vizza carmine dario gli analoghi della prostaciclina nel trattamento dell’ipertensione...

Gli analoghi della prostaciclina nel trattamento dell’ipertensione polmonare

Pulmonary Hypertension UnitLa Sapienza University oi Rome

Carmine Dario Vizza Carmine Dario Vizza Centro Ipertensione Polmonare Centro Ipertensione Polmonare

DAI Malattie Cardiovascolari e Respiratorie DAI Malattie Cardiovascolari e Respiratorie UniversitaUniversita’’ di Roma di Roma ““La SapienzaLa Sapienza””Direttore Prof Francesco FedeleDirettore Prof Francesco Fedele

[email protected]

Rationale of specific PAH treatmentsRationale of specific PAH treatments

PDE5-I ET-1 AntagonistsProstanoids


Decreased production NO,PGI2

Increased productionET1

⇓ Vasodilators anti-proliferative factors⇑ Vasoconstrictor proliferative factors

PDE5-I ET-1 AntagonistsProstanoids

Meccanismo di Azione dei ProstanoidiMeccanismo di Azione dei Prostanoidi


MuscoloMuscololiscioliscio

Epoprostenolo

1982: effetti emodinamici acuti1982: effetti emodinamici acuti(Rubin, Circulation)(Rubin, Circulation)

1984: primo studio a lungo termine in PPH1984: primo studio a lungo termine in PPHcome ponte al tx polmonarecome ponte al tx polmonare

(Higenbottam, Lancet)(Higenbottam, Lancet)1990: primo studio randomizzato 1990: primo studio randomizzato


1990: primo studio randomizzato 1990: primo studio randomizzato (Rubin Ann Int Med)(Rubin Ann Int Med)

1996: miglioramento della sopravvivenza1996: miglioramento della sopravvivenzain trial multicentricoin trial multicentrico

(Barst NEJM)(Barst NEJM)

Approvazione FDA 1996Approvazione FDA 1996

Prospective, randomized, multicentric studyProspective, randomized, multicentric studyEpoprostenol vs conventional therapyEpoprostenol vs conventional therapy81 PPH (NYHA III81 PPH (NYHA III--IV) followed 12 weeksIV) followed 12 weeks


81 PPH (NYHA III81 PPH (NYHA III--IV) followed 12 weeksIV) followed 12 weeks

Improvement of all outcome variablesImprovement of all outcome variables

Exercise toleranceExercise toleranceSymptomsSymptomsNYHA classNYHA classQuality of lifeQuality of life

Sop

ravv

iven

za (

%)

100

80

60

40

Epoprostenolo migliorala sopravvivenza nei

Epoprostenolo e sopravvivenza


Prostaciclina (n=41)Trattamento convenzionale (n=40)

Sop

ravv

iven

za (

%)

Settimane

40

20

00 2 4 6 8 10 12

Barst et al NEJM 1996

pazienti con IP severa

Epoprostenolo

Risultati a lungo termineIpertensione Polmonare Primitiva

27 pazienti trattati con Epoprostenolo per un periodo >1 anno (12-36 mesi), III-IV classe NYHA

Base Follow-up p<Pad, mmHg 15±6 9 ± 7 0.001Pap, mmHg 67±10 52±12 0,001

Pulmonary Hypertension UnitLa Sapienza University oi Rome McLaughlin, N Engl J Med 1998

Pap, mmHg 67±10 52±12 0,001Pas, mmHg 102±18 87±10 0.001

PC, L/min 3.8±1.2 6.3±2 0.001RVP, WU 16.7±5.4 12.1±4.5 0.001

RVS, WU 25.1±8.9 17.7±4.9 0.001 SvO2,% 53±8 64±10 0.001

TreadmillTempo Exer 261±175 631±283 0.001

PAH specific DrugsHalf-life Route Dosage

Epopoprostenol 2-4 min i.v. max tolerated

Iloprost 20-40 min i.v./inhal 2.5-5 mcg x 6-9

Treprostinil 4-6 ore s.c. max tolerated

Beraprost 40-120 min os 480 mcg

Prostanoids


Beraprost 40-120 min os 480 mcg

ET-1 AntagonistsBosentan 360-480 min os 125 mg bidSitaxentan 10 ore os 100 mgAmbrisentan 9-15 ore os 5-10 mg

PDE-5 InhibitorsSildenafil 180-240 min os 20–80 mg tid

Tadalafil 36-40 ore os 10-40 mg tid

Prostanoidi


Epoprostenolo Treprostinil

Effetti sistemici- Dolori muscolari- Diarrea- Flush cutaneo

Infezioni

Iloprost

Frequenti InalazioniBroncospasmo

Short-term Efficacy on 6-min walk distance

Mea

n ch

ange

in th

e 6

’WD

(m

)

20

40

60

80

EpoprostenolPPH SSc81 pts 111 pts

Act

ive

Tx


Tx effect

P value

Mea

n ch

ange

in th

e 6

Open trials

-40

-20

0

+ 47 m

< 0.003

+ 108 m

< 0.001

Double-blind trials

+ 18 m

0.005

+ 36 m

0.004

Con

trol

Short-term Efficacy on Pulmonary Vascular Resistanc e

Mea

n ch

ange

in P

VR

(m

mH

g/L)

2

4

6

8

Epoprostenol

Con

trol


Tx effect

P value

Mea

n ch

ange

in P

VR

(m

mH

g/L)

Open trials

-4

-2

0

- 4.9

<0.001

- 5.5

< 0.001

Double-blind trials

-4.7

0.001

-4/-1.1

0.01 / ns

Act

ive

Tx

Short-term Efficacy on Cardiac Index

Mea

n ch

ange

in C

ardi

ac In

dex

(L/m

in/m

2)

0,2

0,4

0,6

(PPH) (Scl)

0,8

Epoprostenol

(CO)

Con

trol


Tx effect

P value

Mea

n ch

ange

in C

ardi

ac In

dex

(L/m

in/m

2)

Open trials

-0,4

-0,2

0

+0.5

0.01

+ 0.6

0.01

Double-blind trials

+0.18

0.003

+0.75/0.25

0.001

Act

ive

Tx

Quale impatto sulla sopravvivenza ?


Epoprostenolo

epoprostenol

epoprostenol

67%62%


Sitbon O. et al. JACC 2002;40:780-788 Mc Laughlin VV. et al. Circulation 2002;106:1477-82

36%38%

Long-term Epoprostenol &Treprostinil (iPAH)

Epoprostenol

Treprostinil


Lang I. Chest 2006;129:1636-1643

NIH formula

LongLong--Term Outcome in IPAH With TreprostinilTerm Outcome in IPAH With Treprostinil

% S

urvi

val

100

90

80

70

60

82%76%

72%

56%

46%

69%

91%


n at risk 332 231 149 82 10

% S

urvi

val

0 1 year 2 years 3 years 4 years

50

40

30

20

10

0

46%38%

Barst et al. Eur Respir J. 2006;28:1195-1203.

Long-term Iloprost


Opitz C. Eur Heart J 2005; 26: 1895–1902

Quando utilizzare i Prostanoidi ?


Prostanoidi come prima linea • Pazienti con rapida progressione in NYHA III &

emodinamica compromessa (PAD > 15 mmHg; IC < 2.0 L/min/m2):

• IV classe funzionale (solo EPO)


Prostanoidi come 2/3°linea

• Pazienti in NYHA III in terapia di combinazione & emodinamica compromessa (PAD > 10 mmHg; IC < 2.2 L/min/m2):

• IV classe funzionale (solo EPO)

Quale Prostanoide ?

a) Se il paziente è in NYHA IV Epoprostenolo

b) In NYHA III considerare la situazione del singolo soggetto:- Rapidità di risposta terapeutica


- Rapidità di risposta terapeutica - Capacità del paziente di adattarsi alla terapia cronica- Capacità della famiglia di supportare il malato- Esperienza personale- Costi

L’esperienza di un Centro di Riferimento


Methods• 57 patients (5M/10F, 49±11) with severe precapillary PH,

treated with parenteral prostanoids, have been followed for a mean of 1084 ±1114 days.

• Data collected at baseline and during follow-up:

– Medical history


– Medical history– NYHA functional class– 6 MWT– Ecocardiography– Right heart catheterization

• Parenteral prostanoids:

– Epoprostenol (Flolan) – Treprostinil (Remodulin)

Results


# p<0,05

Results


Clinical, echocardiographic and hemodynamic data are consideredbefore prostanoid initiation.

# p<0,05

ResultsSurvival in 57 patients with pulmonary hypertension

from first evaluation at our center.

85%

67%

51%


51%43%

Results


Results

Univariate analysis of clinical, echocardiographicand hemodynamic variables associated with mortality


Results

Multivariate analysis of clinical, echocardiographi cand hemodynamic variables associated with mortality

(χ2 = 24; df = 3; p = 0,00002)


Conclusioni I

• Quando si inizia a trattare un paziente con terapia orale si deve programmare un attento follow-up per decidere


un attento follow-up per decidere quando iniziare terapie più complesse !

• Spesso i pazienti vengono inviati ad un centro che offre la terapia con prostanoidi troppo tardivamente

0,4

0,5

0,6

0,7

0,8

0,9

1,0

no

Breath-1 NEJM 2002

Mc Laughlin ERJ 2005


0

180

360

540

720

900 1080

1260

1440

Time, days

0,0

0,1

0,2

0,3

0,4

Cum

ulative Pro

CW

Vizza CD, Annual Chest meeting 2008

Provencher Thorax 2005

Cum

ulat

ive

surv

ival

0.6

0.8

1

NYHA FC III(n = 120)

Epoprostenolo: sopravvivenza & NYHA


Cum

ulat

ive

surv

ival

0

0.2

0.4

0 12 24 36 48 60 72 84 96 108

Time (months)

p < 0.001

NYHA FC IV(n = 58)

Sitbon O, et al. J Am Coll Cardiol 2002; 40:780-8.

Conclusioni II

• L’efficacia terapeutica dei prostanoidi parenterali (EPO-TREP) è strettamente dipendente dal dosaggio che è possibile raggiungere con farmaco (effetti collaterali)

• La dose di TREP non è equipollente a quella dell’EPO (è


• La dose di TREP non è equipollente a quella dell’EPO (è necessario arrivare a dosi 1.3-1.5 volte di TREP per lo stesso effetto clinico ed emodinamico)

• L’EPOPROSTENOLO è l’unico farmaco che ha l’indicazione per la classe NYHA IV

• L’ILOPROST inalatorio non sembra essere un farmaco ottimale per la monoterapia

PH clinicians (Cardiology ward, CCU, consultation & outpatients management) :

Senior Cardiologists Dr. Vizza, Dr Badagliacca, Dr PosciaFellows: Dr. Nona, Dr. GambardellaIn Training: Dr. Pezzuto, Dr Papa, Dr Scarton

Centro Ipertensione PolmonarePrimitiva e Forme AssociateResponsabile: Carmine Dario Vizza

PFTs-CPX Lab CT & RNM LabEcho LabDr. Sciomer

Right Cath LabDott. Mancone

Un. La SapienzaUn. La SapienzaRomaRoma

Az. PoliclinicoAz. PoliclinicoUmberto IUmberto I


PFTs-CPX LabProf. PalangeDott.Valli

CT & RNM LabDott. CarboneDott. Francone

Reumathologists Liver Transplant Unit

Lung Transplant Program

HIV outpatients clinic

Dr. SciomerDr. Badagliacca

Dott. ManconeDott. Colantoni

Pulmonary WardProf. Parola

http://w3.uniroma1.it/cardiore/iperpolm/iperpolm.htmhttp://w3.uniroma1.it/cardiore/iperpolm/iperpolm.htmhttp://www.ipertensionepolmonare.ithttp://www.ipertensionepolmonare.it

• One from epoprostenol to IV iloprost– Higenbottam et al HEART (1998)

• Four from epoprostenol to treprostinil – Vachiéry et al CHEST (2002) IV EPO to SC TRE– Gomberg-Maitland et al Am J Crit Care Med (2005)

IV EPO to IV TRE– Sitbon et al J Cardiovasc Pharmacol (2007)

SSwitching witching prostanoidsprostanoids


courtesy JL Vachiery

All transitions were successfulAll transitions were successfulDose to maintain equal efficacy ranges from 1:1 to 1:3Dose to maintain equal efficacy ranges from 1:1 to 1:3Two studies on bioTwo studies on bio--equivalence between SC & IV TREequivalence between SC & IV TRE

Laliberte Laliberte et alet al J Cardiovasc Pharmacol 2004 (10ng/kg/min in healthyJ Cardiovasc Pharmacol 2004 (10ng/kg/min in healthyvolunteers)volunteers)McSwain McSwain et alet al J Cardiovasc Pharmacol 2008 (up to 125ng/kg in PAHJ Cardiovasc Pharmacol 2008 (up to 125ng/kg in PAH

– Sitbon et al J Cardiovasc Pharmacol (2007) IV EPO to IV TRE

– Rubenfire et al CHEST (2007) IV EPO to SC TRE (RCT)

Sc Treprostinil Dose in De Novo Sc Treprostinil Dose in De Novo PatientsPatients

Treprostinil dose, ng/kg/min

Study Year Discharge Week 12 1 year

Simonneau 1 2002 NA 9 NA

Barst 2 2006 NA NA 26


Barst 2 2006 NA NA 26

Lang 3 2006 NA ≥20 26

Soto 4-6 2006/7 14 ≥40 44

Dose range: 5-14 9-40 26-44

1. Simonneau et al. Am J Respir Crit Care Med. 2002;165(6):800-804. 2. Barst et al. Eur Respir J. 2006;28(6):1195-1203. 3.. Lang et al. Chest. 2006;129(6):1636-1643. 4. Soto et al. Chest. 2006;120S. 5. Soto et al. Poster presented at: ATS; May 18-23, 2007; San Francisco, CA. 6. Soto. Chest. 2007;132(suppl):634S. 37

Overview of clinical trials Overview of clinical trials –– Issues to considerIssues to consider

No RCT provides blinded headNo RCT provides blinded head--toto--head comparison head comparison between different drugs, excepted for a small study*between different drugs, excepted for a small study*

Consistent study design, although differences inConsistent study design, although differences in��Population (etiology, NYHA class)Population (etiology, NYHA class)��Secondary EP (HD, time to worsening, QOL) Secondary EP (HD, time to worsening, QOL) ��Duration (12Duration (12--18 weeks, up to 12 months)18 weeks, up to 12 months)


The most common primary EP was exercise capacityThe most common primary EP was exercise capacityby the 6by the 6--minute walking distance (6MWD)minute walking distance (6MWD)

Survival has been assessed in 2 RCTs as primary EPSurvival has been assessed in 2 RCTs as primary EPbut events were reported in all trials and assessedbut events were reported in all trials and assessedin long term observationsin long term observations

* * (SERAPH) Wilkins et al Am J Respir Crit Care Med 2005(SERAPH) Wilkins et al Am J Respir Crit Care Med 2005

RCTRCT’’s with prostanoids in PAH (1)s with prostanoids in PAH (1)

EPOPROSTENOLEPOPROSTENOLRubin Ann Intern Med 1990;112:485Rubin Ann Intern Med 1990;112:485Barst NEJM 1996;334:296Barst NEJM 1996;334:296Badesch Ann Intern Med 2000;132:425Badesch Ann Intern Med 2000;132:425

TREPROSTINILTREPROSTINILSimonneau AJRCCM 2002;165:800Simonneau AJRCCM 2002;165:800



Simonneau AJRCCM 2002;165:800Simonneau AJRCCM 2002;165:800

ILOPROSTILOPROSTOlschewski N Engl J Med 2002;347:322Olschewski N Engl J Med 2002;347:322

BERAPROSTBERAPROSTGalié et al J Am Coll Cardiol 2002;39:1496Galié et al J Am Coll Cardiol 2002;39:1496Barst J Am Coll Cardiol 2003;41:2119Barst J Am Coll Cardiol 2003;41:2119

IloprostIloprost(1)(1)

BeraprostBeraprost(2)(2)

TreprostinilTreprostinil(1)(1)

EpoprostenolEpoprostenol(3)(3)


nn includedincluded

WHO class WHO class (%)(%)

IIII

215215

44 1111 6161 00

469469 246246 203203



EtiologyEtiology ((%%))

iPAHiPAHCTDCTDCHDCHDOtherOther

IIIIIIIIIIIVIV

4473732323

1111828277

6161494900

0059594141

58,158,118,718,723,223,200

48,448,451,651,60000

60,560,510,210,229,329,300

50,250,217,217,2002828(CTEPH)(CTEPH)


nn includedincluded

SMWTSMWT

HDynamicsHDynamics

↑↑↓↓

↑↑↓↓

↑↑No changeNo change

↑↑↓↓

215215 469469 246246 203203

IloprostIloprost(1)(1)

BeraprostBeraprost(2)(2)

TreprostinilTreprostinil(1)(1)

EpoprostenolEpoprostenol(3)(3)



HDynamicsHDynamics

Clin eventsClin events

SurvivalSurvival

QOLQOL

Peak VOPeak VO22

↓↓↓↓ ((iPAH)iPAH)↑↑ (iPAH)(iPAH)

↑↑NANA

↓↓↓↓NANA↑↑

NANA

No changeNo change↓↓NANA

No changeNo changeNo changeNo change((US study)US study)

↓↓↓↓NANA↑↑

NANA

DrawbackDrawback Central cath Pain GI disorder DosingCentral cath Pain GI disorder Dosing

PH clinicians (Cardiology ward, CCU, consultation & outpatients management) :

Senior Cardiologists Dr. Vizza, Dr BadagliaccaFellows: Dr. PosciaIn Training: Dr. Nona, Dr. Crescenzi

Centro Ipertensione PolmonarePrimitiva e Forme AssociateResponsabile: Carmine Dario Vizza

PFTs-CPX Lab CT & RNM LabEcho LabDr. Sciomer

Right Cath LabDott. Mancone

Un. La SapienzaUn. La SapienzaRomaRoma

Az. PoliclinicoAz. PoliclinicoUmberto IUmberto I


PFTs-CPX LabProf. PalangeDott.Valli

CT & RNM LabDott. CarboneDott. Francone

Reumathologists Liver Transplant Unit

Lung Transplant Program

HIV outpatients clinic

Dr. SciomerDr. Badagliacca

Dott. ManconeDott. Colantoni

Pulmonary WardProf. Parola

http://w3.uniroma1.it/cardiore/iperpolm/iperpolm.htmhttp://w3.uniroma1.it/cardiore/iperpolm/iperpolm.htmhttp://www.ipertensionepolmonare.ithttp://www.ipertensionepolmonare.it

Terapie di associazione


Patient dispositionSubstitution rules for missing values

RandomizationEpoprostenol +Placebo (n=11)

Epoprostenol +Bosentan (n=22)

Patients randomized (n=33)After epoprostenol IV 2 ng/kg/min during 48 hours


Prematurediscontinuation

Randomization

*Last value carried forward for calculation of hemodynamic variables† “worst”value assigned for analysis of hemodynamic variables,zero attributed to the walk test and Class IV for FC at endpoint

Placebo (n=11)Bosentan (n=22)

1 abnormal LFT*

1 deterioration2 deaths†

1 abnormal LFT*

Humbert et al. Eur Respir J 2004;24:353

Gender M:F

Mean age (years)

45%:55%

47

23%:77%

45

Placebo + Epoprostenol (n=11)

Bosentan +Epoprostenol (n=22)

Patient demographics


Mean age (years)

Etiology of PAH:IdiopathicSystemic sclerosisOther *

47

10 (91%)1 (9%)

0

45

17 (77%)4 (18%) 1 (5%)

* Other: Lupus


Placebo +Epoprostenol (n=11)

Bosentan +Epoprostenol (n=22)

TPR (dyn.sec.cm-5)

CI (L/min/m2)

1628 ± 154

1.7 ± 0.2

1697 ± 142

1.7 ± 0.1

Baseline characteristics


CI (L/min/m2)

mPAP (mm Hg)

mRAP (mm Hg)

6 MW test (meters)

NYHA Class III:IV

1.7 ± 0.2

60.9 ± 2.9

11.9 ± 2.2

305 ± 31

8:3 (73%:27%)

1.7 ± 0.1

59.2 ± 4.0

11.9 ± 1.1

286 ± 24

17:5 (77%:23%)

Mean ± SEM


NS†TPR dyn*sec/cm5 -22.6%* -36.3 %*

Placebo + Epoprostenol Bosentan + Epoprostenol p-value

12421628 1697 1016

Baseline Week 16 Change Baseline Week 16 Change

Mean change in hemodynamics from baseline to week 16


NS

NS

NS

NS

TPR dyn*sec/cm

CI L/ mn/m2

mPAP mmHg

mRAP mmHg(absolute change)

-22.6%*

37.9 %*

-2.2 %

0.3 mmHg

-36.3 %*

48.7 %*

-9.0 %*

-1.9 mmHg

* p < 0.05 compared to baseline † p=0.08 for the difference in the % change

1242

2.3

59.2

12.2

1628

1.7

60.9

11.9

1697

1.7

59.2

11.9

1016

2.5

52.5

10.0


Placebo +epoprostenol (n=10)

Bosentan +epoprostenol (n=19)

0

-20

0

-20

TPR % change from baseline in completers


% c

hang

e

Baseline Week 16Baseline Week 16

-80

-60

-40

-20

-80

-60

-40

-20

29 of 32 patients completed Humbert et al. Eur Respir J 2004;24:353

Change in walk distance from baseline to week 16

1400 20 40 60 10080-60 -20-40

Mean and 95% CI

Placebo + epoprostenol

120Meters


1400 20 40 60 10080-60 -20-40

Bosentan + epoprostenol

Median and 95% CI

Placebo + epoprostenol

Bosentan + epoprostenol

120


Combination Therapy for PAH• Three separate therapeutic pathways available

� Potential to increase efficacy by combining agents targeting different pathways

• Potential to reduce need for invasive therapyControversies/precautions• Virtually all data are from uncontrolled trials with small numbers of


• Virtually all data are from uncontrolled trials with small numbers of patients

• Combination therapy most often studied as add-on treatment to existing monotherapy

• No prospective clinical trial data available on use of triple-class combination therapy

STEP: Inhaled Iloprost added to bosentan Post-inhalation change in 6-MWD (Week 12)

Iloprost Place bo________________________ ______________________ Meters Change Meters Change Walked from Baseline Walked from Baseline

___________________________________________________________________________

•Baseline (m)


•Baseline (m)Mean 336 + 61 340 + 73

•Week 12 (m)Mean 367 + 84 30 m 343 + 99 4 m

p-value 0.001 0.69(vs. baseline)

Placebo-adjusted Difference: +26 m p = 0.051

Sildenafil Add-On toStable Epoprostenol Therapy

• 16-week study (n=267)� Patients on stable

epoprostenol for >3 months� 80% of patients provided with

Clinical Worsening Event at 16 Weeks

Pat

ient

s (%

)


� 80% of patients provided with sildenafil 80 mg tid

• Deaths at 16 weeks� Placebo (n=7)� Sildenafil (n=0)

Pat

ient

s (%

)Placebo Sildenafil

Simonneau G, Rubin L, Gaile N, et al. Ann Intern Med. 2008.

Sildenafil Added to Epoprostenol:Change from Baseline in 6-Minute Walk Distance

Mea

n C

hang

eF

rom

Bas

elin

e (m

) *Sildenafil

30

40

50


Simonneau G, Rubin L, Gaile N, et al.Ann Intern Med. 2008 Oct 21;149(8):521-30.

Mea

n C

hang

eF

rom

Bas

elin

e (m

)

Weeks0 4 8 12 16

Placebo

-10

0

10

20

Inhaled Treprostinil

•Battery operated (rechargeable)•Single breath technology•Each treatment completed


•Each treatment completed in less than one minute

Inhaled TreprostinilHemodynamics at Week 12 (post-inhalation)

(n = 11) PercentMean ± SD Baseline 12 weeks change p-va lue______________________________________________________________

PAPm 49 ± 10 44 ± 12 - 10% 0.041mmHg

PVR 9.3 ± 4.9 6.9 ± 3.5 - 26% 0.052


PVR 9.3 ± 4.9 6.9 ± 3.5 - 26% 0.052Wood units

CI 2.6 ± 1 3.0 ± 0.9 + 15% 0.058 Liters/min/m2

SAPm 85 ± 15 86 ± 14 + 1% 0.83mmHg

Channick et al, JACC 2006

TRIUMPH – 6MWD Median Change

P < 0.0006

P < 0.0002

6MWD Median Change

from Baseline (m)

Peak = between 10 and 60 minutes after dosePeak = between 10 and 60 minutes after dose

Trough = 4 hours or greater after doseTrough = 4 hours or greater after dose

P < 0.007


HodgesHodges--Lehmann Estimate of median Lehmann Estimate of median change from baselinechange from baseline

P = NS

6MWD Median Change

from Baseline (m)

McLaughlin V, et al. Am J Respir Crit Care Med. 2008;177:A965.

6 MWD as an Endpoint: Diminishing Returns6MWD Placebo Corrected

Change from Baseline (m)


Treprostinil Treprostinil –– median; Others median; Others -- MeanMean

6MWD Placebo Corrected

Change from Baseline (m)

WeekWeek

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