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

2. Disease Prevalence in Childhood Congenital heart disease1% Epilepsy3-5% ADHD3-5% Asthma7% Hypertension4-5% Obesity18-25%

3. 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

4. Classification of Hypertension in Children and Adolescents SBP or DBP Percentile Normal<90 th percentile Prehypertension90 th 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

5. SBP (mmHg)DBP (mmHg) Age BPPercentile of HeightPercentile of Height (Year)Percentile5th10th25th50th75th90th95th5th10th25th50th75th90th95th 1250th10210310410510710810961616162636464 90th11611611711912012112275757576777878 95th11912012112312412512679797980818282 99th12712712813013113213386868788888990 Blood Pressure Levels for Boys by Age and Height Percentile

6. 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

7. 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?

8. Etiology of Secondary Hypertension in Pediatrics 78%renal parenchymal 12% renovascular 2% coarctation of the aorta 0.5% pheochromocytoma 7.5% others

9. 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)

10. 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

11. 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%

12. Hypertension and CKD Progression CrCl < 75ml/min/1.73m 2 HTN: >95 th % (Task Force) Normotensive: n=1987 (52%) Hypertensive: n=1874 (48%) Endpoint: –↓ CrCl by 10 ml/min/1.73m 2 –Renal replacement therapy P<0.001 Mitsnefes et al, J Am Soc Nephrol 2003 NAPRTCS CRI Database: 58% 49%

13. New HTN patients (n=53) and NTN controls (n=33) HTN defined as BP > 95th percentile, and overweight BMI >25 kg/m 2

14. ESCAPE TRIAL –CKD patients n=352; Age 3-18 yo; European Multi- center Trail –GFR 11-80 cc/min/1.73m 2 –6 months duration of study; ramipril 6 mg/m 2; 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 50 th percentile –Proteinuria reduced in 50% of patients Wuehl et al. Kidney International 2004;66:768-776

15. Classification of Hypertension in Children and Adolescents: Therapy Recommendations 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 All patients to receive Therapeutic Life-style Changes (TLC)

16. 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

17. 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

18. 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

19. 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

20. Recent Pediatric Phase III or IV Antihypertensive Programs 1.AstraZeneca Felodipine (Plendil)* Metoprolol (Toprol-XL)# Candesartan (Atacand) 2.Bristol-Myers Squibb Fosinopril (Monopril)** Irbesartan (Avapro)# 3.Boehringer Ingelheim Telmisartan (Micardis) 4.CibaGeneva Benazepril (Lotensin)# 5.Merck Enalapril (Vasotec)* Lisinopril* (Prinivil/Zestril) Losartan (Cozaar)* 6.Novartis Valsartan (Diovan) 7.Parke-Davis Quinapril (Accupril)# 8.Pfizer Amlodipine (Norvasc)* Eplerenone (Inspra) 9.Sankyo Olmesartan (Benicar) 10.Wyeth-Ayerst/King Bisoprolol-HCTZ (Ziac)* Altace (Ramipril) 11.ESCAPE Trial* Germany Ramipril in CKD, proteinuria and BP *published Meta-analysis in progress # completed; not yet published

21. 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

22. 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

23. 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

24. Is study of effects on blood pressure adequate? Not anymore

25. 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

26. 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

27. Does the benefit associated with treating hypertension in children apply to adults?" The Child is Father to the Man