Haemodynamics in PAH:

Long Term Outcomes and

Importance in Guiding

PAH–Specific Therapy

Dr. Peter Steele

Director of Cardiology

Royal Adelaide Hospital

South Australia

Schematic Progression of PAH

Time

PAP

PVR

CO

Pre-symptomatic/

Compensated

Symptomatic/

Decompensating

Symptom Threshold

Right Heart

Dysfunction

Declining/

Decompensated

CO=PAP

PVR

Galiè N, Rubin LJ. J Am Coll Cardiol 2004;43(12 Suppl S):1S. Rich S. Progress Cardiovasc Diseases 1988;31(3):205-38.

Humbert MD et al. N Engl J Med 2004;351:1425-36. D’Alonzo GE et al. Ann Intern Med 1991;115:343-49.

ΔP ( pressure )

Q ( output )=

MPA – PCWPPVR

CO=

MPA – PCWPPVRI

CI*=

*CI = adjusted for BSA

(Dyn. sec cm -5) = 1 Wood unit x 80

R (resistance)

Ohm’s Law (hydrodynamic form)

Haemodynamics in PAH

– Cardiac Catheter

• PA, RA, wedge pressures

• Shunts

• Oxygen saturations

• Cardiac output

• PVR calculation

• Left heart disease

• Pulmonary angiography

• Vasodilator challenge

Haemodynamics in PAH

– Importance

• Definition of PAH (mPAP>25mmHg,with a

normal wedge pressure <15mmHg)

• Diagnosis (exclusions, cardiac catheter)

• Prognosis

• Assessment/selection of treatment

Primary Pulmonary Hypertension:

Natural History and the Importance

of Thrombosis

VALENTIN FUSTER, M.D., *PETER M. STEELE, M.B.B.S. (Hons), F.R.A.C.P.

WILLIAM D. EDWARDS, M.D., BERNARD J. GERSH, M.B., CH.B, D. PHIL.,

MICHAEL D. MCGOON M.D., and ROBERT L. FRYE, M.D.

Circulation 70, No.4, 580–587, 1984.

Fuster V et al. Circulation 1984;70(4):580-7.

Mean Range

Pulmonary arterial pressure (mm Hg)

Peak 98 53 – 208

Mean 64 36 – 120

Pulmonary index, (l/min/m2 ) 2.2 0.7 – 5.0

Total pulmonary resistance (Um2) 33 11 – 95

Right ventricular end-diastolic

pressure (mmHg) 13 2 – 30

Right ventricular work index

(kg/min/m2) 1.6 0.4 – 5.8

Systemic arterial oxygen saturation (%) 91 42 – 99

Pulmonary arterial oxygen saturation (%) 60 20 – 80

Haemodynamic features at

diagnosis

Fuster V et al. Circulation 1984;70(4):580-7.

Data were obtained at entry into study from the 115 patients who survived diagnostic heart catheterisation

Factor p value

Pulmonary arterial oxygen saturation < .00001*

Systemic arterial oxygen saturation <.00001

Total pulmonary resistance <.00001

Right ventricular end-diastolic pressure .004

Pulmonary artery pressure, mean .006

Pulmonary index .009

Anticoagulant therapy .02*

Cardiomegaly .03

Age .2

Right ventricular work index .3

Sex .9

Univariate Analysis of

Prognostic Factors

Fuster V et al. Circulation 1984;70(4):580-7.

Percent

surviving

100

90

80

70

60

50

40

30

20

10

1

(62)

(24)

(7)

109876543210

Years

Observed survival to 10 years of patients

with primary pulmonary hypertension

Fuster V et al. Circulation 1984;70(4):580-7.

Results of the NIH registry

D`Alonzo et al Ann Int Medicine 1991

Validation of the

prognostic Equation

Sandoval et al 1994, Circulation

Haemodynamic prognostic indicators

iPAH

McLaughlin et al CHEST 2004

Haemodynamic prognostic

indicators

McLaughlin et al CHEST 2004

Haemodynamics in PAH

– Clinical Relevance

• Advanced disease – death predicted by RV failure (low CO, high RAP, poor RV)

• RV function assessment difficult (MRI better)

• CO/PAWP measurement errors (TR etc.)

• PA pressure alone not accurate

• RA pressure load dependent

• PVR (includes CO) most important indicator of disease status

Drug Study No. of pts D 6 MWD at

3-4 mths

P value

Bosentan BREATHE 1

NEJM 2002

213 + 44 < 0.001

Ambrisentan Galie et al,

JACC 2005

64 + 36* < 0.001

Sitaxsentan STRIDE 1,

AJRCCM 2004

178 + 34 < 0.01

Prostacyclin

(IV)

Meta-Analysis,

Cochrane, 2005

196 + 90 < 0.0002

Iloprost

(Inhaled)

AIR,

NEJM, 2002

203 + 36 0.004

Treprostinil

(SC)

Simmoneau,

AJRCCM, 2002

470 + 16 0.006

Beraprost ALPHABET,

JACC, 2002

130 + 25 0.036

Sildenafil SUPER-1,

NEJM, 2005

278 + 45-50 < 0.001

(* vs baseline, all other trials vs placebo)

ΔP ( pressure )

Q ( output )=

MPA – PCWPPVR

CO=

MPA – PCWPPVRI

CI*=

*CI = adjusted for BSA

(Dyn. sec cm -5) = 1 Wood unit x 80

R (resistance)

Ohm’s Law (hydrodynamic form)

Iloprost

Air Study

Olschewski, H et al, 2002

Olschewski, H et al, 2002

Sildenafil

Super 1

Galie et al NEJM 2005

Haemodynamic response

12 weeks therapy

Galie et al NEJM 2005

Epoprostenol

Barst et al, NEJM 1996

Haemodynamic response at 12 weeks therapy

Barst et al, NEJM 1996

Bosentan

Bosentan Baseline Haemodynamics

Channick et al, 2001 LANCET

Bosentan Haemodynamic response to

treatment after 12 weeks

Channick et al, 2001 LANCET

Bosentan in WHO FC II patients

EARLY Baseline characteristics

Placebo (n=92) Tracleer (n=93)

Mean time from diagnosis,

years

3.7 2.9

Aetiology, n (%)

PPH

CHD

SSc

Other

58 (63%)

16 (17.4%)

5 (5.4%)

13 (14.2%)

54 (58.1%)

16 (17.2%)

9 (9.7%)

14 (15%)

Mean 6MWD, m ± SD 430.9 ± 91.9 442.5 ± 82.9

Mean PVR, dyn.sec.cm5 ±

SD

802 ± 365 851 ± 535

Galie et al ESC, 2007

Haemodynamics

Change from baseline to month 6 v’s placebo

• mPAP treatment effect - 5.7mmHg

p =<.0001

• TPR treatment effect - 207 (dyn.sec/cm5)

p =<.0001

• Cardiac Index treatment effect 0.24 L/ mn/m2

p = 0.0249

• SVO2 treatment effect 4.8% increase

p = 0.0020

Galie et al ESC, 2007

Drug Treatment effect

Cardiac

index

PVR mRAP

Bosentan

SItaxentan (100mg)

1.0 L/Min/m2

0.3 L/Min/m2

415 dyn

270 dyn

-6.2 mmHg

-1 mmHg

Prostacyclin (IV) 0.5 L/Min/m2 400 dyn -2.3 mmHg

Sildenafil

20mg

80mg

0.23 L/Min/m2

0.39 L/Min/m2

171 dyn

310 dyn

-1.1 mmHg

-1.3 mmHg

Iloprost

Pre inhalation

Post inhalation

0.12 L/Min/m2

0.37 L/Min/m2

105 dyn

335 dyn

+1.9 mmHg

+0.6 mmHg

How do these haemodynamic

changes translate into long

term outcomes?

Iloprost

Optizs et al Eur Heart Journ, 2005

Inhaled Iloprost

– Long term efficacy

Opitz et al, Eur Heart J, 2005 Sep;26(18):1895-902

** Bosentan

McLaughlin et al, Eur Resp J, 2005

Event-free survival (freedom from death, transplantation, switch to

Intravenous therapy, or additional oral therapy)

Cu

mu

lati

ve

eve

nt-

fre

e s

urv

iva

l (%

)

SUPER 2 Study

277 149No. at risk:

(Data on file. Pfizer Inc, New York, NY.)

88%

All patients up titrated

to 80mgs TID

Bosentan observed and predicted

survivalKaplan-Meier survival estimates with 99% CI

0 6 12 18 24 30 36 months

169 Patients at risk167 163 153 113 23 16

0102030405060708090

100

Event Rate / year (exponential): 5.5%% o

f event-

fre

e p

atients

Predicted (NIH 2)

Observed 1

2 D’Alonzo et al, Ann Intern Med 1991; 115:343

1 Mc Laughlin et al, Eur Resp J 2005; 25:244-249

96%

69%

92%

Only RCT to show improvements in

Survival – IV Epoprostenol

Barst et al, NEJM, 1996

Matched cohort

Sitbon, THORAX 2005

Drug Treatment effect

Cardiac

index

PVR mRAP

Bosentan

SItaxentan (100mg)

1.0 L/Min/m2

0.3 L/Min/m2

415 dyn

270 dyn

-6.2 mmHg

-1 mmHg

Prostacyclin (IV) 0.5 L/Min/m2 400 dyn -2.3 mmHg

Sildenafil

20mg

80mg

0.23 L/Min/m2

0.39 L/Min/m2

171 dyn

310 dyn

-1.1 mmHg

-1.3 mmHg

Iloprost

Pre inhalation

Post inhalation

0.12 L/Min/m2

0.37 L/Min/m2

105 dyn

335 dyn

+1.9 mmHg

+0.6 mmHg

Haemodynamics in PAH

– Summary

• Haemodynamic data predicts survival

(CO, RAP, PAP, PVR)

• Clinical correlation critical

• PVR best indicator of disease status

• Cardiac catheter essential

• Drugs with greater PVR reduction appear

to produce better long term clinical

outcomes

Sitaxentan

Sitaxentan treatment effect – 100mg OD

• PVR - 270 dyns

• CI +0.3 l/min

What about Time to Clinical

Worsening?

Does this paint a picture of

Morbidity and Mortality in PAH?

BREATHE-1: Time to clinical worsening

in WHO FC III and IV PAH patients

Bosentan

125/250 mg bid

Rubin LJ, et al. N Eng J Med 2002; 346:896-903.

Eve

nt-

fre

e (

%)

Time (weeks)

0 4 8 12 16 20 24 28

p < 0.01

50

75

100

Placebo

p < 0.004

0

144

69

142

68

31

10

141

63

138

62

103

48

25

7

13

3

Patients at riskBosentanPlacebo

Galiè N, et al. N Engl J Med 2005; 353:2148-57.

Sildenafil: SUPER-1Time to clinical worsening

Placebo

(n = 70)

Sildenafil

20 mg

(n = 69)

Sildenafil

40 mg

(n = 67)

Sildenafil

80 mg

(n = 71)

Proportion worsened (%) 10 4 3 7

(95% CI) (3.17) (0.9) (0.7) (1.13)

Incidence of clinical

worsening events

Death 1 (1) 1 (1) 0 (0) 2† (3)

Lung transplantation 0 (0) 0 (0) 0 (0) 0 (0)

Hospitalisation due to PH 7 (10) 2 (3) 2 (3) 2 (3)

Initiation of prostacyclin 1 (1) 0 (0) 0 (0) 0 (0)

Initiation of bosentan 0 (0) 0 (0) 1 (2) 2 (3)

†1 patient died during the 1st week whilst receiving sildenafil 40 mg

BOSENTAN SITAXENTAN AMBRISENTAN SILDENAFIL

Study 351 BREATHE-1 EARLY STRIDE-1 STRIDE-2 ARIES-1 ARIES-2 SUPER-1

6-MWD, m+76,

p = 0.021

+44,

p < 0.001

+19.1

NS

100/300mg:

+35/+33,

p < 0.01

50 mg: NS

100 mg:

+31.4,

p = 0.03

5mg:

+30.6,

p = 0.0084

10mg: +51.4

p = 0.0001

2.5mg:

+32.3,

p = 0.0219

5mg: +59.4

p = 0.0002

20/40/80 mg:

+45/+46/+50

p < 0.001

WHO class p = 0.0039 p = 0.0407

p-value

not

quoted

p < 0.02

50 mg: NS

100 mg:

p <0.04

NS NS p ≤ 0.003

PVR,

dyn·s·cm-5 -415,

p ≤ 0.001

23%,

p < 0.0001

100/300mg:

-221/-194,

p < 0.001

20/40 mg:

-122/-143,

p = 0.01

80 mg:

-261,

p < 0.001

TTCW p = 0.033 p = 0.002 p = 0.0114 NS NS NS

2.5 mg:

p = 0.0048

5 mg:

p = 0.0076

NS

Clinical endpoints:

Summary table

Sitaxentan base line

haemodynamics

Barst et al, AJRCCM 2003

EARLY: Time to clinical worsening in

WHO FC II PAH patients

Patients are censored at the end of the study

100

80

60

40

20

00 4 8 12 16 20 2824 32

92 90 89 86 84 83 1877 9

93 92 87 85 84 83 2780 15

Weeks from treatment start

Patients

witho

ut

the e

vent

(%)

Patients at risk

Placebo

Bosentan

p = 0.0114; log rank

Hazard ratio = 0.227

(95% CL: 0.065, 0.798)

Galiè N, et al. Presented at ESC 2007.

Time to clinical worsening in WHO FC II PAH patients

Sitaxentan: STRIDE programmeTime to clinical worsening

Parametera

STRIDE-1 STRIDE-2

Placebo

(n = 60)

100 mg sitaxentan

(n = 55)

300 mg sitaxentan

(n = 63)

Placebo

(n = 62)

50 mg sitaxentan

(n = 62)

100 mg sitaxentan

(n = 61)

Time to clinical worsening

Delay in time to clinical worsening p = NS p = NS p = 0.27 p = 0.08

No. of clinical worsening events, n

(%)3 (5) 0 (0) 1 (2) 10 (16) 6 (10) 4 (7)

Hospitalisation for PAH 4 (6) 1 (2) 1 (2)

Death Not quoted 0 (0) Not quoted 0 (0) 0 (0) 0 (0)

Transplantation Not quoted 0 (0) Not quoted 0 (0) 0 (0) 0 (0)

Initiation of new chronic PAH

therapyNot quoted 0 (0) Not quoted 4 (6) 4 (6) 3 (5)

Atrial septostomy Not quoted 0 (0) Not quoted 0 (0) 0 (0) 0 (0)

WHO FC deterioration and ≥ 15%

decrease in 6-MWD2 (3) 1 (2) 0 (0)

aAll p-values derived from comparisons with placebo unless otherwise stated

Barst RJ, et al. Am J Respir Crit Care Med 2004; 169:441-7.

Barst RJ, et al. J Am Coll Cardiol 2006; 47:2049-56.

Time to clinical worsening* in RCTs

Trial Agent p-value

Study 351 Bosentan p <0.051

BREATHE-1 Bosentan p <0.052

SUPER-1 Sildenafil NS3

STRIDE-1 Sitaxentan NS4

STRIDE-2 Sitaxentan NS5

ARIES-1 Ambrisentan NS6

ARIES-2 Ambrisentan p <0.057

EARLY Bosentan p <0.058

1.Channick RN, et al. Lancet 2001. 2.Rubin LJ, et al. NEJM 2002. 3.Galiè N, et al. NEJM 2005.

4.Barst RJ, et al. AJRCCM 2004. 5.Barst RJ, et al. JACC 2006. 6.Oudiz R, et al. Chest Meeting Abstracts

2006. 7.Olschewski H, et al. ATS 2006. 8.Galiè N, et al. Presented at ESC 2007.

*Combined end point of death, lung transplantation, hospitalisation for pulmonary hypertension, lack of clinical improvement or worsening leading to discontinuation, need for epoprostenol therapy, or atrial septostomy

Study 351: Time to clinical worsening in

WHO FC III PAH patients

Eve

nt-

fre

e (

%)

Time (weeks)

0 4 8 12 16 20 24 28100

50

75

100

0

Bosentan

Placebo

21

11

21

11

7

1

21

10

21

8

12

4

6

1

2

1

p < 0.05

Channick RN, et al. Lancet 2001; 358:1119-23.