Pulmonary Arterial Hypertension: Assessment of disease’s ... · Pulmonary Hypertension Unit La Sapienza University oi Rome Functional class & with survival Sitbon O, et al. J Am

Pulmonary Hypertension Unit

La Sapienza University oi Rome

Pulmonary Arterial Hypertension:

Assessment of disease’s severity

Carmine Dario VizzaPulmonary Hypertension Unit

Dept. Cardiovascular and Respiratory Diseases

La Sapienza University of Rome

e-mail : [email protected]



Pulmonary Arterial Hypertension:

The disease

Female 40 yrs

PAP = 50 mmHg

CI = 2,3 l/m/m2

NYHA Class III

6MWD = 380 m



Time

PAP

PVR

CO

PAH: natural history

CO exercise

FUNCTIONAL

CLASS

I

Symptoms

RAP

FUNCTIONAL

CLASS

IV

FUNCTIONAL

CLASS

III

FUNCTIONAL

CLASS

II



Prognosis of Idiopatic Pulmonary Arterial

Hypertension (PAH) was poor

0 1 2 3 4 5 6

WHO Class I - II IPAH

WHO Class III IPAH

Advanced breast cancer

Advanced colorectal cancer

WHO Class IV IPAH

Advanced lung cancer

Survival (years)

D'Alonzo GE, et al. Ann Intern Med 1991; 115:343-9.Kato I, et al. Cancer 2001; 92:2211-9.

Felker GM, et al. N Engl J Med 2000; 342:1077-84.

Ischaemic cardiomyopathy

6 months

2.6 years

4.9 years

7



Specific approved drugs in PAH

Prostacyclin Derivatives

• Epoprostenol: IV

• Iloprost: inhaled

• Treprostinil: subcutaneous or IV

Endothelin Receptor Antagonists

• Bosentan: oral

• Ambrisentan: oral

• Sitaxsentan

Phosphodiesterase Type-5 Inhibitors

• Sildenafil: oral



The ESC/ERS 2010 therapeutic

algorithm…

It introduces the concept of

Inadequate clinical response

Need for assessment during

Follow-up

Treatment guided by

Prognostic risk assessment ?



Clinical Evaluation

Walk-Test

Right cath study

ET-1 plasma levels

BNP plasma levels

Run-in

Bosentan 125 mg bid

1 month 3 months

Bosentan

62.5 mg bid

Our experience

Clinical Evaluation

Clinical worsening

1 month every 1/3 months

Phone contact

Clinical Evaluation

Jan

20

08



0

18

0

36

0

54

0

72

0

90

0

10

80

12

60

14

40

Time, days

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0C

um

ula

tive

Pro

po

rtio

n S

urv

ivin

g

no

CW

KM plot: patients without CW



0

18

0

36

0

54

0

72

0

90

0

10

80

12

60

14

40

Time, days

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0C

um

ula

tive

Pro

po

rtio

n S

urv

ivin

g

no

CW

KM plot: patients without CW

Breath-1 NEJM 2002

Mc Laughlin ERJ 2005

Provencher Thorax 2005

Oral therapies are not a cure for PAH !

Need for a strict follow-up !



Prognostic indicators

• Clinical assessment

Symptoms

Clinical Signs

Rate of progression

• Exercise capacity

6 minute walking test

CP exercise test

• RV functionEcho

MR heart

• HemodynamicsRight Atrial Pressure

Cardiac Index

• BiomarkersTroponin-T

BNP, Na, Creatinine

Uric Acid, PCR



Functional class & with survival

Sitbon O, et al. J Am Coll Cardiol 2002; 40:780-8. McLaughlin VV, et al. Circulation 2002; 106:1477-82.

1-year epoprostenol

102030466386112115No. at risk

Surv

ival (%

)

Months

847260483624120

100

80

60

40

20

0

NYHA I

NYHA II

NYHA III

NYHA IV

Months

p < 0.0001

0

20.

40

60

80

100

0 12 24 36 48 60 72 84 96 108

NYHA I or II

(n = 91)

NYHA III or IV

(n = 75)

3-month epoprostenol

Surv

ival (%

)



6-minute walk distance & survival

Sitbon O, et al. J Am Coll Cardiol 2002; 40:780-8.

6-MWD 380 m

Cu

mu

lative

su

rviv

al

1.0

Time (months)

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72 84 96 108

6-MWD < 380 m

p = 0.0005

Subjects

at risk (n)

6-MWD 380 m

6-MWD < 380 m78 54 28 16 8 6 3 3 1

78 71 56 41 28 15 4



Cardiopulmonary exercise test

Wessel R.Circulation. 2002;106:319-324



Prognostic Impact of Echocardigram

Raymond RJ. JACC 2002



Tei Index = (Dur IT- T Eiez VD) / T Eiez VD

Dur IT

T Eiez VD

80

100

40

60

0

20

0 10 20 30

Mesi

Sopra

vviv

enza %

Index < 0.88

Index > 0.88

26 pazienti

Tei C. J Am Soc Echocardiogr. 1996



Heart Magnetic Resonance & Survival



Haemodynamic abnormalities

and prognosis

D'Alonzo, et al. Ann Int Med 1991; 115:343-9.

Me

dia

n s

urv

iva

l (m

on

ths)

< 55 mmHg

85 mmHg

< 10 mmHg

20 mmHg

4 l/min/m2

<2 l/min/m2

Mean PAP0

10

20

30

40

50

Mean RAP Mean CI



Biomarkers

Different mechanism:

- Marker of RV overload (BNP, NT-proBNP)

- Marker of myocardial injury (Troponin)

- Marker of Systemic inflammation (C-reactive protein)


La Sapienza University oi RomeNagaya N, et al. Circulation 2000; 102:865-70.

Brain natriuretic peptide (BNP)S

urv

iva

l ra

te (

%)

Baseline BNP Follow-up BNP

100

80

60

40

20

0

0 12

Time (months)

24 36 48

BNP <150 pg/ml

BNP ≥150 pg/ml

100

80

60

40

20

0

0 12 24 36 48

BNP <180 pg/ml

BNP ≥180 pg/ml

Time (months)



Troponin I and troponin T

Torbicki A, et al. Circulation 2003; 108:844-48.

p = 0.0005

p = 0.005

p = 0.001

cTnT(-)

cTnT(+)

cTnT(+)

cTnT(-)

Subjects at risk, n

48 43 33 30 25

8 4 4 2 2

0 6 12 18 24

Time (months)

Cu

mu

lative

su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0



C Reactive Protein

Quarck RA, et al. JACC 2009; 53:1211-8.



Follow-up

Walking test X X

ECG X X

Baseline Montly 6 Months

Clinical

judgement

Blood gas analysis X X

Pulmmonary Test X X

Echo Doppler X X X

Cardiopulm. test X X X

Hemodynamic X X X

Clinical evaluation X X

BNP(?) X X



A shift of strategy !

We do not have to wait for deterioration,

but combine treatments if the patient does not reach clinical meaningful targets



Treat to goals 2005

• 6MWT > 380 mt

• Peak VO2 10,4 ml/kg/m

• Exerc. BP > 120 mmHg

Hoeper MM, et al. Eur Respir J 2005; 26:858-63.


La Sapienza University oi RomeHoeper MM, et al. Eur Respir J 2005; 26:858-63.

Effect of “treatment to goals” on survival

Historical control group

0.2

0.4

0.6

0.8

1.0First-line bosentan

Addition of slidenafil/iloprost

2002-2004

Historical

control group

1999-2001

Expected

survival

Treatment group vs historical control group, p=0.011

Treatment group vs expected survival, p<0.001 for all time points

Months

Cum

ula

tive s

urv

ival (I

PA

H)

0 6 12 18 24 30 36

89 83 69 61 46 43 37

67 64 47 38 31 23 20

Treatment groupSubjects

at risk (n)



ESC/ERS 2009 PAH guidelines

Galie N et al, Eur Heart J 2009;doi:10.1093/eurheartj/ehp297.



Are these criteria applicable to SSc-PAH ?



Registry data of bosentan therapy

in PAH-SSc

• Royal Free Hospital registry-based evaluation of the

impact of bosentan on exercise capacity, and

survival in patients in class III and class IV PAH and

SSc

• Patients with PAH-SSc treated with bosentan as per

BREATHE-1 protocol were compared to PH-SSc

BREATHE-1 eligible control patients

Williams MH et al. Heart 2006; 92:926-32.



Are these criteria applicable to SSc-PAH ?

Williams MH et al. Heart 2006; 92:926-32.

SSc PAH patients have:

• a worse effort capacity

• a better cardiac index

compared to Idiopathic PAH



Conclusions

• Assessment of PAH severity is important at every

stage of the disease:

– Baseline (decision making: which drug is indicated ?)

– Response to treatment

– Adjustment of treatment regimen

• A combination of end-points is recommended

when evaluating disease severity and

progression (NYHA, 6-minWT, echo,

hemodynamics, biomarkers?)



PH clinicians (Cardiology ward, CCU, consultation & outpatients management):

Senior Cardiologists Dr Vizza, Dr Badagliacca Dr. Poscia

Fellows: Dr. Nona, Dr. Crescenzi,

In Training: Dr Gambardella, Dr. Pezzuto, Dr Papa, Dr Marcon

PH Unit

La Sapienza, University of Rome

Head Carmine Dario Vizza

PFTs-CPX Lab

Prof. Palange

Dott.Valli

CT & RNM Lab

Dott. Carbone

Dott. Francone

Reumathologists

Prof Valesini

Prof.Riccieri

Liver Transplant Unit

Prof. Rossi

Prof. Corradini

Lung Transplant Program

Prof.Coloni

Prof.Venuta

HIV clinic

Prof.Vullo

Echo Lab

Dr. Sciomer

Dr. Badagliacca

Right Cath Lab

Dott. Mancone

Dott. Colantoni

Pulmonologists

Prof. Parola



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Pulmonary Arterial Hypertension: Assessment of disease’s ... · Pulmonary Hypertension Unit La Sapienza University oi Rome Functional class & with survival Sitbon O, et al. J Am