Pulmonary arterial hypertension Definition and classification - PDF document

12/18/16 Pulmonary arterial hypertension • Definition and classification Pulmonary arterial hypertension: • Epidemiology of PH newer therapies • Pathophysiology • Diagnosis and prognosis Ramona L. Doyle, MD • New treatments and treatment paradigms Clinical Professor of Medicine, UCSF Attending Physician UCSF PH Clinic WHO Group classification of PH Definition of PH Slide 4 WHO group 1. Pulmonary arterial hypertension 1.1. Idiopathic (IPAH) — PH is defined by PAPm >25 mm Hg at rest 1.2. Familial (FPAH) measured by right heart catheterization (RHC) 1.3. Associated with (APAH): 1.3.1. Connective tissue disorders — Pulmonary a rterial hypertension (PAH) 1.3.2. Congenital 1.3.3. Portal hypertension describes 1.3.4. HIV infection 1.3.5. Drugs and toxins — a subpopulation of patients with PH 1.3.6. Other (e.g., hemoglobinopathies) — characterized hemodynamically by the presence 1.4. Associated with significant venous or capillary involvement (e.g., PVOD) of pre-capillary PH 1.5. Persistent pulmonary hypertension of the newborn WHO group 2. Pulmonary hypertension with left heart disease — including an end-expiratory PCWP< 15 mm Hg and a WHO group 3. Pulmonary hypertension associated with lung diseases pulmonary vascular resistance >3 Wood units WHO group 4. Pulmonary hypertension due to thromboembolic disease WHO group 5. Miscellaneous 1

12/18/16 WHO Group classification of PH Pathophysiology of PAH Slide 5 WHO group 2. Pulmonary hypertension with left heart disease “Two-hit” Hypothesis : • Systolic dysfunction, diastolic dysfunction, valvular disease • Genetic susceptibility (BMPR2) + “Second hit” (inflammation?) WHO group 3. Pulmonary hypertension associated with lung diseases • “Second hit” required for disease initiation and progression • 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 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 Screening for PAH • Symptoms: dyspnea is most common; others • Improving early diagnosis – screening high risk populations: include fatigue, dizziness, CP – family members of a patient with heritable PAH (HPAH) • Focused history: FHx of sudden cardiac death, – patients with systemic sclerosis (SSc) congenital heart dz,OSA – patients with HIV – patients with portopulmonary hypertension (PoPH) • Social history: drug use (amphetamines) – patients with congenital heart disease • Screening labs: BNP, thrombophilias, liver • European and US guidelines recommend annual screening with Doppler echocardiography 1,2 disease, thyroid disease, HIV, hepatitis • Right heart catheterisation required for definitive diagnosis 8 1. Galiè N et al. Eur Heart J 2009; 2. McGoon M et al. Chest 2004 2

12/18/16 Screening for PAH: The value of screening for PAH the echocardiogram • 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 diagnosis 1 – with screening, PAH was detected at an earlier stage 2 9 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 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

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

12/18/16 PAH: determinants of disease severity Hemodynamic parameters in PAH Determinants of risk Lower risk Higher risk Clinical evidence of RV failure No Yes • As measured by RHC generally correlate with clinical Progression Gradual Rapid status, WHO FC, exercise capacity, and prognosis NYHA functional class II, III IV • Prognosis in PAH is significantly correlated with 6MWD Longer (>400 m) Shorter (<300 m) markers of right ventricular function BNP Minimally elevated Very elevated • Normalization of hemodynamics may therefore be considered a suitable goal or treatment measure Echocardiographic findings Minimal RV dysfunction Significant RV dysfunction, pericardial effusion Hemodynamics Normal/near normal RAP High RAP, low CI and CI BNP = brain natriuretic peptide; CI = cardiac index; RAP = right artery pressure; RV = right ventricular. 1. Humbert M et al. Circulation 2010; 2. McLaughlin VV et al. Circulation 2002; .17 McLaughlin and McGoon. Circulation . 2006;114:1417-1431. 3. Benza RL et al. Circulation 2010 Prognosis in PAH: differs by disease Prognosis in PAH: Functional class association Chest . 2012;142(2):448-456. 5

12/18/16 Prognosis and survival in PAH: RV Prognosis in PAH: biomarkers failure • 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 21 1. Galiè N et al. Eur Heart J 2009; 2. Fijalkowska A et al. Chest 2006 PAH treatment: general PAH treatment: general • Currently no cure for PAH Traditional treatments – Oxygen • Modern advanced PAH therapies can markedly improve a patient’s symptoms and slow the rate of – Diuretics clinical deterioration – Anti-coagulants • Management is complex, involving use of a range of – CPAP for sleep apnea treatment options: Surgical/interventional treatments – general measures – Pulmonary thrombo-embolectomy(PTE) for patients – conventional or supportive therapy with CTEPH – advanced therapy (PAH-specific therapy) – Atrial septostomy – surgical intervention – Transplantation 23 1. Galiè N et al. Eur Heart J 2009; 2. Humbert M et al. Circulation 2010 6

12/18/16 PAH treatment: FDA approved drugs PAH treatment: goal-oriented therapy 1 2 3 • Patients should be monitored regularly and response to therapy assessed using a range of • Approved drugs act parameters predominantly via vasodilation and anti- • Based on set goals, a patient’s condition at proliferation effects follow-up may be: – stable and satisfactory ERA = endothelin receptor antagonist PDE = phosphodiesterase – stable but not satisfactory sCG = soluble guanylate cyclase – unstable and deteriorating ERAs PDE-5 inhibitors Prostacyclin • ‘Stable but not satisfactory’ or ‘unstable and — Bosentan ( oral ) — Sildenafil ( oral ) — Epoprostenol ( IV infusion ) — Ambrisentan ( oral ) — Tadalafil ( oral ) deteriorating’ → re-evaluation and consideration — Treprostinil — Macitentan ( oral ) for escalation of treatment ( SC or IV infusion, sCG stimulator*** inhaled, or oral ) — Riociguat ( oral ) — Iloprost ( inhaled ) — Selexipag PAH treatment: FDA approved drugs PAH treatment: FDA approved drugs • Prostacyclins • “GRIPHON” Trial design New oral formulations – Selexipag: a new oral prostacyclin Oral treprostinil – Phase III RDBPCT, event driven study Selexipag – Number of patients: 1156 • Endothelin receptor antagonists – Type of patients: WHO group 1 PAH patients Macitentan - new oral – On background therapy? Yes, ERA, PDE5 or both • PDE5 inhibitors – Primary endpoint: Composite of death or PAH New data on combination of PDE5/ERA- the AMBITION trial complication • Guanylate cyclase activators (new class) * disease progression, death, lung transplant, Riociguat hospitalization due to PAH, initiation of IV flolan 7

12/18/16 GRIPHON: GRIPHON: patient trial characteristics results GRIPHON: trial results GRIPHON trial: results 8

12/18/16 PAH treatment: FDA approved drugs GRIPHON • Riociguat trial: – First in a new class of drugs – Soluble guanylate cyclase activators act on NO pathway adverse • 2 separate trials events – ”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: Riociguat in PAH: Patient Characteristics Study results 9