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“Does the Benefit Associated with Treating Hypertension Apply to Children?"  PowerPoint PPT Presentation


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“Does the Benefit Associated with Treating Hypertension Apply to Children?"  . Ronald Portman, MD Professor and Director Division of Pediatric Nephrology and Hypertension University of Texas -Houston Past-Chair, International Pediatric Hypertension Association .

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“Does the Benefit Associated with Treating Hypertension Apply to Children?" 

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Does the benefit associated with treating hypertension apply to children l.jpg

“Does the Benefit Associated with Treating Hypertension Apply to Children?" 

Ronald Portman, MD

Professor and Director

Division of Pediatric Nephrology and Hypertension

University of Texas -Houston

Past-Chair, International Pediatric Hypertension Association


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Disease Prevalence in Childhood

  • Congenital heart disease1%

  • Epilepsy3-5%

  • ADHD3-5%

  • Asthma7%

  • Hypertension4-5%

  • Obesity18-25%


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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


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Classification of Hypertension in Childrenand Adolescents

SBP or DBP Percentile

Normal<90th percentile

Prehypertension90th percentile to <95th percentile, or if BP exceeds 120/80 even if below the 90th percentile up to <95th percentile

Stage 1 hypertension95th percentile to the 99th percentile plus 5 mmHg

Stage 2 hypertension >99th percentile plus 5 mmHg


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Blood Pressure Levels for Boys by Age and Height Percentile

SBP (mmHg)DBP (mmHg)

Age BPPercentile of HeightPercentile of Height

(Year)Percentile5th10th25th50th75th90th95th5th10th25th50th75th90th95th

1250th10210310410510710810961616162636464

90th11611611711912012112275757576777878

95th11912012112312412512679797980818282

99th12712712813013113213386868788888990


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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


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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?


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Etiology of Secondary Hypertension in Pediatrics

  • 78%renal parenchymal

  • 12% renovascular

  • 2% coarctation of the aorta

  • 0.5% pheochromocytoma

  • 7.5% others


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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)


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CVD in Children

10000

Death rate per 100,000

Dialysis

1000

Transplant

100

  • Black

  • White

10

General Population

Age (years)

0

0-14 15-19 20-30

Adaptedfrom Parekh et al, J Pediatr, 2002


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Prevalence of Hypertension/LVH in Children with CKD

%

74

60

Use of BP Medications

38

CRI Dialysis Transplant

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


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Hypertension and CKD Progression

NAPRTCS CRI Database:

  • 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

P<0.001

58%

49%

Mitsnefes et al, J Am Soc Nephrol 2003


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NewHTN patients (n=53) and NTN controls (n=33)HTN defined as BP > 95th percentile, and overweight BMI >25 kg/m2


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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


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Pharmacologic Therapy

NormalNone

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

Stage 1 hypertensionInitiate therapy based on indications

Stage 2 hypertensionInitiate therapy

Classification of Hypertension in Childrenand Adolescents: Therapy Recommendations

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


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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


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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


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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


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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


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

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

Boehringer Ingelheim Telmisartan (Micardis)

CibaGenevaBenazepril (Lotensin)#

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

NovartisValsartan (Diovan)

Parke-DavisQuinapril (Accupril)#

PfizerAmlodipine (Norvasc)*Eplerenone (Inspra)

SankyoOlmesartan (Benicar)

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

ESCAPE Trial* Germany

Ramipril in CKD, proteinuria and BP

Recent Pediatric Phase III or IV Antihypertensive Programs

Meta-analysis in progress

*published

# completed; not yet published


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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


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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


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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


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Is study of effects on blood pressure adequate?

  • Not anymore


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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


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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


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The Child is Father to the Man

Does the benefit associated with treating hypertension in children

apply to adults?"


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