Clinical experience with bosentan and sitaxentan in
connective tissue disease-associated pulmonary
Christopher J. Valerio1, Clive E. Handler1, Peter Kabunga1, Colette J. Smith2,
Christopher P. Denton3and John G. Coghlan1
Objectives. To report outcomes in patients with CTD-pulmonary arterial hypertension (CTD-PAH) in an
observational cohort treated with bosentan or sitaxentan and determine whether differences would justify
a randomized, controlled multicentre study in this subpopulation.
Methods. Patients with CTD-PAH, diagnosed by right-heart catheter studies, were assigned to either
bosentan or sitaxentan based on physician choice. All patients were followed up with repeat assessments
and data were collected for the local registry database.
Results. The bosentan- (n=32) and sitaxentan- (n=22) treated groups had comparable haemodynamic
and prognostic measures at baseline. Repeat haemodynamic assessments showed reductions in pulmon-
ary vascular resistance with bosentan (?99dynes/s/cm5, P<0.01) and sitaxentan (?92dynes/s/cm5,
P<0.05). The 6-min walk distance improved at 3 months with sitaxentan (25m, P<0.05). N-terminal
pro-B-type natriuretic peptide levels fell in the bosentan cohort at 6 months (?70 pmol/l, P<0.05) and
1 year (?83pmol/l, P<0.01). Haemoglobin fell with both drugs (at 3 months ?0.5g/dl bosentan, P<0.05
and ?0.9g/dl sitaxentan, P<0.005). Calculations of the difference in treatment effect did not demonstrate
superiority of either therapy. The 1-year estimated clinical worsening event rates were high: 41% sitax-
entan, 62% bosentan (P=0.142), with serious event rates of 27 and 14% (P=0.263, log-rank test), re-
spectively. Six patients discontinued bosentan because of transaminase elevation within the first year.
Estimated 1-year survival was similar in both groups and 96% overall.
Conclusion. Both sitaxentan and bosentan appear effective in CTD-PAH, but the apparent additional
benefit of sitaxentan reported from the open-label Sitaxentan To Relieve ImpaireD Exercise-2X study
was not confirmed in this observational cohort. Although survival has improved, event rates continue to
be substantial and CTD-PAH remains a therapeutic challenge.
Key words: Pulmonary hypertension, Pulmonary circulation, Endothelin receptors, Endothelin-1, Bosentan,
Sitaxentan, Systemic sclerosis, Connective tissue disease, Drugs.
Pulmonary arterial hypertension (PAH) is an important
and potentially fatal complication of CTD, notably SSc
(scleroderma) . Diagnosis depends upon right-heart
catheterization, and despite efforts to screen patients
with CTD, PAH is frequently diagnosed late due to the
limitations of non-invasive screening tools. Prognosis is
generally worse in CTD-PAH than other forms of PAH.
The published UK registry data report a 22% 1-year
mortality rate in CTD-PAH from the time of diagnosis .
The availability of licensed oral therapies for PAH has
been a major medical advance. The first PAH-specific oral
therapy was bosentan, a non-selective endothelin recep-
tor antagonist (ETRA). ET-1 is a potent endogenous vaso-
constrictor and mitogen that has been implicated in the
1The National Pulmonary Hypertension Unit,2Department of Primary
Care and Population Sciences, Royal Free and University College
Medical School and3Centre for Rheumatology, Royal Free Hospital,
Correspondence to: Christopher J. Valerio, The National Pulmonary
Hypertension Unit, Royal Free Hospital, Pond Street,
London NW3 2QG, UK. E-mail: firstname.lastname@example.org
Submitted 2 February 2010; revised version accepted 22 June 2010.
! The Author 2010. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: email@example.com
Advance Access publication 29 July 2010
SCIENCE by guest on December 28, 2015
The authors thank Clare Das, Sally Reddecliffe and Adele
Gallimore for their assistance.
Disclosure statement: P.K. has received an educational
grant from Encysive Pharmaceuticals. C.J.V. has recieved
educational grants from Actelion and Pfizer. C.P.D. has
received lecture fees and acted as a consultant to
Actelion Pharmaceuticals, Pfizer, GlaxoSmithKline and
United Therapeutics. C.E.H. has received educational
support from Actelion and Pfizer. J.G.C. has received
consulting feesand lecture
GlaxoSmithKline, Gilead and Pfizer. His department has
benefited from research grants from Actelion and Pfizer.
The other author has declared no conflicts of interest.
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