Post on 07-May-2015
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
dario.vizza@uniroma1.it
Rationale of specific PAH treatmentsRationale of specific PAH treatments
PDE5-I ET-1 AntagonistsProstanoids
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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 ?
Pulmonary Hypertension UnitLa Sapienza University oi Rome
Epoprostenolo
epoprostenol
epoprostenol
67%62%
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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%
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
Opitz C. Eur Heart J 2005; 26: 1895–1902
Pulmonary Hypertension UnitLa Sapienza University oi Rome
Quando utilizzare i Prostanoidi ?
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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)
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
- 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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
– Medical history– NYHA functional class– 6 MWT– Ecocardiography– Right heart catheterization
• Parenteral prostanoids:
– Epoprostenol (Flolan) – Treprostinil (Remodulin)
Results
Pulmonary Hypertension UnitLa Sapienza University oi Rome
# p<0,05
Results
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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%
Pulmonary Hypertension UnitLa Sapienza University oi Rome
51%43%
Results
Pulmonary Hypertension UnitLa Sapienza University oi Rome
Results
Univariate analysis of clinical, echocardiographicand hemodynamic variables associated with mortality
Pulmonary Hypertension UnitLa Sapienza University oi Rome
Results
Multivariate analysis of clinical, echocardiographi cand hemodynamic variables associated with mortality
(χ2 = 24; df = 3; p = 0,00002)
Pulmonary Hypertension UnitLa Sapienza University oi Rome
Conclusioni I
• Quando si inizia a trattare un paziente con terapia orale si deve programmare un attento follow-up per decidere
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
• 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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
• 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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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)
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
courtesy JL Vachiery
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)
RCTRCT’’s with prostanoids in PAH (2)s with prostanoids in PAH (2)
nn includedincluded
WHO class WHO class (%)(%)
IIII
215215
44 1111 6161 00
469469 246246 203203
Pulmonary Hypertension UnitLa Sapienza University oi Rome
courtesy JL Vachiery
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)
RCTRCT’’s with prostanoids in PAH (3)s with prostanoids in PAH (3)
nn includedincluded
SMWTSMWT
HDynamicsHDynamics
↑↑↓↓
↑↑↓↓
↑↑No changeNo change
↑↑↓↓
215215 469469 246246 203203
IloprostIloprost(1)(1)
BeraprostBeraprost(2)(2)
TreprostinilTreprostinil(1)(1)
EpoprostenolEpoprostenol(3)(3)
Pulmonary Hypertension UnitLa Sapienza University oi Rome
courtesy JL Vachiery
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
Mean age (years)
Etiology of PAH:IdiopathicSystemic sclerosisOther *
47
10 (91%)1 (9%)
0
45
17 (77%)4 (18%) 1 (5%)
* Other: Lupus
Humbert et al. Eur Respir J 2004;24:353
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Humbert et al. Eur Respir J 2004;24:353
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Humbert et al. Eur Respir J 2004;24:353
Placebo +epoprostenol (n=10)
Bosentan +epoprostenol (n=19)
0
-20
0
-20
TPR % change from baseline in completers
Pulmonary Hypertension UnitLa Sapienza University oi Rome
% 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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
1400 20 40 60 10080-60 -20-40
Bosentan + epoprostenol
Median and 95% CI
Placebo + epoprostenol
Bosentan + epoprostenol
120
Humbert et al. Eur Respir J 2004;24:353
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
• 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)
Pulmonary Hypertension UnitLa Sapienza University oi Rome
•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 (%
)
Pulmonary Hypertension UnitLa Sapienza University oi Rome
� 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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
•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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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
Pulmonary Hypertension UnitLa Sapienza University oi Rome
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)
Pulmonary Hypertension UnitLa Sapienza University oi Rome
Treprostinil Treprostinil –– median; Others median; Others -- MeanMean
6MWD Placebo Corrected
Change from Baseline (m)
WeekWeek