Systematic review of efficacy and safety of Bosentan in PAH

1. EFFICACY AND SAFETY OF BOSENTAN IN PULMONARY
ARTERIAL HYPERTENSION (PAH)
A SYSTEMATIC REVIEW OF RANDOMIZED
CONTROLLED TRIALS
SUPERVISED BY: 1) DR. S.Raisuddin
Head Of Department
(Centre for Translational & Clinical Research)
2) Mr Himanshu Sharma
Group Leader (MACR, Ranbaxy)
PRESENTED BY: Haroon Rashid
Student of Clinical Research
JAMIA HAMDARD

2. OBJECTIVE
General Objective
To assess the efficacy and safety profile of bosentan in patients
with PAH based on reported randomized controlled trials
published in peer-review journals.
Specific Objectives
• To analyze the efficacy parameters, percentage change in
six minute walk test, hemodynamic parameters, WHO/NYHA
functional class, clinical worsening and survival in
monotherapy as well as in combination with other drugs.
• To analyze the safety and tolerability of bosentan.

3. .
INTRODUCTION
Description of the Condition
Pulmonary hypertension (PH) is a broad term that refers to elevated
pressure in the pulmonary bronchial tree.
Pulmonary arterial hypertension (PAH), a subcategory of pulmonary
hypertension (PH).
PAH is a chronic, rare and progressive disorder affecting
cardiopulmonary hemodynamics and leading to pulmonary
arteriopathy.

4. .
In PAH, there is
» increase in mean pulmonary arterial pressure (PAP) ≥
25 mmHg at rest or greater than 30 mmHg during
exercise
» increased pulmonary vascular resistance of the lung
microvasculature
» intimal hyperplasia and smooth muscle cell hypertrophy
» in situ thrombosis
» right ventricular pressure overload, dysfunction, and
ultimately right heart failure
» premature death

5. .
Endothelial Dysfunction
Imbalance in Mediators
↓ Nitric Oxide
↓ Prostacyclin
Up Regulation of ET-1
Smooth
muscle
Fibroblast Endothelium
Vasoconstriction
Proliferation
Contraction
Proliferation
Fibrosis
Proliferation
Vasoconstriction
Lung Vascular & Structural Remodelling
PULMONARY ARTERIAL HYPERTENSION (PAH)
ETA&B ETA&B ETB

6. .
Description of the Intervention
PAH is a debilitating, progressive disease associated with poor quality of life, poor
prognosis and few treatment options.
1. Prostacyclin analogues (Epoprostenol , Iloprost)
2. Endothelin receptor antagonists (Bosentan, Ambrisentan)
3. Phosphodiesterase-5 inhibitors (Sildenafil, Tadalafil)
4. Nitric oxide/nitric oxide donors (Nitric oxide)
Bosentan is a potent non-peptide endothelin-receptor antagonist (ERA).
Bosentan is a dual ERA, which competitively antagonises the binding of endothelin
to both endothelin receptors ETA and ETB ,thereby produces systemic and
pulmonary vasodilatation .

7. .
METHODOLOGY
Study Method
A literature search of different data bases like PUBMED and
ClinicalTrials.gov was done to identify Published clinical studies on
Bosentan (conducted till 18th March 2014).
The search terms used were “bosentan”, “pulmonary arterial
hypertension”, “bosentan AND pulmonary arterial hypertension”
Study Design
Systematic Review of Published Clinical studies.

8. .
Selection Criteria
Inclusion Criteria
– Published studies (randomized, prospective, controlled design)
including open-label, single and double-blind designs were
selected.
– Both male and female subjects >12 and <75 years of age that had
current diagnosis of symptomatic PAH.
– Each selected study reported outcomes of interest

9. .
Exclusion Criteria
1. Studies done in pediatric population, healthy volunteers, having
duration of <12 weeks and number of patients <30
2. RCTs reported inadequately or not providing efficacy and safety data
3. APAH other than CTD & CHD
4. Duplicated RCTs and RCTs without results
5. If both abstract and full text are not available
6. RCTs reported PK/PD study

10. Records excluded on
the basis of animal
studies, review articles
and others
(n = 1,970)
RCTs excluded based
on exclusion criteria
(n=124)
Total RCTs included in the
final Systematic review
(n= 15)
Potentially relevant RCTs
identified and evaluated
(n= 94 + 45*)
Records identified through
database searching (n=2004) +
additional records identified
through other source* (105)
Total = 2109

11. Overview of selected randomized clinical trials on bosentan
Reference Study type N Duration Disease
Barst RJ et al, 2011 (PHIRST) DB,PL 405 16 wks PAH
McLaughlin VV et al, 2006 DB, R, OLE 358 36 mo PAH
McLaughlin VV et al, 2005 DB, PL, R & OLE 245 36 mo PPH
Rubin LJ et al, 2002(BREATHE-1) DB, PL 213 16 wks PAH
Galie N et al, 2008 (EARLY) R, DB 185 6 mo PAH
NCT00323297 R, DB, PL 104 1 year PAH
Galie N et al, 2003 R, PL 85 16 wks PAH
McLaughlin VV. et al, 2006 R, DB, MC 67 12 wks PAH
Denton CP et al, 2006 DB, R, PL 66 16 wks PAH - CTD
Berger RM, et al, 2010 MC,R, DB, PL 54 16 wks PAH & ES
Galie N et al, 2006(BREATHE-5) MC, R, DB, PL 54 16 wks PAH & ES
Gatzoulis MA et al, 2008 OLE 37 16 wks PAH & ES
Humbert M et al, 2004(BREATHE-2) DB, PL, Pr 33 16 wks PAH
Channick RN et al, 2001 DB, PL 32 12 wks PAH & APAH
Dalto M et al, 2012 R, OL, Pr 32 6 mo PAH & ES

12. RESULTS
Efficacy analysis results
A. Bosentan Compared with placebo
i. Effect on Six minute walk test (6MWT)
-30
-20
-10
0
10
20
30
40
50
60
70
Rubin LJ (2002) Galie N (2008) Gatzolius MA
(2008)
Berger RM
(2010)
Galie N (2006) Denton CP
(2006)
Channick RN
(2001)
Galie N (2003)
Placebo Bosentan
Distance
walked
in
meters
(m)

13. ii. Effect on WHO Functional class (WHO FC)
.
0%
10%
20%
30%
40%
50%
60%
70%
Rubin LJ (2002) Gatzolius MA (2008) Galie N (2006) Denton CP (2006) Channick RN (2001)
Placebo Bosentan
Percentage
of
Improvement
in WHO
Functional
Class

14. iii. Effect on Hemodynamics
.
-400
-300
-200
-100
0
100
200
300
Berger RM (2010) Galie N (2006) Channick RN (2001)
Placebo Bosentan
Pulmonary
vascular
Resistance
dyn.s.sm-5

15. iii. Effect on Hemodynamics
.
-8
-6
-4
-2
0
2
4
6
Galie N (2008) Berger RM (2010) Galie N (2006) Channick RN (2001)
Placebo Bosentan
Pulmonary
artery
pressure
mmHg

16. iii. Effect on Hemodynamics
.
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
Galie N (2008) Channick RN (2001) Galie N (2003)
Placebo Bosentan
Cardiac
index
l/min/m2

17. ,
iv. Effect on Borg Dyspnea Index
Bosentan monotherapy improved the Borg dyspnea index as
compared to placebo (measured on the 10-point Borg dyspnea scale)
v. Effect on Clinical Worsening
As compared to placebo, bosentan
● Increased the time to clinical worsening
and
● Decreased the number of clinical
worsening events.

18. vi. Effect on Survival
.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 year (PPH) 2 year (PPH) 1 year (PAH-
SSc)
2 year (PAH-
SSc)
3 year (PAH-
SSc)
1 year
(WHOFC)
2 year
(WHOFC)
1 year (PAH-
CTD)
2 year (PAH-
CTD)
Predicted survival Survival after Bosentan Treatment
Improvem
ent
in survival
(%)

19. B. Bosentan in combination with other PAH existing drugs
Many randomized controlled trials have been reported with bosentan
in combination with tadalafil (TD), epoprostenol (EPO), Iloprost (ILO)
and sildenafil (SLD).
I. Combination with Tadalafil
i. Effect on Six minute walk test (6MWT)
-10
-5
0
5
10
15
20
25
30
35
40
45
PL TD 40mg BO + PL BO + TD 40mg
Improvement
in
6MWD
(meters)

20. .
.
ii. Effect on WHOFC
iii. Effect on PVR
0
5
10
15
20
25
30
35
40
PL TD 20mg TD 40mg BO + PL BO + TD 20mg BO + TD 40mg
Percentage
improvement
in
WHO FC
(%)
-35
-30
-25
-20
-15
-10
-5
0
5
10
15
PL TD 20mg TD 40mg BO + PL BO + TD 20mg BO + TD 40mg
Pulmonary
vascular
resistance
dyn.s.sm-5

21. .
.
iv. Effect on Clinical worsening
0
5
10
15
20
25
PL TD 20mg TD 40mg BO + PL BO + TD 20mg BO + TD 40mg
Percentage
of
clinical
worsening
events

22. .
II. Combination with Epoprostenol
i. Effect on Six minute walk test (6MWT)
ii. Effect on WHOFC
65
66
67
68
69
70
71
72
73
74
75
PL + EPO BO + EPO
improvement
in
6MWD
(meters)
0
10
20
30
40
50
60
70
PL + EPO BO + EPO
Percentage
improvement
in
WHOFC

23. .
iii. Effect on hemodynamics
0
200
400
600
800
1000
1200
1400
PVR TPR
PL + EPO BO + EPO
Improvement
in PVR
dyn.s.sm-5
and
TPR
dyn.s.sm-5
2.2
2.25
2.3
2.35
2.4
2.45
2.5
2.55
PL + EPO BO + EPO
Improvement
in
Cardiac
index
l/min/m2

24. .
0
10
20
30
40
50
60
70
PAP RAP
PL + EPO BO + EPO
Improvement
in
PAP mmHg
and
RAP mmHg

25. .
II. Combination with Iloprost
i. Effect on Six minute walk test (6MWT)
ii. Effect on WHOFC
330
335
340
345
350
355
360
365
370
BO + PL BO + ILO
Improvement
in
6MWD
(meters)
0
5
10
15
20
25
30
35
40
BO + PL BO + ILO
Percentage
improvement
in
WHOFC
(%)

26. .
iii. Effect on hemodynamics
0
200
400
600
800
1000
1200
1400
1600
PVR SVR
BO + PL BO + ILO
Improvement
in
PVR
dyn.s.sm-5
and
SVR
dyn.s.sm-5
40
42
44
46
48
50
52
54
56
BO + PL BO + ILO
Improvement
in
PAP
(mmHg)

27. ,
iv. Effect on Borg Dyspnea Index
At 12 weeks the Borg dyspnea score improved in the Iloprost plus
existing bosentan group compared with baseline.
v. Effect on Clinical Worsening
-> Time to clinical worsening was significantly
longer in Iloprost plus existing bosentan group
than in placebo plus bosentan group.
-> None of the patient in Iloprost plus existing
bosentan group had any clinical worsening event
as compared with 15% placebo plus bosentan
group.

28. .
II. Combination with Sildenafil
i. Effect on Six minute walk test (6MWT)
ii. Effect on WHOFC
0
10
20
30
40
50
60
70
80
BO + PL BO + SLD BO + SLD*
Improvement
in
6MWD
(meters)
0
5
10
15
20
25
BO + PL BO + SLD
Percentage
improvement
in
WHOFC
(%)

29. .
iii. Effect on hemodynamics
0
10
20
30
40
50
60
70
80
PAP RAP
BO BO+SLD
Improvement
in
PAP mmHg
and
RAP
mmHg
0
5
10
15
20
25
30
PVR SVR
BO BO+SLD
Improvement
in
PVR
dyn.s.sm-5
and
SVR
dyn.s.sm-5

30. ,
iv. Effect on Borg Dyspnea Index
Bosentan in combination with sildenafil showed improvement in Borg
dyspnea index.
v. Effect on Clinical Worsening
-> In sildenafil plus bosentan group, 2% death of
subjects was reported.
-> Hospitalization due to PAH was reported in 4% of
patients in sildenafil plus bosentan group and
3.7% of patients in bosentan plus placebo group

31. .
Safety analysis results
A. Bosentan Monotherapy
A total of 20 serious adverse events, 30 deaths and 54
discontinuations were reported in the groups receiving bosentan
monotherapy
B. Bosentan in Combination with other PAH therapies.
A total of 72 serious adverse events, 03 deaths and 43
discontinuations were reported in the groups with background
bosentan therapy.

32. a) Safety Results of Bosentan Compared with placebo
.
0
2
4
6
8
10
12
14
16
18
Placebo Bosentan
% of
Adverse
events

33. b) Adverse events due to bosentan in combination with tadalafil
.
0
5
10
15
20
25
30
35
40
45
PL TD20mg TD 40mg BO + PL BO + TD20mg BO + TD 40mg
% of
adverse
events

34. c) Adverse events due to bosentan in combination with Epoprostenol
.
0
10
20
30
40
50
60
Elevated
liver
enzyme
Peripheral
oedema
Headache Diarrhoea RTI Flushing Dizziness Cough Dyspnea Pain in
extremity
PL + EPO Bo + EPO
Percentage
of
adverse
events
(%)

35. d) Adverse events due to bosentan in combination with Iloprost
.
0
10
20
30
40
50
60
Peripheral
oedema
Headache RTI Flushing Chest pain Palpitations Dizziness Cough Dyspnea Pain in
extremity
BO + PL BO + ILO
Percentage of
adverse events
(%)

36. e) Adverse events due to bosentan in combination with Sildenafil
.
0
1
2
3
4
5
6
7
8
9
10
Peripheral
oedema
Nasophyrangitis Diarrhoea RTI Flushing Hb Decrease Dyspnea
BO + PL BO + SLD
Percentage
of
adverse
events
(%)

37. .
CONCLUSION
Bosentan was found to be efficacious in adult patients with PAH of varied
origin (IPAH, PPAH, PAH-CTD, PAH-CHD).
 Bosentan was associated with consistent improvements in all clinical and
hemodynamic parameters .
Bosentan can be ideally used as initial therapy for the majority of patients
with functional class III PAH
Bosentan, with subsequent addition of other PAH treatments (tadalafil,
sildenafil, epoprostenol, iloprost), if required, is safe for long-term treatment
use and may have a positive effect on outcome.

38. .
Bosentan was found to be safe and tolerated when used as monotherapy and
when given in combination with other drugs the frequency of adverse events
was less than the bosentan plus placebo, epoprostenol plus placebo and
tadalafil monotherapy.
The two main safety concerns that arose were increased incidences of
elevated liver enzymes and decreased hemoglobin concentrations.
Treatment with high doses and up-titration was related with worsening of
clinical events
Convenient treatment with considerable clinical benefit that can improve the
quality of life of patients and may modify the clinical course of the disease
 Oral administration--- Convenient dosing, cost-effective and avoids various
complications.

39. LIMITATION
• Failure to fully assess the methodological quality of included
primary studies.
• Literature search limited to PUBMED and http://clinicaltrials.gov
• Exclusion of non-english studies.
• The desired data may not be present in the published papers
due to which the outcome measures with missing data cannot
be included in the analyses.

40. FUTURE DIRECTIONS
 Transitioning patients onto oral therapy from parental forms of
therapy is an attractive goal for patients with PAH.
 Ease of administration and favorable side-effect profile, the strategy
of treatment with first line bosentan should be considered for WHO
Functional Class III patients
 First line bosentan, with subsequent addition of other PAH therapies,
if required, is safe for long-term treatment use and may have a
positive effect on outcome.
 A clear understanding of the guidelines regarding efficacy and safety
of bosentan will be essential for physicians to manage patients with
PAH

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