1. ΝΕΑ ΔΕΔΟΜΕΝΑ ΣΤΗ ΘΕΡΑΠΕΥΤΙΚΗ ΑΝΤΙΜΕΤΩΠΙΣΗ Της ΠΝΕΥΜΟΝΙΚΗς ΑΡΤΗΡΙΑΚΗς ΥΠΕΡΤΑΣΗς
ΣΤΕΛΙΟΣ ΟΡΦΑΝΟΣ
Β’ ΚΛΙΝΙΚΗ ΕΝΤΑΤΙΚΗΣ ΘΕΡΑΠΕΙΑΣ & ΔΙΑΚΛΙΝΙΚΟ ΙΑΤΡΕΙΟ ΠΝΕΥΜΟΝΙΚΗΣ ΥΠΕΡΤΑΣΗΣ
Π.Γ.Ν. «ΑΤΤΙΚΟΝ»

2. Disclosures Actelion Bayer ELPEN Galenica GSK MSD Pharmaserve Lilly
Funding, or sponsoring to attend scientific meetings, or honoraria from:
Actelion
Bayer
ELPEN
Galenica
GSK
MSD
Pharmaserve Lilly
Pfizer
United Therapeutics

3. 3

4. EHJ & ERJ, 2015

5. EHJ & ERJ, 2015

6. Ενδοθηλιακή Δυσλειτουργία επί ΠΑΥNO
PGI2
ET-1
ET-1 is elevated (+)
Vasoconstriction
Cell proliferation / Hypertrophy
NO and PGI2 are reduced (-)
Vasodilation
Anti-proliferation
Anti-inflammation
Endothelin (ET-1) is a potent vasoconstrictor which stimulates cell proliferation and hypertrophy
To counteract the negative effects of ET-1, two important vasodilative, antimitogenic substances are derived from endothelium NO
Prostacyclin
In PAH, endothelium dysfunction refers to the imbalance of endothelium derived vasodilating, antiproliferative (NO, PGI2) and constricting (ET-1)
Basically, there is an excess of ET-1 relative to NO and PGI2.
Spieker LE et al. J Am Coll Cardiol. 2001;37:
Luscher TF and Barton M. Circulation. 2000;102:
Albrecht EW et al. J Pathol. 2003;199:8-17.
Hankins SR and Horn EM. Curr Cardiol Rep. 2000;2:

7. Bosentan Ambrisentan Macitentan Selexipag
Epoprostenol
Treprostinil
Iloprost
Sildenafil
Tadalafil
Bosentan Ambrisentan Macitentan
Selexipag
Riociguat
McLaughlin & McGoon Circulation 2006, 114: 7

10. PATENT-1: Riociguat rapidly improves 6MWD vs placebo
Ghofrani HA et al. N Engl J Med 2013;369:330–40.

16. Seraphin haemodynamic sub-study

18. Upfront combination therapy with ambrisentan/tadalafil reduced the risk of first event of clinical failure
50% Risk Reduction
95% CIs (using log-log transform method) are presented for each treatment group at weeks 4, 8, 16, 24, and then every 12 weeks up to week 96.
N. Galiè, et al. N Engl J Med 2015;373:834-44

19. Upfront combination therapy with ambrisentan/tadalafil reduced TCF events in all subgroups
CONFIDENTIAL
N. Galiè, et al. N Engl J Med 2015;373:834-44

23. Patients without an event KM (%)
Selexipag reduced the risk of the primary outcome composite of death or morbidity due to PH
Patients without an event KM (%) 20 40 80
100 60 12 18 24 30 36 6
Months
Selexipag
Selexipag vs placebo: Risk reduction 40%
HR = 0.60; % CI 0.46–0.78; p <
Placebo
Hospitalisation for PAH worsening and disease progression were the main components of the primary endpoint
Speaker notes
The primary endpoint was measured up to the end of treatment
Here we see the selexipag in green and the placebo in grey
The curves separate early on and this separation is maintained over the whole follow-up
The risk reduction was 40% and was highly statistically significant
Additional information: Absolute risk reduction of 14.6, therefore Number Needed to Treat (NNT) to prevent an event is 7 patients at 24 months
No. at Risk
Placebo
582
433
347
220
149 88 28
Selexipag
574
455
361
246
171
101 40

24. No. of patients/ no. of events
Consistent treatment effect of selexipag on primary composite endpoint according to background therapy
Selexipag Placebo
Selexipag vs placebo
No. of patients/ no. of events
All patients
574/155
582/242
PAH specific therapy at baseline
(interaction p value = 0.95)
ERA + PDE-5i
179/47
197/80
ERA monotherapy
94/23
76/29
PDE-5i monotherapy
189/54
185/84
No PAH-specific therapy
112/31
124/49
Hazard ratio (99% CI)
0.1
0.2
0.4
0.6 1
1.4 2
Source: Figure FMMTGRP_F – Produced by zeeja1 on 28JUL14– Data dump of 12JUN2014
CI: confidence interval; EOT: end-of-treatment; ERAs: endothelin receptor antagonists; M/M: morbidity/mortality; PAH: pulmonary arterial hypertension, PDE-5: phosphodiesterase-5
Note 1: the vertical solid line references the overall treatment effect
Favours selexipag
Favours placebo

25. 2015 ESC/ERS guidelines treatment algorithm
Galiè N, et al. ESC/ERS Guidelines. Eur Respir J & Eur Heart J

26. EHJ & ERJ, 2015

28. 2015 ESC/ERS guidelines treatment algorithm
Galiè N, et al. ESC/ERS Guidelines. Eur Respir J & Eur Heart J

29. Evolution of combination therapy

30. Initial dual combination therapy data

31. Initial combination therapy, ERA+PDE5-i
BONSAI: BOlogNa Sub-study on hAemodynamIcs
Joint Bologna and Calgary study on INiTial bosENTan plus sIldenafil in pulmonary arterial hypertension.
1. Bachetti C et al. Am J Respir Crit Care Med 2015;191:A Palazzini M et al. Am J Respir Crit Care Med 2016;193:A Sitbon O et al. Eur Respir J 2016;47:1727–36.

32. Optima study
Ongoing, multi-centre, prospective, single-arm, open-label, Phase IV study
This is an interim analysis
Estimated Completion Date: November 2017
Aims to evaluate the efficacy, safety and tolerability of initial combination therapy with macitentan and tadalafil in newly diagnosed PAH patients
Sitbon O, et al. Eur Respir J 2016; 47:

33. OPTIMA study
ERS 2017 – Milan, 9-13 September 2017

34. WHY IS THIS PLANT STILL BEING WATERED?
IT’S EASY TO JUST FOLLOW THE INSTRUCTIONS, BUT TREATING TOO LONG WITHOUT RECOGNIZING FAILURE IS DANGEROUS
IRREPLACEABLE TIME IS LOST BEFORE SWITCHING THERAPIES
NEED EXPERIENCED FOLLOWUP
…και Καλή Συνεργασία με Εξειδικευμένα Κέντρα !!!

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