Traitement de l’HTAP associée àla Sclérodermie systémique

Olivier SITBON

Centre de Référence de l’Hypertension Pulmonaire Sévèr eHôpitaux Universitaires Paris-Sud – INSERM U999

Université Paris-Sud 11 – Clamart – France

L’HTAP associée aux connectivites

39%

15%

11%

10%

HTAP idiopathique

Connectivites

Cardiopathies congénitales

Hypertension portale

Humbert M, et al. Am J Respir Crit Care Med 2006; 173:1023-30.

(% de la population)

9.5%

6%

4%

Exposition aux anorexigènes

HTAP familiale

Infection VIH

2 facteurs de risque 4%

HTAP associée à une pathologie concomitante : 47.4% (n = 320)

Connectivites

Hypertension portale 26%

24% 10%Sclérodermie systémique Autres

34%

L’HTAP associée à la sclérodermie systémique

Limited68%

Diffuse 32%

Sclérodermie systémique

Cardiopathies congénitales

Infection VIH

24%

17%

Humbert M, et al. Am J Respir Crit Care Med 2006; 173:1023-30.

Diffuse(32 %) Limitée

(68 %)

50

75

100

IPAH

100

75

50

IPAH

HTAP-SSc : un pronostic sombre…

Time (years)

0

25

50

1 2 3 4

PAH-SSc

p = 0.002

3

50

25

0

PAH-SSc

Time (years) 1 2

p = 0.03

Kawut SM, et al. Chest 2003; 123:344-50.Fisher MR, et al. Arthritis Rheum 2006; 54:3043-50.

Approche multidisciplinaire indispensable

� Par rapport à l’HTAP idiopathique, l’HTAP associée à l a sclérodermie systémique est plus cliniquement plus sévè re et de plus mauvais pronostic

� La fréquence des manifestations cardio-pulmonaires es t élevée

� HTAP, atteinte veinule fréquente (“MVO-like”),

� Myocardiopathie restrictive (insuffisance cardiaque diastolique),� Myocardiopathie restrictive (insuffisance cardiaque diastolique),

� Pneumopathie infiltrante…

� Collaboration indispensable entre internistes/rhuma tologues et pneumologues/cardiologues

� Calqué sur le traitement de l’HTAP idiopathique� HTAP idiopathiques et associées aux connectivites dans la plupart

des essais contrôlés� Réunions d’experts internationaux (4th WSPAH) & recommandations

de sociétés savantes (ACCP, ESC/ERS Guidelines)

� Probablement plus complexe…� Efficacité réelle des traitements « spécifiques » de l’HTAP ?

Traitement de l’HTAP associée connectivites

� Efficacité réelle des traitements « spécifiques » de l’HTAP ?� Place des traitements anti-inflammatoires et immunosuppresseurs ?� Place de la transplantation pulmonaire ?

Statement Class a Level b

In patients with PAH associated with CTD the same t reatment algorithmas in patients with IPAH is recommended I A

Echocardiographic screening for the detection of PH is recommendedin symptomatic patients with scleroderma spectrum o f diseases I B

Echocardiographic screening for the detection of PH is recommended

ESC/ERS Guidelines

in symptomatic patients with all other CTDs I C

RHC is indicated in all cases of suspected PAH asso ciated with CTD,in particular if specific drug therapy is considere d I C

Oral anticoagulation should be considered on an ind ividual basis IIa C

Echocardiographic screening for the detection of PH may be consideredin asymptomatic patients with the scleroderma spect rum of disease IIb C

a Class of recommendationb Level of evidence Galiè N, et al. Eur Heart J 2009; 30:2493-537.

O'Callaghan DS, et al . Nat Rev Cardiol 2011; 8: 526-38.

O'Callaghan DS, et al . Nat Rev Cardiol 2011; 8: 526-38.

Recommendation-

Evidence

INITIAL THERAPY

FC II FC III FC IV

I-A Ambrisentan,

Bosentan, Sildenafil

Ambrisentan, Bosentan,

Sildenafil, Epoprostenol i.v.,

Iloprost inhaled

Epoprostenol i.v.

I-B Tadalafil Tadalafil,

Treprostinil s.c., inhaled

IIa-C Iloprost i.v.,

Treprostinil i.v.

Ambrisentan, Bosentan, Sildenafil, Tadalafil,

Iloprost inhaled, i.v., Treprostinil s.c., i.v., inhaled,

ESC/ERS Guidelines : Algorithme de traitement

Treprostinil i.v. Iloprost inhaled, i.v., Treprostinil s.c., i.v., inhaled,

Initial Combination Therapy

IIb-B Beraprost

Inadequate clinical response

Inadequate clinicalresponse

BAS (I-C) and/or lungtransplantation (I-C)

Sequential combination therapy (IIa-B)ERA

Prostanoids PDE-5 I+ +

+

Adapté de : Galiè N, et al. Eur Heart J 2009; 30:2493-537.

p = 0.003

p < 0.001

63.5

48.540

60

80

Med

ian

chan

ge in

6-M

WD

(m

)

Conventional ( n = 55)Epoprostenol ( n = 56)

HTAP-SSc : Effet de l’epoprostenol i.v.

-36

-14-7

13.25

-60

-40

-20

0

20

Week 1 Week 6 Week 12Med

ian

chan

ge in

6

Badesch D , et al. Ann Int Med 2000; 132:425-34.

70.7%

51.8%47.8%

Pro

babi

lity

of s

urvi

val

0.4

0.6

0.8

1.0

Effet à long terme de l’epoprostenol i.v.

102 66 42 11Numberat risk:

0 1 2 3 4Time on epoprostenol (years)

Pro

babi

lity

0.0

0.2

0.4

Badesch D , et al. J Rheumatol 2009; 36:2244-9.

84 PAH-CTD patients were randomly assigned to placebo, 20 mg, 40 mg or 80 mg sildenafil tid

At week 12 ∆∆∆∆6-MWD (m)Placebo 20 mg 40 mg 80 mg-12 +42 +36 +15NS p < 0.01 p < 0.01 NS

HTAP-CTD : Effet du sildenafil

NS p < 0.01 p < 0.01 NS

At week 12 improvement by ≥ 1 FCPlacebo 20 mg 40 mg 80 mg5% 29% 40% 42%NS p < 0.003 p < 0.003 p < 0.003

Sildenafil is not licensed for the treatment of PAHat doses > 20 mg tid Badesch D , et al. J Rheumatol 2007; 34:2417-22.

Sub-group analysis of patients with PAH-CTD

Placebo TadalafilNo. of subjects Mean

(95% Confidence Intervals)

49 (15, 83)16 17 40 mg tadalafil

HTAP-CTD : Effet du tadalafil (PHIRST)

49 (15, 83)50 (16, 83)22 (-13, 56)18 (-27, 63)

16 17192215

Change in 6-MWD (m)

0 40 80 120-40-80

40 mg tadalafil20 mg tadalafil10 mg tadalafil2.5 mg tadalafil

Galiè N, et al. Circulation 2009; 119:2894-03.

� ARIES-11

� Improved 6-MWD

� Failed to improve timeto clinical worsening

� Results represent entire trial population (IPAH, CT D, HIV-PAH &

� ARIES-21

� Improved 6-MWD and time to clinical worsening

HTAP-CTD : Effet de l’ambrisentan

� Results represent entire trial population (IPAH, CT D, HIV-PAH & anorexigen associated PAH). While 31% of patients ha d CTD, sub-group analysis was not included in publication.

� ARIES-E2

� Long-term extension of ARIES-1 & ARIES-2

� Improvement in 6-MWD sustained after 2 years of treatment

1. Galiè N , et al. Circulation 2008; 117:3010-9.2. Oudiz RJ, et al. J Am Coll Cardiol 2009; 54:1971-81.

� Etudes 351 1 et BREATHE-1 2 ont inclus des patients avec une HTAP associée à une SScou un lupus

� 66 patients avec une HTAP associée à uneconnectivite (SSc, n = 52) ont été randomisés

HTAP-CTD : Effet du bosentan

connectivite (SSc, n = 52) ont été randomisésdans ces deux essais contrôlés 3

1. Channick RN, et al. Lancet 2001; 358:1119-23.2. Rubin, LJ et al. New Engl J Med 2002; 346:896-903.3. Denton CP , et al. Ann Rheum Dis 2006; 65:1336-40.

Bosentan - Open label extensions

AC-052-353 and AC -052-354Placebo

Bosentan

HTAP-CTD : Effet du bosentan

AC-052-353 and AC -052-354

Baseline EndpointAC-052-351: 12 weeksBREATHE-1: 16 weeks

EndpointUp to 2 years

1. Channick RN, et al. Lancet 2001; 358:1119-23.2. Rubin, LJ et al. New Engl J Med 2002; 346:896-903.3. Denton CP , et al. Ann Rheum Dis 2006; 65:1336-40.

Sur

viva

l (%

) 85.9%

73.4%

80

60

100

HTAP-CTD : Effet du bosentan sur la survie

0 6 12 18 24Time (months)

64 57 55 52 32Number at risk:

Sur

viva

l (%

)

Denton CP , et al. Ann Rheum Dis 2006; 65:1336-40.

0

20

40

Bosentan 62.5 mg bid

Bosentan 125 mg bid

79% (n = 53) of patients had SSc

TRUST : Etude ouverte dédiée aux HTAP-CTD

48 weeks

2 weeks

ScreeningInitiation 4 weeks 16 weeks

Denton CP , et al. Ann Rheum Dis 2007; 67:1222-8.

100

80

60

40surv

ivin

g(%

) 92% alive at 48 weeks

TRUST : Etude ouverte dédiée aux HTAP-CTD

40

20

0Pat

ient

s

Time from treatment start (weeks)

0 16 32 48 64 80 96 112 128 144 160

Patients at risk 53 51 49 47 45 40 40 32 12 3 0

Denton CP , et al. Ann Rheum Dis 2007; 67:1222-8.

Cum

ulat

ive

surv

ival

0.4

0.6

0.8

1

Idiopathic PAH 1

PAH-SSc2

All patients were treated with first-line bosentan t herapy

80%

51%56%

HTAP-SSc : Effets à long terme du bosentan

Cum

ulat

ive

Time (months)0 12 24 36 48 60 72

0

0.2

Subjectsat risk, n

Idiopathic PAH

PAH-SSc

103 76 48 20 12

49 33 16 11 6 1

PAH-SSc2

1. Provencher S, et al. Eur Heart J 2006; 27:589-95.2. Launay D , et al. Rheumatology 2010; 49:490-500.

Regular monitoring allows augmentation of treatment

Fun

ctio

nal c

apac

ity

No functional impairment

HTAP-SSc : Comment améliorer le pronostic ?

Progressive remodelling and right-heart failure in absence

of treatment

Time

Early intervention

Late intervention

Fun

ctio

nal c

apac

ity

Sitbon O and Galiè N. Eur Respir Rev 2010; 19:272-8.

Detection of milder disease with screening

mPAP (mmHg) 49 ± 17 30 ± 9

Diagnosis with

Screening

(n=18)

Clinical

practice

(n=29)

Diagnosis with

Screening

(n=5)

Clinical

practice

(n=30)

46 ± 13 30 ± 9

Systemic Sclerosis 1 HIV infection 2

CI (L/min/m2) 2.8 ± 0.7 3.2 ± 1.0

PVR (d.s.cm-5) 1007 ± 615 524 ± 382

3.6 ± 0.8

800 ± 320 320 ± 240

3.0 ± 0.8

1. Hachulla E, et al. Arthritis Rheum 2005;52:3792-800.2. Sitbon O, et al . Am J Respir Crit Care Med 2008;177:108-13.

HTAP-SSc : intérêt du dépistage

100

90

80

70

60

rate

(%)

100% 81%(95%CI 51-93%)

73%(95%CI 43-89%)

64%(95%CI 33-84%)

75%(95%CI 46-90%)

Humbert M, et al . Arthritis Rheum 2011; in press .

50

40

30

20

10

00 1 year 3 years 5 years 8 years

Years of follow-up

p=0.0037HR=4.15(95% CI 1.47-11.71)

Sur

viva

lra

te (%

)

31%(95%CI 11-54%) 25%

(95%CI 8-47%)17%

(95%CI 3-39%)

Recommendation-

Evidence

INITIAL THERAPY

FC II FC III FC IV

I-A Ambrisentan,

Bosentan,

Sildenafil

Ambrisentan, Bosentan,

Sildenafil, Epoprostenol i.v.,

Iloprost inhaled

Epoprostenol i.v.

I-B Tadalafil Tadalafil,

Traitement recommandé en classe NYHA II

I-B Tadalafil Tadalafil,

Treprostinil s.c., inhaled

IIa-C Iloprost i.v.,

Treprostinil i.v.

Ambrisentan, Bosentan, Sildenafil,

Tadalafil, Iloprost inhaled, i.v.,

Treprostinil s.c., i.v., inhaled,

Initial Combination Therapy

IIb-B Beraprost

Adapté de : Galiè N, et al. Eur Heart J 2009; 30:2493-537.

Placebo ( n = 91)Bosentan ( n = 87)

Pat

ient

s (%

)

RR = 0.26 (95% CI: 0.08, 0.90)

p = 0.02858

10

12

14

RR = 1.26 (95% CI: 0.40, 3.96)

p = 0.7629

EARLY : effet du bosentan sur la classe NYHA

Pat

ient

s (%

)

p = 0.0285

0

2

4

6

Improved(II����I)

Worsened(II ���� III or IV)

Galiè N, et al . Lancet 2008; 371:2093-100.

100

80

60

40

Pa

tie

nts

wit

ho

ut

the

ev

en

t (%

)

Placebo

BosentanHR = 0.227

p = 0.0114

EARLY : effet du bosentan sur la détérioration cliniq ue

40

20

00 4 8 12 16 20 2824 32

92 90 89 86 84 83 1877 993 92 87 85 84 83 2780 15

Time from treatment start (weeks)

Pa

tie

nts

wit

ho

ut

the

ev

en

t (%

)

Patients at risk

p = 0.0114

Galiè N, et al . Lancet 2008; 371:2093-100.

Establishpatient’s

Stable and Stable and Unstable and

Set treatment goals

1

2

Rate of progressionWHO-FC6-MWDCPET

SyncopeEcho findings

BNP/NT-proBNPHemodynamics

Clinical evidence of right heart failure

Treat-to -target approach for PAH

Adapted from Galiè N, et al. Eur Heart J 2009; 30:2493-537.

patient’sclinical status

Reviewtreatment regimen

Stable andsatisfactory

Stable and not satisfactory

Unstable and deteriorating

No change Escalation

2

3

Assessment parameter

Stable and satisfactory

Stable and not satisfactory

Unstable and deteriorating

Clinical evidenceof RV failure

No Yes

Rate of progression Slow Rapid

Syncope No Yes

WHO-FC I, II IV

Setting treatment goals in PAH:All patients should be in the “better prognosis“ gr oup

Only some of the “green”

parameters are fulfilled

(Grey zone)

WHO-FC I, II IV

6-MWD Longer (> 500 m) Shorter (< 300 m)

CPETPeak VO2

> 15 ml/min/kgPeak VO2

< 12 ml/min/kg

BNP/NT-proBNPplasma levels

Normal or near-normalVery elevated

and rising

Echocardiographicfindings

No pericardial effusionTAPSE > 2.0 cm

Pericardial effusionTAPSE < 1.5 cm

HaemodynamicsRAP < 8 mmHg

and CI ≥ 2.5 l/min/m 2RAP > 15 mmHg

or CI ≤ 2.0 l/min/m 2

Adapted from Galiè N, et al. Eur Heart J 2009; 30:2493-537.

Nov 05 Mar 06 Aug 06 Jan 07

Treatment None Bosentan bosentan+ sildenafil

Bos. + Sil.+ epoprostenol

NYHA FC III III III II

6MWD, m (% theor.) 519 (79%) 525 (80%) 441 (67%) 601 (91%)

Borg score 6 3 4 3

RAP, mmHg 7 8 8 3

Implementation of treat-to -target strategy in PAH

mPAP, mmHg 55 60 65 47

CI, L/min/m 2 2.01 2.50 2.09 3.35

PVR, dyn.s.cm -5 1248 1066 1368 649

BNP, pg/ml - 217 360 62

Status Stable and unsatisfactory Deteriorating Stable and

satisfactory

Action Start first-line bosentan

Addsildenafil Add epoprostenol No change

Tailor treatment goals to

individual

Body mass index

Co-morbidities

Treatment goals in PAH:They should be adapted to the individual patient

individual

Age

index

GenderAetiology

At baseline (prior to therapy)

Every 3-6 months

3-4 months after initiation or changes in

therapy

In case of clinical worsening

Clinical assessmentNYHA/WHO-FC ECG

���� ���� ���� ����

Monitoring patients with PAH:When and how to assess?

ECG

6-MWD ���� ���� ���� ����

Cardio-pulmonary exercise testing

���� ���� ����

BNP/NT-proBNP ���� ���� ���� ����

Echocardiography ���� ���� ����

RHC ���� ���� ����

Galiè N, et al. Eur Heart J 2009; 30:2493-537.

Current therapy Addedtherapy Patients (n) Study

durationPrimary endpoint

Primary EP met

Secondary EP met

STEP1 Bosentan Iloprost 67 12 weeks 6MWD No TTCW

PACES2 Epoprostenol Sildenafil 267 16 weeks 6MWD Yes TTCW

PHIRST3Naïve

or Tadalafil 405 16 weeks 6MWD Yes / (No) TTCW, (No)

Sequential combination therapy in PAHWhat is the evidence?

PHIRST3 orbosentan

Tadalafil 405(206) 16 weeks 6MWD Yes / (No) TTCW, (No)

TRIUMPH-14Bosentan

orsildenafil

Treprostinil(inhaled) 235 12 weeks 6MWD Yes No

FREEDOM-C5Bosentan

and/orsildenafil

Treprostinil(oral) 354 16 weeks 6MWD No No

1. McLaughlin VV , et al. Am J Respir Crit Care Med 2006;174:1257–63. 2. Simonneau G, et al. Ann Intern Med 2008;149:521–30.3. Galiè N et al. Circulation 2009;119:2894–903. 4. McLaughlin V, J Am Coll Cardiol 2010;55:1915–22.5. www.clinicaltrials.gov identifier NCT00325442

Characteristics Improved

(n = 8)

Not improved

(n = 20)

Age, years 32 ± 12 43 ± 18

Male/female, n 1/7 4/16

SLE 5 (62) 8 (40)

MCTD 3 (38) 5 (25)

CREST 0 (0) 5 (25)

Other 0 (0) 2 (10)

NYHA FC I 0 (0) 0 (0)

II 3 (38) 5 (25)**

50

60

70

80

PAS

P (

mm

Hg)

Patients with PAH

(n = 8)

p = 0.016

p = 0.015p = 0.035

p = 0.30

HTAP-SSc : Echec des immunosuppreurs

II 3 (38) 5 (25)

III 5 (62) 10 (50)

IV 0 (0) 5 (25)

6-MWD, m 294 ± 118 240 ± 107

mRAP, mmHg 5 ± 3 7 ± 5

mPAP, mmHg 49 ± 16 51 ± 12

CI, L/min/m2 3.1 ± 0.5 2.6 ± 0.7

PVR index, Wood U/m2 15.6 ± 4 21.4 ± 8

SvO2, % 68 ± 9 65 ± 8

* p < 0.05

**

**

A B C

20

30

40

PAS

P (

Patients without

PAH (n = 12)

p = 0.30

p = 0.10 p = 0.79

Sanchez O, et al . Chest 2006; 130:182-9. Trad S, et al . Arthritis Rheum 2006; 54:184-91.

Transplantation pulmonaire dans le SSc : réticence d es chirurgiens (Maladie systémique, Raynaud, Ulcères digitaux, RGO …)

100

80

100

7590

SScIPFIPAH

SScIPF

HTAP-SSc : Place de la transplantation pulmonaire

80

70

60

50

Time after lung transplant (months)

0

50

25

0

Time after lung transplant (months)

6 12 18 24 0 12 24 36 48 60

Schachna L, et al. Arthritis Rheum 2006; 54:3954-61. Saggar R, et al. Eur Respir J 2010; 36:893-900.

� Malgré les progrès importants réalisés dans la prise en charge thérapeutique de l’HTAP, le pronostic de l’HTAP associ ée à la SSc reste médiocre

� Les pistes d’amélioration de la survie sont:

� Un dépistage efficace afin de diagnostiquer des formes moinssévères de la maladie

HTAP-SSc : Conclusion

sévères de la maladie

� Une approche thérapeutique plus aggressive ?

� “Treat-to-target strategy” ?

� Combinaisons thérapeutiques précoces ?

� Une approche multidisciplinaire est indispensable dans l a prise en charge des patients souffrant d’HTAP associée à la SSc