Pulmonary Arterial Hypertension: Evolving Strategies and Treatment Opportunities. Faculty

Transcription

1 Pulmonary Arterial Hypertension: Evolving Strategies and Treatment Opportunities Emerging Challenges In Primary Care: 2014! PULMONARY ARTERIAL HYPERTENSION: EVOLVING STRATEGIES AND TREATMENT OPPORTUNITIES Faculty Arunabh Talwar, MD, FCCP Director, Pulmonary Hypertension and Advanced Lung Disease Program North Shore University Hospital, Manhasset, NY Associate Professor of Medicine Hofstra North Shore-LIJ School of Medicine Hofstra University Hempstead, NY FACULTY DISCLOSURE Arunabh Talwar, MD, FCCP Consultant - Bayer 2 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 1

2 LEARNING OBJECTIVES Explain the pathophysiology of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) Determine when pulmonary hypertension (PH) should be suspected and how to determine the specific etiology Define parameters that determine the severity of PH / PAH/ CTEPH and thus, the type of therapy indicated Describe appropriate treatment, monitoring, follow up, appropriate referral to a pulmonary hypertension center, for PAH and CTEPH patients 3 PRE TEST QUESTION 1 On a scale of 1 to 5, please rate how confident you would be in participating in the evaluation, management and referral of a patient with PAH? 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 4 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 2

3 PRE TEST QUESTION 2 You evaluate a 38 year old female with unexplained dyspnea. You suspect that she has pulmonary hypertension.what is the recommended test to best determine the cause of pulmonary hypertension discovered on echocardiogram? 1. Chest Xray 2. Spirometry 3. Right heart catheterization 4. Cardiac stress test 5 PRE TEST QUESTION 3 Which of the following scenarios would be most likely associated with pulmonary arterial hypertension? 1. Severe fatigue without dyspnea 2. Progressive dyspnea, clear lungs and ankle edema 3. Exertional chest pain in the absence of any other symptoms 4. Dyspnea, hypersomnolence and morning headache 5. Patient with known mitral stenosis, bilateral crackles on lung exam 6 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 3

4 PRE TEST QUESTION 4 What do currently published practice guidelines recommend for Group 1 PAH treatment? 1. Always start with a Combination therapy of endothelin receptor blockers, Riocioguat and Phosphodiesterase inhibitiors 2. Coumadin should be only considered if pt has history of Deep vein thrombosis 3. Calcium channel blockers should not be tried without right heart catheterization and reversibility testing 4. Patients with Mild dyspnea can just be observed and need no treatment 7 PRE TEST QUESTION 5 Which is the most appropriate plan to determine clinical status and response to treatment in PAH patients? 1. 6 minute walk, BNP, each clinic visit with echocardiography every 6 to 12 months 2. 6 minute walk and cardiac MRI every 6 to 12 months 3. Cardiopulmonary exercise testing each clinic visit 4. Yearly chest CTA to follow pulmonary artery diameter and right ventricular size 5. 6 minute walk test and pulmonary function testing including diffusing capacity, every 6 to 12 months 8 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 4

5 PRE TEST QUESTION 6 A 55 year old male presents to your office with increasing pedal edema and progressive dyspnea.his echocardiogram shows dilated right ventricle and elevated PASP. He has history of DVT five years ago. You suspect patient has CTEPH. What is the best screening test for CTEPH? 1. Cardiac MRI 2. Chest X ray 3. High resolution CT scan chest 4. Ventilation perfusion Scan 5. Pulmonary function testing including diffusing capacity 9 PULMONARY VASCULAR PRESSURES (8 mmhg) 15/4 (30mmHg) 50/ / /15 Normal Pulmonary HTN 10 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 5

6 Pulm Veno- Occlusive Dz PV IVC/SVC Thrombo- Embolic Dz RA LA ORGAN SYSTEMS LUNGS PA RV LV Cardiac Dysfn SPHTN Hypoxemia Related PH PPHTN AORTA 11 WHO CLASSIFICATION OF PH Former Primary Pulmonary Hypertension (PPH) idiopathic or unknown cause OR Secondary Pulmonary Hypertension (SPH) all other causes Current Group 1. Pulmonary arterial hypertension [PAH] Group 2. Pulmonary hypertension with left heart failure Group 3. PH with lung diseases and/or hypoxemia Group 4. PH due to chronic thrombotic and/or embolic diseases Group 5. Miscellaneous WHO SIMONNEAU G, ET AL. J AM COLL CARDIOL 2009; 12 54:S43-54 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 6

7 5 TH WORLD SYMPOSIUM ON PH: MODIFIED CLASSIFICATION OF PH 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH BMPR ALK1, ENG, SMAD9, CAV1, KCNK Unknown 1.3 Drug- and toxin-induced 1.4 Associated with Connective tissue disease HIV infection Portal hypertension Congenital heart diseases (update) Schistosomiasis 1. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1. PPHN 2. PH due to LHD 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies Simonneau G et al. JACC. 2013;62:D34-D PH due to lung diseases and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases (update) 4. CTEPH 5. PH with unclear multifactorial mechanisms 5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH PAH Pulmonary hypertension 13 UPDATED DEFINITION OF PAH Right Heart Catheterization Confirmed Increased mean pulmonary arterial pressure (mpap)* >25 mm Hg at rest Normal pulmonary capillary wedge pressure (PCWP) Increased pulmonary vascular resistance (PVR) <15 mm Hg >3 Wood units * Normal resting mpap = 8 20 mm Hg. In ACCF/AHA expert consensus; in 4th World Symposium on PH, increased given PVR without a value. Significance of mpap from mm Hg unclear. Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(suppl 1):S55 S66 Adapted from McLaughlin VV, et al. Circulation. 2009;119(16): NACE Emerging Challenges in Primary Care: Update 2014 PAH - 7

8 IDIOPATHIC PAH: SURVIVAL IF UNTREATED Percentage surviving NIH registry Sitbon historical control ACCP estimate Years of follow-up Incidence: 2-6 cases per million in US Poor prognosis in an era lacking therapy Therapeutic options and research efforts now offer more hope Female to male ratio 1.7:1 to 3.5:1 Mostly sporadic, familial in 6% of cases Mean age 45 (range yrs) Adapted from: Sitbon O et al. J Am Coll Cardiol. 2002;40: D Alonzo GE et al. Ann Intern Med. 1991;115: McLaughlin VV et al. Chest. 2004;126:78S-91S. 15 PATHOGENESIS OF PAH Collagen Vascular Disease Congenital Heart Disease Portal Hypertension HIV Infection Drugs and Toxins Pregnancy Intima Aventitia Media Abnormal BMPR2 Gene Other Genetic Factors Early Intimal Proliferation Smooth Muscle Hypertrophy Endothelial Dysfunction Nitric Oxide Synthase Prostacyclin Production Thromboxane Production Endothelin 1 Production Vascular Smooth Muscle Dysfunction Impaired Voltage-Gated Potassium Channel (K v1.5 ) Smooth Muscle Hypertrophy Adventitial and Intimal Proliferation In situ Thrombosis Plexiform Lesion Loss of Response to Short- Acting Vasodilator Trial Vasoconstriction Advanced Vascular Lesion IRREVERSIBLE DISEASE Gaine S. J Am Med Assoc 2000;284: NACE Emerging Challenges in Primary Care: Update 2014 PAH - 8

9 PATHOGENESIS OF PH Unclear, but at least 3 processes believed to contribute to arterial narrowing Vasoconstriction Vascular remodeling Thrombosis in situ Frost A, PATHOGENESIS OF PAH Vasoconstriction Genetic predisposition? Mutation of BMPR-2 Thrombosis Proliferation 18 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 9

10 DIAGNOSIS SIGNS & SYMPTOMS HISTORY Dyspnea (>95% long term) Fatigue (25%) Syncope (10%) - Hemoptysis Raynaud s (10%) Angina (20%) Medication use PHYSICAL EXAM JVD Pulm S2 a wave RV S3 (50%) Hepatomegaly Cyanosis TR murmur (70%) Edema 19 SCHEMATIC PROGRESSION OF PAH Pre-symptomatic/ Compensated Symptomatic/ Decompensating Declining/ Decompensated CO Symptom Threshold PAP PVR PVR= PAP CO Time Right Heart Dysfunction 20 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 10

11 ECG RAD RVH RAE RV Strain McGoon M et al for the American College of Chest Physicians. Chest. 2004;126:14S-34S. 21 CHEST X-RAY 22 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 11

12 SIGNS INDICATIVE OF PH ON ECHO Increased spap or TR jet Right atrial & ventricular hypertrophy Flattening of intraventricular septum Small LV dimension Dilated PA Pericardial effusion RV RA IVS LV LA McGoon et al. Chest. 2004: s14 23 ECHOCARDIOGRAM: TRICUSPID REGURGITATION Modified Bernoulli s Equation: 4 x (V)² + RAP = RVSP (PASP) V=tricuspid jet velocity (m/s); RAP= right atrial pressure; RVSP=right ventricular systolic pressure; PASP=pulmonary artery systolic pressure. Image courtesy of Vallerie McLaughlin, MD 24 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 12

13 ACCURACY OF PH DIAGNOSIS BY ECHOCARDIOGRAPHY IN ADVANCED LUNG DISEASE Cohort study of lung transplant patients (n=374) All patients Doppler echo 24 to 48 hours prior to RHC Prevalence of PH: 25% Echo frequently inaccurate leading to over diagnosis of pulmonary hypertension in patients with advanced lung disease Studies (%) Diagnosis of PH Overestimation Accurate Underestimation No Pulmonary Hypertension Pulmonary Hypertension Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167: CT Thromboembolism Size of PA relative to aorta 26 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 13

14 VENTILATION PERFUSION LUNG SCAN PAH WHO Group I Perfusion Ventilation CTEPH WHO group iv Perfusion Ventilation 27 DIAGNOSIS AND GROUP CLASSIFICATION History Physical CXR - ECG Echocardiography VQ Scan - ABG Overnight Oximetry HIV ANA - LFTs Index of Suspicion Evaluate for LH & RH disease Main Goals: Verify the existence of PH Determine which group Identify PAH patients for Rx Assess the severity of PH CTEPH OSA Underlying Causes Functional Testing Functional Severity Right Heart Catheterization Confirm Diagnosis Adapted from McLaughlin VV, et al. Circulation. 2009;119(16): NACE Emerging Challenges in Primary Care: Update 2014 PAH - 14

15 IS IT THROMBOEMBOLISM (GROUP 4)? One half of those with CTEPH do not have an apparent history of acute PE Lung bruits over peripheral lung fields Is potentially curable with thromboendarterectomy (PEA) Riocioguat approved ed for inoperable CTEPH 3% to 4% of acute PE do not entirely resolve Normal VQ scan excludes chronic PE CT angiogram can detect chronic clot (but the radiologist should be experienced when interpreting the imaging distal disease can be subtle) PEA Less subtle thrombus McLaughlin VV et al. J Am Coll Cardiol. 2009;53: ASSESS SEVERITY OF PAH Symptoms BNP Six-minute walk test ECHO assessment of RV RHC results Right heart pressures PVR CO/CI 30 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 15

16 MODIFIED NYHA FUNCTIONAL CLASS FOR PAH WHO Class Description I II No limitation of usual activities Mild limitation of usual activities Normal physical activity causes increased dyspnea, fatigue, chest pain, or near-syncope III Marked limitation of physical activity Less than ordinary activity causes increased dyspnea, fatigue, chest pain, or near-syncope IV Unable to perform most any physical activity Dyspnea and/or fatigue even at rest Syncope may be present May have signs of right ventricular failure Rich S. World Health Organization THE 6 MINUTE WALK Miyamoto Am J Respir Crit Care Med 2000; 161: NACE Emerging Challenges in Primary Care: Update 2014 PAH - 16

17 CARDIAC CATHETERIZATION Exclude congenital heart disease Measure wedge pressure or LVEDP Establish severity and prognosis Test vasodilator therapy (if PAH, especially IPAH ) Catheterization is required when pulmonary hypertension is suspected 33 VASODILATOR CHALLENGE (INHALED ILOPROST, ADENOSINE, NO) Does the patient have reversible vasoconstriction? [Responder] (defined as a fall in mpap of at least 10 mm Hg to 40 mm Hg, with an increased or unchanged CO) [ PVR = mean PA-PCWP/CO] Responders to NO CCB Non Responders epoprostenol, bosentan, Riocioguat, Tadalafil, revatio.treprostinil, Inhaled Iloprost 34 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 17

18 PROGNOSTIC FACTORS FOR RISK OF PAH DISEASE PROGRESSION Lower Risk Higher Risk Evidence of RV failure No Yes Progression of Gradual Rapid symptoms WHO class II, III IV 6-minute walk distance >400 m <300 m CPET peak VO 2 >10.4 ml/kg/min <10.4 ml/kg/min Echo findings Minimal RV dysfunction Pericardial effusion; significant RV dysfunction, RA enlargement Hemodynamics AHA/ACC Consensus Guidelines RAP <10 mm Hg, CI >2.5 L/min/m 2 RAP >20 mm Hg, CI <2.0 L/min/m 2 Brain natriuretic peptide Minimal elevation Significantly elevated Adapted from McLaughlin VV, et al. Circulation. 2009;119: PULMONARY ARTERIAL HYPERTENSION: GOALS OF THERAPY Improve hemodynamics Improve exercise capacity Improve functional class Prevent clinical worsening Improve survival 36 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 18

19 CHRONIC ADJUVANT THERAPIES IN PAH Oxygen Use to prevent hypoxic vasoconstriction Consider exercise, sleep, altitude Aim for target saturation of 92% Diuretics Most patients need Low systemic BP and elevated Cr often not a contraindication Anticoagulation Recommended in IPAH Warfarin with INR range (can go off for procedures): other Rx not studied Newer agents such as dabigatran, rivaroxaban and apixaban not studied for IPAH Dietary Sodium and fluid restriction often necessary for RV dysfunction and fluid retention Exercise Training Supervised exercise training studied in PAH and useful to increase exercise capacity 37 INDIVIDUAL AUDIENCE RESPONSE All patients deserve a trial of calcium channel blockers (cost effective/available). 1. True 2. False 38 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 19

20 Survival in IPAH with CCB Therapy 100 Response / Warfarin 80 Response / No Warfarin Survival (%) No Response / Warfarin 20 No Response / No Warfarin Months Rich S et al. N Engl J Med 1992; 327: PAH THERAPY (+) Vasodilator Response Calcium channel blockers ( ) Vasodilator Response or Non-sustained Vasodilator Response Endothelin receptor antagonists Phosphodiesterase-5 inhibitors SCG stimulator Prostanoids McLaughlin VV et al. J Am Coll Cardiol. 2009;53: NACE Emerging Challenges in Primary Care: Update 2014 PAH - 20

21 MECHANISMS OF ACTION OF APPROVED THERAPIES FOR PAH Endothelin Pathway Pre-proendothelin Endothelial cells Proendothelin Nitric Oxide Pathway Endothelial cells Prostacyclin Pathway Arachidonic acid Prostaglandin I 2 Endothelin receptor A Endothelinreceptor antagonists Endothelin-1 Smooth muscle cells Endothelin receptor B Vasoconstriction and proliferation L-arginine Phosphodiesterase type 5 Nitric Oxide cgmp L-citrulline Vasodilation and antiproliferation Phosphodiesterase type 5 inhibitor Exogenous nitric oxide SCG stimulator Prostacyclin (prostaglandin I 2 ) camp Vasodilation and antiproliferation Smooth muscle cells Prostacyclin derivatives Humbert M et al. N Engl J Med. 2004;351: PAH-SPECIFIC THERAPIES APPROVED FOR USE IN THE US Endothelin Receptor Antagonists Ambrisentan (PO) Phosphodiester ase-type 5 Inhibitors Soluble Guanylate Cyclase Stimulator Prostanoids Prostacyclin Analogs Sildenafil (PO) Riociguat (PO) Epoprostenol (IV) RTS* epoprostentol (IV) Bosentan (PO) Tadalafil (PO) Iloprost (inhaled) Macitentan (PO) Treprostinil (IV, SC, and PO inhaled) *RTS: Room temperature stable. FDA. Search.Search_Drug_Name. Accessed October 21, NACE Emerging Challenges in Primary Care: Update 2014 PAH - 21

22 EC SMC PROSTACYCLIN PATHWAY AA PGI 2 AC PS ATP camp Vasodilation and antiproliferation McLaughlin VV, et al. Circulation. 2006;114: Prostacyclin Activates camp formation SMC relaxant and antiproliferative molecule Loss leads to vasoconstriction Prostacyclin synthase (PS) Activity decreased in PAH Prostacyclin analogs Epoprostenol Half life 2.7 minutes Treprostinil IV /SC Half life 2.7 minutes Trepostinil (inhaled) Half life minutes / 6 to 9 times daily Iloprost Inhaled - Half life minutes / 6 to 9 times daily AA = arachidonic acid ; PS = prostacyclin synthase; PGI 2 = prostacyclin; AC = adenylate cyclase; ATP = adenosine triphosphate; camp = cyclic adenosine monophosphate; EC = endothelial 43 cell; SMC = smooth muscle cell PROSTACYCLINS: INTRAVENOUS, SUBCUTANEOUS, OR INHALED ORAL Epoprostenol (Flolan or Veletri ) Treprostinil (Remodulin ) Treprostinil (Remodulin ) Iloprost (Ventavis ) Treprostinil (Tyvaso ) 44 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 22

23 INTRAVENOUS EPOPROSTENOL FOR SEVERE PAH: 3-YEAR SURVIVAL Percentage (%) Survival Observed Expected * * * Months N=162 consecutive patients with IPAH in NYHA Class III or IV. 3-year survival with IV epoprostenol compared with expected survival from NIH historical controls. *P<0.001 at all time points. McLaughlin VV, et al. Circulation. 2002;106: LONG-TERM OUTCOMES WITH SUBCUTANEOUS TREPROSTINIL 23% Patients (%) % 16% 11% 15% 0 Discontinue for Deterioration Death Discontinue for Adverse Events Switch Therapy Add Therapy N=860. Patients followed for up to 4 years. Barst RJ, et al. Eur Respir J. 2006;28: NACE Emerging Challenges in Primary Care: Update 2014 PAH - 23

24 INHALATION SYSTEMS FOR INHALED PROSTACYCLINS I-Neb-AAD For Iloprost Inhalation Device For Treprostinil 47 LONG-TERM INHALED ILOPROST IN IPAH: EVENT-FREE SURVIVAL Cumulative Event-Free Survival (%) Time (Years) No. at risk No. of events Event-free = freedom from death, transplantation, switch to intravenous therapy, or addition of oral therapy to inhaled iloprost monotherapy. Opitz CF, et al. Eur Heart J. 2005;26: NACE Emerging Challenges in Primary Care: Update 2014 PAH - 24

25 ORAL TREPROSTINIL IN PAH: CHANGE FROM BASELINE IN 6MWD OVER 12 OR 16 WEEKS p=0.01 p=0.03 p=0.05 p=0.07 p=0.36 p=0.80 p=0.23 p=0.09 Jing ZC et al. Circulation. 2013;127: Tapson VF et al. Chest. 2012;142: Tapson VF et al. Chest. 2013;144: ENDOTHELIN-1 PATHWAY EC SMC Big Endothelin ET A ET-1 ECE ET B Vasoconstriction and proliferation Endothelin-1 (ET-1) ET A and ET B receptors Potent vasoconstrictor peptide Endothelial cells ET B regulates vasodilation Smooth muscle cells ET A regulates vasoconstriction and proliferation ET B regulates vasoconstriction and proliferation Approved ET receptor antagonists Bosentan,--BID Ambrisentan- Once Daily Macetantan -Once daily McLaughlin VV, et al. Circulation. 2006;114: ECE = endothelin converting enzyme; ET-1 = endothelin; ET A = endothelin receptor A; 50 ET B = endothelin receptor B; ; EC = endothelial cell; SMC = smooth muscle cell NACE Emerging Challenges in Primary Care: Update 2014 PAH - 25

26 BREATHE-1: 6-MINUTE WALK TEST CHANGE FROM BASELINE AT WEEK Placebo (n = 69) Bosentan (n = 144) Δ Walk Distance (meters) P = Mean ± SEM -40 Baseline Week 4 Week 8 Week mg bid 125 or 250 mg bid 51 ARIES-E: 6-MINUTE WALK DISTANCE CHANGE FROM BASELINE Improvement Change in 6MWD (meters) Mean ± 95% confidence interval Ambrisentan mg once daily Weeks n=383 n=338 n=248 n=193 n=146 Oudiz RJ, et al. Oral presentation, American Thoracic Society Annual Meeting, meters at 48 weeks 52 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 26

27 MACITENTAN FOR PAH: TIME TO CLINICAL WORSENING OR DEATH Mean change from baseline in 6 MWD (m) Macitentan 10 mg: (n=242) Macitentan 3 mg: (n=250) Placebo (n=250) 61% of patient population were on background PDE-5 inhibitor therapy at study enrollment. 5% were receiving oral/inhaled prostanoids Time from treatment start (months) Macitentan 10 mg: Hazard ratio=0.55; log rank P<0.001 Macitentan 3 mg: Hazard ratio=0.70; log-rank P=0.01 N=742. Double-blind, placebo-controlled Phase III study. Primary endpoint composite endpoint of death, atrial septostomy, lung transplantation, initiation of intravenous/ subcutaneous prostanoids or other worsening of PAH. Pulido T, et al. N Engl J Med. 2013; THE NO PATHWAY PDE5 INHIBITION Degradation Inhibition Sildenafil L-arginine PDE 5 NO S O 2 /Alveolar Ventilation NO Guanylate Cyclase cgmp cgmp-kinase Intracellular Ca 2+ Effects on Smooth Muscle Cells cgmp = cyclic guanosine monophosphate. Please see accompanying full prescribing information. Chart adapted from Ghofrani HA et al. J Am Coll Cardiol. 2004;43:69S. Badesch DB et al. CHEST. 2004;126(suppl):48S. PDE5 is strongly expressed in the lung, and PDE5 gene expression and activity are increased in chronic PH Sildenafil or Tadalafil is an inhibitor of cgmp-specific PDE5 in the smooth muscle of the pulmonary vasculature, where PDE5 is responsible for degradation of cgmp Sildenafil TID Tadalafil QD 54 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 27

28 SUPER-1 IMPROVEMENT IN 6-MINUTE WALK DISTANCE AS EARLY AS WEEK 4 Change From Baseline (m) Placebo (n=66) Sildenafil 20 mg tid (n=67) Sildenafil 40 mg tid (n=64) Sildenafil 80 mg tid (n=69) 32 * 44-4 Week 4 Week 12 (ITT-LOCF) * 41 *P<.0001 vs placebo. * 47 The improvements in 6-minute walk distance were highly significantly different from placebo, but the dose groups were not different from each other; therefore, the approved dosage of REVATIO (sildenafil citrate) is 20 mg tid Baseline 6-min walk: placebo, 348 m; sildenafil 20 mg, 346 m; sildenafil 40 mg, 343 m; sildenafil 80 mg, 338 m. Please see accompanying full prescribing information. Data on file. Pfizer Inc, New York, NY. 55 SOLUBLE GUANYLATE CYCLASE STIMULATOR-- RIOCIGUAT Mechanism of action Guanylate cyclase stimulator Targets nitric oxide (NO) pathway Dosage 1 mg 2.5 mg oral three times daily Do not Combine with PDE-5 Inhibitor Approved for Group I and Group IV Schermuly, et al. Expert Opin Investig Drugs. 2011;20(4): Image: 56 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 28

29 NITRIC OXIDE PATHWAY: SGC STIMULATOR (RIOCIGUAT) PATENT-1 RIOCIGUAT FOR PAH CHEST-1 RIOCIGUAT MONOTHERAPY FOR INOPERABLE OR RESIDUAL CTEPH 40 PATENT-1: PAH 60 CHEST-1: CTEPH Change from baseline in 6MWD (m) No. at risk: Riociguat Placebo Week Riociguat Placebo No. at risk: Riociguat Placebo Week Observed Imputed Ghofrani AH et al. N Engl J Med 2013; 369: Ghofrani AH et al. N Engl J Med 2013; 369: SGC STIMULATOR SIDE EFFECTS Headache Dizziness Dyspepsia/gastritis Nausea Diarrhea Vomiting Anemia Gastroesophageal reflux Constipation Hypotension Contraindicated in pregnancy, with use of nitrates or NO donors in any form, or with use of PDE inhibitors 58 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 29

30 HOW TO TO DETERMINE RESPONSE TO THERAPY AND PROGNOSIS IN PATIENTS WITH PAH Functional class I or II Echocardiography/cardiac magnetic resonance Hemodynamics normal/near normal RV size and function RAP, 8mmHg; CI 2.5 to 3.0 L/min/m2 6-min walk distance >330 to 440 meters may not be aggressive enough in young individuals Cardiopulmonary exercise testing Peak VO2 >15 ml/min/kg ; EQCO2 <45 l/ min/l/min B-type natriuretic peptide level normal V McLaughlin ET AL JAM Coll Card 2013:62 Suppl D 59 PAH TREATMENT ALGORITHM Right Heart Catheterization With Acute Vasodilator Change Positive Response Negative Response Trial With Oral Calcium Channel Blocker Therapy Sustained Response No Yes Lower risk Oral therapies Injectable therapies Continue Therapy Higher Risk Injectable therapies McLaughlin VV et al. J Am Coll Cardiol 2009; 53: NACE Emerging Challenges in Primary Care: Update 2014 PAH - 30

31 UPDATED GUIDELINES: INADEQUATE CLINICAL RESPONSE TO INITIAL PAH THERAPY Failure to show improvement or deterioration with monotherapy Sequential Combination Therapy Endothelin Receptor Antagonists Prostanoids PDE5 Inhibitors or ssgs Atrial septostomy and/or Lung transplantation Modified frombarst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S LONG-TERM MANAGEMENT OF PAH: RECOMMENDED TESTS Baseline Ea 4 6 months 3 4 months after therapy initiation or clinical worsening Clinical Assessment WHO functional class ECG 6MWD or CPET BNP/NT-proBNP Echo Right heart catheterization Adapted from Galie N, et al. Eur Heart J. 2009;30: NACE Emerging Challenges in Primary Care: Update 2014 PAH - 31

32 63 POST TEST QUESTION 1 You evaluate a 38 year old female with unexplained dyspnea. You suspect that she has pulmonary hypertension.what is the recommended test to best determine the cause of pulmonary hypertension discovered on echocardiogram? 1. Chest Xray 2. Spirometry 3. Right heart catheterization 4. Cardiac stress test 64 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 32

33 POST TEST QUESTION 2 Which of the following scenarios would be most likely associated with pulmonary arterial hypertension? 1. Severe fatigue without dyspnea 2. Progressive dyspnea, clear lungs and ankle edema 3. Exertional chest pain in the absence of any other symptoms 4. Dyspnea, hypersomnolence and morning headache 5. Patient with known mitral stenosis, bilateral crackles on lung exam 65 POST TEST QUESTION 3 What do currently published practice guidelines recommend for Group 1 PAH treatment? 1. Always start with a Combination therapy of endothelin receptor blockers, Riocioguat and Phosphodiesterase inhibitiors 2. Coumadin should be only considered if pt has history of Deep vein thrombosis 3. Calcium channel blockers should not be tried without right heart catheterization and reversibility testing 4. Patients with Mild dyspnea can just be observed and need no treatment 66 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 33

34 POST TEST QUESTION 4 Which is the most appropriate plan to determine clinical status and response to treatment in PAH patients? 1. 6 minute walk, BNP, each clinic visit with echocardiography every 6 to 12 months 2. 6 minute walk and cardiac MRI every 6 to 12 months 3. Cardiopulmonary exercise testing each clinic visit 4. Yearly chest CTA to follow pulmonary artery diameter and right ventricular size 5. 6 minute walk test and pulmonary function testing including diffusing capacity, every 6 to 12 months 67 POST TEST QUESTION 5 A 55 year old male presents to your office with increasing pedal edema and progressive dyspnea.his echocardiogram shows dilated right ventricle and elevated PASP. He has history of DVT five years ago. You suspect patient has CTEPH. What is the best screening test for CTEPH? 1. Cardiac MRI 2. Chest X ray 3. High resolution CT scan chest 4. Ventilation perfusion Scan 5. Pulmonary function testing including diffusing capacity 68 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 34

35 On a scale of 1 to 5, please rate how confident you would be in participating in the evaluation, management and referral of a patient with PAH? 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident POST TEST QUESTION 6 69 POST TEST QUESTION 7 Which of the statements below describes your approach to participating in the evaluation, management and referral of patients with PAH? 1. I do not participate in the evaluation, management and referral of patients with PAH, nor do I plan to this year. 2. I did not participate in the evaluation, management and referral of patients with PAH before this course, but as a result of attending this course I m thinking of doing this now. 3. I do participate in the evaluation, management and referral of patients with PAH and this course helped me change my methods. 4. I do participate in the evaluation, management and referral of patients with PAH and this course confirmed that I don t need to change my methods. 70 NACE Emerging Challenges in Primary Care: Update 2014 PAH - 35