Transcript Combining PDE-5 inhibitors and ETRAs: the rationale

Cardiovascular Issues in Scleroderma
James R. Seibold, M.D.
Professor and Chief.
Division of Rheumatology
University of Connecticut Health System
Farmington, Connecticut, USA
Disclosures
Funded Research/Consultancy
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Actelion (bosentan, macitentan, spouse)
Bristol-Myers Squibb (tyrosine kinase inhibitor)
Pfizer (PDGF2α, sitaxsentan, VEGF)
Gilead (ambrisentan)
Roche (tyrosine kinase inhibitor)
Centocor (IL-13, TH17 biology)
FibroGen (antiCTGF)
United Therapeutics (oral treprostinil, tadalafil)
The Heart and Lungs in Scleroderma
• OVERALL SURVIVAL IS IMPROVING
• LUNG INVOLVEMENT IS NOW THE LEADING ISSUE
• PULMONARY HYPERTENSION
versus
• INTERSTITIAL LUNG DISEASE
Changing patterns of mortality
in scleroderma
SRC
50
PAH
p<0.0001 (SRC)
GI
Frequency (%)
40
p<0.001 (PF)
PF
Heart
30
Multiorgan
PAH p=0.05
20
GI
p=0.43
Heart p=0.26
10
0
1972–1976
1977–1981
1982–1986
1987–1991
1992–1996
1997–2001
Years of death
GI = gastrointestinal; PAH = pulmonary arterial hypertension; PF = pulmonary fibrosis; SRC = scleroderma renal crisis
Steen VD and Medsger TA. Ann Rheum Dis 2007;66:940–4.
% Cumulative survival
Survival-limited scleroderma
with and without PAH
Stupi AM, et al:
 Average PA pressure 82/35 (50) mmHg
 Average PA resistance 16 Wood units
 Average cardiac index 2.1 L/min/m2
Steen V, et al:
 Average PASP 76 mmHg
100
80
(n=106)
(n=287)
SSc without PAH
(n=106)
(n=20)
SSc with PAH
60
40
20
0
1
2
3
4
5
Follow up (Years)
PA = pulmonary artery; PASP = pulmonary artery systolic pressure; SSc = systemic sclerosis
Stupi AM, et al. Arthritis Rheum 1986;29:515–24.; Steen V, et al. Arthritis Rheum 2003;48:516–22.
Some Rash Statements!!
• SSc-PAH is overdiagnosed in the community
• SSc-PAH is undertreated in centers
• Evidence-based medicine is lagging behind evolving
standards of practice
Prevalence of PAH-CTD
Disease
Echo prevalence
Catheter/clinical prevalence
Systemic sclerosis
20–50%1,2
7.85–12%3,4
Lupus
4–43%5,6
0.9%3
20%7
<0.01%8
Rheumatoid arthritis
CTD = connective tissue disease; PAH = pulmonary arterial hypertension
1. Rheumatismo 2005;57:114. 2. Battle RW, et al. Chest 1996;110:1515‒9. 3. Eur J Respir Dis 2004;59.
4. Mukerjee D, et al. Ann Rheum Dis 2003;62:1088‒93. 5. Pan TL, et al. Lupus 2000;9:338‒42.
6. Winslow TM, et al. Am Heart J 1995;129:510‒5. 7. Dawson JK, et al. Rheumatology 2000;3:1320‒5.
8. Post Marketing Surveillance Study (Data on File).
Differential diagnosis of “PH” CTD
Pulmonary arterial hypertension (PAH)
Pulmonary
veno-occlusive
disorder
(PVOD)
Myocardial
involvement
PH = pulmonary hypertension
Interstitial lung
disease (ILD)
Chronic
thromboembolic
pulmonary
hypertension (CTEPH)
Others
Pulmonary Hypertension (PH) in CTD
“The Differential Diagnosis”
PVOD LV Systolic
PAH
ILD
or Diastolic
Dysfunction
↑LAP
OMERACT Criteria & Measures of PAH in SSc
Validation
Criterion
Face
NT-pro
BNP
Clinical
Echo
PFT
6MWT
RHC
Y
Y
Y
Y
Y
Y
Content
UK
Y
Y
UK
N
Y
Construct
UK
N
N
N
N
Y
Accuracy
N
N
N
N
N
Y
Reliability
UK
N
N
Y
N
Y
Sensitivity to
Change
Feasibility
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
?
Causes of Shortness of Breath in Scleroderma
 Interstitial Lung Disease
 Pulmonary Arterial Hypertension
 Left Heart Disease
 Anemia
 Physical deconditioning
- Reduced V02 Max
- Reduced Metabolic Equivalent at V02Max
What’s the most physical activity that you do and what symptom limits your
capabilities?
Preliminary Predictors of 6MWD (N=164)
Variable
B
SE.B
β
854
200.2
- 80.3
18.3
-.28**
FVC
3.7
1.8
.17*
DLco
4.2
1.8
.22*
∆ SaO2
20.0
9.8
.15*
∆ HR
8.8
1.4
.38**
SPAP
- 5.1
1.5
-.23*
Age
- 3.9
2.1
-.11
Constant
BFI rest
R2 = .621 , * p < .05, ** p<.01
B: b value, SE.B : standard error of b, β: standardized beta
Seibold JR et al. Arthritis Rheum 2009; 60(10): S640
Ratio of % FVC to % DLCO Influences Survival in
SSc
1.0
% FVC/% DLCO <1.8 (n=337)
0.9
Probability
of
survival
0.8
0.7
p=0.007
0.6
% FVC/% DLCO 1.8 (n=169)
0.5
0 1 2 3 4
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Duration of disease (yr from onset)
Disproportionate and/or isolated reduction in gas exchange (diffusing capacity)
is dominant determinant of survival in all forms of SSc lung.
Seibold JR et al. J Rheumatol (in press)
Signs Indicative of PH on ECHO
 Increased sPAP or TR jet
 Right atrial and ventricular
hypertrophy
 Flattening of intraventricular
septum
 Small LV dimension
 Dilated PA
IVS
RV
LV
RA
LA
McGoon M et al for the American College of Chest Physicians. Chest. 2004;126:14S-34S.
UNCOVER Study: Prevalence of
Abnormal Echo in Patients With CTD
50
42.2%
Patients (%)
40
30
23.6%
20
13.3%
10
6.7%
3.0%
0
>30
>35
>40
>45
ESRVP (mm Hg)
N=815 community patients with SSc or MCTD.
Wigley FM, et al. Arthritis Rheum. 2005;52:2125-2132.
>50
0.9%
>60
Accuracy of PH Diagnosis by
Echocardiography in Advanced Lung Disease
60
% of studies
 Cohort study of 374 lung transplant patients
 All patients had Doppler echo 24–48 h prior
to RHC
 Prevalence of PH: 25%
 Echo frequently inaccurate leading to
overdiagnosis of PH in patients with
advanced lung disease
40
20
0
Arcasoy SM. Am J Respir Crit Care Med. 2003;167:735-740.
Overestimation
Accurate
Underestimation
PH (-)
PH (+)
Should we do annual echocardiography?
•
•
•
•
•
Estimated Event Rate 0.6 per 100 patient years
167 baseline echocardiograms
167 follow up echocardiograms
University of Michigan charges $2200 per test
$734,800 per case
• This assumes 100% sensitivity/specificity
NT-pro-BNP in PAH-SSc
 >395 pg/mL: 56% sensitivity, 95% specificity
 >91 pg/mL: 90% sensitivity, 51% specificity
 Baseline value and change correlated with survival
Correlation of NT-pro-BNP with 6MWD
4.5
4
3.5
3
2.5
Log NT-pro-BNP (pg/mL)
Log NT-pro-BNP (pg/mL)
Correlation of NT-pro-BNP with PVR
2
1.5
1
0.5
0
R = 0.81
0
500
1000
1500
2000
2500
PVR (dyn/8/cm-6)
Williams MH. Eur Heart J. 2006;27:1485-1494.
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
R = -0.46
0
100
200
300
400
6MWD (m)
500
600
700
DETECT STUDY
Canada (10)
USA (24)
Brazil (8)
Austria (3)
Germany (12)
The Netherlands (1)
Romania (1)
Slovakia (1)
Turkey (4)
Bosnia (1)
China (1)
81 sites, 19 countries
Czech Republic (1)
Hungary (2)
Poland (1)
Russia (1)
Switzerland (3)
Norway (3)
UK (1)
Spain (3)
The DETECT study
SSc/MCTD: 3 years+; DLCO <60%; No known PH or
left heart disease: Recruitment = 500 patients (70 with PH)
Baseline
RHC
ECG
Echo
NT-pro-BNP
Year 3
6-monthly clinical &
non-invasive assessment
RHC
ECG
Echo
NT-pro-BNP
RHC if
suspect PH
Prevalence
Incident PH
ECG = electrocardiography; mCTD = mixed connective tissue disease; PH = pulmonary hypertension;
RHC = right heart catheterisation
Study commenced October 2008 – predicted completion end 2013
OMERACT Criteria & Measures of PAH in SSc
(How DETECT Can Refine Clinical Practice)
Validation NT-pro
Criterion
BNP
Face
Y
Clinical
Echo
PFT
6MWT
RHC
Y
Y
Y
Y
Y
Content
UK
Y
Y
UK
N
Y
Construct
UK
N
N
N
N
Y
Accuracy
N
N
N
N
N
Y
Reliability
UK
N
N
Y
N
Y
Sensitivity
to Change
Feasibility
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
?
Early and Reliable DETECTion of PAH in
SSc
• Earlier diagnosis
• Precise diagnosis
• Validation of screening measures
• Definition of role of right heart catheterization
• Earlier intervention for PAH
• Earlier intervention for other forms of PH
• Event rate and risk profile for “prevention” study
• Event rate and risk profile for “vascular
deremodeling” study
PAH–A Distinct Entity
PAH
Idiopathic/Familial
Intimal Proliferation
Associated With
• Connective tissue disease
• Congenital systemic-pulmonary shunts
• Portal hypertension
• HIV infection
• Drugs and toxins
• Other
Medial Hypertrophy
Plexiform lesion
Digital Vascular Injury in Scleroderma
Vasculopathy in Scleroderma
 Masson-Trichrome stain of digital artery from patient
with SSc



Striking fibrotic intimal
hyperplasia
Adventitial fibrosis
Arterial lumen severely
compromised
Vascular Features and Outcome in SSc
 Scleroderma renal crisis
 Pulmonary arterial hypertension
 Myocardial involvement
 Sudden death
 ?? Role in gastrointestinal involvement
Hematoxylin and eosin stain of lung from patient with fatal interstitial lung
disease.
Note interstitial fibrosis, persistent interstitial inflammation, and striking
intimal hyperplasia of a pulmonary arteriole.
Why is SSc-PH/PAH so Difficult to Treat?
 Older Patients
 Interstitial Lung Disease
 LV Diastolic Dysfunction
 RV Diastolic Dysfunction
 More severe structural vasculopathy
 Outcome measures may be inappropriate
 Poor recognition in the community
Molecular pathways
ETB
Endothelial
cells
Preproendothelin
L-arginine
 Proendothelin
Smooth
muscle
cells
Endothelin-1
PGI2
ETB
Exogenous
NO
cAMP
Leucocyte
recruitment
and cytokine
release
e.g.
IL-13
IL-14
cGMP
ETRAs
Vasodilation
and antiproliferation
PAH Pathway
e.g. RANTES,
fractalkine
NOS
NO
ETA
Arachidonic acid
 Prostaglandin I2
PDE-5
PDE-5
inhibitor
Prostacyclin
derivates
Vasodilation and
antiproliferation
Vasoconstriction
Cell
proliferation
Vasodilation
and antiproliferation
ETA = endothelin-A receptor; ETB = endothelin-B receptor; ETRA = endothelin receptor antagonist; NOS = nitric oxide synthase;
cGMP = cyclic guanosine monophosphate; cAMP = cyclic adenosine monophosphate; PDE-5 = phosphodiesterase type 5; IL = interleukin
Median Change in 6MWD (m)
Epoprostenol Effect on Exercise Capacity
Scleroderma with PAH: Treated versus Control
70
60
50
40
30
20
10
0
-10
-20
-30
-40
63.5
Conventional (55)
Flolan (56)
48.5
13.25
p=0.003
-7
p=0.001
-14
-36
Week 1
Week 6
Badesch et al: Ann Int Med 2000;132:425
Week 12
PPH: Barst
et al: NEJM
1996; 334:
296
Effect of IV Treprostinil Dose on Exercise Capacity*
120
140
Dose
6MWD
120
100
100
80
80
60
60
40
40
20
20
0
0
BL
Week 6
Week 12
Week 24
Improvement in 6MWD, m
Treprostinil dose, ng/kg/min
140
Week 48
*Average treprostinil doses for patients receiving SC (46 ng/kg/min) and IV infusion (54 ng/kg/min; July 2007).
1. Tapson et al. Chest. 2006;129:683-688. 2. McLaughlin et al. Chest. 2005;128(suppl):160S. 3. Remodulin [package insert]. United Therapeutics Corp;
2006.
Inhaled Iloprost: Change in 6MWD in PAH
Patients
40
Mean (± SEM)
absolute change
vs baseline (m)
30 minutes
postinhalation
Iloprost
20
0
Placebo
-20
-40
Iloprost group baseline = 332 m
Placebo group baseline = 315 m
Baseline
4 Weeks
8 Weeks
12 Weeks
Placebo-corrected difference at 12 weeks = 40 m (P<0.01)
Olschewski H, et al: N Engl J Med. 2002;347:322.
Inhaled Iloprost: Composite Primary
End Point for PAH Patients
50%
Iloprost
43%
Placebo
P=0.0033
40%
30%
Percent
responders
20%
26%
19%
13%
8%
10%
0%
25%
4%
6-minute walk
10% increase
30 min. after
inhalation
NYHA Class
improvement
Death or
worsening
4%
Composite
clinical end point
Composite response definition: 6 minute walk 10% increase plus
NYHA class improvement without death or clinical worsening
Olschewski H, et al: N Engl J Med. 2002;347:322.
% of patients with a greater 6MWD change
Inhaled Treprostinil
Distribution of Changes in 6MWD
Treprostinil (n=115)
Placebo (n=120)
52%
32%
≤
6MWD change from baseline (m)
6MWD, 6-minute walk distance.
34
The NO pathway
O2/alveolar ventilation
NOS
L-Arginine
NO
Guanylate cyclase
Degradation
cGMP
PDE
cGMP kinase
Intracellular
Ca2+
Vasodilation and antiproliferation
• In presence of O2 and/or alveolar ventilation, NO
synthases produce NO from L-arginine. NO
activates soluble and membrane-bound GC to
synthesise cGMP, which activates cGMP-kinase
• Activates K+ channels and inhibits Ca2+
channels to reduce iCa2+ concentration,
causing vasodilation
• Effects of NO are limited by rapid degradation of
cGMP by PDE-5, which is strongly expressed in the
lung. PDE-5 gene expression and activity increase in
chronic PAH
• Inhaled NO produces pulmonary-specific
vasodilation
• PDE-5 inhibitors promote icGMP accumulation –
thereby enhancing NO-mediated vasodilation
• PDE-5 inhibitors may also have antiproliferative
effects
cGMP, cyclic guanosine monophosphate; GC, guanylate cyclase; NO, nitric oxide; NOS, nitric oxide synthase;
O2, oxygen; PAH, pulmonary arterial hypertension; PDE-5 , phosphodiesterase type 5
SUPER-1: improvements in 6MWD with
sildenafil in PAH-CTD patients
*p<0.003
*
Mean (95% CI) change from
baseline (m)
70
Placebo (n=21†)
*
60
50
20 mg sildenafil TID (n=20)
40 mg sildenafil TID (n=18†)
80 mg sildenafil TID (n=19§)
42
36
40
30
15
20
10
0
–10
–20
–13
–30
–40
without baseline 6MWD: 1 in placebo group and 2 in 40 mg group; §2 patients discontinued due to adverse
events after 4-week evaluation
Badesch DB, et al. J Rheumatol 2007;34:2417–22.
†Patients
Pathophysiological effects of ET-1
Cell
proliferation
Migration
Vasodilation
Vasoconstriction
Vascular
remodelling
Antiproliferation
Fibrosis
Hypertrophy
ET-1 = endothelin-1
Apoptosis
Evidence of a Role for Endothelin-1 in
Connective Tissue Disease Pathogenesis
 Elevated plasma levels of ET-1 in SSc
 Increased levels of ET-1 in bronchoalveolar lavage
fluid in SSc
 Increased ET-1 and ET-B receptors in early diffuse
skin lesions
 Increased ET-1 binding sites in SSc interstitial lung disease
Control
Abraham DJ, et al. Am J Pathol. 1997;151:831-841.
SSc
ET-1 levels in SSc with vascular complications
8
7
ET 1 pg/mL
6
5
4
3
2
1
ULN
0
Control
SSc
PAH
Pre-SRC
At-SRC
ET-1 = endothelin-1; PAH = pulmonary arterial hypertension; SRC = scleroderma renal crisis;
SSc = systemic sclerosis; ULN = upper limit of normal
Penn H and Denton C. Curr Opin Rheumatol 2008;20:692‒6.
Post-SRC
Co-localisation of ET and collagen
in PH-SSc
Sirius red
stain – collagen
Adapted from Black C, unpublished data.
Giaid A, et al. N Engl J Med 1993;328:1732–9.
Immunolocalisation
of ET ligand
Change in 6-Minute Walk Distance (m)
BREATHE-1: Impact of Bosentan on 6-Minute
Walk Distance in WHO Classes III and IV
60
Bosentan 250 mg
(n=70)
*
40
†
Bosentan 125 mg
(n=74)
20
0
Placebo (n=69)
-20
0
4
8
16
Weeks
*P<0.001 vs placebo. †P<0.01 vs placebo.
Rubin LJ, et al. N Engl J Med. 2002;346:896-903.
Bosentan for PAH-CTD:
Time to Clinical Worsening
Event Free (%)
100
90.3%
86.4%
80
Difference not significant
60
Bosentan
40
20
0
0
Patients at risk
44
22
4
8
12
16
Weeks From Treatment Start
44
20
29 Bosentan
16 Placebo
N=66. Retrospective subgroup analysis from placebo-controlled clinical trials and their extension.
Event: death, premature withdrawal or hospitalization due to PAH worsening, or initiation
of epoprostenol therapy.
Denton S, et al. Ann Rheum Dis. 2006;65:1336-1340.
Change in 6MWD
Treprostinil Epo
study group
STRIDE-1 STRIDE- BREATHE-1 ARIES-1
1,2,4
PACES-1
SUPER-1
Placebo
80
Treprostinil
Change in 6MWD (m)
**
60
Conventional treatment
40
Epoprostenol +
conventional treatment
*
***
20
Sitaxentan
***
Bosentan
Ambrisentan
0
Placebo + IV epoprostenol
Sildenafil + IV epoprostenol
-20
Sildenafil 20 mg
-40
Sildenafil 40 mg
Sildenafil 80 mg
-60
N
49;41
55;56
9;33
39;28
14;33
124
25;27
21;20;18;19
Mean change in 6MWD unless stated otherwise
* Placebo-corrected median; ** Median change; *** Placebo-adjusted increase
IV = intravenous; 6MWD = 6-minute walk distance
Oudiz RJ, et al. Chest 2004;126:420–47. Badesch D, et al. Ann Intern Med 2000;132:425–34.
McLaughlin V, et al. Chest 2004;126 (Suppl 4):759. Rubin LJ, et al. N Engl J Med 2002;346:896–903. Seibold J, et al. Chest
2005;128(Suppl 4):S219. Badesch D, et al. Chest 2007;132:488b. Data on File, Pfizer.
Badesch D, et al. J Rheumatol 2007;34:2417–22.
Change in 6MWD (m)
Ambrisentan ARIES-1 Primary Endpoint:
Change in 6MWD at Week 12
50
+43.6 m
25
+22.8 m
0
-7.8 m
-25
Week 0
Week 4
Week 8
Placebo
Week 12
5 mg
10 mg
N=202.
Placebo-adjusted changes: 10 mg = +51.4 m (P=0.0001)
5 mg = +30.6 m (P=0.0084)
Oudiz RJ, et al. Chest. 2006;130:Abstract 121S.
Change From Baseline (meters)
Ambrisentan for CTD-PAH: Change in
6-Minute Walk Distance at 12 Weeks
70
60
PAH (n=166)
PAH-CTD (n=82)
64.0
59.0
49.0
50
40
30
24.0
29.0
20
10
0
-1.0
-6.4
-10
-20
-13.4
2.5 mg
5 mg
10 mg
Ambrisentan
Patients with PAH-CTD, post-hoc subgroup analysis from integrated analysis of
double-blind, placebo-controlled trials.
Coghlan JG, et al. Lupus. 2006;15:138-142.
Change in ET-1 levels
Functional selectivity in vivo correlates with
ETA selectivity in vitro
1 10
100
ETA/ETB selectivity ratio
•
10000
4000
1000
6500
Given the role of the ETB receptor in clearance, measurement of circulating ET-1 levels
following administration of ETRAs indicates functional selectivity
ET-1 = endothelin-1; ETA/B = endothelin A/B receptor; ETRA = endothelin receptor antagonist
1. Goddard J, et al. Circulation 2004;109:1186‒93.
2. Ihara M, et al. J Cardiovasc Pharmacol 1992;20 (Suppl 12):11‒14.
3. Ishikawa K, et al. Proc Natl Acad Sci USA 1994;91:4892‒6.
4. Clozel M, et al. J Pharmacol Exp Ther 1994;270:228‒35.
5. Williamson DJ, et al. Circulation 2000;102:411‒18.
6. Kiowski W, et al. Lancet 1995;346:732‒6.
7. Weber C, et al. Clin Pharmacol Ther 1996;60:124‒37.
8. Clozel M, et al. J Pharmacol Exp Ther 1999;290:840‒6.
9. Torre-Amione G, et al. Circulation 2001;103:973‒80.
10. Luscher TF, et al. Circulation 2002;106:2666‒72.
11. Raschack M, et al. J Cardiovasc Pharmacol 1995;26 (Suppl 3):397‒9.
12. Volibris (ambrisentan) SmPC, April 2008.
13. Givertz MM, et al. Circulation 2000;101:2922‒7.
14. Wu C, et al. J Med Chem 1997;23:1690‒7.
Sitaxentan in CTD Population:
Baseline to Endpoint Change in 6MWD
sitaxentan 100 mg
Change from baseline (m)
40
placebo
30
20
10
P = 0.042
0
-10
-20
-30
-40
-50
6 weeks
12 weeks
18 weeks /
endpoint
Seibold et al. Chest 2005;128:219S
STRIDE-2X: time to first clinical worsening*
Adjudicated by a blinded 3rd-party panel – CTD subgroup
100
85%
Percent without events
90
80
p=0.0005
52%
70
60
50
40
30
Sitaxentan (n=42)
Bosentan (n=25)
20
10
0
0
Number at risk
Sitaxentan
42
Bosentan
25
4
8
12
16
20
24
28
32
36
40
44
48
52
Weeks
40
15
35
12
33
10
*Defined as: on-study death, hospitalisation for PAH, addition of epoprostenol or treprostinil, atrial septostomy, transplantation,
or a combined decline in WHO functional class and ≥15% reduction in 6MWD from baseline
WHO = World Health Organization
Highland KB, et al. Ann Rheum Dis 2006;65 (Suppl II):393.
Survival With Endothelin
Receptor Antagonists in PAH-CTD
98% P = 0.014
95% P = 0.001
100
Survival (%)
90
Bosentan, Girgis et al. 2005
Bosentan, Denton et al. 2006
Bosentan, Williams et al. 2006
80
70
60
87%
86%
81%
80%
P = 0.014
Sitaxentan (n=42)
Bosentan (n=25)
50
Ambrisentan combined 2.5 & 5 mg
0
0
4
8
12 16 20 24 28 32 36 40 44 48 52
Weeks
Olschewski H, et al. ATS 2006. San Diego.
Data on file, Encysive Pharmaceuticals Inc., Houston, TX
Girgis RE, et al. J Heart Lung Transplant. 2005;24:1626-1631.
Denton CP, et al. Ann Rheum Dis. 2006;65:1336-1340.
Williams MH, et al. Heart. 2006;92:926-932.
Survival by PAH Etiology
1.00
0.75
0.50
0.25
0.00
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Years
STRATA:
diagnosis=1. Idiopathic/Familial
Censored diagnosis=1. Idiopathic/Familial
diagnosis=2. Associated with Scleroderma
Censored diagnosis=2. Associated with Scleroderma
diagnosis=3. All other associated
Censored diagnosis=3. All other associated
diagnosis=4. Other
Censored diagnosis=4. Other
3.5
Survival-NOW
British
Johns Hopkins
•
•
•
1-YEAR
2-YEAR
3-YEAR
•
Survival is worse in SSc-ILD vs. isolated PAH
78%
NA
47%
Condliffe, et al. Am J Respir Crit Care Med. 2009
Mathai, et al Arthritis Rheum 2009
Badesch, et al J Rheumatol 2009
86%
68%
56%
US Multicenter
71%
52%
48%
Recommended stepwise approach to
combination therapy
Treatment goals not met
Initial treatment with an ETRA
+
+
+
+
Addition of a PDE-5 inhibitor
Addition of inhaled prostanoid
Transition from inhaled to IV prostanoid
+
Highly urgent lung transplantation
Kaplan-Meier estimates of survival with
combination therapy
Cumulative survival (IPAH)
1.0
First-line bosentan
Addition of sildenafil/iloprost
2002–2004
0.8
Historical
control group
1999–2001
Expected
survival
0.6
0.4
0.2
Subjects
at risk (n)
Treatment vs historical control group, p=0.011
Treatment vs expected survival, p<0.001 for all time points
Time (months)
0
6
12
18
24
30
36
89
83
69
61
46
43
37
Treatment group
67
64
47
38
31
23
20
Historical control group
Hoeper MM, et al. Eur Respir J 2005;26:858–63.
Royal Free Hospital
advanced therapy for PAH-SSc
WHO I and II
WHO III
WHO IV
ETRA
PDE-5 inhib
plus ETRA
Recruit to
trials
No
6MWD + 40
NT-pro-BNP
<40 pmol/L
mPAP >40 mm Hg
or PVR >650 dyn.s/cm5
Yes
No
Yes
Cath 3 mo
mPAP >40 mm Hg
PVR >650 dyn.s/cm5
No
Continue
Any secondary deterioration leads to added therapy
ETRA = endothelin receptor antagonist; mPAP = mean pulmonary arterial pressure; 6MWD = 6-minute walk distance;
NT-pro-BNP = N-terminal pro-brain natriuretic peptide; PDE-5 inhib = phosphodiesterase type 5 inhibitor;
PVR = pulmonary vascular resistance; SSc = systemic sclerosis; WHO = World Health Organization
Yes
Food for Thought??
• PAH-CTD is overdiagnosed in community – primarily due
to excessive reliance on echocardiography
• PAH-CTD is under managed in centers – primarily due to
avoidance of parenteral prostacyclin
• Available data support strategies for EARLIER diagnosis
and intervention
• Available data support use of “step up” combination
therapy in “goal directed approach”
• Earlier use of right heart catheterization may permit true
“prevention” studies