Disclosure Diagnosis and Novel Management Strategies - PDF document

Pulmonary Arterial Hypertension: Disclosure Diagnosis and Novel Management Strategies • Grants/Research Support: 2016 – Lung Biotechnology, Pfizer, Reata Teresa De Marco, MD, FACC • Consultant Professor of Medicine & Surgery – Actelion, Gilead, Bellerophon, Director, Advanced Heart Failure and Cardiokinetix, Theranova/Respirex Pulmonary Hypertension Comprehensive Care Center Medical Director, Heart Transplantation • Speaker’s Bureau: none • I will not discuss off label use and/or Disclosures: • Grant/Research Support: Lung Biotechnology, Pfizer, Reata investigational use of drugs or devices • Consultant: Actelion, Gilead, Bellerophon, Cardiokinetix, Respirix UC SF UC SF • I will not discuss off-label or investigational use of drugs/devices Objectives Pulmonary Hypertension (PH) Review : • Definition and classification of pulmonary hypertension (PH) and pulmonary arterial •Sustained elevation of mean hypertension (PAH) pulmonary artery pressure: • Epidemiology and natural history > 25 mmHg • Diagnostic approach mPAP= 1/3 (PAs - PAd) + PAd Normal: 8 - 20 mmHg • Management UC SF UC UC UC SF SF SF Simonneau et al, J Am Coll Cardiol . 2013;62:D34-41 1

5 th WSPH Updated Classification of Etiology of PH on Echocardiogram Pulmonary Hypertension, Nice 2013 • Single center study from Australia GROUP 1 – Pulmonary Arterial Hypertension GROUP 3 –PH Due to Lung Disease and/or Hypoxia • 6,994 screened à 936 pts (9.1%) with PH on ECHO 1.1 Idiopathic PAH 3.1 Chronic Obstructive Pulmonary Disease 3.2 Interstitial Lung Disease 1.2 Heritable PAH (defined as ePASP >40 mmHg) 3.3 Other Pulmonary Diseases W ith Mixed Restrictive and 1.2.1 BMPR2 Obstructive Pattern 1.2.2 ALK-1, ENG, SMAD9, CAAV1, KCNK3 3.4 Sleep-disordered Breathing 1.2.3 Unknown 3.5 Alveolar Hypoventilation Disorders 1.3 Drug- and Toxin-Induced 3.6 Chronic Exposure to High Altitude 1.4 Associated with: 3.7 Developmental Lung Diseases 1.4.1 Connective Tissue Disease 1.4.2 Human Immunodeficiency Virus (HIV) Infection GROUP 4 – Chronic Thromboembolic PH (CTEPH) 1.4.3 Portal Hypertension 1.4.4 Congenital Heart Disease GROUP 5 – PH With Unclear Multifactorial 1.4.5 Schistosomiasis Mechanisms 1’ Pulmonary Veno-occlusive Disease and/or Pulmonary Capillary Hemangiomatosis 5.1 Hematologic Disorders: Chronic Hemolytic Anemia, Myeloproliferative Disorders, Splenectomy 1” Persistent Pulmonary Hypertension of the Newborn (PPHN) 5.2 Systemic Disorders: Sarcoidosis, Pulmonary Histiocytosis, GROUP 2 – PH Due to Left Heart Disease Lymphangioleiomyomatosis 5.3 Metabolic Disorders: Glycogen Storage Disease, Gaucher 2.1 Left Ventricular Systolic Dysfunction Disease, Thyroid Disorders 2.2 Left Ventricular Diastolic Dysfunction 5.4 Others: Tumoral Obstruction, Fibrosing Mediastinitis, Chronic 2.3 Valvular Disease Renal Failure, Segmental PH 2.4 Congenital/Acquired Left Heart Inflow/Outflow Tract BMPR2 = bone morphogenetic protein receptor type 2; CAV1 Obstruction and Congenital Cardiomyopathies =caveolin 1; ENG = endoglin; KCNK3 = gene encoding K 2P 3.1 (K + channel) Strange G et al . Heart 2012;98:1806-1811. Simmoneau G, et al . JACC. 2013; 62:D34-41. 5 th WSPH Clinical Classification of PAH Group 1: Pulmonary Arterial Hypertension (PAH) (WHO Group 1) Group 1―Pulmonary Arterial Hypertension (PAH) • Subset of PH (15 cases/ million) Idiopathic PAH • US prevalence 50-100,000 Heritable • 15 – 25,000 dx & rx BMPR2 • Vasoconstriction, remodeling, thrombosis in situ ALK-1, endoglin, SMAD9,CAAV1,KCNK3 • Progressive cardiopulmonary deterioration Unknown • Leads to RH failure and death (67% 5-yr survival) Drug and toxin-induced PAH associated with: Humbert M et al. Am J Respir Crit Care Med 2 006;173:1023-30 Connective tissue disease Thenappan T, et al. Eur Respir J . 2010;35:1079-1087. HIV infection • Characterized by progressive and sustained elevation of Portal hypertension pulmonary artery pressure and vascular resistance : Congenital heart disease Schistosomiasis – PA mean > 25 mmHg (nl 8-20 mmHg) 1’ – Pulmonary veno-occlusive disease or pulmonary capillary – PAWP/LVEDP < 15 mmHg (nl 4-12 mmHg) hemangiomatosis – PVR > 3 W units (240 dyn/sec/cm-5) 1’’ – Persistent PH of the newborn Hoeper MM, et al. J Am Coll Cardiol . 2013;62:D42-50 . Simonneau et al, J Am Coll Cardiol . 2013;62:D34-41. 2

Pathogenesis of Pulmonary Arterial Survival of PAH Patients in Current Era: Hypertension Comparison with Historical Controls 100 100 91 Percentage (%) Survival 90 76 80 Observed 67 70 65 60 50 43 40 32 30 Predicted (NIH) 20 10 0 Baseline 1 year 3 year 5 year N = 276, IPAH and HPAH patients diagnosed from 1982-2006; matched for disease variables at baseline with historical controls NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE Thenappan T, et al. Eur Respir J . 2010;35:1079-1087. Gaine S, J Am Med Assoc 2000;284:3160-68 PAH Determinants of Patient Risk Hemodynamic Changes Correlate with and Prognosis Disease Progression ACC/AHA Expert Consensus Low Risk High Risk Determinants of Risk No Clinical evidence of RV failure Yes Declining/ Symptomatic/ Presymptomatic/ Gradual Disease progression Rapid Decompensated Decompensating Compensated II, III WHO functional class IV Longer (> 400 meters) 6-MWD Shorter (< 300 meters) Peak VO 2 > 10.4 mL/kg/min Cardiopulmonary exercise testing Peak VO 2 < 10.4 mL/kg/min CO Minimally elevated and stable BNP/NT-proBNP Significantly elevated PaCO 2 > 34 mm Hg Blood gasses PaCO 2 < 32 mm Hg Symptom Threshold Pericardial effusion, RV Minimal RV dysfunction ECHO findings dysfunction, RA enlargement PAP Right Heart RAP < 10 mm Hg; RAP > 20 mm Hg; PVR Hemodynamics CI > 2.5 L/min/m 2 CI < 2 L/min/m 2 RAP Time McLaughlin, et al. J Am Coll Cardiol 2009;53:1573 Provencher, et al. E Heart J 2006: 27:589 D ’ Alonzo, et al. Ann Int Med 1991;115:343 Nagaya, et al. Circ 2000;102:865 CO=cardiac output; PAP=pulmonary arterial pressure; PVR=pulmonary vascular resistance; Raymond, et al. J Am Coll Cardiol 2002;39:1214 Blyth, et al. Eur Respir J. 2007;29:737 RAP=right atrial pressure. 3

REVEAL Database: Most Frequent Symptoms at Diagnosis Evaluation Dyspnea at rest 11% IPAH 11% APAH 13% Cough 13.0% 14% Dizzy/lightheaded 16.0% 20% Presyncope/syncope 23.0% 20% Edema 21.0% 20% Chest pain/discomfort 23% 27% Other 24.0% 29% Fatigue 26.0% 83% Dyspnea on exertion 84.0% 0 25 50 75 100 Incidence (%) N=1479. UC UC SF SF Elliott EG, et al. Chest. 2007;132(4 suppl):631S. PAH Diagnostic Guidelines: Signs on Physical Examination Decision Analysis • Loud pulmonic valve closure (P 2 ) (93%) • TR murmur (40%) Unexplained Symptoms of Dyspnea on • PR murmur (13%) Exertion, Syncope/Near Syncope, Fatigue • Right-sided fourth heart sound • Right ventricular lift Signs of RHF • Jugular venous distention • RV third heart sound (23%) • Peripheral edema (32%) Clinical History, Examination, • Ascites ECG, Chest X-Ray • Low BP, low PP, cool extremities (low CO, peripheral vasoconstriction, hypoperfusion) • Stigmata of associated causes of PAH McLaughlin VV et al. J ACC. 2009;53:1573-1619 McGoon M, et al. Chest . 2004;126:14S-34S. McGoon M, et al. Chest . 2004;126:14S−34S. UC UC SF SF Rich S, et al. Ann Intern Med. 1987;107:216-223. 4

Chest Radiograph in PAH Electrocardiogram § • Cardiac enlargement • Insufficiently sensitive as screening tool for PH § • No evidence of pulmonary edema § • Prominent proximal PA s •Prognosis: ­ p-wave in II, qR V1, RVH è ­ risk of death § • Lungs appear normal § • “ Pruning ” of distal PA s • RAD, RAE, RBBB,RVH Peripheral Prominent Central Hypovascularity Pulmonary Artery RV Enlargement Right Descending Pulmonary Artery Image courtesy of Vallerie McLaughlin, MD McGoon M, et al. Chest 2004;126:14S-34S Bossone E, et al. Chest 2002;121:513 McLaughlin VV et al. JACC 2009;53:1573-1619. Apical Four Chamber PAH Diagnostic Guidelines: Decision Analysis Clinical History, Examination, LV RV Chest X-Ray, ECG RA LA Is There a Reason to Suspect PH? Parasternal Short Axis Yes No RV Echocardiography Work-Up LV for Other Conditions McGoon M, et al. Chest . 2004;126:14S-34S. Normal PAH 5