““Does the Benefit Does the Benefit Associated with Treating Associated with Treating Hypertension Apply to Hypertension Apply to

Children?"  Children?" 

““Does the Benefit Does the Benefit Associated with Treating Associated with Treating Hypertension Apply to Hypertension Apply to

Children?"  Children?"  Ronald Portman, MDRonald Portman, MD

Professor and DirectorProfessor and DirectorDivision of Pediatric Nephrology and Division of Pediatric Nephrology and

HypertensionHypertensionUniversity of Texas -HoustonUniversity of Texas -Houston

Past-Chair, International Pediatric Past-Chair, International Pediatric Hypertension Association Hypertension Association

Disease Prevalence in Childhood

• Congenital heart disease 1%• Epilepsy 3-5%• ADHD 3-5%• Asthma 7%• Hypertension 4-5%• Obesity 18-25%

Fourth Working Group Report 2004

• 2004: 4th Working Group Report•Measurement techniques and dilemmas•Norms continue to be based

epidemiologically by gender, age, height•New definition of HTN in concert with JNC

7•Presence of end organ damage presented•Evaluation guidelines including co-

morbidities•Most comprehensive therapeutic

guidelines to date

Classification of Hypertension in Children

and Adolescents

SBP or DBP Percentile

Normal <90th percentile

Prehypertension 90th percentile to <95th percentile, or if BP exceeds 120/80 even if below the 90th percentile up to <95th percentile

Stage 1 hypertension 95th percentile to the 99th percentile plus 5 mmHg

Stage 2 hypertension >99th percentile plus 5 mmHg

SBP (mmHg) DBP (mmHg)Age BP Percentile of Height Percentile of Height

(Year) Percentile 5th 10th 25th 50th 75th 90th 95th 5th 10th 25th 50th 75th 90th 95th

12 50th 102 103 104 105 107 108 109 61 61 61 62 63 64 64

90th 116 116 117 119 120 121 122 75 75 75 76 77 78 78

95th 119 120 121 123 124 125 126 79 79 79 80 81 82 82

99th 127 127 128 130 131 132 133 86 86 87 88 88 89 90

Blood Pressure Levels for Boys by Age and Height Percentile

EvaluationThe Four Questions

• Am I really hypertensive?– Repetitive measurements/ABPM

• What other modifiable risk factors for CVD do I have?– Diabetes, smoking,

hypercholesterolemia, proteinuria• What has hypertension done to my

body?– End organ damage

•No hard endpoints of death, MI or stroke;

•Evaluation of subtle subclinical changes

EvaluationThe Four Questions

• What is the cause of my hypertension?– Primary hypertension most prevalent

but secondary causes more common than in adults

– The younger the child and the more severe the hypertension; the more likely to be a secondary etiology

• Final issue: what do we do about all this?

Etiology of Secondary Hypertension in Pediatrics

• 78%renal parenchymal• 12% renovascular• 2% coarctation of the aorta• 0.5% pheochromocytoma• 7.5% others

Target-organ abnormalities are detectable in hypertensive children and adolescents.

• LVH reported (51 g/m2.7) in 34-38% of children with mild, untreated HTN with high correlation to BP and in particular ABPM

• Working Group Recommendations:– Echocardiographic assessment of LV mass

should be performed at diagnosis of HTN and periodically thereafter.

– The presence of LVH is an indication to initiate or intensify antihypertensive therapy.

• NO STUDIES HAVE BEEN DONE TO DEMONSTRATE REGRESSION WITH THERAPY AS YET (one completed and results pending)

CVD in Children

Death rate per 100,000

0

10

100

1000

10000

0-14 15-19 20-30

Age (years)

Adapted from Parekh et al, J Pediatr, 2002

Dialysis

Transplant

General Population

Black White

Prevalence of Hypertension/LVH in Children

with CKD

0

10

20

30

40

50

60

70

80

38

60

74

CRI Dialysis Transplant

%

Use

of

BP M

edic

ati

ons

LVH 22-31% 55-85% 30-75%

Hypertension and CKD Progression

• CrCl < 75ml/min/1.73m2

• HTN: >95th % (Task Force)• Normotensive: n=1987

(52%)• Hypertensive: n=1874

(48%)

• Endpoint:– ↓ CrCl by 10 ml/min/1.73m2

– Renal replacement therapy

Non-HypertensionHypertension

% P

RO

GR

ES

SIO

N T

O E

SR

D/C

R.C

L.

DR

OP

10

0

20

40

60

80

100

MONTHS

0 12 24 36

P<0.001

Mitsnefes et al, J Am Soc Nephrol 2003

NAPRTCS CRI Database:NAPRTCS CRI Database:

58%

49%

HTN-BMI

cIM

T

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

NMT / Nml Wt NMT / Overwt HTN / Nml Wt HTN / Overwt

34191023

p<0.01

p<0.05

Figure 1.

New HTN patients (n=53) and NTN controls (n=33)HTN defined as BP > 95th percentile,

and overweight BMI >25 kg/m2

ESCAPE TRIAL

– CKD patients n=352; Age 3-18 yo; European Multi-center Trail

– GFR 11-80 cc/min/1.73m2 – 6 months duration of study; ramipril 6 mg/m2;

no placebo– BP was reduced by 7.1 ± 8.0 mmHg in all

groups– Higher the initial BP and greater the

proteinuria; the greater the BP lowering effect– 87.3% of patients achieved normotension with

56% less than the 50th percentile– Proteinuria reduced in 50% of patients

•Wuehl et al. Kidney International 2004;66:768-776

Classification of Hypertension in Children

and Adolescents: Therapy Recommendations

Pharmacologic Therapy

Normal None

Prehypertension Do not initiate therapy unless there are compelling indications such as chronic kidney disease (CKD), diabetes mellitus, heart failure, left ventricular hypertrophy (LVH).

Stage 1 hypertension Initiate therapy based on indications

Stage 2 hypertension Initiate therapy

All patients to receive Therapeutic Life-style Changes (TLC)

Indications for Antihypertensive Drug Therapy in Children

with Stage 1 HTN

• Symptomatic hypertension• Secondary hypertension• Hypertensive target-organ damage• Diabetes (types 1 and 2), CKD, ?

obesity• Persistent hypertension despite

nonpharmacologic measures

Pharmacologic Therapy for Childhood Hypertension

• Pharmacologic therapy should be initiated with a single drug.

• The goal for antihypertensive treatment in children should be – reduction of BP to <95th percentile,

unless concurrent conditions are present: <90th percentile.

– resolution of end organ damage

Food and Drug Administration Modernization Act of 1997 (FDAMA)

• Prior to FDAMA– Almost all antihypertensives had been

used for treatment of HTN in children– No drugs had approved for children

with HTN– No doses established for safety nor

efficacy– No available dosage forms

Food and Drug Administration Modernization Act of 1997 (FDAMA)

• If drug has potential for use in children, written request issued

• Suggested study designs furnished and design reviewed by FDA before study begins

• Voluntary program with 6 months additional patent protection as ‘compensation’

• New pediatric rule would make these studies required for drug approval but FDA has discretion to get approval in adults first

• FDAMA is very successful program; • FDA very cooperative, interested, innovative,

advocate for children

Recent Pediatric Phase III or IV Antihypertensive Programs

1. AstraZenecaFelodipine (Plendil)*Metoprolol (Toprol-XL)# Candesartan (Atacand)

2. Bristol-Myers Squibb Fosinopril (Monopril)**Irbesartan (Avapro)#

3. Boehringer Ingelheim Telmisartan (Micardis)

4. CibaGenevaBenazepril (Lotensin)#

5. MerckEnalapril (Vasotec)*Lisinopril* (Prinivil/Zestril)Losartan (Cozaar)*

6. NovartisValsartan (Diovan)

7. Parke-DavisQuinapril (Accupril)#

8. PfizerAmlodipine (Norvasc)*Eplerenone (Inspra)

9. SankyoOlmesartan (Benicar)

10. Wyeth-Ayerst/KingBisoprolol-HCTZ (Ziac)*Altace (Ramipril)

11. ESCAPE Trial* GermanyRamipril in CKD, proteinuria and BP

*published

Meta-analysis in progress

# completed; not yet published

The Agency can require studies of antihypertensive drugs in children prior to approval for use in

adults. Should they do this?

• First question: are antihypertensive drugs used in children and their use warranted?

• Yes, but is there proof of efficacy beyond BP lowering? Not yet.

• Should they do this? No• Any new compound should be thoroughly

tested for safety and efficacy in adults first unless compelling indication

• However, pediatric studies must be done after adult approval

The Agency can also promote studies in children by granting additional exclusivity for

assessing the effects of antihypertensive drugs in children.

Should they do this?

• Yes• This program has yielded

tremendous knowledge about pediatric hypertension

FDAMA• Studies for exclusivity: safety and efficacy

– Initial dose ranging studies had low expectations

– Pharmacokinetic studies required for each drug

– New set of FDA written requests required an interpretable study (age 6-16 yrs) 40-60% African American

• Sub-studies for end organ damage, metabolic effects• Encouragement to obtain labeling • Compounding of pediatric dosage forms• Year long safety study• Beginning to examine effects on development

– Examining younger age groups (1-5 years old)– New study with end point other than BP

lowering

Is study of effects on blood pressure adequate?

• Not anymore

FDAMA: The Next Generation• Studies designed to determine optimum

dose or use; not just an ‘effective’ dose• Study to determine the most effective

drug for pediatric hypertension• Studies to determine EOD and disease

reversibility• Studies using other end points beside BP

lowering• Studies for long-term BP control• Studies of antihypertensive combinations

FDAMA: The Next Generation

• Examine specific therapies for most prevalent diseases such as obesity, CKD

• Commercially available preparations as no medicaid funding for drug compounding

• Begin to examine neonatal/infant hypertension

• PREVENTION

Does the benefit associated with treating hypertension in children Does the benefit associated with treating hypertension in children apply to adults?"apply to adults?"

The Child is Father to the Man