Download SSc: A Vascular Disease

VASCULAR COMPLICATIONS
OF SYSTEMIC SCLEROSIS
Wednesday, November 15, 2006 • Washington, DC • Richard M. Silver, MD, Program Chair
VASCULAR COMPLICATIONS
OF SYSTEMIC SCLEROSIS
Treatment Targets for PAH in
Systemic Sclerosis
Myung H. Park, MD, FACC
Assistant Professor of Medicine
Director, Pulmonary Vascular Diseases Program
University of Maryland Medical Center
Baltimore, Maryland
VASCULAR COMPLICATIONS
OF SYSTEMIC SCLEROSIS
DISCLOSURE STATEMENT
Myung H. Park, MD, FACC
Grants/research support:
Actelion Pharmaceuticals US, Inc., CoTherix, Inc., United Therapeutics
Consultant:
Actelion Pharmaceuticals US, Inc., CoTherix, Inc., Myogen, Inc., Pfizer
Inc, United Therapeutics
Speakers’ bureau:
Actelion Pharmaceuticals US, Inc., Encysive Pharmaceuticals Inc., Pfizer
Inc, United Therapeutics
Off-label uses for products may be discussed.
Definition of Pulmonary
Arterial Hypertension
• Pulmonary arterial hypertension:
– Mean PAP >25 mm Hg at rest
– Mean PAP >30 mm Hg with exercise
• Normal pulmonary capillary wedge
pressure (<15 mm Hg)
Barst, RJ et al. J Am Coll Cardiol. 2004;43:40S- 47S.
Incidence of Pulmonary
Hypertension
• Population Incidence
– Primary
4 : 500,000
– Familial
1 : 30,000,000
• Disease Specific Incidence
Chest 2003.
– Connective Tissue
1 : 10 – 1 : 1,000
– Portopulmonary
8 : 1,000
– HIV
1 : 5,000
– Anorexigens (>3 mo)
1 : 17,000
– Anorexigens (>6 mo)
1 : 10,000
– CTEPH
1 : 10,000
Connective Tissue Disease:
Major Risk Factor for Development of PAH
Connective Tissue Disease (CTD)
• Most common and severe in CREST
– Diffuse scleroderma—up to 33%
– Limited scleroderma (CREST)—25%30%
– SLE—4% to 14%
– RA—up to 21% (mild)
• PH most common cause of death in CREST
• Identical to iPAH pathology
• Medical treatment same as for iPAH
– But benefits less than for iPAH
CREST=Calcinosis cutis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia.
2003 WHO Pulmonary Hypertension
Diagnostic Classification
1. Pulmonary Arterial Hypertension
3. PH With Lung Diseases/Hypoxemia
• Idiopathic PAH (Formerly iPAH)
• COPD
• Familial PAH
• Interstitial lung diseases
• Related to:
• Sleep-disordered breathing
– Connective tissue diseases
– HIV
• Developmental abnormalities
– Portal hypertension
4. PH Due to Chronic Thrombotic
and/or Embolic Disease
– Anorexigens
• TE obstruction of proximal PA
– Congenital heart disease
• TE obstruction of distal PA
• Portopulmonary hypertension
• PAH with venule/cap involvement
• Nonthrombotic pulmonary embolism
5. Miscellaneous
2. Pulmonary Venous Hypertension
• Sarcoidosis
• Atrial or ventricular heart disease
• Pulmonary histocytosis
• Valvular heart disease
• Lymphangiomatosis
Observed 5-Year Survival Without
Treatment in iPAH: National Registry
100
1 yr: 68%
80
3 yr: 48%
%
Surviving
60
5 yr: 34%
40
Median survival: 2.8 yrs
20
0
0
0.5
1.0
1.5
2.0
2.5
3.0
Years of follow-up
Adapted from: D’Alonzo GE et al. Ann Int Med. 1991;115:343-349.
3.5
4.0
4.5
5.0
Survival Comparison of Patients With SScPAH and iPAH With Similar Hemodynamics
1.0
0.8
Survival
(%)
0.6
iPAH
0.4
SSc-PAH
0.2
Log-rank text2=4.88
p=0.03
0
No. at risk:
SSc-PAH:
iPAH:
0
1
22
33
7
24
Kawut SM et al. Chest. 2003;123:344-350.
2
3
Time (yrs)
4
5
–
9
–
3
–
–
3
15
Pulmonary Arterial Hypertension:
Understanding the Pathobiology
Insult
Vascular Injury
Genetic
predisposition
Neurohormonal Imbalance
Vascular Remodeling
and Dysfunction
Disease
Progression
Gaine SP, Rubin LJ. Lancet. 1998;352:719-725.
Cardiac
Hypertrophy
Neurohormonal Imbalance in PAH
Increased Activity
Endothelin-1
Angiopoietin-1
PAI-1
Growth factors
PDGF
Reduced Activity
Prostacyclin
Nitric oxide
VIP
PAI = plasminogen activator inhibitor.
VIP = vasoactive intestinal peptide.
McLaughlin V et al. Circulation. 2006:114.
Therapeutic Options for PAH
General Tx
• Supplemental O2
FDA Approved for PAH
Investigational Tx
• Prostanoids
• Prostanoids
• Diuretics
– epoprostenol
• CCB
– treprostinil (SC,IV)
• Warfarin
– inhaled iloprost
• Digitalis
• ERAs
– bosentan
• PDE-5 Inhibitors
– sildenafil
– Inhaled
treprostinil
– Oral
treprostinil
• ERAs
– sitaxsentan
– ambrisentan
• PDE-5 Inhibitor
– tedalafil
ACCP Grading System for Recommendations
Net Benefit to Patient
(adjusted for risk and based on clinical assessment)
Quality of
Evidence
Good:
Fair:
Low:
Expert Opinion:
Substantial
Intermediate
Small/Weak
None
Conflicting
Negative
Good
A
A
B
D
I
D
Fair
A
B
C
D
I
D
Low
B
C
C
I
I
D
Expert
Opinion
E/A
E/B
E/C
I
I
E/D
Evidence is based on good randomized controlled trials or meta-analysis
Evidence is based on other controlled trials or other RTCs with minor flaws
Evidence is based on non-randomized, case-control, or other observational studies
Evidence is based on consensus of carefully selected panel of experts.
There are no published studies that meet the criteria for inclusion in the
literature review.
McCrory DC et al. Chest 2004;126.
Therapy for PAH
Functional class II/III/IV
General Care
Oral anticoagulants (B for iPAH, E/C for other PAH) + diuretics + oxygen (E/A) + digoxin
Acute Vasoreactivity Testing (A for iPAH, E/C for PAH)
Negative
Positive
Oral CCB (B for iPAH,
E/B for other PAH)
Sustained Response
Functional Class III
Endothelin receptor antagonists
bosentan (A)
or
Yes
No
Continue CCB
Chronic IV epoprostenol (A)
bosentan (B)
Chronic IV epoprostenol (A)
treprostinil (B)
or
Prostanoid Analogues
Chronic IV iloprost (C)
SC treprostinil (B), Inhaled iloprost (B),
beraprost (l)
PDE-5 Inhibitors
(sildenafil) (C)
Badesch D et al. Chest. 2004;126.
Functional Class IV
No improvement
or deterioration
Atrioseptostomy
Lung Transplantation
Therapy for PAH
Functional class II/III/IV
General Care
Oral anticoagulants (B for iPAH, E/C for other PAH) + diuretics + oxygen (E/A) + digoxin
Acute Vasoreactivity Testing (A for iPAH, E/C for PAH)
Negative
Positive
Oral CCB (B for iPAH,
E/B for other PAH)
Sustained Response
Functional Class III
Endothelin receptor antagonists
bosentan (A)
or
Yes
No
Continue CCB
Chronic IV epoprostenol (A)
bosentan (B)
Chronic IV epoprostenol (A)
treprostinil (B)
or
Prostanoid Analogues
Chronic IV iloprost (C)
SC treprostinil (B), Inhaled iloprost (B),
beraprost (l)
PDE-5 Inhibitors
(sildenafil) (C)
Badesch D et al. Chest. 2004;126.
Functional Class IV
No improvement
or deterioration
Atrioseptostomy
Lung Transplantation
Anticoagulation Therapy for
Pulmonary Arterial Hypertension
• Idiopathic PAH
– Improved survival reported with oral anticoagulation in iPAH1,
– In situ microscopic thrombosis documented in patients with
iPAH
– RV failure and venous stasis increases risk of pulmonary
thromboembolism
– Recommended target INR1.5-2.5 but varies from center to
center
• PAH associated with other diseases - controversial
– Consider risk/benefit ratio
• Scleroderma – risk of increased GI bleeding higher
• Consider if right ventricle is enlarged and systolic dysfunction
present
Badesch D et al. Chest. 2004;126.
1Rich S et al. N Engl J Med .1992;327.
Conventional Therapies
• Diuretics
• Digoxin
– Reduce peripheral
– May increase contractility
edema, intravascular
in refractory right heart
volume, and venous
failure
pressure
– Can be useful in patients
– Avoid excessive
with atrial tachyarrhythmia
diuresis
• Oxygen
– Combination of loop
diuretics and
– Supplemental oxygen to
spironolactone may be
maintain oxygen saturation
beneficial
>90% at all times
– Hypoxemia is a potent
vasoconstrictor
Badesch D, et al. Chest. 2004;126
Therapy for PAH
Functional class II/III/IV
General Care
Oral anticoagulants (B for iPAH, E/C for other PAH) + diuretics + oxygen (E/A) + digoxin
Acute Vasoreactivity Testing (A for iPAH, E/C for PAH)
Negative
Positive
Oral CCB (B for iPAH,
E/B for other PAH)
Sustained Response
Functional Class III
Endothelin receptor antagonists
bosentan (A)
or
Yes
No
Continue CCB
Chronic IV epoprostenol (A)
bosentan (B)
Chronic IV epoprostenol (A)
treprostinil (B)
or
Prostanoid Analogues
Chronic IV iloprost (C)
SC treprostinil (B), Inhaled iloprost (B),
beraprost (l)
PDE-5 Inhibitors
(sildenafil) (C)
Badesch D et al. Chest. 2004;126.
Functional Class IV
No improvement
or deterioration
Atrioseptostomy
Lung Transplantation
Correlation of Acute Response to
Vasodilator to Long-Term
Response to CCB in iPAH
• Analyzed acute vasoreactivity testing in 557
patients with iPAH
• Acute vasodilator used: PGI2 (n=150) or NO
(n=407)
• Acute responder: fall in both mPAP and PVR
>20% from baseline – “20/20 criterion”.
– 70 patients (12.6%) demonstrated acute response
• Long term CCB responder:
– NYHA I/II after 1 year on oral CCB without need
for prostanoids and/or ERA
– Only half of acute responders (6.8% of total)
maintained response long-term
Sitbon O et al. Circulation. 2005;111.
Long-term Response to CCB by Disease
Disease
iPAH
Anorectin
CTD
HIV
PortoPH
CHD
Familial PH
PVOD
Sitbon O et al. ATS 2004.
Acute
response
13.4%
11.8%
10%
1.6%
1.3%
0%
0%
12%
Long-term
7.5%
7.9%
2%
1.6%
0.7%
0%
0%
0%
All worsened on CCBs
Therapy for PAH
Functional class II/III/IV
General Care
Oral anticoagulants (B for iPAH, E/C for other PAH) + diuretics + oxygen (E/A) + digoxin
Acute Vasoreactivity Testing (A for iPAH, E/C for PAH)
Negative
Positive
Oral CCB (B for iPAH,
E/B for other PAH)
Sustained Response
Functional Class III
Endothelin receptor antagonists
bosentan (A)
or
Yes
No
Continue CCB
Chronic IV epoprostenol (A)
bosentan (B)
Chronic IV epoprostenol (A)
treprostinil (B)
or
Prostanoid Analogues
Chronic IV iloprost (C)
SC treprostinil (B), Inhaled iloprost (B),
beraprost (l)
PDE-5 Inhibitors
(sildenafil) (C)
Badesch D et al. Chest. 2004;126.
Functional Class IV
No improvement
or deterioration
Atrioseptostomy
Lung Transplantation
Epoprostenol Improves 6-Minute
Walk Test in PAH Due to Scleroderma
80
60
Median
40
change
from
20
baseline
(m)
0
Week 1
Week 6
Epoprostenol (n=56)
Conventional (n=55)
Week 12
p0.001
63.5
p=0.003
48.5
13.3
-7.0
-14.0
-20
-36.0
-40
Baseline: epoprostenol 271.5 m; conventional 240.0 m.
Adapted from Badesch D et al. Ann Intern Med. 2000;132:425-434.
Survival With Long-term Epoprostenol
by
Etiology
1.0
0.8
CHD
Other
Kaplan-Meier 0.6
survival
estimates
0.4
iPAH
Scleroderma
0.2
p=0.002
0
No. at risk:
PAH
CHD
SSc
Other
0
1
2
49
11
19
12
40
8
11
9
26
6
7
5
3
4
Time (yrs)
16
3
5
4
Kuhn KP et al. Am J Respir Crit Care Med. 2003;167:580-586.
11
1
2
4
5
6
7
9
0
0
1
2
0
0
0
1
0
0
0
Challenges Implementing
Epoprostenol Therapy
• Development of tolerance
• Many side effects (diarrhea, flushing,
headache, neuropathy)
• Only approved for advanced stages of
disease (Class III to IV)
• Cost (average cost $50,000-150,000 per
year)
• Need for continuous delivery system
– Risk associated with catheter placement
– Line related complications (infection, thrombosis,
pump failure)
Treprostinil (Remodulin®) SC
• Analog of epoprostenol
• Lasts longer – more stable molecule
(~4 hours vs 3-5 minutes for epoprostenol)
• Room temperature stable – do not need ice
packs
• Rapid and complete absorption
subcutaneously – bioavailability 100%
• Change pump every 3 days with SC
(instead of every day with epoprostenol)
Treprostinil Sodium Injection: Change in
Exercise vs Treprostinil Dose at Week 12
+36 ± 9
(N=58)
Mean ± SE Change from
Baseline (meters)
40
35
N=470
30
25
20
+15 ± 7
(N=58)
15
+7 ± 10
(N=52)
10
5
0
-4 ± 12
(N=34)
-5
1st Quartile
< 5.0
(2.5 ± 0.2)
2nd Quartile
5 to <8.2
(5.6 ± 0.1)
3rd Quartile
8.2 to <13.8
(9.4 ± 0.2)
(Mean ± SE) ng/kg/min
Simonneau G et al, Am J Respir Crit Care Med. 2002;165.
4th Quartile
>13.8
(16.2 ± 0.4)
Limitations of SC Treprostinil
• Site pain is major
impediment
– Affects 85%
– Not dose dependent
– Treatments
• Local measures: ice, heat,
lidocaine
• NSAIDs, narcotics,
gabapentin
• PLOgel
– Patient education and support
imperative for treatment
success
• pain
• erythema
• induration
Open-Label Transition
Study Results
6-Minute Walk Test Results: IV REMODULIN vs Flolan*
Baseline on Flolan
438 m + 16 m
NO Significant
Change From
Baseline
12 weeks on REMODULIN
439 m + 16 m
P=NS
N=27
*Data expressed as mean ± standard error.
Safety results: 27 of 31 patients completed the study; 4 patients transitioned back to Flolan (3 due to leg
pain, 1 with worsening PAH symptoms in setting of pneumonia). The most frequent adverse events were:
extremity pain (71%), headache (45%), diarrhea (26%), and jaw pain (23%). One patient had syncope; 4
reported worsening dyspnea during titration.
.
Gomberg-Maitland M, et al. Am J Respir Crit Care Med.
2005;172:1586-1589.
Inhaled Iloprost
• Indicated for inhalation via the I-neb™
AAD® system only
• 6-9 inhalations daily during waking hours
–
No more than once every two hours
• Dose: maximum of 2.5 or 5 mcg per
treatment
• Side effects (headache, flushing,
diarrhea)
–
Cough, Syncope
• Advantage: Do not need a central line
• Disadvantage: Compliance
Effect of Inhaled Iloprost on
Walk Distance
36 meters
36 meter difference
Olschewski H et al. N Engl J Med. 2002;347.
Endothelin Is A Key
Pathogenic Mediator
Proliferation
Vasoconstriction
vascular smooth muscle
direct or via facilitation of other
vasoconstrictor systems (renin
angiotensin system, sympathetic)
fibroblasts
ET
Hypertrophy
cardiac/vascular
Fibrosis
fibroblast proliferation
 extracellular matrix proteins
 collagenase production
Clozel. Ann Med. 2003:35;1-5.
Inflammation
 vascular permeability
neutrophil / mast cell activation
promotes cellular adhesion
 cytokine production
Endothelin Is a Key Mediator in
PAH and PAH Secondary to Other Diseases
8
6
4
2
0
Non-PAH
PAH
Stewart et al., Ann Inter Med,1991;
Concentration of ET-1(pg/ml)
IrET-1 (pg/ml)
10
10
8
P<0.05
6
4
LcSSc
Non-PAH
LcSSc
PAH
Vancheeswaran et al., J. Rheum, 1994;
Delta ET-LI (PV-RV) (pg/ml)
Scleroderma
iPAH
5
Congenital
Heart Disease
P<0.05
4
3
2
1
0
Non-PH
PH
Yoshibayashi et al., Circulation, 1991
Bosentan: Chemical Structure
First Synthesis: December 1991
O
O
Pharmacokinetic Profile
S
N -H
O
O
Orally active dual endothelin
receptor antagonist
O
Bioavailability is ~50% and
is not affected by food.
N
N
N
N
O H
Clozel M et al. J Pharmacol Exp Ther. 1994;270:228.
Metabolized by the liver
(CYP3A4 and 2C9) and
eliminated via the bile.
Bosentan (Tracleer®): BREATHE-1
• Randomized, double-blind, placebocontrolled
• 16 week study
• 213 patients with NYHA Class III or IV PAH
– Idiopathic PAH (70%)
– PAH associated with connective tissue disease (30%)
•
•
•
•
Gender M / F: 22% / 78%
Baseline 6MWD: 330 ± 74 meters
WHO FC III / IV: 94% / 6%
Mean PAP: 53 ± 17 mm Hg
Rubin LJ et al. N Engl J Med. 2002;346.
Bosentan and SSc-PAH Walk Test
Change From Baseline to Study End
SSc Pooled
40
All BREATHE-1
36
30
20
Placebo
Bosentan
15
 walk 10
distance
0
(m)
-10
-8
-20
-30
-22
Bosentan (n=37)
Placebo (n=15)
Bosentan (n =144)
Placebo (n=69)
Adapted from Rubin LJ et al for the BREATHE Study Group. N Engl J Med. 2002;346:896-903, and
Channick RN et al. Lancet. 2001;358:1119-1123.
Data on file.
BREATHE-1 SSc PATIENTS
Event-Free (%)
Time to Clinical Worsening*
100
90%
Bosentan (n = 33)
75
Placebo (n = 14)
79%
50
25
0
0
4
8
12
16 18
Time (Wks)
*Shortest time to death, premature withdrawal, hospitalization due to PAH worsening, or initiation of
prostacyclin therapy.
Bosentan Indication
• PAH with WHO Class III (or IV)
symptoms “to improve exercise
capacity and decrease the rate of
clinical worsening”
• Caveat: Response may take time - up
to 2 to 3 months
– Patients should be informed
– Should be used with caution in Class IV patients
and not without right heart catheterization to
document presence of PAH
Bosentan Monitoring
• Increase in liver enzymes
– Seen in about 10-12% of patients
– LFTs checked baseline and monthly
– Dose related and reversible
• Confirm elevation with another test
• Stop if ALT/AST >3 ULN – evaluate for concomitant
medication use
• Consider reintroduction after resolution
• Stop treatment if associated with clinical symptoms (eg,
jaundice, fever, nausea, vomiting)
• Dose 62.5 mg BID oral for 4 weeks.
Titrate to 125 mg BID if LFTs stable.
Side Effect Bosentan
• Other side effects
– Mild anemia
– Teratogenic
– Mild edema
• Drug interactions
– May decrease efficacy of hormonal
contraception; barrier method advised
– Contraindicated with glyburide and
cyclosporine
Differences in ET Receptors
• ETA
– Located on smooth muscle cells
– Mediate vasoconstriction
• ETB
– Found on both endothelial and smooth
muscle cells
– Smooth muscle cells: mediates
vasoconstriction
– Endothelial cells: mediates vasodilation
and clearance of ET-1
Selective vs Non-selective ERA?
What Role Does ETB Receptor Play?
• Controversial
• Increased ETB receptor density in PH –
spatial distribution not clear
– Congenital heart disease
• (Am J Respir Crit Care Med 2002;165)
– Chronic thromboembolic PH
• (Circulation 2002;105)
– Scleroderma
Other ERAs
• Sitaxsentan: once daily specific ERA blocker
– Phase III trials completed1
– Marketing application filed with the FDA,
approval pending
– Significant warfarin interaction – need to decrease
dose by 80%
– Less liver toxicity
• Ambrisentan: once-daily specific ERA blocker
(less than sitaxsentan)
– Phase II trial showed ? less liver toxicity (3.1%),
functional and hemodynamic improvements2
– Phase III trials underway
1. Barst RJ, et al. Am J Respir Crit Care Med. 2004;169:441-447.
2. Galie N, et al. J Am Coll Cardiol. 2005;46:529-535.
Sildenafil for PAH: SUPER Study
N
278
Age
Mean: 49 y (range: 18-81 )
Gender
68 (25%) men; 209 (75%) women
Primary Diagnosis
iPAH:
n=175 (63%)
PAH secondary to CTD:
n=84 (30%)
PAH with surgical repair
of congenital heart lesions: n=18 (6%)
Mean 6-MWD distance
344 m
mPAP
53 mm Hg
Functional Classification
Class I: n=1 (0.4%)
Class II: n=107 (39%)
Class III: n=154 (56%)
Class IV: n=9 (3%)
Dose
20, 40, 80 mg sildenafil or placebo in 1:1:1:1
Galie N et al. N Engl J Med. 2005:353:2148-2157.
SUPER-1: Change in 6-MWD
From Baseline to 12 Weeks
Placebo
Week 4
Sildenafil 20 mg
n=278.
Adapted from Galie N et al. N Engl J Med. 2005;353:38-47.
Week 8
Sildenafil 40 mg
50 m
46 m
*p<0.0001
*
*
*
45 m
70
60
50
40
30
 from
baseline 20
(m)
10
0
-10
-20
-30
Week 12
Sildenafil 80 mg
PAH Determinants of Risk
Lower Risk
Determinants of Risk
Higher Risk
No
Clinical evidence of
RV failure
Yes
Gradual
Progression
Rapid
II
WHO class
IV
Longer (>400 m)
6MW distance
Shorter (<300 m)
Minimally elevated
BNP
Very elevated
Minimal RV dysfunction
Echocardiographic
findings
Pericardial effusion,
significant RV
dysfunction
Normal/near normal
RAP and CI
Hemodynamics
High RAP, low CI
McLaughlin VV and McGoon M. Circulation. 2006;114:1417-1431.
Summary
• Multiple pathogenic pathways contribute to CTD-associated
PAH
–  prostacyclin and  NO cause  vasodilatation, and
smooth muscle proliferation
– ET-1 production causes vasoconstriction,
inflammation, fibrosis, cellular proliferation
• Current targeted therapy has been demonstrated to improve
clinical outcomes:
– ERAs
– PDE5 inhibitors
– IV, SQ, or inhaled prostacyclin/prostanoid analogues
• New treatment approaches are focusing on:
– novel targets
– improving delivery systems for current treatments
– combination therapy to target multiple pathogenic
pathways