2008 Post Conference Update:CHEST

Epidemiology

PAH Registries: Functional Class at Diagnosis Indicates Delayed Diagnosis

Frost AE. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

% Patients NYHA Functional Class III-IV at Diagnosis

72 73 7380

7175

0

20

40

60

80

100

REVEAL REVEAL-TR REVEAL NIH PHC NIH French

N=2967 N=2364 N=1009 N=578 N=187 N=674

Per

cen

t (%

)

Survival of Geriatric Patients with IPAH

Uzunpinar A. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331.

N = 20, IPAH patients >65 years.

Per

cen

t (%

) S

urv

ival

100908070605040302010

0

Year 1 Year 2 Year 3

Time

Expected Survival (NIH)

Actual Survival

Prevalence of Resting PH in Patients Referred for Stress Echocardiography

Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

N = 2,306 adults referred for stress echocardiography.

RSVP >35 mmHg 11.9%

RVSP <35 mmHg 88.1%

Diagnostic and Outcomes Markers

BNP Predictive Value For Adverse Outcomes

Garcia-Badillo EV. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

Death

Cardiogenic shock

Inpatient heart failure

Outpatient heart failure

Ventricular dysfunction

WHO Class IV

WHO Class III

WHO Class II

WHO Class I

Control 12.1

20.2

151.7

388.4

470.0

424.7

472.7

545.6

632.1

644.8

BNP (pg/mL)

N = 85

Biomarker Predictors of Clinical Worsening In Bosentan-treated Patients

Vizza CD. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331.

*P = 0.0006. †P = 0.09. Clinical worsening vs no clinical worsening.

ET-1 (pg/mL)

85.0

138.0

19.0

12.7

No Worsening Clinical Worsening

BNP (pg/mL)

†

*

Clinical and Hemodynamic Predictors of Survival in PAH

Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

Co

nco

rdan

ce in

dex

(C

sta

tist

ic)

0.8

0.7

0.6

0.5

P<0.005

P<0.001NS

Other Clinical factors

RHC

Age, Sex, WHO Class

ECHO & PFTs

Doppler Echo Overestimates PAH in Patients with Scleroderma-related Lung Disease

Chan KM. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

60

0

4038

25 25

0

20

40

60

80

100

Overestimate PASP Underestimate PASP Accurate PASP

No PH PH

Per

cen

t (%

)

PAH in Obese Patients: BMI Correlates With Worsening Hemodynamics

Kaw R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

N = 1600, patients undergoing right heart catheterization for suspected PH.*p < 0.05 versus comparator.

70

60

50

40

30

20

10

0RA Mean PA Systolic PA Diastolic PA Mean PCWP Mean

mm

Hg

BMI < 25 25≤BMI>30 30≤BMI>35 BMI≥35

**

*

*

*

*

*

* **

*

*

*

Clinical Pharmacology

No Pharmacokinetic Interactions Between Ambrisentan and Tadalafil

Spence R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.

Cmax AUCAmbrisentan +5.0% -12.5%4-hydroxymethyl ambrisentan

+5.8% -14.5%

Tadalafil +0.6% +0.2%

N = 26, healthy volunteers.Comparison versus single-agent/metabolite.

Sitaxsentan and Acencoumarol Interactions

Pulido T, et al. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.

N = 50. Dose adjustments of 1.6 – 2.0 mg required to reach INR target.

3.0

2.5

2.0

1.5

1.0

0.5

2

Duration (weeks)

INR

6 10 14 18 22 26 30 34 38 42 46 50 54 58 62 66 70 74 78 82 86 90 94 98 102

106

110

Short-term Clinical Trials

Tadalafil for PAH: Change in 6MWD at 16 Weeks

Barst RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

N = 405*p = 0.05; †p = 0.03; ‡p = 0.0004 vs. placebo.

†

*

‡

70

60

50

40

30

20

10

00 4 8 12 16

placebo2.5 mg

10 mg

20 mg40 mg

Weeks

Ch

ang

e i

n 6

-Min

ute

Wal

kin

g D

ista

nce

(m

)

Tadalafil for PAH: Change in WHO Functional Class at 16 Weeks

Barst RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

P = NS for all comparisons.

Per

cen

t (%

)

n = 82 n = 82 n = 82 n = 80 n = 79

20.7 25.6 23.836.6

22.8

63.4 52.4 62.5 45.1 67.1

15.9 22 13.8 18.3 10.1

0%

20%

40%

60%

80%

100%

Placebo 2.5 mg 10 mg 20 mg 40 mg

Improved No Change Worsened

Long-term Clinical Trials

ARIES-E: Survival With Long-term Ambrisentan Therapy

Oudiz RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

0

20

40

60

80

100

0.0 0.5 1.0 1.5 2.0

Years

Su

rviv

al (

%)

ABS 2.5 mg 5 mg 10 mg

At Risk: n=383 n=334 n=315 n=298 n=255

2 Year = 88%1 Year = 94%

ARIES-E: Change in 6MWD Over 2 Years With Ambrisentan

Oudiz RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

Ch

ang

e in

6M

WD

(m

)

Years

-20

-10

0

1020

30

40

50

60

0.0 0.25 0.5 1.0 1.5 2.0

70 2.5 mg, n = 93 5 mg, n = 186 10 mg, n = 96

TRIUMPH-1: Long-term Inhaled Treprostinil Plus Oral Therapy 6MWD Improvements Over Time

Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

300

350

400

450

Baseline Month 6 Month 12 Month 18 Month 24

349

377 380 383

399

N = 206Subjects received either bosentan (n = 143) or sildenafil ( n = 63) in addition to inhaled treprostinil up to 72 µg four times daily

To

tal 6

-Min

ute

Wal

kD

ista

nce

(m

eter

s)

Long-term Inhaled Treprostinil Plus Oral Therapy: Change in NHYA Functional Class Over Time

Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

*p < 0.05

NYHA Unchanged (%) NYHA Worsened (%) NYHA Improved (%)

Month 12N=93

Month 9N=121

Month 6N=160

Month 3N=197

Ch

ang

e fr

om

Bas

elin

e

8070

60

50

40

30

20

10

0

***

*

SUPER-2: Sildenafil Open-label ExtensionClinical Outcomes at 3 Years

Rubin LJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

45.8

17.7 17.3 19.1

0

20

40

60

80

100

Improved6MWD

Worsened6MWD

Discontinued/Lost

Died

Per

cen

t (%

)

N = 259

SUPER-2: Long-term Sildenafil Change in Functional Class at 3 Years

Rubin LJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

3.6

25.631

5.4

15.219.1

0

20

40

60

80

100

N = 259

Improved2 Classes

Improved1 Class

Worsened1 Class

Unchanged DC/Lost Died

Per

cen

t (%

)

Long-term Outcomes in Patients Transitioned From Epoprostenol to SC Treprostinil

Yan C. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

NNYA Functional Class Pre- and Post-Transition (6 months of therapy)

N = 30

60

50

40

30

10

20

0

Pe

rce

nta

ge

o

f P

ati

en

ts (

%)

NYHA CLASS

I II III IV

Pre-transition

Post-transition

Long-term Outcomes in Patients Transitioned From Epoprostenol to SC Treprostinil

Yan C. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

Discontinuation of Treprostinil Over Time(Excluding Death)

N = 30

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60

Time (Months)

Pro

po

rtio

n o

f P

atie

nts

Rem

ain

ing

on

SC

TR

E

Adverse Effects of PAH Therapies

Epoprostenol-related Thrombocytopenia

Jacob S. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.

Platelet count drop >50,000 noted in red

Platelet count at Baseline

Platelet count at 2-4 months

Platelet count at 8-12 months

450

400

350

300

250

200

150

100

50

0

ARIES- 3: Long-term Ambrisentan Following Bosentan or Sitaxsentan Failure for LFT Abnormalities

Feldman JP. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.

N = 226, Subset analysis among 26 patients forced to discontinue alternative ERA therapy for LFT abnormalities.

25

20

15

10

0No LFT

AbnormalitiesALT/AST

>3X AND 5xULN

1 (4%)5N

um

ber

of

Pat

ien

ts

25 (96%)

ARIES-1 & 2: 6MWD of Patients Experiencing Edema Versus No Edema

Shapiro SL. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

Placebo Ambrisentan

All No Yes

All No Yes

-120

-100

-80

-60

-40

-20

0

20

40

60

Ch

ang

e in

6M

WD

(m

)

p = 0.032All Yes

-9 -1

-55

+34 +39

+19

EdemaEdema

Expanding Populations

PH Inhibits Stress Echo Exercise Duration

Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331.

Exercise duration, mins

6 10 14 182

100

80

60

40

20

0

No PH(8.6±3 mins)

Ex - PH(7.4±3 mins)

P<0.0001

Per

cen

tag

e (%

) P

atie

nts

PAH in Sickle Cell Disease

10% of sickle cell patients will have PAH/PH Pathophysiology not necessarily related to

occlusion— Soluble factors have been identified

Mixed PH (PAH combined with diastolic dysfunction) associated with 11-fold relative risk of mortality

Clinical trials of PAH medications in sickle cell have been slow to recruit

Barst RJ, Machado RF, Mubarak KK. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session 15983.

Summary: CHEST 2008

Evidence suggests PAH treatment can be effective in wide range of patient types and ages

Tadalafil may provide a new choice in PDE-5 inhibitor class

Inhaled treprostinil in combination with oral therapy may provide an additional choice in prostacyclin class

Long-term data for ambrisentan, sildenafil show 2+ years of benefit in survival and time to clinical worsening