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Learning Objectives

Learning Objectives. Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors.

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Learning Objectives

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  1. Learning Objectives • Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. • Evaluate patients for comorbid conditions to determine the relative risk for PAH. • Use evidence-based guidelines to select the most appropriate treatment. • Apply determinants of risk to assess a patient’s prognosis and recognize when therapy needs to be augmented. • Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring.

  2. Overview of PAH US prevalence = estimates up to 50,000 to 100,000 15,000 to 25,000 diagnosed and treated Disease of small pulmonary arteries characterized by vascular narrowing and increased vascular resistance Vasoconstriction Cell proliferation and pulmonary vascular remodeling Thrombosis in situ Common cause of death: Right ventricular (RV) failure Humbert, et al. J Am Coll Cardiol. 2004;43:13S-24S.

  3. Mechanisms of Pathology for PAH Endothelinpathway Prostacyclinpathway Nitricoxidepathway Endothelial cells L-arginine Preproendothelin Proendothelin Arachidonicacid Prostaglandin I2 NOS Nitric oxide Prostaglandin I2 Endothelin-1 Endothelin-receptor A Endothelin-receptor B Exogenous nitric oxide Prostacyclinderivates cGMP Endothelin-receptor antagonists cAMP Phosphodiesterase type 5 Vasodilatation and antiproliferation Vasodilatation and antiproliferation Vasoconstriction and proliferation Phosphodiesterase type 5 inhibitor Humbert, et al. N Engl J Med. 2004;351:1425-1436.

  4. Pathophysiology of PAH Genetic Predisposition } Vasoconstriction Cell Proliferation Thrombosis Vascular Remodeling Other Risk Factors (CTD, CHD, toxins, etc.) Altered Pathways And Mediators

  5. Mutations in the gene that codes for BMPR2 BMPR2 mutations are identified in ~ 70% of patients with heritable PAH BMPR2 mutations are also found in ~ 20% of patients with I-PAH » Clinical course – poor response to acute vasodilator testing and treatment with calcium channel blockers Mutations in the gene that codes for: Activin receptor-like kinase type 1 (ALK1) Endoglin (ENG) » Cause hereditary hemorrhagic telangiectasia (HHT) and may lead to the development of PAH Genetic Mutations in PAH Machado, et al. J Am Coll Cardiol. 2009;54:S32-42.

  6. Vasoconstriction in PAH Vasoconstriction Vasodilation Enhanced Vasoconstriction ↑ Endothelin ↑ Serotonin (5-HT) ↑ Thromboxane ↓ Potassium channel expression/activity Impaired Vasodilation ↓ Prostacyclin ↓ Nitric oxide ↓ Nitric oxide synthase

  7. Cell Proliferation in PAH High PVR • Proliferative / angiogenic / apoptosis resistant • ↑ Endothelin, serotonin (5-HT), VEGF, BMPR2 and ALK1 mutations • ↓ Potassium channel expression/activity

  8. Vascular Remodeling in PAH Poorly understood PAH cells are pro-proliferative Many factors implicated in pro-proliferative phenotype Proliferative and obstructive remodeling of the pulmonary vessel wall Some new therapies aimed at controlling cell growth Several potential mediators Alterations in gene expression in growth-controlling pathways Growth factors Inflammatory mediators Galie, et al. Eur Heart J. 2009;30:2493-2537.

  9. Revised Classification ofPulmonary HypertensionGroup 1: Pulmonary Arterial Hypertension (PAH) Criteria mPAP ≥ 25 mm Hg PCWP  15 mm Hg No significant: Obstructive/Restrictive lung disease Left heart disease Thromboembolic disease Types Idiopathic PAH Heritable PAH BMPR2, ALK1, Endoglin Drug- and toxin-induced Associated with: Connective tissue disease HIV Portal pulmonary Congenital heart diseases Schistosomiasis Chronic hemolytic anemia Persistent pulmonary hypertension of the newborn Simonneau, et al. J Am Coll Cardiol. 2009;54:S43-54.

  10. Differential Diagnosis of PAH • Clinical presentation • Electrocardiogram (ECG) • Chest radiograph • Pulmonary function tests and arterial blood gases • ECHO (right heart hemodynamics) • Ventilation / perfusion lung scan • High-resolution CT, contrast CT, pulmonary angiography • Cardiac MRI • Blood tests and immunology • Abdominal ultrasound scan • Right heart catheterization and vasoreactivity Galie, et al. Eur Heart J. 2009;30:2493-2537.

  11. Invasive DiagnosticTesting for PAH Right heart catheterization • Mandatory for all patients being tested for PAH • Pulmonary arterial pressure (PAP) • Cardiac output (CO) • Right atrial pressure (RAP) • Pulmonary arterial wedge pressure (PAWP) Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.

  12. Prevalence of PAH in Associated Conditions4th World Symposium on PH (2008) Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.

  13. Patient Evaluation Confirm presence of PH Determine type of PH present (PAH?) Gauge functional capacity Estimate prognosis (survival) Determine treatment and monitoring plan

  14. NYHA/WHO FunctionalClassification for PAH Taichman, et al. Clin Chest Med. 2007;28:1-22.

  15. Predicting Survival in PAH • Hemodynamics • Response to acute vasodilator therapy (calcium channel blockers, CCB) • Exercise capacity • NYHA/WHO functional class • Biomarkers (i.e., BNP levels) Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.

  16. 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 Response to CCB Therapy andSurvival in Patients with PAH Long-term CCB responders(~50% of acute respondersor ≤ 6% of IPAH patients) P = 0.0007 Cumulative Survival Long-term CCB non-responders Years Long-term CCBresponders 38 33 30 22 13 8 3 3 2 1 Patientsat risk (N) 19 12 7 4 0 Long-term CCBnon-responders Sitbon, et al. Circulation. 2005;111:3105-11.

  17. Impact of Delay in Treatmenton Patient Survival 96% 84% 86% ↑Transition placebo group to ambrisentan 76% Event-Free Survival (% Patients) Weeks N = 251 242 226 209 195 Ambrisentan N = 122 110 100 94 95 Placebo → Ambrisentan ABSTRACT: McLaughlin, et al. Am J Respir Crit Care Med. 2008;177:A697.

  18. Goals for Patients with PAH • Ultimate goals • Feel better • Do more • Live longer • Gap in understanding → ? Promote vasorelaxation ? Suppress cellular proliferation ? Induce apoptosis within pulmonary artery wall Archer, et al. N Engl J Med. 2009;361:1864-71.

  19. Oral anticoagulants (E/B) – IPAH/HPAH Diuretics (E/A) Oxygen (E/A) Digoxin (E/C) Supervised rehabilitation (E/B) Supportive therapy and general measures Avoid excessive physical exertion (E/A) Birth control (E/A) Psychosocial support (E/C) Infection prevention(E/A) Expert referral (E/A) Acute vasoreactivity test(A for IPAH)(E/C for APAH) NO Prostanoids + (B) + (B) PDE-5 I + (B) ERA PAH Evidence-Based Treatment Algorithm ACUTE RESPONDER NON-RESPONDER WHO Class I-IV Amlodipine, diltiazem, nifedipine (B) Sustained response (WHO I-II) YES Amlodipine, diltiazem, nifedipine(B) INADEQUATE CLINICAL RESPONSE Sequential combination therapy INADEQUATE CLINICAL RESPONSE Atrial septostomy(E/B)and/orlung transplant(E/A) 4th World Symposium on PH. Dana Point, CA. 2008. Barst, et al. J Am Coll Cardiol. 2009;54:S78-84.

  20. Acute Vasoreactivity Test for PAH Calcium Channel Blockers (CCB) Acute vasoreactive response = Positive response in < 10% of patients with IPAH Responders are on higher than ordinary doses of CCB: amlodipine 10 mg twice daily; diltiazem 360 mg twice daily Moderate recommendation based on scientific evidence Reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased CO with acute pulmonary vasodilator challenge with either inhaled NO or IV epoprostenol Barst, et al. J Am Coll Cardiol. 2009;54:S78-84.

  21. FDA-Approved Agents for theTreatment of PAH • Prostacyclin analogs (PA) • Epoprostenol • Iloprost • Treprostinil • Endothelin-receptor antagonists (ERA) • Ambrisentan • Bosentan • Phosphodiesterase-5 inhibitors (PDE-I) • Sildenafil • Tadalafil

  22. Comparison of Agents Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. *Benza, et al. ATS. San Diego, CA. May 15-20, 2009.

  23. Epoprostenol for PAH • Prostacyclin analog • Indication – WHO group I - functional class III, IV • Administration – continuous IV infusion via central venous catheter • Dosage – 20-40 ng/kg/min • Storage – must keep medication cold with ice packs (stable for 8 hours at room temp) CADD pump Central line

  24. 100 80 60 40 20 0 0 2 4 6 8 10 12 Epoprostenol for IPAH Patient Survival Epoprostenol (N=41) P = 0.003 Conventional therapy (N = 40) Patient Survival (%) Weeks Barst, et al. N Engl J Med. 1996;334:296-301.

  25. Prostacyclin analog Indication – WHO group I - functional class III, IV Administration Ultrasonic nebulizer Dosage = 2.5 to 5 mg, 6 to 9 times daily; maximum daily dosage evaluated in clinical studies = 45 mg Administration in well-ventilated areas Theoretical advantage of selectivity Pulmonary vs systemic administration Iloprost for PAH

  26. Iloprost for PAHComposite Primary Endpoint at Week 12 P = 0.0033 Responders (% Patients) N = 203 Olschewski, et al. N Engl J Med. 2002;347:322-9.

  27. Treprostinil for PAH Prostacyclin analog Indication – WHO group I -functional class II, III, IV Dosage – 1.25 – 40 ng/kg/min Administration Subcutaneous IV Inhalation Infusion site reaction

  28. 40 35 30 25 20 15 10 5 0 Treprostinil SC for PAHChange in 6-MWD (from Baseline to Week 12) 36.1 P = 0.03 20 Change from Baseline (meters) N = 470 3.3 1.4 < 5.0 ng/kg/min 8.2 – 13.8ng/kg/min > 13.8 ng/kg/min 5.0 - 8.1ng/kg/min Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4.

  29. Treprostinil IV for PAHChange from Baseline to Week 12 Change in Functional Class Change in 6-MWD N = 14 Number of Patients Change from Baseline (meters) Weeks Baseline 12 Weeks Tapson, et al. Chest. 2006;129:683-8.

  30. Treprostinil Inhalation for PAH:TRIUMPH-1 Clinical Trial • Treprostinil inhalation • FDA approval – July, 2009 • Administered four times daily • Study design – phase lll, randomized, double-blind, placebo-controlled, 12-week study • Combination with bosentan or sildenafil • Open-label extension for 24 months • N= 206 • Adverse events – cough, headache, nausea, diarrhea, flushing, throat irritation Change in 6-MWD from Baseline (meters) Months ABSTRACT: Benza, et al. ATS. San Diego, CA. May 15-20, 2009.

  31. Endothelin Receptor AntagonistsComparison of Agents Source: FDA-approved product labeling for individual agents.

  32. Endothelin Receptor AntagonistsComparison of Drug-Drug Interactions Source: FDA-approved product labeling for individual agents. 1) Barst, et al. J Am Coll Cardiol. 2009;54:S78-84. 2) Galie, et al. Eur Heart J. 2009;30:2493-2537. 3) Spence, et al. ATS. San Diego, CA. May 15-20, 2009. 4) Harrison, et al. ATS. San Diego, CA. May 15-20, 2009.

  33. Bosentan for PAH • Endothelin receptor antagonist (ETA/ETB non selective) • Indication – WHO group I - functional class II, III, IV • Dosage – 62.5 mg oral twice daily for 4 weeks then 125 mg oral twice daily

  34. 80 60 40 20 0 -20 -40 Bosentan for PAH:BREATHE Clinical TrialChange in 6-MWD (from Baseline to Week 16) Bosentan (N= 144) P = 0.0002 Change from Baseline (meters) Placebo (N= 69) Baseline Week 4 Week 8 Week 16 125 or 250 mg bid Bosentan 62.5 mg bid Rubin, et al. N Engl J Med. 2002;346:896-903.

  35. Bosentan for PAHComparison of 6-MWD in 6-Month, Open-Label Study N= 29 Change from Baseline (meters) Six-month, open-label study of bosentan (125 mg bid) after a double-blind, placebo-controlled, four-month study Delay in treatment in former placebo patients → less robust improvement in 6-MWD during open-label extension Sitbon, et al. Chest. 2003;124:247-54.

  36. Bosentan for PAH:EARLY Clinical Trial Change in PVR (from Baseline to Week 24) Decrease in PVR: Surrogate marker for delaying disease progression P < 0.0001 % of Baseline PVR at Week 24(geometric means) Treatment effect = - 22.6% Galie, et al. Lancet. 2008.371(9630):2093-100. Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.

  37. Bosentan for PAH:EARLY Clinical Trial Change in 6-MWD (from Baseline to Week 24) 25 20 15 11.2 Placebo (N= 91) 10 Bosentan (N= 86) P = 0.076 5 Change in 6-MWD (meters) 0 12 24 weeks weeks 5 10 - 7.9 15 Treatment effect = + 19.1 meters 20 Galie, et al. Lancet. 2008.371(9630):2093-100. Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.

  38. Bosentan for PAH:EARLY Clinical Trial 92 93 90 92 89 87 85 86 84 84 83 83 77 80 27 18 15 9 Time to Clinical Worsening (from Baseline to Week 32) 100 P < 0.02 80 Placebo 60 Bosentan Event-Free Patients (%) 40 20 0 0 4 8 12 16 20 24 28 32 weeks Patients at risk (N) Galie, et al. Lancet. 2008.371(9630):2093-100. Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.

  39. Ambrisentan for PAH • Endothelin receptor antagonist (ETA selective) • Indication – WHO group I - functional class II, III • Dosage – 5 mg and 10 mg oral daily

  40. Ambrisentan for PAHChange in 6-MWD (from Baseline to Week 12) ARIES 1 ARIES 2 60 50 N=192 N= 202 10 mg: +43.6 m 5 mg: +49.4 m 40 25 5 mg: +22.8 m 2.5 mg +22.2 m 20 Change from Baseline (meters) 0 0 Placebo: -7.8 m Placebo: -10.1 m -20 8 12 weeks 4 12 weeks 4 8 -25 Placebo-adjusted change at week 12: Ambrisentan 2.5 mg = 32 m; 5 mg = 59 m Placebo-adjusted change at week 12: Ambrisentan 5 mg = 31 m; 10 mg = 51 m Galie, et al. Circulation. 2008;117:3010-9.

  41. Ambrisentan for PAH:ARIES 1 and 2 Clinical TrialsTime to Clinical Worsening 100 --- Placebo --- 2.5 mg (P = 0.03) --- 5 mg (P = 0.005) --- 10 mg (P = 0.03) 90 Event-Free Patients (%) 80 70 0 4 8 12 Weeks Ambrisentan → 71% relative risk reduction Galie, et al. Circulation. 2008;117:3010-9.

  42. Ambrisentan for PAH:ARIES-EChange in 6-MWD (from Baseline to 24 Months) 2.5 mg (N = 93) 5 mg (N = 186) 10 mg (N = 96) 70 60 50 40 28 m 30 Change from Baseline (meters) 23 m 20 10 7 m 0 -10 -20 0.25 1.0 1.5 2.0 0.0 0.5 Years Mean ± 95% CI; LOCF for missing data Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.

  43. Ambrisentan for PAH:ARIES-EChange in WHO Functional Class 100 90% 86% 80 79% Maintained or Improved 60 2.5 mg (N= 94) 5 mg (N = 187) 10 mg (N = 96) 40 20 Patients (%) 0 10% 14% 20 Worsened 21% 40 1.5 0.0 0.25 0.5 1.0 2.0 Years LOCF for missing data Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.

  44. Phosphodiesterase-5 InhibitorsComparison of Drug-Drug Interactions Source: FDA-approved product labeling for individual agents. 1) Galie, et al. Eur Heart J. 2009;30:2493-2537.

  45. Sildenafil for PAH PDE-5 inhibitor Indication – to increase exercise capacity, decrease clinical worsening in patients with WHO group I – functional class II, III, IV Dosage – 20 mg oral three times daily IV formulation Approved December, 2009 Dosage – 10 mg three times daily

  46. Sildenafil for PAH:SUPER Clinical TrialChange in WHO Functional Class (from Baseline to Week 12) Placebo (N= 70) Sildenafil (N= 203) 100% 80% 60% Patients (%) 40% 20% 0% Baseline Week 12 Baseline Week 12 Class I Class II Class III Class IV Galie, et al. N Engl J Med. 2005;353:2148-57.

  47. Sildenafil for PAH:Long-Term Extension of SUPER Clinical TrialChange in 6-MWD (from Baseline) Change from Baseline (meters) (N= 222) (N= 273) Galie, et al. N Engl J Med. 2005;353:2148-57.

  48. Sildenafil for PAH:SUPER 2 Clinical Trial • Study design • Open-label, long-term extension of SUPER clinical trial • Patients • N= 259 enrolled; 180 completed 3 years of follow-up • Dosage = 20-80 mg three times daily • Study results at 3 years • Functional class – improved in 30%; unchanged in 31% • Kaplan-Meier estimated survival = 79% • Patient disposition – 53 patients died (29%); 44 discontinued therapy (24%) • Combination therapy – 20% • Adverse effects – mild/moderate in severity ABSTRACT: Rubin, et al. CHEST. Philadelphia, PA. Oct. 25-30, 2008.

  49. Tadalafil for PAH • FDA approval – May, 2009 • PDE-5 inhibitor • Indication – to increase exercise capacity, decrease clinical worsening in patients with WHO group I – functional class II, III, IV • Dosage – 40 mg oral daily

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