BENEFIT IN OUTCOME MEASURES INDUCED BY BOSENTAN AMONG PATIENTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED PULMONARY ARTERIAL HYPERTENSION: RESULTS OF A 5-YEAR CARDIOLOGIC ASSESSMENT

Dott. Riccardo ScagliolaClinica di Malattiedell’Apparato Cardiovascolare e UTICIRCCS A.O.U. San Martino-IST - Genova

10 maggio 2014

The author has declared no conflicts of interest

Hemodynamic and pathophysiological condition defined as an increase in mean pulmonary arterial pressure

(mPAP) ≥ 25 mmHg at rest as assessed by right heart catheterization (RHC)

Prevalence: 15-25 cases / million adultsIncidence: 2-4 new cases / million adults / yearPoor prognosis - mean survival without therapy: 2.8 years

o Pre-capillary PH: PCWP ≤ 15 mmHg

o Post-capillary PH PCWP > 15 mmHg (PCWP: Post-capillary Wedge Pressure)

PULMONARY HYPERTENSION (PH)

MILD 25-35 mmHgMODERATE 36-45 mmHg

SEVERE > 45 mmHg

ESC Guidelines 2009

PH CLINICAL CLASSIFICATION

Geneva

1973Evian

1998Venice

2003Dana Point

2008 Nice 2013

• Group 1: PAH (Pulmonary Arterial Hypertension)• Group 2: PH due to left heart disease• Group 3: PH due to lung disease and/or hypoxia• Group 4: Chronic TromboEmbolic Pulmonary Hypertension (CTEPH)• Group 5: PH with unclear and multifactorial mechanisms

Normal Pulmonary

Artery

Medial Hypertrophy

Intimal Proliferation

In-situ thrombosis

Plexiform Lesion

high flow low resistance

low flowhigh resistance

VASCULAR REMODELING

Adapted from Gaine S. JAMA 2002

Normal PAH

Time

Increasing PVR

Preclinical Symptomatic /stable

Progressive /declining

Leve

l

Cardiacoutputat rest

Pulmonarypressure

Cardiacoutput at

peakexercise

PATHOPHISIOLOGY

PATHOGENESIS

ET-1 NO Prostacyclin (PGI2) 5-HT e 5-HTT RAA system H1 histone Ca²⁺ and K⁺ channels Growth factors

(PDGF; TGF-β;

VEGF)

Humbert M. N Engl J Med 2004;351:1425-36

Vascular remodelling• Smooth muscle cells blood

vessels • Fibroblasts

Fibrosis• Fibroblastic proliferation • E.C. Matrix proteins • Production of collagenase

Inflammation• Vasal permeability • Neutrophiles/mastcells • Promotion of cellular

adhesion citokynes

Hipertrophy• Cardiovascular/

vascular

Vasoconstriction• Direct or by other

vasoconstrictor systems (i.e. RAA system; sympathetic nervous system)

ET-1

Rubin LJ, et al. Expert Opin Investig Drugs 2002;11:991–1002.Clozel M. J Cardiovasc Pharmacol 2000;35 (Suppl):65–8.

ET-1 = endothelin-1

ET-1: a key-role in CTD-PAH

o CTD: 10-30% of pt with PAHo Prevalence of PAH in SSc: 7-15%o Increase of ET-1 levels in SSc BAL

in early SSc cutaneous lesions and in SSc lungs

CTD Prevalence of PAH (%) References

Systemic Sclerosis 12-33%Mukerjee D et al AnnRheumDis2003Morelli S et al AnnRheumDis 1995

MCTD 8-23% Hosoda Y et al J Rheumatol 1987Kondo H et all ArthrRheum 2001

LES 2-14% Simson JS et al JRheumatol 1989

Sjogren Syndrome 2-4% Dawson JK et al Rheumatology 2000

Reumathoid arthritis 6-21% Gonzales C et al Seminars 2004

PAH associated with connective tissue diseases (CTD-PAH)

AMNCO – Pulmonary Hypertension – BARI, 26 Gennaio 2008Denton and Black. Rheum Dis Clin N America 2003: 335-49.

PATIENTS137 hemodynamic DG

↓51 pt: PAH (group 1)

↓22 pt: SSc-PAH

n = 22F/M = 18/4Mean age (years) = 70,4 ± 8,6 (range: 57-87) Mean age at DG = 67 ± 9 (range: 48-83)Respiratory comorbidities:- COPD: 3 pt (14%) - ILD: 6 pt (27%)

23%

29%18%

15%

8% 7%

Final dyagnosis Pulmonary Hipertension

NO PH

Group 1 (PAH)

Group 2

Group 3

Group 4

Group 5

o CLINICAL EVALUATION - World Health Organization Functional Class (WHO-FC)

o INSTRUMENTAL ANALISIS - 2D ECHO systolic Pulmonary Arterial Pressure (sPAP) Tricuspid Annular Plane Systolic Excursion (TAPSE)

- Right Heart Catetherization (RHC)

o EXERCISE CAPACITY - Six-minute walking distance test (6MWD)

o BIOCHEMICAL ANALYSIS - NT-proBNP

- Antibody profyle

METHODS

RESULTS (statistical analisis)Retrospective analisis5-years dedicated service (2008 - 2013)

o U.O. C. Malattie Apparato Cardiovascolare

o U.O. C. Medicina Interna Orientamento Immunologico

58 SSc patients:• SSc - PAH (n=22)• SSc - no PAH (n=36)

  SSc – PAH(n=22)

SSc – no PAH(n=36)

 p

Age (years) 70,4 ± 8,6 66,8 ± 14,6 n.s.

Age at diagnosis (years) 67 ± 9 65,2 ± 14 n.s.

F/M 18/4 34/2 n.s.

lcSSc (%) 17 (77,3%) 15 (41,6%) p = 0,0082

dcSSc (%) 4 (18,2%) 19 (52,8%) p = 0,0090

SSc ‘sine Scleroderma’ (%)

- 1 (2,8%)

Overlap syndromes (%) 1 (2,8%) 1 (2,8%) n.s.

WHO-FC I 1 (4,5%) 11 (30,5%) p = 0,0177

II 12 (54,6%) 23 (63,9%) n,s,

III 9 (40,9%) 2 (5,6%) p = 0,0009

NT-proBNP (ng/l) 6224,9 ± 9063 872,6 ± 1713 p = 0,0389

6MWD (m) 365 ± 153 412 ± 96 p = 0,0025

CR10 Borg dyspnea score 6,9 ± 1,1 4 ± 0,9 p = 0,0001

Echo sPAP (mmHg) 64 ± 20 41 ± 9,6 p = 0,0001

TAPSE (mm) 19,3 ± 5,3 21,9 ± 4,3 n.s.

RHC mPAP (mmHg) 36 ± 13 -  

PCW (mmHg) 10 ± 5 -  

PVR (dyn·s/cm5) 449 ± 36 -  

PAD (mmHg) 8 ± 4 -  

CO (l/min/m2) 2,6 ± 1 -  

BASELINE MEASURES:SSc-PAH vs SSc-no PAH patients

SSc - PAH SSc - no PAH0

2000

4000

6000

8000

10000P = 0,0389

NT-proBNP (ng/l)

SSc - PAH SSc - no PAH0

100

200

300

400

500P = 0,0025

6MWD - Walking distance (m)

SSc - PAH SSc - no PAH0

20

40

60

80P = 0,0001

ECHO PAPs (mmHg)

o Increase of estimated echocardiographic sPAP value (p = 0,0001) o Reduction of walking distance at the 6MWD (p = 0,0025)o Increase of CR10 Borg dyspnea score value (p = 0,0001)o Increase of NT-proBNP plasmatic levels (ng/ml) (p = 0,0389)

BASELINE WHO-FC

SSc - PAH group SSc - no PAH group0%

20%

40%

60%

80%

100%

4,5%*

30,5%*

54,6%

63,9%

40,9%*

5,6%*

WHO-FC I WHO-FC II WHO-FC III

*χ²-test: p < 0,01

SSc - PAH (n=22) WHO - FC o I = 1 pt (4,5%) o II = 12 pt (54,6%)o III = 9 pt (40,9%)

SSc - no PAH (n=36)WHO - FC o I = 11 pt (30,5%)o II = 23 pt (63,9%)o III = 2 pt (5,6%)

o Oral active non-selective ET-1A and ET-1B ERA and the first molecule of its class that was synthesized

o Started in patients in WHO-FC II-III

o Starting at dose of 62,5 mg x 2/die for 4

weeks, followed by 125 mg x 2/die

o Clinical (WHO-FC), instrumental (2D-ECHO),

functional (6MWD) and hemodynamic

(RHC) benefit

o Also indicated to treat active digital ulcers

and to prevent the development of new

digital ulcers among SSc patients.

BOSENTAN

ESC Guidelines 2009

o History of digital ulcers: 30-35% of SSc pt o Active digital ulcers: 15-25% of SSc pto First case report: 1995o BREATHE-1 and BREATHE-2:

Bosentan Randomized Trial of Endothelin-receptor Antagonist THErapyo RAPIDS-1 and RAPIDS-2:

RAndomized placebo-controlled study on Prevention of Ischemic Digital Ulcers

in Scleroderma

‘’ Bosentan prevents the occurrence of new digital ulcers and long term trials

underlines how the ERA Bosentan speed the healing of active digital ulcers’’

Digital ulcers in SSc

Humbert M, Cabane J. Rheumatology 2003;42:191-193

OUTCOME MEASURES SSc-PAH patients (n=22)

Bosentan treatment (2008→2013)

o Reduction of echocardiographic estimated sPAP from 67,7 mmHg ± 18,5 to 57,9 mmHg ± 13,5 (p = 0,0021)

o Increase of walking distance at the 6MWD from 365 m ± 153 to 376,2 m ± 132,4 (p = n.s.)

o Stable CR10 Borg dyspnea score value from 7,1 ± 0,8 to 6,9 ± 1 (p = n.s.)

 

 WHO – FC

 sPAP (mmHg) 6MWD (m)

 CR10 Borg dyspnea

score

T0 T5 p value T0 T5 p value T0 T5 p value T0 T5 p value

Bosentan (n=16) 1,8 ± 0,7 1,6 ± 0,7 

n.s. 

42,7 mmHg

± 5

36,8 mmHg

± 3,6

p = 0,0340

412 m ± 96

497,3 m ± 66

p = 0,0131

4,1 ± 1 3,2 ± 0,7p =

0,0082

Untreated patients (n=20)

1,7 ± 0,4 2,3 ± 0,5p =

0,0002

41,5 mmHg

± 7,6

42,8 mmHg

± 6,8n.s.

478,5 m ± 97,1

404 m ± 101,2

p = 0,0441 4 ± 0,8 4,1 ± 0,6 n.s.

OUTCOME MEASURES SSc-no PAH patients (n=36)

o PAH: a late complication of SSc: a multisystemic connective tissue disease with multiple organ involvement

o Identified risk factors: limited skin disease or CREST syndrome, anti-centromere antibodies, disease duration ≥ 8-10 years, late onset of SSc, reduced nailfold capillary density and elevated serum NT-proBNP

o PAH is characterized by a worse clinical, instrumental and prognostic impact on the quality of life, severe disability and a reduction of any exercise tolerance among SSc patients

o Bosentan treatment is correlated with the evidence of benefit in outcome measures not only among SSc-PAH patients but also among SSc-no PAH patients for the management of other signs of disease, such as digital ulcers

o Bosentan treatment improves systemic vascular function, producing beneficial effects not only to digital microcirculation but also to other vascular districts, such as pulmonary circulation. A pre-clinic treatment may suggest a potential protective effect to pulmonary circulation in patients with systemic sclerosis

o Oral active non-selective ET-1A and ET-1B ERAo cp 10 mgo 18 October 2013: FDA approved Macitentan for

treatment of adults PAH o 20 December 2013: EMA approved Macitentan

for treatment of adults PAHo SERAPHIN clinical trial

(Study with an Endothelin Receptor

Antagonist in Pulmonary Arterial Hypertension to Improve Clinical

Outcome)

‘’…in conclusion, macitentan significantly reduced morbidity and mortality among patients with

pulmonary arterial hypertension…’’

MACITENTAN

N Engl J Med 2013;369:809 - 818

GRAZIE PER L’ ATTENZIONE