bosentan in ssc-pah 2014
TRANSCRIPT
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