PULMONARY HYPERTENSION IN INTERSTITIAL LUNG DISEASE

Transcription

1 PULMONARY HYPERTENSION IN INTERSTITIAL LUNG DISEASE STEVE NATHAN, MD DIRECTOR OF THE ADVANCED LUNG DISEASE PROGRAM INOVA FAIRFAX HOSPITAL FALLS CHURCH, VA Steven D. Nathan, MD, is the Director of the Advanced Lung Disease Program and Medical Director of the lung transplant program at Inova Fairfax Hospital in Falls Church, Virginia. He also is Professor of medicine at Virginia Commonwealth University, Inova Fairfax Campus. Dr. Nathan received his medical degree at the University of the Witwatersrand Medical School in Johannesburg, South Africa, and he completed his internship in internal medicine and general surgery at the Johannesburg Hospital. Dr. Nathan performed his internal medicine residency at Long Island Jewish Hospital in New York City, and completed his fellowships in pulmonary medicine, critical care, and lung transplantation at Cedars-Sinai Medical Center in Los Angeles, California. He is board certified in internal medicine, pulmonary diseases, and critical care medicine. Dr. Nathan has authored more than 380 publications, including original research manuscripts, abstracts, reviews and book chapters. He has also co-edited and authored two books on idiopathic pulmonary fibrosis. Dr. Nathan is a reviewer for multiple journals and is on the editorial board for the journal, Thorax. He has served on multiple committees, including the US Food and Drug Administration advisory boards as well as steering committees for clinical trials in IPF and pulmonary hypertension, where he has also served as chair. Dr. Nathan is a member of several professional medical associations, including the American Thoracic Society, the American College of Chest Physicians, and the International Society for Heart and Lung Transplantation. He has delivered talks and been chairperson of numerous sessions at many national and international conferences. OBJECTIVES: Participants should be better able to: 1. Gain knowledge about the prevalence of pulmonary hypertension (PH) complicating interstitial lung disease (ILD); 2. Appreciate the functional and prognostic implications of PH complicating ILD; 3. Develop an appreciation for indicators of underlying PH in patients with ILD; 4. Understand the potential and pitfalls of pulmonary vasoactive therapies targeting the PH of ILD. SATURDAY, MARCH 25, :00 AM

2 DISCLOSURE Dr. Nathan has received grant/research support from Boehringer Ingelheim, Bayer, Roche, and United Therapeutics; serves as a consultant for Boehringer Ingelheim, Bayer, Gilead, Roche, United Therapeutics, and Bellepharon and serves on the speakers bureau at Boehringer Ingelheim, Roche, Bayer, and Gilead, but these do not create conflicts related to his presentation. Pulmonary Hypertension in Interstitial Lung Disease Steven Nathan, MD Medical Director, Advanced Lung Disease & Transplant Program Inova Fairfax Hospital Falls Church, VA Inova Advanced Lung Disease & Transplant Program 1

3 Presenter Disclosures Steven Nathan, MD My presentation may include mention of off-label use of the following for PH in lung disease: Sildenafil Tadalafil Bosentan Ambrisentan Inhaled Iloprost Treprostinil Epoprostenol Macitentan Riociguat Clinical classification of pulmonary hypertension WHO GROUP 1 PAH Idiopathic PAH Heritable PAH o BMPR2 o ALK-1, ENG, SMAD9, CAV1, KCNK3 o Unknown Drug- and toxin-induced Associated with: o Connective tissue disease o HIV infection o Portal hypertension o Congenital heart diseases o Schistosomiasis WHO Group 1 PVOD and/or pulmonary capillary hemangiomatosis WHO Group 1 Persistent PH of the newborn WHO GROUP 2 Left-heart related Systolic dysfunction Diastolic dysfunction Valvular disease Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies WHO GROUP 3 Lung/hypoxia related COPD ILD Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities WHO GROUP 4 CTEPH Chronic thromboembolic pulmonary hypertension WHO GROUP 5 Unclear multifactorial mechanisms Hematologic disorders Systemic disorders Metabolic disorders Others Sarcoidosis PLCH Simonneau G et al. J Am Coll Cardiol. 2013;62(suppl):D34-D41. 2

4 Prevalence of PH in IPF Hamada, Chest (2007) Raghu, AIM (2010) Patel, Chest (2007) Song, Res Med (2009) Nathan, Chest (2007) Zisman, Chest (2007) Shorr, ERJ (2007) Minai, ISHLT (2009) Nadrous, Chest (2005) Nathan, Res Med (2008) 8% n=70 15% n=342 20% n=41 25% n=131, RVSP >40 mmhg 41% n=11 42% n=65 46% n= % n=148 39% 84% 86% n=88, RVSP >40 mmhg n= (%) IPF, idiopathic pulmonary fibrosis; RVSP, right ventricle systolic pressure. PH in Pulmonary Fibrosis & NSIP: Prevalence % of Patients % 63.6% No PH (mpap<25 mmhg) 26.8% PH (mpap25-35 mmhg) IPF (N=224) NSIP (N=33) 18.2% 18.2% 12.9% Severe PH (mpap>35 mmhg) Inova Fairfax data: August

5 Mean Pulmonary Artery Pressure: Prognostic Value in IPF Cumulative Probability to Survival P < n = 54 No (mpap 25 mm Hg) n = 25 Yes (mpap > 25 mm Hg) Years to Event 7 Chest. 2006;129: Survival curves of all subjects: stratified according to their spap level. Percent survival % 53% 24% N=131 spap <40 mmhg spap mmhg spap >60 mmhg Time (months) Song et al. Resp Med 2009;103:

6 1.0 mpap < 25; PAOP 15 COPD Probability of Survival mpap 25; PAOP 15 mpap 25; PAOP > 15 mpap < 25; PAOP > Listing Time (Days) IPF n = 54 No (mpap 25 mm Hg) n = 25 Yes (mpap > 25 mm Hg) P < PH Progression in IPF mpap (mmhg) % Pretransplant 87% Transplant Respiration 2008;76:

7 PH in IPF: impact on 6MWT mpap <25 mm Hg (N=24) mpap > 25 mm Hg (N=10) P value 6MWD (m) 366 ± ± 66 <0.001 SpO 2 nadir (%) 88 ± 4 80 ± 4 <0.001 Lettieri et al. Chest 2006 Acute exacerbations and PH 6

8 Survival: IPAH vs PH-IIP PH IN LUNG DISEASE: PATHOGENESIS more than just the extent of parenchymal disease? 7

9 PH in IPF: No correlation with Restriction N FVC% DL CO % mpap (mmhg) Patients with PH % FVC range > 70% % % % < 40% Chest. 2007;131: Relationship between CT-fibrosis and mpap Zisman, D. A. et al. Chest 2007;132:

10 Vasculocentric Parenchymal Comorbidities Cytokines Neovascularization Fibrosis COPD Obstructive Sleep Apnea Vessel distortion Capillary Bed Destruction And Vascular Ablation Periadventitial Fibrosis Vasculopathy Shear stress Ventilation/Perfusion Mismatch Vascular capacitance Diastolic Dysfunction Acute and Chronic Pulmonary Emboli PVOD Hypoxic Vasoconstriction Coronary Artery Disease ILD ASSOCIATED PULMONARY HYPERTENSION Eur Respir Mono 2012;57:1-13. IPF Sarcoidosis COPD NSIP 9

11 PH IN ILD: When to suspect How to diagnose DIAGNOSIS PH in Lung Disease: when to suspect? History SOB that is disproportionate to the extent of ILD Physical Examination PFTs 6MWT Imaging Blood tests Loud P2 DLco < 40% Distance<200 Ratio of PA to Elevated meters aorta diameter pro ntbnp > 1 on CT of or BNP the chest Signs of right heart failure FVC%/DLCO% ratio > 1.5 Desaturation<88% on room air Pulse rate recovery < 13 beats/minute following 6MWT Echo Elevated RVSP Dilated RV/RA RV dysfunction 10

12 CT IPF 100 Percent survival PAA =< 1 PAA>1 N = 30 N = 68 p< Months Eur Respir J 2016;47:

13 Comparison of survival curves between the patients with BNP ratio 1 and BNP ratio < 1. Percent survival BNP ratio >1 BNP ratio < Time (months) N=131 Song et al. Respir Med : Echocardiography Does Not Accurately Predict PH in Patients With Idiopathic Pulmonary Fibrosis % 40% Patients (%) % Over Estimation Under Estimation Accurate N = 110, idiopathic pulmonary fibrosis patients with both echo and RHC. Comparison of RVSP by echo to PASP by RHC Nathan SD, et al. Respir Med. 2008;102:

14 Performance characteristics of RVSP thresholds for Pulmonary Hypertension (N=60) RVSP (mmhg) Sensitivity Specificity Positive Predictive Value Negative Predictive Value RVSP > RVSP > RVSP > RVSP > RVSP > RVSP > RVSP > Respir Med 2008;102: Performance characteristics of PFTs and six minute walk data alone and in combination with the RVSP for the detection of pulmonary hypertension. DLCO% Spo2 rest RVSP Excluded* RVSP (mmhg) >30 >40 >50 >60 < / / / / / 98.0 < / / / / / 97.6 < / / / / / 97.4 < / / / / / 100 < / / / / / 100 SpO2 < / / / / / 97.6 exercise < / / / / / 100 6MW Sensi 50 speci 68 < / / / / / 98.0 Distance < / / / / / 97.9 (meters) < / / / / / 97.9 *sensitivity/specificity Respir Med 2008;102:

15 What we know PH commonly complicates the course of DPLD PH associated with - worsened survival - reduced functional status -? AE s What we think we know The etiology How to diagnose PH What we don t know Is PH the driver of outcomes or a surrogate of other badness? What is disproportionate PH? Is PH adaptive or maladaptive? What we don t know, but shouldn t be too scared to ask Should we treat PH? Does it affect functional status? Survival? More harm than good? PH IN ILD: TREATMENT 14

16 Drug approvals for PAH IV Epoprostenol Bosentan 2002 SQ Treprostinil 2004 Inhaled Iloprost & IV Treprostinil 2005 Sildenafil 2006 Ambrisentan 2009 Tadalafil & Inhaled Treprostinil 2013 Riociguat &Macitentan 2014 Oral Trep Selexipag 2016 Lung Disease Investigator Year Study Design Subject Number Therapy Results Comments ILD Olschewski 1999 Open label 8 Nitric oxide, Epo IV and inhaled Inhaled prostanoids improved gas exchange ILD Ghofrani 2002 Open label 16 Sildenafil or Epo Sildenafil V/Q matching and oxygena on Prostacyclin worsened V/Q matching IPF Krowka 2007 RCT 51 Inhaled Iloprost IPF Gunther 2007 Open label 12 Bosentan IPF Collard 2007 Open label 14 Sildenafil no differences 6MWT, NYHA class, Dyspnea score, exercise O 2 sat No worsening of gas exchange 57% improved 6MWT by 20% Median follow up of 91 days ILD Minai 2008 Retrospective 19 Epo(n=10) Bosentan(n=9) 79% with 6MWT > 50 m ILD Chapman 2009 Retrospective 5 Sildenafil Improved 6MWT Decreased mpap 2 12 months IPF Zisman 2010 RCT 180 Sildenafil Failed to improve 6MWT by 20% Improved oxygen saturation and QOL 15

17 Lung Disease Investigator Year Study Design Subject Number Therapy Results Comments IPF Jackson 2010 RCT 29 Sildenafil ILD Corte 2010 Retrospective 15 Sildenafil No difference in 6MWT or Borg score Improved 6MWT and lower BNP ILD Badesch 2011 Open label 21 Ambrisentan 6MWT distance ; BNP Studied mixed PH population IPF Raghu 2013 RCT 492 Ambrisentan ILD Hoeper 2013 Open label 22 Riociguat Terminated early: lack of efficacy in time to clinical worsening Improved CO and PVR but not mpap 32 patients with PH: no change in time to disease progression O2 sat, mixed venous ILD Zimmerman 2014 Open label, observational 10 Sildenafil(n=5) Tadalafil(n=5) CO and PVR No change in 6MWT or BNP ILD Corte 2014 RCT 60 Bosentan ILD Saggar 2014 Open label 15 Treprostinil ILD Brewis 2015 Retrospective 118 PDE5 inhibs IIP Nathan 2016 RCT 143 Riociguat Unchanged:hemo s, symptoms,fc Improved hemo s without hypoxemia Improved BNP, unchanged 6MWT Terminated early: AE s & mortality RHC confirmed PH All had mpap 35 mmhg WTF! IPF prognosis can it be altered by targeting prognostic indicators? mpap 25 mm Hg mpap > 25 mm Hg P < Years 7 Lettieri CJ, et al. Chest. 2006;129: Zisman, et al. Chest 2009;135:

18 PH in Pulmonary Fibrosis: the low hanging fruit Treat the underlying condition Co-morbidities Diastolic heart failure IPF 10-18% Sarcoidosis 19% Hypoxia/nocturnal desaturation OSA PE Caveats to empiric therapy Worsening oxygenation PVOD IPF Sarcoidosis Drug/Radiation-induced fibrosis Scleroderma Occult heart failure 17

19 Step Study:? Proof of concept STEP IPF Advanced IPF (Dlco<35%) 6MWT 10%+ Sildenafil 20 mg tid Placebo 12 7%+ weeks Two-arm phase 6MWT Open-label phase Sildenafil 20 mg tid 6MWT 12 weeks The Idiopathic Pulmonary Fibrosis Clinical Research Network. N Engl J Med 2010; 363:

20 PH-ILD phase IIa study Multicenter, open label, uncontrolled study n=22 12 weeks plus 12-month extension Primary endpoint: safety and tolerability Secondary endpoints included hemodynamic changes and 6MWD Key findings Safety (n=22) AEs: dyspnea, peripheral edema (27%), dyspepsia, headache, feeling hot (14%), hypotension (9%) SAEs (possibly drug related): syncope, respiratory disorder, respiratory failure (n=1), pancytopenia (n=2), dyspnea (n=3) Efficacy 1. 6MWD, +25 m 2. Hemodynamics Cardiac index: +0.7 L/min -1. m -2 (+25%) PVR: -120 dyn s. cm -5 (-19%) PAP: no change (+1 mmhg) The results of this pilot trial indicate that riociguat appears to be well tolerated by the majority of patients with PH-ILD. It is associated with a substantial increase in cardiac output and reductions in SVR and PVR and may have the potential to improve exercise capacity in some patients 19

21 =improved by>57 m +=improved by>17 m =declined by 10 m Corte T, et al. Am J Respir Crit Care Med. 2014;190:

22 BPHIT Study: No Efficacy Signal Corte T, et al. Am J Respir Crit Care Med. 2014;190: IIP-PH: Spectrum of PH targeted therapies (COMPERA registry, n=151) Meds Baseline 1 Year ERA monotherapy 7.3% 4.7% PDE-5 inhibitor monotherapy Prostacyclin analogue 88.1% % ERA+PDE5 2.6% 2.3% Other dual therapy 2% 0% No therapy 4.7% Hoeper et al. PLOS ONE DOI: /journal.pone December 2,

23 Change in 6MWT distance: IIP-PH vs ipah (COMPERA registry, n=151 vs 798) Change in 6WMT IPAH PH-IIP >20 meters % >30 meters 53.8% 45.8% >40 meters 45.9% >50 meters 36.4% 31.3% Any worsening 26.3% 29.2% No (0-19m) 14.2% 16.6% Hoeper et al. PLOS ONE DOI: /journal.pone December 2, 2015 PH-IIP: Survival based on clinical response to PAH med (6MWT or NYHA functional class) No. patients at risk Hoeper et al. PLOS ONE DOI: /journal.pone December 2,

24 Study Design: Many Moving Parts To Get it Right! A drug that works and is well tolerated The right dose, frequency and route of administration The right patient population Disease stage, phenotype The right duration that is likely to be retained the right endpoint(s) Important inclusionary criteria: Choosing the best patient phenotype Likely to respond to therapy How to define this? Balance of amount of parenchymal lung disease versus severity of pulmonary vascular disease Casting a wide enough net Distinct entity vs distinct group of entities 23

25 Prevalence of disease:pah Data from Nathan s head Prevalence of disease:ild 24

26 Pulmonary fibrosis: a final common path? Unclassifiable ILD Am J Respir Crit Care Med 2003;168: Eur Respir J 2013;42: ILD primary determinant of outcomes PH primary determinant of outcomes Decreasing: -FVC% -Dlco% -6MWD Inflection point Vascular ablation & vasculopathy A Increasing: -mpap, -PVR Decreasing: RV function Time 25

27 IPF: Which patient group should be targeted? 70 N=178, PH in 32% 60 mpap (mmhg) FVC% Choosing the best endpoint: what does PH effect? Survival Functional status 6MWT Functional class QOL PROs AE s Hospitalization Transplantation 26

28 RIOCIGUAT PHASE 2 STUDIES: RISE-IIP RISE-IIP Study Diagnosed with a major idiopathic interstitial pneumonias Major Inclusion criteria FVC 45% 6MWD 150 m and 450 m PH confirmed by RHC with mpap 25 mmhg and PCWP 15 mmhg at rest Systolic blood pressure 95 mmhg and no signs or symptoms of hypotension WHO functional class II-IV disease Major Exclusion criteria Known significant left heart disease: Symptomatic coronary artery disease or LVEF <45% Active state of hemoptysis or pulmonary hemorrhage Difference >15% between the eligibility and the baseline 6MWD FEV 1 /FVC <0.65 after bronchodilator administration Approved IPF drug initiated within 3 months prior to screening RIOCIGUAT PHASE 2 STUDIES: RISE-IIP Efficacy endpoints Primary efficacy variables Mean change in 6MWD from baseline to week 26 Secondary efficacy variables Time to clinical worsening as evidenced by the first of any of the following four events All-cause mortality Need for hospitalization due to worsening cardiopulmonary status, attributable to progression of disease (including but not limited to increased shortness of breath or increased leg swelling) 15% decrease in 6MWD from baseline Worsening of WHO functional class 27

29 RISE-IIP, 13605: participating countries and # sites Germany / 7 France / 4 Switzerland/ 3 United Kingdom / 4 Canada / 4 USA / 12 Belgium / 1 Turkey/ 1 Japan / 5 Italy / 4 Spain / 3 Portugal / 3 New Zealand / 2 Australia / 7 14 Countries /60 Sites Portugal and Turkey added Dec 2014 New Zealand added Jan 2015 ATS

30 ATS 2016 ATS

31 ATS 2016 ATS

32 ATS 2016 DMC Teleconference with Sponsor and PI 5/5/2016 Recommended that the study be halted for increased harm to treatment arm! 31

33 Are there patients who can or should be considered for off-label PAH therapy? Unable to endorse Caveat: there are patients with hemodynamics=pah. -?group 1 PAH with comorbid DPLD The option to treat such cases can be difficult to ignore in the clinical trenches, even with a lack of supportive RCT evidence. Is this where clinical judgment and the art of medicine trump the paradigm of only practicing within the constraints of evidence-based medicine? If treatment is to be considered Pulmonary Hypertension Centers with expertise in this area, First priority populate any available clinical trials. LESSONS FROM RISE-IIP More questions than answers Should we treat complicating PH? Adaptive vs. maladaptive Compound-specific vs. concept-specific Why were these patients apparently harmed? What of V/Q mismatch What of hypotension? What of other drug AE s? Should we study IIP/ILD together? Should we do more studies? 32

34 Taking Solace from the Sages The great tragedy of science- the slaying of a beautiful hypothesis by an ugly fact T.H Buxley We hate the very idea that our own ideas may be mistaken, so we cling dogmatically to our conjectures Karl Popper Some problems are so complex that you have to be highly intelligent and well informed just to be undecided about them Laurence Peter QUESTION 1 The prevalence of PH complicating ILD is in the approximate range of: a. 5-10% b.10-35% c % d.10-85% 33

35 QUESTION 1 The prevalence of PH complicating ILD is in the approximate range of: a. 5-10% b % c % d % 6% 38% 31% 25% a. b. c. d. QUESTION 2 PH complicating ILD is associated with all of the following except: a. Shorter six minute walk distances b. Less desaturation c. Acute exacerbations of disease d. Higher mortality 34

36 QUESTION 2 PH complicating ILD is associated with all of the following except: a. Shorter six minute walk distances b. Less desaturation c. Acute exacerbations of disease d. Higher mortality 63% 31% 0% 6% a. b. c. d. QUESTION 3 PH complicating ILD should only be treated: a. When the mean pulmonary artery pressure (mpap) is >25mmHg b. When the mpap>35 mmhg c. When PH is accompanied by evidence of cor pumonale d. At an expert center 35

37 QUESTION 3 PH complicating ILD should only be treated: a. When the mean pulmonary artery pressure (mpap) is >25mmHg b. When the mpap>35 mmhg c. When PH is accompanied by evidence of cor pumonale d. At an expert center 9% 0% 0% 91% a. b. c. d. QUESTION 3 There is a strong correlation between PH in ILD and: a. The degree of restrictive physiology b. The fibrosis score on CT imaging c. The presence of underlying comorbidities d. None of the above 36

38 QUESTION 3 There is a strong correlation between PH in ILD and: a. The degree of restrictive physiology b. The fibrosis score on CT imaging c. The presence of underlying comorbidities d. None of the above 3% 5% 14% 78% a. b. c. d. 37