Presentation on theme: "Bosentan for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and post- pulmonary endarterectomy pulmonary hypertension A pre-defined subgroup."— Presentation transcript:
Bosentan for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and post- pulmonary endarterectomy pulmonary hypertension A pre-defined subgroup analysis of the randomised, placebo controlled trial: BENEFiT Lang I, Ghofrani A, Hoeper MM, Mayer E, Pepke-Zaba J, Rubin LJ, Jaïs X, Jansa P, D’Armini AM, Simonneau G
BENEFIT investigators Australia: A Keogh, K McNeil, T Williams, E Gabbay Austria: I Lang Belgium: M Delcroix, R Naeije Canada: J Granton, S Provencher, S Mehta, F Rubens, R Levy Czech Republic: P Jansa France: X Jaïs, V Cottin Germany: M Hoeper, D Prüfer, A Ghofrani Italy: N Galiè, AM D'Armini, M Confanolieri, C Albera Netherlands: A Boonstra, RJ Snijder, P Bresser Poland: A Torbicki Spain: J Barbera UK: J Pepke-Zaba, A Peacock USA: H Kim, V Tapson, R Frantz
‘Venice’ clinical classification of pulmonary hypertension (PH) 5.Miscellaneous Sarcoidosis 1.PAH Idiopathic PAH (IPAH) Familial PAH Associated PAH (APAH) Connective tissue disease Congenital systemic-to- pulmonary shunts Portal hypertension HIV infection Drugs and toxins Other Associated with significant venous or capillary involvement Persistent pulmonary hypertension of the newborn 2.PH associated with left heart disease 3.PH associated with respiratory disease COPD Interstitial lung diseases 4.PH due to chronic thrombotic and/or embolic disease CTEPH Adapted from Simonneau G, et al. J Am Coll Cardiol 2004; 43:5S-12S.
Chronic thromboembolic pulmonary hypertension (CTEPH) Organised thrombotic material in pulmonary arteries
Operable Inoperable Pulmonary endarterectomy (PEA) is the treatment of choice for CTEPH Surgically accessible thrombi Acceptable operative risk Small vessel disease Unacceptable operative risk Mismatch between haemodynamics and extent of occlusions Recurrent PH
Rationale for the use of bosentan, a dual endothelin receptor antagonist Up-regulation of endothelin receptors distal to the ligation in pulmonary arteries in animal models of CTEPH 1 Increased expression of ET B receptors on vascular smooth muscle cells 2 Increased systemic production of endothelin 2 Positive findings from open-label studies 3,4 1 Kim et al. Exp Lung Res 2000; 2 Bauer et al. Circulation 2002; 3 Hoeper et al. Chest 2005; 4 Hughes et al. Eur Respir J 2006
BENEFiT: study objectives To demonstrate the efficacy of bosentan in patients with inoperable CTEPH or persistent / recurrent PH post-PEA To evaluate the safety and tolerability of bosentan in this patient population
BENEFiT: endpoints Independent co-primary endpoints : PVR at rest at week 16 expressed as a percent of the baseline value (type-1 error = 0.01) and/or Change from baseline to week 16 in 6MWD (type-1 error = 0.04) Other endpoints included change from baseline to week 16 in: Other haemodynamic parameters Borg dyspnoea index Plasma levels of the biomarker NT-pro-BNP
BENEFiT: summary of key results Clinically relevant improvement in cardiac haemodynamics: PVR decreased (p < 0.0001) Cardiac index increased NT-pro-BNP decreased No effect on exercise capacity (p = 0.5449) Improvement in Borg dyspnoea index Safety and tolerability: Consistent with previous controlled trials with bosentan in PAH
Overall population: bosentan significantly reduced PVR 60% 70% 80% 90% 100% 110% Treatment effect: 22.0% (95% CL: 29.6, 13.5) p<0.0001; Wilcoxon test Placebo n = 75 Bosentan n = 75 % of baseline PVR at week 16 (geometric means)
BENEFiT subgroup analysis The purpose of this analysis was to compare the treatment effects between the subgroups of patients who had inoperable CTEPH (n=113) vs. those who had previously undergone PEA (n=44)
Similar effect of bosentan observed between treatment groups for other endpoints Endpoint Persistent/Recurrent PH Inoperable CTEPH Cardiac index, L/min/m 2 0.25 (–0.08, 0.57) 0.31 (0.12, 0.50) mPAP, mmHg –6.4 (–11.2, –1.7) –1.0 (–3.9, 1.9) NT-pro-BNP, ng/L –526 (–1054, 2) –654 (–1170, –138) Mean treatment effect (95% CL)
Conclusions Similar treatment effect observed in both patients with inoperable CTEPH and those with persistent/recurrent PH after PEA In both groups, bosentan treatment resulted in: Improved haemodynamics Decreased PVR Positive treatment effect observed for cardiac index, mPAP and NT-pro-BNP
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