1. Gli analoghi della prostaciclina nel
trattamento dell’ipertensione
polmonare
Carmine Dario Vizza
Centro Ipertensione Polmonare
DAI Malattie Cardiovascolari e Respiratorie
Universita’
Universita’ di Roma “La Sapienza”
Sapienza”
Direttore Prof Francesco Fedele
dario.vizza@uniroma1.it
Pulmonary Hypertension Unit
La Sapienza University oi Rome

2. Rationale of specific PAH treatments
PDE5-I Prostanoids ET-1 Antagonists
Decreased production Increased production
NO,PGI2 ET1
⇓ Vasodilators anti-proliferative factors
⇑ Vasoconstrictor proliferative factors
Pulmonary Hypertension Unit
La Sapienza University oi Rome

3. Meccanismo di Azione dei Prostanoidi
Muscolo
liscio
Pulmonary Hypertension Unit
La Sapienza University oi Rome

4. Epoprostenolo
1982: effetti emodinamici acuti
(Rubin, Circulation)
1984: primo studio a lungo termine in PPH
come ponte al tx polmonare
(Higenbottam, Lancet)
1990: primo studio randomizzato
(Rubin Ann Int Med)
1996: miglioramento della sopravvivenza
in trial multicentrico
(Barst NEJM)
Pulmonary Hypertension Unit
La Sapienza University oi Rome
Approvazione FDA 1996

5. Prospective, randomized, multicentric study
Epoprostenol vs conventional therapy
81 PPH (NYHA III-IV) followed 12 weeks
III-
Improvement of all outcome variables
Exercise tolerance
Symptoms
NYHA class
Quality of life
Pulmonary Hypertension Unit
La Sapienza University oi Rome

6. Epoprostenolo e sopravvivenza
100
80
Sopravvivenza (%)
60
Epoprostenolo migliora
la sopravvivenza nei
40 pazienti con IP severa
Prostaciclina (n=41)
20
Trattamento convenzionale (n=40)
0
0 2 4 6 8 10 12
Settimane
Pulmonary Hypertension Unit Barst et al NEJM 1996
La Sapienza University oi Rome

7. Epoprostenolo
Risultati a lungo termine
Ipertensione 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 0.001
Pap, mmHg 67±10 52±12 0,001
Pas, mmHg 102±18 87±10 0.001
PC, L/min 3.8±1.2 6.3±2 0.001
RVP, 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
Treadmill
Tempo Exer 261±175 631±283 0.001
Pulmonary Hypertension Unit
La Sapienza University oi Rome McLaughlin, N Engl J Med 1998

8. PAH specific Drugs
Half-life Route Dosage
Prostanoids
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
ET-1 Antagonists
Bosentan 360-480 min os 125 mg bid
Sitaxentan 10 ore os 100 mg
Ambrisentan 9-15 ore os 5-10 mg
PDE-5 Inhibitors
Sildenafil 180-240 min os 20–80 mg tid
Tadalafil
Pulmonary Hypertension Unit
36-40 ore os 10-40 mg tid
La Sapienza University oi Rome

9. Prostanoidi
Epoprostenolo Treprostinil Iloprost
Effetti sistemici Infezioni Frequenti
- Dolori muscolari Inalazioni
- Diarrea Broncospasmo
- Flush cutaneo
Pulmonary Hypertension Unit
La Sapienza University oi Rome

10. Short-term Efficacy on 6-min walk distance
Epoprostenol
PPH SSc
81 pts 111 pts
80
Mean change in the 6 ’WD (m)
60
Active Tx
40
20
0
-20
Control
-40
Tx effect + 47 m + 108 m + 18 m + 36 m
P value < 0.003 < 0.001 0.005 0.004
Pulmonary Hypertension Unit Open trials Double-blind trials
La Sapienza University oi Rome

11. Short-term Efficacy on Pulmonary Vascular Resistance
Epoprostenol
8
Mean change in PVR (mmHg/L) 6
Control
4
2
0
-2
Active Tx
-4
Tx effect - 4.9 - 5.5 -4.7 -4/-1.1
P value <0.001 < 0.001 0.001 0.01 / ns
Pulmonary Hypertension Unit Open trials Double-blind trials
La Sapienza University oi Rome

12. Short-term Efficacy on Cardiac Index
Mean change in Cardiac Index (L/min/m2)
Epoprostenol
(PPH) (Scl)
0,8
0,6
Control
(CO)
0,4
0,2
0
-0,2
Active Tx
-0,4
Tx effect +0.5 + 0.6 +0.18 +0.75/0.25
P value 0.01 0.01 0.003 0.001
Pulmonary Hypertension Unit Open trials Double-blind trials
La Sapienza University oi Rome

13. Quale impatto sulla sopravvivenza ?
Pulmonary Hypertension Unit
La Sapienza University oi Rome

14. Epoprostenolo
epoprostenol
67%
62%
epoprostenol
36%
38%
Pulmonary Hypertension Unit
Sitbon O. et al. JACC 2002;40:780-788 Mc Laughlin VV. et al. Circulation 2002;106:1477-82
La Sapienza University oi Rome

15. Long-term Epoprostenol
&Treprostinil (iPAH)
Treprostinil
Epoprostenol
NIH formula
Pulmonary Hypertension Unit
Lang I. Chest 2006;129:1636-1643
La Sapienza University oi Rome

16. Long-
Long-Term Outcome in IPAH With Treprostinil
100 91%
90 82%
76%
80 72%
69%
70
56%
% Survival
60
50 46%
38%
40
30
20
10
0
0 1 year 2 years 3 years 4 years
n at risk 332 231 149 82 10
Pulmonary Hypertension Unit
La Sapienza University oi Rome Barst et al. Eur Respir J. 2006;28:1195-1203.

17. Long-term Iloprost
Opitz C. Eur Heart J 2005; 26: 1895–1902
Pulmonary Hypertension Unit
La Sapienza University oi Rome

18. Pulmonary Hypertension Unit
La Sapienza University oi Rome

19. Quando utilizzare i Prostanoidi ?
Pulmonary Hypertension Unit
La Sapienza University oi Rome

20. 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)
Pulmonary Hypertension Unit
La Sapienza University oi Rome

21. 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
- Capacità del paziente di adattarsi alla terapia cronica
- Capacità della famiglia di supportare il malato
- Esperienza personale
- Costi
Pulmonary Hypertension Unit
La Sapienza University oi Rome

22. L’esperienza di un
Centro di Riferimento
Pulmonary Hypertension Unit
La Sapienza University oi Rome

23. 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
– NYHA functional class
– 6 MWT
– Ecocardiography
– Right heart catheterization
• Parenteral prostanoids:
– Epoprostenol (Flolan)
– Treprostinil (Remodulin)
Pulmonary Hypertension Unit
La Sapienza University oi Rome

24. Results
# p<0,05
Pulmonary Hypertension Unit
La Sapienza University oi Rome

25. Results
# p<0,05
Clinical, echocardiographic and hemodynamic data are considered
before prostanoid initiation.
Pulmonary Hypertension Unit
La Sapienza University oi Rome

26. Results
Survival in 57 patients with pulmonary hypertension
from first evaluation at our center.
85%
67%
51%
43%
Pulmonary Hypertension Unit
La Sapienza University oi Rome

27. Results
Pulmonary Hypertension Unit
La Sapienza University oi Rome

28. Results
Univariate analysis of clinical, echocardiographic
and hemodynamic variables associated with mortality
Pulmonary Hypertension Unit
La Sapienza University oi Rome

29. Results
Multivariate analysis of clinical, echocardiographic
and hemodynamic variables associated with mortality
(χ2 = 24; df = 3; p = 0,00002)
Pulmonary Hypertension Unit
La Sapienza University oi Rome

30. Conclusioni I
• Quando si inizia a trattare un paziente
con terapia orale si deve programmare
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
Pulmonary Hypertension Unit
La Sapienza University oi Rome

31. 1,0 Breath-1 NEJM 2002
0,9
0,8 Mc Laughlin ERJ 2005
0,7
0,6
0,5
no CW
0,4
0,3 Provencher Thorax 2005
0,2
0,1
Cumulative Pro
0,0
0
180
360
540
720
900
1080
1260
1440
Time, days
Pulmonary Hypertension Unit
Vizza CD, Annual Chest meeting 2008
La Sapienza University oi Rome

32. Epoprostenolo: sopravvivenza & NYHA
1
0.8
Cumulative survival
NYHA FC III
(n = 120)
0.6
0.4 p < 0.001
0.2 NYHA FC IV
(n = 58)
0
0 12 24 36 48 60 72 84 96 108
Time (months)
Pulmonary Hypertension Unit Sitbon O, et al. J Am Coll Cardiol 2002; 40:780-8.
La Sapienza University oi Rome

33. 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
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
Pulmonary Hypertension Unit
La Sapienza University oi Rome

34. Centro Ipertensione Polmonare
Primitiva e Forme Associate
Responsabile: Carmine Dario Vizza
Un. La Sapienza Az. Policlinico
Roma Umberto I
PH clinicians (Cardiology ward, CCU, consultation & outpatients
management):
Senior Cardiologists Dr. Vizza, Dr Badagliacca, Dr Poscia
Fellows: Dr. Nona, Dr. Gambardella
In Training: Dr. Pezzuto, Dr Papa, Dr Scarton
Echo Lab Right Cath Lab
Dr. Sciomer PFTs-CPX Lab CT & RNM Lab Dott. Mancone
Dr. Badagliacca Prof. Palange Dott. Carbone Dott. Colantoni
Dott.Valli Dott. Francone
Reumathologists Liver Transplant Unit HIV outpatients clinic
Pulmonary Ward Lung Transplant Program
Prof. Parola
http://w3.uniroma1.it/cardiore/iperpolm/iperpolm.htm
http://www.ipertensionepolmonare.it
Pulmonary Hypertension Unit
La Sapienza University oi Rome

35. Pulmonary Hypertension Unit
La Sapienza University oi Rome

36. Switching prostanoids
• 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)
IV EPO to IV TRE
– Rubenfire et al CHEST (2007) IV EPO to SC TRE (RCT)
All transitions were successful
Dose to maintain equal efficacy ranges from 1:1 to 1:3
Two studies on bio-equivalence between SC & IV TRE
bio-
Laliberte et al J Cardiovasc Pharmacol 2004 (10ng/kg/min in healthy
volunteers)
McSwain et al J Cardiovasc Pharmacol 2008 (up to 125ng/kg in PAH
courtesy JL Vachiery
Pulmonary Hypertension Unit
La Sapienza University oi Rome

37. Sc Treprostinil Dose in De Novo
Patients
Treprostinil dose, ng/kg/min
Study Year Discharge Week 12 1 year
Simonneau1 2002 NA 9 NA
Barst2 2006 NA NA 26
Lang3 2006 NA ≥20 26
Soto4-6 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
Pulmonary Hypertension Unit
al. PosterSapienza University oi Rome18-23, 2007; San Francisco, CA. 6. Soto. Chest. 2007;132(suppl):634S.
La presented at: ATS; May 37

38. Pulmonary Hypertension Unit
La Sapienza University oi Rome

39. Overview of clinical trials – Issues to consider
No RCT provides blinded head-to-head comparison
head-to-
between different drugs, excepted for a small study*
Consistent study design, although differences in
Population (etiology, NYHA class)
Secondary EP (HD, time to worsening, QOL)
Duration (12-18 weeks, up to 12 months)
(12-
The most common primary EP was exercise capacity
by the 6-minute walking distance (6MWD)
6-
Survival has been assessed in 2 RCTs as primary EP
but events were reported in all trials and assessed
in long term observations
Pulmonary Hypertension Unit
La Sapienza University oi Rome * (SERAPH) Wilkins et al Am J Respir Crit Care Med 2005

40. Pulmonary Hypertension Unit
La Sapienza University oi Rome

41. RCT’
RCT’s with prostanoids in PAH (1)
EPOPROSTENOL
Rubin Ann Intern Med 1990;112:485
Barst NEJM 1996;334:296
Badesch Ann Intern Med 2000;132:425
TREPROSTINIL
Simonneau AJRCCM 2002;165:800
ILOPROST
Olschewski N Engl J Med 2002;347:322
BERAPROST
Galié et al J Am Coll Cardiol 2002;39:1496
Barst J Am Coll Cardiol 2003;41:2119
courtesy JL Vachiery
Pulmonary Hypertension Unit
La Sapienza University oi Rome

42. RCT’
RCT’s with prostanoids in PAH (2)
Epoprostenol Treprostinil Beraprost Iloprost
(3) (1) (2) (1)
n included 215 469 246 203
WHO class (%)
II 4 11 61 0
III 73 82 49 59
IV 23 7 0 41
Etiology (%)
iPAH 48,4 58,1 60,5 50,2
CTD 51,6 18,7 10,2 17,2
CHD 0 23,2 29,3 0
Other 0 0 0 28
courtesy JL Vachiery
Pulmonary Hypertension Unit (CTEPH)
La Sapienza University oi Rome

43. RCT’
RCT’s with prostanoids in PAH (3)
Epoprostenol Treprostinil Beraprost Iloprost
(3) (1) (2) (1)
n included 215 469 246 203
SMWT ↑ ↑ ↑ ↑
HDynamics ↓ ↓ No change ↓
Clin events ↓ (iPAH) ↓ ↓ ↓
↑ (iPAH) NA NA NA
Survival
↑ ↑ No change ↑
QOL
NA NA No change NA
Peak VO2 (US study)
Drawback Central cath JLPain GI disorder Dosing
courtesy Vachiery
Pulmonary Hypertension Unit
La Sapienza University oi Rome

44. Centro Ipertensione Polmonare
Primitiva e Forme Associate
Responsabile: Carmine Dario Vizza
Un. La Sapienza Az. Policlinico
Roma Umberto I
PH clinicians (Cardiology ward, CCU, consultation & outpatients
management):
Senior Cardiologists Dr. Vizza, Dr Badagliacca
Fellows: Dr. Poscia
In Training: Dr. Nona, Dr. Crescenzi
Echo Lab Right Cath Lab
Dr. Sciomer PFTs-CPX Lab CT & RNM Lab Dott. Mancone
Dr. Badagliacca Prof. Palange Dott. Carbone Dott. Colantoni
Dott.Valli Dott. Francone
Reumathologists Liver Transplant Unit HIV outpatients clinic
Pulmonary Ward Lung Transplant Program
Prof. Parola
http://w3.uniroma1.it/cardiore/iperpolm/iperpolm.htm
Pulmonary Hypertension Unit
La Sapienza University oi http://www.ipertensionepolmonare.it
Rome

45. Terapie di associazione
Pulmonary Hypertension Unit
La Sapienza University oi Rome

46. Patient disposition
Substitution rules for missing values
Patients randomized (n=33)
After epoprostenol IV 2 ng/kg/min during 48 hours
Epoprostenol + Epoprostenol +
Randomization Bosentan (n=22) Placebo (n=11)
Premature 1 abnormal LFT*
discontinuation 1 deterioration 1 abnormal LFT*
2 deaths†
*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
Pulmonary Hypertension Unit
La Sapienza University oi Rome
Humbert et al. Eur Respir J 2004;24:353

47. Patient demographics
Placebo + Bosentan +
Epoprostenol (n=11) Epoprostenol (n=22)
Gender M:F 45%:55% 23%:77%
Mean age (years) 47 45
Etiology of PAH:
Idiopathic 10 (91%) 17 (77%)
Systemic sclerosis 1 (9%) 4 (18%)
Other * 0 1 (5%)
* Other: Lupus
Pulmonary Hypertension Unit
La Sapienza University oi Rome
Humbert et al. Eur Respir J 2004;24:353

48. Baseline characteristics
Placebo + Bosentan +
Epoprostenol (n=11) Epoprostenol (n=22)
TPR (dyn.sec.cm-5) 1628 ± 154 1697 ± 142
CI (L/min/m2) 1.7 ± 0.2 1.7 ± 0.1
mPAP (mm Hg) 60.9 ± 2.9 59.2 ± 4.0
mRAP (mm Hg) 11.9 ± 2.2 11.9 ± 1.1
6 MW test (meters) 305 ± 31 286 ± 24
NYHA Class III:IV 8:3 (73%:27%) 17:5 (77%:23%)
Mean ± SEM
Pulmonary Hypertension Unit
La Sapienza University oi Rome
Humbert et al. Eur Respir J 2004;24:353

49. Mean change in hemodynamics from
baseline to week 16
Placebo + Epoprostenol Bosentan + Epoprostenol p-value
Baseline Week 16 Change Baseline Week 16 Change
TPR dyn*sec/cm5 1628 1242 -22.6%* 1697 1016 -36.3 %* NS†
CI L/ mn/m2 1.7 2.3 37.9 %* 1.7 2.5 48.7 %* NS
mPAP mmHg 60.9 59.2 -2.2 % 59.2 52.5 -9.0 %* NS
mRAP mmHg 11.9 12.2 0.3 mmHg 11.9 10.0 -1.9 mmHg NS
(absolute change)
* p < 0.05 compared to baseline † p=0.08 for the difference in the % change
Pulmonary Hypertension Unit
La Sapienza University oi Rome
Humbert et al. Eur Respir J 2004;24:353

50. TPR % change from baseline in
completers
Placebo + Bosentan +
epoprostenol (n=10) epoprostenol (n=19)
0 0
-20 -20
% change
-40 -40
-60 -60
-80 -80
Baseline Week 16 Baseline Week 16
29 of 32 patients completed
Pulmonary Hypertension Unit
Humbert et al. Eur Respir J 2004;24:353
La Sapienza University oi Rome

51. Change in walk distance from
baseline to week 16
Meters
-60 -40 -20 0 20 40 60 80 100 120 140
Mean and 95% CI
Placebo + epoprostenol
Bosentan + epoprostenol
Median and 95% CI
Placebo + epoprostenol
Bosentan + epoprostenol
-60 -40 -20 0 20 40 60 80 100 120 140
Pulmonary Hypertension Unit
La Sapienza University oi Rome
Humbert et al. Eur Respir J 2004;24:353

52. 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 therapy
Controversies/precautions
• 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
Pulmonary Hypertension Unit
La Sapienza University oi Rome

53. STEP: Inhaled Iloprost added to bosentan
Post-inhalation change in 6-MWD (Week 12)
Iloprost Placebo
________________________ ______________________
Meters Change Meters Change
Walked from Baseline Walked from Baseline
___________________________________________________________________________
•Baseline (m)
Mean 336 + 61 340 + 73
•Week 12 (m)
Mean 367 + 84 30 m 343 + 99 4m
p-value 0.001 0.69
(vs. baseline)
Placebo-adjusted Difference:
Pulmonary Hypertension Unit
+26 m p = 0.051
La Sapienza University oi Rome

54. Sildenafil Add-On to
Stable Epoprostenol Therapy
Clinical Worsening Event at
16 Weeks
• 16-week study (n=267)
Patients on stable
epoprostenol for >3 months
Patients (%)
80% of patients provided with
sildenafil 80 mg tid
• Deaths at 16 weeks
Placebo (n=7)
Sildenafil (n=0)
Placebo Sildenafil
Simonneau G, Rubin L, Gaile N, et al. Ann Intern Med. 2008
Pulmonary Hypertension Unit .
La Sapienza University oi Rome

55. Sildenafil Added to Epoprostenol:
Change from Baseline in 6-Minute Walk Distance
50
From Baseline (m) Sildenafil *
40
Mean Change
30
20
10
Placebo
0
-10
0 4 8 12 16
Weeks
Simonneau G, Rubin L, Gaile N, et al.Ann Intern Med. 2008 Oct
21;149(8):521-30
Pulmonary Hypertension Unit .
La Sapienza University oi Rome

56. Inhaled Treprostinil
•Battery operated
(rechargeable)
•Single breath technology
•Each treatment completed
in less than one minute
Pulmonary Hypertension Unit
La Sapienza University oi Rome

57. Inhaled Treprostinil
Hemodynamics at Week 12 (post-inhalation)
(n = 11) Percent
Mean ± SD Baseline 12 weeks change p-value
______________________________________________________________
PAPm 49 ± 10 44 ± 12 - 10% 0.041
mmHg
PVR 9.3 ± 4.9 6.9 ± 3.5 - 26% 0.052
Wood units
CI 2.6 ± 1 3.0 ± 0.9 + 15% 0.058
Liters/min/m2
SAPm 85 ± 15 86 ± 14 + 1% 0.83
mmHg
ChannickHypertensionJACC 2006
Pulmonary et al, Unit
La Sapienza University oi Rome

58. TRIUMPH – 6MWD Median Change
Peak = between 10 and 60 minutes after dose
Trough = 4 hours or greater after dose
P < 0.0006
P < 0.0002
6MWD Median Change
from Baseline (m)
P < 0.007
P = NS
Hodges-
Hodges-Lehmann Estimate of median
change from baseline
McLaughlin V, HypertensionRespir Crit Care Med. 2008;177:A965.
Pulmonary et al. Am J Unit
La Sapienza University oi Rome

59. 6 MWD as an Endpoint: Diminishing Returns
Change from Baseline (m)
6MWD Placebo Corrected
Treprostinil – median; Others - Mean Week
Pulmonary Hypertension Unit
La Sapienza University oi Rome