PULMONARY VASODILATORS

1. SELEXIPAG IN THE TREATMENT OF PH
ASSESSMENT, CLASSIFICATION, RISK
STRATIFICATION OF PH
VIKAS KOHLI AMERICAN BOARD CERTIFIED PEDIATRIC
CARDIOLOGIST
DIRECTOR DELHI CHILD HEART CENTER
SENIOR CONSULTANT APOLLO HOSPITAL
FOUNDER CHILD HEART FOUNDATION (NGO)

2. WHEN TO ADD SELEXEPAG

3. STARTING OR CHANGING DRUG THERAPY
WHO CLASS
RISK
CALCULATION

4. FUNCTIONAL
CLASSIFICATION
OF PH

5. RISK CALCULATION

6. RISK CALCULATION

7. US-BASED PROGNOSTIC RISK
STRATIFICATION

8. SURVIVAL WITH
RISK CALCULATION

9. EARLY DIAGNOSIS IS
IMPORTANT

10. Challenges in
diagnosis and
treatment of
PAH
(The
multicenter
RePHerral
study)
• Reveal registry –
median time of 1 year
from symptoms to right
heart catheterization
(RHC), 21% of patients
have symptoms from 2
years
• Younger age and
atypical symptoms leads
to the workup of other
common diseases
• Delayed initiation of
treatment
• At the time of
referral, 61% of the
patients in this study
were already in
advanced stages of
disease, and of these
patients only 30%
were on any PAH-
specific medications
• JAMA Intern Med. 2013
May 27;173(10):887-93.

11. OUTCOMES IN 2010: CIRCULATION
NIH, National Institutes of Health.
Circulation 2010;122:156–63
352 PATIENTS
1 YR SURVIVAL 82%
2 YR SURVIVAL 67%
3 YR SURVIVAL 58%
MORTALITY PREDICTORS
MALE GENDER
RV FUNCTION
EXERCISE LIMITATION

12. Early treatment
benefits
• Eur Respir Rev 2010;19:272–8.

13. Treating to low-risk status can improve
prognosis
Formal risk calculations can help you determine your patient’s
predicted 5-year survival rate.
In multiple registries involving thousands of patients with
PAH:
Those who achieve low-risk status, particularly in their first
year after diagnosis, have a better likelihood of survival.
Therefore, treating to a goal of low-risk status can help you
give your patient a better long-term prognosis.1-4

14. TREAT TO
LOW RISK
NOT TO
STABILITY

15. PAH targeted therapies
Phosphodiesterase
type 5 inhibitors
• Sildenafil
• Tadalafil
Soluble guanylate
cyclase stimulants
• Riociguat
Prostanoid analogues
• Treprostinil IV/SC
• Epoprostenol IV
Endothelin receptor
antagonists
• Bosentan
• Ambrisentan
• Macitentan
Prostacyclin
receptor agonists
• Selexipag
ORAL

16. Selexipag in treatment of Pulmonary
Arterial Hypertension

17. Selexipag in Pulmonary Arterial Hypertension – GRIPHON trial
GRIPHON: ProstaGlandin I2 Receptor agonist In Pulmonary arterial
HypertensiON
• Large, international, multicenter, long-term phase 3 study
• Double-blind, placebo-controlled study assessing the safety and efficacy of
selexipag on morbidity and mortality in patients with PAH
• Event-driven study
• Primary outcome measure: Time to first adjudicated morbidity or mortality
event (up to 7 days after last study-drug intake)
N Engl J Med 2015; 373:2522-2533

18. GRIPHON trial – Objectives
• 1156 PAH adult patients included and treated for up to 4.3 years
• 80% on background treatment with endothelin-receptor antagonist, a
phosphodiesterase type 5 inhibitor, or both (ERA and/or PDE-5i)
• Uptitration of selexipag allows each patient's maintenance dose to be
individualized based on tolerability (to a maximum of 1600 mcg bid)
N Engl J Med 2015; 373:2522-2533

19. Time to first occurrence of death or morbidity due to PH up to EOT
N Engl J Med 2015; 373:2522-2533

20. GRIPHON trial – Results
Selexipag reduced the risk of a
morbidity/mortality event
(primary endpoint) by 40%
compared with placebo
N Engl J Med 2015; 373:2522-2533

21. GRIPHON trial – Results
N Engl J Med 2015; 373:2522-2533

22. GRIPHON trial – Conclusion
• The GRIPHON study with selexipag met its primary objective in patients with PAH
• Selexipag reduced the risk of a morbidity/mortality event (primary endpoint) by 40%
compared with placebo
• The efficacy of selexipag was consistent across subgroups: Age, gender, FC, PAH
etiology, and background PAH therapy
• The overall tolerability profile of selexipag in GRIPHON was consistent with
prostacyclin therapies
• The patients in the selexipag group received selexipag for a median duration of 70.7
weeks
N Engl J Med 2015; 373:2522-2533

23. Selexipag reduced the risk of the primary outcome composite of death
or morbidity due to PH
McLaughlin V, et al. Presented at ACC Annual Congress 2015.

24. Dose titration scheme for Selexipag (Prescribing information)
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207947s000lbl.pdf
Respiratory Medicine 143 (2018) 139–146

27. Oral selexipag may be considered for patients with idiopathic, heritable, drug- or
toxin-induced, or repaired congenital heart disease-associated PAH who are
receiving dual oral therapy with an ERA and a PDE5i
CHEST 2020; 157(4):955-965
ERA = endothelin receptor antagonist; HD = hemodynamic parameters; PAH = pulmonary arterial hypertension;
PDE5i = phosphodiesterase type 5 inhibitor; RV ¼=right ventricular

28. Oral selexipag may be considered for patients with connective tissue disease
associated PAH who are receiving dual oral therapy with an ERA and a PDE5i
CHEST 2020; 157(4):955-965
6MWD = 6-min walk distance; BNP =B-type natriuretic peptide; NT-proBNP =N-terminal
prohormone BNP

29. • SELEXEPAG IS NOT FIRST LINE TRETTMENT
• SELEXEPAG IS NOT TO BE USED IN A DYING PATIENT AS A LAST-DITCH EFFORT
• A PATIENT WITH DUAL THERAPY SHOWING CONSISTENT CHANGES CLINICALLY OR
ECHOCARDIOGRAPHICALLY DO NOT IGNORE OR WAIT, ADD THIRD-LINE MANAGEMENT
• CALCULATE RISK SCORE, CLASSIFY WHO CLASS ON ALL VISITS
• FREQUENT EVALUATIONS: 3 MONTHLY OR 4 MONTHLY AND REASSESS
Take Home Points

30. QUESTIONS?

31. Take Home Points
• Current practice guidelines for the treatment of PAH propose a treatment algorithm according
to the patient’s risk factors
• Patients considered lower risk based on clinical assessment can initially be treated with an oral
agent, whereas higher-risk patients, including those with NYHA/WHO FC IV, should receive
intravenous prostacyclin
• Selexipag is a non-‐prostanoid agonist selective for the IP receptor and mediates vasodilation of
pulmonary vasculature (USFDA approved 2015)
• Selexipag reduced the risk of a morbidity/mortality event by 40% (Griphon trial)
• Selexipag may have a better side effects profile than other oral prostanoids

32. Thank You!!

33. RV>LV domination
Eur Heart J 2015 doi:10.1093/eurheartj/ehv317, Eur Respir J, 2015
Echocardiographic signs suggesting pulmonary hypertension (in
addition to tricuspid regurgitation velocity measurements)

34. RV failure
Eur Heart J 2015 doi:10.1093/eurheartj/ehv317, Eur Respir J, 2015
Echocardiographic signs suggesting pulmonary hypertension (in
addition to tricuspid regurgitation velocity measurements)

35. RV/PA coupling
Eur Heart J 2015 doi:10.1093/eurheartj/ehv317, Eur Respir J, 2015
Echocardiographic signs suggesting pulmonary hypertension (in
addition to tricuspid regurgitation velocity measurements)

36. Eur Heart J 2015 doi:10.1093/eurheartj/ehv317,
Eur Respir J, 2015 10.1183/13993003.01032-2015
Diagnostic algorithm for pulmonary hypertension - 1
RV>LV
domination
RV/PA
coupling
RV failure

37. Eur Heart J 2015 doi:10.1093/eurheartj/ehv317,
Eur Respir J, 2015 10.1183/13993003.01032-2015
Diagnostic algorithm for pulmonary hypertension - 2

38. PH in heart failure with preserved ejection fraction, heart failure with reduced
ejection fraction, and valvular heart disease
(What Cardiologist needs to know?)
Several studies
indicate that 50–70%
of patients with
severe aortic stenosis
develop PH and
associated with
about a doubled
increase in mortality
risk
Lancet Respir Med 2016; 4: 306–322

39. PAH management: How to do better?

40. CHEST 2020; 157(4):955-965
6MWD =6-min walk distance;
BNP = B-type natriuretic
peptide; CTD = connective
tissue disease; ERA =
endothelin receptor
antagonist; FC = World
Health Organization functional
class; IPAHþ = idiopathic,
heritable, drug- or toxin-
induced, or repaired
congenital heart disease-
associated PAH; NTproBNP =
N-terminal prohormone BNP;
PAH = pulmonary arterial
hypertension; PDE5i =
phosphodiesterase type 5
inhibitor; RV = right
ventricular

41. CHEST 2020; 157(4):955-965
6MWD =6-min walk distance; BNP = B-type natriuretic peptide;
CTD = connective tissue disease; ERA = endothelin receptor
antagonist; FC = World Health Organization functional class; IPAHþ
= idiopathic, heritable, drug- or toxin-induced, or repaired
congenital heart disease-associated PAH; NTproBNP = N-terminal
prohormone BNP; PAH = pulmonary arterial hypertension; PDE5i =
phosphodiesterase type 5 inhibitor; RV = right ventricular