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Nazzareno Galiè
Istituto di Cardiologia
Università di Bologna
PAH: Standard of Care
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A. Do we have additional information on the role of rehabilitation in PAH patients?
B. Should first-line combination therapy be the gold standard of severe WHO FC IV PAH (and what about other FC)?
C. How can we modify the current treatment algorithm including the new approved drugs?
D. Should we adapt the treatment algorithm to the different PAH types and to different countries (country organization)?
TF 7 Therapy ‐ Standard of CareQuestions
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1st WHO PH
Geneva
1973
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PH Classification 1950-1998
(1st WHO PH Geneva 1973)
1. Primary Pulmonary Hypertension
2. Secondary Pulmonary Hypertension
3. Associated Pulmonary Hypertension
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PAH time course of Treatments
„50 „80 „90 „00 „10
Tolazoline, Hydralazine, Acetylcholine, Phentolamine, Isoproterenol, Diazoxide, Nitrates,…
Calcium Channel Blockers in vasoreactive pts
„09
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Rich S et al. N Engl J Med 1992, 32:76-81
~ 10%
Vasoreactivity – NO test
BaselineNO 10 ppm
mPAP = 58 mm Hg mPAP = 25 mm Hg
Definition
↓ mPAP > 10, < 40 mmHg abs; CO =/↑
Calcium Channel Blockers
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Treatment Algorithm before 1998
Oral CCB (I C)
Vasoreactive
Pulmonary Arterial Hypertension
Acute Vasoreactivity Test
Supportive Therapy and
General Measures
Non-vasoreactive
Oral anticoagulants
Diuretics
Oxygen(Iia)
Digoxin
NYHA Class I-IV
Exercise Limitation
Birth Control
Psychological Assistance
Infections Prevention
???????
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New Engl J Med 1996; 334:296-301
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1. Rubin, Epoprostenol in PPH. Ann Intern Med 1990
2. Barst, Epoprostenol in PPH. N Engl J Med 1996
3. Badesch, Epoprostenol scleroderma PAH. Ann Intern Med 2000
Published RCTs in PAH
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2nd WHO PH
Evian
1998
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Treatment Algorithm …1998 - 2003
Oral CCB (I C)
Vasoreactive
Epoprostenol
Pulmonary Arterial Hypertension
Acute Vasoreactivity Test
Supportive Therapy and
General Measures
NYHA Class III-IV
Non-vasoreactive
Oral anticoagulants
Diuretics
Oxygen(Iia)
Digoxin
NYHA Class I-IV
Exercise Limitation
Birth Control
Psychological Assistance
Infections Prevention
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1. Rubin, Epoprostenol in PPH. Ann Intern Med 1990
2. Barst, Epoprostenol in PPH. N Engl J Med 1996
3. Badesch, Epoprostenol scleroderma PAH. Ann Intern Med 2000
4. Channick, Bosentan in PAH. Lancet 2001
5. Langleben, Terbogrel in PPH. Am J Cardiol 2002
6. Simonneau, Treprostinil in PAH. Am J Respir Crit Care Med 2002
7. Galié, Beraprost in PAH. J Am Coll Cardiol 2002
8. Olschewski, Inhaled Iloprost in PH. N Engl J Med 2002
9. Rubin, Bosentan in PAH. N Engl J Med 2002
10. Barst, Beraprost in PAH. J Am Coll Cardiol 2003
11. Sastry, Sildenafil in IPAH. J Am Coll Cardiol 2004
12. Humbert, Bosentan + Epoprostenol in PAH. Eur Respir J 2004
13. Barst, Sitaxsentan. Am J Respir Crit Care Med 2004
14. Galié, Sildenafil in PAH. N Engl J Med 2005
Published RCTs in PAH
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3rd WSPAH
Venice
2003
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Approved Drugs for PAH
Bosentan
Epoprostenol iv
Iloprost inhal
Sildenafil
Treprostinil sc
Bosentan
Epoprostenol iv
Iloprost inhal
Sildenafil
Treprostinil sc
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Endothelin R Antagonists
Bosentan (I A)
or
Prostanoid Analogues
Iloprost inh (I A)
Treprostinil (IIa B)
Beraprost (IIb B)
or
PDE-5 inhibitors
Sildenafil (IA)
or
Continuous IV prostacyclin
Epoprostenol (I A)
BAS (IIa C)
and/or
Lung Transplant (I C)
Oral CCB (I C)
Continue CCB
Sustained Response
(NYHA I-II)
Yes No
Vasoreactive
Epoprostenol (I A)
Bosentan (IIa B)
Treprostinil (IIa B)
Iloprost iv (IIa C)
No improvement or deterioration:
Combination Therapy ? (IIa B)
Expert Referral
Pulmonary Arterial Hypertension
Acute Vasoreactivity Test
Supportive Therapy and
General Measures (IIa C)
NYHA Class IVNYHA Class III
Non-vasoreactive
Oral anticoagulants (IIa C)
Diuretics (I C)
Oxygen(IIa C)
Digoxin (IIb C)
NYHA Class I-IV
Exercise Limitation
Birth Control
Psychological Assistance
Infections Prevention
Galiè N, et al. Eur Heart J 2004; 25:2243-2278.
PAH treatment algorithm - 2004
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1990 1996 2000
Epoprostenol
‘01 ‘02 ‘03 ‘04 ‘05 ‘06 ‘08 ‘09
Bosentan
Terbogrel
Treprostinil
AIR
BREATHE1
ALPHABETBeraprost
Sildenafil
BREATHE2
STRIDE1
SUPER
SERAPH
STEP
Sildenafil
STRIDE2
COMBI
BREATHE5
ARIES
EARLY
PACES
PHIRST
Epoprostenol
Epoprostenol
Monotherapy
Monotherapy and/or Sequential Combination
Upfront Combination
TRIUMPH
‘10
N.Galiè, M.Palazzini, A.Manes, Eur Heart J 2010
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Approved Drugs for PAH
Ambrisentan
Bosentan
Epoprostenol iv
Iloprost inhal
Sildenafil
Sitaxentan
Tadalafil
Treprostinil sc
Ambrisentan
Bosentan
Epoprostenol iv
Iloprost inhal
Sildenafil
Tadalafil
Treprostinil sc, iv, inhal
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• Medline search from January 1990 to April 2010
• 25 RCTs, 3839 patients
Pulmonary arterial hypertension: from the
kingdom of the near-dead to multiple clinical trial
meta-analyses
CURRENT OPINION
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Heterogeneity between groups: p = 0.788
Overall (I-squared = 0.0%, p = 0.908)
Galiè-2005
Sastry-2004
McLaughlin-2010
Langleben-2002
Thromboxane synthase inhibitor
Simonneau-2008
Subtotal (I-squared = 0.0%, p = 0.682)
Endothelin Receptor Antagonists
Badesch-2000
Galiè-2008
Subtotal (I-squared = 0.0%, p = 0.597)
Barst-2003
Galiè-2008
Galiè-2009
Phosphodiesterase Type 5 Inhibitors
Singh-2006
Channick-2001
Simmoneau-2002
Rubin-2002
ID
Barst-1996
Subtotal (I-squared = 0.0%, p = 0.696)
Prostacyclin Analogues
Galiè-2002
Subtotal (I-squared = .%, p = .)
Rubin-1990
Barst-2006
McLaughlin-2006
Olschewski-2002
Study
Galiè-2006
Barst-2004
0.56 (0.35, 0.90)
1.01 (0.11, 9.55)
0.39 (0.02, 8.73)
0.35 (0.01, 8.45)
1.66 (0.07, 39.30)
0.07 (0.00, 1.15)
0.62 (0.34, 1.12)
0.79 (0.22, 2.77)
0.41 (0.11, 1.49)
0.60 (0.12, 2.86)
0.47 (0.04, 5.01)
0.99 (0.06, 15.58)
0.51 (0.05, 5.53)
(Excluded)
(Excluded)
0.92 (0.38, 2.21)
0.24 (0.02, 2.60)
RR (95% CI)
0.06 (0.00, 0.96)
0.40 (0.16, 1.01)
1.00 (0.06, 15.65)
1.66 (0.07, 39.30)
0.36 (0.04, 3.00)
(Excluded)
(Excluded)
0.25 (0.03, 2.22)
(Excluded)
1.54 (0.06, 37.19)
100.00
4.32
2.27
2.14
2.18
2.68
62.91
13.72
12.95
8.86
3.88
2.87
3.83
0.00
0.00
28.03
3.84
Weight
2.74
26.05
2.88
2.18
4.90
0.00
0.00
4.62
%
0.00
2.15
0.56 (0.35, 0.90)
1.01 (0.11, 9.55)
0.39 (0.02, 8.73)
0.35 (0.01, 8.45)
1.66 (0.07, 39.30)
0.07 (0.00, 1.15)
0.62 (0.34, 1.12)
0.79 (0.22, 2.77)
0.41 (0.11, 1.49)
0.60 (0.12, 2.86)
0.47 (0.04, 5.01)
0.99 (0.06, 15.58)
0.51 (0.05, 5.53)
(Excluded)
(Excluded)
0.92 (0.38, 2.21)
0.24 (0.02, 2.60)
RR (95% CI)
0.06 (0.00, 0.96)
0.40 (0.16, 1.01)
1.00 (0.06, 15.65)
1.66 (0.07, 39.30)
0.36 (0.04, 3.00)
(Excluded)
(Excluded)
0.25 (0.03, 2.22)
(Excluded)
1.54 (0.06, 37.19)
100.00
4.32
2.27
2.14
2.18
2.68
62.91
13.72
12.95
8.86
3.88
2.87
3.83
0.00
0.00
28.03
3.84
Weight
2.74
26.05
2.88
2.18
4.90
0.00
0.00
4.62
%
0.00
2.15
1.00342 1 292
Favors Treatments I Favors Controls
Heterogeneity between groups: p = 0.788
Overall (I-squared = 0.0%, p = 0.908)
Galiè-2005
Sastry-2004
McLaughlin-2010
Langleben-2002
Thromboxane synthase inhibitor
Simonneau-2008
Subtotal (I-squared = 0.0%, p = 0.682)
Endothelin Receptor Antagonists
Badesch-2000
Galiè-2008
Subtotal (I-squared = 0.0%, p = 0.597)
Barst-2003
Galiè-2008
Galiè-2009
Phosphodiesterase Type 5 Inhibitors
Singh-2006
Channick-2001
Simmoneau-2002
Rubin-2002
ID
Barst-1996
Subtotal (I-squared = 0.0%, p = 0.696)
Prostacyclin Analogues
Galiè-2002
Subtotal (I-squared = .%, p = .)
Rubin-1990
Barst-2006
McLaughlin-2006
Olschewski-2002
Study
Galiè-2006
Barst-2004
0.56 (0.35, 0.90)
1.01 (0.11, 9.55)
0.39 (0.02, 8.73)
0.35 (0.01, 8.45)
1.66 (0.07, 39.30)
0.07 (0.00, 1.15)
0.62 (0.34, 1.12)
0.79 (0.22, 2.77)
0.41 (0.11, 1.49)
0.60 (0.12, 2.86)
0.47 (0.04, 5.01)
0.99 (0.06, 15.58)
0.51 (0.05, 5.53)
(Excluded)
(Excluded)
0.92 (0.38, 2.21)
0.24 (0.02, 2.60)
RR (95% CI)
0.06 (0.00, 0.96)
0.40 (0.16, 1.01)
1.00 (0.06, 15.65)
1.66 (0.07, 39.30)
0.36 (0.04, 3.00)
(Excluded)
(Excluded)
0.25 (0.03, 2.22)
(Excluded)
1.54 (0.06, 37.19)
100.00
4.32
2.27
2.14
2.18
2.68
62.91
13.72
12.95
8.86
3.88
2.87
3.83
0.00
0.00
28.03
3.84
Weight
2.74
26.05
2.88
2.18
4.90
0.00
0.00
4.62
%
0.00
2.15
0.56 (0.35, 0.90)
1.01 (0.11, 9.55)
0.39 (0.02, 8.73)
0.35 (0.01, 8.45)
1.66 (0.07, 39.30)
0.07 (0.00, 1.15)
0.62 (0.34, 1.12)
0.79 (0.22, 2.77)
0.41 (0.11, 1.49)
0.60 (0.12, 2.86)
0.47 (0.04, 5.01)
0.99 (0.06, 15.58)
0.51 (0.05, 5.53)
(Excluded)
(Excluded)
0.92 (0.38, 2.21)
0.24 (0.02, 2.60)
RR (95% CI)
0.06 (0.00, 0.96)
0.40 (0.16, 1.01)
1.00 (0.06, 15.65)
1.66 (0.07, 39.30)
0.36 (0.04, 3.00)
(Excluded)
(Excluded)
0.25 (0.03, 2.22)
(Excluded)
1.54 (0.06, 37.19)
100.00
4.32
2.27
2.14
2.18
2.68
62.91
13.72
12.95
8.86
3.88
2.87
3.83
0.00
0.00
28.03
3.84
Weight
2.74
26.05
2.88
2.18
4.90
0.00
0.00
4.62
%
0.00
2.15
1.00342 1 292
Hoeper-2006 (Excluded) 0.00
RR = - 44%
P = 0.016
All Cause Mortality
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4th WSPH
Dana Point
2008
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Galiè.N et al
Eur Heart J
and Eur
Respir J,
2009
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Areas of Algorithm Improvement
• Upfront combination therapy
• Place for new drugs (Imatinib, Macitentan
Riociguat, Selexipag)
• Transplantation indication
• RV assistance
• Indications for complications
• Definition of expert center/Country organization
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Areas of Algorithm Improvement
• Upfront combination therapy
• Place for new drugs (Imatinib, Macitentan
Riociguat, Selexipag)
• Transplantation indication
• BAS indication
• RV assistance
• Indications for complications
• Definition of expert center/Country organization
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Areas of Algorithm Improvement
• Upfront combination therapy
• Place for new drugs (Imatinib, Macitentan
Riociguat, Selexipag)
• Transplantation indication
• BAS indication
• RV assistance
• Indications for complications
• Definition of expert center/Country organization
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Combination Strategies
Drug AInadequate
response
Drug B
Sequential Combination
Drug A+BUpfront Combination
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TPR change from baseline (%)
BREATHE-2
Epoprostenol + bosentan
29 of 32 patients completed at week 16
Humbert M, et al. Eur Respir J 2004; 24:353-9.
Placebo + epo (n=10)
Baseline Wk 16
-80
-60
0
-40
-20
Bos + epo (n=19)
Baseline Wk 16
-80
-60
0
-40
-20
% c
ha
ng
e
140
Median and 95% CIPlacebo/epo
Bos/epo
0 20 40 60 10080-60 -20-40
Metres
Mean and 95% CIPlacebo/epo (n=10)
Bos/epo (n=19)
6-MWD (metres)
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PV
R (
d.s
.cm
-5)
500
1000
1500
0
2000
Baseline Baseline 3-month4-month
Epoprostenol
monotherapy
(n=46)0
0.2
0.4
0.6
0.8
1
0 12 24 36 48 60 72 84 96 108120132144
Time (months)
P=0.07
Epo + bosentan
combination
therapy (n=23)
Cu
mu
lati
ve
su
rviv
al
Epo + bosentan
combination therapy
(n = 23)
Epoprostenol
monotherapy
(n = 46)
p = 0.0001
-48 ± 17% -29 ± 17%
Kemp K, et al. J Heart Lung Transpl. In press.
Effect of up-front combination therapyBREATHE-2: bosentan & epoprostenol
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2 diapo trithérapie à compléter
- 69 ± 8%
PV
R (
d.s
.cm
-5)
-29 ± 17%
500
1000
1500
0
2000
Baseline 4-mo.
PV
R (
d.s
.cm
-5)
-48 ± 17%
500
1000
1500
0
2000
Baseline 4-mo.0
400
800
1200
1600
2000
Base 4 mois
PV
R (
d.s
.cm
-5)
Epo + bosentan + sildenafil
combination therapy
(n=11)
Epoprostenol + bosentan
combination therapy
(n=23)
Epoprostenol
monotherapy
(n=46)
Baseline 4-mo.
Up-front triple combination therapy in PAH
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Ambition Study
Phase III randomised controlled study
comparing upfront combination therapy
(Ambrisentan+Tadalafil) to initial monotherapy
(Ambrisentan or Tadalafil)
Time to treatment failure as primary end-point
Event driven sample size and duration starting
with 510 patients and a minimum F-U of 10
months
A randomized, double-blind, placebo-controlled, multicenter
study of first-line combination therapy with AMBrIsentan
and Tadalafil vs. monotherapy in subjects with pulmonary
arterial hypertensION
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Ambrisentan 10 mg
Tadalafil 40 mg
Ambrisentan 10mg+Tadalafil 40mg
Efficacy of up-front combination
Naive
Patients
Phase III: AMBITION
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Primary End Point “Time to Clinical Failure”
Time to clinical failure is defined as the time from randomization to the first
occurrence of:
Death (all-cause)
Hospitalization for worsening PAH (adjudicated)
- Non-elective hospitalization for worsening PAH
- Lung or heart/lung transplant
- Atrial septostomy
- Initiation of parenteral prostanoid therapy
Disease progression (adjudicated)
- >15% decrease from baseline in 6MWD combined with WHO class III or
IV symptoms (at two consecutive post-baseline clinic visits separated
by ≥14 days)
Unsatisfactory long-term clinical response (adjudicated, all criteria required)
- Receiving randomized treatment for at least 6 months
- Any decrease from baseline in 6MWD at two consecutive post-baseline
clinic visits separated by ≥14 days
- Sustained WHO class III symptoms for ≥6 months (WHO class III
symptoms assessed at two clinic visits separated by ≥ 6
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Areas of Algorithm Improvement
• Upfront combination therapy
• Place for new drugs (Imatinib, Macitentan
Riociguat, Selexipag)
• Transplantation indication
• RV assistance
• Indications for complications
• Definition of expert center/Country organization
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ADVENTITIAInflammatory Cells†‡
Fibrosis↑Cyto/Chemokines†‡↑MMP and tenascin†‡
↑B-FGF†
MEDIASMC Hyperplasia*†
K+ch dysfunction and related ↑ [Ca++ ]*
↓BMPRs†↑Angiopoietin†
INTIMAMFB Hyperplasia†
Fibrosis†↑PDGF receptors†
↑Cyto/Chemokines†‡
ENDOTELIUM↑Endothelin*†↓Prostacyclin*†
↓Nitric Oxide/cGMP*†↑TxA2*†§
↑VEGF†↓BMPRs†
BLOODHypercoagulability §
Platelets Dysfunction §
↑Serotonin*†↑PDGF†↓VIP*†
N.Galiè, M.Palazzini, A.Manes, Eur Heart J 2010
Anticoagulants
*Vasoconstriction; †Proliferation/migration; ‡Inflammation; §Thrombosis
PDE-5 inhibitors
Prostanoids
Endothelin Receptor Antagonists
Ca++ -Channel blockers
(Vasoreactivity responders)
PathobiologyTreatments
Seroronin Antagonists
Vasoactive Intestinal Peptide
Tissular ERA
Oral IP Receptor Agonist
Direct Stimulator of GC Tyrosin-Kinase inhibitors
Upfront Combo Therapy
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RCTs in PAH with new oral therapies
Pathway
IMPRES (imatinibI) TK inhibitor
PDGF-R inhibitor
SERAPHIN (macitentan) Endothelin
Tissue-specific ERA
PATENT (riociguat) Nitric oxide
GC stimulator
FREEDOM (treprostinil) Prostacyclin
GRIPHON (selexipag) Prostacyclin
P-R agonist
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RCTs in PAH with new oral therapies
Primary EP
IMPRES (imatinib-TKI) 6-MWD
SERAPHIN (macitentan-ERA) M/M
PATENT (riociguat-GS) 6-MWD
FREEDOM (treprostinil-P) 6-MWD
GRIPHON (selexipag-PRS) M/M
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Enrolment of patients
and completion of the study
Randomized
n=202
Completed
24 weeks
n=69 (67.0%)
Completed
24 weeks
n=81 (81.8%)
Discontinued: n=34 (33.0%)
• AEs: 27 (26.2%)
• Unsatisfactory therapeutic effect: 1 (1.0%)
• Death: 2 (1.9%)
• Withdrew consent: 2 (1.9%)
• Abnormal laboratory value: 1 (1.0%)
• Protocol deviation: 1 (1.0%)
• Administrative problems: 0 (0.0%)
Discontinued: n=18 (18.2%)
• AEs: 7 (7.1%)
• Unsatisfactory therapeutic effect: 5 (5.1%)
• Death: 2 (2%)
• Withdrew consent: 1 (1%)
• Abnormal laboratory value: 1 (1%)
• Protocol deviation: 1 (1%)
• Administrative problems: 1 (1%)
Imatinib
n=103
Placebo
n=99
Screened
n=326
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LS mean 6MWD was significantly higher at Week 24 in patients receiving imatinib (383±9.8 m)
than in those receiving placebo (351±9.8 m)
– between-group difference: 31.8±10.1 m (p=0.002)
Primary endpoint: change in 6MWD
5,46,9
39,6
48,5
56,6 52,1
0,9
14,7
16,0
28,0
23,1
17,6
0
10
20
30
40
50
60
70
0 4 8 12 16 20 24
Change in 6
MW
D fro
m b
aselin
e (
m)
Time (weeks)
Imatinib
Placebo
p<0.001p=0.050p=0.009 p=0.001
Values are means and standard errors. p-values are for between-group comparisons.
The primary variable was analyzed using the full analysis set and a mixed effects model for repeated measures.
Missing values imputed with plausible values. LS = least squares
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Change in haemodynamic
parameters at Week 24
Cardiac OutputPulmonary arterial pressure
–3.54
1,63
-8
-6
-4
-2
0
2
4
LS
me
an
ch
an
ge
in P
AP
(m
mH
g)
12,1
-600
-500
-400
-300
-200
-100
0
100
LS
me
an
ch
an
ge
in
PV
R
(dyn
es.s
.cm
-5)
–366.5
Pulmonary Vascular
Resistance
Imatinib Placebo
∆–5.18 mmHg, p<0.001 ∆–378.6 dynes.sec.cm-5, p<0.001∆+0.88 L/min, p<0.001
1,17
0,29
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1,6
LS
me
an
ch
an
ge
in C
O (
L/m
in)
Data is least squares (LS) means, full analysis set
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Time to clinical worsening
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Perc
en
t fr
ee s
urv
iva
l
Time to first clinical worsening event (weeks)
0 4 8 12 16 20 24 28
Imatinib
Placebo
No. of patients
Imatinib 103 93 70 66 60 58 45
Placebo 98 91 85 80 75 72 54
Hazard ratio: 1.16 (95% CI, 0.71–1.90)
p=0.563 (Cox regression)
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Subdural Hematomas in the QTI Clinical Program
There have been 11 cases of subdural hematoma (SDH)s:
– 9 in the QTI571 clinical trials
• 8 Phase III trial: core and extension (n=181)
• 1 Phase II trials core (n= 45)
• 0 Drug-drug interaction trial (n=18)
– 1 spontaneous report in Patient Supply Programs (requests from physicians for drug)
• 0 Japan Named Patient Program (n=9)
• 0 Individual Patient Supply Program UK (n=4)
• 1 Individual Patient Supply Program Switzerland (n=23)
– 1 spontaneous report from off label use in patient with prior h/o SDH
7 females and 2 males between the ages of 47-66 years old
Time to event ranges from 12 days to 18 months
All SDH cases were also anticoagulated; no SDH cases have occurred in non-
anticoagulated patients
40
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Macitentan in the SERAPHIN trial
Study objectives
www.clinicaltrials.gov, NCT00660179.
Primary objective
To demonstrate that macitentan prolongs the time to the first morbidity
or mortality event in patients with symptomatic PAH
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Primary efficacy endpoint
Macitentan reduced the risk of a morbidity and mortality event
Dose of macitentan (mg) Observed risk reduction (%) p value
3 30 0.0108
Actelion. Press release 2012
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Primary efficacy endpoint
A dose-related effect has been observed
Dose of macitentan (mg) Observed risk reduction (%) p value
10 45 < 0.0001
3 30 0.0108
Actelion. Press release 2012
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Secondary efficacy endpoints
*Over the whole treatment period.
Both doses of macitentan demonstrated a statistically
significant effect on secondary objectives:
• Change from baseline to month 6 in 6-MWD
• Change from baseline to month 6 in WHO functional class
• Time to either death due to PAH or hospitalisation due to
PAH*
Actelion. Press release 2012
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Macitentan: Aminotransferase elevations
PlaceboMacitentan
3 mg
Macitentan
10 mg
ALT or AST > 3 x
upper limit of
normal
4.5% 3.6% 3.4%
ALT: alanine transaminase
AST: aspartate transaminase Actelion. Press release 2012
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–500
–400
–300
–200
–100
0
PV
R (
dyn
.se
c/c
m5)
PAH(n = 19)
***
CTEPH(n = 29)
***
All patients(n = 48)
***
***p <0.001
Bars show 95% confidence intervals
120
80
60
40
20
0
6-M
WD
(m
)
2 4 6 8 10 12
Titration phase
Duration of treatment (weeks)
100
0
***
All
CTEPH (n=33)
PAH (n=42)
N=75 patients with PAH or CTEPH
No PDE5i or PGI2 – 6 on bosentan
Most tolerated a dose of 2.5 mg tid
Riociguat for chronic thromboembolic pulmonary hypertension
and pulmonary arterial hypertension: a phase II study.Ghofrani HA, Hoeper MM, Halank M, Meyer FJ, Staehler G, Behr J, Ewert R, Weimann G, Grimminger F.
Ghofrani A et al. Eur Respir J 2010;36:792-9.
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Freedom Studies
Author AcronymStudydrug
Patients NDuration (wks)
1 EPEfficacy1EP TtCW
Tapson V
CHEST
2012
FREEDOM C UT 15 C PAH 354 16 6MWD - -
Tapson V
ATS 2012
Freedom M UT 15 C PAH 300 16 6MWD + -
Tapson V
ATS 2012
A2493
FREEDOM C 2 UT 15 C PAH 310 16 6MWD - -
Unpublished data.
6mwt, 6-minute walk test; CHD, congenital heart disease; CTD, connective-tissue disease; I EP, initial endpoint;
IPAH, idiopathic PAH; ND, no significant difference; SLE, systemic lupus erythematosus; SSc, systemic sclerosis;
TPR, total pulmonary resistance; TtCW, time to clinical worsening.
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*Wilcoxon rank-sum test
Simonneau G, et al. Eur Respir J 2012 Feb 23 (Epub ahead of print)
Treatment effect: −30.3%
(95% CL: −44.7, −12.2;
p=0.0045*)
% o
f baselin
e P
VR
at
Week 1
7
[95%
CL] (g
eom
etr
ic m
eans)
70
80
90
100
110
120
130
Placebo
n=6
Selexipag
n=29
ITT analysis: Treatment effect: −33.0% (95% CL: −47.0, −15.2; p=0.0022*)
N=43 patients with PAH on ERA, PDE5i or both
3:1 randomization selexipag (200-800 µg bid) vs pbo
Final optimized dose at day 35 – assessment at 17 weeks
Selexipag Phase II study
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Question C :How can we modify the current treatment algorithm including the new
approved drugs?(Nazzareno Galiè)
• First line therapy, if any
• Place for newly approved drugs (inhaled remodulin, iv sildenafil)
• Place for new drugs with available phase III data (imatinib, macitentan, oral treprostinil, riociguat)
• Place for upfront combination therapy
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Question C :How can we modify the current treatment algorithm including the new
approved drugs?
First line therapy should be based on the following principles:
• Benefit to risk ratio (first more safe drugs, last drugs with more side effects)
• Specific labeling (exercise capacity vs outcome)
• Experience of the treating physician
• Pharmacoeconomy (drug costs, hospitalizations costs, etc)
• Country approvals
• Head to head comparison?
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Question C :How can we modify the current treatment algorithm including the new
approved drugs?
The place of new drugs in the algorithm should be based on:
• Grade of recommendation (I, IIa, IIb, III) and level of evidence (A, B, C)
• Characteristics of the pivotal(s) RCT(s) (primary end-point, secondary end-points, patients population, background therapy,… )
• Innovation as compared to already existing drugs in the same (class or group)
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Galiè.N et al
Eur Heart J
and Eur
Respir J,
2009
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Question C :How can we modify the current treatment algorithm including the new
approved drugs?
Some uncertanties
• Is it appropriate an algorithm based on the primary end-point (exercise capacity vsoutcome/effect on mortality?
• Are PDE-5 inhibitors & GC stimulators in the same group of drugs?
• Place of imatinib if approved (issue of transplantation?)
• Can we include iv sildenafil in the treatment algorithm without clinical data on PAH patients for the theoretical indication (forced fasting in patients already treated with the oral form due to surgery etc.)?
• BAS? Still to be included??? Survey?
• If oral treprostinil is approved (1 RCT positive in monotherapy and 2 RCTs negative in combo) should be indicated only in naïve patients? Should then we re-evaluate oral beraprost?
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Areas of Algorithm Improvement
• Upfront combination therapy
• Place for new drugs (Imatinib, Macitentan
Riociguat, Selexipag)
• Transplantation indication
• RV assistance
• Indications for complications
• Definition of expert center/Country organization
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PAH complications
• PA aneurisms/Rupture/Dissection
• PA thrombosis
• Left main CA compression
• Emopthysis
• Supraventricular arrhythmias
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Areas of Algorithm Improvement
• Upfront combination therapy
• Place for new drugs (Imatinib, Macitentan
Riociguat, Selexipag)
• Transplantation indication
• RV assistance
• Indications for complications
• Definition of expert center/Country organization
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Definitions of PH Expert Center
Background-1
• Pulmonary hypertension is a rare chronic progressive
condition which is lethal, disabling, costly and treatable.
• Diagnosis and treatment options are complex.
• Patients often look well, even when they are
deteriorating, and in inexperienced hands this may result
in missed opportunities for treatment
• Current therapies slow disease progression and are not
curative.
• There are many novel drugs which may be effective but
require testing in clinical trials.
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Definitions of PH Expert Center
Background-2
• High volume units have been recurrently shown in
medicine to obtain best outcomes for patients while
maintaining greatest patient satisfaction, lowest
complication rates, shortest length of hospital stay and
best value for healthcare payors
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Definitions of PH Expert Center
Proposal
1. Each country should have at least two adult expert
centres.
2. Each country should have at least one paediatric
expert centre.
3. The ideal number of patients seen by an adult or
paediatric centre per annum should be no less than 200
(either PAH or CTEPH)
4. In countries with a population >10 million, adult centres
should ideally expand to >300 patients seen per annum
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Galiè.N et al
Eur Heart J
and Eur
Respir J,
2009
Upfront –
combo
2 d Class II
3 d Class
III-IV
Imatinib?Complications
New
Definition
RV
Assistance
Macitentan
Riociguat
Selexipag
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