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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 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 Apply to Children?"  in Childhood

  • Congenital heart disease 1%

  • Epilepsy 3-5%

  • ADHD 3-5%

  • Asthma 7%

  • Hypertension 4-5%

  • Obesity 18-25%


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Fourth Working Group Report 2004 Apply to Children?" 

  • 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 Children Apply to 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


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Blood Pressure Levels for Boys Apply to Children?"  by Age and Height Percentile

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


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Evaluation Apply to Children?"  The 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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Evaluation Apply to Children?"  The 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 Apply to Children?" 

  • 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 children and adolescents

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 children and adolescents

%

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 children and adolescents

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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New children and adolescentsHTN 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 children and adolescents

  • 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 children and adolescents

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

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 children and adolescentsTherapy 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 children and adolescentsfor 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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AstraZeneca (FDAMA)Felodipine (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 additional exclusivity for assessing the effects of antihypertensive drugs in children.

  • 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? additional exclusivity for assessing the effects of antihypertensive drugs in children.

  • Not anymore


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FDAMA: The Next Generation additional exclusivity for assessing the effects of antihypertensive drugs in children.

  • 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 additional exclusivity for assessing the effects of antihypertensive drugs in children.

  • 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 additional exclusivity for assessing the effects of antihypertensive drugs in children.

Does the benefit associated with treating hypertension in children

apply to adults?"


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