Speaker:吳俊賢 醫師

1. Current diagnosis and
management of PAH
from cardiologist point of view
吳俊賢醫師
三軍總醫院 心臟內科

2. Galiè,et al. The European respiratory journal vol. 53(1) 24 Jan. 2019,

3. Definition of PH : Mean PAP  25 mmHg
• Clinical symptoms : Breathlessness , Fatigue , Weakness
, Chest pain, Syncope, palpitation
• Diagnosis: Often misdiagnosed or diagnosis is delayed,
Right heart catheterization is gold standard diagnostic test
Overview: Pulmonary Hypertension
Galiè N et al. Eur Respir J 2015;46:903–975

4. 1. Pulmonary arterial hypertension
1.1 Idiopathic PAH
1.2 Heritable PAH
1.3 Drugs and toxins induced
1.4 Associated with:
1.4.1 Connective tissue disease
1.4.2 Human immunodeficiency virus (HIV) infection
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1.5 PAH long term response to calcium channel blockers
1.6 PAH with overt features of venous/capillaries ( PVOD/PCH) involvement
1.7 Persistent PH of the newborn syndrome
3. Pulmonary hypertension due to lung diseases and/or hypoxia
3.1 Obstructive pulmonary disease
3.2 Restrictive lung disease
3.3 Other lung diseases with mixed restrictive
and obstructive pattern
3.4 Hypoxia without lung disease
3.5 Developmental lung diseases
5. Pulmonary hypertension with unclear and/or
multifactorial mechanisms
5.1 Haematological disorders: chronic haemolytic
anaemia, myeloproliferative disorders.
5.2 Systemic and metabolic disorders, pulmonary
langerhans cell histiocytosis, gaucher disease ,
glucogen storage disease, neurofibromatosis,
Sarcoidosis
5.3 Others: chronic renal failure with or without
hemodialysis ,fibrosing mediastinitis
5.4 Complex congenital heart disease ( table P4 )
4. Chronic thromboembolic pulmonary hypertension
and other pulmonary artery obstructions
4.1 Chronic thromboembolic pulmonary hypertension
4.2 Other pulmonary artery obstructions
2. Pulmonary hypertension due to left heart disease
2.1 PH due to heart failure with preserved LVEF
2.2 PH due to heart failure with reduced LVEF
2.3 Valvular heart disease
2.4 Congenital/Acquired cardiovascular conditions
leading to post-capillary PH
<5%
80%
10%
<5%
<5%
Updated clinical classification of PH
6th WSPH 2018

5. Different CTD manifestation may lead to different
group of P(A)H
Increased pulmonary
vascular resistance
Abnormal vascular
remodeling
Impaired smooth muscle,
endothelial and adventitial
cell proliferation, and
apoptosis
↑ HIF
↑ EPO
Cytokines
Growth factors
AECA
Pulmonary involvement: interstitial
lung disease, diaphragmatic
dysfunction, pulmonary vasculitis,
alveolar hemorrhage
Cardiac involvement: diastolic
dysfunction, ischemic
cardiomyopathy, valvular
disease
Thrombosis
thromoembolism
Antiphospholipid antibodies
Other prothrombotic factors
Impaired ET-1,
TXA-2/PGI2 equilibrium
Inflammation: accumulation of
neutrophils, monocytes, dendritic cells
into the elastic lamina
Hypoxia and
vasoconstriction
Group 3
PH due to lung disease
Group 2
PH due to left heart
Group 4
CTEPH
Group 1
CTD-PAH
Adapted from Tselios K et al. Open Access Rheum: Res & Rev 2017; 9:1-9

6. N. Galiè said : “ The most critical
part of the treatment of PAH is
proper diagnosis, more
important than medication “
PAH drugs in PH-chronic lung disease
evidence for risk-to-benefit ratio
Treatment of underlying disease
No established vascular therapy except
for LOT in COPD
ases, may also contribute to PH. As a general rule, patients
gwithsymptomsthat aremoreseverethan expected based
PFTresultsshouldbefurther evaluated,inparticular byecho-
phy, to search for concomitant LHD or PH.
ardiography remains the most widely used non-invasive
c tool for the assessment of PH. Indicationsfor echocardi-
n patients with lung diseases include the clinical suspicion
ant PH or theevaluation of concomitant LHD.It should be
owever, that the accuracy of echocardiography in patients
anced respiratory diseasesislow.403–405
Patientswith clin-
hocardiographic signsof severe PH and/or severe RV dys-
should be referred to a PH centre.
nite diagnosisof PH relieson measurementsobtained dur-
Potential indicationsfor RHC in advanced lungdiseaseare
r diagnosis or exclusion of PH in candidates for surgical
ts (transplantation, lung volume reduction), (ii) suspected
CTEPH, (iii) episodes of RV failure and (iv) inconclusive
iographic findings in cases with a high level of suspicion
ntial therapeutic implications.
herapy
y there is no specific therapy for PH associated with lung
Long-term O2 administration has been shown to partially
he progression of PH in COPD. Nevertheless, PAPrarely
o normal values and the structural abnormalities of pul-
vessels remain unaltered.169
In interstitial lung diseases,
of long-term O2 therapy on PH progression is less clear.
ment withconventional vasodilatorssuchasCCBsisnot re-
of suspected PH in patients with lung
disease
I C
405
Referral to an expert centre is
recommendedd
in patients with
echocardiographic signs of severe PH
and/or severe right ventricular
dysfunction
I C
The optimal treatment of the underlying
lung disease, including long-term O2
therapy in patients with chronic
hypoxaemia, is recommended in
patients with PH due to lung diseases
I C 169
Referral to PH expert center should be
considered for patients with signs of
severe PH/severe RV failure for
individual-based treatment
IIa C
RHC isnot recommended for suspected
PH in patients with lung disease, unless
therapeutic consequences are to be
expected (e.g. lung transplantation,
alternative diagnoses such as PAH or
CTEPH, potential enrolment in aclinical
trial)
III C 169
The use of drugs approved for PAH is
not recommended in patients with PH
due to lung diseases
III C
411–
416
CTEPH ¼ chronic thromboembolic pulmonary hypertension;
PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary hypertension;
RHC ¼ right heart catheterization.
a
Class of recommendation.
b
Level of evidence.
6th WSPH 2018

7. PAVC RA RV PV
PC
LA LV Ao
Pulmonary venous hypertension (group 2)
Elevated PAWP >15 mmHg, normal PVR <3WU
PAH (group 1)
PH with respiratory disease (group 3)
CTEPH (group 4)
Normal PCWP ≤ 15 mmHg, elevated PVR≥ 3WU
PH: The Importance of Hemodynamics
Pre-capillary PH
post-capillary PH

8. Haemodynamic definition of PH
6th WSPH 2018
Simonneau et al Eur Respir J 2019; 53: 1801913
mPAP: mean pulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure; PVR:
pulmonary vascular resistance; WU: Wood Units.

9. PH: Updated clinical classification
1. Pulmonary arterial hypertension
1.1 Idiopathic PAH
1.2 Heritable PAH
1.3 Drugs and toxins induced
1.4 Associated with:
1.4.1 Connective tissue disease
1.4.2 Human immunodeficiency virus (HIV) infection
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1.5 PAH long term response to calcium channel blockers
1.6 PAH with overt features of venous/capillaries ( PVOD/PCH) involvement
1.7 Persistent PH of the newborn syndrome
6th WSPH 2018

10. Gaine S. JAMA. 2000;284:3160-3168.
Normal Reversible Disease Irreversible Disease
Risk Factors and
Associated Conditions
Collagen Vascular Disease
Congenital Heart Disease
Portal Hypertension
HIV Infection
Drugs and Toxins
Pregnancy
Vascular Injury
Endothelial Dysfunction
↓ Nitric Oxide Synthase
↓ Prostacyclin Production
↑ Thromboxane Production
↑ Endothelin 1 Production
Vascular Smooth Muscle Dysfunction
Impaired Voltage-Gated
Potassium Channel (KV1.5)
Disease Progression
Loss of Response to
Short-Acting
Vasodilator Trial
Susceptibility
Abnormal BMPR2 Gene
Other Genetic Factors
Intima
Adventitia
Media Smooth muscle
hypertrophy
Early intimal
proliferation
Smooth muscle
hypertrophy
Adventitial and
intimal proliferation
In situ
thrombosis
Plexiform
lesion
1 2 3
Pathogenesis of PAH

11. Interaction between microcirculatory pathologic
changes and right ventricular dysfunction progression
European Heart Journal Supplements (2007) 9 (Supplement H), H68–H74
Smooth Muscle
Hypertrophy
Intimal
Proliferation Vasoconstriction PVR, PAP 上升

12. NORMAL
Adventitia
Media
Intima
Smooth Muscle
Hypertrophy
Early Intimal
Thickening
REVERSIBLE DISEASE IRREVERSIBLE
DISEASE
Plexiform
Lesions
Thrombosis
Adventitial, Intimal
Proliferation
Smooth Muscle
Hypertrophy
Time
PAP
PVR
CO
I II III IVWHO
Adapted from Gaine S. JAMA. 2000;284:3160-3168.
PAH: Hemodynamic and Clinical Course

13. Natural History of PAH: NIH Registry
A Disease of Decline and Deterioration
NIH = National Institutes of Health.
Predicted survival according to the NIH equation. Predicted survival rates were 69%, 56%, 46%, and 38% at 1, 2, 3, and 4
years, respectively. The numbers of patients at risk were 231, 149, 82, and 10 at 1, 2, 3, and 4 years, respectively. *Patients with
primary pulmonary hypertension, now referred to as idiopathic pulmonary hypertension.
1. Rich et al. Ann Intern Med. 1987;107:216-223. 2. D’Alonzo et al. Ann Intern Med. 1991;115:343-349.
Predicted survival*
69%
56%
46%
38%
Percentsurvival
Years
Median survival
2.8 year
WHO Fc IV : 6 months
WHO Fc III : 2.6 years

14. 0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Percent
survival
McLaughlin VV et al. Chest. 2004;126:78S-92S.
Congenital heart
disease
Portopulmonary
IPAH
CTD
HIV
Years
Survival in PAH
Risk of death:
CTD-PAH vs. IPAH:
(HR)=1.93
Only 37% survived at 3 year

15. Symptoms, signs, history suggestive
of PH
High or intermediate
Echocardiography probability of PH
Consider other causes
and/or f/u
Consider left heart disease
and lung disease
See algorithms for left
heart disease and lung
disease /hypoxia
related PH
No clinically significant left heart
disease of lung disease
Refer to PH expert
centre
6th WSPH: New algorithm for diagnosis of PH
Fast tract referral of
selected patients
low
Consider V/Q scan to
screen for CTEPH
V/Q scan
abnormal
Eur Respir J 2019; 53: 1801904

16. ESC guideline : Screening for PAH in SSc patients
Recommendations Classa Levelb
In patients with PAH associated with CTD,
the same treatment algorithm as for patients
with IPAH is recommended
I C
Resting echocardiography is recommended
as a screening test in asymptomatic patients
with SSc, followed by annual screening with
echocardiography, DLCO and biomarkers
I C
RHC is recommended in all cases of
suspected PAH associated with CTD
I C
Oral anticoagulation may be considered on
an individual basis and in the presence of
thrombophilic predisposition
IIb C
aClass of recommendation. bLevel of evidence.

17. Symptoms, signs, history suggestive
of PH
Echocardiography probability
of PH
6th WSPH: New algorithm for diagnosis of PH
RVSP＝ 4(TR velocity ) 2+ RAP (10~20mmHg) , mean PAP = RVSP x 0.61 + 2
≤ 40
mmHg
41-56
mmHg
Echo PH sigh: the ventricle, IVC and RA Eur Respir J 2019; 53: 1801904
sPAP
or
RVSP

18. Symptoms, signs, history suggestive
of PH
Echocardiography probability
of PH
6th WSPH: New algorithm for diagnosis of PH
RA, RV enlargement, IVS straightening
RV systolic dysfunction :TAPSE
(Tricuspid annular plane systolic excursion)
TR severity, Estimated RVSP
IVC dilation
Tricuspid Regurgitation (TR)
Velocity
by continuous wave Doppler and subsequentby continuous wave Doppler and subsequent
derivation to pressure data through the use of
the Bernoulli equation ( P = 4V2) allows for
the determination of the RV-right atrium (RV-
RA) pressure gradient An estimated rightRA) pressure gradient. An estimated right
atrial pressure (RAP) is then added to the RV-
RA gradient to determine peak RV systolic
pressure (RVSP).
11
Estimation of Pulmonary Pressure
PA systolic pressure
• Tricuspid regurgitation jet velocityp g g j y
Eur Respir J 2019; 53: 1801904
Echo
PH signs

19. Symptoms, signs, history suggestive
of PH
High or intermediate
Echocardiography probability of PH
Consider other causes
and/or f/u
Consider left heart disease
and lung disease
See algorithms for left
heart disease and lung
disease /hypoxia
related PH
No clinically significant left heart
disease of lung disease
Refer to PH expert
centre
6th WSPH: New algorithm for diagnosis of PH
Fast tract referral of
selected patients
low
Consider V/Q scan to
screen for CTEPH
V/Q scan
abnormal

20. Normal perfusion
Refer to PH expert centre
6th WSPH: New algorithm for diagnosis of PH
CTEPH diagnositic
algorithm
Multimodality diagnostic
assessment
Any mismatched
perfusion defect
Review or perform
V/Q scan
Multimodality investigations helpful for the
differential diagnosis of PH
• Cardiac : ECG, echocardiography/cardiac MR
• Pulmonary : PFT, ABG, overnight oximetry,
CPET
• PAH serology : CTD, HIV, liver disease
• Image: CXR, HRCT, CTPA, abdominal
ultrasound, catheter pulmonary angiography

21. Normal perfusion
Refer to PH expert centre
6th WSPH: New algorithm for diagnosis of PH
CTEPH diagnositic
algorithm
Multimodality diagnostic
assessment
Any mismatched
perfusion defect
Review or perform
V/Q scan
RHC for PH diagnostic
and haemoynamic
characterization
Haemodynamic definition of PH
6th WSPH 2018
Simonneau et al Eur Respir J 2019; 53: 1801913
mPAP: mean pulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure; PVR:
pulmonary vascular resistance; WU: Wood Units.

22. Right Heart Catheterization
右側心臟導管檢查
是檢測肺動脈高壓最準確有用的檢查。(e.g. PAH
vs left heart disease vs no-PH)
用導管來測量右側心臟與肺動脈壓及心輸出量
(CO, RAP, PVR, central venous O2 saturation)
Test for vasoreactivity
急性血管擴張劑試驗
Monitoring tool

23. ESC guideline : Screening for PAH in SSc patients
Recommendations Classa Levelb
In patients with PAH associated with CTD,
the same treatment algorithm as for patients
with IPAH is recommended
I C
Resting echocardiography is recommended
as a screening test in asymptomatic patients
with SSc, followed by annual screening with
echocardiography, DLCO and biomarkers
I C
RHC is recommended in all cases of
suspected PAH associated with CTD
I C
Oral anticoagulation may be considered on
an individual basis and in the presence of
thrombophilic predisposition
IIb C
aClass of recommendation. bLevel of evidence.

24. Risk stratification and
medical therapy of PAH

25. WHO classification of function status
Class Description
I
病患在日常生活上身體活動沒有限制，一般的身體活動不會造成呼
吸困難、疲勞、胸痛或幾乎昏厥。
II
病患在日常生活上身體活動稍微受到限制，休息時感到舒適，一般
的身體活動會造成呼吸困難、疲勞、胸痛或幾乎昏厥。
III
病患在日常生活上身體活動明顯受到限制，休息時感到舒適，少量
一般的身體活動會造成呼吸困難、疲勞、胸痛或幾乎昏厥。
IV
病患在日常生活上完全無法進行任何身體活動，有明顯右心衰竭症
狀，即使休息時也會感覺呼吸困難及疲勞，任何的身體活動都會增
加不舒服的感覺。
Galie` et al Eur Heart J. 2015 Aug 29

26. Exercise capacity evaluation
6 mins walk test
Disease severity evaluation
• O2 uptake at the anaerobic threshold
• Peak exercise peak work rate
• Peak heart rate
• O2 pulse
• Ventilatory efficiency
Prediction of worse prognosis
• Low peak O2 consumption
(< 10.4 ml O2/kg/min)
Cardiopulmonary exercise test

27. Determinants of
prognosisa Low risk < 5% Intermediate risk 5-10% High risk > 10%
Clinical signs of right
heart failure
Absent Absent Present
Progression of symptoms No Slow Rapid
Syncope No Occasional syncopeb Repeated syncopec
WHO functional class I, II III IV
6MWD > 440 m 165-440 m < 165 m
Cardiopulmonary exercise
testing
Peak VO2
> 15 ml/min/kg
(> 65% pred.)
VE/VCO2 slope < 36
Peak VO2
11-15 ml/min/kg
(35-65% pred.)
VE/VCO2 slope 36–44.9
Peak VO2
< 11 ml/min/kg
(< 35% pred.)
VE/VCO2 ≥ 45
NT-proBNP plasma levels
BNP < 50 ng/l
NT-proBNP < 300 ng/ml
BNP 50-300 ng/l
NT-proBNP 300-1400 ng/l
BNP > 300 ng/l
NT-proBNP > 1400 ng/l
Imaging (echocardiography,
CMR imaging)
RA area < 18 cm2
No pericardial effusion
RA area 18-26 cm2
No or minimal, pericardial
effusion
RA area > 26 cm2
Pericardial effusion
Haemodynamics
RAP < 8 mmHg
CI ≥ 2.5 l/min/m2
SvO2 > 65%
RAP 8-14 mmHg
CI 2.0-2.4 l/min/m2
SvO2 60-65%
RAP > 14 mmHg
CI < 2.0 l/min/m2
SvO2 < 60%
aEstimated 1-year mortality. bOccasional syncope during brisk or heavy exercise, or occasional orthostatic syncope in an otherwise
stable patient. cRepeated episodes of syncope, even with little or regular physical activity.
Risk assessment in PAH: Clinical symptoms ,
Exercise capacity, Biomaker, image and
hemodynamics (RV function )

28. 6th WSPH 2018
Simplified risk stratification in PAH
Risk
Criteria
Determination of
Prognosis
(estimated 1-year
mortality)
Low Risk
Variable
(<5%)
Intermediate Risk
Variables
(5-10%)
High Risk
Variables
(> 10%)
A WHO Function class I,II III IV
B 6MWD > 440 m 165-440 m < 165 m
C
NT-proBNP/BNP
Plasma levels
Or
RAP
BNP < 50 ng/l
NT-proBNP < 300
ng/ml
Or
RAP < 8 mmHG
BNP 50-300 ng/l
NT-proBNP 300-1400
ng/
Or
RAP 8-14 mmHgl
BNP > 300 ng/l
NT-proBNP > 1400
ng/l
Or
RAP > 14 mmHg
D
CI
or
SvO2
CI ≥ 2.5 l/min/m2
or
SvO2 > 65%
CI 2.0-2.4 l/min/m2
or
SvO2 60-65%
CI < 2.0 l/min/m2
or
SvO2 < 60%
Individual Risk
Category Definition
Low Risk
Definition
Intermediate
Risk Definition
High Risk
Definition
At least 3 low risk
criteria and no high
risk criteria
Definitions of low or
high risk not fulfilled
At least 2 high risk
criteria including CI
or SvO2

29. Simplified table for risk stratification
in patients with CTD-PAH
2018 ESC
ediate risk strata in patients with CHD-PAH that have not a significantly different
<0.05 for all comparisons but intermediate vs high risk strata in patients with CTD-PAH
ferent prognosis).
CHD-PAHCTD-PAH
CHD-PAHCTD-PAH
-
er
s
I/H/Drug-PAH CTD-PAH
I/H/Drug-PAH CTD-PAH
er
s
t
I/H/Drug-PAH CTD-PAH
I/H/Drug-PAH CTD-PAH
Low-risk profile at follow-up:
Better long-term survival rates

30. Meeting more low-risk criteria have
better survival of PAH patients
Invasive low-risk criteria
• WHO FC I-II
• 6MWD >440 m
• RAP <8 mmHg
• CI ≥2.5 L/min/m2
Noninvasive low-risk criteria
• WHO FC I-II
• 6MWD >440 m
• BNP < 50ng/L or NT-proBNP <300 ng/mL
4 criteria
3 criteria
2 criteria
1 criteria
0 criteria
3 criteria
2 criteria
1 criteria
0 criteria
Boucly A, et al. Eur Respir J. 2017 50:1700889; doi:10.1183/13993003.00889-2017.

31. How to treat CTD-PAH ?

32. ESC guideline
Recommendations Classa Levelb
In patients with PAH associated with
CTD, the same treatment algorithm as for
patients with IPAH is recommended
I C
Resting echocardiography is recommended
as a screening test in asymptomatic patients
with SSc, followed by annual screening with
echocardiography, DLCO and biomarkers
I C
RHC is recommended in all cases of
suspected PAH associated with CTD
I C
Oral anticoagulation may be considered on
an individual basis and in the presence of
thrombophilic predisposition
IIb C
aClass of recommendation. bLevel of evidence.

33. Treatment of CTD-PAH: Treat to 2 targets
Underlying CTD CTD-PAH
Immuno-therapies
Low disease
activity
Disease remission
PAH targeted
therapies
Clinical symptom
relief
Functional class
improvement
Reduce mortality
and morbidity

34. Approval of PAH therapies
Bosentan
(Tracleer)
2001 – US
2002 – Europe
Epoprostenol
i.v.
(Flolan)
1995 – US
2001 – Europe
Treprostinil i.v. or
s.c. (Remodulin)
2002 – US
2005 – Europe
2013
Macitentan†
(Opsumit)
Treprostinil
oral†
(Orenitram)
US
Riociguat†
(Adempas)
Iloprost inhaled
(Ventavis)
2004 – US
2003 – 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

35. F1000Research 2016, 5(F1000 Faculty Rev):2755
sGC: soluble guanylate cyclase; cAMP: cyclic adenosine
monophosphate; cGMP: cyclic guanosine monophosphate
There are now multiple targeted therapies for PAH

36. Recommendations for efficacy of drug monotherapy for
PAH (group 1) according to WHO FC
• Table 19
Measure/treatment
Class of recommendation – Level of evidence
WHO-FC II WHO-FC III WHO-FC IV
Calcium channel blockers I Cc I Cc - -
ERAs
Ambrisentan I A I A IIb C
Bosentan I A I A IIb C
Macitentand I B I B IIb C
PDE-5 inhibitors
Sildenafil I A I A IIb C
Tadalafil I B I B IIb C
Vardenafilf IIb B IIb B IIb C
sGC stimulators Riociguat I B I B IIb C
PGl2 analogs
Epoprostenol Intravenousd - - I A I A
Iloprost Inhaled - - I B IIb C
Intravenousf - - IIa C IIb C
Treprostinil Subcutaneous - - I B IIb C
Inhaledf - - I B IIb C
Intravenouse - - IIa C IIb C
Oralf - - IIb B - -
Beraprostf - - IIb B - -
IP receptor
agonists
Selexipag (oral)f I B I B - -
cOnly in responders to acute vasoreactivity tests: class I, for IPAH, HPAH and PAH due to drugs; class IIa, for conditions associated with PAH; dTime to
clinical worsening as primary endpoint in RCTs or drugs with demonstrated reduction in all-cause mortality; eIn patients not tolerating the subcutaneous form;
fThis drug is not approved by the EMA at the time of publication of these guidelines.

37. PAH confirmed by
expert centre
CCB therapy
Non-vasoreactive
Consider
referral for
lung tx
evaluation
Add on Double or triple
sequential combination
Initial
monotherapyb
Vasoreactive
Acute vasoreactivity test
(IPAH/HPAH/DPAH only)
Patient already
on treatment
Treatment
naïve patient Supportive therapy
General measures
Initial oral
combinationb
Initial combination
including i.v. PCAc
Updated treatment algorithm
Low or Intermediate risk
After 3-6 months of treatment
Low risk
Structured follow up
High risk
Intermediate or High risk
After 3-6 months of treatment
Intermediate or High risk
Maximal medical treatment
and listing for lung
transplantation
6th WSPH 2018

38. PAH confirmed by
expert centre
Treatment
naïve patient Supportive therapy
General measures
Updated treatment algorithm
6th WSPH 2018
Group I PAH :
• IPAH
• Drugs and toxins induced
• Associated PAH
• Connect tissue disease
• Congental heart disease
• Portal hypertension
• HIV infection
• Schistosomiasis

39. Avoid
pregnancy
Influenza and
pneumococcal
immunization
Psychological
conselling
Supervised
exercise training
Regional anesthesia
should be preferred
over GA whenever
possible
General measures for patients with PH
Life style considerations
Sodium and fluid restriction
Abstinence from smoking
Avoid high altitude

40. Supportive therapies in PAH
-Traditional Therapy
Diuretic : loop
diuretics,
aldosterone
antagonist
long-term
oxygen
therapy
SO2<90%
Anticoagulation:
CTEPH ,IPAH
Treatment of
arrhythmias
Diuretics:  excessive preload and edema
Oxygen : Target saturation > 90%
Anticoagulation (Warfarin) : keep INR 1.5 – 2.5
（not recommended in associated forms of PAH）
Digoxin : inotropic effect

41. PAH confirmed by
expert centre
CCB therapy
Vasoreactive
Acute vasoreactivity test
(IPAH/HPAH/DPAH only)
Treatment
naïve patient Supportive therapy
General measures
Updated treatment algorithm
6th WSPH 2018

42. PAH confirmed by
expert centre
CCB therapy
Non-vasoreactive
Consider
referral for
lung tx
evaluation
Initial
monotherapyb
Vasoreactive
Acute vasoreactivity test
(IPAH/HPAH/DPAH only)
Treatment
naïve patient Supportive therapy
General measures
Initial oral
combinationb
Initial combination
including i.v. PCAc
Updated treatment algorithm
Low or Intermediate risk High risk
6th WSPH 2018

43. Sildenafil Used in CTD-PAH
post-hoc subgroup analysis of SUPER-1 trial
Badesch DB et al. J Rheumatol. 2007 v34(12) p2417-22

44. Sildenafil improved 6MWD & FC
Badesch DB et al. J Rheumatol. 2007 v34(12) p2417-22
6MWD FC

45. However, not all PAH patients benefit
from sildenafil monotherapy (SUPER-2)
Long-term data (3y) showed only 29-46% patients had improvement from baseline

46. PAH confirmed by
expert centre
CCB therapy
Non-vasoreactive
Consider
referral for
lung tx
evaluation
Add on Double or triple
sequential combination
Initial
monotherapyb
Vasoreactive
Acute vasoreactivity test
(IPAH/HPAH/DPAH only)
Patient already
on treatment
Treatment
naïve patient Supportive therapy
General measures
Initial oral
combinationb
Initial combination
including i.v. PCAc
Updated treatment algorithm
Low or Intermediate risk
After 3-6 months of treatment
Low risk
Structured follow up
High risk
Intermediate or High risk
6th WSPH 2018
當單一藥物治療
沒有達標，考慮合併治療Prostanoids
PDE5i
or sGC+
++
ERA

47. 傲朴舒 Macitentan (Opsumit ®)
Oral Dual ET Receptor Antagonist
Approved by FDA in 2013 :
novel dual ERA of PAH Fc II~ III
symptoms
Dose : 10 mg QD
奧欣明®膜衣錠
OPSUMIT® (CM)
for CTD

48. SERAPHIN
First event-driven, randomized, controlled
trial in PAH (N=742)
Placebo vs Macitentan 3mg vs
Macitentan 10mg (1:1:1)
Background PAH therapy allowed
(excluding ERAs) : 63% of SERAPHIN
patients were on background therapy
Primary end point: morbidity and mortality

49. Risk reduction of primary
endpoint event vs placebo
SERAPHIN: Macitentan 10 mg reduced overall
45% mortality and morbidity in PAH patients
Time from treatment start (months)
Macitentan 10 mg
Macitentan 3 mg
Placebo
Patients at risk
Treatment effect 3 mg 10 mg
Hazard ratio 0.70 0.55
Log-rank p-value 0.01 < 0.001
Macitentan 10 mg: 45%
Macitentan 3 mg: 30%
242 208 187 171 155 91 41 Macitentan 10 mg
250 213 188 166 147 80 32 Macitentan 3 mg
250 188 160 135 122 64 23 Placebo
Pulido T, et al. N Engl J Med 2013; 369: 809-18.
0
0
20
40
80
100
60
12 18 24 30 366
Patientswithouttheevent(%)

50. Morbidity and mortality in patients on
background PAH therapy
Macitentan 10 mg: 38%
Patientswithouttheevent(%)
0 12 18 24 30 36
0
20
40
80
100
60
6
Macitentan 10 mg
Macitentan 3 mg
Placebo
Treatment
difference
3 mg 10 mg
Hazard ratio (HR) 0.83 0.62
Log-rank p-value 0.27 0.009
Risk reduction of primary
endpoint event vs placebo
Macitentan 3 mg: 17%
Patients at risk
154 134 119 107 97 53 24 Macitentan 10 mg
164 139 125 107 91 51 19 Macitentan 3 mg
154 122 106 90 80 40 10 Placebo
Time from treatment start (months)
Pulido T, et al. N Engl J Med 2013; 369: 809-18.

51. SERAPHIN: Macitentan shows improvement in 6MWD
6-MWD(m)
Adjustedmeanchange
Placebo
Macitentan 10 mg
+37.0 m, p = 0.009
FC I/II FC III/IV-20
-15
-10
-5
0
5
10
15
20
Pulido T, et al. N Engl J Med 2013; 369: 809-18.
6MWD

52. SERAPHIN: More patients on macitentan 10 mg have
improved FC at month 6
13%
(n = 33)
22%
(n = 53)
0
5
10
15
20
25
Placebo Macitentan 10 mg
PatientswithimprovedFC
frombaselinetomonth6(%)1
p = 0.006
• Patients on macitentan 10 mg had a 74% greater chance to improve FC status2
Pulido T, et al. N Engl J Med 2013; 369: 809-18.
Function class Placebo
Macitentan 10 mg

53. Macitentan for CTD-PAH in Taiwan
2018.12.1 修正後給付規定
經右⼼導管檢查，證實確實符合肺動脈⾼血壓之
診斷。
確定為結締組織病變導致之肺動脈⾎血壓，且使
用現有藥物(如:sildenafil)治療3個⽉後成
效仍不佳，且無其他藥物可供選擇者。
排除其他病因:肺功能、⾼解析胸部電腦斷層
、肺部通氣及灌流核醫掃瞄、⾎液檢查、心臟
超⾳波檢查。
經風濕免疫專科醫師會診，確認有需使用者 。

54. Simplified “3-1-1” rule for identify
inadequate responders?
Boucly A, et al. Eur Respir J. 2017 50:1700889; doi:10.1183/13993003.00889-2017.;
Galiè N, et al. Eur Heart J 2016; 37(1):67-119,
3
non-invasive
criteria evaluation
• WHO FC I-II
• 6MWD >440 m
• BNP < 50ng/L or
NT-proBNP <300 ng/mL
1
echocardiography
probability
1
RHC
confirmation
Consider add on 2nd-line PAH therapy for combination

55. PAH confirmed by
expert centre
CCB therapy
Non-vasoreactive
Consider
referral for
lung tx
evaluation
Add on Double or triple
sequential combination
Initial
monotherapyb
Vasoreactive
Acute vasoreactivity test
(IPAH/HPAH/DPAH only)
Patient already
on treatment
Treatment
naïve patient Supportive therapy
General measures
Initial oral
combinationb
Initial combination
including i.v. PCAc
Updated treatment algorithm
Low or Intermediate risk
After 3-6 months of treatment
Low risk
Structured follow up
High risk
Intermediate or High risk
After 3-6 months of treatment
Intermediate or High risk
Maximal medical treatment
and listing for lung
transplantation
6th WSPH 2018
最大藥物治療反應
不佳考慮肺部移植

56. Long-term outcomes are improved
1. Humbert M, et al. Eur Respir J 2010; 36:549–555.
2. Benza RL, et al. Chest 2012; 142:448-56
100
80
60
40
0
0 1 2 3 4 5 6 7
Survival(%)
Time from diagnosis (years)
No. at risk: 279 377 390 388 328 240 153 88
90.5 ± 2.2
74.5 ± 2.5
64.5 ± 2.5
58.9 ± 2.7
68.2
46.9
35.6
32.0
*
*
*
20 * REVEAL unweighted NIH cohort2
Predicted survival by NIH equation2
French Registry1

57. Early diagnosis and treatment are of
paramount importance

58. Advanced RV failure management in
PAH patients
 Treatment of triggering factors ( anemia, arrhythmia,
infection, or other co-morbidities )
 Optimization of fluid balance ( usually with IV
diuretics)
 Reduction of RV afterload( usually with parenteral
prostacyclin analoques and other PAH drugs )
 Improvement of CO with inotropes ( dobutamine)
 Maintenance of systemic blood pressure with
vasopressors. ( favor Norepinephrine )
 Intubation should be avoided in patients with RV
failure as it frequently results in haemodynamic
collapse.
6th WSPH 2018

59. Take home message
Compared to IPAH, patients with CTD- PAH
have poor prognosis .
Early detection and treatment of PAH has
proven to be important.
Right heart catheterization is gold standard
diagnostic test
Some indicators such as Functional class,
6MWD, BNP/NT-proBNP and hemodynamic
parameters ( RAP , cardiac index, SvO2 ) are
useful predictors for the risk stratification.

60. Take home message
Guidelines recommend a
treat-to-low risk approach to PAH treatment.
The management principles of severe PH are to
maintain systemic pressure, improve RV
function, optimal fluid balance and reduce RV
afterload.
PAH-specific therapies have improved long-
term outcomes.