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


.

Galie N (2008) Berger RM (2010) Galie N (2006) Channick RN (2001)-8

-6

-4

-2

0

2

4

6

Placebo Bosentan

PulmonaryarterypressuremmHg


.

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


BO + PL BO + ILO0

5

10

15

20

25

30

35

40

Chart Title

PercentageimprovementinWHOFC(%)

.


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)

,


At 12 weeks the Borg dyspnea score improved in the Iloprost plus

existing bosentan group compared with baseline.


-> 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


BO + PL BO + SLD0

5

10

15

20

25

PercentageimprovementinWHOFC(%)

.


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

,


Bosentan in combination with sildenafil showed improvement in Borg

dyspnea index.


-> 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.

http://clinicaltrials.gov/

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

REFRENCES

1) Valerio JC, Coghlan JG. Bosentan in the treatment of pulmonary arterial hypertension with the focus on

the mildly symptomatic patient. Vascular Health and Risk Management; 2009; 5:607–619

2) McCrory DC, Coeytaux RR, Schmit KM, Kraft B, Kosinski AS,Mingo M.A et al. Pulmonary Arterial

Hypertension: Screening, Management, and Treatment [Internet]. Rockville (MD): Agency for

Healthcare Research and Quality (US); 2013 Apr. Report No.: 13-EHC087-EF.

3) Gabbay E, Fraser J, McNeil K. Review of Bosentan in the management of Pulmonary Arterial

Hypertension. Vascular Health and Risk Management; 2007 :3(6) 887–900

4) Jamieson SW, Kapelanski DP. Pulmonary endarterectomy. Curr Probl Surg. 2000 Mar; 37(3):165-252.

5) Kenyon KW and Nappi JM (2003). Bosentan for the treatment of pulmonary arterial hypertension. Ann

Pharmacother. 37:1055-62.

6) Rubin LJ, Hoeper MM, Klepetko W, et al. 2006. Current and future management of chronic

thromboembolic pulmonary hypertension: from diagnosis to treatment responses. Proc Am Thorac Soc,

3:601–7

7) Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated Clinical

Classification of Pulmonary Hypertension. Journal of the American College of Cardiology Vol. 54, No.

1, Suppl S, 2009.

.

8) Clozel M et al (1994). Pharmacological characterisation of Bosentan, a new potent orally active non-

peptide endothelin receptor antagonist. Pharmacol Exp Ther 270:228–235

9) Green S. Systematic reviews and meta-analysis. Singapore Med J. 2005; 46(6):270-274.

10) Moher d, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group. Preferred reporting items for systematic

reviews and meta- analyses: The PRISMA Statement. PLoS Med. 2009;6(7).

11) Jadad AR, Moore RA, Carroll D. Assessing the quality of reports of randomized clinical trials: is blinding

necessary? Control Clin Trials 1996; 17:1-12.

12) Khalid S, Kunz R, Kleijnen J, Antes G. Five steps to conducting a systematic review. J R Soc Med

2003;96:118–121

13) Barst RJ, Oudiz RJ, Beardsworth A, Brundage BH, Simonneau G, Ghofrani HA, Sundin DP, Galiè N;

Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil

monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension.. J

Heart Lung Transplant. 2011 Jun; 30(6):632-43.

14) Barst RJ. A review of pulmonary arterial hypertension: role of ambrisentan. Vascular Health and Risk

Management 2007:3(1) 11–22

15) Berger RM, Beghetti M, Galiè N, Gatzoulis MA, Granton J, Lauer A, Chiossi E, Landzberg M. Atrial

septal defects versus ventricular septal defects in BREATHE-5, a placebo-controlled study of pulmonary

arterial hypertension related to Eisenmenger's syndrome: a subgroup analysis. Int J Cardiol. 2010 Oct 29;

144(3):373-8.

.

16) D'Alto M, Romeo E, Argiento P, Sarubbi B, Santoro G, Grimaldi N, Correra A, Scognamiglio G, Russo MG, Calabrò R.

Bosentan–sildenafil association in patients with congenital heart disease-related pulmonary arterial hypertension and

Eisenmenger physiology. International Journal of Cardiology 155 (2012) 378–382

17) C P Denton, M Humbert, L Rubin, C M Black. Bosentan treatment for pulmonary arterial hypertension related to connective

tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions. Ann Rheum Dis 2006;65:1336–

1340

18) Humbert M, Barst R.J, Robbins I.M, Channick R.N, Galie N, Boonstra A et al. Combination of Bosentan with epoprostenol in

pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004. 24:353–359.

19) McLaughlin VV. Survival in patients with pulmonary arterial hypertension treated with first-line bosentan. Eur J Clin Invest.

2006 Sep;36 Suppl 3:10-5

20) McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N.. Survival with first line bosentan in patients with primary

pulmonary hypertension. EurRespir J, 2005; 25:244–9.

21) McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN. Randomized study of adding inhaled iloprost to

existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med,2006; 174:1257–63.

22) Galie N, Hinderliter AL, Torbicki A, Fourme T, Simonneau G, Pulido T. Effects of the oral endothelin-receptor antagonist

bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol 2003;

41(8):1380-6.

23) Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RMF, Lauer, Chiossi E et al. Bosentan Therapy in Patients with

Eisenmenger Syndrome: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study. Circulation.2006; 114:48-54.

24) Galie N, Rubin LJ, Hoeper MM, Jansa P, Al-Hiti H, Meyer GMB, A Kusic-Pajic, G Simonneau. Treatment of patients with

mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial.

Lancet 2008; 371(9630):2093-100.

.

25) Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL,Barbera JA et al. Guidelines for the

diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of

Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory

Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur

Heart J 2009; 30(20):2493-537.

26) Gatzoulis MA, Beghetti M, Galiè N, Granton J, Berger RMF, Lauer A et al. Longer-term bosentan

therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 open-label

extension study. Int J Cardiol 2008. 127(1):27-32.

27) Robberts KE and Preston IR. Safety and tolerability of bosentan in the management of pulmonary

arterial hypertension. Drug Des Devel Ther 2009; 3:111-8.

28) Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A et al. Bosentan therapy for pulmonary

arterial hypertension. N Engl J Med 2002; 46(12):896-903.

29) NCT00323297. Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment

of Pulmonary Arterial Hypertension. accessed online from Clinicaltrial.gov on 18th March 2014.

30) Summary of Product Characteristics, Tracleer (bosentan) 125mg film-coated tablets of Actelion

Registration Ltd UK, September 2013

THANK YOU