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Chiara Arcangeli Dipartimento del Cuore e dei Vasi AOU Careggi, Firenze

Moderna terapia della ipertensione arteriosa polmonare. Chiara Arcangeli Dipartimento del Cuore e dei Vasi AOU Careggi, Firenze. Pulmonary hypertension Diagnostic classification. Third World Symposium on Pulmonary Arterial Hypertension. Venice 2003. 1. Pulmonary arterial hypertension.

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Chiara Arcangeli Dipartimento del Cuore e dei Vasi AOU Careggi, Firenze

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

  2. Pulmonary hypertensionDiagnostic classification Third World Symposium on Pulmonary Arterial Hypertension. Venice 2003 1. Pulmonary arterial hypertension 3. 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) • COPD • Interstitial lung disease • Sleep-disordered breathing • Developmental abnormalities 10% 3.5% 4. PH due to chronic thrombothic and/or embolic disease • TE obtruction of proximal PA • TE obstruction of distal PA • Non thrombotic P embolism 1,5% 2. PH with left heart disease 5. Miscellaneous • Atrial or ventricular disease • Valvular heart disease 78% 7%

  3. Bosentan Sitaxentan Ambrisentan Sildenafil Epoprostenolo Iloprost Treprostenil

  4. Nuovi farmaci

  5. 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 Risultati terapia medica

  6. ET-1 Activities Are Mediated by ETA and ETB Receptors BOSENTAN non selettivo SITAXENTAN selettivo AMBRISENTAN selettivo

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

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

  9. 92 93 90 92 87 89 85 86 84 84 83 83 77 80 27 18 15 9 EARLY: Effect of bosentan on time to clinical worsening 100 80 Placebo 60 Bosentan Hazard ratio = 0.22795% CL: 0.065, 0.798 Patients without the event (%) 40 20 p = 0.0114; log rank Patients are censored at the end of the study 0 0 4 8 12 20 24 28 32 16 Weeks from treatment start Patients at risk Galiè et all, Lancet 2008

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

  11. sitaxentan 100mg (n=39) placebo (n=28) 40 30 20 38 m 10 p = 0.042 0 Meters -10 -20 -30 -40 6 weeks 12 weeks 18 weeks -50 STRIDE-1,2,4: Change in 6MWD CTD Subgroup Seibold J, et al. Chest. 2005;128[4 suppl]:219S

  12. 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

  13. 12.5 11% 10.0 7.5 Percent of Patients 6% 5.0 5% 3% 2.5 0.0 sitaxentan 50 mg placebo sitaxentan 100 mg bosentan STRIDE-2: Hepatic Aminotransaminase Elevations > 3x ULN Barst RJ, et al. J Am Coll Cardiol. 2006;47:2049-2056

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

  15. Inibitori PDE5 sildenafil

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

  17. PROSTANOIDI ILOPROST EPOPROSTENOLO TREPROSTENIL

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

  19. 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). Strive for Early Intervention - Functional classEARLY IMPROVEMENT IN FUNCTIONAL CLASS PREDICTS INCREASED SURVIVAL1 *After 12 weeks of treatment. McLaughlin VV et al. Circulation. 2002;106:1477-1482. *Epoprostenol

  20. “Inhaled Iloprost for severe pulmonary hypertension” Olschewsky H, et al. N Engl J Med 2002;347:322 Hemodynamic improvement * * * CI PVR mPAP SvO2

  21. Effects of first-line prostacyclin therapyon survival in idiopathic PAH 100 90 80 70 60 50 Survival in IPAH (%) 40 30 Observed Expected (after D’Alonzo et al. Ann Intern Med 1991) IV epoprostenol (Mc Laughlin et al. Circulation 2002) 20 10 0 0 13 26 39 52 65 78 91 104 117 130 143 156 169 182 195 208 At risk (n) 32 30 21 16 9 Time (weeks) Lang et al Chest 2006

  22. S.Gibbs, 2008

  23. Jean-Luc Vachiéry, 2008

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

  25. Combination therapy: Iloprost & Sildenafil

  26. Combination therapy: Bosentan & Sildenafil Bos Sild • No deaths • No ALT/AST elevation • No hypotension or syncope Hoeper M et al. Eur Respir J 2004

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

  28. ACCP Guidelines 2007

  29. ACCP Guidelines 2007 ERAs

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