Pulmonary arterial hypertension. Pulmonary arterial hypertension: newer therapies. Definition of PH 12/18/16. WHO Group classification of PH

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1 Pulmonary arterial hypertension Pulmonary arterial hypertension: newer therapies Ramona L. Doyle, MD Clinical Professor of Medicine, UCSF Attending Physician UCSF PH Clinic Definition and classification Epidemiology of PH Pathophysiology Diagnosis and prognosis New treatments and treatment paradigms Definition of PH PH is defined by PAPm >25 mm Hg at rest measured by right heart catheterization (RHC) Pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized hemodynamically by the presence of pre-capillary PH including an end-expiratory PCWP< 15 mm Hg and a pulmonary vascular resistance >3 Wood units WHO Group classification of PH WHO group 1. Pulmonary arterial hypertension 1.1. Idiopathic (IPAH) 1.2. Familial (FPAH) 1.3. Associated with (APAH): Connective tissue disorders Congenital Portal hypertension HIV infection Drugs and toxins Other (e.g., hemoglobinopathies) 1.4. Associated with significant venous or capillary involvement (e.g., PVOD) 1.5. Persistent pulmonary hypertension of the newborn WHO group 2. Pulmonary hypertension with left heart disease WHO group 3. Pulmonary hypertension associated with lung diseases WHO group 4. Pulmonary hypertension due to thromboembolic disease WHO group 5. Miscellaneous Slide 4 1

2 12/18/16 WHO Group classification of PH Pathophysiology of PAH Slide 5 WHO group 2. Pulmonary hypertension with left heart disease Systolic dysfunction, diastolic dysfunction, valvular disease WHO group 3. Pulmonary hypertension associated with lung diseases Chronic obstructive pulmonary disease (COPD), Interstitial lung disease (ILD) Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing, Alveolar hypoventilation disorders Chronic exposure to high altitude, Developmental abnormalities Two-hit Hypothesis: Genetic susceptibility (BMPR2) + Second hit (inflammation?) Second hit required for disease initiation and progression WHO group 4. Pulmonary hypertension due to thromboembolic disease (CTEPH) WHO group 5. Miscellaneous Hematological disorders: myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, lymphangioleiomyomatosis, Diagnosis of PH Symptoms: dyspnea is most common; others include fatigue, dizziness, CP Focused history: FHx of sudden cardiac death, congenital heart dz,osa Social history: drug use (amphetamines) Screening labs: BNP, thrombophilias, liver disease, thyroid disease, HIV, hepatitis Screening for PAH Improving early diagnosis screening high risk populations: family members of a patient with heritable PAH (HPAH) patients with systemic sclerosis (SSc) patients with HIV patients with portopulmonary hypertension (PoPH) patients with congenital heart disease European and US guidelines recommend annual screening with Doppler echocardiography1,2 Right heart catheterisation required for definitive diagnosis 1. Galiè N et al. Eur Heart J 2009; 2. McGoon M et al. Chest

3 12/18/16 Screening for PAH: the echocardiogram The value of screening for PAH Results of a disease registry in France without screening, the majority of patients were diagnosed in WHO FC III or FC IV and only 24% of patients were in WHO FC II at diagnosis1 with screening, PAH was detected at an earlier stage2 1. Humbert M et al. Am J Respir Crit Care Med 2006; 2. Hachulla E et al. Arthritis Rheum 2005 PAH: staged approach to diagnosis 9 Diagnosis of PH: V/Q Scan Clinical suspicion of PAH symptoms, known risk factors Exclusion of Group 2 (left heart disease) and Group 3 (lung disease) PH ECG, chest radiograph, echocardiography, PFTs, HRCT Exclusion of Group 4 (CTEPH) PH ventilation/perfusion lung scan PAH evaluation and characterisation CT pulmonary angiography, CMRI, haematology, biochemistry, serology, and ultrasonography functional class and exercise capacity right heart catheterization (RHC) 3

4 12/18/16 Diagnosis of PH: CT scans Diagnosis of PH: CT scans PVOD *Smooth interlobular septal thickening *Regions of ground-glass opacity *Enlarged central pulmonary arteries *Mosaic pattern of lung attenuation Diagnosis of PH: pulmonary function tests Definitive diagnosis of PAH requires RHC! Patients may have normal lung volumes unless they have concomitant interstitial lung disease Typical pattern is restriction, decreased lung capacity (TLC) in ILD; obstruction in COPD Isolated low DLCO often seen early in connective tissue diseases (scleroderma) 4

5 Hemodynamic parameters in PAH As measured by RHC generally correlate with clinical status, WHO FC, exercise capacity, and prognosis Prognosis in PAH is significantly correlated with markers of right ventricular function Normalization of hemodynamics may therefore be considered a suitable goal or treatment measure PAH: determinants of disease severity Determinants of risk Lower risk Higher risk Clinical evidence of RV failure No Yes Progression Gradual Rapid NYHA functional class II, III IV 6MWD Longer (>400 m) Shorter (<300 m) BNP Minimally elevated Very elevated Echocardiographic findings Minimal RV dysfunction Significant RV dysfunction, pericardial effusion Hemodynamics Normal/near normal RAP and CI High RAP, low CI 1. Humbert M et al. Circulation 2010; 2. McLaughlin VV et al. Circulation 2002; 3. Benza RL et al. Circulation BNP = brain natriuretic peptide; CI = cardiac index; RAP = right artery pressure; RV = right ventricular. McLaughlin and McGoon. Circulation. 2006;114: Prognosis in PAH: Functional class Prognosis in PAH: differs by disease association Chest. 2012;142(2):

6 Prognosis in PAH: biomarkers Increases in serum NT-proBNP shown to be associated with prognosis in PAH 1 Serum NT-proBNP < 1400 pg/ml seems to identify patients with good prognosis 1,2 Cut-off levels still need to be verified in controlled trials Prognosis and survival in PAH: RV failure 1. Galiè N et al. Eur Heart J 2009; 2. Fijalkowska A et al. Chest PAH treatment: general Currently no cure for PAH Modern advanced PAH therapies can markedly improve a patient s symptoms and slow the rate of clinical deterioration Management is complex, involving use of a range of treatment options: general measures conventional or supportive therapy advanced therapy (PAH-specific therapy) surgical intervention PAH treatment: general Traditional treatments Oxygen Diuretics Anti-coagulants CPAP for sleep apnea Surgical/interventional treatments Pulmonary thrombo-embolectomy(pte) for patients with CTEPH Atrial septostomy Transplantation 1. Galiè N et al. Eur Heart J 2009; 2. Humbert M et al. Circulation

7 PAH treatment: goal-oriented therapy PAH treatment: FDA approved drugs Patients should be monitored regularly and response to therapy assessed using a range of parameters Based on set goals, a patient s condition at follow-up may be: stable and satisfactory stable but not satisfactory unstable and deteriorating Stable but not satisfactory or unstable and deteriorating re-evaluation and consideration for escalation of treatment ERAs Bosentan (oral) Ambrisentan (oral) Macitentan (oral) PDE-5 inhibitors Sildenafil (oral) Tadalafil (oral) scg stimulator*** Riociguat (oral) Prostacyclin Epoprostenol (IV infusion) Treprostinil (SC or IV infusion, inhaled, or oral) Iloprost (inhaled) Approved drugs act predominantly via vasodilation and antiproliferation effects ERA = endothelin receptor antagonist PDE = phosphodiesterase scg = soluble guanylate cyclase Selexipag PAH treatment: FDA approved drugs Prostacyclins New oral formulations Oral treprostinil Selexipag Endothelin receptor antagonists Macitentan - new oral PDE5 inhibitors New data on combination of PDE5/ERA- the AMBITION trial Guanylate cyclase activators (new class) Riociguat PAH treatment: FDA approved drugs GRIPHON Trial design Selexipag: a new oral prostacyclin Phase III RDBPCT, event driven study Number of patients: 1156 Type of patients: WHO group 1 PAH patients On background therapy? Yes, ERA, PDE5 or both Primary endpoint: Composite of death or PAH complication * disease progression, death, lung transplant, hospitalization due to PAH, initiation of IV flolan 7

8 GRIPHON: patient characteristics GRIPHON: trial results GRIPHON: trial results GRIPHON trial: results 8

9 PAH treatment: FDA approved drugs GRIPHON trial: adverse events Riociguat First in a new class of drugs Soluble guanylate cyclase activators act on NO pathway 2 separate trials PATENT-1 in PAH patients PATENT-2 in CTEPH patients Riociguat PAH trial design: Phase III double blind RCT, 3 arms (2 doses, 1 pbo) Number of patients: 443 Type of patients: on ERAs or non IV prostanoids; EXCLUDED patients on PDE5 therapy On background therapy or not? YES Primary endpoint: Six minute walk distance at 12 weeks Riociguat in PAH: Patient Characteristics Riociguat in PAH: Study results 9

10 Riociguat In PAH: Adverse events PAH treatment: FDA approved drugs Riociguat CTEPH trial design: Phase III RCT Number of patients: 261 Type of patients: Inoperable CTEPH and PH On background therapy or not? NO Primary endpoint: Six minute walk distance week 16 Riociguat in CTEPH: Study patients Riociguat In CTEPH: Study Patients 10

11 Riociguat In CTEPH: Study results Riociguat In CTEPH Adverse events PAH treatment: FDA approved drugs Upfront combination - the AMBITION trial PDE5 + ERAs : the AMBITION trial AMBITION Trial design Phase III- event-driven, double blind, pbo controlled RCT Number of patients: 500 (253 on combo, 121 on tadalafil alone, 126 ambrisentan alone) Type of patients: WHO group 1 (PAH) with NYHA class II or III symptoms On background therapy or not only for less than 2 weeks Primary endpoint: first event of clinical failure 11

12 PDE5 + ERAs : the AMBITION trial AMBITION trial: patient characteristics AMBITION trial: results AMBITION trial: patient characteristics 12

13 AMBITION trial: results PH in congenital heart disease Study and year published METHODS METHODS RESULTS PATENT-1, 2015 LTE of CHD patients on riociguat, n=35, Subgroup analysis of pivotal trial Improvements in 6MWD, BNP, fxn at 2 years Xu XL, et al 2010 OL 12 week study of sildenafil in CHD, n=60 RHC and 6 MWD before and after rx Improvements in hemodynamics, 6MWD Mukhopadhyay, 2011 RDB crossover trial Tadalafil in ES pts N=28 6 wk, 2 wk washout, 6 wk RHC, 6mwd Improvements in hemodynamics, 6MWD WHO Group 5 PH: some negative trials to remember THANK YOU! Study and year published METHODS INCLUSION CRITERIA RESULTS ARTEMIS-IPF, 2013 RCT, Ambrisentan 34 weeks, n=494 IPF by HRCT yo Stopped early, incr. hospitalization MUSIC-IPF, 2013 RCT, Macitentan 52 weeks, n=178 IPF by lung biopsy No change in lung fxn, IPF worsening Conte et al, 2014 Bosentan 16 weeks ILD, IPF or NSIP mpap=36 mmhg No change in hemodynamics Boeck et al, 2012 Inhaled Iloprost COPD, n=16, mpap=50 mmhg Worsening hypoxia No change 6MWD Blanco et al, 2013 Sildenafil 20 TID X 3 months COPD, n=63 mpap=40 mmhg Slight decr PVR, Worse exercise tolerance 13