Title: Bosentan for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and post-pulmonary endarterectomy pulmonary hypertension
1Bosentan 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
2BENEFIT 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
3Venice 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.
4Chronic thromboembolic pulmonary hypertension
(CTEPH)
Organised thrombotic material in pulmonary
arteries
5Pulmonary 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
6Rationale 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
7BENEFiT 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
8BENEFiT 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
9BENEFiT 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
10BENEFiT 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
11Overall 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
12BENEFiT 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)
13Bosentan 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
14Change 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
15Borg 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
16Similar 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)
17Conclusions
- 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