This document discusses medical treatment options for pulmonary arterial hypertension (PAH). It notes that while there is no cure for PAH, mortality has decreased due to over 40 randomized controlled trials in the past 25 years that have led to approval of 14 PAH therapies. Combination therapy, either upfront or sequential, is now the standard of care according to guidelines to improve outcomes like functional class, quality of life and survival. For newly diagnosed patients, guidelines advise assessing risk and providing initial combination therapy for high-risk patients while lower-risk patients may start on monotherapy. Beyond medical therapies, interventions like atrial septostomy or lung transplantation, which remain limited due to availability, can play a role in selected patients.

1. Dr.MADHU.K
MEITRA HOSPITAL
KOZHIKODE
Combination therapy in pulmonary arterial
hypertension

2. 1. What medical treatment options are available for PAH?

3. PULMONARY HYPERTENSION
Over 40 RCT in past 25 years
14 approved PAH therapy
Drug delivery through four routes, SC/IV/Oral/Inhalation
Currently there is no cure forPAH
Mortality remains high in primary pulmonary Hypertension
Unpredictable magnitude of response, necessitates close follow up

4. Treatment
principles
Basic principle
• Proper diagnosis, Make sure it is PAH
• Risk assessment
• Close follow up
Combination therapy is now proven
• Up front vs Sequential
• Double vs Triple

5. Goalsoftreatment
PREVENT DISEASE
PROGRESSION
IMPROVE SURVIVAL IMPROVE QUALITY OF
LIFE
IMPROVE
FUNCTIONAL CLASS
TO I OR II
MAINTAIN GOOD
RIGHT VENTRICULAR
FUNCTION

6. TreatmentofPAH
Treatment
naivepatient
PAHconfirmedby
expert center
Generalmeasures
Supportive therapy
Acutevasoreactivitytest
(iPAH,H-PAH,D-PAHonly)
Vasoreactive
CCBTherapy
Non-vasoreactive
(or notiPAH/HPAH/DPAH)
Low/intRisk HighRisk
Oral
Monotherapy
Initial oralCombo
Therapy
Initialcombo
includingIVPC
Inadequateresponse
Double/triple sequentialtherapy
.
Galie N, ESC/ERS2015Guidelines
LungTransplant
Inadequate
response

7. General Measures and Supportive Therapies
are more important as prognosis improves
Cologne Consensus Conference 2016:
Modified from: Grünig-E et al. DMW 2016; 141:S26-S32

8. TreatmentofPAH
Treatment
naivepatient
PAHconfirmedby
expert center
Generalmeasures
Supportive therapy
Acutevasoreactivitytest
(iPAH,H-PAH,D-PAHonly)
Vasoreactive
CCBTherapy
Non-vasoreactive
(or notiPAH/HPAH/DPAH)
Low/intRisk HighRisk
Oral
Monotherapy
Initial oralCombo
Therapy
Initialcombo
includingIVPC
Inadequateresponse
Double/triple sequentialtherapy
.
Galie N, ESC/ERS2015Guidelines
LungTransplant
Inadequate
response

9. An acute vasodilator challenge
• Performed during RHC can identify patients who may benefit from long-term treatment with CCBs
• Nitricoxide(NO) is the agent most often used in acute testing i.v.epoprostenol and i.v.adenosine may
also be used
• A positive acute vasoreactive response
• 10 mmHg reduction of mean pulmonary arterial pressure to reach an absolute value off<40mmHg
mean Ppa with an increased or unchanged cardiac output
•
only about 10% of patients with IPAH will meet Criteria

10. Dosage of calcium channel blockers
• Empirical treatment with CCBs without an acute vasoreactivity test is strongly
discouraged due to possible severe adverse effects
• Nifedipine 120–240mg/day
• Diltiazem 240–720mg/day
• Amlodipine 20mg/day
• To start with reduced doses
• Nifedipine 30mg bd
• Diltiazem 60mg tds
• Amlodipine 5 mg od

11. TreatmentofPAH
Treatment
naivepatient
PAHconfirmedby
expert center
Generalmeasures
Supportive therapy
Acutevasoreactivitytest
(iPAH,H-PAH,D-PAHonly)
Vasoreactive
CCBTherapy
Non-vasoreactive
(or notiPAH/HPAH/DPAH)
Low/intRisk HighRisk
Oral
Monotherapy
Initial oralCombo
Therapy
Initialcombo
includingIVPC
Inadequateresponse
Double/triple sequentialtherapy
.
Galie N, ESC/ERS2015Guidelines
LungTransplant
Inadequate
response

12. Current medical treatment of PAH
3. How do we assess risk in PAH?

13. What parameters can be used
to assess risk in PAH?
Risk assessment
Adapted from Galiè N, et al. Eur Heart J 2016;37:67-119.
CPET 6MWD
Exercise
tests
NT-proBNP
Biochemical
markers
Signs of right
heart failure
Syncope
Progression
of symptoms
FC
Clinical
assessment Echocardiographic
evaluations
RAarea
Pericardial
effusion
Haemodynamic
evaluations
RAP
CI
Mixed
venous

15. RiskassessmentinPAH
Galie N, ESC/ERS2015Guidelines

16. Visit
Risk assessment : Baseline and at early
follow-up
Risk ?
Modified from slide courtesy of Actelion slidelibrary.
3 month follow up to assess
the impact of the initial
combination therapy

18. M Humbert et al N. Engl. J Med 2004;351:1425
Bosentan
Ambrisentan
macitentan Sildenafil
Tadalafil
Solubleguanylate
cyclase stimulator
Riociguat
Epoprostenol IV
Treprostinil.IV,SC,Inhald oral
Iloprost inhaled
IP Receptor agonist. selexipag

19. Pregnancyrisk: X B X B N
TargetsforcurrentPAH-specifictherapy

20. Current medical treatment of PAH
2. What do the current ERS/ESC guidelines advise us about
medical treatment of PAH?

21. Current medical treatment of pAH
• Monotherapy
• Sequential combination therapy
• Upfront combination

22. +
Drug 1
+
Drug 2
Drug 2Drug 1
Sequential
High risk group
Low risk group
Upfront
Combination TherapyMonotherapy
PDE5I
OR
ERA
OR
PGI2

23. UpfrontCombination
Therapy
SequentialCombination
Therapy
GalieN, ESC/ERS2015Guidelines

24. Authors/Task Force Members: et al. Eur Heart J 2015;eurheartj.ehv317
What do the new guidelines tell us?
Guidance on combination therapy
Sequential
combination
Monotherapy Initial
combination

25. AMBITION: Initial combination of ambrisentan AND tadalafil is
superior to monotherapy with ambrisentan OR tadalafil
Galiè N, et al. N Engl J Med 2015;273:834:44.
• N=500 treatment-naïve patients with
PAH (31% FC II)
• Primary endpoint:
Time to the first occurrence of a
composite endpoint of
• death,
• hospitalization for PAH worsening,
• disease progression,
• or unsatisfactory long-term
clinical response

26. The AMBITION Trial
Galiè N et al. N Engl J Med 2015; 373; 834–844.
Change from baseline to Week 24 in 6MWD
Ambrisentan
Ambrisentan mono

27. Initial triple combination therapy is notably
efficacious in the most severe PAH patients
17 18
8
1
10
0
5
10
15
20
Baseline 4 months* Last visit*
Patients(n)
FC I/II FC III FC IV
#
0%
20%
40%
60%
80%
100%
0 12 24 36 48 60 72 84 96 108 120
Transplant-freesurvival
Time (months)
19 18 18 17 16 15 15 9 5 1
Patients at risk (n)
Median f-up 81 months [Q1–Q3: 77 – 96]
- 1 death (30 months)
- 2 lung transplantations (4 & 41 months)
Data on file – Adapted from Sitbon O, et al. Eur Respir J. 2014;43:1691–7.
#32 ± 19 months ; *p < 0.01 versus baseline;
Baseline Month 4 Final follow-up visit*#
3500
2500
1500
500
0
PVR(dyn·s/cm5)
3000
2000
1000
Prospective, observational analysis of idiopathic or heritable PAH patients (n = 19) treated with
upfront combination therapy (epoprostenol, bosentan and sildenafil)

28. Impact of initial treatment strategy on long-term
survival in pulmonary arterial hypertension (PAH)
A. Boucly1, L. Savale1, J. Weatherald1, D. Montani1, M. Jevnikar1,
X. Jaïs1, G. Simonneau1, M. Humbert1, O. Sitbon1
Centre de Référence de l’Hypertension Pulmonaire Sévère
Université Paris-Sud – Le Kremlin-Bicêtre – France

29. Background and aim of the study
• The impact of initial treatment strategy on long-term survival is still
unknown.
• Aim: Evaluate the long-term survival of newly diagnosed patients
with PAH
according to the initial treatment regimen:
• monotherapy
• upfront dual combination therapy
• upfront triple combination therapy, including parenteral prostacyclin (PGI2)

30. Methods
• Data from the French PH Registry between 2006 and 2016
• Incident patients with idiopathic, heritable or anorexigen-induced
PAH
• In functional class II, III or IV at diagnosis, and initiated with PAH-
targeted medications within two months of PAH diagnosis
• Survival was analyzed in each treatment group (initial
monotherapy, dual combination therapy, triple combination therapy
including parenteral PGI2) and compared to predicted survival
from the French Registry equation1
• Uni- and multivariate Cox regression analysis were performed to
determine the impact of initial treatment strategy on survival
1. Humbert M, et al. Eur Respir J 2010.

31. Study population
n=1591
Incident idiopathic/heritable/anorex.-induced PAH
2006 - 2016
Calcium channel blockers,
n=104
No treatment, n=117
n=1516
NYHA II-III-IV
NYHA I, n=75
n=1295
Initiation of PAH targeted-therapy
n=814 (63%)
Monotherapy
n=410 (32%)
Dual combination therapy
n=71 (5%)
Triple combination therapy

32. Change in PAH therapy over time
63%
Monotherapy
32%
Dual combination therapy
5%
Triple combination therapy
34%
Monotherapy
43%
Dual combination therapy
23%
Triple combination therapy
27%32% 14%
Median follow-up: 28 months (Q1–Q3: 9–51)

33. Overall survival according to initial treatment
strategy
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5
Survival
Years
Monotherapy 814 577 462 343 244 175
Dual combo. 410 274 202 148 91 54
Triple combo. 71 54 41 34 23 15
__ Monotherapy
__ Dual combination therapy
__ Triple combination therapy
p=0.0086
Patients, at risk (n)

34. Conclusion
• Initial triple combination therapy including parenteral
prostacyclin may improve survival in incident patients with
idiopathic, heritable or anorexigen-induced PAH.
• This further supports the notion of an aggressive treatment
strategy for newly diagnosed patients with PAH, in particular in
the youngest population.

36. Choosing the correct
PAH Treatment
The Clinic
Cost of therapy
National availability
Clinic experience
EMEA/FDA
The Patient
Drug interactions
Side effects
Age and comorbidities
Dosing frequency Patient choice
How do we choose the correct treatment for our PAH patients?
The Data
Short-term trials
with sequential
combination
subgroups
Meta-analysis
Long-term dedicated
sequential combinationtrials
(SERAPHIN, COMPASS-2,
GRIPHON)
Guidelines
Real life data

37. Current medical treatment of pAH
5. A look beyond medical treatment

38. Depending upon local expertise interventions such as atrial septostomy or Potts
Shunt can have role in PAH
Diabolo stent
Roy AK, et al Heart Lung Circ. 2013 Aug;22(8):668-71; Esch JJ, et al J Heart Lung Transplant. 2013 Apr;32(4):381-7.
Turkay S, et al J Cardiovasc Dis Res 2010;1:181-90; Blanc, J et al N Engl J Med 2004;350:623

39. Availability of Lung Transplant
 Over 15,000 lung transplants performed in
the 20 yrs since the procedure became a
reality.
 1,400 new transplants are performed
annually in approximately 100 centres
worldwide.
 5% for PH
 i.e. 70 transplants a year worldwide
Levy, RD et al Eur Respir J 2003; 22: 721–722
Bruce Reitz and Norman Shumway, perform the world's
first successful combined heart-lung transplant on
March 9, 1981.

40. Approach to Pulmonary hypertension