Update in Pulmonary Arterial Hypertension

Transcription

1 Update in Pulmonary Arterial Hypertension Michael J Sanley, MD April 12, 2018 Disclosures I have nothing to disclose 2 1

2 Case Presentation 67 yo male with atrial fibrillation, CLL on IVIG, presents with progressive exertional dyspnea Short of breath after 20 feet Has checked O2 sats drops into 70s Prior smoker, history of asbestos exposure as he works in auto repair Case Presentation Cardiac workup with stress test unremarkable PFTs showed DLCO 60% predicted, normal lung volumes, no obstruction CT chest no PE or ILD VQ scan did show some air trapping, normal perfusion Echo showed RVSP 107.2, moderately enlarged RV and moderately reduced function, EF 55-60%, grade 2 diastolic dysfunction 2

3 Case Presentation RHC: RA 21/18/15 RV 102/17 PA 100/28/47 PCWP 17 Definition Pulmonary hypertension is caused by restricted flow through the pulmonary arteries Results in increased pulmonary vascular resistance Eventually leads to right heart failure 3

4 Pulmonary Arterial Hypertension Rare disease, prevalance of 15/1,000,000 PH due to other causes much more common Very poor prognosis Up to 15% mortality within first year of diagnosis, even on modern therapy Pulmonary Arterial Hypertension Mean PA pressure > 25mmHg Normal pulmonary artery occlusion pressure (<15) Increased pulmonary vascular resistance, > 3 Wood units 4

5 Clinical classification, Nice PAH 3. PH Owing to Lung Diseases and/or Hypoxia 1.1 Idiopathic 1.2 Heritable BMPR ALK1, ENG, SMAD9, KCNK Unknown 1.3 Drug and Toxin induced 1.4 Associated with Connective tissue disease HIV Portal Hypertension Congenital Heart Disease Schistosomiasis 1' PVOD and/or PCH 1'' Persistent PH of the newborn 3.1 COPD 3.2 ILD 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 abnormalities 4. CTEPH 2. PH Owing to Left Heart Disease 5. PH With Unclear Multifactorial Mechanisms Modified from Simonneau et al. JACC Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired L heart inflow/outflow tract obstruction and congenital cardiomyopathies 5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, LAM, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage, Gaucher, thyroid 5.4 Others: tumoral obstruction, fibrosing mediastinitis, CKD, segmental PH WHO Functional Class Class I: no limitation of usual physical activity Class II: Mild limitation of normal physical activity Class III: Marked limitation of physical activity Class IV: Inability to perform any activity; symptoms at rest 5

6 Rising Incidence in PH Population-based cohort study in Ontario from ,529 patients with PH 68.5% Group 2 47% Group % Group 1 9% Group 4 Annual Prevalence increased from 87.6 to 114.9/100,000 Wijeratne et al Wijeratne et al

7 Wijeratne et al Survival appears to be improving Standardized Mortality Ratios of all groups of PH decreased from 2003 to 2011 Group All PH Group Group Group Group Wijeratne et al

8 Prognostic Indicators and Survival Data from REVEAL registry, 2010 Prognosis according to predicted risk factors Benza RL et al. Circulation Better prognosis Determinants of prognosis Worse prognosis No Clinical evidence of RV failure Yes Slow Rate of progression of symptoms Rapid No Syncope Yes I, II WHO-FC IV Longer (>500 m) 6-MWT Shorter (<300 m) Peak O 2 consumption >15 ml min 1 kg 1 Cardiopulmonary exercise testing Peak O 2 consumption <12 ml min 1 kg 1 Normal or near-normal BNP/NT-proBNP plasma levels Very elevated and rising No pericardial effusion TAPSE >2.0 cm Echocardiographic findings Pericardial effusion TAPSE <1.5 cm RAP <8 mmhg and CI 2.5 L min 1 m 2 Hemodynamics RAP >15 mmhg or CI 2.0 L min 1 m 2 Gallie N et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009l34:

9 Benza RL et al. CHEST 2012 Serial Risk score assessment When REVEAL risk calculator was applied to REVEAL registry patients at baseline and 12 months, change in score had significant correlation with mortality HR 1.67 for patients with increase in score HR 0.57 for patient with decrease in score Benza et al. J Heart Lung Transpl

10 PAH related morbidities are prognostic of mortality Recent analysis of SERAPHIN (macitentan) and GRIPHON (selexipag) studies Looked at patients who had experienced a morbidity event at 3, 6, and 12 months and assessed their risk of death McLaughlin VV et al. JACC 2018 Morbidity Event vs. No Prior Morbidity Event SERAPHIN Main analysis 3.39 ( ) Sensitivity analysis GRIPHON Month 3 Month 6 Month ( ) Main analysis 4.48 ( ) Sensitivity analysis 3.05 ( ) 1.84 ( ) 1.24 ( ) 4.10 ( ) 3.03 ( ) 1.98 ( ) 1.52 ( ) 3.52 ( ) 2.87 ( ) 10

11 Goals of therapy Improve quality of life Improve functional class Improve survival Improve 6 minute walk Prevent clinical worsening Improve hemodynamics Decrease hospitalizations Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. NEJM 2004;351:1425:36 11

12 FDA-Approved Therapies Calcium channel blockers PDE-5 inhibitors cgmp inducers Endothelin receptor antagonists Prostanoids Calcium channel blocker therapy Only to be used in those with positive vasodilator challenge on RHC Better prognosis High doses required Amlodipine 20mg daily Nifedipine mg daily Diltiazem mg daily No use for verapamil decrease in inotropy 12

13 PDE-5 inhibitors Sildenafil 20 to 80mg TID Improved 6MWD, functional class, mean PA pressure Tadalafil 20 to 40mg daily Improved 6MWD, quality of life, time to clinical worsening SGC stimulators Riociguat Titrated up to 2.5mg TID Only approved medical therapy for Group 4 disease Improved 6MWD, PVR, NT-proBNP, time to clinical worsening and functional class 13

14 Endothelin receptor antagonists Bosentan Dual ERA, improves 6MWD, functional class, Borg dyspnea score, time to clinical worsening, PVR Liver toxicity and better alternatives in class limit use Macitentan Dual ERA Better tissue penetration Improved composite endpoint of long term morbitity and mortality, reduces clinical worsening Ambrisentan Selective Improves 6MWD, time to clinical worsening, functional class, QOL, NTproBNP Prostacyclins IV: epoprostenol and treprostinil SQ: treprostinil Inhaled: iloprost and treprostinil Oral: trepostinil, beraprost, selexipag 14

15 Traditional Goal Directed Therapy AMBITION and Up-front combination therapy Galie N et al. NEJM 2015 Compared ambrisentan plus tadalafil to ambrisentan + placebo and tadalafil + placebo in treatment naïve PAH Primary end point: first event of clinical falilure Composite of death, hospitalization for worsened PAH, disease progression, unsatisfactory long-term clinical response 15

16 AMBITION and Up-front combination therapy 500 patients 253 combination therapy 18% primary end point 126 ambrisentan only 34% primary end point 121 tadalafil only 28% primary end point Hazard ratio for combination therapy vs pooled monotherapy = 0.5 Greater reductions in NT-proBNP, higher percentage of significant clinical response, greater improvement in 6MWD GRIPHON 2015 Phase III trial, studied selexipag in treatment naïve or on stable doses of oral ERA/PDE-5i or both Primary end point death from any cause or complication related to PAH 16

17 GRIPHON 2015 Primary end point reached: Placebo: 41.6% Selexipag 27% 81.9% Disease progression/hospitalization Sitbon et al. NEJM 2015 Choosing therapies wisely While very common, there are no effective therapies currently for WHO group 2 or 3 disease The ACCP and ATS recommend not routinely offering vasodilator therapy to these groups Not effective, and may in fact be harmful Choosing Wisely Campaign, ABIM foundation 17

18 PDE5 inhibitors and WHO group 2 disese... Despite multiple trials showing no significant clinical improvement, and in some cases worsening, the use of sildenafil in group 2 disease is not uncommon PDE5 inhibitors and WHO group 2 disese... Recent cohort analysis of VA patients from , patients prescribed PDE5i for PH 108,177 vets with PH 2790 received PDE5i daily 541 were deemed appropriate use (WHO group 1 disease) 1711 potentially inappropriate therapy 358 undetermined In a random chart abstraction cohort of patients (230) prescribed PDE5i for PH 74 (32%) diagnosed by echo alone Of those who had RHC (110), only 27 (11%) had clearly appropriate therapy 86 (37.4%) had clearly inappropriate therapy 18

19 Cost of therapy PDE5i - $10,000-$24,000 annually SGC - $120,000 annually ERA - $50,000- $100,000 annually Prostacylin - $50,000- $200,000 annually Goodrx.com Back to our patient Currently on tadalafil 40mg daily and ambrisentan 10mg daily Started on treatment for OSA Dyspnea is markedly improved Recent echo shows improved RVSP to 71 6MWD increased from 380 to 395 meters, no longer requires oxygen with activity 19

20 References Simonneau G et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62(25) Supl:D Wijeratne et al. Increasing incidence and prevalence of world health organization groups 1 to 4 pulmonary hypertension: a population-based cohort study in Ontario, Canada. Circ Cardiovasc Qual Outcomes. 2018;11:e Benza RL et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-term Pulmonary arterial hypertension disease management (REVEAL). Circulation. 2010;122(2): Gallie N et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34: McLaughlin VV et al. Pulmonary arterial hypertension-related morbidity is prognostic for mortality. J Am Coll Cardiol 2018;71(7) Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. NEJM 2004;351:1425:36 Thenappan T et al. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ 2018;j5492 Benza RL et al. The REVEAL registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest 2012;141(2): Benza RL et al. Prognostic implications of serial risk score assessments in patients with pulmonary arterial hypertension: a registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL) analysis. J Heart Lung Trans 2015;34(3): Sitbon O et al. Selexipag for the treatment of pulmonary arterial hypertention. NEJM 2015;373: Galie N et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. NEJM 2015;373: Kim D et al. Phosphodiesterase-5-inhibitor therapy for pulmonary hypertension in the US: Actual vs recommended use. Annals ATS. Published online Feb 27, Questions? 20

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