A New Horizon in Pulmonary Hypertension Management

1; 6 April 2014

A New Horizon in PH Management

BY

Medhat A. Soliman Chest Department

Cairo University

5th World Symposium on PH: Haemodynamic definition of PAH

PAWP ≤ 15 mmHg

Mean PAP ≥ 25 mmHg

PVR > 3 Wood units

PAP: pulmonary arterial pressure; PAWP: pulmonary artery

wedge pressure; PVR: pulmonary vascular resistance

Definition of PH

Definition of PAH

Mean PAP ≥ 25 mmHg

Hoeper MM, et al. J Am Coll Cardiol 2013; 62:D42-50.

The three pathways in PAH pathogenesis

Humbert M, et al. N Engl J Med 2004; 351:1425-36.

cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; ERA: endothelin receptor antagonist; ET: endothelin; PDE-5: phosphodiesterase-5; PDE-5i: phosphodiesterase-5 inhibitor; PGI2: prostacyclin; SMCs: smooth muscle cells

5th World Symposium on PH: Modified classification of PH

1. Pulmonary arterial hypertension1.1 Idiopathic PAH1.2 Heritable PAH

1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown

1.3 Drug- and toxin-induced1.4 Associated with

1.4.1 Connective tissue diseases1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart disease

1.4.5 Schistosomiasis1’ Pulmonary veno-occlusive disease and/orpulmonary capillary haemangiomatosis1’’ Persistent PH of the newborn (PPHN)

2. PH due to LHD2.1 LV systolic dysfunction

2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart

inflow/outflow obstruction

3. PH due to lung diseases and/or hypoxia3.1 COPD3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive and obstructive

pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases

4. CTEPH

5. PH with unclear multifactorial mechanisms5.1 Haematological disorders: chronic haemolytic anaemia,

myeloproliferative disorders, splenectomy5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,

lymphangioleiomyomatosis5.3 Metabolic disorders: glycogen storage disease, Gaucher disease,

thyroid disorders5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic

renal failure, segmental PH

Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41.

COPD: chronic obstructive pulmonary disease; CTEPH: chronic thromboembolic pulmonary hypertension;

LHD: left heart disease; LV: left ventricular

Characterisation of pre- and post-capillary PH

RVLA

PAPAtrialpressure

Pre-capillary PH:

• Mean PAP ≥ 25 mmHg• PAWP < 15 mmHg• TPG is increased

Post-capillary PH:

• Mean PAP ≥ 25 mmHg• PAWP ≥ 15 mmHg• TPG may/may not be increased

LA: left atrium; PAP: pulmonary arterial pressure; PAWP: pulmonary artery wedge pressure; RV: right ventricle; TPG: transpulmonary pressure gradient (mean PAP-PAWP)

Guazzi M, et al. Circulation 2012; 126:975-90.Galiè N, et al. Eur Heart J 2009; 30:2493-537.

PH due to left heart disease can be caused by multiple disorders

Fang JC, et al. J Heart Lung Transplant 2012; 31:913-33.

PH due to LHD

• LV systolic dysfunction• Heart failure with reduced ejection

fraction (HFrEF)

• LV diastolic dysfunction• Heart failure with preserved ejection

fraction (HFpEF)

Valvular left heart disease• Mitral stenosis• Mitral regurgitation• Aortic stenosis• Aortic regurgitation

LHD: left heart disease; LV: left ventricular

Differentiating between PH-LHD and PAH

Hansdottir S, et al. Chest 2013; 144:638-50.

It is particularly challenging to differentiate the subset of patients with PH due to HFpEF from PAH patients

Diastolic dysfunction

Both groups of patients have the following:

Normal EF

Elevated PAP estimates

Distinguishing PH due to HFpEF from PAH is vital since the management is significantly different for the 2 conditions

EF: ejection fraction; HFpEF: heart failure with preserved ejection fraction;

LHD: left heart disease; PAP: pulmonary arterial pressure

Remodelling

HyperinflationHypoxemia Alveolair destruction

Pulmonary hypertensionPolycythemia

Hypercapnia

Fluid retention

Cor Pulmonale

Genotype

Smoking

Multiple Causes of pulmonary hypertension in COPD

Courtesy of Dr Gopalan.

PH Imaging ModalitiesV/Q scan

Thromboembolic Disease IPAH

Courtesy of Dr Gopalan.

PH Imaging ModalitiesCT Pulmonary Angiography

Courtesy of Dr Gopalan.

CT Pulmonary AngiographyAcute vs Chronic PE

Courtesy of Dr Gopalan.

CT Pulmonary AngiographyProximal vs Distal CTEPH

PH Imaging ModalitiesCatheter Pulmonary Angiography

Courtesy of Dr Gopalan.

5th World Symposium on PH: Recommendations for PAH screening

Recommendations on screening of high-risk populations for PAH

Annual screening for PAH is recommended in asymptomatic patients with the SScspectrum of diseases

Screening should include a two-step approach using clinical assessment in the initial stage, followed by echocardiography and consideration of RHC in patients with abnormal findings*†

Screening programs for patients with SSc should be part of a scientific protocol, or a registry, whenever possible

Patients with SSc and other CTDs with clinical signs and symptoms of PH should be evaluated by RHC

Adapted from Hoeper MM, et al. J Am Coll Cardiol 2013; 62:D42-50.*Coghlan JG, et al. Ann Rheum Dis 2013; Epub ahead of print.

*Based on the DETECT study†There is a lack of data with DLCO > 60%

CTD: connective tissue disease;

DLCO: carbon monoxide diffusing capacity;

RHC: right heart catheterisation; SSc: systemic sclerosis

Impact of screening in PAH-SSc:Improved long-term outcomes

100

90

80

70

60

50

40

30

20

10

0

Surv

ival

rat

e (%

)

1 year 3 years 5 years 8 years

Follow-up (years)

100%

75%

31%

25%

17%

81%73%

64%

Routine practice PAH-SSc(n = 16)

ScreenedPAH-SSc(n = 16)

p = 0.0037HR = 4.15

(95% CI 1.47 - 11.71)

Humbert M, et al. Arthritis Rheum 2011; 63:3522-30.

CI: confidence interval; HR: hazard ratio; SSc: systemic sclerosis

Edward’s Life Science VIP Thermodilution Catheter

PA Distal

Proximal Injectate

RA infusion port

Thermistor port

Balloon inflationport

The standard catheter is 7.5 FR and 110 cm long. Maximal balloon volume 1.5cc

Once inserted balloon should remain DEFLATED and ONLYreinflated for periodic measurement of PCWP. PAP waveform should be displayed at all other times.

Distal tip(Yellow)

Proximal tip(Blue)

Right ventricular Port (Gray)

Distal tip measures PAP and PCWPProximal tip measures RA and is site

for CO measurement and fluidadministration

Right ventricular port site for fluid administration

RA infusionport (white)

Summary of Pulmonary Artery Pressure Waveforms

Normal 2-6 mmHg Normal 20-30/0-5 Normal 20-30/8-14 Normal 8-14 mmHgmmHg mmHg

The three pathways in PAH pathogenesis

Humbert M, et al. N Engl J Med 2004; 351:1425-36.

cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; ERA: endothelin receptor antagonist; ET: endothelin; PDE-5: phosphodiesterase-5; PDE-5i: phosphodiesterase-5 inhibitor; PGI2: prostacyclin; SMCs: smooth muscle cells

Approval of PAH therapies

Bosentan

(Tracleer) 2001 – US2002 – Europe

Epoprostenol

i.v.(Flolan)1995 – US

2001 – Europe

Treprostinil i.v. or s.c.

(Remodulin)2002 – US2005 – Europe

2013

Macitentan†

(Opsumit)

Treprostinil oral†

(Orenitram)

US

Riociguat†

(Adempas)

Iloprost inhaled

(Ventavis)2004 – US2003 – Europe

Iloprost i.v.

(Ilomedin) only approved in New Zealand

2010 201520051995 2000

2009

Treprostinil inhaled†

(Tyvaso)

Tadalafil (Adcirca)

Sildenafil

(Revatio) 2005

Beraprost

(Careload†) 2007

*Approval in other European countries is ongoing†Approval of these therapies varies by country, and thus might not be approved in the indications mentioned in your country. Please refer to

your local full SmPC before prescribing

Ambrisentan (Letairis –

US; Volibris – EU/Canada)2007 – US 2008 – Europe

Epoprostenol i.v.

(Veletri – US and Europe; Caripul – Canada and Italy; Epoprostenol ACT – Japan)2012 – US, Switzerland* & Canada

2013 – Japan

5th World Symposium on PH: Evidence-based treatment algorithmGeneral measures and supportive therapy

Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72.

Supervised exercise training (I-A)Psycho-social support (I-C)Avoid strenuous physical activity (I-C)Avoid pregnancy (I-C)Influenza and pneumococcal immunisation (I-C)

General measures and supportive therapy

Oral anticoagulants:• IPAH, heritable PAH and PAH due

to anorexigens (IIa-C)•APAH (IIb-C)

Diuretics (I-C)Oxygen (I-C)Digoxin (IIb-C)Expert referral (I-C)

Acute vasoreactivity test(I-C for IPAH) (IIb-C for APAH)

Initial therapy with PAH-approved drugs

Non-vasoreactiveFC I-III

CCB (I-C)Sustained response

(FC I-II)

Continue CCB No

Vasoreactive

Yes

APAH: associated PAH; CCB: calcium channel blockers;

FC: functional class; IPAH: idiopathic PAH

5th World Symposium on PH: Evidence-based treatment algorithm Combination therapy and interventional procedures

Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72.

Inadequate clinical response

Sequential combination

therapy (I-A)

ERAs

ProstanoidsPDE-5i

or sGCS

+

+

Initial therapy with PAH approved drugs

+

Referral forLUNG TRANSPLANTATION

(I-C)

Consider eligibility for

lung transplantation

BAS (IIa-C)

Inadequate clinical

response on

maximal therapy

BAS: balloon atrial septostomy; ERA: endothelin receptor antagonist; PDE-5i: phosphodiesterase-5 inhibitor;

sGCS: soluble guanylate cyclase stimulator

• Central location PA

• 5-L/min blood flow

• Thin-walled vessel

• Dual circulation

Pulmonary EndarterectomyDifficulties to Overcome

Courtesy of Mr Jenkins.

• Median sternotomy incision, for approach to both lungs

• Cardiopulmonary bypass, with cooling to 20o C (circulatory arrest for 20 minutes)

• Clearance of PA obstruction to reduce PVR

• Full distal dissection to every segmental vessel

Pulmonary EndarterectomyTechnique Overview

Courtesy of Mr Jenkins.

CTEPH: The potential role of medical therapy

When is medical therapy for CTEPH appropriate?

Patients with predominantly distal

disease that is not surgically accessible1

PEA contraindicated due to prognostically significant

comorbidity1

Patients with persistent or residual

PH post-PEA1,2

Patients who are ‘high-risk’ due to extremely poor

haemodynamics prior to PEA1

1. Hoeper MM, et al. J Am Coll Cardiol 2009; 54:S85-96.

2. Kim NH, et al. J Am Coll Cardiol 2013; 62:D92-9.

? ?

CTEPH: chronic thromboembolic pulmonary hypertension;

PEA: pulmonary endarterectomy