Disclosure. Pulmonary Hypertension (PH) Pulmonary Arterial Hypertension: Diagnosis and Novel Management Strategies. Objectives

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

2 5 th WSPH Updated Classification of Pulmonary Hypertension, Nice 2013 GROUP 1 Pulmonary Arterial Hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH BMPR ALK-1, ENG, SMAD9, CAAV1, KCNK Unknown 1.3 Drug- and Toxin-Induced 1.4 Associated with: Connective Tissue Disease GROUP 3 PH Due to Lung Disease and/or Hypoxia 3.1 Chronic Obstructive Pulmonary Disease 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 Etiology of PH on Echocardiogram Single center study from Australia 6,994 screened à 936 pts (9.1%) with PH on ECHO (defined as epasp >40 mmhg) Human Immunodeficiency Virus (HIV) Infection Portal Hypertension Congenital Heart Disease Schistosomiasis 1 Pulmonary Veno-occlusive Disease and/or Pulmonary Capillary Hemangiomatosis 1 Persistent Pulmonary Hypertension of the Newborn (PPHN) GROUP 2 PH Due to Left Heart Disease 2.1 Left Ventricular Systolic Dysfunction 2.2 Left Ventricular Diastolic Dysfunction 2.3 Valvular Disease 2.4 Congenital/Acquired Left Heart Inflow/Outflow Tract Obstruction and Congenital Cardiomyopathies Simmoneau G, et al. JACC. 2013; 62:D GROUP 4 Chronic Thromboembolic PH (CTEPH) GROUP 5 PH With Unclear Multifactorial Mechanisms 5.1 Hematologic 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 BMPR2 = bone morphogenetic protein receptor type 2; CAV1 =caveolin 1; ENG = endoglin; KCNK3 = gene encoding K2P3.1 (K + channel) Strange G et al. Heart 2012;98: th WSPH Clinical Classification of PAH (WHO Group 1) Group 1 Pulmonary Arterial Hypertension (PAH) Idiopathic PAH Heritable BMPR2 ALK-1, endoglin, SMAD9,CAAV1,KCNK3 Unknown Drug and toxin-induced PAH associated with: Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis 1 Pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis 1 Persistent PH of the newborn Simonneau et al, J Am Coll Cardiol. 2013;62:D Group 1: Pulmonary Arterial Hypertension (PAH) Subset of PH (15 cases/ million) US prevalence , ,000 dx & rx Vasoconstriction, remodeling, thrombosis in situ Progressive cardiopulmonary deterioration Leads to RH failure and death (67% 5-yr survival) Humbert M et al. Am J Respir Crit Care Med 2006;173: Thenappan T, et al. Eur Respir J. 2010;35: Characterized by progressive and sustained elevation of pulmonary artery pressure and vascular resistance: PA mean > 25 mmhg (nl 8-20 mmhg) PAWP/LVEDP < 15 mmhg (nl 4-12 mmhg) PVR > 3 W units (240 dyn/sec/cm-5) Hoeper MM, et al. J Am Coll Cardiol. 2013;62:D

3 Pathogenesis of Pulmonary Arterial Hypertension Percentage (%) Survival Survival of PAH Patients in Current Era: Comparison with Historical Controls NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE ACC/AHA Expert Consensus Determinants of Risk Yes Gradual Disease progression Rapid II, III W HO functional class IV Longer (> 400 m eters) 6-MW D Shorter (< 300 m eters) Cardiopulmonary exercise testing Peak VO 2 < 10.4 m L/kg/m in Minim ally elevated and stable BNP/NT-proBNP Significantly elevated PaCO 2 > 34 m m Hg Blood gasses RAP < 10 m m Hg; CI > 2.5 L/m in/m Predicted (NIH) Baseline Presymptomatic/ Compensated 1 year 3 year 5 year Symptomatic/ Decompensating Declining/ Decompensated CO PaCO 2 < 32 m m Hg Symptom Threshold Pericardial effusion, RV ECHO findings dysfunction, RA enlargem ent Hemodynamics McLaughlin, et al. J Am Coll Cardiol 2009;53:1573 D Alonzo, et al. Ann Int Med 1991;115:343 Raymond, et al. J Am Coll Cardiol 2002;39:1214 Observed 67 High Risk Peak VO 2 > 10.4 m L/kg/m in Minim al RV dysfunction Hemodynamic Changes Correlate with Disease Progression and Prognosis Clinical evidence of RV failure 91 Thenappan T, et al. Eur Respir J. 2010;35: PAH Determinants of Patient Risk No 100 N = 276, IPAH and HPAH patients diagnosed from ; matched for disease variables at baseline with historical controls Gaine S, J Am Med Assoc 2000;284: Low Risk RAP > 20 m m Hg; CI < 2 L/m in/m 2 Provencher, et al. E Heart J 2006: 27:589 Nagaya, et al. Circ 2000;102:865 Blyth, et al. Eur Respir J. 2007;29:737 PAP PVR RAP Right Heart Time CO=cardiac output; PAP=pulmonary arterial pressure; PVR=pulmonary vascular resistance; RAP=right atrial pressure. 3

4 Evaluation REVEAL Database: Most Frequent Symptoms at Diagnosis Dyspnea at rest Cough Dizzy/lightheaded Presyncope/syncope Edema Chest pain/discomfort Other Fatigue 11% 11% 13% 13.0% 14% 16.0% 20% 23.0% 20% 21.0% 20% 23% 27% 24.0% 29% 26.0% IPAH APAH 83% Dyspnea on exertion 84.0% N=1479. Incidence (%) Elliott EG, et al. Chest. 2007;132(4 suppl):631s. PAH Diagnostic Guidelines: Decision Analysis Unexplained Symptoms of Dyspnea on Exertion, Syncope/Near Syncope, Fatigue McGoon M, et al. Chest. 2004;126:14S-34S. Clinical History, Examination, ECG, Chest X-Ray Signs of RHF Signs on Physical Examination Loud pulmonic valve closure (P 2 ) (93%) TR murmur (40%) PR murmur (13%) Right-sided fourth heart sound Right ventricular lift Jugular venous distention RV third heart sound (23%) Peripheral edema (32%) Ascites 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: McGoon M, et al. Chest. 2004;126:14S 34S. Rich S, et al. Ann Intern Med. 1987;107:

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

6 Signs of PAH with Echo/Doppler Increased spap or TR jet Right atrial and ventricular hypertrophy/enlargement Flattening of intraventricular septum Tricuspid regurgitation Small LV dimension RV RA LV LA IVS Normal RVF: cm Mild RVD: cm Moderate RVD: cm Severe RVD: <1.5 cm RV function: Tricuspid Annular Plane Systolic Excursion Traditional ECHO does not accurately measure: Mean PA pressure PAWP Cardiac output (blood flow) Cannot calculate PVR Other limitations-15% no TR jet, not all congenital lesions obvious, small errors in TRV tracing can alter results McGoon M, et al. Chest. 2004;126:14S 34S epasp = 4V 2 + erap Contraction of RV is mainly longitudinal; tricuspid annulus displaced toward apex during systole Imaging through lateral wall with M-mode to measure this motion known as tricuspid annular plane systolic excursion (TAPSE) Less displacement as RV becomes more dysfunctional Baseline TAPSE <1.8 cm has negative prognostic implications Forfia PR et al. Am J Respir Crit Care Med. 2006;174: PAH Diagnostic Guidelines PAH Diagnostic Guidelines Echocardiography Indicates PH Echocardiography Indicates PH Evaluate for Associated Causes V/Q scan PFTs Arterial Saturation Evaluate for Associated Causes V/Q scan PFTs Arterial Saturation HIV Infection, Scleroderma, SLE, Other CTD, Liver Disease, CHD, Drug- Associated Suspected Chronic PE Parenchymal Lung Disease, Hypoxemia, or Sleep Disorder HIV Infection, Scleroderma, SLE, Other CTD, Liver Disease, CHD, Drug- Associated Suspected Chronic PE Parenchymal Lung Disease, Hypoxemia, or Sleep Disorder McGoon M, et al. Chest. 2004;126:14S-34S. McGoon M, et al. Chest. 2004;126:14S-34S. 6

7 Ventilation Perfusion Lung Scan Ø 3 4% of acute PE do not entirely resolve Ø 50% of those with CTEPH do not have hx of acute PE Ø V/Q scan is sensitive, should be performed to exclude CTEPH even when another explanation for PH is present Ø CTEPH: >1 segmental-sized or larger mismatched perfusion defects Ø Normal or very low probability V/Q scan excludes CTEPH CTEPH: A Curable Form of PH Not to Be Missed Pouch Bands Idiopathic PAH Chronic PE Absent branches Perfusion Ventilation Perfusion Ventilation PAH Diagnostic Guidelines Echocardiography Indicates PH Evaluate for Associated Causes HIV Infection, Scleroderma, SLE, Other CTD, Liver Disease, CHD, Drug- Associated McGoon M, et al. Chest. 2004;126:14S-34S. V/Q scan Suspected Chronic PE PFTs Arterial Saturation Parenchymal Lung Disease, Hypoxemia, or Sleep Disorder Pulmonary Function Tests, Arterial Blood Gases, and Oxygen Saturation Findings suggestive of PAH ê DLCO 40% - 80% of expected Mild to moderate ê of lung volumes Peripheral airway obstruction Arterial O 2 tension normal or slightly ê at rest Arterial CO 2 is ê SpO 2 preserved at rest, may be ê with exercise/ambulation Findings suggestive of alternate PH diagnoses Hypoxic PH due to COPD Irreversible airway obstruction + increased residual volumes reduced DLCO + normal or increased CO 2 tension Interstitial lung disease Decrease in lung volume + Decreased DLCO Galie N, et al. Eur Heart J. 2009;30(20):

8 PAH Diagnostic Guidelines: Confirmation of PAH Echocardiography Indicates PH PAWP: Normal 4-12 mmhg TPG= mpap - PAWP Normal < 10 mmhg DPG= dpap PAWP Normal < 5 mmhg PVR= mpap - PAWP/CO Normal < 1 Wu PH Hemodynamic Profiles: Where is the lesion? (mean PAP > 25 mmhg) Pre-capillary PH Isolated post-capillary (Passive PH ) Right Heart Catheterization Establish diagnosis Ascertain etiology Establish severity & prognosis Verify presence and severity of shunts Evaluate vasoreactivity Guide treatment Adapted from McGoon M, et al. Chest. 2004;126:14S-34S. VC RA RV PA PV PC Vachiery JL et al, J Am Coll Cardiol 2013;62: D100-8 Fang J et al, J Heart Lung Transplant 2012;31: Galie N et al, Eur Respir J 2009;34(6): Combined postpre-capillary PH (Mixed PH) LA LV Ao High flow PH nl range or épvr (CHD, AV fistula, thyrotoxicosis, chronic anemia) Algorithm for Assessment of Vasoreactivity in Patients with PAH mpa 10 mmhg mpa < 40 mmhg No D CO Right Heart Catheterization With Acute Vasoreactivity Testing (ino, epoprostenol, adenosine) Responder (<15%) Non - responder PAH Diagnostic Workup Right Heart Catheterization Confirms PAH 6-minute walk, Borg score NYHA/WHO functional class Consider: Hemodynamically- Monitored Trial of Calcium Channel Blocker (<10% respond long-term) Consider: Oral ERAs/PDEI-5/sGCS/IPA Inhaled Iloprost SQ/IV/inhaled/PO Treprostinil IV Epoprostenol Establish Baseline, Prognosis, and Document Progression/Response to Treatment With Serial Re-assessment McGoon M, et al. Chest. 2004;126:14S-34S. 8

9 Management Goals of Management of PAH Prevent right heart failure Alleviate symptoms Improve exercise capacity Improve functional class Improve hemodynamics Prevent clinical worsening Reduce morbidity, mortality Overview: 2013 WSPH Treatment Algorithm Supervised Exercise Training Psychosocial Support Avoidance of Strenuous Activity Pregnancy Avoidance Immunizations (influenza) WHO-FC I-III CCB Continue CCB Vasoreactive Sustained Response YES (WHO FC I-II) Adapted from Galié N et al JACC. 2013;62 (25, Suppl. D):D60-D72. General Measures and Supportive Therapy Expert Referral (PH Center) Acute Vasoreactivity Testing NO Oral Anticoagulants IPAH, heritable PAH anorexigen-induced PAH APAH Diuretics Oxygen Digoxin (controversial) Non-Vasoreactive Initial Therapy With PAH Approved Drugs Depending on WHO-FC Status and risk profile Endothelin receptor A Endothelin receptor antagonists Endothelin pathway Pre-proendothelin à Proendothelin Smooth muscle cells Therapeutic Targets for PAH Endothelin cells Nitric oxide pathway L-arginine à L-citrulline Endothelin 1 Nitric oxide Exogenous + nitric oxide Endothelin cgmp sgc stimul. receptor B Vasoconstriction Phosphodiesterase Vasodilation and and proliferation type 5 antiproliferation Phosphodiesterase type 5 inhibitor Vessel lumen Modified from Humbert M, Sitbon O, Simonneau G. N Engl J Med 2004;351: Prostacyclin pathway Arachidonic acid à Prostaglandin I2 Prostacyclin (prostaglandin I2) Prostacyclin derivatives + camp IP rec. agonist Vasodilation and antiproliferation 9

10 FDA -Approved Specific Therapies for PAH Class of Agent Name Route of Administration Oral Inhaled IV/SC Endothelin Receptor Antagonist Phosphodiesterase Type 5 Inhibitor Ambrisentan Bosentan Macitentan Sildenafil Tadalafil Inhalational Iloprost Inhalational Treprostinil Soluble Guanylate Cyclase Stimulator Riociguat Prostacyclin Receptor Agonist Selexipag Epoprostenol IV Prostacyclin analog Iloprost Treprostinil IV and SC US Food and Drug Administration. Approved product list as of December 22, Subcutaneous treprostinil Intravenous epoprostenol 2015 ESC/ERS Guidelines: Treatment Algorithm for PAH-specific Therapy Low or intermediate risk (WHO FC II-III) Initial monotherapy* Patient already on treatment Initial oral combination Inadequate clinical response Double or triple sequential combination Inadequate clinical response Consider listing for lung transplantation High risk (WHO FC IV) Initial combination including IV prostacyclin Consider referral for lung transplantation *Initial combination with ambrisentan plus tadalafil has proven to be superior to monotherapy in delaying clinical failure. Galie N, et al. Eur Respir J. 2015;46: th WSPH: Prognostic Variables Used in Clinical Practice To Set Treatment Goals Variable NYHA Functional class Echocardiography/CMR Hemodynamics 6 Minute walk distance Cardiopulmonary exercise testing B-type natriuretic peptide Recommended Goal I or II Normal/near normal RV size and function Normalization of RV function RAP < 8 mm Hg and CI > 2.5 to 3.0 L/min/m 2 > m (or more in younger pts) Peak VO2 >15 ml/min/kg and EqCO2 <45 L/min/min Normal range McLaughlin VV, et al. J Am Coll Cardiol. 2013;62:D

11 Inadequate Clinical Response to Initial PAH Therapy Failure to show improvement or deterioration with monotherapy Inadequate Clinical Response on Maximal Therapy? BAS (Iia- C) Adapted from Galié N et al JACC. 2013;62 (25):D60-D72. Consider eligibility for lung transplant Lung transplant (I-C) No. at Risk: GRIPHON: Selexipag for PAH Primary Endpoint: Time to First Event Patients without an event (KM)% At baseline: 20% PAH therapy naive 47% on monotherapy (ERA or PDE-5i) 33% on combination therapy (ERA & PDE-5i) Selexipag vs placebo: RR 40% HR = 0.60; 99% CI, P< Months Placebo Selexipag Selexipag Placebo Sitbon O, et al. N Engl J Med. 2015:373: Event-Free (%) Number at risk: New Paradigm- AMBITION: Ambrisentan-Tadalafil Up-front Combination Therapy Primary Endpoint: Time to First Clinical Failure Event Primary Analysis Set HR: % CI(0.348, 0.724) p= year 88.9% 1 year 75.5% Combination therapy Pooled monotherapy 2 year 79.7% 2 year 63.2% Time (weeks) 3 year 67.6% 3 year 56.1% Combination: PAH: Therapy Transplantation - lung / heart-lung Indicated for patients who continue to deteriorate with poor QOL despite aggressive therapy 1 year survival 70-90% 5 year survival 50-60% Mortality on waiting list remains high (20% per yr despite LAS) Aggressive pre-transplant management can ê mortality Pooled monotherapy: Galie N, et al. N Engl J Med. 2015;373: Chen H De Marco et al. Am J Resp Crit Care Med 2009;180:468 11

12 PAH: Summary PAH is a progressive disease associated with significant morbidity and mortality Echocardiography and right heart catheterization are the primary diagnostic modalities Strides made thus far in pathogenesis and pathobiology have lead to more effective therapies Current therapies have significant limitations and are costly New therapeutic agents and strategies are available and emerging 12