PULMONARY HYPERTENSION UPDATE Dianne L. Zwicke, MD Clinical Associate Professor of Medicine University of Wisconsin School of Medicine and Public Health Milwaukee Clinical Campus Milwaukee, Wisconsin

FINANCIAL DISCLOSURE Dianne L. Zwicke, MD Dianne L. Zwicke, MD I have been an investigator and received study grants from the following companies: Glaxo – Welcome *United Therapeutics *Pfizer Medtronic Myogen Encysive Co Therix Ikaria PRE-DIX *Gilead Actileon Novartis Lilly Bayer GENO * Participated in Advisory Boards

PULMONARY HYPERTENSION Vascular (PAH) Non-Vascular Mixed Idiopathic COPD Congenital Collagen Vascular OSA ? COPD Sickle Cell ILD ? ILD HIV PE ? PE Hepatopulmonary Restrictive

Clinical Classification: Where Is the Lesion? VC RA RV PA PC PV LA LV Ao ALK-1, activin receptor-like kinase 1; Ao, aorta; BMPR2, bone morphogenetic receptor type 2; HHT, hereditary hemorrhagic telangiectasia; HIV, human immunodeficiency virus; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PC, pulmonary capillary bed; PV, pulmonary vein; RA, right atrium; RV, right ventricle; VC, vena cava. Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S54. Graphic adapted from http://cme.medscape.com/viewarticle/530730.

PULMONARY ARTERIAL HYPERTENSION Mean PA pressure > 24 mmHg PCWP < 15mmHg PVR > 2.5 / 3.0

PATHOLOGIC CHANGES Vascular PH Smooth muscle hypertrophy Intimal hyperplasia In situ thrombosis Arteritis Plexogenic lesion

PULMONARY HYPERTENSION Severity by Mean PAP 26-35 Mild 36-45 Moderate 46-55 Severe > 55 Systemic

Epidemiology of PAH (WHO Group 1)1 Prevalence of PAH in associated conditions: CTDa: 8%-12%2,3 CHD: 15%-30%4 PoPH: 2%-6%5,6 HIV: 0.5%7 Distribution of PAH in French Registry8 Appetite suppressant >1 Risk factor IPAH HIV PoPH CHD FPAH a Systemic sclerosis. CTD CHD, congenital heart disease; CTD, connective tissue disease; FPAH, familial pulmonary arterial hypertension; HIV, human immunodeficiency virus; IPAH, idiopathic pulmonary arterial hypertension; PoPH, portopulmonary hypertension. 1. Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S54. 2. Hachulla et al. Arthritis Rheum. 2009;60:1831-1839. 3. Mukerjee et al. Ann Rheum Dis. 2003;62:1088-1093. 4. Landzberg. Clin Chest Med. 2007;28:243-253. 5. Hadengue et al. Gastroenterology. 1991;100:520-528. 6. Krowka et al. Hepatology. 2006;44:1502-1510. 7. Sitbon et al. Am J Respir Crit Care Med. 2008;177:108-113. 8. Humbert et al. Am J Respir Crit Care Med. 2006;173:1023-1030.

VASCULAR PH EPIDEMIOLOGY Idiopathic 1/500,000 Idiopathic (Necropsy) 750/500,000 Idiopathic (Familial) 191/1926 Connective Tissue 1-100/1000 HIV 5/100 Hepatopulmonary 5-8/100 Anorexic drug 12-25/500,000

1-Year Mortality Remains High in FC IV Patients1,2 <30% on prostanoid 1-Year mortality (%) WHO FC FC, functional class; QuERI, Quality Enhancement Research Initiative; WHO, World Health Organization. 1. McLaughlin et al. Am J Respir Crit Care Med. 2009;179:A1043. 2. Mathier et al. Am J Respir Crit Care Med. 2009;179:A2658.

PULMONARY HYPERTENSION RIGHT HEART FAILURE SYMPTOMS DOE - 2 Years - 70% CP - RV ischemia - 30% Syncope / near syncope – 30% Fatigue - 90% Raynauds phenomonon – 10% Ascites - 20% Peripheral edema - 10% Early satiety - 50% Hoarseness - 10%

PULMONARY HYPERTENSION Diagnostics - Basics History & Physical Labs- CBC, CMP, TSH, ANA, RF, CRP, ESR, HIV, ANTICARDIOLIPIN AB EKG, CXR Full PFT’S Lung scan Echo with contrast / TEE

PULMONARY HYPERTENSION Diagnostics - Advanced HR Chest CT Pulmonary Angiography Sleep study / screen 6 minute walk Cardiac cath with pharmacologic challenge -- LAST STUDY!

Hemodynamic Progression of PAH Time PAP PVR RAP CO Pre-symptomatic/ Compensated Symptomatic/ Decompensating Symptom Threshold Right Heart Dysfunction Declining/ Decompensated Symptoms CO, cardiac output; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure. 15

Vasoactive Mediators Involved In PAH ABNORMALITIES Nitric oxide deficiency Prostacyclin deficiency Endothelin overexpression THERAPIES PDE-5 inhibitors Block the activity of PDE-5, restoring vasodilation through an increase in cGMP1 Prostacyclin Supplement the deficiency in PGI2, resulting in vasodilation and inhibition of platelet aggregation2 ERAs Block the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-13 cGMP, cyclic guanosine monophosphate; ERA, endothelin receptor antagonist; ET-1, endothelin; PDE-5, phosphodiesterase type 5; PGI2, prostacyclin. 1. Humbert et al. J Am Coll Cardiol. 2004;43(suppl S):13S-24S. 2. Humbert et al. N Engl J Med. 2004;351:1425-1436. 3. Galiè et al. Eur Heart J. 2004;25:2243-2278. 16 16

Overall PAH Therapy Use in Enrolled Population1,2 Patients (%) ERA, endothelin receptor antagonist; PDE-5I, phosphodiesterase type 5 inhibitor; QuERI, Quality Enhancement Research Initiative. 1. McLaughlin et al. Am J Respir Crit Care Med. 2009;179:A1043. 2. Mathier et al. Am J Respir Crit Care Med. 2009;179:A2658.

Has Survival Meaningfully Improved With Modern Therapies? 12 24 36 48 60 n=269 n=260 n=118 Before 1992 (no specific Tx) 1992-1999 (only IV PGI2) After 2000 (current therapies) NS P<0.05, log-rank test Months 25 50 Survival (%) 75 100 IPAH, HPAH, and anorexigen-associated PAH HPAH, hereditary pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; NS, not significant; PGI2, prostacyclin; Tx, treatment. Sitbon et al. Slides presented at European Respiratory Society; September 16-18, 2007; Stockholm, Sweden.

PULMONARY ARTERIAL HYPERTENSION MEDICAL THERAPIES

EPOPROSTINIL (Flolan, Veletri) Prostacyclin 75% sustained ¯ in PVR 10% are non responders Double lumen catheter Requires continuous infusion

BOSENTAN (Tracleer) ET – 1 antagonist Binds ETA – ETB receptors in endothelium and vascular smooth muscle P450 pathway (2C9, 3A4) 3-5 hour max plasma concentration t½ is five hours 95% bound to albumin, excreted in bile 62.5 – 125 mg bid orally, 1-2 month Rx

TREPROSTINIL (Remodulin) UT – 15 Prostacyclin analogue SQ or IV infusion Modified insulin pump – SQ

INHALED NITRIC OXIDE Endothelial derived relaxing factor Endogenous mediator for smooth muscle relaxation Selective pulmonary vasodilator through cGMP pathway Increases oxygenation

SILDENAFIL (Revatio) PDE – 5 Inhibitor Found abundantly in pulmonary vasculature Inhibits proliferation Potent pulmonary vasodilation Increased epistaxis and GI bleed Can’t prescribe nitrates

ILOPROST (Ventavis) Inhaled prostacyclin derivative 6-9 treatments/day 10-15 minutes/treatment Mini Nebulizer

AMBRISENTAN (Letairis) Endothelin receptor blocker WHO group 1-3, WHO class 2 or 3 symptoms 5 or 10mg daily, tablet IPH, CTD, HIV, diet drugs Caution=pregnancy; liver toxicity (Label removed)

INHALED EPOPROSTINIL (Flolan) 30-80ng / kg / min Special delivery system

TREPROSTINIL (Tyvaso) Prostaglandin – inhaled. 2-12 breaths / treatment qid Same side effects as any Prostaglandin during titration

TADALAFIL (Adcirca) PDE-5 inhibitor 20-40mg daily po 36 hour ½ life Avoid with Rifampin and Antifungals

PERCUTANEOUS INTERVENTION IN PULMONARY HYPERTENSION Coil Closure of PDA ASD Closure VSD Closure Atrial Septostomy

SURGICAL PROCEDURES IN PULMONARY HYPERTENSION ASD / VSD Closure Mitral Valve Repair / Replacement Anomolous Pulmonary Venous Return Pulmonary Thrombo-Endarterectomy Open Lung Biopsy Pericardial Window / Drainage

CURRENT CLINICAL TRIALS Oral Remodulin - (United Therapeutics) Selexipag - (Actileon) Combo Study vs single drug - Adcirca +/-Letairis (United Therapeutics / Gilead) Riociguat with LV Failure and PHTN - (Bayer) Tyvaso Registry - (United Therapeutics) Implantable pump / continuous infusion Remodulin - (Medtronics) Inhaled nitric oxide - (GENO) - Inhaled Nitric Oxide via Ambulatory Device (Ikaria) Taladafil with LV Failure and PHTN (NIH) Oral Beraprost (LungRx) ▪ Prostacyclins ▪ Nitric Oxide ▪ PD’s ▪ ERA ▪ Combo

CASES

48 y/o female PAH / ICM CREST syndrome x 6 years Anterior wall MI → LVEF 15-20% PAH – RA-18, RV-86/22, PA-88/22 (55), W-16, CI-1.8, PA-Sat 48%, Ao-92%, PVR-12.18 WU IV Remodulin titrated to 100ng/kg/min Ambrisentan 5→10mg po daily Digoxin 0.25mg daily

48 y/o female PAH / ICM – (continued) Lasix 40mg daily K/Mg replacement Lisinopril 20mg daily / DC Coreg More Aggressive immunosuppression ___________________________________________ * LVAD – Heartmate II for 6-7 months * Successfully transplanted (heart) * Weaned off Remodulin

42 y/o male - Hep C ETOH Liver Dz Massive ascites, LE edema, severe RH failure Normal LV, no significant valve disease Right Heart Cath…. Hepatic wedge - 18 CI – 1.9 RA – 18 PVR – 9 WU RV – 19 / 22 PA – 92 / 25 (54)

42 y/o male - Hep C ETOH Liver Dz (continued) IV Lasix, Dobutamine, Flolan Digoxin 0.25mg daily, K/Mg replacement Flolan changed to Veletri for home infusion Revatio 20mg tid added ________________________________________________ Liver transplant after PVR ↓ to 5 WU, CI >2.8 ECHO = marked improvement of RVEF * 3 months after transplant – weaned off IV Veletri * 9 months after transplant – weaned from Revatio * Stable 1 year after cessation of all PAH drugs

69 y/o old female - HCM NYHA 3, 3+ edema to mid thighs, + ascites Severe DOE and muscle wasting ECHO – mild RVH, mod LVH, RVSP 55, LVEF 65% PHTN work up – negative Cath – RA-18, RV-58/19, PA-55/22, CI-2.8, W-20, PA-Sat 55%, PVR-3.2 WU, Treatment – IV Lasix → CVVH ________________________________________________________________ * Home on peritoneal dialysis x 9 months * Evaluate for transplant – status 7

PAH – Pulmonary Emboli Well until 3 years ago, 02 6L NC now 56 year old female with PE after Hysterectomy Well until 3 years ago, 02 6L NC now Denied PTE at another institution Reviewed Pulmonary Angiogram RHC – RA 8, RV 65/20(35), CI 2.3, Sat-62% Coronary Angiogram Sent to San Diego

Vague Symptoms

Major presenting symptoms are syncope, shortness of breath and fatigue

Syncope is prodrome to death

Correct diagnosis must be established

Empiric vasodilator therapy is not recommended

Treatment options are frequently available if not seen at end stage