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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. Pulmonary Arterial Hypertension: Aggressive Treatment for a Progressive Disease Complete Slide Set Learning Objectives Generalized Audience • Identify patients at high risk for the development of PAH. • Utilize right heart catheterization to confirm the diagnosis of PAH. • Evaluate right ventricular function using screening tools and imaging tests. • Weigh the risks versus benefits for a given mediation, in terms of indication for use, route of administration, side effects, and longterm study data. • Decide if and when combination therapy is a clinical necessity. • Analyze multiple clinical endpoints to determine if treatment is successful. Learning Objectives Specialized Audience • Suspect PAH when symptoms are out of proportion to “underlying disease” or if patient is not responding to traditional therapies. • Monitor high-risk patients for the hemodynamic and clinical features associated with PAH. • Design a course of treatment that takes into consideration drug administration, efficacy, and overall safety. • Intensify the treatment plan and consider combination therapy when right ventricular impairment or clinical decline is evident. • Appraise newly-approved agents for inclusion in the treatment algorithm for PAH. • Assess a patient’s prognosis based on proven determinants of risk. Lecture Outline • • • • • • • • Pathology and genetics Diagnostics The right ventricle in PAH High-risk patients Evidence-based treatment Ongoing research Combination therapy Prognostication and patient monitoring Epidemiology and History of PAH • Prevalence in the U.S. – ≈ 50,000 to 100,000 (15,000 to 25,000 diagnosed and treated) • Circa 1987 – Due to rapid progression of morbidity and mortality, once patients were diagnosed with pulmonary hypertension they were described as entering “the kingdom of the near-dead” • 2015 – Patient survival has dramatically improved as treatment options for PAH have increased McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. PAH is a diagnosis of exclusion Clinical Classification of Pulmonary Hypertension Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. Types of PAH Idiopathic Heritable • BMPR2 • ALK-1, ENG, SMAD9, CAV1, KCNK3 • Unknown Drug- and toxin-induced Associated with: • • • • • Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. Types of PAH: REVEAL Registry N = 2967 5.3% 5.3% 1.9% 3.5% 46.2% 9.8% 25.3% 2.7% Badesch, et al. Chest. 2010;137(2):376-87. Drug- and Toxin-Induced PAH Definite Likely Possible Unlikely • Aminorex • Fenfluramine • Dexfenfluramine • • • • • Toxic rapeseed oil • Benfluorex • SSRIs Amphetamines L-Tryptophan Methamphetamines Dasatinib • Cocaine • Phenylpropanolamine • St. John’s wort • Oral contraceptives • Estrogen • Cigarette smoking Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. • Chemotherapeutic agents • Interferon α and β • Amphetamine-like drugs PAH Associated With Connective Tissue Disease Scleroderma • Most prevalent and studied type of PAH associated with CTD • Rate of occurrence of PAH = 7 to 12% of patients with scleroderma; more common in limited scleroderma (CREST syndrome) • Prognosis is poorer than other types of PAH • PAH is the leading cause of death; 1 year mortality rate = 30% Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. Associated Conditions PAH Associated With: HIV infection Portal hypertension Rate of Occurrence of PAH 0.5% 2 – 6% Clinical Features Improvement in survival since HAART; 5-year survival > 70% Prognosis negatively impacted by cardiac dysfunction, severity of liver disease / cirrhosis Congenital heart disease 10% Presence of PAH has negative impact on clinical course Schistosomiasis 5% 3-year survival ≈ 85% Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. Patient Registries for PAH Registry Time Period N NIH 1981 – 1985 187 French 2002 – 2003 674 U.S. REVEAL 2006 – 2009 3515 U.S. PHC 1982 – 2006 578 PAH-QuERI 2005 – 2007 791 Scottish-SMR 1986 – 2001 374 Chinese 1999 – 2004 72 Spanish 1998 – 2008 866 U.K. 2001 – 2009 482 New Chinese Registry 2008 – 2011 956 Mayo 1995 – 2004 484 Compera 2007 – 2011 587 McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. Observations From Patient Registries for PAH • Older age at diagnosis – NIH registry: 36 (± 15 years) – REVEAL: 50 - 65 (± 15 years) • Population cohorts at greater risk – Patient demographic – advanced age, male gender – Etiology – heritable PAH, PAH associated with CTD or portal hypertension McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. Older Patients with PAH • Older age at diagnosis – More advanced, severe disease – Greater number of comorbidities Presence of comorbid conditions can mask symptoms of PAH and delay diagnosis, and may contribute to morbidity and mortality • Treatment strategies for older patients – Exact influence of age on treatment success is unknown – Older patients are underrepresented in clinical studies Hoeper, et al. Eur Resp Rev. 2014;23(134):450-7. Comorbid Conditions in Patients with PAH Patients (%) N = 2959 Poms, et al. Chest. 2013;144(1):169-76. Patient Registries for PAH: Outcome Predictors Low Risk High Risk Male gender, advanced age Etiology – heritable, associated with CTD or portal hypertension Patient demographics Functional capacity Lower FC Longer 6-MWD Higher FC Shorter 6-MWD Laboratory / Biomarkers Lower BNP, NT-proBNP Higher BNP, NT-proBNP Higher creatinine ECHO – pericardial effusion Imaging Lung function studies Higher predicted DLCO Lower predicted DLCO Hemodynamics Higher CO or CI Higher mRAP or PVR Lower CO or CI McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. Patient 3-Year Survival Rates: REVEAL Registry P < 0.05 N = 263 Barst, et al. Chest. 2013;144(1):160-8. N = 645 N = 74 Pathology of Pulmonary Hypertension Plexiform lesion Thrombus Overview • Obstructive lung panvasculopathy • Prognosis is primarily determined by the functional status of the RV • Most common cause of death is RV failure Dilated vessels Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. Image: www.pathhsw5m54.ucsf.edu/Image61.html Pathology of Pulmonary Hypertension Interplay of several pathobiological and environmental factors on a “background of genetic predisposition” Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. Pathology of Pulmonary Hypertension Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. 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 Genetic Mutations in PAH • BMPR2 – – – – Major predisposing gene Over 300 mutations have been identified Found in >70% of patients with H-PAH Found in ≈ 20% of patients with IPAH • ALK-1 – Major gene when PAH is associated with hereditary hemorrhagic telanglectasia (HHT) • Less common mutations: – Endoglin, SMAD9, Caveolin-1, KCNK3 Soubrier, et al. J Am Coll Cardiol. 2013;62(25):S13-21. BMPR2 Group 1’ Pulmonary Hypertension • Overlapping pathological features – Disordered endothelial growth or proliferation – Histologic changes in pulmonary parenchyma – Development of pulmonary arterial intimal thickening and medial hypertrophy • May have similar clinical presentation • Genetic predisposition – Mutations in BMPR2, EIF2AK4? Langleben. Chest. 2014;145(2):197-8. Simonneau, et al. J Am Coll Cardiol. 2009;54:S43-54. Genetic Screening and Counseling • Screening recommendations – Subject to debate since it is impossible to determine which carriers of a mutation will develop PAH Patients with a family history of H-PAH Patients with IPAH, to determine if they are genetic carriers • Counseling – Schedule for routine evaluation – Considerations for family planning Soubrier, et al. J Am Coll Cardiol. 2013;62(25):S13-21. Definition of Pulmonary Hypertension • General definition – Mean PAP ≥ 25 mm Hg at rest, measured by right heart catheterization • Hemodynamic characterization of PAH – Mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm Hg, elevated PVR (> 3 Wood Units) Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. Diagnostic Algorithm for PAH: Consensus From 5th WSPH PAH is a diagnosis of exclusion Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. Clinical Presentation of PAH Symptoms • • • • • • • Dyspnea Fatigue Syncope Weakness Angina Abdominal distension Edema McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. Signs • Loud P2 (listen at apex) • RV lift (left parasternal – fingertips) • RV S3, RV S4 • Systolic murmur (TR; inspiratory augmentation) • Early systolic click • Midsystolic ejection murmur • Diastolic murmur (PR) • Increased jugular “a” wave Echocardiography for PAH • Screening tool, NOT a diagnostic tool • Non-invasive estimation of PAP • Examine ECHO results for: – RV size and function – Left ventricular systolic and diastolic dysfunction – Left-sided chamber enlargement – Valvular heart disease • Examine ECHO with contrast results for intracardiac shunt Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66. Screening Tools and Tests Test Results ECG RV hypertrophy and strain; right atrial dilatation CXR Enlarged pulmonary arteries, right heart structures PFT and ABG Airflow obstruction V/Q scan Pulmonary disease; CTEPH Blood tests and immunology Liver disease, CTD, HIV Galie, et al. Eur Heart J. 2009;30:2493-2537. Preston. Am J Cardiol. 2013;111(8):S2-9. Right Heart Catheterization for PAH Required test for diagnostic confirmation • Measures: – – – – PAP PAWP CO RAP • Allows calculation of pulmonary and systemic vascular resistance Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66. Anatomy and Physiology of the RV and LV Complex interplay between contractility, afterload, compliance, and heart rate Subject to significant size and shape change Rich. Cardiol Clin. 2012;30:257-69. Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7. RV Failure Syndrome Pulmonary hypertension ↑ PAP (pressure overload) Adaptive RV hypertrophy Progressive contractile impairment RV dilatation Contractile dysfunction progresses RV failure: High RV filling pressures, diastolic dysfunction, ↓ CO Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. Continuum of RV Impairment and Action Towards Reversal • When compensatory mechanisms in the RV are exceeded, RV dysfunction develops • RV failure manifests clinically as exercise limitation and fluid retention • FDA-approved therapies for PAH reverse RV remodeling – Reduction of afterload – Vasodilation Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. RV Failure Syndrome • Clinical evidence – Peripheral edema, angina, syncopal episodes, RV S3, elevated JVP, hepatojugular reflux, ascites, hepatomegaly, cool extremities • Treatment – Decrease afterload with drugs targeting pulmonary circulation – Manage fluids to optimize volume overload and ventricular diastolic interactions – Use inotropic interventions to reverse cardiogenic shock Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. Evaluation of RV Function Echocardiography • • • • • Pericardial effusion TAPSE Right atrial area LV eccentricity 2D, 3DE volumes / ejection fraction • RV strain • Tei index Right Heart Catheterization • Right atrial pressure • Cardiac index • Cardiac output (CO) Cardiac MRI • RV mass • RV volume • RV ejection fraction Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7. Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. Impact of RV Function on Therapy • RV function can highlight the subtle changes in early disease and prompt rapid initiation of therapy • RV function determines the patient’s functional capacity and survival • Deterioration in RV function mirrors disease progression • Treatment escalation can be guided by RV function correlates Badano, et al. Eur J Echocardiography. 2010;11(1):27-37. Diagnostic Issues • Misdiagnosis1 – Most patients see three or more physicians over a threeyear period before an accurate diagnosis is made • Diagnostic delay1 – Time to reach diagnosis has not improved in 20 years • Advanced disease at diagnosis2 – Approximately 75% of patients have advanced disease at diagnosis (functional class III and IV) 1) Deano, et al. JAMA Intern Med. 2013;173(10):887-93. 2) Thenappan, et al. Eur Respir J. 2007;30(6):1103-10. Diagnostic Delay REVEAL •Interim analysis1 (N = 2967) – Mean duration between symptom onset and RHC = 2.8 years •Cohort study2 (N = 2493) – 21% of patients had symptoms for > 2 years before diagnosis – Delay was more common in younger patients (< 36 years old) and those with a history of respiratory disorders – Clinicians should be suspicious if symptoms are out of proportion to “underlying disease” or unresponsive to treatment 1) Badesch, et al. Chest. 2010;137(2):376-87. 2) Brown, et al. Chest. 2011;140(1):19-26 Patient Screening • “Systematic testing of asymptomatic individuals to search for preclinical disease and mildly symptomatic patients to prevent progression and / or development of the disease” • Appropriate for PAH since symptoms are nonspecific and condition is uncommon and progressive; however, presentation is confounded by diversity of PAH • Determine which screening populations to preselect Schwaiger, et al. Eur Resp Rev. 2013;22(130):515-25. Patients at High Risk for PAH Heritable PAH • Patients with a family history of PAH Drug- and toxin-induced PAH • Patients with a history of high-risk drug / toxin use Associated conditions • Patients with an associated condition: • Connective tissue disease • HIV infection • Portal hypertension • Congenital heart disease • Schistosomiasis Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. Guidelines for Screening High-Risk Patients • Heritable PAH – Yearly echocardiography in asymptomatic carriers of BMPR2 mutation and RHC if the echocardiograph is abnormal • Associated conditions – Scleroderma – yearly echocardiography in symptomatic patients, optional in asymptomatic patients – HIV infection – echocardiography recommended if unexplained dyspnea Schwaiger, et al. Eur Resp Rev. 2013;22(130):515-25. Treatment of PAH Strategy: – – – – – Evaluation of disease severity Adoption of general measures and supportive therapy Assessment of vasoreactivity Estimation of drug efficacy Combination of different drugs and interventions Goals of therapy: – Improve symptoms, hemodynamics, exercise capacity, functional class, quality of life – Prevent clinical decline – Reduce hospitalizations – Extend survival Ghofrani, et al. Int J Cardiol. 2011;154(1):S20-33. General Measures and Supportive Therapy General Measures • Rehabilitation / exercise • Psychosocial support • Family planning • Vaccinations Supportive Therapy • • • • Anticoagulants Diuretics Oxygen Digoxin Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Referral to a PAH Clinic • Multidisciplinary care • Continuous monitoring • Patient and family education • Psychosocial support • Access to clinical trials • Disease advocacy • Society participation General Measures and Supportive Therapy Cardiac catheterization / acute vasoreactivity testing – Mandatory if IPAH (optional if associated condition) – Identifies patients who are responders – Inhaled nitric oxide (10 – 20 parts per million) or inhaled epoprostenol (50 ng/kg/min) are the preferred testing agents Chronic CCB therapy – Appropriate for patients with a positive response = reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased CO – Therapeutics – amlodipine, nifedipine, or diltiazem Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Agarwal, et al. Am Heart J. 2011;162:201-13 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 Pathways and Agents Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 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 Treprostinil Subcutaneous, IV, inhalation, oral Iloprost Inhalation 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 L-Citrulline NO sGC PDE-5 GMP Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. NOS cGMP Vasodilation 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 WHO Functional Classification for PAH Class I No limitation of physical activity. Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope. Class II Slight limitation of physical activity; no discomfort at rest. Ordinary activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class III Marked limitation of physical activity; no discomfort at rest. Less than ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class IV Inability to perform any physical activity without symptoms; signs of right ventricular failure or syncope; dyspnea and / or fatigue may be present at rest; discomfort is increased by any physical activity. Taichman, et al. Clin Chest Med. 2007;28:1-22. Evidence-Based Treatment Algorithm: Consensus From 5th WSPH FC II Bosentan Ambrisentan Macitentan IA/B Sildenafil Tadalafil Riociguat FC III Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Epoprostenol IV Treprostinil sc, inhalation Iloprost inhalation Epoprostenol IV Treprostinil IV Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Treprostinil sc, inhalation, IV Iloprost inhalation IIaC IIbC FC IV Initial combination therapy Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Sequential Combination Therapy + PA Initial combination therapy ERA + + PDE-5i sGCS Inadequate clinical response on maximal therapy Interventional Procedure BAS Lung Transplantation Initial Therapy for PAH: Consensus From 5th WSPH Strength of recommendation and clinical evidence IA/B FC II Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat FC III Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Epoprostenol IV Treprostinil sc, inhalation Iloprost inhalation Epoprostenol IV Treprostinil IV Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Treprostinil sc, inhalation, IV Iloprost inhalation Initial combination therapy Initial combination therapy IIaC IIbC FC IV Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Prostacyclin Analogs Epoprostenol Treprostinil Iloprost III, IV II, III, IV III, IV Administration Continuous IV Inhalation SC IV Inhalation Oral Inhalation Dosage 20-40 ng/kg/min Initial = 1.25 ng/kg/min Usual = 2.5-5 µg, Usual = 30-100 ng/kg/min 6-9 times per day Other 2 branded versions available Only PAH clinical study to demonstrate survival benefit Indication / FC Administer in wellventilated areas Max dosage = 45 µg Treprostinil for PAH Clinical Study Route of Administration N Study Duration Study Results Simonneau1 SC 470 12 weeks SS improvement in 6-MWD Tapson2 IV 14 12 weeks SS improvements in 6-MWD, FC McLaughlin3 Inhalation + Bosentan or sildenafil RCT = 212 12 weeks OL = 206 24 months Benza4 SS improvements in 6-MWD, QOL with combination therapy, which were sustained for OL extension 1) Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4. 2) Tapson, et al. Chest. 2006;129:683-8. 3) McLaughlin, et al. J Am Coll Cardiol. 2010;55(18):1915-22. 4) Benza, et al. J Heart Lung Transplant. 2011;30(12):1327-33. Treprostinil Oral for PAH: FREEDOM-C Clinical Trial • Study design – RCT – 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) – RCT – 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. Endothelin Receptor Antagonists Bosentan Ambrisentan Macitentan Indication / FC II, III, IV II, III, IV II, III, IV Administration Oral Oral Oral Dosage 62.5 mg twice daily for 4 weeks then 125 mg twice daily 5 mg and 10 mg daily 10 mg daily Other Sustained receptor binding and enhanced tissue penetration 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 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 16 20 24 28 32 Weeks Galie, et al. Lancet. 2008.371(9630):2093-100. Valerio et al. Vasc Health Risk Manag. 2009;5:607-19. 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 • 6-MWD – Increased by 21 meters (P < 0.05) • BNP levels – Decreased by 26% (NSS) 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 28 23 7 0 -10 -20 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: SERAPHIN Clinical Trial *P < 0.05 Macitentan 10 mg (N = 242) Average duration of treatment (event driven)1 103.9 weeks Risk reduction in the occurrence of morbidity and mortality events versus placebo1 45%* All-cause hospitalizations2 Risk reduced by 32%* and rate reduced by 33%* PAH-related hospitalizations2 Risk reduced by 52%* and rate reduced by 50%* 1) Pulido, et al. NEJM. 2013;369(9):809-18. 2) Channick, et al. JACC Heart Fail. 2015;3(1):1-8. Nitric Oxide Pathway Agents Sildenafil Tadalafil Riociguat Type PDE-5 inhibitor PDE-5 inhibitor Soluble guanylate cyclase stimulator Indication / FC II, III, IV II, III, IV II, III, IV Administration Oral IV Oral Oral Dosage 20 mg oral three times daily 10 mg IV three times daily 40 mg daily 1 mg – 2.5 mg three times daily Sildenafil for PAH Clinical Study SUPER-11 SUPER-22 PACES3 Study Design Agents N RCT Sildenafil 20 - 80 mg 278 three times daily OL • Sildenafil 80 mg three times daily • 2nd agent added in 18% of patients RCT • Epoprostenol • Epoprostenol + sildenafil 80 mg three times daily 170 • 53 • 214 Study Duration Study Results 12 weeks SS improvements in 6MWD, FC 3 years 46% maintained or improved 6-MWD 60% maintained or improved FC Patient survival = 79% 16 weeks Patients on combination therapy had SS improvement in 6-MWD, fewer clinical worsening events, and delayed TTCW 1) Galie, et al. N Engl J Med. 2005;353:2148-57. 2) Rubin, et al. Chest. 2011:140(5):1274-83. 3) Simonneau, et al. Ann Intern Med. 2008;149(8):521-30. Tadalafil for PAH Clinical Study PHIRST-11 PHIRST-22 Study Design Agents N 189 RCT • Tadalafil 20 or 40 mg daily • Tadalafil + bosentan 135 OL • Tadalafil 20 or 40 mg daily • Tadalafil + bosentan Study Duration 16 weeks SS improvements in 6-MWD, QOL, clinical worsening events, TTCW, especially in treatment-naïve patients 52 weeks Improvements in 6-MWD, clinical worsening events were sustained 216 158 Study Results 1) Galie, et al. Circulation. 2009;119(22):2894-903. Barst, et al. J Heart Lung Transplant. 2011;30(6):632-43. 2) Oudiz, et al. J Am Coll Cardiol. 2012;60:768-74. Riociguat for PAH Clinical Study PATENT Study Design RCT Agents Riociguat 1 mg, 1.5 mg, 2 mg, or 2.5 mg three times daily Ghofrani, et al. NEJM. 2013;369(4):330-40. N 443 Study Duration 12 weeks Study Results SS improvements in 6-MWD, PVR, NT-proBNP, FC, Borg Dyspnea Scale score, QOL measures, TTCW Riociguat for PAH: RESPITE Clinical Trial Study design • • • • Open-label N = 60 patients with poor response to a PDE-5i Study duration = 24 weeks Study endpoints – 6-MWD, cardiac index, NT-proBNP, functional class, quality of life, TTCW • Study is ongoing www.clinicaltrials.gov/ct2/show/NCT02007629 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 and progressive treatment protocols Selexipag for PAH • Investigational agent • Mechanism of action – Prostacyclin IP receptor agonist – Targets the prostacyclin pathway • Administration – oral Image: www.chemspider.com/Chemical-Structure.8089417.html Selexipag for PAH: GRIPHON Clinical Trials RCT1 • N = 1156 • Selexipag 200 to 800 µg oral twice daily • Study duration = event driven • Study endpoint = TTCW • Preliminary results – reduced the risk of an adverse clinical event by 39% Open-label extension2 • N = 670 • Selexipag 200 to 800 µg oral twice daily • Study duration = event driven • Study endpoint = safety 1) www.clinicaltrials.gov/ct2/show/NCT01106014 2) www.clinicaltrials.gov/ct2/show/NCT01112306 Combination Therapy for PAH Background • Rationale – to target multiple disease pathways • REVEAL: 34% of patients on 2 or more treatments Sequential Therapy • Starting in one drug class and adding an agent from another class • Used when therapy needs to be augmented because response to initial therapy is inadequate Upfront Therapy • Used in early PAH disease • May improve patient outcomes, slow disease progression, and reduce costs associated with managing clinical worsening 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: Published Studies Clinical Study Agents N Study Duration Study Endpoints Statistical Significance BREATHE-21 Epoprostenol Bosentan 33 16 weeks Hemodynamics, 6-MWD, FC No STEP-12 Iloprost Bosentan 67 12 weeks Hemodynamics, 6-MWD, FC, TTCW Yes COMBI3 Iloprost Bosentan 40 12 weeks Zhuang4 Ambrisentan Tadalafil 124 16 weeks 6-MWD, FC, TTCW 6-MWD, clinical worsening events No Yes 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. 4) Zhuang, et al. Hypertens Res. 2014;37(6):507-12. Combination Therapy for PAH: Ongoing and Recent Studies Clinical Study Agents N Study Duration Study Endpoints Study Results 12 weeks 6-MWD, TTCW Publication pending NCT00323297 Bosentan +/- Sildenafil 105 FREEDOM-Ev1 • Treprostinil oral + PDE-5i or ERA • PDE-5i or ERA 858 ATHENA-12 Sildenafil or Tadalafil +/- Ambrisentan 33 Event driven 6-MWD, TTCW 24 weeks 6-MWD, PVR, mPAP, CI 1) NCT01560624 2) Oudiz, et al. Chest. 2011;140(4):ABSTRACT (NCT00617305) Study ongoing SS improvements Combination Therapy for PAH: COMPASS Clinical Trials COMPASS-21 • • • • RCT N = 334 Sildenafil +/- bosentan Study duration = event driven • Study endpoint = TTCW • Study results = NSS COMPASS-32 • • • • • • Open-label extension N = 100 Bosentan +/- sildenafil Study duration = 28 weeks Study endpoint = 6-MWD Study results = 31% reached 6-MWD goal, 34% improved FC 1) McLaughlin, et al. Chest. 2014;146(4):ABSTRACT (NCT00303459) 2) Benza, et al. Chest. 2010;138(4):ABSTRACT (NCT00433329) Upfront Combination Therapy Patient Survival (%) P = 0.07 Months Kemp, et al. J Heart Lung Transplant. 2012;31(2):150-8. Upfront Combination Therapy: AMBITION Clinical Trial Study design Study results *P < 0.05 • RCT • Combination therapy reduced the risk of clinical • N = 500 treatment-naïve patients failure events by 50%* • Study groups • SS* improvements in: – Ambrisentan – 6-MWD – NT-proBNP – Tadalafil – % Patients with a – Ambrisentan + tadalafil satisfactory clinical • Study duration = event driven response • Primary endpoint = TTCW Galie, et al. Eur Respir J. 2014;44(58):ABSTRACT. Upfront Triple Combination Therapy Study design • Retrospective review • N = 18 treatment-naïve patients in FC III or IV • Epoprostenol + bosentan + sildenafil • First assessment of endpoints at 4 months Sitbon, et al. Eur Respir J. 2014;43(6):1691-7. Study results *P < 0.05 • SS* improvements in – 6-MWD – Hemodynamics • Functional class – Improvement to FC I or II for 17 patients • Overall patient survival – 100% at 1, 2, and 3 years Interventional Procedures: Balloon Atrial Septostomy • Creation of an interatrial right-to-left shunt • In order to: › › › › › Decompress right heart chambers Increase LV preload Increase CO Improve systemic oxygen transport Decrease sympathetic hyperactivity • 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 – rare – Bilateral (sequential) lung transplant – most common – Heart-lung transplant – increasingly less common; only 70 – 90 performed per year* • Lung transplantation remains the standard of care for select patients who fail aggressive medical therapy, with specific eligibility criteria determined by 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 FC III or IV despite maximal medical therapy Low (< 350 meters) or declining 6-MWD Failing even while on a parenteral prostacyclin analog CI < 2 L/min/m2 RAP > 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, FC 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 Low Risk Determinants of Risk High Risk No Clinical evidence of RV failure Yes Gradual Disease progression Rapid II, III Functional class IV Longer (> 400 meters) 6-MWD Shorter (< 300 meters) Peak VO2 > 10.4 mL/kg/min CPET 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 FC I -2 Vital signs 6-MWD BNP ≥ 440 meters -1 < 165 meters +1 < 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 PAH-SYMPACT Questionnaire • PAH symptoms and impact questionnaire • Disease-specific patient reported outcome (PRO) instrument • Ongoing studies to validate its widespread use – Studies using macitentan to psychometrically validate the questionnaire: NCT02081690, NCT02112487, NCT01841762, NCT01847014 McCollister, et al. ATS. 2013;5:ABSTRACT. Longitudinal Patient Monitoring: ACCF / AHA Recommendations Patient Evaluation Stable patient 6-MWD FC BNP ECHO RHC Every 3-6 months Every visit Every visit Center dependent Every 12 months If clinical deterioration Unstable Every 1-3 patient months Every visit Every visit Center dependent Every 6-12 months Every 6-12 months or if deterioration McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. McLaughlin. Am J Cardiol. 2013;111:S10-5. Treatment Goals: Consensus From 5th WSPH 6-MWD CPET FC BNP ECHO Hemodynamics Peak VO2 > > 380 – 15 mL/min/kg I or II 440 meters EqCO2 < 45 L/min Normal levels Normal or near normal RV size and function RAP < 8 mm Hg CI > 2.5 - 3 L/min/m2 McLaughlin, et al. J Am Coll Cardiol. 2013;62(25):S73-81. Summary • Expedient diagnosis sets in motion timely and focused patient care. • The continuum of RV impairment in PAH must be met with aggressive action towards reversal. • The evidence-based treatment algorithm provides a foundation for disease management. • Upfront combination therapy may become the standard of care for patients. • In order to capture and address any subtle change in a patient’s clinical condition, comprehensive patient monitoring is essential.