The COPD-PH Consult. When to Consider Pulmonary Vascular Disease. Diagnostic Algorithm for Pulmonary Hypertension

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Chrystal Shepherd
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The COPD-PH Consult 52-year-old white male with COPD, HTN, presents with progressive DOE Current Meds: LABA/LAMA 5 years ACEI year 2 exacerbations in last year 2 LPM oxygen 6 mo An echo is ordered

0 (23%) DOE, dyspnea on exertion; HTN, hypertension; LPM, liters per minute; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; ACEI ACE inhibitor; TLC, total lung capacity; RV,

$Abnormal PFTs Continue present management of HTN IT S NOT THE HEART IT S THE LUNGS RV, right ventricle; LV, left ventricle; EF, ejection fraction; PASP, pulmonary artery systolic pressure; RAP, right$ Systolic dysfunction.2 Heritable 2.2 Diastolic dysfunction.2. BMPR2 2.3 Valvular disease.2.2 ALK-, endoglin, SMAD 9, CAV-, KCNK3.2.3 Unknown Group 3 PH owing to lung diseases or hypoxia.

Systolic dysfunction.2 Heritable 2.2 Diastolic dysfunction.2. BMPR2 2.3 Valvular disease.2.2 ALK-, endoglin, SMAD 9, CAV-, KCNK3.2.3 Unknown Group 3 PH owing to lung diseases or hypoxia.

4 Sleep-disordered breathing.4.2 HIV infection 3.5 Alveolar hypoventilation disorder.4.3 Portal hypertension 3.6 Chronic exposure to high altitude.4.4 Congenital systemic to pulmonary shunts 3.

1 The COPD-PH Consult 52-year-old white male with COPD, HTN, presents with progressive DOE Current Meds: LABA/LAMA 5 years ACEI year 2 exacerbations in last year 2 LPM oxygen 6 mo An echo is ordered Function Testing FVC 3.79 (75%) 3.87 (77%) +2 FEV 2.39 (62%) 2.56 (66%) +7 FEV/FVC ratio TLC 7.0 (03%) RV 3.05 (36%) DLCO (adj) 7.0 (23%) DOE, dyspnea on exertion; HTN, hypertension; LPM, liters per minute; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; ACEI ACE inhibitor; TLC, total lung capacity; RV, residual volume; DLCO, diffusing capacity of lungs for carbon monoxide The COPD-PH Consult When to Consider Vascular Disease Bi-atrial enlargement RV dilated LV EF normal Elevated PASP 59 mm Hg +RAP Decreased RV Function TAPSE =.5 Consult Moderate obstructive lung disease stable Abnormal echo Continue present management of COPD IT S NOT THE LUNGS IT S THE HEART Cardiology Consult Normal left ventricular systolic function Abnormal PFTs Continue present management of HTN IT S NOT THE HEART IT S THE LUNGS RV, right ventricle; LV, left ventricle; EF, ejection fraction; PASP, pulmonary artery systolic pressure; RAP, right atrial pressure; TAPSE, tricuspid, annular plane systolic excursion WHO Clinical Classification of PH Guidelines 203 (Nice, France) Group Group 2 PH owing to left heart disease. Idiopathic 2. Systolic dysfunction.2 Heritable 2.2 Diastolic dysfunction.2. BMPR2 2.3 Valvular disease.2.2 ALK-, endoglin, SMAD 9, CAV-, KCNK3.2.3 Unknown Group 3 PH owing to lung diseases or hypoxia.3 Drug- and toxin-induced 3. Chronic obstructive pulmonary disease 3.2 Interstitial lung disease.4 associated with: 3.3 Other pulmonary diseases with mixed restrictive and.4. Connective tissue diseases obstructive pattern 3.4 Sleep-disordered breathing.4.2 HIV infection 3.5 Alveolar hypoventilation disorder.4.3 Portal hypertension 3.6 Chronic exposure to high altitude.4.4 Congenital systemic to pulmonary shunts 3.7 Developmental abnormalities.4.5 Schistosomiasis Group 4 Chronic thromboembolic PH Persistent pulmonary hypertension of newborn veno-occlusive disease or pulmonary Group 5 PH with unclear multifactorial capillary hemangiomatosis mechanisms 5. Hematologic disorders : Chronic hemolytic anemia, MPD, The 6th World Symposium on was held in Nice, France from February 27 to March, 208 and 5.2 Systemic disorders : sarcoid updates derived from this meeting are expected to be 5.3 Metabolic disorders released in late 208 or early Others Simonneau et al. J Am Coll Cardiol. 203;62(25 supp D):D34-D4. Diagnostic Algorithm for Pivotal Tests History Exam EKG CXR PFTs ECHO VQ Scan Serologies: HIV LFT s ANA Contingent Tests ABG TEE Exercise Echo CT Angio PA gram Hypercoag serologies Other CTD Serologies Contributes to the assessment of: Index of suspicion for PH Ventilatory Function Gas Exchange RVE, RAE, RVSP, RV Function Left Heart Disease VHD, CHD Eval for CTD: SSc, SLE, MCTD Occult liver disease, HIV Overnight Oximetry PSG Sleep disorder, Noc. Hypoxemia Six Minute Walk Test CPET Baseline Function Prognosis Right Heart Catheterization Testing Fluid Challenge Exercise Challenge Left Heart Cath GOLD STANDARD Defines PH Prognostic and therapeutic implications PFTs, pulmonary function tests; ECHO, echocardiogram; VQ, ventilation/perfusion; LFTs, liver function tests; ANA, anti-nuclear antibody; ABG, arterial blood gases; TEE, transesophageal echocardiography; PA gram, pulmonary angiograph; CTD, connective tissue disease; PSG, polysomnogram; CPET, cardiopulmonary exercise testing; RVE, right ventricle enlargement; RAE, right atrial enlargement; RVSP, right ventricle systolic pressure; SSc, systemic sclerosis; SLE, systemic lupus erythematosus; MCTD, mixed CTD

Clinical Classification of Class : mpap at rest 25 mm Hg PCWP 5 mm Hg PVR >3 Wood Smooth Muscle Hypertrophy Endothelial Cell

neovascularization Medial Thickening Occlusive Venopathy Change in pressure/ flow Class 4: PH Right mpap heart Pressure at rest

lung disease mpap at rest >25 mm Hg Underlying chronic lung disease Factor VIII Staining mpap, mean pulmonary artery pressure;

$(<3.5 cm) No LVH Normal to high ejection fraction Septal bowing (systole > diastole) Pericardial effusion Doppler: Variable$ $fraction RV/LV ratio < LV remains round in short axis Doppler Variable PASP > 2+ MR E>A diastolic dysfunction (Grade 2-3) LA,$ left atrium; LV, left ventricle; LVH, left ventricle hypertension; RV, right ventricle; PASP, pulmonary artery systolic

left atrium; LV, left ventricle; LVH, left ventricle hypertension; RV, right ventricle; PASP, pulmonary artery systolic

Arterial Venous Lung Disease WHO Group How Common is?

WHO Group I Prevalence 0 20 cases/million population* US population 3 million US cases of : 4,665 (orphan disease <200K in US)

Group I () Group II () Group III (PH due to O 2 ) Group IV (chronic PE) Estimated US prevalence (n) 4,665 Pubmed citations* (n)

2 Clinical Classification of Class : mpap at rest 25 mm Hg PCWP 5 mm Hg PVR >3 Wood Smooth Muscle Hypertrophy Endothelial Cell Proliferation (monoclonality) Class 2: mpap at rest 25 mm Hg PCWP 5 mm Hg Vascular Resistance (PVR): Neointima formation neovascularization Medial Thickening Occlusive Venopathy Change in pressure/ flow Class 4: PH Right mpap heart Pressure at rest >25 Left mm heart Hg Pressure Cardiac Output PCWP 5 mm Hg Evidence of chronic perfusion defects Class 3: PH associated with lung disease mpap at rest >25 mm Hg Underlying chronic lung disease Factor VIII Staining mpap, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance;, pulmonary arterial hypertension;, pulmonary venous hypertension Smooth Muscle Hypertrophy Echocardiographic Features of vs Arterial 2-D echo: Normal LA, LV size; small LV (<3.5 cm) No LVH Normal to high ejection fraction Septal bowing (systole > diastole) Pericardial effusion Doppler: Variable PASP No MR Grade diastolic dysfunction (E<A) Venous 2-D echo Dilated LA Normal of dilated LV ± LVH Variable LV ejection fraction RV/LV ratio < LV remains round in short axis Doppler Variable PASP > 2+ MR E>A diastolic dysfunction (Grade 2-3) LA, left atrium; LV, left ventricle; LVH, left ventricle hypertension; RV, right ventricle; PASP, pulmonary artery systolic pressure; MR, mitral regurgitation Echocardiographic Features of vs Where is the Lesion? Arterial Venous Lung Disease WHO Group How Common is? How Common is? WHO Group I Prevalence 0 20 cases/million population* US population 3 million US cases of : 4,665 (orphan disease <200K in US) Worldwide population: 6 billion Worldwide cases of : 90,000 WHO Group I is a rare, orphan disease But PH is not WHO Category Group I () Group II () Group III (PH due to O 2 ) Group IV (chronic PE) Estimated US prevalence (n) 4,665 Pubmed citations* (n) 36,629 (6,34) Google hits** (n).8 million (586,000) millions 4,724 64,900 >200,000 5,86 355,000 90,000 3,29 38,00 Clinical trials (n)* Completed (N=330) 40 (42%) 8 (2%) 74 (22%) 33 (0%) Ongoing (n=94) 58 (30%) 28 (4%) 34 (7%) 5 (3%) *Humbert M et al. AJRCCM. 2006; 73(9): Hoeper M et al ERR, : * ** 2

>200,000 WHO Category Group IV (chronic PE) 90,000 Ongoing (n=94).

Non-Specific Clinical trials (n)* Completed (N=330) Palpitations 5% Raynauds 0% Syncope Pre-syncope 3% REVEAL Registry Ortners Syndrome <% Dates 3/2006

± 4.4 NYHA III-IV (%) 73.6 At diagnosis NYHA III-IV (%) 55.6 At enrollment (25mo) Time from Symptom to RHC (mo) * http://www.pubmed.org; ** http://www.

The Importance of Early Diagnosis How sick were patients at the time of enrollment into the registry? Humbert 34. ±.2 EARLY TRIAL WHO Group M, et al.

2005;52:3792-800. Galiè N, et al. Lancet. 2008;37:2093-00.

3 Presenting Symptoms of How Common is? Estimated US prevalence (n) Pubmed citations* (n) Google hits** (n) Group I () 4,665 36,629 (6,34) Group II () millions Group III (PH due to O2) >200,000 WHO Category Group IV (chronic PE) 90,000 Ongoing (n=94).8 million (586,000) 40 (42%) 58 (30%) 4,724 64,900 8 (2%) 28 (4%) 5,86 355, (22%) 34 (7%) 33 (0%) 5 (3%) 3,29 38,00 Symptoms Are Often Non-Specific Clinical trials (n)* Completed (N=330) Palpitations 5% Raynauds 0% Syncope Pre-syncope 3% REVEAL Registry Ortners Syndrome <% Dates 3/2006 9/2007 Number Pts % Female Chest pain or discomfort 7% Progressive onset exertional dyspnea 60% Fatigue 9% 2525 All Patients 79.5 Age, yr (range) 50. ± 4.4 NYHA III-IV (%) 73.6 At diagnosis NYHA III-IV (%) 55.6 At enrollment (25mo) Time from Symptom to RHC (mo) * ** RHC, right heart catheterization Badesch D, et al. CHEST. 200;37; The Importance of Early Diagnosis How sick were patients at the time of enrollment into the registry? Humbert 34. ±.2 EARLY TRIAL WHO Group M, et al. AJRCCM. 2006;73: Performed a study of screening new scleroderma patients for Primary Indication Hachula E, et al. Arthritis Rheum. 2005;52: Galiè N, et al. Lancet. 2008;37: Treatment of Group Treatment Goals in Group Epoprostenol (Flolan ) Ambrisentan (Letairis ) Bosentan (Tracleer ) Sildenafil (Revatio ) Macitentan (Opsumit ) Tadalafil (Adcirca ) Treprostinil (Remodulin - IV/SQ) (Tyvaso Inhaled) (Orenitram Oral) Iloprost (Ventavis Inhaled) Riociguat (Adempas ) Humbert M, et al. N Engl J Med. 2004;35: Selexipag (Uptravi ) RAP, right atrial pressure; CI, cardiac index; TAPSE, tricuspid annular plane systolic excursion Sitbon O, Galiè N. Eur Respir Rev. 200;9:

Treatment Algorithm of Treatment Algorithm of 9 Galiè N, et al. J Am Coll Cardiol. 203;62(25 Suppl):D60-72. 20 Galiè N, et al. J Am Coll Cardiol. 203;62(25 Suppl):D60-72. Treatment Algorithm of Treatment Algorithm of Galiè N, et al.

4 Treatment Algorithm of Treatment Algorithm of 9 Galiè N, et al. J Am Coll Cardiol. 203;62(25 Suppl):D Galiè N, et al. J Am Coll Cardiol. 203;62(25 Suppl):D Treatment Algorithm of Treatment Algorithm of Galiè N, et al. J Am Coll Cardiol. 203;62(25 Suppl):D Galiè N, et al. J Am Coll Cardiol. 203;62(25 Suppl):D s in Group 2: WHO Group Lung Transplant Optimize heart failure What about pulmonary vasodilators? Theoretical risk of pulmonary edema Prostacyclin ERA Trial Outcome Trial Outcome FIRST Incr. Mortality VERITAS Lack of efficacy ENABLE Incr heart failure adm. ENCOR Trend increase mortality EARTH Lack of efficacy 4

5 s in Group 2: PDE-5 inhibitors: Most promising Small trials with encouraging results Lewis 2007 Guazzi 2007 TRIAL Lewis GD, et al. Circulation. 2007;6: Guazzi M, et al. J Am Coll Cardiol. 2007;50: PDE-5 Inhibitor OUTCOME Improved exercise capacity and QOL in systolic HF with PH Improved exercise capacity, improved PAP, decreased hospitalization WHO Group Optimize heart failure No role for prostacyclin Optimize lung disease s in Group 3: PH lung disease Theoretical risk of increasing VQ mis-matching and worsening hypoxemia PH Lung Dz PH-ILD No clear benefit from specific therapy Trend towards increased oxygen requirements* VQ, ventilation/perfusion; ILD, interstitial lung disease *Le Pavec J, et al. Arthritis Rheum. 20;63: s in Group 3: PH PH-COPD Multiple small studies, poorly-defined patients Prostacyclins IV showed worsening oxygenation a Inhaled showed improved oxygenation b ERA Showed trends towards worsening oxygenation, decline in 6MWT, and worse QOL c PDE-5 Well tolerated, attenuated exercise, induced rise in mpap d a Archer SL, et al. CHEST. 996;09: b Dernaika TA, et al. Respiration. 200;79: c Stolz D, et al. Eur Respir J. 2008;32: d Holverda S, et al. Pulm Pharmacol Ther. 2008;2: WHO Group WHO Group Optimize heart failure No role for prostacyclin Optimize lung disease? role for inh prostacyclin? Optimize heart failure No role for prostacyclin Optimize lung disease? role for inh prostacyclin? Anticoagulate s Referral for Thromboendarterectomy 5

s in Group 4: Anticoagulation is the backbone Clear role for pulmonary vasodilators in nonoperative candidates Thromboendarterectomy is treatment of choice as it offers a durable cure.

Lung Disease Hyperinflation Hypoxia Inflammation Vasoconstriction Vascular Remodeling PH in COPD PH in COPD out of proportion Type PHD * Type 2 PHD * * Forfia PR, et al. Pulm Circ. 203:3:5-9.

6 s in Group 4: Anticoagulation is the backbone Clear role for pulmonary vasodilators in nonoperative candidates Thromboendarterectomy is treatment of choice as it offers a durable cure. Systolic Dysfunction CAD Elevated Left Heart Filling Pressures Venous Passive Congestion Vascular Disease In WHO In Group COPD 2 and 3 PH Diastolic Dysfunction Reactive out of proportion Parenchymal Lung Disease Hyperinflation Hypoxia Inflammation Vasoconstriction Vascular Remodeling PH in COPD PH in COPD out of proportion Type PHD * Type 2 PHD * * Forfia PR, et al. Pulm Circ. 203:3:5-9. s in Select COPD-PH? How Do We Know What To Treat? What is the difference between severe COPD-PH and with comorbid COPD? 2959 subjects with Group followed at 30 centers COPD one of the most commonly reported comorbid conditions On average GOLD 2 severity 498/2959 7% reporting COPD WHO Group Primary Indication Optimize heart failure? Optimize lung disease Anticoagulate s Referral for PTE surgery Poms AD, et al. CHEST. 203;44: Seeger W, et al. J Am Coll Cardiol. 203;62(25 Suppl):D09-6. How Do We Know What To Treat? How Do We Know What To Treat? Out of Proportion Lung Disease without PH (COPD/ILD/CPFE) Lung Disease with PH (COPD/ILD/CPFE) Lung Disease with severe PH (COPD/ILD/CPFE) WHO Group Primary Indication? Out of Proportion Type 2 PHD reactive PH combined pre and post capillary PH Anticoagulate s Referral for PTE surgery mpap <25 mm Hg mpap >25 mm Hg mpap 35 mm Hg or mpap >25 mm Hg and low CI (<2.0 L/min/m 2 ) Seeger W, et al. J Am Coll Cardiol. 203;62(25 Suppl):D09-6. Seeger W, et al. J Am Coll Cardiol. 203;62(25 Suppl):D

Lung Disease with Severe PH Conclusions Represents a minority of chronic lung disease patients suspected to have severe vascular abnormalities Circulatory impairment is primary driver of reduced

Minai OA, et al. Respir Med. 202;06:63-2. hypertension is a complex comorbid condition with many faces and therefore many potential treatment pathways.

7 Lung Disease with Severe PH Conclusions Represents a minority of chronic lung disease patients suspected to have severe vascular abnormalities Circulatory impairment is primary driver of reduced exercise capacity rather than the ventilatory impairment related to the lung disease Seeger W, et al. J Am Coll Cardiol. 203;62(25 Suppl):D09-6. Boerrigter BG, et al. CHEST. 202;42: Minai OA, et al. Respir Med. 202;06:63-2. hypertension is a complex comorbid condition with many faces and therefore many potential treatment pathways. Hemodynamic distinctions (need for right heart catheterization) Pathologic distinctions (driving the question where is the lesion ) Treatment distinctions (not all PH benefits from PH drugs) Data to guide decision-making outside of WHO Group and are limited. We need to better understand. how it develops? how the different faces effect patients? does intervention actually effect outcomes? 7

ACTIVITY DESCRIPTION Target Audience Learning Objectives

ACTIVITY DESCRIPTION Target Audience This continuing medical education activity is planned to meet the needs of primary care providers who can contribute to early detection of disease and who are responsible