PULMONARY HYPERTENSION UPDATE Dianne L Zwicke MD Clinical

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

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; BMPR 2, 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): S 43 -S 54. Graphic adapted from http: //cme. medscape. com/viewarticle/530730.

PULMONARY ARTERIAL HYPERTENSION ►Mean PA pressure > 24 mm. Hg ►PCWP < 15 mm. Hg ►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 36 -45 46 -55 > 55 Mild Moderate Severe Systemic

Epidemiology of PAH (WHO Group 1)1 ► Prevalence of PAH in associated conditions: Distribution of PAH in French Registry 8 § CTDa: 8%-12%2, 3 Appetite suppressant § CHD: 15%-30%4 >1 Risk factor IPAH HIV § Po. PH: 2%-6%5, 6 § HIV: 0. 5%7 Po. PH 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; Po. PH, portopulmonary hypertension. 1. Simonneau et al. J Am Coll Cardiol. 2009; 54(1 suppl S): S 43 -S 54. 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 (Necropsy) ► Idiopathic (Familial) ► Connective Tissue ► HIV ► Hepatopulmonary ► Anorexic drug 1/500, 000 750/500, 000 191/1926 1 -100/1000 5/100 5 -8/100 12 -25/500, 000

1 -Year Mortality Remains High in FC IV Patients 1, 2 N=782 1 -Year mortality (%) <30% on prostanoid WHO FC FC, functional class; Qu. ERI, Quality Enhancement Research Initiative; WHO, World Health Organization. 1. Mc. Laughlin et al. Am J Respir Crit Care Med. 2009; 179: A 1043. 2. Mathier et al. Am J Respir Crit Care Med. 2009; 179: A 2658.

PULMONARY HYPERTENSION RIGHT HEART FAILURE SYMPTOMS ► DOE - 2 Years - 70% ► Ascites - 20% ► CP - RV ischemia - 30% ► Peripheral edema - 10% ► Syncope / near syncope – 30% ► Early satiety - 50% ► Fatigue - 90% ► Hoarseness - 10% ► Raynauds phenomonon – 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 Symptomatic/ Decompensating Pre-symptomatic/ Compensated Declining/ Decompensated CO Symptom Threshold PAP PVR RAP ms to p m y Right Heart Dysfunction S Time CO, cardiac output; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure.

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 c. GMP 1 Prostacyclin Supplement the deficiency in PGI 2, resulting in vasodilation and inhibition of platelet aggregation 2 ERAs Block the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-13 c. GMP, cyclic guanosine monophosphate; ERA, endothelin receptor antagonist; ET-1, endothelin; PDE-5, phosphodiesterase type 5; PGI 2, prostacyclin. 1. Humbert et al. J Am Coll Cardiol. 2004; 43(suppl S): 13 S-24 S. 2. Humbert et al. N Engl J Med. 2004; 351: 1425 -1436. 3. Galiè et al. Eur Heart J. 2004; 25: 2243 -2278.

Overall PAH Therapy Use in Enrolled Population 1, 2 Patients (%) N=782 ERA, endothelin receptor antagonist; PDE-5 I, phosphodiesterase type 5 inhibitor; Qu. ERI, Quality Enhancement Research Initiative. 1. Mc. Laughlin et al. Am J Respir Crit Care Med. 2009; 179: A 1043. 2. Mathier et al. Am J Respir Crit Care Med. 2009; 179: A 2658.

Has Survival Meaningfully Improved With Modern Therapies? IPAH, HPAH, and anorexigen-associated PAH 100 After 2000 (current therapies) 1992 -1999 (only IV PGI 2) Before 1992 (no specific Tx) Survival (%) 75 n=269 NS n=260 50 25 n=118 0 P<0. 05, log-rank test 0 12 24 36 48 60 Months HPAH, hereditary pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; NS, not significant; PGI 2, 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 ► P 450 pathway (2 C 9, 3 A 4) ► 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 ► SQ analogue or IV infusion ► Modified insulin pump – SQ

INHALED NITRIC OXIDE ► Endothelial derived relaxing factor ► Endogenous mediator for smooth muscle relaxation ► Selective pulmonary vasodilator through c. GMP 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 ► 6 -9 prostacyclin derivative treatments/day ► 10 -15 ► Mini minutes/treatment Nebulizer

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

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

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

TADALAFIL (Adcirca) ► PDE-5 inhibitor ► 20 -40 mg ► 36 daily po 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) ▪ Prostacyclins ▪ Nitric Oxide - Oral Beraprost (Lung. Rx) ▪ 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 100 ng/kg/min ► Ambrisentan ► Digoxin 5→ 10 mg po daily 0. 25 mg daily

48 y/o female PAH / ICM – (continued) ► Lasix 40 mg daily ► K/Mg replacement ► Lisinopril 20 mg 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 ► Normal ascites, LE edema, severe RH failure LV, no significant valve disease ► Right Heart Cath…. Hepatic wedge - 18 RA – 18 RV – 19 / 22 PA – 92 / 25 (54) CI – 1. 9 PVR – 9 WU

42 y/o male - Hep C ETOH Liver Dz (continued) IV Lasix, Dobutamine, Flolan ► Digoxin 0. 25 mg daily, K/Mg replacement ► Flolan changed to Veletri for home infusion ► Revatio 20 mg 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 56 year old female with PE after Hysterectomy ► Well until 3 years ago, 02 6 L 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