al.

BrJClinPharmacol. 2007 ; 63(5): 628–

31.

Taste and smell acceptability of five angio-

tensin II receptor blockers were compared

among 21 nephropathic children using a

visual analogue scale palatability score.

6

5

2

Flynn, JTet al.

This was a multicenter double-blind, ran-

domized, multicenter study

performed at 36 centers

Hypertension.

2

.

008;52:222-228

.

35

Hazan, L et al.

Hypertension.

A randomized, multicenter, double-blind,

parallel-group,

Olmesartan medoxomil was safe and

efficacious in children with hyperten-

2

010;55:1323-1330.

prospective dose-ranging study in patients 6 sion, resulting in significant blood

to 16 years of age with primary or secon-

dary hypertension

12-week, double-blind, multinational study

pressure reductions.

3

9

Webb NJ et al.

Clin J Am Soc

Nephro l2010. 5: 417–424,

Losartan significantly lowered pro-

teinuria and was well tolerated after

12 weeks in children aged 1 to 17

years with proteinuria with or without

hypertension.

Valsartan appeared to provide dose-

dependent reductions in SSBP and

SDBP in children with hypertension

3

1

Wells, T. et al.

J Clinhypertens2011 ;13(5):357-65.

Children aged 6 to 16 years old with a

mean sitting systolic BP (SSBP) _95th

percentile for age, sex, and height with

documented hypertension were studied in a over a dose range of 0.1 mg⁄ kg to 4.6

prospective 4-week,double-blind, random-

ized,multicenter study

A 12-week, randomized, double-blind,

parallel-group, active-controlled study

mg⁄ kg (10 mg–160 mg).

3

Schaefer et al

J Hypertens 29:000–000 2011

Valsartan and enalapril provided

comparable BP reductions and effec-

tive BP control and were well toler-

ated in hypertensive children aged 6–

1

7 years.

5

Wells TG et al

Paediatr Drugs

2

An open-label, multicenter, single-dose

study was conducted in children and ado-

lescents aged 12 months-16 years with

hypertension

Olmesartan medoxomil was well

tolerated and demonstrated a pharma-

cokinetic profile in pediatric patients

similar to that of adults when adjusted

for body size

inadvertent exposure to ACE inhibi-

tors/ARBs in the first trimester of

pregnancy may not present significant

risks for malformations in live births

but may be associated with higher

rates of spontaneous abortion.

In a dose dependent manner.

Valsartan demonstrated significant

reductions in BP compared with base-

line and provided consistent reduc-

tions over26 weeks.

012 1;14(6):401-9.

4

Moretti, ME. et al

Obstetrics and Gynecology International cohort

a prospective, observational, controlled

Volume 2012,

study.

3

4

Schaefera, F et al

J Hypertens2013 31:993–1000

I A multicenter, randomized, double-

blind,parallel-group study, 75 patients with

a documented history of hypertension

sion and its antiproteinuric effect in renal disease .

Discussion

Efficacy

Currently, multiple antihypertensive agents are approved

2

3

for use in children . Data on the use of renin angio-

tensin system antagonists in the₄_-₂t₉reatment of child-

Two recent trials have demonstrated the efficacy of

angiotensin receptor blocker monotherapy in the pediat-

ric population aged 1–16 years. Once-daily oral prepara-

tions of valsartan achieve adequate blood pressure con

2

hood hypertension are available . This review high-

lights the efficacy, safety tolerability and kinetics of

angiotensin receptor blockers in childhood hyperten-

1

83

3

0

trol in the pediatric population . In children and adoles-

cents aged 6-16 years significant dose-dependent reduc-

tions from baseline in mean sitting systolic BP (msSBP)

were observed for recipients of valsartan following 2

offers better control of proteinuria and cardiovascular

parameters without causing adverse side effects. In the

short term, the combination of angiotensin-converting

enzyme inhibitors and angiotensin II type 1 receptor

antagonists for children with proteinuria of renal origin

reduced proteinuria significantly, compared with base-

line or either drug alone. Furthermore, echocardio-

graphic studies gave evidence of reduction of left ven-

tricular hypertrophy. Additional studies will evaluate

31

weeks' treatment . Compared to enalapril in hyperten-

sive children and adolescents aged 6-17 years, valsartan

was no less effective than enalapril in reducing BP. Fol-

lowing 12 weeks' treatment, the least square mean re-

duction from baseline in mean systolic blood pressure

in recipients of valsartan was non-inferior to that in re-

40

long-term results .

32,33

cipients of enalapril and was well tolerated

.

In a multicenter, randomized, double-blind, parallel-

group study, 75 patients with a documented history of

hypertension were randomized to receive valsartan

Safety and tolerability

There are very few da₄t₁a on the safety of antihypertensive

drugs in pregnancy . Generally the class of angio-

(

0.25, 1 or 4 mg/kg per day) for 6 weeks, then reran-

domized to receive placebo or valsartan for 2 weeks. At

tensin II receptor blockers (ARBs) has proved to be

better tolerate₄d₂_,₄t₃han other leading classes of antihyper-

Week 6, significant reductions in MSSBP (P<0.05) f₄rom

3

baseline were observed for all three valsartan doses .

tensive agents

.

The efficacy and safety of olmesartan medoxomil in

children with hypertension, defined as systolic blood

pressure measured at or above the 95th percentile (90th

percentile for patients with diabetes, glomerular kidney

disease, or family history of hypertension) for age, gen-

der, and height while off any antihypertensive medica-

tion current was investigated. Efficacy results showed

a dose-dependent, statistically significant reduction in

seated trough systolic and diastolic blood pressure. The

olmesartan medoxomil dose response remained statisti-

cally significant when adjusted for body weight. Olme-

sartan medoxomil was safe and efficacious in children

with hypertension, resulting in significant blood pres-

Exposure to angiotensin II receptor blockers during the

second part of pregnancy can lead to reduced fetal kid-

ney perfusion that may result in oligoamnios and neo-

natal renal insufficiency, and these are similar to ab-

normalities observed after exposure to angiotensin-

44

converting enzyme inhibitors , Intrauterine growth re-

striction, prematurity, patent ductus arteriosus, severe

neonatal hypotension, neonatal anuria, and neonatal or

fetal death have also been observed with these drugs .

Anuria associated with oligohydramnios may produce

fetal limb contractu₄r₅e_,₄s₆, craniofacial deformities,and pul-

monary hypoplasia

41,44,46-50

Although published cohort studies and series

.

35

sure reductions .

showed different malformation rates after first trimester

exposure to ACE inhibitors/ARBs, angiotensin II recep-

tor blockers should be avoided in pregnancy. However

if these agents are prescribed accidentally to a pregnant

Regardless of underlying aetiology, the presence of hy-

pertension is associated with cardiovascular morbidity

3

6

and progressive kidney injury . In the Chronic Kidney

Disease in Children study, 37% of children with chronic

kidney disease were diagnosed with elevated BP, and

yet 39% of₇ these were not receiving antihypertensive

2

woman, monitoring of amniotic fluid volume and beta -

microglobulin fetal blood levels after discontinuation of

the AT1 antagonist can provide critical data for advising

3

43

medication .

parents on pregnancy and fetal outcome . In a study

The use of Angiotensin II receptor blockers is largely

established in adult patients with kidney disease be-

cause, like converting enzyme inhibitors, they are more

effective than most other antihypertensive drugs in

slowi₈ng the progression towards end-stage kidney dis-

there were no differences in rates of major malforma-

tions. Both the ACE-ARBs and disease-matched groups

exhibited significantly lower birth weight and gesta-

tional ages than the healthy controls (P <0.001 for both

variables). There was a significantly higher rate of mis-

carriage noted in the ACE/ARB group (P <0.001).

These results suggest that ACE inhibitors/ARBs are not

major human teratogens; however, they may be associ-

3

ease .

A subgroup analysis of a 12-week, double-blind study

demonstrated that losartan significantly lowered protein-

uria versus placebo and amlodipine and was well toler-

ated in children (1-17 years old) with proteinuria secon-

dary to Alport syndrome. Losartan maintained proteinu-

ria reduction, and enalapril produced a further protein-

uria reduction over the 3-year study period. Both agents

45

ated with an increased risk for miscarriage .

A trial of angiotensin II receptor blockers (ARBs) was

performed in children 0-5 years of age. Three deaths

occurred in the 183 (1.6%) hypertensive children partici-

pating in the two trials. At least two of these deaths

occurred in children known to be susceptible to drugs

acting on the renin-angiotensin system, that is, children

with ongoing nephrotic syndrome and acute gastroen-

teritis. Clinicians who prescribe ARBs in preschool chil-

dren need to be aware of the risk of drug toxicity espe-

cially in children susceptible to intravascular dehydra-

tion. Clinicians should consider discontinuing the drugs

.

were generally well tolerated. ARAs can be considered

effective and safe in₉ lowering BP and proteinuria in the

3

pediatric age group .

A study enrolled 10 children (mean age: 12.3 _ 4.06

years) with proteinuria resulting from chronic renal dis-

eases of various causes and investigated whether the

combination of an angiotensin-converting enzyme in-

hibitor and an angiotensin II type 1 receptor antagonist

51

in the presence of acute diarrhoea .

1

84

The efficacy and safety of valsartan were studied in 90

children (mean age: 3.2 years; 60% male; 30% black)

with systolic blood pressure (SBP) _95th percentile.

Nineteen percent received valsartan in addition to previ-

ous antihypertensive therapy. Adverse events were mi-

nor and serious adverse events and drug-related adverse

events occurred infrequently .Valsartan treatment had no

demon₅s₂trable negative effects on growth and develop-

ment.

Doses 160 mg (4.7 mg/kg) have no₄t been tested in chil-

4

dren and may not be recommended .

In another study patients aged <6 years received an

oral suspension of olmesartan medoxomil at a dose of

0.3ꢀmg/kg of bodyweight (not to exceed 20ꢀmg), those

aged ≥6 years who weighed ≥35ꢀkg received olmesartan

medoxomil 40ꢀmg tablets, and those who weighed₅₅ <35ꢀ

kg received olmesartan medoxomil 20ꢀmg tablets.

The safety of valsartan were studied in 90 children

(

mean age: 3.2 years; 60% male;_t_h30% black) with sys-

Lack of paediatric formulations such as suspensions

or other age-appropriate drug formulations for drugs

originally designed for use in adults, is a major barrier

to the use of angiotensin antagonists in drug therapy

of hypertension in children and palatability of the

medication is crucial for adherence to prescribed drug

tolic blood pressure (SBP) ≥95 percentile. Adverse

events were minor and occurred at similar frequencies in

both the valsartan and placebo arms . All of the valsartan

doses evaluated in studies were well tolerated. The

majority of adverse events were mild or moderate and

transient in nature, the most frequent being cough, fever,

upper respiratory infection, and diarrhea and are simi-

lar to findings in other clinical trials of an₅₃t_,i₅h₄yperten-

sive medications conducted in older children

63

regimen . From the perspective of the child with kidney

disease, the taste of pulverized candesartan measured

by means of a visual analogue scale the palatability

score. Is significantly superior to that of pulverized irbe-

63

sartan, losartan, telmisartan or valsartan . Tablets are

crushed by parents and admi₆n₄i_,s₆₅tered mixed with

solid food or a palatable drink . An extemporane-

ously formulated solution of valsartan can be prepared

for children who₂ are unable to swallow commercially

Pharmacokinetics

An open-label, multicenter, single-dose study character-

ized the pharmacokinetics and short-term safety of

olmesartan medoxomil in children and adolescents aged

5

available tablets

1

2 months-16 years with hypertension. Olmesartan me-

doxomil was well tolerated and demonstrated a pharma-

cokinetic profile in pediatric patients similar to that of

Generally angiotensin receptor blockers can be used

66

as monotherapy or as fixed dose combinations . The

combination of a diuretic and an angiotensin receptor

blocker works well because diuretics induce reflex acti-

vation of the renin angiotensin system potentiating the

action of renin angiotensin system blockers. The combi-

nation of a renin angiotensin system blocker and a cal-

cium channel blocker (CCB) has also been widely used

in adu₆l₇t_,s₆₈and these agents also have complementary ac-

tions.

55

adults when adjusted for body size . Losartan unlike

valsartan , requi₅r₆es oxidative transformation to the ac-

tive compound . In children, plasma valsartan levels

peak at two hours after oral administratio₅n₇ and subse-

quently reduce in a biexponential manner. The plasma

half-life is about four hours in children under six years

of age. In children age₅d₇ 6–12 years, the plasma half-life

is about five hours.

Clearance is not significantly

affected by age after correcting for fat free body mass.

The rate of clearance is 0.076–0.098 L/hour/kg in chil-

dren aged 1–16 years. No significant dosage adjustment

i₅s₆_,₅n₇eeded in mild to moderate kidney or liver disease.

Conclusion

Angiotensin II receptor blockers selectively block the

angiotensin type I receptor. Given its effects on angio-

tensin blockade, angiotensin II receptor blockers re-

duce blood pressure in hypertension and proteinuria

in kidney disease. For these reasons, and good safety

and tolerability profile, angiotensin II receptor blockers

are an attractive drug for use in children with hyperten-

sion. However angiotensin receptor antagonists should

be prescribed cautiously for sexually active adolescent

females due to concern about angiotensin receptor

blocker fetopathy.

Dosage and palatability

Currently available data indicate that extrapolating adult

5

8

doses of the an₆₀giotensin antagonis₆t₁s, valsartan , irbesar-

59

tan , losartan and, candesartan is safe and effective

in treating children with arterial hypertension or protein-

uria.

A dose response study in children aged 6–16 years dem-

onstrated that valsartan was efficacious and well toler-

ated in doses rang₁in_,₅g₂ from 10 to 160mg

3

(

0.1–4.6 mg/kg) . The recommended dosage of val-

Conflict of interest: None

Funding: None

sartan for treating hypertension in the pediatric popula-

tion is 1.3–2.7 mg/kg, with a starting dose of 1.3 mg/

6

2

kg . This amounts to a starting dose of 40 mg in chil-

dren below 35 kg and 20 mg for children below 15 kg.

1

85

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