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Chiara Arcangeli Dipartimento del Cuore e dei Vasi AOU Careggi, Firenze Moderna terapia della ipertensione arteriosa polmonare.

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Presentation on theme: "Chiara Arcangeli Dipartimento del Cuore e dei Vasi AOU Careggi, Firenze Moderna terapia della ipertensione arteriosa polmonare."— Presentation transcript:

1 Chiara Arcangeli Dipartimento del Cuore e dei Vasi AOU Careggi, Firenze Moderna terapia della ipertensione arteriosa polmonare

2 Pulmonary hypertension Diagnostic classification 1. Pulmonary arterial hypertension3. PH with lung diseasesHypoxemia Idiopathic PAH Familial PAH Related to: - Connective tissue diseases - HIV - Portal Hypertension - Anorexigens - Congenital heart diseases PPHN PAH venulae/cap.involv. (PVOD) 2. PH with left heart disease Atrial or ventricular disease Valvular heart disease COPD Interstitial lung disease Sleep-disordered breathing Developmental abnormalities 4. PH due to chronic thrombothic and/or embolic disease TE obtruction of proximal PA TE obstruction of distal PA Non thrombotic P embolism 5. Miscellaneous Third World Symposium on Pulmonary Arterial Hypertension. Venice 2003 3.5% 78% 10% 1,5% 7%

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4 Bosentan Sitaxentan Ambrisentan Sildenafil Epoprostenolo Iloprost Treprostenil

5 Nuovi farmaci EmivitaSomministrazione Prostanoidi Epoprostenolo (Flolan)2-4 min.e.v. Iloprost (Ventavis)20-40 min.e.v./inal. Treprostinil (Remodulin)20-40 min.s.c. Beraprost40-50 min.os Antagonisti ETa/b Bosentan (Tracleer) Sitaxentan (Thelin) Ambrisentan (Volibris) 360-480 min.os Inibitori PDE5 Sildenafil (Revatio)240-300 min.os

6 Risultati terapia medica Tolleranza sforzo 30-50 mt Classe funzionale 1-2 classe ( 20-40%) Deterioramento clinico riduzione variabile Emodinamica 3-5% mPap, 10-20% IC Qualità di vita miglioramento marginale Sopravvivenza 20-30% vs NIH formula

7 ET-1 Activities Are Mediated by ET A and ET B Receptors BOSENTAN non selettivo SITAXENTAN selettivo AMBRISENTAN selettivo

8 Long-term outcome with first-line bosentan therapy in idopathic pulmonary hypertension survival Event-free status S Provencher, Eur Heart J, 2006

9 -400 -300 -200 -100 0 100 200 300 Placebo (n=17)Bosentan (n=36) PVRi (dyn·sec·cm -5 ) Cambiamenti dal baseline p=0.04 T.E.* = -472 dyn.sec.cm -5 *T.E. = Effetto del Trattamento Galiè et al.: Circulation 2006 BREATHE-5: first randomized placebo-controlled trial in Eisenmenger physiology

10 EARLY: Effect of bosentan on time to clinical worsening Hazard ratio = 0.227 95% CL: 0.065, 0.798 Patients are censored at the end of the study 100 80 60 40 20 0 04812 16 20282432 92908986848318779 939287858483278015 Weeks from treatment start Patients without the event (%) Patients at risk Placebo Bosentan p = 0.0114; log rank Galiè et all, Lancet 2008

11 EARLY Co-primary endpoint: Bosentan significantly reduced PVR Treatment effect:* 22.6% 95% CL: 33.5, 10.0 80 85 90 95 100 105 110 Placebo n = 88 Bosentan n = 80 % of baseline PVR at month 6 (geometric means) p < 0.0001; Wilcoxon *(ratio of geometric means 1) x 100 Galiè et all, Lancet 2008

12 STRIDE-1,2,4: Change in 6MWD CTD Subgroup 6 weeks12 weeks18 weeks p = 0.042 Meters sitaxentan 100mg (n=39) placebo (n=28) -50 -40 -30 -20 -10 0 10 20 30 40 38 m Seibold J, et al. Chest. 2005;128[4 suppl]:219S

13 Ambrisentan for the Treatment of Pulmonary Arterial Hypertension Results of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy (ARIES) Study 1 and 2 Galiè et all, Circulation 2008

14 STRIDE-2: Hepatic Aminotransaminase Elevations > 3x ULN 0.0 2.5 5.0 7.5 10.0 12.5 placebo sitaxentan 50 mg sitaxentan 100 mg bosentan 11% 3% 5% 6% Percent of Patients Barst RJ, et al. J Am Coll Cardiol. 2006;47:2049-2056

15 STRIDE-2: Hepatic Aminotransaminase Elevations > 3x ULN 0.0 2.5 5.0 7.5 10.0 12.5 placebo sitaxentan 50 mg sitaxentan 100 mg bosentan 11% 3% 5% 6% Percent of Patients Barst RJ, et al. J Am Coll Cardiol. 2006;47:2049-2056 Ambrisentan

16 sildenafil Inibitori PDE5

17 Observed and predicted survival (n = 141) Observed: sildenafil treated Predicted: NIH 99% 78% 96% 71% 95% 65%

18 PROSTANOIDI EPOPROSTENOLO ILOPROST TREPROSTENIL

19 87.8% 76.3% 62.8% n= 162 58.9% 46.3% 35.4% A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. n= 81 Survival in primary pulmonary hypertension. The impact of epoprostenol therapy. 80% Epoprostenol in IPAH McLaughlin VV, et al. Circulation 2002;106:1477. Barst RJ, et al. N Engl J Med 1996;334:296.

20 Strive for Early Intervention - Functional class EARLY IMPROVEMENT IN FUNCTIONAL CLASS PREDICTS INCREASED SURVIVAL 1 Functional class (FC) is highly correlated to survival. Survival was significantly improved for patients who rapidly achieved FC I or II compared with FC III and IV patients (P<0.001; FC after 12 weeks of treatment). McLaughlin VV et al. Circulation. 2002;106:1477-1482. *Epoprostenol *After 12 weeks of treatment.

21 Inhaled Iloprost for severe pulmonary hypertension Olschewsky H, et al. N Engl J Med 2002;347:322 Hemodynamic improvement CIPVRmPAPSvO 2 ***

22 0 Survival in IPAH (%) At risk (n) 323021169 Observed Expected (after DAlonzo et al. Ann Intern Med 1991) IV epoprostenol (Mc Laughlin et al. Circulation 2002) Effects of first-line prostacyclin therapy on survival in idiopathic PAH Time (weeks) 20 132639526591104781171301431561691821952080 10 30 50 60 40 80 70 90 100 Lang et al Chest 2006

23 S.Gibbs, 2008

24 Jean-Luc Vachiéry, 2008

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26 Possibili terapie di associazione Antagonisti Recettoriali della ET-1 Prostanoidi (e.v., s.c., os, inal) Inibitori della Fosfodiesterasi 5

27 Combination therapy: Iloprost & Sildenafil

28 Combination therapy: Bosentan & Sildenafil Hoeper M et al. Eur Respir J 2004 BosSild - No deaths - No ALT/AST elevation - No hypotension or syncope

29 Interazioni farmacologiche Il meccanismo più probabile sembra una induzione del citocromo CYP3A4 da parte del bosentan Br Clinic Pharmacol, 2005

30 ACCP Guidelines 2007

31 ERAs ACCP Guidelines 2007

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33 CALCIOANTAGONISTI Rubin,2005


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