1. Pulmonary Arterial Hypertension: Disease State and Treatment Options Dr. William Harvey Director Pulmonary Artery Hypertension Clinic IU Health North Hospital

2. 2 Presentation Outline Definition of PAH Pathophysiology Epidemiology Clinical classification Natural history Signs and symptoms Diagnosis Treatment of PAH

4. 4 Pulmonary Arterial Hypertension: Definition and Histological Characteristics Mean PA pressure >25 mm Hg or 30 mm Hg with exercise (PCWP ≤15 mm Hg) PVR >3 Wood units Increased pressure load on RV Eventual right-sided heart failure and death lumen media intima adventitia Normal pulmonary arteriole Plexiform lesion Pulmonary arteriole in PAH Barst et al. J Am Coll Cardiol. 2004;43:40S-47S.

5. Pathophysiology Pulmonary Artery Hypertension 5

6. Pathogenesis of PAH: Vasoconstriction Decreased NO synthase Prostacyclin NO Increased Endothelin Serotonin Thromboxane Vasodilation Vasoconstriction

7. Mechanisms of Pathology for PAH Humbert, et al. N Engl J Med. 2004;351:1425-1436. Nitric oxide cGMP Vasodilatation and antiproliferation Endot helial cells Nitric oxide pathway PreproendothelinProendothelin L-arginine NOS Arachidonic acidProstaglandin I 2 cAMP Vasodilatation and antiproliferation Vasoconstriction and proliferation Endothelin- receptor A Endothelin- receptor B Endothelin pathwayProstacyclin pathway Endothelin-1 Endothelin- receptor antagonists Exogenous nitric oxide Prostacyclin derivates Phosphodiesterase type 5 inhibitor Phosphodiesterase type 5

8. Pathophysiology

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10. Epidemiology/Classification Pulmonary Artery Hypertension 10

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12. 12 Epidemiology of PAH (WHO Group I) 1 Idiopathic PAH 2 –Incidence is approximately 2 to 5 per million per year –2 to 3 times more prevalent in women –Mean age of 37 years at diagnosis 3 Familial PAH –Observed in about 6% to 10% of PAH cases 3 Associated PAH –Approximately 27% of patients with CTD (scleroderma or mixed CTD) have PAH 4 ­Equally high prevalence in limited and diffuse disease 5 –Each year, 0.5% of patients with HIV develop PAH 6 –Prevalence of portopulmonary hypertension is 4% to 15% among patients undergoing evaluation for liver transplantation 7-8 –15% to 30% of all patients with congenital heart disease have PAH 9 1. Simonneau et al. J Am Coll Cardiol. 2004;43(12 suppl):5S-12S. 2. Gaine and Rubin. Lancet. 1998;352:719-725. 3. Rich et al. Ann Intern Med. 1987;107:216-223. 4. Wigley et al. Arthritis Rheum. 2005;52:2125-2132. 5. Launay et al. J Rheumatol. 2007;34:1005-1011. 6. Limsukon et al. Mt Sinai J Med. 2006;73:1037-1044. 7. Colle et al. Hepatology. 2003;37:401-409. 8. Kuo et al. Chest. 1997;112:980-986. 9. Landzberg. Clin Chest Med. 2007;28:243-253.

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16. 16 Epidemiology of PAH Rare disease (orphan designation) of the pulmonary microvasculature affecting 50,000 to 100,000 people in the United States 1 –Affects all ages and races –Most prevalent in 4th and 5th decades of life –Higher prevalence in females True incidence and prevalence may be underestimated –Due to under diagnosis (e.g., in patients with HIV) and misdiagnosis (e.g., asthma) 2 Prevalence of PAH may increase because of demographic trends in associated conditions 1. Rubin. Chest. 1993;104:236-250. 2. Ghamra and Dweik. Cleve Clin J Med. 2003;70:S2-S8.

17. 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 1 Idiopathic (IPAH) Heritable (PAH) –BMPR2 –ALK1 –Endoglin (with or without hereditary hemorrhagic telangiectasia) –Unknown Drugs and Toxins induced Associated with –Connective Tissue Diseases –HIV Infection –Portal Hypertension –Congenital Heart Diseases –Schistosomiasis –Chronic hemolytic anemia Persistent pulmonary hypertension of the newborn Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

18. 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 2 Pulmonary hypertension owing to left heart disease –Systolic dysfunction –Diastolic dysfunction –Valvular disease Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

19. 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 3 Pulmonary hypertension owing to lung diseases and/or hypoxia –Chronic obstructive pulmonary disease –Interstitial lung disease –Other pulmonary diseases with mixed restrictive and obstructive pattern –Sleep-disordered breathing –Alveolar hypoventilation disorders –Chronic exposure to high altitude –Developmental abnormalities Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

20. 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 4 Chronic thromboembolic pulmonary hypertension (CTEPH) Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

21. 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 5 Pulmonary hypertension with unclear multifactorial mechanisms Hematologic disorders: myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

22. 22 NYHA Functional Classification Rich, ed. Executive summary from the World Symposium on Primary Pulmonary Hypertension, Evian, France, 1998:6-10. NYHA Definition Class I No symptoms with ordinary physical activity Class II Some symptoms with ordinary activity and slight limitation of physical activity Class III Symptoms with less than ordinary activity and increased limitation of physical activity Class IV Symptoms with any activity, possibly even while at rest

23. 23 WHO Functional Classification WHO Definition Class I No limitation of physical activity; no symptoms with ordinary physical activity Class II Slight limitation of physical activity; ordinary physical activity causes PAH symptoms Class III Marked limitation of physical activity; less than ordinary physical activity causes PAH symptoms Class IV PAH symptoms with any physical activity and even at rest; discomfort with any physical activity; signs of right heart failure Rubin. Chest. 2004;126(suppl 1):7S-10S.

24. Natural History Pulmonary Artery Hypertension 24

25. 25 Natural History of PAH: NIH Registry 1,2 NIH = National Institutes of Health. Predicted survival according to the NIH equation. Predicted survival rates were 69%, 56%, 46%, and 38% at 1, 2, 3, and 4 years, respectively. The numbers of patients at risk were 231, 149, 82, and 10 at 1, 2, 3, and 4 years, respectively. *Patients with primary pulmonary hypertension, now referred to as idiopathic pulmonary hypertension. 1. Rich et al. Ann Intern Med. 1987;107:216-223. 2. D’Alonzo et al. Ann Intern Med. 1991;115:343-349. Predicted survival* 69% 56% 46% 38% Predicted survival Percent survival Years

26. 26 Survival by PAH Etiology CHD = congenital heart disease; CVD = collagen vascular disease; HIV = human immunodeficiency virus; PAH = pulmonary arterial hypertension; PPH = primary pulmonary hypertension; PoPH = portopulmonary hypertension. McLaughlin et al. Chest. 2004;126:78S-92S. Years Percent survival Prognosis in Mixed Treated/Untreated Cohorts

27. PAH/SSc Progresses Even More Rapidly Koh, et al. Br J Rheumatol 1996 0 10 20 30 40 50 60 70 80 90 100 012345678910111213 Years from Diagnosis of Pulmonary Hypertension Percent Survival PAH Lung Involvement without PAH No Lung involvement

28. Signs/Symptoms Pulmonary Artery Hypertension 28

29. Symptoms of PAH McLaughlin et al. J Am Coll Cardiol. 2009;53:1573-1619. Shortness of breath (dyspnea) Chest pain (angina) Swollen ankles and legs (edema) Dizziness and/or fainting (syncope) Feeling tired or worn out (fatigue) See slides 33-39 for Important Safety Information about Remodulin and refer to the Full Prescribing Information provided.

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32. REVEAL Database: Most Frequent Symptoms at Diagnosis Elliott EG, et al. Chest. 2007;132(suppl 4):631S. Dyspnea at rest Cough Dizzy/lightheaded Presyncope/syncope Edema Chest pain/discomfort Other Fatigue Dyspnea on exertion 0 25 50 75 100 Incidence (%) IPAH APAH N=1479. Abstract

33. Implications of Syncope in Patients with PAH Le RJ, et al. Chest. 2010;138:927A. N=475 adults with Group 1 PAH completing standardized symptom assessment at time of diagnosis. P<0.01. Hazard ratio 2.56 [95% CI, 1.26, 4.84]. 100 80 60 40 20 0 012345 P<0.01 Syncopal at diagnosis Non-syncopal at diagnosis Survival, % Follow-up, years

34. Diagnosis of PAH

35. 35 Diagnosis of PAH* DiagnosticOutcomes History and physical † Evaluate signs and symptoms, family history, associated diseases, ANAs Chest x-ray † Assess for RV enlargement, peripheral hypovascularity (pruning), and prominent pulmonary arteries Echocardiogram Assess for RV and RA enlargement, RV dysfunction, TR velocity to measure RVSP Electrocardiogram Evaluate for right heart enlargement and strain, cardiac rhythm Cardiac catheterization † Evaluate for CHD; measure wedge pressure or LVEDP; establish severity and prognosis; test vasodilator therapy PFTs Assess obstructive and restrictive airway disease VQ scan Rule out thromboembolic disease *Additional tests may be ordered to rule out possible causes of PAH (pulmonary arteriography, blood tests [HIV, hepatic disease, scleroderma], polysomnography [sleep-disordered breathing]). † Required for referral. ANA = antinuclear antibody; CHD = congenital heart disease; LVEDP = left ventricular end-diastolic pressure; PFT = pulmonary function test; RA = right atrial; RV = right ventricular; RVSP = right ventricular systolic pressure; TR = tricuspid regurgitation; VQ = ventilation-perfusion.

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38. Chest X-Ray Consistent With PH Image courtesy of Vallerie McLaughlin, MD

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40. Signs of PAH on Echocardiogram with Doppler Apical Four Chamber Increased sPAP or TR jet Right atrial and ventricular hypertrophy Flattening of intraventricular septum Small LV dimension Dilated PA LV RV LA RA IVS McGoon, et al. Chest 2004

41. Echocardiogram: Parasternal Short Axis Image courtesy of Vallerie McLaughlin, MD

42. Echocardiogram: Apical Four Chamber Image courtesy of Vallerie McLaughlin, MD

43. Echocardiogram: Tricuspid Regurgitation Modified Bernoulli’s Equation: 4 x (V)² + RAP = RVSP (PASP) V=tricuspid jet velocity (m/s); RAP= right atrial pressure; RVSP=right ventricular systolic pressure; PASP=pulmonary artery systolic pressure. Image courtesy of Vallerie McLaughlin, MD

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47. Accuracy of PH Diagnosis by Echocardiography in Advanced Lung Disease Cohort study of lung transplant patients (n=374) All patients –Doppler echo 24 to 48 hours prior to RHC Prevalence of PH: 25% Echo frequently inaccurate leading to over diagnosis of pulmonary hypertension in patients with advanced lung disease Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167(5):735-740. Diagnosis of PH Studies (%) Overestimation Accurate Underestimation No Pulmonary Hypertension Pulmonary Hypertension

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49. Actual Diagnoses of Patients Referred to PH Specialty Clinic Moghbelli MH, et al. Am J Respir Crit Care Med. 2008;177:A923. Interstitial Lung Disease Venous Thromboembolism Other Structural Heart Disease Obstructive Sleep Apnea LV Dysfunction Obstructive Lung Disease All Alternative Diagnoses Abstract

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58. Vasodilator Agents Nitric Oxide: –Inhaled gas, short half life, prospective studies, 20- 80ppm for 3- 5 minutes Flolan: –2-10 ng/kg/min –Increase by 2ng/kg/min q 15 minutes until goal –SE: headache, flushing nausea Response: mean PAP <40mmHg, 10 mmHg average drop, maintain CO

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64. Treatment of Pulmonary Arterial Hypertension

65. Supportive Therapy and General Measures in PAH Oral anticoagulants (IPAH/HPAH) –Favorable data primarily from retrospective trials Diuretics –Standard of care for right-heart failure –Clinician preference on choice of agents Oxygen –Low-flow supplemental O2 improved outcome in clinical case series; maintain SaO2 >92% Not evaluated in randomized controlled trial Digoxin –Modest increase in cardiac output –No data available on long-term management Supervised exercise program rehabilitation Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.

66. Additional General and Supportive Measures in PAH Avoid excessive exertion Avoid pregnancy Avoid constipation Encourage smoking cessation Appropriately refer to ensure psychological and social support Provide appropriate training and counseling on infection prevention –Including, but not limited to, infections related to infusion/injection-based PAH therapy –Pneumococcal and flu vaccines Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.

67. When to Initiate PAH-specific Therapy No data support “wait-and-see” approach to diagnosed PAH Data suggests that patients assigned to placebo in randomized controlled trials may fail to “catch-up” when enrolled into long-term observational arms In FC II patients, bosentan improved outcomes consistent with usefulness of early intervention Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.

68. PAH-specific Therapies Approved for Use in the US Endothelin Receptor Antagonists Phosphodiesterase-type 5 Inhibitors Prostanoids – Prostacyclin Analogs Ambrisentan (PO)Sildenafil (PO)Epoprostenol (IV) Bosentan (PO)Tadalafil (PO)Iloprost (inhaled) Treprostinil (IV, SC, and inhaled) FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction= Search.Search_Drug_Name. Accessed November 1, 2009.

69. Updated Guidelines: PAH-Specific Therapies Available in the US Adapted from Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Strength of Recommendation WHO Class IIWHO Class IIIWHO Class IV AAmbrisentan, bosentan, sildenafil Ambrisentan, bosentan, epoprostenol IV, iloprost inh, sildenafil Epoprostenol IV BTadalafilTadalafil, treprostinil SC Iloprost inh CTreprostinil SC E/BTreprostinil IVTreprostinil IV, initial combo tx E/CAmbrisentan, bosentan, sildenafil, tadalafil Recently approvedTreprostinil inh

70. Choice of Initial PAH-specific Therapy Dependent on many factors –Disease severity –Approval status –Route of administration –Side-effect profile –Patient preference –Physician experience and clinical judgment Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.

71. 71 Determinants of Disease Severity BNP = brain natriuretic peptide; CI = cardiac index; RAP = right artery pressure; RV = right ventricular. McLaughlin and McGoon. Circulation. 2006;114:1417-1431. Determinants of riskLower riskHigher risk Clinical evidence of RV failure NoYes Progression GradualRapid WHO functional class II, IIIIV 6MWD Longer (>400 m)Shorter (<300 m) BNP Minimally elevatedVery elevated Echocardiographic findings Minimal RV dysfunctionSignificant RV dysfunction, pericardial effusion Hemodynamics Normal/near normal RAP and CI High RAP, low CI From McLaughlin and McGoon. With permission.

72. Comparison of Agents Agent Route of Administratio n Adverse Events EpoprostenolContinuous IV infusion Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain IloprostAdaptive aerosol device Headache, cough, flushing, jaw pain Treprostinil» Subcutaneous » IV » Pain and erythema at injection site, headache, nausea, diarrhea, rash » Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain AmbrisentanOral Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 2%), lower extremity edema BosentanOral Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 10%), lower extremity edema, anemia SildenafilOral Headache, flushing, dyspepsia, epistaxis TadalafilOral Headache, dyspepsia, back pain, myalgia, flushing McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619.

73. 73 Pulmonary Arterial Hypertension Treatment Options* Flolan is a registered trademark of GlaxoSmithKline. Ventavis and Tracleer are registered trademarks of Actelion Pharmaceuticals US, Inc. Letairis is a trademark of Gilead Sciences, Inc. Revatio is a trademark of Pfizer Inc. Remodulin is a registered trademark of United Therapeutics Corp. ProductDeliveryFrequencyIndicated population PDE-5 inhibitor Revatio™ (sildenafil citrate)Oralt.i.d.WHO group I Endothelin receptor antagonists Letairis™ (ambrisentan)Oralq.d.WHO class II-III Tracleer ® (bosentan)Oralb.i.d.WHO class III-IV Prostacyclins Flolan ® (epoprostenol sodium) Injection IVContinuousNYHA FC III-IV Remodulin ® IV (treprostinil sodium) Injection IVContinuousNYHA FC II-IV Remodulin ® SC (treprostinil sodium) Injection SCContinuousNYHA FC II-IV Ventavis ® (iloprost) Inhalation Solution Inhaled6-9 x dailyNYHA III-IV *It is important to note that peer-reviewed, head-to-head analyses of the effectiveness of these products have never been conducted. Only a healthcare provider can determine the proper PAH therapy for each patient.

74. 74 Treatment Guidelines: Algorithm CCB = calcium channel blocker; ETRA = endothelin receptor antagonist; PDE-5 = phosphodiesterase type-5. McLaughlin and McGoon. Circulation. 2006;114:1417-1431. General care Oral anticoagulants ± diuretics ± oxygen ± digoxin Acute vasoreactivity testing Oral CCBLower riskHigher risk Sustained response Continue CCB ETRAs or PDE-5 inhibitors (oral) Epoprostenol or treprostinil (IV) Iloprost (inhaled) Treprostinil (SC) Epoprostenol or treprostinil (IV) Iloprost (inhaled) ETRAs or PDE-5 inhibitors (oral) Treprostinil (SC) Atrioseptostomy Lung transplantation Clinical reassessment: consider additional therapy if goals are not met Investigational protocols Combination regimens Positive Negative Yes No From McLaughlin and McGoon. With permission.

75. 75 Calcium Channel Blocker Therapy Indicated for IPAH patients who respond to acute vasodilator* testing at the time of cardiac catheterization –Response defined by reduction in mPAP ≥10 mm Hg to a mPAP ≤40 mm Hg, with an unchanged or increased CO 1 Approximately 12.8% of patients respond to acute vasodilator testing 2 –Only 6.8% had a favorable clinical response to chronic CCB therapy at 1 year Other PAH treatments should be evaluated if patient does not improve to FC I or II CO = cardiac output; mPAP = mean pulmonary arterial pressure. *Inhaled nitric oxide, adenosine, or epoprostenol. 1. Badesch et al. Chest. 2007;131:1917-1928. 2. Sitbon et al. Circulation. 2005;111:3105-3111.

76. 76 Key Treatment Goals Improve quality of life and survival Improve to FC I or II Improve 6MWD to ≥380 m Improve hemodynamics Alleviate symptoms McLaughlin and McGoon. Circulation. 2006;114:1417-1431.

77. 77 Treatment Algorithm According to Risk ETRA = endothelin receptor antagonist; PDE-5 = phosphodiesterase type-5. McLaughlin and McGoon. Circulation. 2006;114:1417-1431. LOWER-RISK PATIENTS* ETRAs PDE-5 inhibitors ORAL MED Intravenous Inhaled Subcutaneous PROSTACYCLIN HIGHER-RISK PATIENTS † Intravenous Inhaled Subcutaneous PROSTACYCLIN *Important characteristics of lower risk include WHO FC II and III, 6MWD >400 m, and minimal RV dysfunction. † Key characteristics of higher risk include WHO FC IV, 6MWD <300 m, and significant RV dysfunction.

78. Updated Guidelines: Inadequate Clinical Response to Initial PAH Therapy Atrial septostomy and/or Lung transplantation Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Failure to show improvement or deterioration with monotherapy Sequential Combination Therapy Prostanoids Endothelin Receptor Antagonists PDE5 Inhibitors

79. Conclusions Recognize potential for PH based on signs and symptoms Identify etiology of PH and treat reversible causes Use right heart cath to confirm dx, and help risk stratify Once start therapy have close clinical f/u to follow response Decide on treatment goals Consider referral to PAH center or clinic Future may be combination therapy 79