Bosentan- Systematic Review
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Transcript of Bosentan- Systematic Review
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
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.
.
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.
.
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
.
Endothelial Dysfunction
Imbalance in Mediators
↓ Nitric Oxide↓ Prostacyclin
Up Regulation of ET-1
Smooth muscle
Fibroblast Endothelium
VasoconstrictionProliferation
ContractionProliferation
Fibrosis
ProliferationVasoconstriction
Lung Vascular & Structural Remodelling
PULMONARY ARTERIAL HYPERTENSION (PAH)
ETA&B ETA&B ETB
.
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 .
.
METHODOLOGYStudy 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.
.
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
.
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
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
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
RESULTSEfficacy analysis results
A. Bosentan Compared with placebo i. Effect on Six minute walk test (6MWT)
Rubin LJ (2002) Galie N (2008) Gatzolius MA (2008)
Berger RM (2010) Galie N (2006) Denton CP (2006) Channick RN (2001)
Galie N (2003)-30
-20
-10
0
10
20
30
40
50
60
70 Placebo Bosentan
Dis-tance walked in meters(m)
ii. Effect on WHO Functional class (WHO FC)
.
Rubin LJ (2002) Gatzolius MA (2008) Galie N (2006) Denton CP (2006) Channick RN (2001)0%
10%
20%
30%
40%
50%
60%
70%
Placebo Bosentan
PercentageofImprovement in WHO FunctionalClass
iii. Effect on Hemodynamics
.
Berger RM (2010) Galie N (2006) Channick RN (2001)-400
-300
-200
-100
0
100
200
300Placebo Bosentan
PulmonaryvascularResistancedyn.s.sm-5
iii. Effect on Hemodynamics
.
Galie N (2008) Berger RM (2010) Galie N (2006) Channick RN (2001)-8
-6
-4
-2
0
2
4
6
Placebo Bosentan
PulmonaryarterypressuremmHg
iii. Effect on Hemodynamics
.
Galie N (2008) Channick RN (2001) Galie N (2003)-0.6
-0.4
-0.2
0
0.2
0.4
0.6Placebo Bosentan
Cardiacindexl/min/m2
,
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.
vi. Effect on Survival
.
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)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%Predicted survival Survival after Bosentan Treatment
Im-prove-mentin sur-vival(%)
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 Tadalafili. Effect on Six minute walk test (6MWT)
PL TD 40mg BO + PL BO + TD 40mg
-10
0
10
20
30
40
50
Chart Title
Improvementin6MWD(meters)
.
.
ii. Effect on WHOFC
iii. Effect on PVR
PL TD 20mg TD 40mg BO + PL BO + TD 20mg BO + TD 40mg0
5
10
15
20
25
30
35
40
Chart Title
PercentageimprovementinWHO FC(%)
PL TD 20mg TD 40mg BO + PL BO + TD 20mg BO + TD 40mg-35
-30
-25
-20
-15
-10
-5
0
5
10
15
Chart Title
Pulmonaryvascularresistancedyn.s.sm-5
.
.
iv. Effect on Clinical worsening
PL TD 20mg TD 40mg BO + PL BO + TD 20mg BO + TD 40mg0
5
10
15
20
25
Percentageofclinicalworseningevents
.II. Combination with Epoprostenoli. Effect on Six minute walk test (6MWT)
ii. Effect on WHOFC
PL + EPO BO + EPO65
66
67
68
69
70
71
72
73
74
75
improvementin6MWD(meters)
PL + EPO BO + EPO0
10
20
30
40
50
60
70
PercentageimprovementinWHOFC
.
iii. Effect on hemodynamics
PVR TPR0
200
400
600
800
1000
1200
1400PL + EPO BO + EPO
Improvementin PVRdyn.s.sm-5
andTPRdyn.s.sm-5
PL + EPO BO + EPO2.15
2.2
2.25
2.3
2.35
2.4
2.45
2.5
2.55
Chart Title
ImprovementinCardiacindexl/min/m2
.
PAP RAP0
10
20
30
40
50
60
70PL + EPO BO + EPO
ImprovementinPAP mmHgandRAP mmHg
.II. Combination with Iloprost
i. Effect on Six minute walk test (6MWT)
ii. Effect on WHOFCBO + PL BO + ILO
330
335
340
345
350
355
360
365
370
Chart Title
Improvementin6MWD(meters)
BO + PL BO + ILO0
5
10
15
20
25
30
35
40
Chart Title
PercentageimprovementinWHOFC(%)
.
iii. Effect on hemodynamics
PVR SVR0
200
400
600
800
1000
1200
1400
1600 BO + PL BO + ILO
ImprovementinPVR dyn.s.sm-5
andSVRdyn.s.sm-5
BO + PL BO + ILO40
42
44
46
48
50
52
54
56
Chart Title
ImprovementinPAP(mmHg)
,
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.
.II. Combination with Sildenafil
i. Effect on Six minute walk test (6MWT)
ii. Effect on WHOFCBO + PL BO + SLD BO + SLD*
0
10
20
30
40
50
60
70
80
Improvementin6MWD(meters)
BO + PL BO + SLD0
5
10
15
20
25
PercentageimprovementinWHOFC(%)
.
iii. Effect on hemodynamics
PAP RAP0
10
20
30
40
50
60
70
80BO BO+SLD
ImprovementinPAP mmHgandRAPmmHg
PVR SVR0
5
10
15
20
25
30 BO BO+SLD
ImprovementinPVRdyn.s.sm-5
andSVRdyn.s.sm-5
,
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
.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.
a) Safety Results of Bosentan Compared with placebo .
Elevated liver e
nzyme
Peripheral o
edema
Headache
Nasophyrangitis
Diarrhoea RTI
Flushing
Athralgia
Chest pain
Palpitations
Syncope
Dizziness
Hb Decrease
Cough
Dyspnea
Pain in extr
emity0
2
4
6
8
10
12
14
16
18 Placebo Bosentan
% ofAdverseevents
b) Adverse events due to bosentan in combination with tadalafil.
Peripheral o
edema
Headache
Nasophyrangitis
Diarrhoea RTI
Flushing
Athralgia
Chest pain
Palpitations
Dizziness
Cough
Dyspnea
Pain in extr
emity0
5
10
15
20
25
30
35
40
45 PL TD20mg TD 40mg BO + PL BO + TD20mg BO + TD 40mg
% ofadverseevents
c) Adverse events due to bosentan in combination with Epoprostenol.
Elevated liver enzyme
Peripheral oedema
Headache Diarrhoea RTI Flushing Dizziness Cough Dyspnea Pain in extremity
0
10
20
30
40
50
60PL + EPO Bo + EPO
Percentageofadverseevents (%)
d) Adverse events due to bosentan in combination with Iloprost.
Peripheral oedema
Headache RTI Flushing Chest pain Palpitations Dizziness Cough Dyspnea Pain in extremity
0
10
20
30
40
50
60 BO + PL BO + ILO
Percentage of adverse events(%)
e) Adverse events due to bosentan in combination with Sildenafil.
Peripheral oedema
Nasophyrangitis Diarrhoea RTI Flushing Hb Decrease Dyspnea0
1
2
3
4
5
6
7
8
9
10
BO + PL BO + SLD
Percentageofadverseevents(%)
.
CONCLUSIONBosentan 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.
.
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.
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.
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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