Consensus Updates in PAH Classification, Screening and Treatment

Consensus Updates in PAH Classification, Screening and Treatment
ROBYN BARST, MD Professor Emerita of Pediatrics Columbia University College of Physicians & Surgeons New York, New York

Faculty: Content Development and Training
Robyn J. Barst, MD Professor Emerita of Pediatrics Columbia University College of Physicians & Surgeons New York, New York Vallerie McLaughlin, MD Professor of Medicine Director, Pulmonary Hypertension Program University of Michigan Ann Arbor, Michigan Slide: Faculty: Content Development and Training 2 2

Learning Objectives (CME, CE, CPE)
At the completion of this educational activity, participants should be able to: Describe the new classification scheme for pulmonary hypertension Discuss important changes in the PH classification scheme and how this impacts patient management Discuss the current diagnostic algorithms for PAH Report on the updated guidelines regarding initial PAH therapy Slide: Learning Objectives (CME, CE, CPE) At the completion of this educational activity, participants should be able to: Describe the new classification scheme for pulmonary hypertension Discuss important changes in the PH classification scheme and how this impacts patient management Discuss the current diagnostic algorithms for PAH Report on the updated guidelines regarding initial PAH therapy 3 3

Updated Clinical Classification of Pulmonary Arterial Hypertension (PAH)
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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) <15 mm Hg Increased pulmonary vascular resistance (PVR)† >3 Wood units At the recent World Conference on Pulmonary Hypertension, the definition of PAH was modified. PAH induced by exercise testing was removed from the diagnostic criteria, in part because of the technical difficulties in making such an assessment, and the lack of standards for performing such assessments. The ACCF/AHA guidelines contain increased PVR in their definition of PAH, but the World Conference classification does not. References: Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S55–S66. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. Circulation. 2009;119(16): * Normal resting mPAP = 8 – 20 mm Hg. † In ACCP/AHA expert consensus; in 4th World Symposium on PH, increased PVR given without a value. Significance of mPAP from 21 – 24 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): 5 5

Updated Hemodynamic Definitions of Pulmonary Hypertension
Characteristics Clinical group Pre-capillary PH Mean PAP ≥25 mm Hg PWP ≤15 mm Hg CO normal or reduced Pulmonary arterial hypertension PH due to lung disease CTEPH PH with unclear or multifactorial mechanisms Post-capillary PH PWP >15 mm Hg Passive = TPG ≤12 mm Hg Reactive = TPG >12 mm Hg PH due to left heart disease Updated definitions of PH include pre- and post-capillary PH. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): CO = cardiac output. TPG = transpulmonary pressure gradient. Adapted from: Galie N, et al. Eur Heart J. 2009;30(20): 6 6

2009 Updated Clinical Classification of Pulmonary Hypertension: Group 1
Idiopathic (IPAH) Heritable (PAH) BMPR2 ALK1 Endoglin (with or without hereditary hemorrhagic telangiectasia) Unknown Drugs and Toxins induced Associated with Connective Tissue Diseases HIV Infection Portal Hypertension Congenital Heart Diseases Schistosomiasis Chronic hemolytic anemia Persistent pulmonary hypertension of the newborn The updated Group 1 clinical classification of PH. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 7 7

2009 Updated Clinical Classification of Pulmonary Hypertension: Group 1'
Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) A new 1’ classification of PH has been added to include PVOD/PCH. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 8 8

Pulmonary hypertension owing to left heart disease Systolic dysfunction Diastolic dysfunction Valvular disease The updated Group 2 classification of PH. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 9 9

Pulmonary hypertension owing to lung diseases and/or hypoxia Chronic obstructive pulmonary disease Interstitial lung disease Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities Group 3 classifies PH due to obstructive pulmonary disease, fibrosis, and other diseases with similar features. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 10 10

Chronic thromboembolic pulmonary hypertension (CTEPH) CTEPH has been designated to be a separate and distinct classification. It is the only form of PH that is considered potentially curable with surgical intervention. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 11 11

Pulmonary hypertension with unclear multifactorial mechanisms Hematologic disorders: myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis Group 5 contains PH from a wide range of etiologies. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 12 12

Important Changes in Updated Clinical Classification Schema
Change from “familial” to “heritable” PAH With or without mutations Classifying PAH due to schistosomiasis as Group 1 PAH due to PVOD and/or PCH in separate Group 1' as a combined subcategory Separation of CTEPH into separate, single-entity category (Group 4) The important changes from the previous classification scheme includes a change of “familial” to “heritable” PAH. PAH due to schistosomiasis has been reclassified as Group 1 PAH. Chronic hemolytic anemias have been added to Group 1. A separate PVOD/PCH category has been created. As noted, CTEPH has been given its own separate classification group. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 13 13

Updated Diagnostic Algorithm for Pulmonary Arterial Hypertension (PAH)
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Diagnostic Algorithm for PH
History, Symptoms, Signs Suggestive of PH Diagnosis of PH and suspected PAH begins with history and physical exam. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 15 15

Diagnostic Algorithm for Pulmonary Hypertension: Clinical Presentation
Symptoms Breathlessness Fatigue Syncope Weakness Angina Abdominal distension Signs Accentuated pulmonary component of second heart sound (P2) at apex Early systolic ejection click Midsystolic ejection murmur Left parasternal lift Right ventricle S4 gallop Prominent jugular “a” wave Diastolic murmur of pulmonary regurgitation Holosystolic murmur of tricuspid valve regurgitation Cool extremities A wide range of signs and symptoms are suggestive of PH/PAH. Dyspnea on exertion is the most common presenting complaint. References: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(suppl 1):14S-34S. Galie N, et al. Eur Heart J. 2009;30(20): McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S. 16 16

Other Physical Findings: Differential Diagnosis/PH Etiology
Differential Diagnosis/PAH Etiology Cyanosis Right-to-left shunt Clubbing Rare in IPAH Congenital heart or pulmonary veno-occlusive disease Rales, fine rales, abnormal breath sounds Pulmonary congestion, parenchymal airway disease, PVOD, PCH, etc. Obesity, kyphoscoliosis, enlarged tonsils Hypoventilatory disorders Sclerodermal skin changes, rashes, nail-fold capillary abnormalities Associated connective tissue disorder Peripheral venous insufficiency Venous thrombosis, pulmonary thromboembolic disease Other physical findings may indicate etiology of PAH, or assist in the differential diagnosis. Clubbing, for example, is rare in IPAH, but can indicate congenital heart or pulmonary veno-occlusive disease. Cyanosis is seen more often in right-to-left shunts than in other forms of PAH. Other physical findings may indicate lung disease, connective tissue disorders or thromboembolic disease. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(suppl 1):14S-34S. McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S. 17 17

REVEAL Database: Most Frequent Symptoms at Diagnosis
Dyspnea at rest Cough Dizzy/lightheaded Presyncope/syncope Edema Chest pain/discomfort Other Fatigue Dyspnea on exertion IPAH APAH The REVEAL database also reported initial presenting symptoms among 1479 patients enrolled. As can be seen here, symptoms did not differ between patients who were found to have IPAH versus those whose PAH was associated with other medical conditions (APAH). Reference: Elliott CG, Farber H, Frost A, et al. REVEAL registry: medical history and time to diagnosis of enrolled patients. Chest. 2007;132(suppl 4):631S. N=1479. Incidence (%) Elliott EG, et al. Chest. 2007;132(suppl 4):631S. 18 18

History, Symptoms, Signs Suggestive of PH Consider Common Causes of PH Group 2: Left Heart Disease Group 3: Lung Diseases and/or Hypoxia Before considering the less-common PAH, common causes of PH should be excluded. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 19 19

Initial Evaluation of Patients with Suspected PH
ECG Chest X-ray Transthoracic echocardiography Pulmonary function test High-resolution CT scan Fundamental tests for PH include ECG, X-ray, echo, PFTs, and high-resolution CT scans. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Galie N, et al. Eur Heart J. 2009;30(20): 20 20

ECG Associated With Right Axis Deviation (RAD) and Right Ventricular Hypertrophy (RVH)
Image courtesy of Vallerie McLaughlin, MD 21 21

Electrocardiogram Associated With Right Bundle Branch Block Plus RVH

Chest X-Ray Findings Consistent with PH
Enlarged main and hilar pulmonary artery shadows “Pruning” of peripheral pulmonary vasculature Right ventricular enlargement Patients may have normal chest x-ray Chest x-ray may reveal underlying causes of PH Chest X-ray findings suggestive of PAH may show enlarged main and hilar pulmonary artery shadows, or pruning of the peripheral pulmonary vasculature and/or right ventricular enlargement. However, many patients with symptomatic PAH do not have abnormal X-rays. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(suppl 1):14S-34S. McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S. 23 23

Chest X-Ray Consistent With PH
1. Findings that suggest PAH Enlarged main and hilar pulmonary artery shadows “Pruning” of peripheral pulmonary vasculature Right ventricular enlargement 2. Many patients with asymptomatic disease have normal CXR 3. CXR may also reveal underlying causes of PAH Image courtesy of Vallerie McLaughlin, MD 24 24

Echocardiogram: Parasternal Long Axis

Echocardiogram: Parasternal Short Axis

Echocardiogram: Apical Four Chamber

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 28 28

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 Diagnosis of PH Overestimation Accurate Underestimation Studies (%) While echocardiography can discern right-heart morphology and provide an estimate of hemodynamics, it is not sensitive as a diagnostic tool. In this study of lung transplant patients, echocardiography frequently led to an inaccurate diagnosis of pulmonary hypertension in patients with advanced lung disease. Reference: Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med. 2003;167(5): No Pulmonary Hypertension Pulmonary Hypertension Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167(5): 29 29

Pulmonary Function Tests and Arterial Blood Gases
Findings suggestive of PAH DLCO 40% - 80% of expected Mild to moderate reduction of lung volumes Peripheral airway obstruction Arterial O2 tension normal or slightly reduced at rest Arterial CO2 is reduced Findings suggestive of alternate PH diagnoses Hypoxic PH due to COPD Irreversible airway obstruction + increased residual volumes + reduced DLCO + normal or increased CO2 tension Interstitial lung disease Decrease in lung volume + decreased DLCO PFTs and ABGs can help distinguish between PAH and alternative PH diagnoses. Hypoxic PH due to COPD and PH due to ILD and other interstitial lung diseases are common and should be ruled out. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Galie N, et al. Eur Heart J. 2009;30(20): 30 30

Actual Diagnoses of Patients Referred to PH Specialty Clinic
Interstitial Lung Disease Venous Thromboembolism Other Structural Heart Disease Obstructive Sleep Apnea LV Dysfunction Obstructive Lung Disease All Alternative Diagnoses 85% of patients referred to a specialty PAH center for evaluation of potential PAH were determined to have an alternative diagnosis. These data represent 268 referrals made over a 2-year period. The most common reason for referral was an abnormal echocardiogram. 45% of patients were referred to the center by primary care clinicians, 15% by cardiologists, 10% by rheumatologists, and 5% by pulmonologists. The rest (25 %) were referred by other specialties or self referred. PAH was ruled out with a normal echocardiogram in 76% and by right heart catheterization in 24% of patients. Obstructive lung disease was the most common alternative diagnosis established in these patients. Reference: Moghbelli MH, Heresi GA, Newman J, et al. Alternative diagnoses in patients referred to a pulmonary hypertension program. Am J Respir Crit Care Med. 2008;177:A923. Moghbelli MH, et al. Am J Respir Crit Care Med. 2008;177:A923. 31 31

Algorithm for Diagnosing and Rating Severity of PH
History – Physical – CXR - ECG Index of Suspicion – Evaluate for LH & RH disease Echocardiography VQ Scan - ABGs CTEPH Overnight Oximetry OSA HIV – ANA - LFTs The ACCF/AHA consensus panel recommends this pathway for diagnostic testing for PAH of varying etiologies. Reference: McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. Circulation. 2009;119(16): Underlying Causes Functional Testing Functional Severity Right Heart Catheterization Confirm Diagnosis Adapted from McLaughlin VV, et al. Circulation. 2009;119(16): 32 32

History, Symptoms, Signs Suggestive of PH Consider Common Causes of PH Group 2: Left Heart Disease Group 3: Lung Diseases and/or Hypoxia If more-common causes of PH have been ruled out, the clinician should move on to further assessments. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): No Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 33 33

Consider Group 2 or 3 PH Yes No “Out of proportion” PH Perform V/Q Scan CTEPH Yes Segmental Perfusion Defects V/Q scan is extremely important to rule out segmental perfusion defects that indicated thromboembolic or veno-occlusive disease. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): PVOD/PCH Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 34 34

V/Q Scan for Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
Normal V/Q scan makes CTEPH unlikely Sensitivity: 90% to 100% Specificity: 94% to 100% >1 segmental-sized or larger mismatched perfusion defects seen with CTEPH Spiral CT may underestimate degree of obstruction in chronic CTEPH ~7% false negative Ventilation-perfusion (V/Q) scans should be performed in all patients with pulmonary arterial hypertension identified by echocardiography, in order to distinguish between other causes of PAH and chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is a potentially curable condition, with appropriate surgical management. Normal V/Q scans have demonstrated a sensitivity of 90% - 100% with specificity of 94% to 100% in differentiating between idiopathic PAH and CTEPH. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(suppl 1):14S-34S. McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S. 35 35

Consider Group 2 or 3 PH Yes No “Out of proportion” PH Perform V/Q Scan CTEPH Yes Segmental Perfusion Defects If the V/Q scan is normal, clinicians should perform right-heart catheterization. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): PVOD/PCH No Perform RHC Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 36 36

Recommended Measurements during Right Heart Catheterization
Systemic artery pressure Pulmonary capillary wedge pressure (or left ventricular end diastolic pressure if not obtainable) Pulmonary artery pressure Right ventricle pressure Right atrium pressure Left atrium (if entered via a patent foramen ovale or atrial septal defect) pressure Mixed venous oxygen saturation Site dependent if congenital systematic to pulmonary shunt present; if no shunt, SVO2 = PA oxygen saturation Systemic arterial oxygen saturation The following measurements should be made during RHC. Reference: Gibbs JSR for the National Pulmonary Hypertension Centres of the UK and Ireland. Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Heart. 2008;94(suppl 1):i1-i41. Gibbs JSR, et al. Heart. 2008;94(suppl 1):i1-i41. 37 37

Measuring Pulmonary Capillary Wedge Pressure
Pulmonary Artery Pressure Decay Curve 160 140 120 100 80 60 40 20 Balloon Occlusion ARDS IPAH Pressure (mm Hg) Pulmonary artery occlusion is currently the most frequently used method for estimating pulmonary capillary pressure (PCP) in a broad range of clinical conditions. This study tested the four commonly used algorithms to measure PCP in patients with IPAH and with adult respiratory distress syndrome (ARDS). The time constants of pulmonary artery emptying may differ according to the disease process. The authors concluded that the time constants may be useful for increasing the accuracy of PCP measurement using the arterial occlusion technique. Reference: Souza R, Amato M, Demarzo S, et al. Pulmonary capillary pressure in pulmonary hypertension. Crit Care. 2005;9:R132-R138. 2 4 6 8 10 12 Time (seconds) Time Steady State is Longer in IPAH than in ARDS ARDS: acute respiratory distress syndrome. Souza R, et al. Crit Care. 2005;9:R132-R138. 38 38

Inaccurate Readings of PCWP
PA and RV Recordings in Patient with PAH RV Pressure Mistakenly Recorded as PCWP Inaccurate pressure tracing may occur when the right-heart balloon flotation catheter is not in proper position, resulting in an incorrect interpretation of pulmonary capillary wedge pressure. Inaccurate readings can lead to an inaccurate diagnosis of pulmonary venous hypertension, rather than PAH. Reference: Oudiz RJ, Langleben D. Cardiac catheterization in pulmonary arterial hypertension: an updated guide to proper use. Advances PAH. 2005;4(3):26-30. Oudiz RJ, et al. Advances PAH. 2005;4(3):26-30. 39 39

Misclassification of PAH Through Reliance on PCWP vs LVEDP
Percent (%) Almost half of patients diagnosed as having PAH by right heart catheterization including a pulmonary capillary wedge pressure were misclassified when results of left heart catheterization and left ventricular end diastolic pressure were measured. This was a single-center study of 11,523 patients over a 10-year period who underwent both LHC and RHC, for which complete hemodynamic data were available for 3,926. 580 patients (14.8%) met the criteria for PAH with a PCWP <15 mm Hg, but 310 of these patients (53.5%) had an LVEDP >15 mm Hg. Reference: Halpern SD, Taichman DB. Misclassification of pulmonary arterial hypertension due to reliance on pulmonary capillary wedge pressure rather than left ventricular end-diastolic pressure. Chest. 2009;136(1):37-43. PCWP ≤15 mm Hg LVEDP >15 mm Hg PCWP ≤15 mm Hg LVEDP ≤15 mm Hg N = 11,523, all patients undergoing LHC and RHC over 10 years at single center. Halpern SD, et al. Chest. 2009;136(1):37-43. 40 40

Diagnostic Algorithm for PAH: Results of RHC
mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Perform RHC No Yes Search for other causes If during RHC, the diagnostic criteria for PAH are measured, clinicians should then perform specific diagnostic tests to determine the underlying etiology for the PAH. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Specific diagnostic tests for PAH causes: Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 41 41

Evaluating Causes of PAH
mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD PAH due to connective tissue disease is probably the most-common form of PAH. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 42 42

3-year Incidence of Pulmonary Hypertension in Systemic Sclerosis
Estimated incidence (per 100 patient years) 95% CI All forms of pulmonary hypertension 1.37 0.74 – 2.00 Pulmonary arterial hypertension 0.61 0.26 – 1.20 PAH in limited cutaneous systemic sclerosis 0.40 0.11 – 1.03 PAH in diffuse cutaneous systemic sclerosis 1.25 0.34 – 3.20 Postcapillary pulmonary hypertension PH secondary to pulmonary fibrosis 0.15 0.02 – 0.55 Patients with systemic sclerosis can develop different forms of PH, including PAH and PVH. Reference: Hachulla E, de Groote P, Gressin V, et al. The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France. Arthritis Rheum. 2009;60(6): Hachulla E, et al. Arthritis Rheum. 2009;60(6): 43 43

mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins Drugs and toxins remain an important cause of PAH. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 44 44

PAH Due to Drugs and Toxins
Definite Risk Aminorex Fenfluramine Dexfenfluramine Toxic rapeseed oil Possible Risk Cocaine Phenylpropanolamine St. John’s wort Chemotherapeutic agents SSRI Likely Risk Amphetamines L-tryptophan Methamphetamines Unlikely Risk Oral contraceptives Estrogen Cigarette smoking The recent classification guidelines noted several agents that have a definite risk of PAH, while others have a more-tenuous association with PAH. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 45 45

SSRIs in Late Pregnancy and Risk of Persistent Pulmonary Hypertension in the Newborn
Maternal use of SSRIs PPHN (N=377) Matched Controls (N=836) Adjusted Odds Ratio (95% CI) P value Never during pregnancy (%) 361 (95.8) 812 (97.1) 1 NS Before wk 20 (%) 2 (0.5) 18 (2.2) 0.3 ( ) 0.08 After wk 20 (%) 14 (3.7) 6 (0.7) 6.1 ( ) 0.001 SSRI (selective serotonin reuptake inhibitors) used for depression late in pregnancy have been associated with the risk of persistent pulmonary hypertension in the newborn (PPHN). Reference: Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354(6):579–587. Chambers CD, et al. N Engl J Med. 2006;354(6):579–587. 46 46

mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Persons with HIV infection also are at risk for developing PAH. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 47 47

PAH and HIV Disease Seen in approximately 0.5% of HIV-infected patients Etiology appears related to HIV itself No evidence for direct infection of HIV of vascular endothelium Higher prevalence among injection drug users PAH incidence and course unaffected by HIV disease (stage or use of antiretrovirals) ~66% of mortality related to PAH A correlation between persons with HIV infection and PAH has been noted for several years. PAH is seen in approximately 0.5% of persons infected with HIV disease, compared with a background rate of 1 to 2 cases per 1 million in the general population ( %). The pathogenesis of PAH in HIV disease is unclear, but it does not appear that HIV affects the vascular endothelium. There is a higher prevalence of PAH among injection drug users infected with HIV disease, but the majority of PAH appears to be unrelated to causes such as methamphetamine or cocaine use. PAH disease course is disconnected with the stage or the course of the patient’s HIV disease. Two-thirds of patients identified with PAH succumb to PAH-related complications and not other HIV-related diseases. Reference: Limsukon A, Saeed AI, Ramasamy V, et al. HIV-related pulmonary hypertension. Mt Sinai J Med. 2006;73(7): Limsukon A, et al. Mt Sinai J Med. 2006;73(7): 48 48

Prevalence of Methamphetamine Use in HIV-PAH
12% 29% 18% Methamphetamine Methamphetamine + cocaine Cocaine Denied stimulant use A retrospective chart review identified patients with PAH-HIV seen at a single pulmonary vascular clinic between June 30, 1997 and June 30, Of the 17 patients, 12 reported use of stimulants that have been associated with PAH. Of those, eight had a history of significant methamphetamine use. This study suggests that the etiology of HIV-related PH could be confounded by stimulant use. Reference: Lewis JE, Rubin LJ, Channick RN. The Prevalence of Methamphetamine Use in Patients with HIV-Associated Pulmonary Hypertension (HIVPH). Am J Respir Crit Care Med. 2008;177:A444. 41% N = 17 patients with HIV-PAH Lewis JE et al. Am J Respir Crit Care Med. 2008;177:A444. 49 49

mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease Congenital heart disease is also associated with PAH. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 50 50

Congenital Heart Disease and PAH
Systemic to pulmonary shunts Prevalence of PAH associated with shunts estimated at 1.6 to 12.5 cases per million adults May result in PAH if not repaired early in life Eisenmenger Syndrome – severe PAH with reversal of shunt direction Post switch repair transposition of the great vessels PAH due to congenital heart disease is primarily related to systemic to pulmonary shunts. Eisenmenger syndrome can result in severe PAH. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 51 51 51

mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease Portopulmonary hypertension (PoPH) is another important category of PAH. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Portopulmonary Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 52 52

Portopulmonary Hypertension (PoPH)
Portal hypertension is main risk Prevalence is 2% to 6% in this population Pathologic changes in small arteries appears identical to IPAH Right heart catheterization mandatory for diagnosing PoPH PoPH has distinct clinical features, and is primarily associated with the presence of portal hypertension. The pathology of PoPH appears identical to that of IPAH. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 53 53

Survival in Portopulmonary Hypertension Related to Cirrhosis
0.2 0.4 0.6 0.8 1.0 PoPH without cirrhosis p = 0.003 Cumulative Survival PoPH with cirrhosis Cirrhosis is associated with a worse outcome in PoPH, regardless of treatment. Reference: Le Pavec J, Souza R, Herve P, et al. Portopulmonary hypertension survival and prognostic factors. Am J Respir Crit Care Med. 2008;178(6): 12 24 36 48 60 72 84 96 108 120 Months N = 154. Le Pavec J, et al. Am J Respir Crit Care Med. 2008;178(6): 54 54

mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease Schistosomiasis-associated PAH has been reclassified into Group 1. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Portopulmonary Schistosomiasis Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 55 55

Schistosomiasis-associated PAH
PH associated with schistosomiasis can have a similar clinical presentation to IPAH Similar histologic findings Development of plexiform lesions May include PoPH 200 million people are infected with any of the 3 species of Schistosoma 4% to 8% of patients will develop hepatosplenic disease Invasive hemodynamics required for diagnosis Post-capillary PH also prominent in this population More than 200 million persons worldwide are infected with Schistosoma. Clinical presentation is similar to IPAH, including the formation of plexiform lesions. Clinicians should be aware that the parasitic worms may also cause PoPH and PVH as well as PAH. Invasive hemodynamics are required to make a definitive diagnosis. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 56 56

mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease PVOD/PCH has been grouped into a 1’ clinical class. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Portopulmonary Schistosomiasis PVOD/PCH Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 57 57

Pulmonary Venous Occlusive Disease / Pulmonary Capillary Hemangiomatosis
Shares characteristics of IPAH Histology Clinical features Genetic alterations– familial forms for PVOD/PCH (with or without identified mutations) Distinct features Crackles and clubbing, ground glass opacities, septal thickening, mediastinal adenopathy, hemosiderin-laden macrophages, lower DLCO and PaO2 Response to therapy also different Risk for pulmonary edema with PAH-specific medications While PVOD/PCH share characteristics of IPAH, they can be distinguished from “classical” PAH by a number of distinctive features. Importantly, response to therapy is different. An accurate diagnosis is essential to prevent risk of pulmonary edema, that has been associated with use of PAH-specific medications in this population. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 58 58

mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease Diseases associated with chronic hemolysis have also been newly classified into Group 1 PAH. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Portopulmonary Schistosomiasis PVOD/PCH Chronic hemolysis Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 59 59

New Group 1 Classification Category: PAH Due to Chronic Hemolytic Anemia
Chronic hemolytic anemias associated with PAH Sickle cell disease Thalassemia Hereditary spherocytosis Stomatocytosis Microangiopathic hemolytic anemia Prevalence not established Mechanism of PAH in this population still not well understood PH also occurs with hemolytic anemias due to LVDD with pulmonary venous hypertension PH may also be “mixed” pulmonary vasculopathy with increased PCWP and increased PVR Although the clinical features of PAH in this population are similar to IPAH, the pathologic mechanism is still not well understood, and the overall prevalence is not established for each type of CHA. Reference: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 60 60

mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease No known cause Only after all known causes of PAH have been ruled out can a diagnosis of idiopathic or heritable PAH be established. Reference: Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20): Portopulmonary Schistosomiasis PVOD/PCH Chronic hemolysis Idiopathic or heritable PAH Adapted from Galie N, et al. Eur Heart J. 2009;30(20): 61 61

Assessment of PAH 62 62

Prognostic Factors for Risk of PAH Disease Progression
Lower Risk Higher Risk Evidence of RV failure No Yes Progression Gradual Rapid WHO Class II, III IV 6-minute walk distance >380 m <325 m Brain natriuretic peptide <180 pg/mL >180 pg/mL Echo findings Minimal RV dysfunction Pericardial effusion; significant RV dysfunction Hemodynamics Normal/near normal RAP and CI High RAP, Low CI Disease progression in PAH is variable. Factors associated with higher risk of disease progression are noted here, including evidence of right ventricular failure, a rapidly advancing symptomology, being diagnosed at WHO class IV, and not being able to walk 325 meters in 6 minutes. BNP (>180 pg/mL) is elevated in right ventricular pressure overload and correlates with severity of right ventricular dysfunction and mortality in PAH. Other factors associated with poorer prognosis include evidence of pericardial effusion and significant RV dysfunction on echocardiography, and high RAP and low CI on catheterization. Patients in this higher risk group should be referred to specialty centers of excellence in PAH for evaluation and initial management. Reference: McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114(13): McLaughlin VV, et al. Circulation. 2006;114(13): 63 63

Assessment of PH Severity: WHO Functional Classification (NYHA Modification for PH)
WHO Class Description I No limitation of usual activities II Mild limitation of usual activities No discomfort at rest Normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope III Marked limitation of physical activity Less than ordinary activity causes increased dyspnea, fatigue, IV Patient unable to perform any physical activity at rest and may have signs of right ventricular failure Dyspnea and/or fatigue and/or syncope/near-syncope may be present at rest, and symptoms are increased by almost any physical activity The severity of PAH is defined by functional limitations associated with severity of disease. Early in the course of PAH, patients may be largely unaffected in their usual activities. By the time patients reach Class IV, they are unable to perform any physical activities, and may have dyspnea and fatigue at rest, with an increase in symptoms in reaction to almost any physical activity. Reference: Rich S. Primary pulmonary hypertension: Executive summary. Evian, France: World Health Organization, 1998. Rich S. World Health Organization 64 64

6-Minute Walk Distance Correlates With IPAH Disease Severity
* Distance Walked in 6 Minutes (m) *† Many prognostic tests have been proposed for patients with IPAH. However, one of the simplest and most effective is the 6-minute walk test. Patients are asked to walk on a level treadmill for as far as they can for 6 minutes. The distance achieved is highly correlated with NYHA/WHO functional classification. Reference: Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161: *†‡ Control NYHA II NYHA III NYHA IV *P<0.05 versus control. †P<0.05 versus NYHA Class II. ‡P<0.05 vs NYHA Class III. Miyamoto S, et al. Am J Respir Crit Care Med. 2000;161: 65 65

Impact of Baseline 6-Minute Walk Distance on Survival in IPAH/HPAH
Epoprostenol Versus Placebo 100 6-Minute Walk Distance Survivors (n=73) Deaths (n=8) 80 60 Percent Survival Intravenous epoprostenol was the first therapy approved for use in patients with IPAH (known at the time as primary pulmonary hypertension). This 12-week, randomized, prospective, open-label trial showed a survival advantage for patients assigned to epoprostenol compared with the conventional therapy available at the time. Epoprostenol infusion was also associated with symptomatic and hemodynamic improvements. In addition, indices of quality of life improved only for patients on epoprostenol therapy. Reference: Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5): 40 6-minute walk distance at baseline was the only independent predictor of survival (P<0.003) Epoprostenol (n=41) 20 Conventional Therapy (n=40) 2 4 6 8 10 12 Week Barst RJ, et al. N Engl J Med. 1996;334(5): 66 66

NT-proBNP Elevations Correlate With Right Ventricular Systolic Dysfunction (RVSD) in PH
4127 NT-proBNP (ng/L) B-type natriuretic peptide (BNP) and N-terminal-proBNP (NT-proBNP) are released from both cardiac ventricles in response to raised heart chamber pressure or volume overload. Reference: Blyth KG, Groenning BA, Mark PB, et al. NT-proBNP can be used to detect right ventricular systolic dysfunction in pulmonary hypertension. Eur Respir J. 2007;29(4):737–744 354 With RVSD Without RVSD Threshold value RVD detection: 1,685 ng/L-1. Sensitivity for RVD 100%; specificity 94%. Blyth KG, et al. Eur Respir J. 2007;29(4): 67 67

Composite Scoring System Predicts Disease Progression in PAH
^ Composite Scoring System Predicts Disease Progression in PAH Composite Score 3-year Survival 0-6 Survival (%) 100 75 50 1 2 3 25 6-9 9-12 Time (years) 1 2 3 Walk (m) 340 <190 FC 4 NT-proBNP <2000 >2000 QOL (CAMPHOR) <12 >12 Activity <11 >11 Symptoms <16 >16 Case records of all subjects with right heart catheter proven PAH between 1997 and 2006 were reviewed to determine whether a composite score of non-invasive measurements could predict survival. A total of 269 patients were included (96 idiopathic PAH, 79 CTD PAH, 57 chronic thromboembolic pulmonary hypertension and 37 other associated causes of PAH). A composite scoring system including 6MWD, NYHA functional class, quality of life indices, and scoring of activity and symptom levels was developed. Patients were ranked into tertiles, with distinct risk of death between the three groups. Reference: Anderson D, Caballero L, Peacock, A, et al. A Composite Scoring System Based on Non-Invasive Variables Strongly Predicts Survival in Pulmonary Hypertension. Am J Respir Crit Care Med. 2008;177:A922. Anderson D, et al. Am J Respir Crit Care Med. 2008;177:A915. 68 68

Heritable PAH: Frequency of BMPR2 and ALK1 Mutations
^ Heritable PAH: Frequency of BMPR2 and ALK1 Mutations Percent (%) 222 patients with PAH were included in this analysis of BMPR2 and/or ALT1 mutations and their association with various forms of PAH. As expected, almost 100% of patients with HPAH showed the BMPR2 mutation; those who did not displayed mutations in the ALK1. Among patients with IPAH, 23.8% had BMPR2 mutations and 5.4% had ALK1 mutations. However, the presence of mutations of either gene were notably absent in patients with APAH, including patients with collagen vascular disease, congenital heart disease, and portopulmonary hypertension. Reference: Nakanishi N, Kyotani S, Ono F, et al. The Frequency of BMPR2 and ALK1 Mutations in Patients with Various Form of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2008;177:A256. HPAH IPAH APAH N = 222. Nakanishi N, et al. Am J Respir Crit Care Med. 2008;177:A256. 69 69

Updated Treatment Algorithm For PAH
70 70

Supportive Therapy and General Measures in PAH
Oral anticoagulants (IPAH/HPAH) Favorable data primarily from retrospective trials Diuretics Standard of care for right-heart failure Clinician preference on choice of agents Oxygen Low-flow supplemental O2 improved outcome in clinical case series; maintain SaO2 >92% Not evaluated in randomized controlled trial Digoxin Modest increase in cardiac output No data available on long-term management Supervised exercise program rehabilitation In addition to PAH-specific medications, a wide range of supportive measures are also considered standard of care. However, clinicians should be aware that controlled clinical trials of any of these approaches have not been conducted. Reference: Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. 71 71

Additional General and Supportive Measures in PAH
Avoid excessive exertion Avoid pregnancy Avoid constipation Appropriately refer to ensure psychological and social support Provide appropriate training and counseling on infection prevention Including, but not limited to, infections related to infusion/injection-based PAH therapy Pneumococcal and flu vaccines These additional measures for the management of PAH have been established by consensus. Reference: Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. 72 72

When to Initiate PAH-specific Therapy
No data support “wait-and-see” approach to diagnosed PAH Data suggests that patients assigned to placebo in randomized controlled trials may fail to “catch-up” when enrolled into long-term observational arms In FC II patients, bosentan improved outcomes consistent with usefulness of early intervention PAH-specific therapy should most likely be initiated at the time of definitive diagnosis of PAH. No clinical trial data support a “wait-and-see” approach. In addition, patients who were assigned to placebo arms in controlled clinical trials, then received active medication during open-label extension phases, failed to achieve the clinical benefits seen in patients initially assigned to the active treatment arms. Reference: Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. 73 73 73

EARLY: 6MWD Results With Bosentan for NYHA Class II PAH
30 Bosentan (n=86) 25 Placebo (n=91) 20 15 10 Mean Change in 6-Minute Walking Distance (m) 5 -5 In the EARLY trial, patients with NYHA/WHO Class II PAH were assigned to bosentan or placebo. Patients were originally treatment naive; however, sildenafil was provided to approximately 15% of both groups after it was approved for a PAH indication. Patients were stratified by sildenafil use. At the end of 6 months, patients receiving bosentan displayed a modest increase in 6MWD compared with placebo, which did not reach statistical significance (p=0.0758). Reference: Galie N, Rubin LJ, Hoeper MM, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371(9630): -10 -15 -20 -25 3 Months 6 Months Note: 15% of both groups also received open-label sildenafil. Galie N, et al Lancet. 2008;371(9630):2093–2100. 74 74

Role of Calcium Channel Blockers (CCBs) in PAH
Acute vasodilator challenge should be performed during right heart catheterization Use inhaled NO or IV epoprostenol for acute challenge Favorable responders to vasodilator challenge may be treated with CCBs Decrease in mPAP of at least 10 mm Hg to <40 mm Hg Increased or unchanged cardiac output Amlodipine, diltiazem, nifedipine recommended agents Avoid verapamil Patients who fail acute vasodilator challenge should NOT be treated with CCBs Patients should NOT be treated empirically with CCBs Calcium channel blockers should be used only in patients who have responded favorably to an acute vasodilator challenge during RHC. Patients who fail to demonstrate at least a 10 mm Hg decrease in mPAP during RHC to <40 mm Hg should not be provided with calcium channel blockers. Verapamil should not be used to treat PAH. Amlodipine, diltiazem and nifedipine are the preferred agents. References: Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(suppl 1):35S-62S. Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Badesch DB, et al. Chest. 2004;126(suppl 1):35S-62S. 75 75

French Registry: Response to Acute Vasodilator Challenge
10.3% 6.8% Response (%) 3.3% 2.6% When challenged with acute vasodilators at the time of right heart catheterization, patients enrolled in the French PAH registry demonstrated that responses differed by etiology of their disease. Patients with idiopathic PAH or those whose disease was an adverse effect of anorexigen use were more likely to respond to acute vasodilators, and therefore would be appropriate candidates for calcium channel blocker therapy. However, only about 10% of patients with idiopathic PAH responded to acute vasodilators and other forms of PAH do not seem to respond at all. Reference: Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9): 1.6% 0% 0% 0% Idiopathic Familial Connective Tissue Congenital Heart Portal Hypertension Anorexigens HIV >2 Factors N=649. Challenge with vasodilator at time of right heart catheterization. Humbert M, et al. Am J Respir Crit Care Med. 2006;173(9): 76 76

Survival in IPAH on Oral Calcium Channel Blocker Therapy
Long-term Calcium Channel Blocker Therapy 1.0 0.8 0.6 0.4 0.2 2 4 6 8 10 12 14 16 18 38 33 30 22 13 3 1 Years Failures Cumulative Survival Responders 19 7 Subjects at Risk (n) This is the Kaplan-Meier estimate of 57 of 70 acute responder patients who survived after 1 year onward on chronic oral calcium channel blockers (CCB). Within the first year, 13 patients in the failure subgroup had died (n=6), received transplants (n=4), or were lost to follow-up (n=3, considered “dead” in the analysis). Nineteen patients were included in the long-term CCB failure subgroup for analysis beyond the first year. There was a highly significant statistical difference between the group of long-term CCB responders and that of patients who failed on CCB (P<0.0007). These data support the conclusion that even patients who respond to vasodilator challenge must be carefully monitored on oral CCB therapy. Reference: Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111(23): Survival endpoint included those who received transplants or were lost to follow-up. Sitbon O, et al. Circulation. 2005;111(23): 77 77

PAH-specific Therapies Approved for Use in the US
Endothelin Receptor Antagonists Phosphodiesterase-type 5 Inhibitors Prostanoids – Prostacyclin Analogs Ambrisentan (PO) Sildenafil (PO) Epoprostenol (IV) Bosentan (PO) Tadalafil (PO) Iloprost (inhaled) Treprostinil (IV, SC, and inhaled) Seven agents are currently approved in the US for the treatment of PAH. Treprostinil is the only agent which has multiple forms of delivery. References: US Food and Drug Administration (FDA). Package inserts available at Search.Search_Drug_Name. Accessed November 1, 2009. FDA. Search.Search_Drug_Name. Accessed November 1, 2009. 78 78

Updated Guidelines: PAH-Specific Therapies Available in the US
Strength of Recommendation WHO Class II WHO Class III WHO Class IV A Ambrisentan, bosentan, sildenafil Ambrisentan, bosentan, epoprostenol IV, iloprost inh, sildenafil Epoprostenol IV B Tadalafil Tadalafil, treprostinil SC Iloprost inh C Treprostinil SC E/B Treprostinil IV Treprostinil IV, initial combo tx E/C Ambrisentan, bosentan, sildenafil, tadalafil Recently approved Treprostinil inh This chart shows the consensus opinion of the various agents and the level of evidence supporting their use in various disease severity, with the strength of recommendation moving from top to bottom on this chart. Treprostinil for inhalation was approved after this algorithm was published. Reference: Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Adapted from Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. 79 79

Choice of Initial PAH-specific Therapy
Dependent on many factors Disease severity Approval status Route of administration Side-effect profile Patient preference Physician experience and clinical judgment Despite consensus opinion, choice of therapy in PAH is dependent on a number of factors, including disease severity, the route of administration and dosing interval, the expected side-effect profile, and patient preference. Physician experience is also a critical component of medication choice. Reference: Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. 80 80

Updated Guidelines: Inadequate Clinical Response to Initial PAH Therapy
Failure to show improvement or deterioration with monotherapy Sequential Combination Therapy Prostanoids Atrial septostomy and/or Lung transplantation Endothelin Receptor Antagonists PDE5 Inhibitors While no therapy for PAH is approved for use in combination therapy, clinical guidelines recommend combination therapy for patients failing to respond or deteriorating on therapy. Surgical options, such as atrial septostomy and/or lung transplantation, may also be considered. Reference: Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. 81 81

Consensus Updates in PAH Classification, Screening and Treatment

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Consensus Updates in PAH Classification, Screening and Treatment

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