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Presentation on theme: "Acknowledgements ABcomm, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for."— Presentation transcript:

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2 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.

3 Targeted Approach to Treatment of PAH

4 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.

5 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

6 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.

7 General Measures and Supportive Therapy Adapted from: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

8 General Measures and Supportive Therapy Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 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

9 General Measures and Supportive Therapy Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Supportive Therapy Anticoagulants Diuretics Oxygen Digoxin

10 General Measures and Supportive Therapy Adapted from: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 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

11 General Measures and Supportive Therapy Agarwal, et al. Am Heart J. 2011;162:201-13. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 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 Amlodipine20 – 30 mg/day Nifedipine180 – 240 mg/day Diltiazem720 – 960 mg/day

12 Mechanisms of Pathology for PAH Adapted from: Humbert, et al. N Engl J Med. 2004;351:1425-1436. Nitric oxide cGMP Vasodilatation and antiproliferation Endothelial 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 GTP sGC stimulator

13 Prostacyclin Pathway Prostacyclin –Produced primarily by endothelial cells –Induces potent vasodilation of vascular beds –Inhibits platelet aggregation –Cytoprotective and antiproliferative properties Prostacyclin analogs Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. EpoprostenolContinuous IV infusion, inhalation IloprostInhalation TreprostinilSubcutaneous, IV, inhalation, oral

14 Endothelin Pathway Endothelin –Plasma levels are elevated in patients with PAH –Increases vasoconstriction –Mitogenic properties Endothelin receptor antagonists Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. BosentanOral AmbrisentanOral MacitentanOral

15 Nitric Oxide Pathway Nitric oxide –Impairment of nitric oxide (NO) synthesis and signaling in patients with PAH –Mediated through the NO-sGC-cGMP pathway NOSNOsGCcGMP Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. L-ArginineL-Citrulline GMP Vasodilation PDE-5

16 Nitric Oxide Pathway Phosphodiesterase-5 inhibitors –Inhibit the cGMP degrading enzyme, PDE-5 –Enhance the pathway, slowing cGMP degradation –Vasodilation and antiproliferative effects Soluble guanylate cyclase stimulators –Increase cGMP production –Antiproliferative and antiremodeling properties Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. SildenafilOral, IV TadalafilOral RiociguatOral

17 Evidence-Based Treatment Algorithm Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. WHO FC IIWHO FC IIIWHO FC IV Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Epoprostenol IV Iloprost inhalation Treprostinil sc, inhalation Epoprostenol IV Treprostinil IVBosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Iloprost inhalation Treprostinil sc, inhalation, IV Initial combination therapy Sequential Combination Therapy Interventional Procedure IA/B IIbC IIaC ERA PAPDE-5i sGCS BAS Lung Transplantation Inadequate clinical response Inadequate clinical response on maximal therapy + + + Lung Transplantation Interventional Procedure Sequential Combination Therapy 39

18 Initial Therapy for PAH WHO FC IIWHO FC IIIWHO FC IV Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Epoprostenol IV Iloprost inhalation Treprostinil sc, inhalation Epoprostenol IV Treprostinil IVBosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Iloprost inhalation Treprostinil sc, inhalation, IV Initial combination therapy Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. IA/B IIbC IIaC Strength of recommendation and clinical evidence Strength of recommendation and clinical evidence

19 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

20 100 80 60 40 20 0 Weeks Epoprostenol (N = 41) 024681210 Conventional therapy (N = 40) Patient Survival (%) P = 0.003 Barst, et al. N Engl J Med. 1996;334:296-301. Epoprostenol for PAH Patient Survival

21 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

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

23 Treprostinil IV for PAH Change in 6-MWD* Change from Baseline (meters) Tapson, et al. Chest. 2006;129:683-8. Weeks Number of Patients Change in Functional Class 12 Weeks Baseline N = 14 *P < 0.05

24 Treprostinil Inhalation for PAH: TRIUMPH Clinical Trials RCT 1 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 Open-label extension 2 N = 206 Treprostinil with bosentan (69%) or sildenafil (31%) for 24 months Study results – treatment benefit and improvements in 6- MWD, 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.

25 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.

26 Treprostinil Oral for PAH: FREEDOM-M Clinical Trial Study Design –Randomized, double- blind, placebo-controlled study –N = 228 treatment-naïve patients, no background therapy permitted –Study duration = 12 weeks Jing, et al. Circulation. 2013;127:624-33. Weeks Change in 6-MWD Change from Baseline (meters) * P < 0.05 * *

27 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

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

29 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

30 62.5 mg twice daily 125 or 250 mg twice daily -40 -20 0 20 40 60 80 Bosentan (N = 144) Placebo (N = 69) 48 16 Weeks P = 0.0002 Change from Baseline (meters) Rubin, et al. N Engl J Med. 2002;346:896-903. Bosentan for PAH: BREATHE Clinical Trial Change in 6-MWD (From Baseline to Week 16)

31 Bosentan for PAH: EARLY Clinical Trial Change in 6-MWD (From Baseline to Week 24)  10 55 0 5 10 15 20 12 Weeks24 Weeks Placebo (N = 91) Bosentan (N = 86) P = 0.076 25  20 1515 Change from Baseline (meters) Galie, et al. Lancet. 2008.371(9630):2093-100. Valerio et al. Vasc Health Risk Manag. 2009;5:607-19. 11.2 - 7.9

32 Bosentan for PAH: EARLY Clinical Trial Time to Clinical Worsening (From Baseline to Week 32) 100 80 60 40 20 0 048121620282432 Event-Free Patients (%) Placebo Bosentan P < 0.02 Weeks Galie, et al. Lancet. 2008.371(9630):2093-100. Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.

33 Ambrisentan for PAH Endothelin receptor antagonist Indication – functional class II, III, and IV Administration – oral Dosage = 5 mg and 10 mg daily

34 Ambrisentan for PAH Change in 6-MWD (From Baseline to Week 12) Galie, et al. Circulation. 2008;117:3010-9.

35 Ambrisentan for PAH: ARIES Clinical Trials Time to Clinical Worsening (From Baseline to Week 12) --- Placebo --- 2.5 mg (P = 0.03) --- 5 mg (P = 0.005) --- 10 mg (P = 0.03) 70 80 90 100 04812 Weeks Event-Free Patients (%) Ambrisentan → 71% relative risk reduction Galie, et al. Circulation. 2008;117:3010-9.

36 Ambrisentan for PAH: ARIES-3 Clinical Trial 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. Patient Population (N = 224)

37 Ambrisentan for PAH: ARIES-E Clinical Trial Change in 6-MWD (From Baseline to 24 Months) Change from Baseline (meters) Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.

38 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

39 Macitentan for PAH: SERAPHIN Clinical Trials RCT 1 N = 742 Macitentan 3 mg or 10 mg once daily Study duration = event driven Study endpoint = time to clinical worsening Open-label extension 2 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/NCT00667823www.clinicaltrials.gov/ct2/show/NCT00660179www.clinicaltrials.gov/ct2/show/NCT00667823

40 Macitentan for PAH: SERAPHIN Clinical Trial 3 mg10 mg N = 250N = 242 Duration of treatment (event driven)99.5 weeks103.9 weeks Risk reduction in the occurrence of morbidity and mortality events versus placebo (N = 250) 30% (P < 0.05) 45% (P < 0.05) Overall risk reduction:  With background therapy  Without background therapy 17% 47% 38% 55% Pulido, et al. NEJM. 2013;369(9):809-18.

41 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

42 Sildenafil for PAH: SUPER-1 Clinical Trial Galie, et al. N Engl J Med. 2005;353:2148-57. Placebo-Adjusted Change from Baseline (meters) Change in 6-MWD P < 0.05 Change in Functional Class Patients With an Improvement In Functional Class (%) P < 0.05

43 Sildenafil for PAH: SUPER-2 Clinical Trial Study Design 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) Study Results 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.

44 Sildenafil for PAH: PACES Clinical Trial Study Design 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 Study Results 6-MWD –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* Simonneau, et al. Ann Intern Med. 2008;149(8):521-30. *P < 0.05

45 Tadalafil for PAH Phosphodiesterase-5 inhibitor – targets the nitric oxide pathway Indication – functional class II, III, IV Administration – oral Dosage = 40 mg daily

46 Tadalafil for PAH: PHIRST-1 Clinical Trial Study Design Randomized, double-blind, placebo-controlled study Tadalafil in combination with bosentan (N = 216) compared to tadalafil monotherapy (N = 189) Study duration = 16 weeks Study Results 6-MWD –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. *P < 0.05 (40 mg dose)

47 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 Study Results 6-MWD –Sustained improvement through long-term extension (68 weeks total) Clinical worsening events –Significantly less in patients on combination therapy Oudiz, et al. J Am Coll Cardiol. 2012;60:768-74.

48 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

49 Riociguat for PAH: PATENT Clinical Trials RCT 1 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 extension 2 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/NCT00863681www.clinicaltrials.gov/ct2/show/NCT00810693www.clinicaltrials.gov/ct2/show/NCT00863681

50 Riociguat for PAH: PATENT Clinical Trial Significant Improvement* PVR NT-proBNP Functional class Borg Dyspnea Scale score Quality of life measures Time to clinical worsening Ghofrani, et al. NEJM. 2013;369(4):330-40. Change in 6-MWD P < 0.05 Change from Baseline (meters) N = 443 *P < 0.05

51 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 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

52 Combination Therapy for PAH Clinical StudyAgentsN Study DurationStudy Endpoints Statistical Significance BREATHE-2 1 Epoprostenol Bosentan 3316 weeks Hemodynamics, 6-MWD, functional class No STEP-1 2 Iloprost Bosentan 6712 weeks Hemodynamics, 6-MWD, functional class, TTCW Yes COMBI 3 Iloprost Bosentan 4012 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.

53 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.

54 Combination Therapy for PAH Clinical StudyStatus Study DesignAgentsN Study Duration Study Endpoints COMPASS-2 1 OngoingRCT Sildenafil +/- Bosentan 334 Event driven TTCW COMPASS-3 2 CompletedOL Bosentan +/- Sildenafil 10028 weeks6-MWD NCT00323297CompletedRCT Bosentan +/- Sildenafil 10412 weeks 6-MWD TTCW FREEDOM-Ev 3 Ongoing RCT * Treprostinil oral + PDE-5i or ERA PDE-5i or ERA 858 Event driven TTCW 6-MWD AMBITION 4 Ongoing RCT * Ambrisentan +/- Tadalafil 614 Event driven TTCW ATHENA-1 5 CompletedOL Sildenafil or Tadalafil +/- Ambrisentan 3824 weeksPVR 1) NCT00303459; 2) NCT00433329; 3) NCT01560624; 4) NCT01178073; 5) NCT00617305 * Early combination therapy

55 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.

56 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.

57 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/m 2 Right atrial pressure > 15 mm Hg ISHLT = International Society for Heart Lung Transplantation Long, et al. Pulm Circ. 2011;1(3):327-33.

58 Diagnosis of PAH Vasoreactivity test: negative 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 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 Add ERA or PDE-5i Parenteral PA and / or enrollment in clinical trials Urgent lung transplantation Continue treatment Goal-Directed Therapy Adapted from: Hoeper, et al. Eur Respir J. 2005;26:858-63.

59 Low riskDeterminants of riskHigh risk NoClinical evidence of RV failureYes GradualDisease progressionRapid II, IIIWHO functional classIV Longer (> 400 meters)6-MWDShorter (< 300 meters) Peak VO 2 > 10.4 mL/kg/min Cardiopulmonary exercise testing Peak VO 2 < 10.4 mL/kg/min Minimally elevated and stableBNP / NT-proBNPSignificantly elevated PaCO 2 > 34 mm HgBlood gassesPaCO 2 < 32 mm Hg Minimal RV dysfunctionECHO cardiography Pericardial effusion, RV dysfunction, RA enlargement RAP < 10 mm Hg; CI > 2.5 L/min/m 2 Pulmonary hemodynamics RAP > 20 mm Hg; CI < 2 L/min/m 2 McLaughlin, et al. Circulation. 2006;114:1417-31. McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. Prognostication: Determinants of Patient Risk ACC / AHA Expert Consensus

60 REVEAL Risk Calculator ParameterLow riskScoreHigh riskScore Type of PAH Heritable CTD Portal hypertension +2 +1 +2 Demographics/ Comorbidities Male > 60 years old Renal insufficiency +2 +1 Functional classI-2 III IV +1 +2 Vital signs SBP < 110 mm Hg HR > 92 bpm +1 6-MWD ≥ 440 meters< 165 meters+1 BNP < 50 pg/mL-2> 180 pg/mL+1 ECHO Pericardial effusion+1 PFT % pred DLCO ≥ 80% pred DLCO ≤ 32%+1 RHC mPAP > 20 mm Hg PVR > 32 WU +1 +2 Benza, et al. Circulation. 2010;122:164-72. Benza, et al. Chest. 2012;141:354-62.

61 Clinical Endpoints Exercise Capacity 6-MWD CPET Treadmill Functional Class Biomarkers BNP / NT-proBNP Hemodynamics (PVR, PAP, CO) Imaging Cardiac MRI 2D 3DE Clinical Variables Quality of life TTCW Gomberg-Maitland, et al. J Am Coll Cardiol. 2013;62(25):S82-91.

62 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.

63 Longitudinal Patient Monitoring ACCF / AHA Recommendations Patient Evaluation6-MWD Functional ClassBNPECHORHC Stable patient Every 3-6 months Every visit Center dependent Every 12 months If clinical deterioration Unstable patient Every 1-3 months Every visit Center dependent Every 6-12 months Every 6-12 months or if clinical deterioration McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. McLaughlin. Am J Cardiol. 2013;111:S10-5.

64 Treatment Goals 6-MWDCPET Functional ClassBNPECHOHemodynamics > 380 – 440 meters Peak VO 2 > 15 mL/min/kg EqCO 2 < 45 L/min I or II Normal levels Normal or near normal RV size and function RAP < 8 mm Hg CI > 2.5 - 3 L/min/m 2 McLaughlin, et al. J Am Coll Cardiol. 2013;62(25):S73-81.

65 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

66 Investigational Agents for PAH Selexipag Prostacyclin IP receptor agonist Targets the prostacyclin pathway GRIPHON clinical trials 1,2 Research is ongoing Imatinib Tyrosine kinase inhibitor PDGF receptor inhibitor (vascular remodeling) Antiproliferative IMPRES clinical trials 3,4,5 Regulatory consideration has been terminated 1) NCT01106014; 2) NCT01112306; 3) NCT00902174; 4) NCT01117987; 5) Hoeper, et al. Circulation. 2013;127(10): 1128-38.

67 Summary Management of patients with PAH involves a complex strategy which includes supportive therapy and disease- targeted 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.


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