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PULMONARY HYPERTENSION UPDATE

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

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PULMONARY HYPERTENSION UPDATE

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

  2. 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 MyogenEncysive Co TherixIkaria PRE-DIX *Gilead ActileonNovartis Lilly Bayer GENO * Participated in Advisory Boards

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

  4. Clinical Classification: Where Is the Lesion? 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. VC RV PA LA LV Ao RA PC PV Graphic adapted from http://cme.medscape.com/viewarticle/530730.

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

  6. PATHOLOGIC CHANGESVascular PH • Smooth muscle hypertrophy • Intimal hyperplasia • In situ thrombosis • Arteritis • Plexogenic lesion

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

  8. Epidemiology of PAH (WHO Group 1)1 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. Distribution of PAH in French Registry8 Appetite suppressant >1 Risk factor IPAH HIV PoPH CHD FPAH CTD a Systemic sclerosis. • Prevalence of PAH in associated conditions: • CTDa: 8%-12%2,3 • CHD: 15%-30%4 • PoPH: 2%-6%5,6 • HIV: 0.5%7

  9. 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

  10. 1-Year Mortality Remains High in FC IV Patients1,2 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. N=782 <30% onprostanoid 1-Year mortality (%) WHO FC

  11. 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 RIGHT HEART FAILURE SYMPTOMS

  12. PULMONARY HYPERTENSIONDiagnostics - 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

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

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

  15. Vasoactive Mediators Involved In PAH 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. ABNORMALITIES Nitric oxide deficiency Prostacyclin deficiency Endothelin overexpression THERAPIES ERAs Block the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-13 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

  16. Overall PAH Therapy Use in Enrolled Population1,2 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. N=782 Patients (%)

  17. Has Survival Meaningfully Improved With Modern Therapies? After 2000 (current therapies) IPAH, HPAH, and anorexigen-associated PAH 100 1992-1999 (only IV PGI2) Before 1992 (no specific Tx) 75 n=269 NS n=260 Survival (%) 50 25 n=118 P<0.05, log-rank test 0 Months 0 12 24 36 48 60 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.

  18. PULMONARY ARTERIAL HYPERTENSIONMEDICALTHERAPIES

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

  20. 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

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

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

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

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

  25. 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)

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

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

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

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

  30. 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

  31. 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

  32. CASES

  33. 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

  34. 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

  35. 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)

  36. 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

  37. 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

  38. PAH – Pulmonary Emboli 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

  39. Vague Symptoms

  40. Major presenting symptoms are syncope, shortness of breath and fatigue

  41. Syncope is prodrome to death

  42. Correct diagnosis must be established

  43. Empiric vasodilator therapy is not recommended

  44. Treatment options are frequently available if not seen at end stage

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