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Management of Pulmonary Arterial Hypertension with Sitaxentan Sodium

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Pulmonary arterial hypertension (PAH) is a chronic and progressive disease with a poor prognosis if left untreated. Pathophysiological alterations in this disease lead to vasoconstriction, endothelial and smooth muscle cell proliferation, and in situ thrombosis. Endothelin-1 (one of the most potent vasconstrictors known), has been shown to be increased in PAH, contributing, in part at least, to these abnormalities. Endothelin acts through the binding of two receptors, ETA and ETB. Sitaxentan is a selective ETA endothelin receptor antagonist that has been demonstrated, in several clinical trials, to improve exercise capacity, functional class and hemodynamics. Sitaxentan has a good safety profile, is well tolerated and has a low incidence of liver toxicity.
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Clinical Medicine Insights: Therapeutics
REVIEW
Clinical Medicine Insights: Therapeutics 2011:3 31
Management of Pulmonary Arterial Hypertension
with Sitaxentan Sodium
Tomas Pulido, Carla Murillo, Paulina Ramírez-Neria, Viridiana Hurtado, Paola de la Garza,
Sandra Astorga, María Teresa Miranda and Julio Sandoval
Cardiopulmonary Department, National Heart Institute, Mexico City, Mexico.
Corresponding author email: tpulido@prodigy.net.mx
Abstract: Pulmonary arterial hypertension (PAH) is a chronic and progressive disease with a poor prognosis if left untreated.
Pathophysiological alterations in this disease lead to vasoconstriction, endothelial and smooth muscle cell proliferation, and in situ
thrombosis. Endothelin-1 (one of the most potent vasconstrictors known), has been shown to be increased in PAH, contributing, in
part at least, to these abnormalities. Endothelin acts through the binding of two receptors, ETA and ETB. Sitaxentan is a selective ETA
endothelin receptor antagonist that has been demonstrated, in several clinical trials, to improve exercise capacity, functional class and
hemodynamics. Sitaxentan has a good safety prole, is well tolerated and has a low incidence of liver toxicity.
Keywords: pulmonary arterial hypertension, endothelin receptor antagonists, sitaxentan
Pulido et al
32 Clinical Medicine Insights: Therapeutics 2011:3
Introduction
Pulmonary arterial hypertension (PAH) is a chronic
and devastating condition characterized by a pro-
gressive increase in pulmonary vascular resistance
(PVR) that ultimately produces right heart failure
and death.1,2 This increment in PVR is produced by
endothelial dysfunction, abnormal proliferation of
the smooth muscle cell and in situ thrombosis.1,2 The
term PAH includes a group of diseases that share
some pathophysiological mechanisms that make them
suitable to be treated with the same drugs.3,4 These
diseases are: idiopathic PAH; hereditary PAH; PAH
induced by drugs or toxins; and PAH associated with
systemic-to-pulmonary shunts, collagen vascular dis-
ease, portal hypertension, human immunodeciency
virus, schistosomiasis and chronic hemolytic anemia
(group 1 of the Dana Point pulmonary hypertension
classication).3,4 PAH is still an incurable disease;
however, with the rapid advance in the knowledge of
the main altered pathways responsible for its devel-
opment and progression (endothelin, nitric oxide and
prostacyclin pathways),2 new compounds to treat this
disease have been made available in recent years.
Sitaxentan sodium, one of these new drugs, is a highly
selective endothelin A receptor antagonist (ETA) that
has proven effective for the treatment of patients with
PAH, improving exercise capacity, World Health
Organization functional class (WHO FC; Table 1)
and hemodynamics. In this paper, we will discuss the
pharmacology, evidence for and indications of the use
of sitaxentan in the treatment of PAH.5
The Endothelin System
Endothelin (ET) was rst isolated from porcine
endothelial cells in 1988.6 Since then, the ET system
has been found to be involved in multiple physiologic
functions related to the nervous, renal, cardiovascular,
respiratory, gastrointestinal and endocrine systems.7–11
The endothelins are a family of isopeptides named
ET-1, ET-2 and ET-3, where ET-1 is the most abundant
and clinically important. ET is synthesized from pre-
proendothelin, a 212-amino acid peptide, and subse-
quently cleaved to yield a 38-amino acid propeptide,
big ET. Big ET is converted to the 21-amino acid pep-
tide ET by the endothelin-converting enzyme.12–14 ET
is produced mainly in the vascular endothelial cells
and, to a lesser extent, in pulmonary smooth muscle
cells and broblasts.12 A variety of factors can stimu-
late the production of ET, including hypoxia, isch-
emia, angiotensin II, vasopressin, catecholamines,
cytokines, growth factors and thrombin.15 ET is one
of the most potent vasoconstrictors known, but also
has proliferative effects and has been implicated in
many disease states including carcinogenesis, bron-
choconstriction, brosis, heart failure and pulmo-
nary hypertension.7 A great amount of evidence has
shown the important role that the ET system plays in
the pathophysiology of PAH: patients with PAH have
increased levels of ET in small pulmonary arteries,16
and increased levels of ET correlate with the sever-
ity of disease in adults with idiopathic primary PAH.
A strong correlation was found between increased
plasma concentrations of ET and increased pulmonary
vascular resistance, as well as increased mean pulmo-
nary arterial pressure, in a small cohort of subjects
with primary pulmonary hypertension. In addition, a
decreased six-minute walk distance (6MWD) corre-
lated with ET levels.17 Once activated, ET has a dual
paracrine and autocrine role:15 it binds to two receptors
known as endothelin receptor A (ETA) and endothe-
lin receptor B (ETB). ETA and ETB are expressed on
smooth muscle cells and cardiac myocites; however,
only ETB receptors are expressed in the endothelial
cells.13 Activation of both ETA and ETB receptors in
the pulmonary smooth muscle cell produces vaso-
constriction and proliferation, while the activation
of ETB receptors in the endothelial cell mediates ET
Table 1. WHO functional classication for pulmonary
arterial hypertension.
Class I Symptoms do not limit physical
activity. Ordinary physical activity
does not cause undue discomfort.
Class II Slight limitation of physical activity.
The patient is comfortable at rest, yet
experiences symptoms with ordinary
physical activity.
Class III Marked limitation of physical activity.
The patient is comfortable at rest, yet
experiences symptoms with minimal
physical activity.
Class IV Inability to carry out any physical
activity. The patient may experience
symptoms even at rest. Discomfort
is increased by any physical activity.
These patients manifest signs of
right heart failure.
Abbreviation: WHO, World Health Organization.
Sitaxentan for pulmonary arterial hypertension
Clinical Medicine Insights: Therapeutics 2011:3 33
clearance, and regulates vascular tone through the
production of nitric oxide and prostacyclin.13,15 Two
types of endothelin receptor antagonists (ERAs) have
been developed for the treatment of PAH, one nonse-
lective ERA (bosentan) and two selective ETA receptor
antagonists (sitaxentan and ambrisentan).13 The ratio-
nale for using an ETA-selective antagonist is based
on the evidence that the ETB receptor is involved in
endothelin clearance from the blood, so blocking this
receptor could increase circulating ET. Also, block-
ade of endothelial luminal side ETB receptor might
theoretically decrease nitric oxide and prostacyclin
production, favoring vasoconstriction.13,15,18
Sitaxentan is an orally active competitive ERA that
has more selectivity for the ETA receptor.5,19 In vitro
studies have shown that sitaxentan binds almost com-
pletely to the ETA receptor, and its ETA:ETB afnity
ratio is about 6000:1 (compared to bosentan (40:1) or
ambrisentan (77:1)).15 Sitaxentan decreases mean pul-
monary arterial pressure (mPAP), pulmonary vascu-
lar resistance (PVR) and right atrial pressure (RAP),
with no effect on heart rate, mean arterial pressure,
capillary wedge pressure, cardiac index or systemic
vascular resistance during intravenous infusion.5 In
addition, sitaxentan reversed and prevented vascular
remodeling in animal studies.5,15 Sitaxentan is orally
active with a bioavailability of 89% and reaches max-
imum plasma concentrations 1–4 hours after admin-
istration.5 It is highly bound to plasma proteins and
metabolizes in the liver through cytochrome P450
(CYP)2C9 and CYP3A4 isoenzymes. Sitaxentan
is a weak inhibitor of CYP2C19 and CYP3A4, and
is a moderate-to-strong inhibitor of CYP2C9. The
interaction with CYP2C9 causes inhibition of war-
farin metabolism, a clinically frequent interaction,
considering the need for anticoagulation in patients
with PAH. Therefore, dosing adjustments may be
necessary. It is recommended to decrease the warfa-
rin dose by 80%, with subsequent dose tritation as
needed.5 Approximately 50%–60% of a single sitax-
entan dose is excreted as metabolites in the urine.5,15
Clinical Evidence for the Use
of Sitaxentan in PAH
Barst et al20 published the result of an open-label pilot
study to evaluate the safety and efcacy of the oral
administration of sitaxentan sodium in patients with
PAH (Study 211). It enrolled 14 adults and 6 children
with idiopathic PAH and PAH associated with
systemic-to-pulmonary shunts or collagen vascular
disease, WHO FC II to IV. The sitaxentan dose range
was established according to body weight between
100 mg and 500 mg twice a day (6 mg/kg BID) for
12 weeks. 6MWD tests and right heart catheteriza-
tion were performed at baseline and after 12 weeks.
All patients showed a signicant improvement in
exercise capacity (37 ± 60 m; P = 0.01) and hemo-
dynamics (a decrease in mPAP and PVRi). Serious
adverse events included two cases of acute hepatitis
(fatal in one patient) that developed in the extension
phase of the study; after these events, all patients were
discontinued from the extension study without fur-
ther complications. The cases of acute hepatitis were
ultimately attributed to the high dose that patients
received and to the non-linear pharmacokinetics
observed in the study.
The Sitaxentan To Relieve ImpaireD Exercise
(STRIDE) program was developed to evaluate the
safety and efcacy of sitaxentan in patients with
PAH and included three randomized placebo con-
trolled trials (STRIDE-1, STRIDE-2 and STRIDE-4),
one non-controlled study (STRIDE-6) and three
long-term studies (STRIDE-1X, STRIDE-2X and
STRIDE-3).18
STRIDE-121 was a randomized, double-blind,
placebo-controlled study that enrolled 178 patients
with PAH at WHO FC II to IV. The study was car-
ried out in 23 centers in USA and Canada to evalu-
ate the safety and efcacy of two different doses of
sitaxentan (100 mg and 300 mg once a day (OD)) for
12 weeks. The primary end-point was change in peak
oxygen consumption (VO2) at Week 12 evaluated via
cardiopulmonary exercise testing (CPET). Secondary
end-points included 6MWD, functional class, VO2 at
anaerobic threshold, VE per carbon dioxide produc-
tion at anaerobic threshold, hemodynamics, quality of
life and time to clinical worsening. Only the 300 mg
group increased peak VO2 as compared to the placebo
group (+3.1%; P , 0.01). The other endpoints derived
from the cardiopulmonary exercise testing were not
met. However, both the 100 mg and 300 mg dose sig-
nicantly increased 6MWD test results (Fig. 1), and
also improved functional class and cardiac index, and
decreased indexed PVR (PVRi). The incidence of
increased liver enzymes was greater in the 300 mg
group than the 100 mg group (10% vs. 3%), and the
Pulido et al
34 Clinical Medicine Insights: Therapeutics 2011:3
incidence of serious adverse events was infrequent,
with no signicant differences among treatment groups
(placebo 15%, 100 mg 5%, 300 mg 16%). There was
one death in the 300 mg group that was ascribed to
aggravation of PAH and not linked to the STRIDE-
1study. While the overall results of this study were
promising, the primary end-point was not met and this
may have obscured the impact of the efcacy results.5
The discrepancy between the results of the CPET and
the 6MWD test was unexpected and raised concerns
about the reliability of CPET and 6MWD as primary
end-points.5 Oudiz et al22 showed that while the intra-
center correlation of change in CPET and 6MWD was
reliable, the inter-center results were not comparable.
This was partly due to the lack of CPET and 6MWD
validation protocols. Also, the population included in
STRIDE-1 was, at that time, somehow different from
previous multicenter controlled trials of PAH. Func-
tional class II was included and there were no “upper
limit” exclusion criteria for the 6MWD at baseline. It
has recently been showed that the 6MWD is limited
by a point where performance is so good or so bad that
further clinically and/or statistically signicant dete-
rioration or improvement is hard to detect (a “oor
or ceiling effect”).5,23 Langleben et al24 performed a
post hoc analysis in a subset of patients included in
STRIDE-1 that met the traditional criteria for PAH
studies (functional class III/IV and 6MWD , 450 m)
comparing exercise capacity and hemodynamics at
baseline and after 12 weeks of treatment, and found a
statistically signicant treatment effect in the treated
group compared to the placebo group in 6MWD
(39 ± 10.65 vs. 26 ± 13.39 m); right atrial pressure
(1.2 ± 0.5 vs. 2.1 ± 0.8 mmHg); mean pulmonary
arterial pressure (4.7 ± 1.5 vs. 0.4 ± 0.5 mmHg);
cardiac index (0.38 ± 0.06 vs. 0.09 ± 0.09 L/min/m2)
and pulmonary vascular resistance (274 ± 47 vs.
85 ± 60 dyne/s/cm5). He found also an improvement
in functional class (P , 0.0005).
STRIDE-2,25 a 18-week multicenter random-
ized placebo-controlled trial, compared two doses
of sitaxentan (50 mg and 100 mg, OD) versus a pla-
cebo. Also, an open-label bosentan arm (the only oral
therapy approved for the treatment of PAH at that
time) was included. Two hundred and forty-seven
PAH patients, with idiopathic PAH or PAH associated
with connective tissue disease or congenital heart
disease, were enrolled. The primary end-point was
a change in 6MWD from the baseline to Week 18.
Secondary end-points included change in WHO FC,
time to clinical worsening and change in Borg dys-
pnea score. Patients treated with 100 mg sitaxentan
had an increased in 6MWD compared to the placebo
group (treatment effect of 31.4 m; P = 0.03) (Fig. 2)
and improved WHO FC (P = 0.04). The incidence of
elevated hepatic transaminases was 6% for the pla-
cebo, 5% for 50 mg sitaxentan, 3% for 100 mg sitax-
entan and 11% for bosentan. Sitaxentan performed in
a similar manner to bosentan, which was included in
the study to allow a qualitative comparison in a simi-
larly randomized population.
*P < 0.01; Prom +/− DE
Meters
*
*
−20
−10
0
10
20
30
Week 6 Week 12
Placebo (n = 60)
100 mg (n = 59)
300 mg (n = 59)
Figure 1. STRIDE-1. Mean change in 6MWD from baseline to Week 6
and Week 12 in placebo and sitaxentan groups; P , 0.01 for the
comparison between each sitaxentan dose and the placebo.
Data from Barst et al.21
*P < 0.01; Prom +/− DE
Meters
**
−20
−10
0
10
20
30
Placebo (n = 62)
STX 50 mg (n = 62)
STX 100 mg (n = 61)
Bosentan (n = 60)
Figure 2. STRIDE-2. Mean change in 6MWD from baseline to Week 18 in
the placebo, 50 mg sitaxentan, 100 mg sitaxentan and bosentan groups.
There was a signicant improvement in 6MWD in the 100 mg sitaxentan
group and the bosentan group compared with the placebo group.
Modied from Barst RJ, et al.25
Sitaxentan for pulmonary arterial hypertension
Clinical Medicine Insights: Therapeutics 2011:3 35
STRIDE-4 (unpublished) was a multicenter, placebo-
controlled study that was conducted in Latin America and
Europe, its design was the same as that of STRIDE-2
except for the open-label bosentan arm. Ninety patients
were enrolled. Sitaxsentan at a dosage of 100 mg
improved functional class in PAH patients, who were
mostly WHO FC II at baseline. No patient receiving
100 mg sitaxsentan experienced clinical worsening. The
primary end-point (imrovement in 6MWD) was not
met, probably because this study was not able to account
adequately for the large placebo effect observed and the
high proportion of funcitonal class II patients included
(61%). The safety prole was similar to other STRIDE
studies.
STRIDE-6,26 a double-blind exploratory study,
was completed in 48 PAH patients discontinuing
bosentan because of safety issues or lack of efcacy.
These patients were randomized to receive sitaxen-
tan at doses of 50 mg or 100 mg OD for 12 weeks.
Thirty-three percent of patients receiving the 100 mg
dose and 10% of patients in the 50 mg group improved
their 6MWD by more than 15%, while 20% and 15%
of these patients had a 15% decrease in 6MWD in
the 100 mg and 50 mg groups, respectively. Of the
12 patients discontinuing bosentan because of hepa-
totoxicity, only one had elevated liver enzymes at
13 weeks after sitaxentan therapy. From these data, it
appears that sitaxentan may represent a safe and efca-
cious alternative in patients discontinuing bosentan.
Only the results from two extension studies
(STRIDE-1X and STRIDE-2X)27,28 to evaluate the
long-term efcacy and safety of sitaxentan have been
reported. In STRIDE-1X,27 11 patients that completed
the placebo-controlled 12-week study were allowed to
continue in a extension phase receiving either 100 mg
or 300 mg sitaxentan OD. 6MWD, functional class
and hemodynamics were assessed before sitaxentan
was initiated and after one year of drug therapy. After
one year of sitaxentan use, 6MWD increased by 50 m
(P = 0.04) and functional class improved (before ther-
apy, nine patients were in WHO FC III and one patient
was in WHO FC II; at follow-up, all patients were in
FC II (P , 0.01). Although the mPAP did not change,
cardiac index and PVR improved signicantly. There
were no serious adverse events and, notably, no eleva-
tions of hepatic enzymes. STRIDE-2X28 was an inter-
national open-label study that evaluated all-cause
mortality, time to discontinuation (all causes) from
monotherapy, time to discontinuation due to adverse
events, time to elevation in hepatic enzymes, time
to discontinuation due to elevated hepatic enzymes
and time to rst clinical worsening in the group of
patients receiving 100 mg sitaxentan (145 patients)
and bosentan (84 patients) at one year. Patients that
were initially randomized (STRIDE-2) to the 50 mg
group continued receiving 100 mg sitaxentan during
the open-label phase but were excluded from the nal
analysis. At one year, patients treated with 100 mg
sitaxentan OD had 96% overall survival and a 34%
risk for clinical worsening. There was a 6% risk of
elevated transaminases (3x upper level of normal
(ULN)) and a 15% risk of discontinuation due to
adverse events. Patients receiving bosentan had 88%
overall survival and a 40% risk of clinical worsening
at one year. In addition, there was a 14% greater risk
for elevated hepatic enzymes (3x ULN) and 30%
discontinuation due to adverse events. Interpretation
of the results of STRIDE-2X must be made with cau-
tion, as the authors point out, because of the lack of
blinding of the sitaxentan and bosentan groups. Fur-
thermore, the one-year survival estimates for sitax-
entan (96%) and bosentan (88%) reect the initiation
with ERA monotherapy for the treatment of PAH but
are not necessarily attributable to the ERA therapy
alone.28 These two long-term studies support the nd-
ings of prior studies evaluating sitaxentan with respect
to safety and efcacy, and they also provide support
for durability of efcacy.
Our group presented the results of a three-year
follow-up of 36 patients with PAH, functional class II
and III, receiving 100 mg sitaxentan OD. Cumulative
0
20
40
60
80
100
012345
Time (years)
% Survival
Figure 3. Survival estimates at ve years from sitaxentan initiation (n = 55).
From Pulido et al.29
Pulido et al
36 Clinical Medicine Insights: Therapeutics 2011:3
survival at one, two and three years was 96%, 79%
and 75% respectively (Fig. 3). Five patients required
combination therapy (sildenal) because of clinical
deterioration.29
We can conclude that sitaxentan signicantly
improved functional class (STRIDE-1, STRIDE-2,
STRIDE-4), 6MWD (STRIDE-1 and STRIDE-2),
dyspnea score (STRIDE-1) and hemodynamics
(Study 211 and STRIDE-1). Improvements in time to
clinical worsening could only be demonstrated in a
post hoc analysis using the data from the three pivotal
studies.18
Safety
The most frequent adverse events with sitaxentan
treatment include headache, peripheral edema, nau-
sea and nasal congestion, which are well tolerated.
The most important adverse event, however, is the
increase in hepatic transaminases. This abnormality
appears to be a class effect of ERA therapy and has
also been reported with bosentan and, less frequently,
with ambrisentan.5 Abbott et al30 found an average
increase in transaminases of 4% after four different
clinical trials were analyzed. In these studies, sitax-
entan exposure ranged from 12 to 28 weeks. Longer
studies have shown a one-year risk of elevation of
hepatic transaminases (3x ULN) of less than 4%
(Kaplan–Meier analysis) at a dose of 100 mg OD,
which is lower than that reported with bosentan
(14%–15%).27,28
To our knowledge, ve patients have developed
acute hepatitis and liver failure while receiving
sitaxentan.20,31–33 The rst two cases (one of them fatal)
received sitaxentan at a dose of 300 mg OD, which is
much higher than the presently approved dosage of
100 mg.20 The second report31 was that of a 25-year-
old female with Eisenmenger’s syndrome, who had
been treated with bosentan for 6 months. This treat-
ment was stopped due to elevation of hepatic transam-
inases and when they returned to normal, sitaxentan
was initiated. After four months of sitaxentan ther-
apy, liver enzymes increased again and the ERA was
stopped, but the enzymes continued to increase and
the patient developed hyperbilirubinemia. She was
started on corticosteroids, and made a rapid and sus-
tained improvement. Subsequently, two other similar
cases were published. In these two patients, liver biop-
sies showed extensive hepatocellular damage with
eosinophil and lymphocyte inltration, which was
compatible with drug toxicity.32 Physicians should
be aware that severe hepatic toxicity may be seen in
patients receiving any of the current ERA therapies,
and that ERA may interact with other potentially
hepatotoxic medications. Monthly liver function tests
are mandatory and patients must be advised to con-
sult their prescribing physician urgently at the rst
signs and symptoms of hepatic toxicity, irrespective
of previous normal liver function tests, even within a
month earlier.34–36
As mentioned earlier, one of the most important
drug interactions of sitaxentan is with oral anticoagu-
lants. sitaxentan increases warfarin’s half-life, with
a consequent increase in international normalized
ratio (INR). A recent analysis of data from STRIDE-2
and STRIDE-2X showed similar rates of bleeding
events in PAH patients treated with either sitaxen-
tan or bosentan,5 but no difference in bleeding rate in
patients that were receiving oral anticoagulation and
those who were not.37 Pulido et al38 reported on the
follow-up of 50 PAH patients that received sitaxentan
and acenocoumarol (the most frequent oral antico-
agulant used in various centers in Europe and Latin
America). Following treatment, an INR 5 in at least
one INR determination was observed in 13 patients,
although none of these patients had a clinically sig-
nicant bleeding event. Two patients died of massive
hemoptysis, but these episodes were not attributed to a
drug interaction: both had Eisenmenger’s physiology
(which carries intrinsic bleeding abormalities39,40) and
INR was kept constant at ,2.0. These results suggest
that coadministration of sitaxentan and acenocouma-
rol is clinically manageable and well tolerated.
Teratogenicity appears to be also a class effect
of ERAs. In animal studies, disruption of endothe-
lin receptor A or B isoforms during embryogenesis
causes severe developmental abnormalities associ-
ated with an increment in perinatal morbidity.14,41
Experimental studies have not shown a carcinogenic
effect in animals treated with sitaxentan.41 Pregnancy
should be excluded before initiation of treatment and
prevented thereafter by use at least two methods of
contraception.15
In summary, sitaxentan showed a similar safety
prole and tolerability to other ERAs, with a smaller
increase in liver transaminases (average of 2%–4% for
the 100 mg dose) and a manageable effect on INR.
Sitaxentan for pulmonary arterial hypertension
Clinical Medicine Insights: Therapeutics 2011:3 37
Conclusions
PAH is still an incurable disease. However, new drugs
have shown an improvement in patient survival.
Sitaxentan is a selective ETA receptor antagonist that
produces pulmonary vasodilatation, and inhibits vas-
cular growth, remodeling and brosis. It has been
shown to improve exercise capacity, functional class
and hemodynamic parameters with a good safety pro-
le. Also, long-term data at one and two years sug-
gests that this improvement is maintained making it
a good option for the treatment of patients with PAH.
Future studies with sitaxsentan will focus on patients
with PAH associated with collagen vascular disease
and will evaluate combined sitaxentan and sildena-
l therapy, with the intention to make it available to
underserved communities suffering from PAH.
Disclosures
This manuscript has been read and approved by all
authors. This paper is unique and not under consid-
eration by any other publication and has not been
published elsewhere. Dr. Pulido was a principal inves-
tigator of the STRIDE-4 study, is a consultant for
Pzer and has received research grants from Encysive
(now owned by Pzer) and Pzer. Dr. Sandoval was
a clinical advisor for Encysive (now part of Pzer).
The rest of the authors report no conicts of interest.
The authors conrm that they have permission to
reproduce any copyrighted material.
List of Abbreviations
6MWD, six-minute walk distance test; BID, twice a day;
CPET, cardiopulmonary exercise testing; ERA, endothein
receptor antagonists; ET, endothelin; ETA, endothelin A
receptor; ETB, endothelin B receptor; INR, international
normalized ratio; mPAP, mean pulmonary arterial pres-
sure; OD, once a day; PAH, pulmonary arterial hyper-
tension; PVR, pulmonary vascular resistance; PVRi,
pulmonary vascular resistance, indexed; RAP, right
atrial pressure; STRIDE, sitaxentan to relieve impaired
exercise; ULN, upper limit of normal; VE, minute ven-
tilation; VO2, oxygen consumption; WHO FC, World
Health Organization functional class classication.
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Article
Full-text available
To the Editors: We were interested to read the letter from Lavelle et al . 1, together with the accompanying editorial 2, regarding liver toxicity in patients receiving endothelin receptor antagonist therapy (ERA) for pulmonary arterial hypertension. Both of these articles highlight the potential for severe liver toxicity in patients receiving sitaxentan and stress the continued need for regular monitoring of liver function tests in all patients receiving ERAs. In fact, the details of the reported cases show that severe liver toxicity can occur …
Article
Full-text available
To the Editor: Sitaxentan sodium is an endothelin receptor antagonist (ERA) recently approved for the management of pulmonary arterial hypertension (PAH) 1. While hepatotoxicity is a recognised side-effect of treatment with the ERA bosentan, it is considered to be less common with sitaxentan 2–4. We recently admitted two patients with severe hepatotoxicity on sitaxentan to the Pulmonary Hypertension Unit at the Mater Misericordiae University Hospital (Dublin, Ireland). The first patient was a 47-yr-old male with PAH associated with congenital heart disease. He had a past history of ventricular septal defect closure at 12 yrs of age and was referred to our service with a history of gradual diminishing exercise capacity. His right heart catherisation demonstrated a pulmonary artery systolic pressure of 80 mmHg and a normal pulmonary capillary wedge pressure. He was commenced on sitaxentan 100 mg q.d. Initial liver function tests (LFTs) were normal, and the patient continued to undergo monthly LFT monitoring. At 3 months, he was experiencing an improvement in his symptoms and 6-min walking distance. However, 1 month later, he became generally unwell, with nausea, vomitting, anorexia and weight loss. He denied abdominal pain or pruritis. …
Article
Elevated blood pressure in the pulmonary vasculature, known as pulmonary arterial hypertension (PAH), stresses the right side of the heart and can increase the risk for functional disability and death. In advanced disease, several drugs can be employed, including calcium-channel blockers, phosphodiesterase-5 inhibitors, prostacyclin analogues, and endothelin (ET)-receptor antagonists. ET is an endogenous peptide vasoconstrictor that is present in excessive concentrations in patients with PAH. Sitaxsentan, an ET-receptor antagonist undergoing FDA review, is selective for the ET A receptors. By selectively antagonizing the ET A receptors, sitaxsentan causes pulmonary arterial vasodilation and allows normal functioning of the ET B receptor, thus reducing the effects of ET. Clinical trials have demonstrated that orally administered sitaxsentan improves both 6-minute walking distance and World Health Organization functional class in patients with RAH. Trials have also demonstrated that sitaxsentan is relatively safe, although cases of hepatotoxicity have been reported. Further studies are necessary to better demonstrate the adverse event profile of this agent and to determine how sitaxsentan could be integrated into therapy for patients with PAH.
Article
PURPOSE: Pulmonary arterial hypertension (PAH) is a progressive disease with a median survival of 2.8 years from diagnosis. Recently, the development of target-specific drugs including endothelin receptor antagonists, have improved time to clinical worsening and survival in patients with PAH. Sitaxsentan is a highly-selective endothelin-A receptor antagonist with proven efficacy in exercise capacity and quality of life in patients with PAH; however, limited data are available on the long-term survival of patients with PAH treated with this drug. Within our center in Mexico City, we sought to evaluate the effects on survival of long-term treatment with sitaxsentan, in a subset of patients from the STRIDE-3 trial. METHODS: STRIDE-3, is an ongoing, open-label trial evaluating the long-term safety of sitaxsentan 100mg qd in PAH. Survival was assessed in patients treated with sitaxsentan for up to 4 years and rates compared with predicted survival according to the NIH equation at 1, 2 and 3 years. RESULTS: Thirtysix patients with PAH from our department, who were included in STRIDE-3, were analysed. Of these, 33 were diagnosed with idiopathic PAH and 3 with PAH associated with connective tissue disease (mPAP 66±22mmHg, RAP 9.7±6mmHg, CI 2.6±0.9L/min/m2). All 36 patients (30 females, age range 30±11years) were treated with sitaxsentan 100mg qd long-term plus conventional therapy (mean time 148±54weeks; range 26−220weeks). At baseline, patients were in WHO functional class II, n=31; or III, n=5, and 6 minute walk distance was 320±98m. After treatment with sitaxsentan, cumulative survival in patients was 96%, 79% and 75% at 1, 2 and 3 years, respectively, versus predicted survival of 71%, 60% and 50%, based on the NIH equation (p<0.05). Four patients withdrew voluntarily from the study (withdrawal was not drug related). Five patients required combination therapy (sildenafil) because of clinical deterioration and 18 patients remain on sitaxsentan monotherapy at 3 years. CONCLUSION: Sitaxsentan improves long-term survival in patients with PAH in WHO functional class II and III. CLINICAL IMPLICATIONS: Sitaxsentan monotherapy is another option for target-specific treatment of pulmonary arterial hypertension. DISCLOSURE: Tomas Pulido, Grant monies (from industry related sources) The author has been a principal investigator for some of the STRIDE studies and his institution has received research grants from Encysive.; No Product/Research Disclosure Information
Article
Sitaxentan inhibits the metabolism of warfarin, resulting in a need for adjustment of warfarin dose when both drugs are coadministered. We report the long-term effects on bleeding of acenocoumarol co-administered as part of conventional therapy for pulmonary hypertension with sitaxentan in a subset of patients enrolled in the Sitaxentan To Relieve ImpaireD Exercise-3 (STRIDE-3) study. STRIDE-3 is an ongoing, long-term, open-label trial, evaluating the safety and efficacy of sitaxentan, 100 mg once daily, in patients with pulmonary arterial hypertension. Information on bleeding events was collected prospectively, including the type of event, severity, anticoagulant use and investigator attribution of causality. Coagulation tests were performed on a monthly basis. A clinically significant interaction was defined as an international normalized ratio (INR) >/= 5.0, or any minor bleeding event plus an INR > 2.0 and < 5.0. Of 55 patients enrolled in STRIDE-3, 50 received acenocoumarol. Average follow-up was 158.6 +/- 57.6 weeks. The average dose of anticoagulant therapy was 3.9 +/- 1.3 mg week(-1) (range, 1.5-7.0 mg week(-1)). Following treatment, an INR >/= 5 in at least one INR determination was observed in 13 patients, although none of these patients had a clinically significant bleeding event. Dose reductions in acenocoumarol were performed to adjust target INR to 1.5-2.0. Two patients died of massive haemoptysis, but these episodes were not attributed to a drug interaction. Four patients with an INR > 2.0 and < 5.0 experienced a minor bleeding event (nosebleeds/gingivitis). No clinically significant bleeding events were recorded with coadministration of sitaxentan and acenocoumarol in this patient subgroup. These results suggest that coadministration of sitaxentan and acenocoumarol is clinically manageable and well tolerated.
Article
he medical community has been alerted by case reports of serious liver injury associated with sitaxentan, an endothelin receptor antagonist (ERA) used for the treatment of pulmonary arterial hypertension (PAH). The first of these case reports was published in the June issue of the European Respiratory Journal and described a patient with PAH who was initially treated with bosentan, another ERA (1). This treatment was stopped after 6 months because of an increase in liver aminotransferases. The liver enzymes quickly returned to normal upon withdrawal of bosentan and, a few months later, sitaxentan therapy was started. Four months after this, liver aminotransferases started to increase again and the drug was discontinued, but the liver enzymes continued to rise to almost
Article
To the Editors: Endothelin receptor antagonists (ERA) have become standard therapy for patients with pulmonary arterial hypertension (PAH), next to phosphodiesterase-5 inhibitors and prostanoids 1–3. One of the most common side-effects associated with ERA therapy is hepatotoxicity, usually detected by an increase in the serum aminotransferases 1, 4. The underlying mechanism may be related to inhibition of a bile-salt transporter pump 5. The typical pattern of this type of liver injury is that of a toxic mechanism, i.e. dose-related and rapidly reversible upon dose reduction or drug withdrawal. Herein, we present a case of liver injury associated with the ERA sitaxentan, which showed a different pattern in that liver injury worsened despite drug discontinuation and aminotransferases normalised after glucocorticoid therapy had been initiated, raising the hypothesis that hepatotoxicity might have been related to an idiosyncratic, i.e. immune-mediated, mechanism. The patient, a 25-yr-old female (height: 178 cm; weight: 58 kg) with Eisenmenger's …