Hope in 2011 Clinical Advances Where is the road taking us?

Transcription

1 Hope in 2011 Clinical Advances Where is the road taking us? Richard Channick, MD Arlene Schiro, NP Disclosures Arlene Schiro no relevant financial and/or commercial relationships to disclose Hope is like a road in the country; there was never a road, but when many people walk on it, the road comes into existance Lin Yutang 1

2 Goals of our presentation Where we have been.. World Health Conferences on PH WHO Classification and Functional Class Diagnostic Approach Medication Timeline Where we are going in Top 10 Clinical Advances World Health Conferences on PH st World Conference on Primary PH - Geneva Two categories PPH and PH nd World Conference on PAH Evian, France Categorized based on shared pathologic and clinical features with 5 major groups rd World Conference on PAH Venice, Italy Abandoned term PPH for IPAH, added FPAH, and associated PAH; abandoned secondary PH th World Conference on PH Dana Point, Calif. Modified classifications to reflect 5 years of information 2

3 Causes of PH Anatomically: Where is the Triggering Lesion WHO Group 1: Intrinsic Arteriopathy 1. Pulmonary arterial hypertension Idiopathic PAH Heritable PAH Drug or toxin induced PAH Associated PAH WHO Group 2: Left Heart Trigger 2. PH Owing to Left Heart Disease Systolic or diastolic dysfunction Valvular disease 3

4 WHO Group 3: Lung/Respiratory Trigger 3. PH Owing to Lung/Respiratory Disease COPD Interstitial lung disease Sleep apnea/ hypoventilation Restrictive lung disease Mixed obstructive/restrictive disease WHO Group 4: Lung/Respiratory Trigger 4. Chronic Thromboembolic Disease (CTEPH) WHO Group 5: Lung/Respiratory Trigger 5. PH with multifactorial mechanisms Hematologic - splenectomy Systemic sarcoid, LAM Metabolic - Glycogen Storage Disease Other - chronic renal failure on dialysis 4

5 Challenges with the Classification System Overlap patients When is PH not PAH? Diastolic dysfunction, Valvular disease COPD, Sleep Apnea Are what is out of proportion to underlying disease? Mild heart or lung disease with severe PH. Functional Class PH Class I: Patients with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. Class II: Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class III: Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class IV: Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. ACCP Evidence-Based Clinical Practice Guidelines. Introduction. Chest. 2004;126:7S- 10S. 5

6 Pivotal Tests Contingent Tests Contribute to Assessment of: History Exam Index of Suspicion of PH CXR ECG RVE, RAE, RVSP, RV TEE Function Echocardiogram Exercise Echo Left Heart Disease VHD, CHD Pulmonary Angiography Chest CT Angiogram Chronic PE VQ Scan Coagulopathy Profile PFT s ABG s Ventilatory Function Gas Exchange Overnight Oximetry Polysomnography Sleep Disorder HIV ANA LFT s Other CTD Serologies HIV Infection Scleroderma, SLE, RA Portopulmonary Htn Functional Test (6MWT, CPET) RH Cath Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Establish Baseline Prognosis Confirmation of PH Hemodynamic Profile Vasodilator Response Algorithm in 2011 Diagnostic algorithm is clear but not always followed In QuERI initiative, only half of PAH patients had V/Q scan performed Right heart catheterizations are not always done, even in patients started on PAH therapies 6

7 Early Recognition In 2011? Data from Registries are available to interpret: REVEAL Registry data French Registry REVEAL Data: Diagnosis of PAH REVEAL Registry: Functional Class at Enrollment of Newly Diagnosed Patients* (N=412) % WHO FC III or WHO FC IV at diagnosis Patients (%) n=94 n= n=21 n=42 WHO FC I WHO FC II WHO FC III WHO FC IV *Newly diagnosed patients are those whose diagnostic right heart catheterization (RHC) fell within 90 days prior to enrollment. Patients whose confirmatory diagnostic RHC occurred after consent date will be considered newly diagnosed. REVEAL=Registry to Evaluate Early and Long Term PAH Disease Management; WHO FC=World Health Organization functional class. Adapted from Badesch DB. Chest 2010;137:376 French National Registry: Functional Class at Time of Presentation Registry including 17 university hospitals in France Consecutive adult patients ( 18 years of age) with PAH between October 2002 and October PAH patients (mean age: 50 years) IPAH: 39.2% (n=264) Heritable: 3.9% (n=26) PAH-CTD: 15.3% (n=103) PAH-CHD: 11.3% (n=76) Portopulm: 10.4% (n=70) Anorexigens: 9.5% (n=64) PAH-HIV: 6.2% (n=42) Mean time between symptom onset and diagnosis: 27 months % % 24% 63% 75% 12% I II III IV NYHA Functional Class (N=674) IPAH=idiopathic pulmonary arterial hypertension; NYHA=New York Heart Association; PAH-CHD=pulmonary arterial hypertension associated with congenital heart disease; PAH-CTD=pulmonary arterial hypertension associated with connective tissue disease; PAH- HIV=pulmonary arterial hypertension associated with human immunodeficiency virus; portopulm=portopulmonary hypertension. Humbert M et al. Am J Respir Crit Care Med. 2006;173:

8 Which patients are delayed? Patients with onset of disease before age 36 years showed the highest likelihood of delayed recognition as well as those with concomitant pulmonary disease Several possible reasons for delayed diagnosis: 1. Symptoms point to common disorders such as asthma 2. Younger patients are more active and symptoms can be more subtle and less testing 3. Young patients are the largest group of uninsured Americans and are less likely to seek help 4. If treatment for pulmonary problems do not resolve, no further testing is initiated Lynette Brown et.al. ScienceDaily July 2011 Known Pathophysiological Pathways for Treatment Endothelin Receptor Antagonists Bosentan Ambrisentan PDE-5 inhibitors Sildenafil Tadalafil Prostacyclins Epoprostenol Treprostinil Iloprost 1. Peacock AJ, Rubin LJ, eds. Pulmonary Circulation: Diseases and Their Treatment. 2nd ed. Arnold Kaplan NM. Systemic hypertension: mechanisms and diagnosis. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald s Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Saunders; 2005: Spieker LE et al. J Am Coll Cardiol. 2001;37: Badesch DB. Chest. 2004;126:

9 C l i Clinical Advances in n2011 i Global Impact of PH The breadth of illnesses associated with PH suggests that the worldwide impact of PH is quite formidable. Elliott, C. G. MD, FCCP, Barst, R. MD et.al Chest Vol.137, Supp Schistosomiasis Worldwide Worldwide Physician Education and Training in Pulmonary Hypertension: Pulmonary Vascular Disease: The Global Perspective. Elliott, C; Gregory MD, FCCP; Barst, Robyn; MD, FCCP; Seeger, Werner; Porres Aguilar, Mateo; Brown, Lynette; MD, PhD; Zamanian, Roham; MD, FCCP; Rubin, Lewis; MD, FCCP Chest. 137( ) Supplement 1:85S 94S, June DOI: /chest

10 HIV Worldwide Worldwide Physician Education and Training in Pulmonary Hypertension: Pulmonary Vascular Disease: The Global Perspective. Elliott, C; Gregory MD, FCCP; Barst, Robyn; MD, FCCP; Seeger, Werner; Porres Aguilar, Mateo; Brown, Lynette; MD, PhD; Zamanian, Roham; MD, FCCP; Rubin, Lewis; MD, FCCP Chest. 137( ) Supplement 1:85S 94S, June DOI: /chest Hemoglobinopathies Worldwide Worldwide Physician Education and Training in Pulmonary Hypertension: Pulmonary Vascular Disease: The Global Perspective. Elliott, C; Gregory MD, FCCP; Barst, Robyn; MD, FCCP; Seeger, Werner; Porres Aguilar, Mateo; Brown, Lynette; MD, PhD; Zamanian, Roham; MD, FCCP; Rubin, Lewis; MD, FCCP Chest. 137( ) Supplement 1:85S 94S, June DOI: /chest

11 Hope in 2011:Top Ten Roads to Progress The PH community NEVER stands still #10 Registry to EValuate Early And Long-Term PAH Disease Management (REVEAL) Continued knowledge gained with several publications already Analysis of outcomes, even retrospectively will provide invaluable information Example of beneficial Industry- Academia collaboration # 9 Cell Therapy: Still a Holy Grail Pulmonary Hypertension: Assessment of Cell Therapy (PHAceT) Sponsor: Northern Therapeutics Purpose The primary objective is to establish the safety of autologous progenitor cell-based gene therapy of henos in patients with severe Pulmonary Arterial Hypertension refractory to conventional treatment 11

12 # 8 New Target: Guanalyl Cyclase PATENT: A Study to Evaluate Efficacy and Safety of Oral BAY (Riociguat) in Patients with Pulmonary Arterial Hypertension Purpose The aim of the study is to assess the efficacy and safety of different doses of BAY given orally for 12 weeks, in patients with symptomatic Pulmonary Arterial Hypertension #7 A New Animal Model Sugen (SU) 5416, semaxinib, combined with exposure of the rats to 3 weeks of chronic hypoxia (10% O2) followed by 2 weeks of reexposure to normoxia.13,14 By 5 weeks (3 weeks of chronic hypoxia and 2 weeks of reexposure to normoxia) Circulation 2010, 121: : # 6 New Target: Tyrosine Kinases Imatinib in Pulmonary Arterial Hypertension (IMPRES) Sponsor: Novartis Purpose A multinational, multicenter, double blind, parallel group study design to assess treatment with QT1571 vs. Placebo as add on therapy in the treatment of severe PAH Study completed, results pending 12

13 #5 Non Prostanoid IP Receptor Agonist ACT (selixipag) in Pulmonary Arterial Hypertension Sponsor: Actelion Purpose The AC- 065A302 GRIPHON study is an event-driven Phase III study to demonstrate the effect of ACT on time to clinical worsening in patients with PAH Event driven trials in PAH: Another top development #4 Just say NO (?again) Study with Subjects with Pulmonary Arterial Hypertension and PH secondary to Idiopathic Pulmonary Fibrosis using Inhaled NITROsyl (PHiano) Sponsor: Geno LLC Purpose This is a Phase 2 open label dose escalation study to find the minimally effective and the maximum effective dose of inhaled GeNO NITROsyl #3 Implantable Pump DellVery for Pulmonary Arterial Hypertension Sponsor: Medtronic cardiac Rhythm Management Purpose The purpose of DellVery is to evaluate the safety of the Medtronic Model Implantable Infusion System to deliver Remodulin Injection 13

14 Infusion Technology #2 Patient Education #1 Global Opportunities 14

15 Thank you! 15