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

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

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

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?

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

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

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

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

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

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

Diagnosing Pulmonary Hypertension Andrew Bensky, MD Pediatric Cardiology SHVI

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

Typical PAH ECG

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

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

Estimating RVSP by TR Velocity

Estimating PA Diastolic Pressure

Right to Left PDA

Left to Right PDA

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

Normal Short Axis

Flattened Septum

Suprasystemic RVSP

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

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

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

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 = 25.05 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 = 25.09 units (10.79 units x m²) Qp/Qs = 4.46 : 1 | Rp/Rs = 0.11

Medications Utilized for PAH Kari Crawford Plant, CPNP-AC

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;114:1417- 1431. 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;328:1732-1739. Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol. 1999;61:391-415.

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 2001. 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

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 (www.phaorganization.org, 7/10)

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™)

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

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

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

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

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®)

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

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.

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 1-866-474-8326 www.curascript.com 1-866-344-4874 www.accredotx.com 1-877-242-2738 www.caremark.com 40 40

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