Transcript SSPAH Template

Current Controversies in PAH
AARON WAXMAN, MD
Assistant Professor of Medicine
Director, Pulmonary Vascular Disease
Pulmonary and Critical Care Unit
Brigham and Women’s Hospital
Harvard Medical School
Boston, Massachusetts
Learning Objectives (CME, CE, CPE)
 At the completion of this educational activity,
participants should be able to:
̶ Debate clinical management options for patients with symptoms of
̶
̶
̶
2
PAH who do not fall within the diagnostic cut-off values for initiating
PAH therapy
Report on the changes to the PAH diagnostic criteria and how this
impacts patients with exercise-related symptoms of PAH who do not
demonstrate PAH at rest
Discuss the current controversies in PAH treatment with regard to
initial therapy selection and agent sequencing, including choice of
drug class and drugs within a class
Discuss the current controversies in PAH management with regard
to providing de novo combination therapy in patients with NYHA
Class III or IV disease severity
Controversy #1
Is “Pre-PAH” a Distinct Entity?
Updated Definition of PAH
Right Heart Catheterization Confirmed
Increased mean pulmonary
arterial pressure (mPAP)*
>25 mm Hg at rest
Normal pulmonary capillary
wedge pressure (PCWP)
<15 mm Hg
Increased pulmonary
vascular resistance (PVR)†
>3 Wood units
* Normal resting mPAP = 8 – 20 mm Hg.
† In ACCP/AHA expert consensus; in 4th World Symposium on PH, increased PVR
given without a value.
Significance of mPAP from 21 – 24 mm Hg unclear.
Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(suppl 1):S55–S66
Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294.
4
Gap Between Normal mPAP and mPAP
Diagnostic of PAH
Normal mPAP in healthy
volunteers
8 – 20 mm Hg at rest
mPAP diagnostic of PAH
>25 mm Hg at rest

What should be done with patients in the
mPAP gap?
— Pursue alternate diagnoses?
— Watchful waiting?
— Consider therapy?
Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(Suppl 1):S55–S66.
5
Is the Gap an Important Clinical Issue? mPAP
Reported in Selected Clinical Trials
Study Medication
Baseline mPAP (mm Hg)
Control/
Active
Placebo
59 +/- 2
61 +/- 2
Epoprostenol1
Treprostinil (SC)2
Sildenafil3
Ambrisentan4 (ARIES-1)
Bosentan5 (EARLY)
60 +/- 1
56 +/-16
50 +/- 15
52.3 +/- 16
1. Barst RJ, et al. N Engl J Med. 1996;334:296–302.
2. Simonneau G, et al. Am J Respir Crit Care Med. 2002;165:800-844.
3. Galie N, et al. N Engl J Med. 2005;353:2148-2157.
4. Galie N, et al. Circulation. 2008; 117:3010-3019.
5. Galie N, et al. Lancet. 2008; 371:2093–2100.
6
62 +/- 1
49 to 54
47 to 51
52.5 +/- 18.5
Increasing mPAPs Affect Outcomes:
Survival in IPF Stratified by mPAP
1
Survival rate
.8
mPAP <17 mm Hg
.6
.4
mPAP >17 mm Hg
.2
0
0
N = 78.
10
20
40
Survival time (months)
Hamada K, et al. Chest. 2007;131(3):650-656.
7
30
50
60
Improvement of mPAP During PAH
Therapy
Meta-analysis of mPAP value improvements in clinical trials of PAH therapy
Study ID
ES (95% CI)
Rubin – 1990
Barst – 1996
Badesch – 2000
Channick – 2001
Simmoneau – 2002
Galiè – 2002
Olschewski – 2002
Barst – 2003
Galiè – 2005
Galiè – 2006
McLaughlin – 2006
Galiè – 2008
Simmoneau – 2008
Overall
-9.30 (-32.50, 13.90)
-1.00 (-4.40, 2.40)
-5.97 (-8.98, -2.96)
-6.70 (-11.90, -1.50)
-3.00 (-3.10, -2.89)
-2.00 (-2.30, -1.65)
-4.40 (-6.60, -2.10)
-1.00 (-1.57, -0.42)
-3.70 (-7.60, 1.25)
-5.50 (-10.40, -0.60)
-8.00 (-11.20, -4.70)
-5.70 (-10.40, -0.90)
-3.90 (-5.60, -2.10)
-2.87 (-2.96, -2.77)
-30
-20
-10
Favors Treatment
0
|
10
20
Favors Control
30
0.00
0.08
0.11
0.04
87.06
9.09
0.19
2.90
0.05
0.04
0.09
0.04
0.31
100.00
Pulmonary Artery Pressure
(mmHg)
No successful study reported normalization of mPAP. Statistically significant
improvements seen in all trials.
8
% Weight
Galie N, et al. Eur Heart J. 2009;30(4):394-403. Supplementary material available
online.
Does Pre-PAH Progress to PAH?
PHAROS Data in SSc-PAH
^
Significant Variables in
Progression to PAH
Among 156 high
risk* SSc patients
followed over 2
years
Variable
Pre
Race (%AA^)
18
% Nucleolar Ab 12
DLCO %
50.5
PAH
29
26
40.1
Time from Baseline to New PAH
% developing new PAH

50
40
30
New PAH
(n=14)
20
10
0
0
0.5
1
1.5
Years
*High risk = DLCO <55%, FVC%/DLCO% >1.6, PASP >40 mm Hg.
^AA = African-American
Hsu VM. Presented at the ACR/ACHP Scientific Meeting. Oct. 17-21, 2009.
Philadelphia, PA. 1199.
9
2
2.5
Intervention in Early PAH

No data exists on treating patients in WHO
functional class I with PAH-specific medication
 Longitudinal data have not yet identified risk
factors associated with progression to PAH
10
Mean Change in 6-Minute
Walking Distance (m)
EARLY Trial: 6MWD Results With
Bosentan for NYHA Class II PAH
30
Bosentan (n=86)
25
20
Placebo (n=91)
15
10
5
0
-5
-10
-15
-20
-25
3
Months
Note: 15% of both groups also received open-label sildenafil.
Galie N, et al. Lancet. 2008; 371:2093–2100.
11
6
Months
Conclusions
“Pre-PAH” appears to define a group of patients
who may be at future risk for developing PAH
 No data currently exists regarding therapy for
patients in this category
 Patients in high-risk groups (genetic markers,
systemic sclerosis) should be carefully
monitored

12
Controversy #2
Exercise-Induced PAH
Exercise Eliminated from Diagnostic
Criteria for PAH
2003 Criteria:
Increased mean pulmonary
arterial pressure (mPAP)
>25 mm Hg at rest
or
>30 mm Hg during
exercise
2009 Criteria:
Increased mean pulmonary
arterial pressure (mPAP)
Badesch DB, et al. J Am Coll Cardiol. 2009;54(Suppl 1):S55–S66.
14
>25 mm Hg at rest
Reasoning Behind Eliminating Exerciseinduced PAH in Diagnostic Criteria

Level, type, and posture of exercise to reveal
exercise-induced PAH not well defined
 Normal exercise pulmonary artery pressures vary
with age
 Prior descriptions of exercise-induced PAH have
utilized echocardiography
— Test not validated during exercise, difficult to perform

PVR values also not addressed in previous
descriptive efforts
Badesch DB, et al. J Am Coll Cardiol. 2009;54(Suppl 1):S55–S66.
Tolle JJ, et al. Circulation. 2008;118:2183–2189.
15
Relationship Between mPAP and CO in
Healthy Volunteers Undergoing Stress Echo
mPAP (mmHg)
45
40
35
30
25
20
15
10
5
0
0
N =- 25.
5
10
15
20
25
Cardiac Output, Q (L/min)
30
Adapted from: Argiento P, et al. EJR Express. 2009; doi: 10.1183/09031936.00076009.
16
Calculated sPAP in Normal Adult Men
and Highly-conditioned Athletes
70
sPAP (mm Hg)
60
50
Athletes
Non-athletes
p = 0.0001
40
30
20
10
Rest
WP
Legs up
80
40
160
120
240
200
Workload (watts)
Highly-conditioned athletes (n = 26) and healthy, active, non-athlete volunteers (n = 14).
Bossone E, et al. Ann NY Acad Sci. 1999;33:1662– 1666.
17
PA Pressures During Exercise Vary
With Age in Healthy Adults
18 – 29 years
(n = 144)
mPAP (mm Hg)
40
30 – 49 years
(n = 169)
30
>50 years
20
(n = 91)
10
0
Rest
Slight Exercise
From a retrospective analysis of RHC data from 1,187 healthy individuals.
Kovacs G, et al. Eur Respir J. 2009;34:888-894.
18
Reasons To Believe Exercised-induced PAH
Might Be an Important Clinical Entity

Initial presenting symptoms for vast majority of
PAH patients includes dyspnea on exercise
 NYHA/WHO functional classification breakpoints are defined, in part, on increasing levels
of exertional dyspnea
Tolle JJ, et al. Circulation. 2008;118:2183–2189.
19
Relationship of Exercise Capacity to
PASP in Scleroderma
50
 PASP
 METS
40
30
20
10
0
1st
2nd
3rd
4th
Lowest  Highest, Exercise Time Quantities
N = 65 patients with scleroderma. Evaluated during Doppler stress echocardiography.
Allkotob ML, et al. Chest. 2006;130:176-181.
20
PASP (mm Hg)
Normal vs Abnormal Exercise Response in
Asymptomatic Carriers of FPAH Gene
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
Rest
50
100
150
Normal Responders
n = 27
Rest
50
100
Abnormal Responders
n = 14
All abnormal responders to exercise testing were carriers of diseaseassociated haplotype compared with 2 of 27 normal responders. Resting
PASPs were normal in both groups.
Grunig E, et al. Circulation. 2000;102:1145-1150.
21
150
% Frequency of Positive
Exercise Echo
Exercise Echocardiogram Correlated with
Exercise Catheterization in PAH-SSc
100
90
80
70
60
50
40
30
20
10
0
p<0.05
DLCO>50%
DLCO<50%
p<0.05
FVC/DLCO>1.6 FVC/DLCO<1.6
An increase of 20 mmHg on exercise echocardiogram significantly correlated
with  DLCO and  FVC/DLCO. 81% of patients with a positive exercise echo
had PAH or exercise PH.
Steen V, et al. Chest. 2008;134:146-151.
22
Increases in sPAP During Stress Echo of
Patients with Connective Tissue Disorders
90
80
70
mm Hg
60
50
40
30
20
10
0
1
2
sPAP Pre
sPAP Post
n = 50.
sPAP >35 mm Hg seen in 59% of evaluable patients among registrants of an autoimmune disease
database undergoing stress echocardiography.
Collins N, et al. Eur J Echocardiography. 2006;7:439-466.
23
Differences in Resting TRJ Velocity
Indicates Exercise-induced PAH Phenotype
7
Tricuspid Regurgitation Velocity
6
m/sec
5
4
3
2
1
PHT
Ex PHT
Normal
N = 52. Patients undergoing Doppler echocardiography.
Bossone E, et al. Int J Card Imag. 2000;16:429-436.
24
Exercise-induced PAH Measured by
Right Heart Catheterization: mPAP
mPAP (mm Hg)
60
50
40
Normal
EIPAH
RPAH
30
20
10
0
Resting mPAP
Max mPAP
n = 109. From a series of patients undergoing RHC with exercise, primarily for
exercise intolerance.
Tolle JJ, et al. Circulation. 2008;118:2183–2189.
25
mPAP Patterns Measured by Right
Heart Catheterization During Exercise
1.7
1.6
1.5
1.4
m1
m2
1.3
1.2
2.0
2.5
3.0
3.5
4.0
Log VO2 (% Predicted)
Representative Plateau Pattern
Log mPAP (mmHg)
Log mPAP (mmHg)
Representative Take-off Pattern
1.8
1.6
1.4
m1
m2
1.2
1.0
2.4 2.6 2.8 3.0 3.2 3.4 3.6
Log VO2 (% Predicted)
n = 109. From a series of patients undergoing RHC, primarily for exercise intolerance.
Normals = 14 take-off, 1 plateau.
Exercise PAH = 40 take-off, 32 plateau, 4 uninterpretable.
Resting PAH = 2 take-off, 9 plateau, 4 uninterpretable.
Tolle JJ, et al. Circulation. 2008;118:2183–2189.
26
Controversy #3
Therapy Selection and Sequencing
PAH-specific Therapies Approved
for Use in the US
Endothelin Receptor
Antagonists
Phosphodiesterasetype 5 Inhibitors
Prostanoids –
Prostacyclin Analogs
Ambrisentan (PO)
Sildenafil (PO)
Epoprostenol (IV)
Bosentan (PO)
Tadalafil (PO)
Iloprost
(inhaled)
Treprostinil (IV, SC,
and inhaled)
FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=
Search.Search_Drug_Name. Accessed November 1, 2009.
28
Mechanisms of Action of
Approved Therapies for PH
Endothelin pathway
Prostacyclin pathway
Endothelial
cells
Preproendothelin
Nitric oxide pathway
L-arginine
Proendothelin
Arachidonic acid
Prostaglandin I2
NOS
Endothelinreceptor A
Nitric oxide
Endothelin-1
Endothelinreceptor B
cGMP
Endothelinreceptor
antagonists
Prostaglandin I2
Phosphodiesterase
type 5
Exogenous
nitric oxide
Vasodilation and
antiproliferation
Vasoconstriction and
proliferation
Phosphodiesterase
type 5 inhibitor
Humbert M, et al. N Engl J Med. 2004;351(14):1425-1436.
29
cAMP
Prostacyclin
derivates
Vasodilation and
antiproliferation
Cellular Processes Implicated in PAH:
Potential Targets for Future Therapies
Circulating Cells and Mediators
Platelets
ALK/End or
BMPR 1-2
PDGF
EGF
TNF
ANG II
BMPs or
TGF
5HT (serotonin)
Cell Surface Receptors
5HT Transporter
G protein
angiopoietin
anorexigens
NO Blocks
A TIE
endothelin
B
VEGF
KDR
SMADs
ERK
JNH
– +
growth
cytokines
apoptosis
Intracellular
Signaling
MAP
Kinases
ES Receptor
Nuclear Transcription Factors
AML1
+
–
gene activation or
repression
apoptosis
other products
elastase
tenascin-c
Newman JH, et al. Circulation. 2004;109:2947-2952.
30
K+ channels
apoptsosis
SMC tone
+
proliferative
phenotype
+
–
NO restores
hypoxia blocks
Virus infection?
HIV, HHV-8
Estrogen
Decision Analysis:
First Class of Oral Agent
ERAs

2 agents currently approved in
US
— Ambrisentan, bosentan
PDE5 Inhibitors

2 agents currently approved
—
Sildenafil, tadalafil

Indicated for improvement of
exercise tolerance (both) and
delay clinical worsening
(sildenafil)
Safe and tolerable

Indicated for improvement of
exercise tolerance and to delay
clinical worsening

Once-daily (ambrisentan) or
twice-daily dosing (bosentan)

Generally safe and tolerable

Once-daily (tadalafil) or three
times-daily dosing (sildenafil)

Potential synergy with
prostacyclins

—
— Monthly liver function tests
Adverse effects generally mild
Full prescribing information for ambrisentan, bosentan, sildenafil, and tadalafil.
31
Decision Analysis:
First Class of PAH Agent
Inhaled Prostacyclins
Parenteral Prostacyclin
(iloprost, treprostinil)
(IV epoprostenol or IV/SC treprostinil)


Indicated to improve walk
distance (treprostinil) or
composite endpoint
(iloprost)
Cumbersome administration
— Taken 6 to 9 times a day
(iloprost)

Adverse effect of cough
limits tolerability




Proven survival benefit
(epoprostenol)
Most appropriate for sickest
patients
Difficult administration
Ubiquitous adverse effects
— Including adverse effects
of routes of administration
Full prescribing information for epoprostenol, Iloprost, and inhaled and parenteral
treprostinil. Opitz CF, et al. Eur Heart J. 2005;26:1895-1902.
32
Issues in Selection of First ERA
Dosing
Titratability
Important DrugDrug Interactions
Monitoring
Safety
Bosentan
Ambrisentan
Twice-daily
No*
Once-daily
Yes†
Warfarin, sildenafil,
cyclosporin A, glyburide
Monthly liver function
tests required
Cyclosporin A
Monthly liver function
tests required
Anemia
Peripheral edema
Elevated LFTs
Anemia
Peripheral edema
Minimal LFT increases
*Bosentan full prescribing information. 2009. Initiate treatment at 62.5 mg bid for 4 weeks and then increase to
the maintenance dose of 125 mg bid.
†Ambrisentan full prescribing information. 2007. Initiate treatment at 5 mg once daily and
consider increasing the dose to 10 mg once daily if 5 mg is tolerated.
33
ARIES-1: Change in 6-Minute Walk
Distance at Week 12 With Ambrisentan
Change in 6-Minute
Walk Distance (meters)
50
25
Placebo
Ambrisentan
5 mg
10 mg
+43.6 m
+22.8 m
0
-7.8 m
-25
Week 0
Week 4
N=202.
Placebo-adjusted change:
10 mg: +51.4 meters (P=0.0001).
5 mg: +30.6 meters (P=0.0084).
Galie N, et al. Circulation. 2008;117:3010-3019.
34
Week 8
Week 12
BREATHE-1: Impact of Bosentan on 6-Minute
Walk Distance in WHO Classes III and IV
Change in 6-Minute
Walk Distance (meters)
60
Bosentan 250 mg
(n=70)
40
Bosentan 125 mg
(n=74)
20
*
†
0
Placebo (n=69)
-20
0
4
8
Weeks
*P<0.001 versus placebo.
†P<0.01 versus placebo.
Rubin LJ, et al. N Engl J Med. 2002;346:896-903.
35
16
Issues in Selection of First PDE-5
Inhibitor
Dosing
Sildenafil
Tadalafil
Three times a day
Once-daily
Yes*
No
Nitrates, alpha blockers
Nitrates, alpha
blockers
Epistaxis, headache,
dyspepsia
Headache
Titratability
Important DrugDrug Interactions
Safety
* Dose adjustments performed in clinical practice, not approved FDA.
Sildenafil full prescribing information. 2006.
Tadalafil full prescribing information. 2009.
36
SUPER-1: 6-Minute Walk Distance Improvements
Through 12 Weeks of Therapy With Sildenafil
Change in 6-Minute
Walk Distance (meters)
70
60
50
40
Placebo
Sildenafil
20 mg
40 mg
80 mg
30
20
10
0
-10
-20
0
4
8
Weeks
N=266.
P<0.001 versus placebo for all sildenafil doses.
Galie N, et al. N Engl J Med. 2005;353:2148-2157.
37
12
Long-term Tadalafil: 6MWD by
Initial Treatment Assignment
Placebo:40mg
20mg:20mg
420
2.5-20mg:40mg
40mg:40mg
400
380
360
340
16-Week Study
Extension Study
320
0
4
Abbreviation: 6MWD = 6-minute walk distance
8
10
13
Months
Open-label extension of 16 week blinded study. Most patients titrated to 40 mg qd in
open-label phase.
2009 ATS Abstract. Oudiz RJ, et al. Am J Respir Crit Care Med. 179;2009:A1042.
38
16
^
^
Prostanoid Use Varies in US by Region
Use of any prostacyclin in WHO class III/IV by geographic region
NH
VT
MA
51%
40%
RI
CT
NJ
DE
MD
DC
West
Midwest
Northeast
South
AK and Hi are
part of west region
N=2732.
Frantz RP. Am J Respir Crit Care Med. 179;2009:A3350.
39
Inhaled Iloprost for Severe PAH
Mean Change in
Distance Walked (m)
40
Iloprost
20
P=0.004
0
Placebo
-20
-40
Base Line
4 Wk
N=203. NYHA Class III or IV at baseline.
Olschewski H, et al. N Engl J Med. 2002;347:322-329.
40
8 Wk
12 Wk
Change from Baseline
Long-term Inhaled Treprostinil Plus Oral Therapy: ^
Change in NYHA Functional Class Over Time
80
70
NYHA Unchanged (%)
NYHA Improved (%)
NYHA Worsened (%)
60
50
40
*
30
20
*
*
*
10
0
Month 3
Month 6
Month 9
Month 12
N=197
n=160
n=121
n=93
Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
41
*P<0.05.
Intravenous Treprostinil:
Impact on 6-Minute Walk Distance
Total 6-Minute Walk
Distance (meters)
450
400†
378*
400
350
319
300
Baseline
N=16.
*P=0.008 and †P=0.001 versus baseline.
Tapson VF, et al. Chest. 2006;129:683-688.
42
Week 6
Week 12
Epoprostenol for Severe PAH: 3-Year
Survival vs Historical Controls
Survival (%)
100
80
*
60
*
*
40
20
Observed
Expected
0
6
12
18
24
30
Months
N=162 consecutive patients with IPAH in NYHA Class III or IV.
3-year survival with IV epoprostenol compared with expected survival from historical controls.
*P<0.001 at all time points.
McLaughlin VV, et al. Circulation. 2002;106(12):1477-1482.
43
36
Does Patient Preference Matter?

Some patients unwilling to accept parenteral
therapy, even when seriously ill
 Dosing interval for inhaled iloprost may limit its
usefulness
 Adverse-effect profiles of various agents may
impact patient tolerability and acceptance
44
Controversy #4
De Novo Combination Therapy
in Class III/IV PAH
Options for Patients Failing to Improve
or Deteriorating Under Initial Therapy
Functional Class III or IV
Combination Therapy(?)
Prostanoids
Endothelin
Receptor
Antagonists
PDE5
Inhibitors
Badesch DB, et al. Chest. 2007;131:1917-1928.
46
Atrial septostomy
and/or
Lung transplantation
^
Predictors of PAH Mortality
Odds ratio: death within 2 years versus >5 year survival
NYHA=4
6MWD<320
Age > 60
Scleroderma
Pericardial effusion
BNP > 100
No epoprostenol therapy
0
0
5
10
15
20
25
Comparison of baseline characteristics of PAH patients with <2 year survival (n=22)
versus those with >5 years survival (n=61).
Batal O. Am J Respir Crit Care Med. 179;2009:A4863.
47
30
35
40
Issue: Add-on Therapy
Versus Sequential Monotherapy

Little data available to support either approach
 Add-on therapy is common in clinical practice
 Triple-class therapy (ERA, PDE5, prostacyclin)
is maintained in substantial proportion of
patients without clinical trial data
 Is an induction/maintenance model possible?
48
REVEAL Database:
Therapy Choices at Enrollment
Prostacyclin (IV, IM and Inhaled)
No PAH Therapy = 266
295
224
305
190
PDE5 Inhibitor
417
290
ERA
452
At-enrollment therapy of first 2438 patients in REVEAL. Excludes patients enrolled in blinded
controlled trials.
Badesch DB, et al. Chest. 2009; DOI 10.1378/chest.09-1140. Epub ahead of print.
49
Add-on Oral Therapy:
Bosentan and Sildenafil
9 patients with IPAH
initially responsive to
bosentan
monotherapy
— Sildenafil added when
6-minute walk
distance declined
— Mean interval of 11
months

Addition of sildenafil
improved 6-minute
walk distance at 3
months
— Improvement was
sustained for 6 to 12
months
Hoeper MM, et al. Eur Respir J. 2004;24:1007-1010.
50
6-Minute Walk Distance
450
Distance (meters)

400
350
300
250
200
150
Baseline
Bosentan
Baseline
Monotherapy
Add
3 Months Sildenafil
3
6-12
Combination
Therapy
(months)
Sildenafil Added to Stable Epoprostenol
Therapy: Clinical Worsening Events
Clinical Worsening Event at Week 16

16-week study (N=267)
20
— Patients on stable

Deaths at 16 weeks
— Placebo (n=7)
— Sildenafil (n=0)
18
16
Patients (%)
epoprostenol for >3
months
— 80% of patients provided
with sildenafil 80 mg tid
14
12
10
8
6
4
2
0
Simonneau G, et al. Ann Intern Med. 2008;149:521-530.
51
Placebo
Sildenafil
Sildenafil Added to Epoprostenol:
Change From Baseline in 6-Minute Walk Distance
Mean Change
From Baseline (m)
50
Sildenafil
40
30
20
10
Placebo
0
-10
0
4
8
Weeks
N=267; *P<0.0009 versus placebo (ITT population).
Simonneau G, et al. Ann Intern Med. 2008;149:521-530.
52
*
12
16
Add-on Inhaled Iloprost to Stable
Bosentan Monotherapy (STEP Study)
Change From Baseline in NYHA Class
100
91.0%
Iloprost
Placebo
Patients (%)
80
62.5%
60
40
34.4%
20
15.2%
6.0%
0
Improved 1 Class
0%
No Change
3%
Worsened 1 Class
0%
Clinical
Deterioration
N=67. Inhaled iloprost added to stable bosentan monotherapy for a mean of 17.6 to 18.8 months.
94% of patients were NYHA class III at baseline.
McLaughlin VV, et al. Am J Respir Crit Care Med. 2006;174(11):1257-1263.
53
Failure of Add-on Inhaled Iloprost
to Bosentan Monotherapy
6-Minute Walk Distance (meters)
12-Week Change in 6-Minute Walk Distance
500
400
300
200
100
0
Control (n=21)
Iloprost (n=19)
Trial was terminated early after a futility analysis predicted failure with full sample size.
Hoeper MM, et al. Eur Respir J. 2006;28:691-694.
54
^
Short-term Delay Initiating Ambrisentan Associated
with Poorer Long-term 6MWD but Not Survival
6-Minute Walk Distance
Improvement
Mean Change in 6MWD (m)
50
40
30
20
10
0
-10
0
0.25
0.5
1.0
Time (years)
Placebo group
starts ABS
Mean ± SEM
1.5
2.0
ABS/ABS n=195
PLB/ABS n=97
Survival
100
Survival (%)
80
Placebo group
starts ABS
60
1-Year
93% (88% to 96%)
92% (84% to 96%)
40
20
2-Year
88% (83% to 92%)
86% (77% to 91%)
ABS/ABS n=195
PLB/ABS n=97
0
Kaplan-Meier estimate
(95% Cl)
0
0.25
0.5
1.0
Time (years)
2.0
At Risk
n=197
n=186
n=173
n=158
n=158
At Risk
n=100
n=89
n=84
n=79
n=64
Waxman AB. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8573
55
^
2-year Ambrisentan Outcomes: Monotherapy
vs Combination Therapy Groups
Survival, Monotherapy vs Combination Therapy
Survival (%)
100
80
91% (87% to 94%)
76% (63% to 84%)
60
40
ABS-M
ABS-C
80
0
0.0
0.5
1.0
1.5
2.0
Years
At Risk
n=302
n=264
n=250
n=237
n=209
At Risk
n=81
n=70
n=65
n=61
n=45
Key Baseline Variables
Monotherapy
(n = 302)
Combination
(n = 81)
6MWD (m)
356 + 83
329 + 91
Borg Dyspnea Index
3.7 + 2.3
4.4 + 2.5
WHO Class II (%)
47
26
WHO Class III (%)
41
65
Torres F. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8525
56
Prognostic Factors for Risk of
PAH Disease Progression
Lower Risk
Higher Risk
No
Yes
Progression
Gradual
Rapid
WHO Class
II, III
IV
>380 m
<325 m
<180 pg/mL
>180 pg/mL
Minimal right ventricular
dysfunction
Pericardial effusion;
significant right
ventricular dysfunction
Normal/near normal
RAP (<12 mm Hg) and
CI (>2.5 L/min/m2)
High RAP, Low CI
Evidence of RV failure
6-minute walk distance
Brain natriuretic peptide
Echo findings
Hemodynamics
McLaughlin VV, et al. Circulation. 2006;114(13):1417-1431.
57
Composite Scoring System Predicts ^
Disease Progression in PAH
Survival (%)
Composite Score 3-year Survival
100
0-6
75
50
6-9
25
9-12
00
Points
Walk (m)
FC
NT-proBNP
1
0
1
2
3
340
260-340
190-260
<190
1
2
3
4
<2000
>2000
QOL (CAMPHOR)
<12
>12
Activity
<11
>11
Symptoms
<16
>16
Anderson A, et al. Am J Respir Crit Care Med. 2008;177:A922.
58
3
2
Time (years)
Survival in PAH by Etiology: Does CTD-PAH
Require A More Aggressive Approach?
1.0
Congenital
Heart Disease
0.9
Percent Survival
0.8
0.7
Portopulmonary
0.6
0.5
IPAH
0.4
Connective Tissue Disease
0.3
0.2
HIV
0.1
0
0
1
2
3
Years
McLaughlin VV, et al. Chest. 2004;126:78S-92S.
59
4
5
Systemic Sclerosis Progresses More
Rapidly When PAH is Diagnosed
100
Percent Survival
90
80
70
No Lung Involvement
60
50
Lung Involvement without PAH
40
30
20
PAH
10
0
0
1
2
3
4
5
6
7
8
9
10
11
Years from Diagnosis of Pulmonary Hypertension
Koh ET, et al. Br J Rheumatol. 1996;35:989-993.
60
12
13
Goal-directed Combination Therapy:
Suggested Treatment Algorithm
Baseline and 2- to 6-Month Evaluation for Treatment Goals
6-Minute Walk Distance >380 meters; Peak VO2 >10.4 mL/min/kg
Peak systolic BP >120 mm Hg during exercise
Oral Monotherapy
Dual-Class Oral Combination Therapy
Addition of Inhaled Prostanoid
Transition to Intravenous Prostanoid
Refer for Lung Transplantation
Hoeper MM, et al. Eur Respir J. 2005;26(5):858-863.
61
Should PAH Therapy
Follow a Different Model?

Current guidelines suggest monotherapy,
followed by add-on therapy
 In HIV, cancer, coronary disease, and other
common diseases, de novo combination
therapy is the norm
 Is there potential to stabilize disease with multimodal therapy, then peel away to minimum
required?
62
Theoretical Advantages of
De Novo Combination Therapy

More rapid improvement in clinical symptoms
 Potential to alter the pathophysiologic
processes
— Disease modification vs symptom management

Attack the disease through multiple pathways
 Larger improvements in hemodynamics
 Reduced risk of disease progression
63
Theoretical Disadvantages of
De Novo Combination Therapy





64
Additive adverse effects make adherence
difficult
Additive cost with unknown benefit
De novo combination therapy eliminates the
role of monotherapy when it might be effective
in certain patients
Potential unwillingness to remove therapy in
patients doing well
Reduced choices in the event of disease
progression, lack of tolerability
Low-dose Treprostinil Added to Existing Oral ^
Therapy: Change in 6-Minute Walk Distance
Mean Improvement in 6-Minute
Walk Distance (m)
12 Weeks
70
63
60
50
40
36
35
30
20
10
0
5
Overall
PDE5i
ERA
N=20. PDE5i: phosphodiesterase type 5 inhibitor; ERA: endothelin receptor antagonist.
Mean treprostinil dose at 12 weeks was 24 ng/kg/min.
Feldman JP, et al. Chest. 2007;132(4 suppl):474S.
65
PDE5i + ERA
“Class Switching”

Usually done only when all agents within a
class are intolerable
 In event of single-agent class, trial transition to
investigational agent may be preferable
66
Role of Investigational Therapies/
New Classes of Agents

Investigational therapies should be utilized
— In context of clinical trials
— In compassionate use settings where no other
option exists
67
Upcoming/Ongoing Clinical Trials

A wide range of clinical trials are currently
enrolling patients
— Investigational agents and approaches
— Combination therapy trials of approved agents

68
Complete list of approved studies is available at
www.clinicaltrials.gov