Bosentan for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and post-pulmonary endarterectomy pulmonary hypertension - PowerPoint PPT Presentation

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Bosentan for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and post-pulmonary endarterectomy pulmonary hypertension

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PAH is divided into different aetiologies, one of these is PAH associated with CHD (PAH-CHD). This training module focuses on this sub-classification of PAH. – PowerPoint PPT presentation

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Title: Bosentan for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and post-pulmonary endarterectomy pulmonary hypertension


1
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, DArmini
AM, Simonneau G
2
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

3
Venice clinical classification of pulmonary
hypertension (PH)
  • 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
  • 5. Miscellaneous
  • Sarcoidosis

Adapted from Simonneau G, et al. J Am Coll
Cardiol 2004 435S-12S.
4
Chronic thromboembolic pulmonary hypertension
(CTEPH)
Organised thrombotic material in pulmonary
arteries
5
Pulmonary endarterectomy (PEA) is the treatment
of choice for CTEPH
Inoperable
Operable
  • Surgically accessible thrombi
  • Acceptable operative risk
  • Small vessel disease
  • Unacceptable operative risk
  • Mismatch between haemodynamics and extent of
    occlusions
  • Recurrent PH

6
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 CTEPH1
  • Increased expression of ETB receptors on vascular
    smooth muscle cells2
  • Increased systemic production of endothelin2
  • Positive findings from open-label studies3,4

1Kim et al. Exp Lung Res 2000 2Bauer et al.
Circulation 2002 3Hoeper et al. Chest
20054Hughes et al. Eur Respir J 2006
7
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

8
BENEFiT study design
  • Prospective, double-blind, randomised,
    placebo-controlled, multicentre study

Bosentan 125 mg bid
Bosentan 62.5 mg bid
Screening
Placebo
Placebo
3 weeks
4 weeks
12 weeks
Baseline randomisation
16 weeks
9
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

10
BENEFiT summary of key results
  • Clinically relevant improvement in cardiac
    haemodynamics
  • PVR decreased (p lt 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

11
Overall population bosentan significantly
reduced PVR
110
100
Bosentan n 75
Placebo n 75
90
of baseline PVR at week 16(geometric means)
80
70
Treatment effect ?22.0(95 CL ?29.6,
?13.5) plt0.0001 Wilcoxon test
60
12
BENEFiT subgroup analysis
  • The purpose of this analysis was to compare the
    treatment effects between the subgroups of
    patients who had inoperable CTEPH (n113) vs.
    those who had previously undergone PEA (n44)

13
Bosentan reduced PVR
Treatment effect ?32.5(95 CL ?44.4, ?18.1)
Treatment effect ?17.5(95 CL ?27.0, ? 6.7)
110
100
Placebo
90
Bosentan
of baseline PVR at week 16(geometric means)
80
70
60
n 22
n 20
n 53
n 55
Persistent/Recurrent PH
Inoperable CTEPH
14
Change in 6MWD
Treatment effect ?11.5 m(95 CL ?39.6, 16.6)
Treatment effect 8.8 m (95 CL ?22.5, 40.0)
Placebo
Change in 6MWD (m) at week 16
Bosentan
n 55
n 22
n 21
n 57
Persistent/Recurrent PH
Inoperable CTEPH
15
Borg dyspnoea index improved
Treatment effect ?0.8 (95 CL ?1.6, ?0.1)
Placebo
Treatment effect 0.1(95 CL ?0.9, 1.2)
0.6
Bosentan
0.4
0.2
0
Change at week 16
?0.2
?0.4
?0.6
?0.8
n 22
n 21
n 57
n 55
Inoperable CTEPH
Persistent/Recurrent PH
16
Similar effect of bosentan observed between
treatment groups for other endpoints
Mean treatment effect (95 CL)
Endpoint Persistent/Recurrent PH Inoperable CTEPH
Cardiac index, L/min/m2 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)
17
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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