RON OUDIZ, MDRON OUDIZ, MDAssociate Professor of Medicine

David Geffen School of Medicine at UCLA LA Biomedical Research Institute at

Harbor-UCLA Medical CenterTorrance, California

Long-term Management of Patients with PAH

2

Learning Objectives (CME, CE, CPE)

● At the completion of this educational activity, participants should be able to:

& Discuss the data regarding long-term medical therapy for PAH

& Describe the limitations to the long-term data of medical therapy for PAH

& Report on the data regarding combination medical therapy for PAH

& Discuss interventional and surgical approaches to PAH

Trends in Long-term Survival with PAH

4

Updated Definition of PAH

Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(suppl 1):S55–S66Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294.

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

Right Heart Catheterization Confirmed

* 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.

5

Survival of PAH Patients in Current Era: Comparison with NIH Historical Controls

Thennapan T, et al. Chest. 2007;132(4 suppl):487S.

N = 276, IPAH and FPAH patients diagnosed from 1982-2006; matched for disease variables at baseline with historical controls

6765

32

10091

76

43

0

10

20

30

40

50

60

70

80

90

100

Baseline 1 year 3 year 5 year

Per

cen

tag

e (%

) S

urv

ival Observed

Predicted (NIH)

^

6

PAH Survival in Current Era: Insights from REVEAL Registry

● REVEAL is an ongoing registry of patients with PAH

● Participating centers include 54 major PAH referral sites in the US

● >3000 patients screened; initial data set includes 2967 patients meeting entry criteria

Badesch DB et al. Chest. 2009; DOI 10.1378/chest.09-1140. E-pub ahead of print.

7

REVEAL: Heritable (Familial) PAH and IPAH Comparisons

Sarkar PK. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8906

^

Two-year Survival HPAH/IPAH

HPAH IPAHAge at diagnosis, years 37 + 16 47 + 18mPAP at diagnosis, mm HG 57 + 14 53 + 14PVRI at diagnosis, units.m2 29 + 13 23 + 12Use of parenteral prostacyclins, % 51 35

IPAH 1439 1403 1345 1325 1288 1244 1225 1182 1130 1117 1052 961 953

FPAH 91 90 89 87 82 78 77 73 71 70 65 62 62

100

90

IPAH, n=1439FPAH, n=91

0

Per

cen

tag

e (%

) S

urv

ival

80

240 2 4 6 8 10 12 14 16 18 20 22Time from Enrollment (month)

Number at Risk

Key HPAH/IPAH Comparisons in REVEAL

100

90

IPAH, n=1439FPAH, n=91

0

Per

cen

tag

e (%

) S

urv

ival

80

240 2 4 6 8 10 12 14 16 18 20 22Time from Enrollment (month)

Number at Risk

P=0.14

8

REVEAL Registry: Two-year Survival of SSc-PAH and SLE-PAH

Chung L. Presented at the ACR/ACHP Scientific Meeting. Oct. 17-21, 2009. Philadelphia, PA. 1730.

^

Per

cen

tag

e (%

) S

urv

ival

SSc-APAH (n=399)SLE-APAH (n=110) log rank P value =0.0009

0 2 4 6 8 10 12 14 16 18 20 22 240

50

60

70

80

90

100

Time from Enrollment (months)

9

REVEAL: Outcomes of PAH Due to Anorexigen Use

Barst RJ. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8379

Females aged 19 and over at diagnosis

^

Fen/Dex Exposure 75 73 71 71 68 68 65 64 63 63 61 55 55

IPAH/FPAH 609 604 595 588 580 569 561 553 542 535 513 466 463

Number at Risk Time from Enrollment (month)

Fen/Dex Exposure, n=75IPAH/FPAH, n=609P

erce

nta

ge

(%)

Su

rviv

al 100

90

0

80

240 2 4 6 8 10 12 14 16 18 20 22

10

Gender Differences in PAH 5-year Mortality: REVEAL Registry

Shapiro S, et al. Am J Respir Crit Care Med. 179;2009:A2648.

Time from Diagnosis (Years)

Per

cen

tag

e (

%)

Mo

rtal

ity

Mortality EstimateMale (n=649)Female (n=2318)

0 1 2 3 4 50

5

10

15

20

25

30

35

40

45

50

^

Measuring Outcomes in PAH Therapy

12

Goals of Management of PAH

● Improve survival

● Prevent clinical worsening

● Improve hemodynamics (right-heart function)

● Maintain or improve functional class

● Improve exercise capacity

● Improve daily functioning and quality of life

13

The Problem is…

● Clinical trial endpoints do not necessarily study endpoints that are relevant to the goals of clinical management

● Definition of “clinical worsening” and related terms can be very variable across clinical trials

● Functional class assessment is subjective

● 6MWD test has inherent problems in reproducibility and correlation with disease severity

● Accurate hemodynamic measurements are invasive; improvements do not necessarily correlate with clinical status

McLaughlin VV, et al. J Am Coll Cardiol. 2009; 54 (Suppl S):S97–S107.

14

Prognostic Factors for Risk ofPAH Disease Progression

Adapted from McLaughlin VV, et al. Circulation. 2009;119:2250-2294.

Lower Risk Higher Risk

Evidence of RV failure No YesProgression of symptoms

Gradual Rapid

WHO class II, III IV6-minute walk distance >400 m <300 m

CPET peak VO2>10.4 mL/kg/min <10.4 mL/kg/min

Echo findings Minimal RV dysfunction

Pericardial effusion; significant RV

dysfunction, RA enlargement

Hemodynamics RAP <10 mm Hg, CI >2.5 L/min/m2

RAP >20 mm Hg,CI <2.0 L/min/m2

Brain natriuretic peptide Minimal elevation Significantly elevated

15

Change in 6MWD Did Not Predict Survival in Long-term Epoprostenol Therapy

Sitbon O, et al. J Am Coll Cardiol. 2002;40:780–788.

78

78

63

60

48

35

31

25

19

16

13

8

5

2

2

1

1Subjects at risk, n

∆ 6’ WT ≥ 112 m

∆ 6’ WT < 112 m

∆ 6’ WT < 112 m

∆ 6’ WT ≥ 112 m

Su

rviv

al

0

0.4

0.6

0.8

1.0

0.2

(Months)0 1089684726048362412

16

Long-term Management of PAH: Recommended Tests

Adapted from Galie N, et al. Eur Heart J. 2009;30:2493-2537.

Baseline Ea 4 – 6 months

3 – 4 months after therapy initiation or

change

@ clinical worsening

Clinical AssessmentWHO functional class

ECG

6MWD

CPET

BNP/NT-proBNP

Echo

Right heart catheterization

or

PAH Therapy

18

Mechanisms of Action ofTherapies for PH

Humbert M, et al. N Engl J Med. 2004;351:1425-1436.

Nitric oxide

cGMP

Vasodilation and antiproliferation

Endothelial cells

Nitric oxide pathway

Preproendothelin ProendothelinL-arginine

NOS

Arachidonic acid Prostaglandin I2

Prostaglandin I2

cAMPVasodilation and antiproliferation

Vasoconstriction and proliferation

Endothelin-receptor A Endothelin-

receptor B

Endothelin pathway Prostacyclin pathway

Endothelin-1

Endothelin-receptor

antagonists

Exogenous nitric oxide

Prostacyclinderivates

Phosphodiesterase type 5 inhibitor

Phosphodiesterase type 5

19

REVEAL Database: Therapy Choices at Enrollment

PDE5 Inhibitor ERA

305

417 452290

190

224

At-enrollment therapy of first 2438 patients in REVEAL. Excludes patients enrolled in blinded controlled trials.

Prostacyclin (IV, IM and Inhaled)

295No PAH Therapy = 266

Badesch DB, et al. Chest. 2009; DOI 10.1378/chest.09-1140. Epub ahead of print.

^

PAH Monotherapy

21

PAH Long-term Monotherapy Trials - Caveats

● Most long-term trials were open-label extensions of placebo-controlled trials without a comparator arm

● All trials allowed add-on therapy in the setting of clinical worsening

- Some trials do not define add-on therapy as a clinical endpoint

● The relative contribution of the “primary” study medication is therefore difficult to assess

22

Intravenous Epoprostenol forSevere PAH: 3-Year Survival

N=162 consecutive patients with IPAH in NYHA Class III or IV. 3-year survival with IV epoprostenol compared with expected survival from NIH historical controls. *P<0.001 at all time points.

McLaughlin VV, et al. Circulation. 2002;106:1477-1482.

0 6 12 18 24 30 36Months

20

40

60

80

100

Per

cen

tag

e (%

) S

urv

ival

*

*

*

ObservedExpected

23

Long-Term OutcomesWith Subcutaneous Treprostinil

Barst RJ, et al. Eur Respir J. 2006;28:1195-1203.

0

10

20

30

Pat

ien

ts (

%)

Discontinue forDeterioration

Death

N=860.Patients followed for up to 4 years.

SwitchTherapy

AddTherapy

Discontinue forAdverse Events

14%16%

11%

15%

23%

24

Long-term Inhaled Iloprost In IPAH:Event-free Survival

Opitz CF, et al. Eur Heart J. 2005;26:1895-1902.

Event-free = freedom from death, transplantation, switch to intravenous therapy, or addition of oral therapy to inhaled iloprost monotherapy.

Cu

mu

lati

ve E

ven

t-F

ree

Su

rviv

al (

%)

Time (Years)

0

40

60

80

100

20

0 54321

No. at risk 76 39 20 13 4 2No. of events 0 335 52 58 59 60

25

Survival WithInitial Bosentan Therapy in IPAH

McLaughlin VV, et al. Eur Respir J. 2005;25:244-249.

N=169. Data from 2 placebo-controlled trials and their extensions.Includes 39 patients who received additional therapy instead of or in addition to bosentan.

Bosentan

Predicted

100

Eve

nt-

Fre

e P

atie

nts

(%

) 90

80

70

60

50

40

30

20

0

10

0 6 12 18 24 30 36Months

26

Long-term Outcome with Initial Bosentan Therapy

Provencher S, et al. Eur Heart J. 2006;27:589-595.

Event-free = survival without lung transplantation, initiation of prostanoid therapy, or hospitalization for right-heart failure.

Survival

Event-free

103

103

76

49

48

26

20

11

12

6

0

0

Subjects at risk, n

of mortality

of event

Per

cen

tag

e S

urv

ival

an

dE

ven

t-F

ree

Sta

tus

0

40

60

80

100

20

(Months)

0 6048362412

27

ARIES-E: Survival WithLong-Term Ambrisentan Therapy

Oudiz RJ, et al. J Am Coll Cardiol. 2009;54:1975-1981.

0

20

40

60

80

100

0.0 0.5 1.0 1.5 2.0Years

Su

rviv

al (

%) 2 Year = 88%1 Year = 94%

Combined doses 2.5 mg5 mg10 mg

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

^

28

ARIES-E: Long-term Ambrisentan Survival by Etiology

2009 ATS Abstract. Pulido T. Am J Respir Crit Care Med. 179;2009:A3356.

0

Eve

nt

Fre

e (%

)

100

60

0

20

80

40

0.5 1.0 1.5

1 Year94% (90% to 97%)

2.0

91% (82% to 95%)

2 Year89% (83% to 93%)87% (77% to 92%)

YearsAt Risk n=178 n=161 n=151 n=145 n=122At Risk n=94 n=81 n=71 n=69 n=57

IPAHPAH-CTD

^

29

SUPER-2: Sildenafil Open-label Extension Clinical Outcomes at 3 Years

Improved6MWD

Worsened6MWD

Discontinued/Lost

Died

45.8%

17.7% 17.3% 19.1%

0%

20%

40%

60%

80%

100%

Per

cen

tag

e (%

)

N=259.

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

^

30

Long-term Tadalafil: 6MWD by Initial Treatment Assignment

2009 ATS Abstract. Oudiz RJ, et al. Am J Respir Crit Care Med. 179;2009:A1042.

Open-label extension of 16 week blinded study. Most patients titrated to 40 mg qd in open-label phase.

420

400

380

360

340

3200 4 8 10 13 16

Months

Extension Study16-Week Study

Abbreviation: 6MWD = 6-minute walk distance

Mea

n 6

MW

D (

m)

Placebo:40mg

20mg:20mg

2.5-20mg:40mg

40mg:40mg

^

PAH Combination Therapy

32

Combination Therapy Trials Caveats

● No trial to date has studied the question of monotherapy versus de novo combination therapy

● All currently reported trials featured “add-on” protocols

● Relative contribution of individual agents to treatment success difficult to assess

● Combination therapy trials often have only a short-term component, with no long-term follow-up

33

Combination Therapy: Sildenafil Added to Failing Inhaled Iloprost Monotherapy

Ghofrani HA, et al. J Am Coll Cardiol. 2003;42:158-164.

N = 14. Patients with inadequate response to inhaled iloprost.

6 M

inu

te W

alk

Dis

tan

ce (

m)

400

380

360

340

320

300

280

260

240

220

200

180

Inhaled iloprost+ oral sildenafil

p=0.002

p=0.002p=0.014+

+ +

Treatment interval18+/-4 months

Baseline Ilo3 mo. Pre-Sil

Sil-Ilo3 mo.

Sil-Ilo6 mo.

Sil-Ilo9-12 mo.

34

PACES: Sildenafil Add-On to Stable Epoprostenol Therapy

● 16-week study (N=267)

- Patients on stable epoprostenol for >3 months

- 80% of patients provided with sildenafil 80 mg tid

● Deaths at 16 weeks

- Placebo (n=7)

- Sildenafil (n=0)

0

2

4

6

8

10

12

14

16

18

20

Any Clinical Worsening Event at 16 Weeks

Pat

ien

ts (

%)

Placebo Sildenafil

Simonneau G, et al. Ann Intern Med. 2008;149:521-530.

35

BREATHE-2: Bosentan Add-On to Stable Epoprostenol Therapy

● Placebo-controlled prospective 16-week study (N=33)

● Patients initiated on epoprostenol, then assigned 2:1 to bosentan or placebo

● No statistical improvements in hemodynamics or WHO functional class

0

20

40

60

80

100

Mean Improvement in 6MWD

6MW

D (

m)

Bosentan

Humbert M, et al. Eur Respir J. 2004;24:353-359.

Placebo

6874

36

STEP: Add-On Inhaled Iloprost to Stable Bosentan Monotherapy

0

20

40

60

80

100

Pat

ien

ts (

%)

Improved 1 Class

34.4%

ClinicalDeterioration

6.0%

62.5%

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.

IloprostPlacebo

McLaughlin VV, et al. Am J Respir Crit Care Med. 2006;174:1257-1263.

0%

15.2%

No Change

Change From Baseline in NYHA Class

91.0%

Worsened 1 Class

3% 0%

37

Goal-Directed Combination Therapy: Suggested Treatment Algorithm

Baseline and 2- to 6-Month Evaluation for Treatment Goals6-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;26:858-863.

38

Tra

nsp

lan

tati

on

an

d In

trav

eno

us

Pro

stag

lan

din

-Fre

e T

reat

men

t

Goal-Directed Therapy: Transplantation- and IV Prostanoid-Free Survival

Hoeper MM, et al. Eur Respir J. 2005;26:858-863.

*P=0.002 versus historical controls.Dual therapy (43.2%), triple therapy (16.1%), and IV prostanoid (4.2%).

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36

Subjectsat Risk (n)

Patient Population

Historical Control Group

123 113 87 70 57 53 38

84 70 54 42 34 27 18

Months

Historical Controls

Goal-DirectedTreatment*

Interventional and Surgical Modalities in PAH

40

Surgical Interventions for PAH: When to Refer for Transplantation

● Although drug therapy may delay transplantation, a class IV patient who fulfills criteria should be referred for consideration for transplantation

● Patients who improve to WHO class II with therapy may be removed from the waiting list

● Patients remaining in or progressing to WHO class III after combination therapy should be assessed for transplantation

● Patients with PVOD/PCH should be referred immediately at time of diagnosis

Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.

41

Type of Transplantation in PAH

● Heart-lung or bilateral lung transplants are preferred

- Single-lung transplantation has been abandoned as ineffective in IPAH

● Choice of surgery dependent on several variables

- Etiology of PAH

- Donor organ availability

- Center experience

Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.

42

IPAH Long-term Transplant Survival at University of Pittsburgh Transplant Center

Toyoda Y, et al. Ann Throac Surg. 2008;86:1116-1122.

8675

66

0

20

40

60

80

100

Per

cen

tag

e (%

) S

urv

ival

1 year 5 year 10 year

N = 30. Transplanted between 1994 to 2006 with a diagnosis of IPAH.

43

Transplant Survival – IPAH, PAH-SSc and IPF

Schachna L, et al. Arthritis Rheum. 2006;54:3954-3961.

Su

rviv

al

No. at risk: SSc 29 20 17 16 15IPF 70 56 41 33 26

IPAH 38 30 28 24 22

Months after Transplantation

1.0

0.9

0.8

0.7

0.6

0.5

0 6 12 18 24

SScIPF

IPAH

Johns Hopkins and University of Pittsburgh transplant centers.

44

Atrial Septostomy

● Indications

- Failure of maximal medical therapy with persisting RV failure and/or recurrent syncope

- Bridge to transplantation

- When no other therapeutic options exist

● Right-to-left shunting increases systemic output, decompresses failing RV and LV

● Increases O2 transport

● Stepwise balloon dilatation is procedure of choice

Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.

45

Recommendations to Reduce Procedure-related Morality in Atrial Septostomy

● Only perform in a PAH center

● Contraindications

- Severe RV failure or cardiorespiratory support

- mRAP >20 mm Hg

- PVRI >55 U/m2

- Resting O2 saturation <90% on room air

- LVEDP >18 mm Hg

Adapted from Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.

46

Recommendations to Reduce Procedure-related Morality in Atrial Septostomy

● Pre-procedure

- Optimize cardiac function with adequate RH filling pressure and inotropic support

● During procedure

- Supplemental O2

- Appropriate sedation

- Monitoring LAP SaO2%, and mPAP

- Tailor defect to <10% decrease in O2 saturation

● Postprocedure

- Optimize O2 delivery with transfusion or packed red blood cells or darbepoetin before and after

Adapted from Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.

47

Summary: Long-term Management of Patients with PAH

● Patients with PAH appear to be surviving longer on medical therapy

● Long-term data on choice of initial medical therapy, de novo combination therapy, or therapy sequencing are still incomplete

● Considerations for initial therapy selection should include decisions on long-term efficacy, safety, and second-line choices

● In patients with severe disease or failing under medical therapy, early referral for possible surgical interventions is important