# Presentation: 677284

## “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

## 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: 4****th**** 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

## Blood Pressure Levels for Boys by Age and Height Percentile

**	****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

**	**

## Evaluation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**

## Evaluation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?**

## 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/m****2.7****) 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 

**38**

**60**

**74**

-   CRI               Dialysis         Transplant

**%**

- Use of BP Medications

**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

**P<0.001**

- Mitsnefes et al, J Am Soc Nephrol 2003

**NAPRTCS CRI Database:**

- 58%
- 49%

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

- 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

**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 

_**AstraZeneca**_Felodipine (Plendil)*Metoprolol (Toprol-XL)# Candesartan (Atacand)_** **_
_**Bristol-Myers Squibb **_Fosinopril (Monopril)**Irbesartan (Avapro)#
_**Boehringer Ingelheim **_Telmisartan (Micardis)
_**CibaGeneva**_Benazepril (Lotensin)#
_**Merck**_Enalapril (Vasotec)*Lisinopril* (Prinivil/Zestril)Losartan (Cozaar)*

_**Novartis**_Valsartan (Diovan)
_**Parke-Davis**_Quinapril (Accupril)#
_**Pfizer**_Amlodipine (Norvasc)*Eplerenone (Inspra)
_**Sankyo**_Olmesartan (Benicar)
_**Wyeth-Ayerst/King**_Bisoprolol-HCTZ (Ziac)*Altace (Ramipril)
**ESCAPE Trial*** Germany
- 	Ramipril 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?"

- The Child is Father to the Man