Pulmonary arterial hypertension Definition and classification - - PDF document

12/18/16 1

Pulmonary arterial hypertension: newer therapies

Ramona L. Doyle, MD Clinical Professor of Medicine, UCSF Attending Physician UCSF PH Clinic

Pulmonary arterial hypertension

• 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

• f 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): 1.3.1. Connective tissue disorders 1.3.2. Congenital 1.3.3. Portal hypertension 1.3.4. HIV infection 1.3.5. Drugs and toxins 1.3.6. 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

12/18/16 2

WHO Group classification of PH

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

WHO group 4. Pulmonary hypertension due to thromboembolic disease (CTEPH) WHO group 5. Miscellaneous

• Hematological disorders: myeloproliferative disorders, splenectomy
• Systemic disorders: sarcoidosis, lymphangioleiomyomatosis,

Slide 5

Pathophysiology of PAH

“Two-hit” Hypothesis:

• Genetic susceptibility (BMPR2) + “Second hit” (inflammation?)
• “Second hit” required for disease initiation and progression

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

8

• 1. Galiè N et al. Eur Heart J 2009; 2. McGoon M et al. Chest 2004

12/18/16 3

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

9

• 1. Humbert M et al. Am J Respir Crit Care Med 2006; 2. Hachulla E et al. Arthritis Rheum 2005

Screening for PAH: the echocardiogram PAH: staged approach to diagnosis

• 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)

Diagnosis of PH: V/Q Scan

12/18/16 4

Diagnosis of PH: CT scans

PVOD

*Smooth interlobular septal thickening *Regions of ground-glass

• pacity

*Enlarged central pulmonary arteries *Mosaic pattern of lung attenuation

Diagnosis of PH: CT scans

Diagnosis of PH: pulmonary function tests

• 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)

Definitive diagnosis of PAH requires RHC!

12/18/16 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

.17

• 1. Humbert M et al. Circulation 2010; 2. McLaughlin VV et al. Circulation 2002;
• 3. Benza RL et al. Circulation 2010

BNP = brain natriuretic peptide; CI = cardiac index; RAP = right artery pressure; RV = right ventricular.

McLaughlin and McGoon. Circulation. 2006;114:1417-1431.

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

Prognosis in PAH: Functional class Prognosis in PAH: differs by disease association

• Chest. 2012;142(2):448-456.

12/18/16 6

Prognosis in PAH: biomarkers

• Increases in serum NT-proBNP shown to be

associated with prognosis in PAH1

• Serum NT-proBNP < 1400 pg/mL seems to identify

patients with good prognosis1,2

• 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

Prognosis and survival in PAH: RV failure

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

23

• 1. Galiè N et al. Eur Heart J 2009; 2. Humbert M et al. Circulation 2010

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

12/18/16 7 PAH treatment: goal-oriented therapy

• 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

PAH treatment: FDA approved drugs

Prostacyclin

— Epoprostenol (IV infusion) — Treprostinil (SC or IV infusion, inhaled, or oral) — Iloprost (inhaled) — Selexipag

ERAs

— Bosentan (oral) — Ambrisentan (oral) — Macitentan (oral)

sCG stimulator***

— Riociguat (oral)

PDE-5 inhibitors

— Sildenafil (oral) — Tadalafil (oral)

ERA = endothelin receptor antagonist PDE = phosphodiesterase sCG = soluble guanylate cyclase

1 3 2

• Approved drugs act

predominantly via vasodilation and anti- proliferation effects

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

12/18/16 8

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

GRIPHON: trial results

12/18/16 9

GRIPHON trial: adverse events

PAH treatment: FDA approved drugs

• 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

12/18/16 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

12/18/16 11

Riociguat In CTEPH: Study results Riociguat In CTEPH Adverse events

PAH treatment: FDA approved drugs Upfront combination - 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

PDE5 + ERAs : the AMBITION trial

12/18/16 12

PDE5 + ERAs : the AMBITION trial

AMBITION trial: patient characteristics

AMBITION trial: patient characteristics

AMBITION trial: results

12/18/16 13

AMBITION trial: results PH in congenital heart disease

Study and year published METHODS METHODS RESULTS PATENT-1, 2015 LTE of CHD patients

• n riociguat, n=35,

Subgroup analysis

• f pivotal trial

Improvements in 6MWD, BNP, fxn at 2 years Xu XL, et al 2010 OL 12 week study

• f 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

Study and year published METHODS INCLUSION CRITERIA RESULTS ARTEMIS-IPF, 2013 RCT, Ambrisentan 34 weeks, n=494 IPF by HRCT 40-80 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

THANK YOU!