1. Pulmonary Hypertension: The Other High Blood Pressure
Pediatric Grand Rounds
November 2, 2011

2. Speaker Disclosures Alan Harsch, MD – None Andrew Bensky, MD – None
Kari Crawford Plant, CPNP-AC – Consultant for United Therapeutics

3. CMC Pediatric Pulmonary Hypertension Center
Alan Harsch M.D.
NorthEast Pediatric Pulmonology
Jeff Gordon Children’s Hospital

4. Introduction to the CMC Pediatric Pulmonary Hypertension Center
What is PPH?
What causes PPH?
How does PPH present?
How is it diagnosed?
How is it treated?
What is the purpose of a Pediatric Pulmonary Hypertension Center and why do we need one?
What are the outcomes?

5. Pulmonary Arterial Hypertension
PAH is a disease of the small pulmonary arteries, characterized by vascular proliferation and remodeling
PAH results in a progressive increase in pulmonary vascular resistance and, ultimately, right ventricular failure and death
Over the past 20 years, treatment options have evolved to prolong survival and improve quality of life

6. Pediatric Pulmonary Hypertension Clinic
Multidisciplinary clinical program to provide state of the art care to children with pulmonary hypertension
Collaborative effort between providers from Levine Children’s Hospital and Jeff Gordon Children’s Hospital
Cardiology: Sanger Heart and Vascular Institute
Pulmonary Medicine: NorthEast Pediatric Pulmonology

7. Difficult Disease Fatal disease but patients usually look healthy
No cure; treatment is aimed at arresting or slowing the progression of the disease
Treatment choices:
conventional therapy
oral or intravenous vasodilator therapy
lung transplantation
It is very difficult to judge whether treatment is helping
Patients are likely to deteriorate rapidly with little warning

8. Pulmonary Arterial Hypertension
Definition:
mean pulmonary artery pressure of greater than 25 mm Hg at rest or 30 mm Hg during exercise
Pathophysiology
Classification

9. Previous Nomenclature for PAH
Primary pulmonary hypertension (PPH) = no known cause
Secondary pulmonary hypertension = associated with other disease known to cause pulmonary hypertension

10. Current Nomenclature Pulmonary arterial hypertension
sporadic
familial
collagen vascular disease
congenital systemic to pulmonary shunts
portal hypertension
HIV infection
drugs and toxins
persistent pulmonary hypertension of the newborn (PPHN)
Pulmonary arterial hypertension with other associations
disorders of the respiratory system or hypoxemia
chronic thromboembolic disease
direct disorders of the pulmonary vasculature

11. Diagnosing Pulmonary Hypertension
Andrew Bensky, MD
Pediatric Cardiology
SHVI

12. Electrocardiography
Patients with PAH may have several findings consistent with the diagnosis
RVH
RAD
RV conduction delay
ECG findings are sensitive, but not specific

13. Typical PAH ECG

14. Echocardiography Primary diagnostic test for evaluating PAH
Findings are specific and sensitive in patients with most patients with PAH
Non-invasive in most pediatric patients, though sedation may be required

15. Estimating PA Pressures
Using Doppler measurement of flow velocities to estimate pressure differences
D P = 4 (Velocity in m/sec)2
Direct systemic to pulmonary connections
PDA
VSD
Valve regurgitation PI TR

16. Estimating RVSP by TR Velocity

17. Estimating PA Diastolic Pressure

18. Right to Left PDA

19. Left to Right PDA

20. Echo Signs of PAH Right ventricular hypertrophy
Right ventricular dysfunction
Abnormal septal position
Circular LV- RVSP is less than ½ systemic
Flat septum – “D” shaped ventricles, RVSP is nearly systemic
Circular RV – Suprasystemic RVSP

21. Normal Short Axis

22. Flattened Septum

23. Suprasystemic RVSP

24. Echo Signs of Chronic PAH
RVH
RVE with reduced systolic function
Often associated with clinical signs and symptoms of cor pulmonale
Fatigue, dyspnea, cough, chest pain
Hepatomegaly, edema, crackles, JVD

25. When Echo Isn’t Diagnostic
No intracardiac shunts
Inadequate valve insufficiency to measure regurgitant velocities
Normal septal position
Normal RV size and function
PA pressures may be elevated, but not be able to be estimated

26. Cardiac Catheterization
Gold standard, but invasive, method of both measuring pressures and calculating resistance
Measurements are made at baseline, and repeated using pulmonary vasodilators such as oxygen and nitric oxide
Reactivity assessment can guide medical therapy and help assess status serially

27. Catheterization Data GA, 21% FiO2 Qp = 4.82 L/min (11.21 L/min/m²)
Qs = 1.68 L/min (3.90 L/min/m²)
Rp = 6.02 units (2.59 units x m²)
Rs = units (10.77 units x m²)
Qp/Qs = 2.88 : 1 | Rp/Rs = 0.24
100% FiO2 / 40ppm NO
Qp = 7.82 L/min (18.18 L/min/m²)
Qs = 1.75 L/min (4.08 L/min/m²)
Rp = 2.69 units (1.15 units x m²)
Rs = units (10.79 units x m²)
Qp/Qs = 4.46 : 1 | Rp/Rs = 0.11

28. Medications Utilized for PAH
Kari Crawford Plant, CPNP-AC

29. Targets of Therapy for PAH*
In PAH, the three major pathways thought to be integrally involved with disease development and progression are the nitric oxide (NO), endothelin, and prostacyclin pathways. These pathways also correspond to the targets of the currently available therapeutic agents to treat PAH.
The NO pathway: phosphodiesterase type 5 (PDE-5) inhibitors enhance NO- dependent, cGMP-mediated pulmonary vasodilatation by inhibiting the breakdown of cGMP by PDE-5.
The endothelin (ET) pathway: endothelin receptor antagonists (ERAs) inhibit the binding of ET-1 to the ET receptors (A and B).
The prostacyclin pathway: prostacyclin analogues (or, prostanoids) enhance exogenously deficient levels of prostacylin in patients with PAH.
*Based on observations reported from in vitro, animal, or human trials. The clinical significance is unknown.
References
McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:
Braunwald E, Zipes DP, Libby P, eds. Heart Disease. 2 vols. 6th ed. Philadelphia, PA; WB Saunders Co; 2001.
Giaid A, Yanagisawa M, Langleben D et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:
Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol. 1999;61:

30. PAH Treatments―a Historical Overview
CCB, anticoagulation, digitalis, diuretics
IV treprostinil
Sildenafil
Tadalafil
Tyvaso
SC treprostinil
Ambrisentan
Epoprostenol
Iloprost
Bosentan
<1995
1995
2001
2002
2004
2005
2007
2009
• The timeline provides historical context for key events in the evolution of pulmonary hypertension, including pivotal drug introductions and clinical events
• Before the introduction of epoprostenol (Flolan) in the mid-1990s, the prognosis for patients with pulmonary hypertension was poor (National Institutes of Health registry suggested median survival of 2.8 years)
• Epoprostenol, and later treprostinil (Remodulin), ushered in a new era characterized by improved hemodynamic function, improved symptoms, and extended survival
• Remodulin was initially introduced as a continuous subcutaneous infusion in 2002, and was later expanded in 2004 as a continuous intravenous infusion. In 2006, Remodulin was approved for transitioning patients from Flolan to continuous intravenous treprostinil
• The first oral therapy was introduced in Twice-daily bosentan (Tracleer) was the first of 4 currently approved oral therapies; the other 3 are Revatio (sildenafil), Letairis (ambrisentan), and Adcirca (tadalafil)
• The pace of product introductions has accelerated in recent years and, coupled with the unique mechanisms of action, combination therapy is emerging as an important treatment approach
CCB, calcium channel blocker; IV, intravenous; PAH, pulmonary arterial hypertension; SC, subcutaneous. 30 30

31. Conventional Therapies
Calcium Channel Blockers (CCB) – Help decrease blood pressure (Only appropriate for a small minority of patients demonstrating a favorable response to vasodilator testing at the time of heart catheterization.)
Digoxin
Diuretics
Oxygen
Warafin (Coumadin®)
Aspirin
( 7/10)

32. New Oral/Inhaled Therapy
Oral Therapy
Endothelin Receptor Antagonists (ERAs) help prevent blood vessels from narrowing.
Ambrisentan (Letairis®) Bosentan (Tracleer®)
Phosphodiesterase Inhibitors (PDE 5 Inhibitors) allow the lungs to produce more of its own natural vasodilators.
Sildenafil (Revatio™)
Tadalafil (Adcirca®)
Inhaled Treatment Options, such as Prostacyclins, relieve shortness of breath.
Iloprost (Ventavis®)
Inhaled Treprostinil (Tyvaso™)

33. Phosphodiesterase 5-Inhibitors
Sildenafil
Revatio
Tadalafil
Adcirca
20mg (1 tablet) TID
40mg (2 x 20mg tablets) QD
pahdiseasestate_v.1 33 33 33 33

34. Endothelin Receptor Antagonists
Bosentan
Tracleer
Ambrisentan
Letairis
62.5 mg
1 tablet BID
125 mg
5 mg
1 tablet QD
10 mg
pahdiseasestate_v.1 34 34 34 34

35. From Referral to Exposure and Renewal
Illustrated here is the updated enrollment process for starting and renewing patients on Tracleer® (bosentan) therapy.

36. Prostanoids – Inhaled Iloprost Treprostinil OPTINEB®- I-neb® AAD® 36
pahdiseasestate_v.1 36 36 36 36

37. Intravenous Therapy Intravenous Treatment Options
Intravenous Treatment Options open up the blood vessels and help ease symptoms of PH, including chest pain and shortness of breath.
Treprostinil (Remodulin®)(available SQ)
Epoprostenol (Flolan®)

38. What is Infused Prostacyclin Therapy?
Continuously infused prostacyclins are delivered in 1 of 2 ways:
Through a small catheter right under the skin, generally in the abdominal area
Subcutaneous or SQ
Directly into a central vein in the chest using a surgically placed flexible catheter
Intravenous or IV
Continuous infusion is a method by which the drug is administered to the patient on a steady basis using a delivery pump and a catheter (tube). 38
pahdiseasestate_v.1

39. What Should You Teach Familes?
Resources:
Medication pharmacy, clinic RNs, PHAssociation.org
- Keep a log of medications, bring all medications to appointments, protect indwelling lines (staff unfamiliar with therapy should not draw from or manipulate gtt or line)
- Have PAH clinic contact information with them at all times
Blood cultures should only be done by experienced staff, those trained. Look up the medications if you are not familiar. These are new therapies so no one is expected to know everything, but know to ask.

40. Specialty Pharmacy Service Offerings
All 3rd party reimbursement management
Assessment and evaluation
Pre-teaching
In home, hospital, or clinic
Coordination of services
Discharge planning support
Hotline access
Functions, limitations, service values 40 40

41. Wholesale Cost of Medications (Oral and Inhaled)
Revatio- $17,262
Adcirca- $14,892
Tracleer- $69,715
Letairis- $69,302
Ventavis- $142,350
Tyvaso- $146,913
These are wholesale prices for a one year supply and do not reflect any discounts to Medicare