1; 6 April 2014 A New Horizon in PH Management BY Medhat A. Soliman Chest Department Cairo University
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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
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