Acknowledgements • ABcomm, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. • Support for this educational activity is provided by an independent educational grant from Gilead Sciences Medical Affairs. Targeted Approach to Treatment of PAH Learning Objectives • Intensify the treatment plan when right ventricular impairment is evident. • Adopt a goal-directed treatment approach to adjust the treatment plan when clinical decompensation occurs. • Utilize a combination of agents with proven combined efficacy and an acceptable safety profile. • Monitor relevant prognostic variables in patients with PAH. • Incorporate progressive treatment strategies and protocols when appropriate. Lecture Outline • • • • • • • General measures and supportive therapy Pathways and mechanisms of action Evidence-based treatment algorithm FDA-approved treatment options Combination therapy Prognostication and patient monitoring Ongoing research Treatment of PAH • Complex strategy which includes: – Evaluation of disease severity – Adoption of general measures and supportive therapy – Assessment of vasoreactivity – Estimation of drug efficacy – Combination of different drugs and interventions (e.g. balloon atrial septostomy, lung transplantation) Ghofrani, et al. Int J Cardiol. 2011;154(1):S20-33. General Measures and Supportive Therapy General measures Supportive therapy Referral to specialized PAH patient care center Cardiac catheterization / Acute vasoreactivity testing Chronic CCB therapy Adapted from: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. General Measures and Supportive Therapy General Measures • Rehabilitation / Exercise – Recommended after stabilized and on therapy – Requires close supervision by an experienced PAH care center – Optimal method, duration, and intensity of activity are unknown • Psychosocial support • Family planning – Pregnancy is associated with a considerable mortality rate in patients with PAH, and oral contraceptives are not contraindicated • Vaccinations – Influenza and pneumococcal immunization Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. General Measures and Supportive Therapy Supportive Therapy • Anticoagulants • Diuretics • Oxygen • Digoxin Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. General Measures and Supportive Therapy Cardiac Catheterization / Acute Vasoreactivity Testing • Mandatory in patients with idiopathic PAH, may be considered in patients with PAH associated conditions • Identifies patients who will respond to chronic treatment with high-dose CCBs • Inhaled nitric oxide (10 – 20 parts per million) is the preferred testing compound – Alternates: epoprostenol IV or adenosine IV Adapted from: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. General Measures and Supportive Therapy Chronic CCB Therapy • Responders – Patients with a positive response to acute vasoreactivity testing – Positive response = reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased cardiac output – < 10% of patients with idiopathic PAH • Therapeutics Amlodipine 20 – 30 mg/day Nifedipine 180 – 240 mg/day Diltiazem 720 – 960 mg/day Agarwal, et al. Am Heart J. 2011;162:201-13. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Mechanisms of Pathology for PAH Endothelin pathway Prostacyclin pathway Nitric oxide pathway Endothelial cells Preproendothelin L-arginine Proendothelin Arachidonic acid Prostaglandin I2 NOS Nitric oxide Endothelinreceptor A Endothelin-1 Endothelinreceptor B sGC stimulator Prostaglandin I2 GTP Exogenous nitric oxide cGMP Endothelinreceptor antagonists Phosphodiesterase type 5 Vasodilatation and antiproliferation Vasoconstriction and proliferation Phosphodiesterase type 5 inhibitor Adapted from: Humbert, et al. N Engl J Med. 2004;351:1425-1436. cAMP Prostacyclin derivates Vasodilatation and antiproliferation Prostacyclin Pathway • Prostacyclin – – – – Produced primarily by endothelial cells Induces potent vasodilation of vascular beds Inhibits platelet aggregation Cytoprotective and antiproliferative properties • Prostacyclin analogs Epoprostenol Continuous IV infusion, inhalation Iloprost Inhalation Treprostinil Subcutaneous, IV, inhalation, oral Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Endothelin Pathway • Endothelin – Plasma levels are elevated in patients with PAH – Increases vasoconstriction – Mitogenic properties • Endothelin receptor antagonists Bosentan Oral Ambrisentan Oral Macitentan Oral Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Nitric Oxide Pathway • Nitric oxide L-Arginine – Impairment of nitric oxide (NO) synthesis and signaling in patients with PAH – Mediated through the NO-sGC-cGMP pathway NOS L-Citrulline NO sGC PDE-5 cGMP GMP Vasodilation Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Nitric Oxide Pathway • Phosphodiesterase-5 inhibitors – Inhibit the cGMP degrading enzyme, PDE-5 – Enhance the pathway, slowing cGMP Sildenafil degradation Tadalafil – Vasodilation and antiproliferative effects Oral, IV Oral • Soluble guanylate cyclase stimulators Riociguat – Increase cGMP production – Antiproliferative and antiremodeling properties Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Oral Evidence-Based Treatment Algorithm WHO FC II IA/B Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat WHO FC III Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Epoprostenol IV Iloprost inhalation Treprostinil sc, inhalation Treprostinil IV IIaC WHO FC IV Epoprostenol IV Sequential Sequential Combination Combination Therapy Therapy + PA Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Iloprost inhalation Treprostinil sc, inhalation, IV ERA + + PDE-5i sGCS Inadequate clinical response on maximal therapy Interventional Procedure BAS IIbC Initial combination therapy Initial combination therapy Lung Transplantation Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 39 Initial Therapy for PAH Strength of recommendation and clinical evidence IA/B WHO FC II Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat WHO FC III Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Epoprostenol IV Iloprost inhalation Treprostinil sc, inhalation Epoprostenol IV Treprostinil IV Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Iloprost inhalation Treprostinil sc, inhalation, IV Initial combination therapy Initial combination therapy IIaC IIbC WHO FC IV Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Epoprostenol for PAH • Prostacyclin analog • Indication – functional class III and IV • Administration – Continuous IV infusion via central venous catheter – Inhalation form is available in the hospital • Dosage = 20 – 40 ng/kg/min • Two branded versions of epoprostenol are available: – One is only stable at room temperature for 8 hours; therefore, it must be kept cool (ice packs or refrigeration) – Other is a thermostable formulation Epoprostenol for PAH Patient Survival Epoprostenol (N = 41) 100 Patient Survival (%) P = 0.003 80 Conventional therapy (N = 40) 60 40 20 0 0 2 Barst, et al. N Engl J Med. 1996;334:296-301. 4 6 8 10 12 Weeks Treprostinil for PAH • Prostacyclin analog • Indication – functional class II, III, and IV • Administration – – – – Subcutaneous (SC) IV Inhalation Oral (extended-release tablets; twice daily dosing) • Dosage – Initial dosage = 1.25 ng/kg/min – Usual dosage = 30 – 100 ng/kg/min Treprostinil SC for PAH Change in 6-MWD (From Baseline to Week 12) 40 36.1 N = 470 35 P = 0.03 30 25 20 20 15 10 5 3.3 1.4 0 < 5.0 ng/kg/min 5.0 - 8.1 ng/kg/min Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4. 8.2 – 13.8 ng/kg/min > 13.8 ng/kg/min Treprostinil IV for PAH N = 14 *P < 0.05 Change in Functional Class Number of Patients Change from Baseline (meters) Change in 6-MWD* Weeks Tapson, et al. Chest. 2006;129:683-8. Baseline 12 Weeks Treprostinil Inhalation for PAH: TRIUMPH Clinical Trials RCT1 Open-label extension2 • N = 212 patients who were symptomatic on bosentan or sildenafil • Addition of treprostinil up to 54 μg, four times daily for 12 weeks • Study results – significantly greater improvement in 6-MWD and quality of life with combination therapy • N = 206 • Treprostinil with bosentan (69%) or sildenafil (31%) for 24 months • Study results – treatment benefit and improvements in 6MWD, symptoms, functional class, and quality of life were maintained for 24 months 1) McLaughlin, et al. J Am Coll Cardiol. 2010;55(18):1915-22. 2) Benza, et al. J Heart Lung Transplant. 2011;30(12):1327-33. Treprostinil Oral for PAH: FREEDOM-C Clinical Trial • Study design – Randomized, double-blind, placebo-controlled study – N = 350 patients with background ERA or PDE-5 inhibitor – Study duration = 16 weeks • Study results – High discontinuation rate: 22% of treprostinil-treated patients and 14% of placebo-treated patients – Improvement in 6-MWD did not reach statistical significance – Reduced efficacy may be due to the low dose of treprostinil or presence of background therapy Tapson, et al. Chest. 2012;142(6):1383-90. Treprostinil Oral for PAH: FREEDOM-M Clinical Trial • Study Design * Change from Baseline (meters) – Randomized, doubleblind, placebo-controlled study – N = 228 treatment-naïve patients, no background therapy permitted – Study duration = 12 weeks Change in 6-MWD *P < 0.05 * Weeks Jing, et al. Circulation. 2013;127:624-33. Iloprost for PAH • Prostacyclin analog • Indication – functional class III and IV • Administration – Ultrasonic nebulizer used in well-ventilated areas – Theoretical advantage of pulmonary vs systemic drug delivery • Dosage – Usual dosage = 2.5-5 μg, 6 to 9 times daily – Maximum dosage = 45 μg Iloprost for PAH Composite Primary Endpoint (at Week 12) Responders (% Patients) 45 43 40 35 P = 0.0033 30 25 20 26 25 19 15 10 5 0 13 8 4 10% Improvement in 6-MWD Improvement in Functional Class Olschewski, et al. N Engl J Med. 2002;347:322-9. 4 Death or Clinical Composite Primary Worsening Endpoint N = 203 Placebo Iloprost Bosentan for PAH • Endothelin receptor antagonist • Indication – functional class II, III, and IV • Administration – oral • Dosage = 62.5 mg twice daily for 4 weeks, then titrate to 125 mg twice daily Bosentan for PAH: BREATHE Clinical Trial Change in 6-MWD (From Baseline to Week 16) Change from Baseline (meters) 80 60 Bosentan (N = 144) 40 20 P = 0.0002 0 -20 Placebo (N = 69) -40 62.5 mg twice daily 4 Rubin, et al. N Engl J Med. 2002;346:896-903. 125 or 250 mg twice daily 8 16 Weeks Bosentan for PAH: EARLY Clinical Trial Change in 6-MWD (From Baseline to Week 24) Change from Baseline (meters) 25 20 15 11.2 10 Bosentan (N = 86) P = 0.076 5 0 5 10 - 7.9 15 20 12 Weeks Galie, et al. Lancet. 2008.371(9630):2093-100. Valerio et al. Vasc Health Risk Manag. 2009;5:607-19. Placebo (N = 91) 24 Weeks Bosentan for PAH: EARLY Clinical Trial Time to Clinical Worsening (From Baseline to Week 32) Event-Free Patients (%) 100 P < 0.02 80 Placebo Bosentan 60 40 20 0 0 4 8 12 Galie, et al. Lancet. 2008.371(9630):2093-100. Valerio et al. Vasc Health Risk Manag. 2009;5:607-19. 16 20 24 28 32 Weeks Ambrisentan for PAH • Endothelin receptor antagonist • Indication – functional class II, III, and IV • Administration – oral • Dosage = 5 mg and 10 mg daily Ambrisentan for PAH Change in 6-MWD (From Baseline to Week 12) ARIES-1 Change from Baseline (meters) 50 ARIES-2 N = 202 44* 60 *P < 0.05 N = 192 49* 10 mg 5 mg 40 23* 25 22* 5 mg 2.5 mg 20 0 0 -8 Placebo -10 Placebo -20 -25 4 8 Galie, et al. Circulation. 2008;117:3010-9. 12 Weeks 4 8 12 Weeks Ambrisentan for PAH: ARIES Clinical Trials Time to Clinical Worsening (From Baseline to Week 12) Event-Free Patients (%) 100 --- Placebo --- 2.5 mg (P = 0.03) --- 5 mg (P = 0.005) --- 10 mg (P = 0.03) 90 80 70 0 4 8 12 Weeks Ambrisentan → 71% relative risk reduction Galie, et al. Circulation. 2008;117:3010-9. Ambrisentan for PAH: ARIES-3 Clinical Trial Patient Population (N = 224) Study Results • Change in 6-MWD from baseline to week 24 – Increased by 21 meters (P < 0.05) • Change in BNP levels from baseline to week 24 – Decreased by 26% Badesch, et al. Cardiovasc Ther. 2012;30(2):93-9. Ambrisentan for PAH: ARIES-E Clinical Trial Change from Baseline (meters) Change 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 30 20 10 0 -10 -20 28 23 7 0.0 0.25 0.5 1.0 1.5 2.0 Years Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81. Macitentan for PAH • Endothelin receptor antagonist – Sustained receptor binding and enhanced tissue penetration • Indication – functional class II, III, and IV • Administration – oral • Dosage = 10 mg daily Macitentan for PAH: SERAPHIN Clinical Trials RCT1 Open-label extension2 • N = 742 • Macitentan 3 mg or 10 mg once daily • Study duration = event driven • Study endpoint = time to clinical worsening • N = 550 • Macitentan 10 mg once daily • Study duration = event driven • Study endpoint = safety 1) www.clinicaltrials.gov/ct2/show/NCT00660179 2) www.clinicaltrials.gov/ct2/show/NCT00667823 Macitentan for PAH: SERAPHIN Clinical Trial 3 mg 10 mg N = 250 N = 242 Duration of treatment (event driven) 99.5 weeks 103.9 weeks Risk reduction in the occurrence of morbidity and mortality events versus placebo (N = 250) 30% (P < 0.05) 45% (P < 0.05) With background therapy 17% 38% Without background therapy 47% 55% Overall risk reduction: Pulido, et al. NEJM. 2013;369(9):809-18. Sildenafil for PAH • Phosphodiesterase-5 inhibitor – targets the nitric oxide pathway • Indication – functional class II, III, and IV • Administration and dosage – Oral = 20 mg three times daily – IV = 10 mg three times daily Sildenafil for PAH: SUPER-1 Clinical Trial Change in Functional Class Change in 6-MWD Galie, et al. N Engl J Med. 2005;353:2148-57. Patients With an Improvement In Functional Class (%) Placebo-Adjusted Change from Baseline (meters) P < 0.05 P < 0.05 Sildenafil for PAH: SUPER-2 Clinical Trial Study Design Study Results • Long-term, open-label extension • N = 170 patients who completed both studies • Sildenafil 80 mg three times daily • Second agent added in 18% of patients by end of study period (3 years) • 6-MWD – Maintained or improved in 46% of patients • Functional class – Maintained or improved in 60% of patients • Estimated patient survival rate at 3 years = 79% Rubin, et al. Chest. 2011:140(5):1274-83. Sildenafil for PAH: PACES Clinical Trial Study Design Study Results • Randomized, double-blind, placebo-controlled study • Sildenafil 80 mg three times daily in combination with epoprostenol (N = 214) compared to epoprostenol monotherapy (N = 53) • Study duration = 16 weeks • 6-MWD Simonneau, et al. Ann Intern Med. 2008;149(8):521-30. *P < 0.05 – Placebo-adjusted improvement = 28 meters* • Clinical worsening event – 6% vs 18.5% of patients on monotherapy* • Time to clinical worsening – Significant delay compared to monotherapy* Tadalafil for PAH • Phosphodiesterase-5 inhibitor – targets the nitric oxide pathway • Indication – functional class II, III, IV • Administration – oral • Dosage = 40 mg daily Tadalafil for PAH: PHIRST-1 Clinical Trial Study Design Study Results • Randomized, double-blind, placebo-controlled study • Tadalafil in combination with bosentan (N = 216) compared to tadalafil monotherapy (N = 189) • Study duration = 16 weeks • 6-MWD *P < 0.05 (40 mg dose) – Significant improvement* but less than monotherapy • Quality of life – Significant improvement • Clinical worsening events – Significantly less* – 68% relative risk reduction • Time to clinical worsening – Significant delay* Galie, et al. Circulation. 2009;119(22):2894-903. Barst, et al. J Heart Lung Transplant. 2011;30(6):632-43. Tadalafil for PAH: PHIRST-2 Clinical Trial Study Design • Long-term, open-label extension • N = 293 patients from PHIRST-1 • Tadalafil 20 mg or 40 mg once daily • Background bosentan permitted (54% of patients) • Study duration = 52 weeks Oudiz, et al. J Am Coll Cardiol. 2012;60:768-74. Study Results • 6-MWD – Sustained improvement through long-term extension (68 weeks total) • Clinical worsening events – Significantly less in patients on combination therapy Riociguat for PAH • Soluble guanylate cyclase stimulator – targets the nitric oxide pathway • Indication – functional class II, III, and IV • Administration – oral • Dosage = 1 mg – 2.5 mg three times daily Riociguat for PAH: PATENT Clinical Trials RCT1 • N = 445 • Riociguat 1 mg, 1.5 mg, 2 mg, or 2.5 mg three times daily • Study duration = 12 weeks • Study endpoint = 6-MWD Open-label extension2 • N = 396 • Riociguat 1 mg, 1.5 mg, 2 mg, or 2.5 mg three times daily • Study duration = event driven • Study endpoint = safety 1) www.clinicaltrials.gov/ct2/show/NCT00810693 2) www.clinicaltrials.gov/ct2/show/NCT00863681 Riociguat for PAH: PATENT Clinical Trial Change from Baseline (meters) Change in 6-MWD N = 443 *P < 0.05 P < 0.05 Ghofrani, et al. NEJM. 2013;369(4):330-40. Significant Improvement* PVR NT-proBNP Functional class Borg Dyspnea Scale score Quality of life measures Time to clinical worsening Combination Therapy for PAH • To target multiple disease pathways • Used when therapy needs to be augmented because response to initial therapy is inadequate • Sequential combination therapy – Starting in one drug class and adding an agent from another drug class when necessary • REVEAL: 34% of patients on 2 or more treatments Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Badesch, et al. Chest. 2010;137(2):376-87. Combination Therapy for PAH Clinical Study Agents N Study Duration Study Endpoints Statistical Significance BREATHE-21 Epoprostenol Bosentan 33 16 weeks Hemodynamics, 6-MWD, functional class No STEP-12 Iloprost Bosentan 67 12 weeks Hemodynamics, 6-MWD, functional class, TTCW Yes COMBI3 Iloprost Bosentan 40 12 weeks 6-MWD, functional class, TTCW No 1) Humbert, et al. Eur Respir J. 2004;24:353-9. 2) McLaughlin, et al. Am J Respir Crit Care Med. 2006;174:1257-63. 3) Hoeper, et al. Eur Respir J. 2006;28:691-4. Early Initiation of Combination Therapy for PAH • Combination therapy used in early PAH disease • Debated by clinicians and researchers • May improve patient outcomes • May prevent or slow disease progression • May reduce costs associated with managing clinical worsening • Well-controlled studies are needed to test this practice Affuso, et al. World J Cardiol. 2010;2(3):68-70. Combination Therapy for PAH Clinical Study Status Study Design Study Study Duration Endpoints Agents N RCT Sildenafil +/Bosentan 334 Event driven TTCW COMPASS-21 Ongoing COMPASS-32 Completed OL Bosentan +/Sildenafil 100 28 weeks 6-MWD NCT00323297 Completed RCT Bosentan +/Sildenafil 104 12 weeks 6-MWD TTCW 858 Event driven TTCW 6-MWD FREEDOM-Ev3 Ongoing RCT* • Treprostinil oral + PDE-5i or ERA • PDE-5i or ERA AMBITION4 Ongoing RCT* Ambrisentan +/Tadalafil 614 Event driven TTCW ATHENA-15 Completed OL Sildenafil or Tadalafil +/- Ambrisentan 38 24 weeks PVR 1) NCT00303459; 2) NCT00433329; 3) NCT01560624; 4) NCT01178073; 5) NCT00617305 *Early combination therapy Interventional Procedures: Balloon Atrial Septostomy • In order to: – – – – – Decompress right heart chambers Increase left ventricle preload Increase cardiac output Improve systemic oxygen transport Decrease sympathetic hyperactivity • Creation of an interatrial right-to-left shunt • Considered a palliative or bridging procedure – Patients refractory to medical therapy – Patients awaiting lung transplantation Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Interventional Procedures: Lung Transplantation • Surgical procedures – Single lung transplant – Bilateral lung transplant – most common – Heart-lung transplant – increasingly less common, with about 70 – 90 performed every year* • Lung transplantation remains the standard of care for patients with PAH who fail aggressive medical therapy, until the age of 75 (depending on the transplant center) *Long, et al. Pulm Circ. 2011;1(3):327-33. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. ISHLT Guidelines for Lung Transplantation Persistent functional class III or IV despite maximal medical therapy Low (< 350 meters) or declining 6-MWD Failing even while on a parenteral prostacyclin analog Cardiac index < 2 L/min/m2 Right atrial pressure > 15 mm Hg ISHLT = International Society for Heart Lung Transplantation Long, et al. Pulm Circ. 2011;1(3):327-33. Goal-Directed Therapy Diagnosis of PAH Vasoreactivity test: negative Baseline exam and 3 - 6 monthly re-evaluation to assess treatment goals: Clinically stable, functional class II, 6-MWD > 400 meters, RAP / CI normal Treatment goals NOT met Treatment goals met Start ERA or PDE-5i Continue treatment Add ERA or PDE-5i Continue treatment Parenteral PA and / or enrollment in clinical trials Continue treatment Urgent lung transplantation Adapted from: Hoeper, et al. Eur Respir J. 2005;26:858-63. Prognostication: Determinants of Patient Risk ACC / AHA Expert Consensus Low risk Determinants of risk High risk No Clinical evidence of RV failure Yes Gradual Disease progression Rapid II, III WHO functional class IV Longer (> 400 meters) 6-MWD Shorter (< 300 meters) Peak VO2 > 10.4 mL/kg/min Cardiopulmonary exercise testing Peak VO2 < 10.4 mL/kg/min Minimally elevated and stable BNP / NT-proBNP Significantly elevated PaCO2 > 34 mm Hg Blood gasses PaCO2 < 32 mm Hg Minimal RV dysfunction ECHO cardiography Pericardial effusion, RV dysfunction, RA enlargement RAP < 10 mm Hg; CI > 2.5 L/min/m2 Pulmonary hemodynamics RAP > 20 mm Hg; CI < 2 L/min/m2 McLaughlin, et al. Circulation. 2006;114:1417-31. McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. REVEAL Risk Calculator Parameter Low risk Score High risk Score Type of PAH Heritable CTD Portal hypertension +2 +1 +2 Demographics/ Comorbidities Male > 60 years old Renal insufficiency +2 +1 III IV +1 +2 SBP < 110 mm Hg HR > 92 bpm +1 +1 Functional class I -2 Vital signs 6-MWD ≥ 440 meters -1 < 165 meters +1 BNP < 50 pg/mL -2 > 180 pg/mL +1 Pericardial effusion +1 % pred DLCO ≤ 32% +1 mPAP > 20 mm Hg PVR > 32 WU +1 +2 ECHO PFT RHC % pred DLCO ≥ 80% -1 Benza, et al. Circulation. 2010;122:164-72. Benza, et al. Chest. 2012;141:354-62. Clinical Endpoints Exercise Capacity 6-MWD CPET Treadmill Functional Class Imaging Cardiac MRI 2D 3DE Gomberg-Maitland, et al. J Am Coll Cardiol. 2013;62(25):S82-91. Biomarkers BNP / NT-proBNP Hemodynamics (PVR, PAP, CO) Clinical Variables Quality of life TTCW Time to Clinical Worsening • Composite endpoint of adverse clinical events: - Death - Lung transplantation - Hospitalization for worsening PAH - Initiation of IV therapy due to worsening PAH - Worsening of function - Worsening of PAH symptoms Gomberg-Maitland, et al. J Am Coll Cardiol. 2013;62(25):S82-91. Longitudinal Patient Monitoring ACCF / AHA Recommendations Stable patient Unstable patient Patient Evaluation 6-MWD Every 3-6 months Every visit Every 1-3 months Every visit Functional Class Every visit Every visit BNP ECHO RHC Center dependent Every 12 months If clinical deterioration Every 6-12 months Every 6-12 months or if clinical deterioration Center dependent McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. McLaughlin. Am J Cardiol. 2013;111:S10-5. Treatment Goals 6-MWD CPET > 380 – 440 meters Peak VO2 > 15 mL/min/kg EqCO2 < 45 L/min Functional Class I or II McLaughlin, et al. J Am Coll Cardiol. 2013;62(25):S73-81. BNP ECHO Hemodynamics Normal levels Normal or near normal RV size and function RAP < 8 mm Hg CI > 2.5 - 3 L/min/m2 Ongoing Clinical Research in PAH • PAH is a chronic, debilitating disease with significant associated morbidity and mortality • A cure for PAH has yet to be discovered • Standard treatment eventually becomes inadequate • Enrollment in clinical trials posits patients for cutting-edge therapies Investigational Agents for PAH Selexipag • Prostacyclin IP receptor agonist • Targets the prostacyclin pathway • GRIPHON clinical trials1,2 • Research is ongoing Imatinib • Tyrosine kinase inhibitor • PDGF receptor inhibitor (vascular remodeling) • Antiproliferative • IMPRES clinical trials3,4,5 • Regulatory consideration has been terminated 1) NCT01106014; 2) NCT01112306; 3) NCT00902174; 4) NCT01117987; 5) Hoeper, et al. Circulation. 2013;127(10): 1128-38. Summary • Management of patients with PAH involves a complex strategy which includes supportive therapy and diseasetargeted medications. • The evidence-based treatment algorithm for PAH streamlines decision making and drug selection. • Combination therapy is the standard of care when initial therapy becomes inadequate. • Prognostication and patient monitoring involves the use of clinically-relevant parameters and endpoints.