Θεραπεία με βάση τη βαρύτητα ή εξαρχής επιθετική συνδυαστική θεραπεία. Φραντζέσκα Φραντζεσκάκη Πνευμονολόγος-Εντατικολόγος ΠΓΝ «ΑΤΤΙΚΟΝ»

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1 Θεραπεία με βάση τη βαρύτητα ή εξαρχής επιθετική συνδυαστική θεραπεία Φραντζέσκα Φραντζεσκάκη Πνευμονολόγος-Εντατικολόγος ΠΓΝ «ΑΤΤΙΚΟΝ»

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3 S.Gaine and V.McLaughlin, Eur Respi Rev 2017;26

4 Ultimate goal of treatment: To achieve a low risk status

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6 M.Hoeper et al. Eur Resp J,2017;50:

7 A. Boucly et al. Eur Respir J,2017;50

8 Kylhammar D et al. Eur H J (2017) 0,1-7

9 Goals?? 6MWD: Inappropriate surrogate marker of disease progression Not predicting clinically relevant events COPD: Not subjective improvement for distances <54m Hemodynamics do not predict clinical events in RCTs Savareze et al. J Am Coll Cardiol 2012; 60(13) Redelmeier et al. Am J Respir Crit Care Med 155

10 Composite outcome All cause death Hospitalization Initiation of PAH rescue therapy Savareze et al. J Am Coll Cardiol 2012; 60(13)

11 Savareze et al. Eur Respir J 2013;42:414-24

12 Treatment goal: FC I-II FC-II: 20% mortality in 3 ys Humbert M et al.circulation 2010;122:

13 Van der Veerdonk et al. Chest 2015;147:

14 Stable?? Not appropriate even in low risk category Poor tolerance to acute situations Disturbances in status quo Augmentation of patient s treatment regimen Regular and frequent risk assessments Deteriorations: escalation of treatment? S.Gaine, V. McLaughlin. Eur Respir Rev 2017; 26

15 Clinical worsening Hospitalization Symptomatic progression of disease Treatment escalation Transplantation Atrial septostomy Death Lajoie et al. Pulmonary Circulation 2017;7(2)

16 Targeting multiple pathways Additive beneficial effects Improving outcomes Minimizing drug interactions and adverse events Meta-analyses: 35-40% relative risk reduction of clinical worsening Lajoie et al. Lancet Respir Med 2016(4): Fox et al. Can J Cardiol 2016;32(12):

17 Lajoie et al. Lancet Respir Med 2016 (4):

18 Combination therapy

19 Goal oriented therapy Sequential combination Adequate treatment when targets are met Better prognosis in patients achieving the goals Nickel et al. Eur Resp J 2012 (39)

20 Double bind, placebo-controlled phase 3 study. 740 PAH patients Macitentan 10 mg vs placebo 45% reduction of morbidity/mortality event (p<0.001) 2/3 of pt: Background PAH-specific therapy (96%:PDE- 5i) 38% reduction morbidity/mortality event Similar percentage of adverse events N Engl J Med 2013;369:

21 Pulido et al. N Engl J Med 2013; 369,809-18

22 Activation of PGI2 signalling Placebo-control RCT Selexipag or placebo in treatment naive or on ERA, PDE-5 or both WHO-FC II, III 47% on background monotherapy 40% reduction of the risk of morbidity/mortality (vs placebo) (p<0,001)

23 PDE-5i ERA

24 Initial combination therapy tadalafil/ambrisentan vs monotherapy 500 newly diagnosed PAH pt (FC-WHO:II/III) 50% reduction of clinical failure events (p<0.001) Peripheral oedema, headache, nasal congestion, anaemia

25 Galie et al. N Engl J Med, 2015;373

26 Retrospective analysis 97 newly diagnosed PAH pts Initial combination therapy (ERA-PDE-5i) Follow up 30 months

27 Sitbon et al. Eur Resp J, 2016 (47)

28 Sequential triple combination therapy GRIPHON study 376 pts on dual ERA and PDE-5i Selexipag vs placebo/dual vs triple Reduction of the risk of a primary end-point event 37% (99% CI ) Sitbon et al. N Engl J Med 2015;373:

29 Retrospective study 19 pts WHO-FC III, IV Epoprostenol, bosentan, sildenafil

30 Phase 3b trial Initial triple vs initial dual combination therapy in pts with newly diagnosed pulmonary arterial hypertension (TRITON) Sitbon et al. Eur Resp J 2014; 43:

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32 Monotherapy? Exception!! Close Gaine S, Mc Lauphlin. Eur Respir J 2017 (26)

33 Risk stratification? Monotherapy in low risk pts: Close monitoringcontraindication for PDE-5/ERA Triple combination therapy in low risk pts: Phenotypic characteristics or comorbidities with poor prognosis Older patients Connective tissue disease Gaine et al. Eur Respir Rev (2017) 26

34 Sitbon et al. Eur Resp Rev (2016) 25

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37 Take home messages Monotherapy no longer acceptable (exceptions) 2 or 3 drugs to delay disease progression Pts should be offered the benefits of combination therapy Initially or sequentially Sequential therapy: reassessment every 3-6 mo Initial comb therapy: assessment of safety profil Targeting 3 pathways Oral therapies targeting PGI2: Triple comb therapy in pts WHO-FC II/III Epoprostenol in severe PAH

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39 Ευχαριστώ!!!