Θεραπεία Πνευμονικής Υπέρτασης Συμβατική Αγωγή, Ειδική Αγωγή, Νέες Θεραπευτικές Προσεγγίσεις Στυλιανός Ορφανός Β Κλινική Εντατικής Θεραπείας & Ιατρείο Πνευμονικής Υπέρτασης Π.Γ.Ν. ΑΤΤΙΚΟΝ
ΠΝΕΥΜΟΝΙΚΗ ΥΠΕΡΤΑΣΗ ΟΡΙΣΜΟΣ ΑΥΞΗΜΕΝΗ ΠΙΕΣΗ ΠΝΕΥΜΟΝΙΚΗΣ ΑΡΤΗΡΙΑΣ (>25 mm Hg μέση) ΛΟΓΩ ΠΑΘΟΛΟΓΙΚΑ ΑΥΞΗΜΕΝΩΝ ΑΓΓΕΙΑΚΩΝ ΠΝΕΥΜΟΝΙΚΩΝ ΑΝΤΙΣΤΑΣΕΩΝ ΛΟΓΩ ΠΝΕΥΜΟΝΙΚΗΣ ΑΓΓΕΙΑΚΗΣ ΑΝΑΔΟΜΗΣΗΣ & ΑΓΓΕΙΟΣΥΣΠΑΣΗΣ
Μέχρι τον Ιούνιο 2009 ίσχυαν η κατάταξη της νόσου και οι κατευθυντήριες οδηγίες του συνεδρίου της Βενετίας
Τρέχουσες οδηγίες & κατάταξη Συνέδριο Dana Point California 2008
ERJ & EHJ 2009
ΠΑΘΟΦΥΣΙΟΛΟΓΙΑ ΠΑΥ Πολύπλοκη και πολυπαραγοντική Αγγειοσύσπαση Θρόμβωση (αιμοπετάλια) Aγγειοδραστικές ουσίες, αυξητικοί παράγοντες, φλεγμονώδεις μεταβιβαστές, συστατικά πήξης Remodeling ΓΕΝΕΤΙΚΕΣ ΑΝΩΜΑΛΙΕΣ (BMPR2: αναστολή υπερπλασίας λεία μυική ίνα) ΕΝΔΟΘΗΛΙΑΚΟ ΚΥΤΤΑΡΟ
Intensive Care Med 2004; 30:1702-14
Intensive Care Med 2004; 30:1702-14
ΘΕΡΑΠΕΙΑ Βασική αγωγή: δίαιτα, διουρητικά, διγοξίνη, αντιαρρυθμικά Δικουμαρινικά INR: 2-3 ή 1.5-2 Οξυγονοθεραπεία SaO2 ~ 90% ΑΓΓΕΙΟΔΙΑΣΤΑΛΤΙΚΗ (αντιυπερπλαστική) ΑΓΩΓΗ
HIGH DOSE CALCIUM BLOCKER THERAPY FOR PPH RICH ET AL, NEJM 1992
ERJ & EHJ 2009
Endothelial Cell Dysfunction in PAH ET-1NO PGI 2 ET-1 1 is elevated (+) Vasoconstriction Cell proliferation / Hypertrophy NO and PGI 2 are reduced (-)( Vasodilation Anti-proliferation Anti-inflammation inflammation Spieker LE et al. J Am Coll Cardiol. 2001;37:1493-1505. Luscher TF and Barton M. Circulation. 2000;102:2434-2440. Albrecht EW et al. J Pathol. 2003;199:8-17. Hankins SR and Horn EM. Curr Cardiol Rep. 2000;2:244-251.
McLaughlin & McGoon Circulation 2006, 114:1417-1431
McLaughlin & McGoon Circulation 2006, 114:1417-1431
PROSTACYCLIN ANALOGUES
CHRONIC INFUSIONS OF EPOPROSTENOL (FLOLAN)
Τριετής Επιβίωση McLaughlin et al., Circulation 2002, 106:1477-1482
Επταετής επιβίωση, FC στην έναρξη θεραπείας McLaughlin et al., Circulation 2002, 106:1477-1482
PROSTACYCLIN ANALOGUES
AIR-Study Results 20.0% 17% 15.0% 10.0% 5.0% 5% p = 0,007 Iloprost Placebo 0.0% Patients in % Combined clinical end point: Improvement in NYHA Stadium (at least one class) AND improvement of 6 min walk test for at least 10% AND no deterioration or death Source: Olschewski et al, New England Journal of Medicine 2002;347:322-9
AIR-2 Survival in IPAH 1.0 All IPAH and FPAH patients who started iloprost treatment 87% 0.8 74% survival 0.6 0.4 predicted PPH survival according to d'alonzo 63% 0.2 Event-free survival on inhaled iloprost monotherapy 0.0 0 100 200 300 400 500 600 700 800 900 time [days]
PROSTACYCLIN ANALOGUES
UNIPROST (TREPROSTINIL, UT-15) IN PULMONARY ARTERIAL HYPERTENSION Active as a subcutaneous injection Stable at room temperature Plasma half-life: life: SC ~ 3h, IV ~ 45min Smaller pump Lower risk of infections Disadvantages: Severe skin reactions (No Flolan to Remodulin match (mg to mg)
UNIPROST (TREPROSTINIL, UT-15) IN PULMONARY ARTERIAL HYPERTENSION
Effect of long-term subcutaneously infused treprostinil on exercise capacity and NYHA class Lang, I. et al. Chest 2006;129:1636-1643
Four-year comparative Kaplan-Meier survival analyses of ipah patients in the study (n = 32) in relation to previously reported data obtained with IV epoprostenol Lang, I. et al. Chest 2006;129:1636-1643
R. Voswinckel et al., JACC 48, 1672-1681, 2006
ATS Annual Meeting 2009
McLaughlin & McGoon Circulation 2006, 114:1417-1431
Endothelin, having a potent, strong and characteristically long- lasting vasoconstrictor activity, may be important in the control of systemic blood pressure and / or local blood flow; disturbances in the control of endothelin production could contribute to the pathogenesis of hypertension and that of pathological vascular spasm." Nature 1988;332:411-415
McLaughlin & McGoon Circulation 2006, 114:1417-1431
ENDOTHELIN RECEPTOR ANTAGONISTS BOSENTAN Blocks ET-A and ET-B receptors (nonselective) SITAXSENTAN Blocks ET-A selectively AMBRISENTAN Less ET-A selective
ΠΡΩΤΗ ΑΠΟ ΤΟΥ ΣΤΟΜΑΤΟΣ ΑΓΩΓΗ ΠΑΥ LANCET 2001; 358:1119-1123
L/min/m 2 0.8 0.4 0-0.4 Hemodynamics Change from baseline to week 12 Mean pulmonary Pulmonary Cardiac arterial vascular index pressure resistance P < 0.0001 mm Hg 10 5 0 P = 0.013 Dyn.sec.cm -5 400 200 0-200 P = 0.0001-0.8 Week 12-5 Week 12-400 Week 12 Placebo (n = 10) Bosentan (n = 20) Channick et al. Lancet 2001;358:1119
BREATHE-1 Bosentan randomized trial of endothelin receptor antagonist therapy for pulmonary hypertension: 11 countries, 27 sites, 213 patients Mid-July 2000 to Dec 2000 Last patient last visit: March 30, 2001
SUSTAINED BENEFIT WITH BOSENTAN IN PAH Sitbon et al, Chest 2003;124:247-254
ENDOTHELIN RECEPTOR ANTAGONISTS BOSENTAN Blocks ET-A and ET-B receptors (nonselective) SITAXSENTAN Blocks ET-A selectively AMBRISENTAN Less ET-A selective
STRIDE-2 trial Barst RJ et al. J Am Coll Cardiol 2006; 47:2049-2056 2056
Barst RJ et al. J Am Coll Cardiol 2006; 47:2049-2056 2056
STRIDE-2X Sitaxentan 100 mg Analysis Population Benza R, Barst RJ, Galie N, et al. Sitaxsentan for the treatment of pulmonary arterial hypertension: A one year, prospective, open-label observation of outcome and survival. Chest. 2008; in press
STRIDE-2X: Time to Percent Without Events 100 90 80 70 60 50 40 30 20 10 Number at risk sitaxentan 92 bosentan 83 84 75 Benza R, et al. Chest. 2008; in press 0 Discontinuation from Monotherapy sitaxentan (n=92) bosentan (n=84) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks 79 73 60 58 53 43 70% 57% 100 mg Analysis Population
Managing Sitaxsentan-Warfarin Patients 1. Reduce the dose of warfarin 2. Initiate THELIN at 100 mg/day 1. If initiating warfarin therapy, begin at lowest available dose In clinical trials (STRIDE-2), the dose of warfarin was decreased by 80% when starting sitaxsentan and then increased in increments of 0.5 mg/day to reach the desired INR - The mean dose at study end was approximately 40% of baseline Data on File, Encysive Pharmaceuticals Inc., Houston, TX
Έγκριση για χορήγηση σε Ασθενείς Λειτουργικού Σταδίου ΙΙ Όχι ηπατικές επιπλοκές
Survival With Endothelin Receptor Antagonists in PAH-CTD Survival (%) 100 90 80 70 60 50 0 Bosentan, Girgis et al. 2005 Bosentan, Denton et al. 2006 Bosentan, Williams et al. 2006 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks Olschewski H, et al. ATS 2006. San Diego. Data on file, Encysive Pharmaceuticals Inc., Houston, TX Girgis RE, et al. J Heart Lung Transplant. 2005;24:1626-1631. Denton CP, et al. Ann Rheum Dis. 2006;65:1336-1340. Williams MH, et al. Heart. 2006;92:926-932. Sitaxentan (n=42) Bosentan (n=25) 98% 95% 87% 86% 81% 80% Ambrisentan combined 2.5 & 5 mg
100 Long-Term Survival by etiology in the pivotal trials of bosentan 96% 89% Event Free (%) 80 60 40 20 IPAH PAH-CTD 86% 0 0.0 0.5 1.0 1.5 2.0 Years 73% PH-CTD is more refractory to therapy compared to the ipah Kaplan-Meier estimate (95% CI) McLaughlin, et al. Eur Respir J 2005; 25:244-9 Denton et al. Ann Rheum Dis 2006.65;1336-1340
Long-Term Survival in AIRES-E cohort 100 Event Free (%) 80 60 40 20 IPAH PAH-CTD 1 Year 94% (90% to 97%) 91% (82% to 95%) 2 Year 89% (83% to 93%) 87% (77% to 92%) 0 0.0 0.5 1.0 1.5 2.0 Years Kaplan-Meier estimate (95% CI) At Risk n=178 n=161 n=151 n=145 n=122 At Risk n=94 n=81 n=71 n=69 n=57 Ambrisentan improved survival in PH-CTD patients to a similar extend as in ipah patients Pulido T et al. American Thoracic Society Annual Meeting 2009 [Abstract]
McLaughlin & McGoon Circulation 2006, 114:1417-1431
McLaughlin & McGoon Circulation 2006, 114:1417-1431
Evgenov et al. Am J Respir Crit Care Med 2007 176:1138
Grimminger et al Eur Resp J 2009 33:785-792
Grimminger et al Eur Resp J 2009 33:785-792
AIR Study: Inclusion Criteria PPH (IPAH/ FPAH) and Selected forms of PAH and CTEPH PH associated with collagen vascular disease PH associated with appetite suppressant use Non-operable operable chronic thromboembolic PH (CTEPH) NYHA class III or IV 6-min walk 50-500 500 m Olschewski H, etc al. N Engl J Med 2002;347(5):322-9
Πρώτες σκέψεις για Αντικατάσταση των διπλών τυφλών τυχαιοποιημένων μελετών (drug vs placebo) με: Longer inferiority-superiority studies comparing compounds of the same group (e.g. ERAs), instead of placebo.
ERJ & EHJ 2009
ERJ & EHJ 2009
ERJ & EHJ 2009
ERJ & EHJ 2009
αλγόριθμος McLaughlin & McGoon Circulation 2006, 114:1417-1431