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Chiara Arcangeli
Dipartimento del Cuore e dei Vasi
AOU Careggi, Firenze
Moderna terapia della ipertensione arteriosa polmonare
Pulmonary hypertensionPulmonary hypertensionDiagnostic classificationDiagnostic classification
1. Pulmonary arterial hypertension 3. PH with lung diseasesHypoxemia
• Idiopathic PAH• Familial PAH• Related to: - Connective tissue diseases - HIV - Portal Hypertension - Anorexigens - Congenital heart diseases• PPHN• PAH venulae/cap.involv. (PVOD)
2. PH with left heart disease
• Atrial or ventricular disease• Valvular heart disease
• COPD• Interstitial lung disease• Sleep-disordered breathing • Developmental abnormalities
4. PH due to chronic thrombothic and/or embolic disease
• • TE obtruction of proximal PA• TE obstruction of distal PA• Non thrombotic P embolism
5. Miscellaneous
Third World Symposium on Pulmonary Arterial Hypertension. Venice 2003
3.5%
78%
10%
1,5%
7%
Bosentan
Sitaxentan
Ambrisentan
Sildenafil Epoprostenolo
Iloprost
Treprostenil
Nuovi farmaciEmivita Somministrazio
ne
Prostanoidi
Epoprostenolo (Flolan) 2-4 min. e.v.
Iloprost (Ventavis) 20-40 min. e.v./inal.
Treprostinil (Remodulin)
20-40 min. s.c.
Beraprost 40-50 min. os
Antagonisti ETa/b
Bosentan (Tracleer)Sitaxentan (Thelin)Ambrisentan (Volibris)
360-480 min. os
Inibitori PDE5
Sildenafil (Revatio) 240-300 min. os
Risultati terapia medica
Tolleranza sforzo 30-50 mt
Classe funzionale 1-2 classe ( 20-40%)
Deterioramento clinico riduzione variabile
Emodinamica 3-5% mPap, 10-20% IC
Qualità di vita miglioramento marginale
Sopravvivenza 20-30% vs NIH formula
ET-1 Activities Are Mediated by ETA and ETB Receptors
BOSENTAN non selettivo
SITAXENTAN selettivo
AMBRISENTAN selettivo
Long-term outcome with first-line bosentan therapy in idopathic pulmonary hypertension
survival
Event-free status
S Provencher , Eur Heart J, 2006
-400
-300
-200
-100
0
100
200
300
Placebo (n=17) Bosentan (n=36)
PV
Ri (d
yn
·sec·c
m-5
)C
am
bia
men
ti d
al b
aselin
e
p=0.04
T.E.* = -472 dyn.sec.cm-
5
*T.E. = Effetto del Trattamento
Galiè et al.: Circulation 2006
BREATHE-5:BREATHE-5:first randomized placebo-controlled trial in Eisenmenger physiologyfirst randomized placebo-controlled trial in Eisenmenger physiology
EARLY: Effect of bosentan on time to clinical worsening
Hazard ratio = 0.22795% CL: 0.065, 0.798
Patients are censored at the end of the study
100
80
60
40
20
00 4 8 12 16 20 2824 32
92 90 89 86 84 83 1877 9
93 92 87 85 84 83 2780 15
Weeks from treatment start
Pat
ien
ts w
ith
ou
t th
e ev
ent
(%)
Patients at risk
Placebo
Bosentan
p = 0.0114; log rank
Galiè et all, Lancet 2008
EARLY Co-primary endpoint:Bosentan significantly reduced PVR
Treatment effect:* 22.6%95% CL: 33.5, 10.0
80
85
90
95
100
105
110
Placebon = 88
Bosentann = 80
% o
f b
asel
ine
PV
R a
t m
on
th 6
(geo
met
ric
mea
ns
)
p < 0.0001; Wilcoxon
*(ratio of geometric means 1) x 100 Galiè et all, Lancet 2008
STRIDE-1,2,4: Change in 6MWD CTD Subgroup
6 weeks 12 weeks 18 weeks
p = 0.042
Me
ters
sitaxentan 100mg (n=39)placebo (n=28)
-50
-40
-30
-20
-10
0
10
20
30
40
38 m
Seibold J, et al. Chest. 2005;128[4 suppl]:219S
Ambrisentan for the Treatment of Pulmonary Arterial Hypertension
Results of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy
(ARIES) Study 1 and 2
Galiè et all, Circulation 2008
STRIDE-2: Hepatic Aminotransaminase Elevations > 3x ULN
0.0
2.5
5.0
7.5
10.0
12.5
placebo sitaxentan50 mg
sitaxentan 100 mg
bosentan
11%
3%
5%
6%
Per
cent
of
Pat
ient
s
Barst RJ, et al. J Am Coll Cardiol. 2006;47:2049-2056
STRIDE-2: Hepatic Aminotransaminase Elevations > 3x ULN
0.0
2.5
5.0
7.5
10.0
12.5
placebo sitaxentan50 mg
sitaxentan 100 mg
bosentan
11%
3%
5%
6%
Per
cent
of
Pat
ient
s
Barst RJ, et al. J Am Coll Cardiol. 2006;47:2049-2056
Ambrisentan
sildenafil
Inibitori PDE5
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 50 100 150 200 250 300 350 400 450 500 550Number of days since start of sildenafil treatment
Kap
lan-
Mei
er p
roba
bilit
y of
eve
nt
Observed and predicted survival (n = 141)
Observed: sildenafil treated
Predicted: NIH
99%
78%
96%
71%
95%
65%
PROSTANOIDI
EPOPROSTENOLO
ILOPROST
TREPROSTENIL
87.8%
76.3%
62.8%
n= 162
58.9%
46.3%
35.4%
“A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group.”
n= 81
“Survival in primary pulmonary hypertension. The impact of epoprostenol therapy.”
80%
Epoprostenol in IPAH
McLaughlin VV, et al. Circulation 2002;106:1477.
Barst RJ, et al. N Engl J Med 1996;334:296.
Strive for Early Intervention - Functional class
EARLY IMPROVEMENT IN FUNCTIONAL CLASS PREDICTS INCREASED SURVIVAL1
Functional class (FC) is highly correlated to survival.
Survival was significantly improved for patients who rapidly achieved FC I or II compared with FC III and IV patients (P<0.001; FC after 12 weeks of treatment).McLaughlin VV et al. Circulation. 2002;106:1477-1482.
*Epoprostenol
*After 12 weeks of treatment.
“Inhaled Iloprost for severe pulmonary hypertension”Olschewsky H, et al. N Engl J Med 2002;347:322
Hemodynamic improvement
CI PVR mPAP SvO2* * *
0
Su
rviv
al i
n I
PA
H (
%)
At risk (n) 32 3030 2121 1616 99
ObservedExpected (after D’Alonzo et al. Ann Intern Med 1991)IV epoprostenol (Mc Laughlin et al. Circulation 2002)
Effects of first-line prostacyclin therapyon survival in idiopathic PAH
Time (weeks)
20
13 26 39 52 65 91 10478 117 130 143 156 169 182 195 2080
10
30
50
60
40
80
70
90
100
Lang et al Chest 2006 Lang et al Chest 2006
S.Gibbs, 2008
Jean-Luc Vachiéry, 2008
Possibili terapie di associazione
Antagonisti Recettoriali della ET-1
Prostanoidi(e.v., s.c., os, inal)
Inibitori della Fosfodiesterasi 5
Combination therapy: Iloprost & Sildenafil
Combination therapy: Bosentan & Sildenafil
Hoeper M et al. Eur Respir J 2004
Bos Sild
- No deaths- No ALT/AST elevation- No hypotension or syncope
Interazioni farmacologiche
Il meccanismo più probabile sembra una induzione del
citocromo CYP3A4 da parte del bosentan
Br Clinic Pharmacol, 2005
Badesch, D. B. et al. Chest 2007;131:1917-1928
Treatment algorithm for PAHACCP Guidelines 2007
Badesch, D. B. et al. Chest 2007;131:1917-1928
Treatment algorithm for PAH
ERAs
ACCP Guidelines 2007