wednesday, november 15, 2006 washington, dc richard m. silver, md, program chair vascular...

Wednesday, November 15, 2006 • Washington, DC • Richard M. Silver, MD, Program Chair

VASCULAR COMPLICATIONS OF SYSTEMIC SCLEROSIS

VASCULAR COMPLICATIONSOF SYSTEMIC SCLEROSIS

Treatment Targets for PAH in Systemic Sclerosis

Myung H. Park, MD, FACCAssistant Professor of Medicine

Director, Pulmonary Vascular Diseases ProgramUniversity of Maryland Medical Center

Baltimore, Maryland

VASCULAR COMPLICATIONSOF 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 PulmonaryArterial Hypertension

Barst, RJ et al. J Am Coll Cardiol. 2004;43:40S- 47S.

• 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)

Incidence of Pulmonary Incidence of Pulmonary HypertensionHypertension

• Population IncidencePopulation Incidence

– Primary 4 : 500,000Primary 4 : 500,000

– Familial 1 : 30,000,000Familial 1 : 30,000,000

• Disease Specific IncidenceDisease Specific Incidence

– Connective TissueConnective Tissue 1 : 10 – 1 : 1 : 10 – 1 : 1,0001,000

– PortopulmonaryPortopulmonary 8 : 1,0008 : 1,000

– HIVHIV 1 : 5,0001 : 5,000

– Anorexigens (>3 mo)Anorexigens (>3 mo) 1 : 17,0001 : 17,000

– Anorexigens (>6 mo)Anorexigens (>6 mo) 1 : 10,0001 : 10,000

– CTEPHCTEPH 1 : 10,0001 : 10,000Chest 2003.

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 iPAHCREST=Calcinosis cutis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia.

2003 WHO Pulmonary Hypertension2003 WHO Pulmonary HypertensionDiagnostic ClassificationDiagnostic Classification

1. Pulmonary Arterial Hypertension1. Pulmonary Arterial Hypertension

• Idiopathic PAH (Formerly iPAH)Idiopathic PAH (Formerly iPAH)

• Familial PAHFamilial PAH

• Related to:Related to:

– Connective tissue diseasesConnective tissue diseases

– HIVHIV

– Portal hypertensionPortal hypertension

– AnorexigensAnorexigens

– Congenital heart diseaseCongenital heart disease

• Portopulmonary hypertensionPortopulmonary hypertension

• PAH with venule/cap involvementPAH with venule/cap involvement

2. Pulmonary Venous Hypertension2. Pulmonary Venous Hypertension

• Atrial or ventricular heart diseaseAtrial or ventricular heart disease

• Valvular heart diseaseValvular heart disease

3. PH With Lung Diseases/Hypoxemia3. PH With Lung Diseases/Hypoxemia

• COPDCOPD

• Interstitial lung diseasesInterstitial lung diseases

• Sleep-disordered breathingSleep-disordered breathing

• Developmental abnormalitiesDevelopmental abnormalities

4. PH Due to Chronic Thrombotic 4. PH Due to Chronic Thrombotic and/or Embolic Diseaseand/or Embolic Disease

• TE obstruction of proximal PATE obstruction of proximal PA

• TE obstruction of distal PATE obstruction of distal PA

• Nonthrombotic pulmonary embolismNonthrombotic pulmonary embolism

5. Miscellaneous5. Miscellaneous

• SarcoidosisSarcoidosis

• Pulmonary histocytosisPulmonary histocytosis

• LymphangiomatosisLymphangiomatosis

1 yr: 68%1 yr: 68%

Median survival: 2.8 yrsMedian survival: 2.8 yrs

3 yr: 48%3 yr: 48%

5 yr: 34%5 yr: 34%

00

2020

4040

6060

8080

100100

00 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.5 4.04.0 4.54.5 5.05.0

Years of follow-upYears of follow-up

%% Surviving Surviving

Adapted from: D’Alonzo GE et al. Ann Int Med. 1991;115:343-349.

Observed 5-Year Survival Without Observed 5-Year Survival Without Treatment in iPAH: National RegistryTreatment in iPAH: National Registry

Time (yrs)Time (yrs)11 22 33 4400 55

SSc-PAHSSc-PAH

iPAHiPAHSurvival Survival

(%)(%)

0.20.2

0.80.8

0.40.4

1.01.0

0.60.6

00

Log-rank textLog-rank text22=4.88 =4.88 pp=0.03=0.03

No. at risk:No. at risk:SSc-PAH:SSc-PAH: 2222 77 33 –– –– ––iPAH:iPAH: 3333 2424 1515 99 33 ––

Kawut SM et al. Chest. 2003;123:344-350.

Survival Comparison of Patients With SSc-Survival Comparison of Patients With SSc-PAH and iPAH With Similar HemodynamicsPAH and iPAH With Similar Hemodynamics

Vascular Injury

Vascular Remodelingand Dysfunction

DiseaseProgression

CardiacHypertrophy

Neurohormonal ImbalanceNeurohormonal Imbalance

Gaine SP, Rubin LJ. Lancet. 1998;352:719-725.

InsultInsultGenetic Genetic predispositionpredisposition

Pulmonary Arterial Hypertension: Pulmonary Arterial Hypertension: Understanding the PathobiologyUnderstanding the Pathobiology

Increased ActivityIncreased Activity

Endothelin-1Endothelin-1

Angiopoietin-1Angiopoietin-1

PAI-1PAI-1

Growth factorsGrowth factors

PDGFPDGF

Reduced ActivityReduced Activity

ProstacyclinProstacyclin

Nitric oxideNitric oxide

VIPVIP

PAI = plasminogen activator inhibitor.VIP = vasoactive intestinal peptide.

Neurohormonal Imbalance in PAHNeurohormonal Imbalance in PAH

McLaughlin V et al. Circulation. 2006:114.

Therapeutic Options for PAHTherapeutic Options for PAH

General TxGeneral Tx

• Supplemental OSupplemental O22

• DiureticsDiuretics

• CCBCCB

• WarfarinWarfarin

• DigitalisDigitalis

FDA Approved for PAH

• Prostanoids

– epoprostenol

– treprostinil (SC,IV)

– inhaled iloprost

• ERAs

– bosentan

• PDE-5 Inhibitors

– sildenafil

Investigational Tx

• Prostanoids

– 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)

Substantial Intermediate Small/Weak None Conflicting Negative

Quality of Evidence

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

Good: Evidence is based on good randomized controlled trials or meta-analysis Fair: Evidence is based on other controlled trials or other RTCs with minor flaws Low: Evidence is based on non-randomized, case-control, or other observational studiesExpert Opinion: 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 PAHFunctional class II/III/IV

General CareOral anticoagulants (B for iPAH, E/C for other PAH) + diuretics + oxygen (E/A) + digoxin

Acute Vasoreactivity Testing (A for iPAH, E/C for PAH)

Functional Class III Functional Class IV

Sustained Response

Oral CCB (B for iPAH, E/B for other PAH)

Continue CCB

Chronic IV epoprostenol (A)

bosentan (B)

treprostinil (B)

Chronic IV iloprost (C)

Endothelin receptor antagonistsbosentan (A)

or

Chronic IV epoprostenol (A)or

Prostanoid Analogues SC treprostinil (B), Inhaled iloprost (B),

beraprost (l)

PDE-5 Inhibitors(sildenafil) (C)

Atrioseptostomy Lung Transplantation

Yes No

PositiveNegative

No improvement or deterioration

Badesch D et al. Chest. 2004;126.

• 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.

Anticoagulation Therapy for Pulmonary Arterial Hypertension

Conventional Therapies

• Diuretics– Reduce peripheral

edema, intravascular volume, and venous pressure

– Avoid excessive diuresis

– Combination of loop diuretics and spironolactone may be beneficial

• Digoxin– May increase contractility

in refractory right heart failure

– Can be useful in patients with atrial tachyarrhythmia

• Oxygen– Supplemental oxygen to

maintain oxygen saturation >90% at all times

– Hypoxemia is a potent vasoconstrictor

Badesch D, et al. Chest. 2004;126





Sustained Response


Continue CCB


bosentan (B)

treprostinil (B)



or



beraprost (l)



Yes No

Positive

Negative



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-termSitbon O et al. Circulation. 2005;111.

DiseaseAcute

response Long-term

iPAH 13.4% 7.5%

Anorectin 11.8% 7.9%

CTD 10% 2%

HIV 1.6% 1.6%

PortoPH 1.3% 0.7%

CHD 0% 0%

Familial PH 0% 0%

PVOD 12% 0%All worsened on CCBs

Sitbon O et al. ATS 2004.

Long-term Response to CCB by Disease





Sustained Response


Continue CCB


bosentan (B)

treprostinil (B)



or



beraprost (l)



Yes No

PositiveNegative



13.313.3

Baseline: epoprostenol 271.5 m; conventional 240.0 m.Adapted from Badesch D et al. Ann Intern Med. 2000;132:425-434.

Median changefrom

baseline (m)

-40

-20

0

20

40

60

80

-7.0-7.0-14.0-14.0

-36.0-36.0

48.548.5

63.563.5

Week 1 Week 6 Week 12

Epoprostenol (n=56)

Conventional (n=55)p=0.003

p0.001

Epoprostenol Improves 6-MinuteEpoprostenol Improves 6-MinuteWalk Test in PAH Due to SclerodermaWalk Test in PAH Due to Scleroderma

Time (yrs)

Kaplan-Meier survival estimates

0.2

1.0

0.4

0

0.6

0.8CHD

Scleroderma

0 2 3 4 5 61 7

Other

iPAH

p=0.002

Kuhn KP et al. Am J Respir Crit Care Med. 2003;167:580-586.

Survival With Long-term Epoprostenol Survival With Long-term Epoprostenol by Etiologyby Etiology

No. at risk: PAH 49 40 26 16 11 9 2 1 CHD 11 8 6 3 1 0 0 0 SSc 19 11 7 5 2 0 0 0 Other 12 9 5 4 4 1 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)

-5

0

5

10

15

20

25

30

35

40

1st Quartile < 5.0

2nd Quartile 5 to <8.2

3rd Quartile 8.2 to <13.8

4th Quartile >13.8

Treprostinil Sodium Injection: Change in Exercise vs Treprostinil Dose at Week 12

-4 ± 12(N=34)

+7 ± 10(N=52)

+15 ± 7(N=58)

+36 ± 9(N=58)

(2.5 ± 0.2) (16.2 ± 0.4)(9.4 ± 0.2)(5.6 ± 0.1)

Mea

n ±

SE

Ch

ang

e fr

om

B

asel

ine

(met

ers)

(Mean ± SE) ng/kg/min

Simonneau G et al, Am J Respir Crit Care Med. 2002;165.

N=470

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

• pain

• erythema

• induration

Open-Label Transition Study Results

6-Minute Walk Test Results: IV REMODULIN vs Flolan*

.

NO SignificantChange From

Baseline

Baseline on Flolan

12 weeks on REMODULIN

438 m + 16 m

439 m + 16 m

P=NSN=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

Olschewski H et al. N Engl J Med. 2002;347.

Effect of Inhaled Iloprost onWalk Distance

36 meters

36 meter difference

Proliferation vascular smooth muscle fibroblasts

Fibrosis fibroblast proliferation extracellular matrix proteins collagenase production

Inflammation vascular permeability neutrophil / mast cell activation promotes cellular adhesion cytokine production

Hypertrophy cardiac/vascular

Endothelin Is A KeyPathogenic Mediator

Vasoconstrictiondirect or via facilitation of other vasoconstrictor systems (renin angiotensin system, sympathetic)

Clozel. Ann Med. 2003:35;1-5.

ET

Endothelin Is a Key Mediator in PAH and PAH Secondary to Other Diseases

Stewart et al., Ann Inter Med,1991; Vancheeswaran et al., J. Rheum, 1994; Yoshibayashi et al., Circulation, 1991

Congenital Heart Disease

Non-PH PH0

1

2

3

4

5

P<0.05

Del

ta E

T-L

I (P

V-R

V)

(pg/

ml)

iPAH

IrE

T-1

(pg

/ml)

Non-PAH PAH0

2

4

6

8

10

Scleroderma

Con

cent

ratio

n of

ET

-1(p

g/m

l)

4

6

8

10

LcSSc PAH

LcSSc Non-PAH

P<0.05

Clozel M et al. J Pharmacol Exp Ther. 1994;270:228.

Bosentan: Chemical StructureFirst Synthesis: December 1991First Synthesis: December 1991

N

N

N - HS

O O

O

O

O H

O

N

N

Pharmacokinetic Profile

Orally active dual endothelin receptor antagonist

Bioavailability is ~50% and is not affected by food.

Metabolized by the liver (CYP3A4 and 2C9) and eliminated via the bile.

Bosentan (Tracleer®): BREATHE-1

• Randomized, double-blind, placebo-controlled

• 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.

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.

Bosentan (n=37)Placebo (n=15)

walk distance

(m)

-22

-8

15

36

-30

-20

-10

0

10

20

30

40

PlaceboBosentan

Bosentan (n =144)Placebo (n=69)

SSc Pooled All BREATHE-1

Bosentan and SSc-PAH Walk Test Bosentan and SSc-PAH Walk Test Change From Baseline to Study EndChange From Baseline to Study End

BREATHE-1 SSc PATIENTS

Time to Clinical Worsening*

*Shortest time to death, premature withdrawal, hospitalization due to PAH worsening, or initiation of prostacyclin therapy.

100

25

50

75

0

Time (Wks)Time (Wks)0 4 8 12 16 18

Eve

nt-

Fre

e (

%)

Eve

nt-

Fre

e (

%) Bosentan (n = 33)

Placebo (n = 14)

90%90%

79%79%

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 underway1. 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.

NN 278 278

AgeAge Mean: 49 y (range: 18-81 )Mean: 49 y (range: 18-81 )

GenderGender 68 (25%) men; 209 (75%) women68 (25%) men; 209 (75%) women

Primary DiagnosisPrimary Diagnosis

iPAH: n=175 (63%)iPAH: n=175 (63%)PAH secondary to CTD: n=84 (30%)PAH secondary to CTD: n=84 (30%)PAH with surgical repair PAH with surgical repair of congenital heart lesions: n=18 (6%)of congenital heart lesions: n=18 (6%)

Mean 6-MWD distanceMean 6-MWD distance 344 m344 m

mPAPmPAP 53 mm Hg53 mm Hg

Functional ClassificationFunctional Classification

Class I: n=1 (0.4%)Class I: n=1 (0.4%)Class II: n=107 (39%)Class II: n=107 (39%)Class III: n=154 (56%)Class III: n=154 (56%)Class IV: n=9 (3%)Class IV: n=9 (3%)

DoseDose 20, 40, 80 mg sildenafil or placebo in 1:1:1:120, 40, 80 mg sildenafil or placebo in 1:1:1:1

Galie N et al. N Engl J Med. 2005:353:2148-2157.

Sildenafil for PAH: SUPER StudySildenafil for PAH: SUPER Study

-30-30-20-20-10-10

001010202030304040505060607070

Week 4Week 4 Week 8Week 8 Week 12Week 12

from from baseline baseline

(m)(m)

PlaceboPlacebo Sildenafil 20 mgSildenafil 20 mg Sildenafil 40 mgSildenafil 40 mg Sildenafil 80 mgSildenafil 80 mg

**pp<0.0001<0.0001

** ****

45 m

46 m

50 m

n=278.Adapted from Galie N et al. N Engl J Med. 2005;353:38-47.

SUPER-1: Change in 6-MWDSUPER-1: Change in 6-MWDFrom Baseline to 12 WeeksFrom Baseline to 12 Weeks

PAH Determinants of Risk

Lower RiskLower Risk Determinants of Risk Higher RiskHigher Risk

NoClinical evidence of

RV failureYes

Gradual Progression Rapid

II WHO class IV

Longer (>400 m) 6MW distance Shorter (<300 m)

Minimally elevated BNP Very elevated

Minimal RV dysfunctionEchocardiographic

findings

Pericardial effusion,significant RV dysfunction

Normal/near normalRAP and CI

Hemodynamics High RAP, low CI

McLaughlin VV and McGoon M. Circulation. 2006;114:1417-1431.

SummarySummary

• Multiple pathogenic pathways contribute to CTD-associated Multiple pathogenic pathways contribute to CTD-associated PAHPAH

prostacyclin and prostacyclin and NO cause NO cause vasodilatation, and vasodilatation, and smooth muscle proliferationsmooth muscle proliferation

ET-1 production causes ET-1 production causes vasoconstriction, vasoconstriction, inflammation, inflammation, fibrosis, fibrosis, cellular proliferationcellular proliferation

• Current targeted therapy has been demonstrated to improve Current targeted therapy has been demonstrated to improve clinical outcomes:clinical outcomes:

– ERAsERAs– PDE5 inhibitorsPDE5 inhibitors– IV, SQ, or inhaled prostacyclin/prostanoid analoguesIV, SQ, or inhaled prostacyclin/prostanoid analogues

• New treatment approaches are focusing on:New treatment approaches are focusing on:– novel targetsnovel targets– improving delivery systems for current treatmentsimproving delivery systems for current treatments– combination therapy to target multiple pathogenic combination therapy to target multiple pathogenic

pathwayspathways

wednesday, november 15, 2006 washington, dc richard m. silver, md, program chair vascular...

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