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