Pulmonary Hypertension in Lung diseases - a case-based ...

PD Dr. Silvia Ulrich

Clinic for Pulmonology

University Hospital of Zurich

Pulmonary Hypertension in

Lung diseases

- a case-based discussion

A 68 year old former floorer

• married, 4 adult children

• formerly very active

• had his own business as floorer until 3 years ago,

when he retired

• suffers from progressive dyspnea on exertion over the

last 1-2 years (WHO III)

• stopped smoking 20 years ago

Pulmonary function tests

• FEV1 2.2 l 87%

• FVC 2.6 l 80%

• FEV1/FVC 84%

• TLC 4.2 l 75%

• RV 1.1 l 60%

• DLCO 24%

Lung biopsy confirms usual interstitial pneumonia and upper-lobe emphysema

Diagnosis

• Long-term oxygen therapy

• Diuretics

• Trial of Nintendanib – stopped with side-effects

Therapy

• Pulmonary fibrosis and upper lobe emphysema

Echocardiography

• Tricuspid pressure gradient 48mmHg

• Systolic pulmonary artery pressure 53mmHg

• Normal right- and left-ventricular function

• TAM 24 mm, FAC 38%

Heart Catheterisation

• Pulmonary artery pressure 64/36/22 mmHg

• Wedge-pressure 12 mmHg

• Cardiac output 4.2 l/min

• Cardiac index 2.4 l/min/mmHg

• PVR 5.7 WU

• SaO2 88 %

• SmvO2 68 %

precapillary pulmonary hypertension

Classification of PH

I. Pulmonary arterial hypertension (PAH)

II. Pulmonary hypertension due to left heart diseases

III. Pulmonary hypertension due to lung diseases and/or hypoxia

IV. Chronic thromboembolic pulmonary hypertension (CTEPH)

V. PH with unclear mulitfactorial mechanisms

Simonneau JACC 2013, Galie 2015

Pulmonary hypertension may be

prevalent in most lung diseases

Galie ERJ/EHJ 2015

Diagnosis of PH in lung disease

• mPAP 36mmHg

• CI 2.4

• severe PH

Galie ERJ/EHJ 2015

Prevalence of PH in ILDAuthor % with PH Method Population

Lettieri CJ:Chest 2006:129:746

32

2

RHC, mPAP> 25mmHg

RHC, mPAP>40mmHg

IPF, pretransplant (n=79)

Lederer D:AJRCCM 2006:174:659

44 RHC, mPAP>25mmHg IPF, pretransplant (n=376)

Nathan SD:Chest 2007:131:657


Shorr AF:ERJ 2007:30:715

46

9

RHC, mPAP> 25mmHg

RHC, mPAP>40mmHg


Zisman DA:Resp Med 2007:101:2153


Modrykamen AM:Resp Care 2010:55:584


Minai OA:Resp Med 2012:106:1613

44

5

RHC, mPAP> 25mmHg

RHC, mPAP>40mmHg


Treatment of PH in Lung

diseases

The problem of vasodilation in the

diseased lung: V/Q-Mismatch

The problem of vasodilation in the

diseased lung V/Q-Mismatch

http://0-advan.physiology.org.library.pcc.edu/content/32/3/192/F5.large.jpg

http://0-advan.physiology.org.library.pcc.edu/content/32/3/192/F5.large.jpg

-40

-30

-20

-10

0

10c

ha

ng

e i

n m

PA

P (

%)

NO

(inh.)

PGI (

i.v.)

Sil (o

ral)

Sildenafil is an intrapulmonary selective

vasodilator

Ghofrani et al.,

Lancet 2002; 360(9337):895-900

0

5

10

15

20

25

30

35

40

Sh

un

t P

erf.

(%

)

Base

NO (inh.)

PGI (i.v

.)

Sil (o

ral)

•Same PAP decrease

•inhaled NO

•iv PGI2

•oral Sildenafil

•Increased shunt blood flow

•PGI iv

•No shunt blood flow increase

•inhaled NO

•oral sildenafilGhofrani A, Lancet 2002

PAH-therapy in interstitial lung diseasesAuthor/Year Drug Method/time N Characteristics Outcome +/-

Ghofrani Lancet

2007

Sildenafil Open, RCT, Acute RHC 16 IPF, FVC≈66 (25-87)%,

mPAP 41

PVR↓& V/Q↑

PVR/SVR↓

+

+

Collard Chest 2007 Sildenafil Observational, 12 weeks 11 IPF, FVC≈70±18%

mPAP 31±6

6 MWD + 49m + 49m

Günther ERJ 2007 Bosentan Observational, 12 weeks 12 IPF, FVC≈56±15%

mPAP 22±5

Gas exchange: no change

Build-1 AJRCCM

2008

Bosentan RCT, blinded, 12 month 158 IPF, FVC≈68±11%

PAPsys ≤50 (Echo)

6MWT -

Raghu ERJ 2010 (subBild-1)

Bosentan BILD-1 QOL 158 IPF, FVC≈68±11%

PH?

QoL +

Zisman et al. NEJM

2010

Sildenafil RCT, 12 weeks 180 IPF, FVC≈55±14%

PH?

PE: Proportion who ↑ 6MWD by

≥20%

SE: PaO2, dyspnea, QoL

-

+

Jackson Lung 2010 Sildenafil RCT, 6 month 29 IPF, FVC≈63±10%

PAPsys 25-50 (Echo)

6MWD -

Build-3 AJRCCM

2011

Bosentan RCT, event driven 252┼ 616 IPF, FVC≈75±15%

PH?

Time to IPF worsening -

Zisman et al. NEJM 2010; 363: 620-628

Primary outcome:

proportion of patients

that increase 6MWD by

> 20%:

→ negativ

But positive secondary

outcomes…

Sildenafil group: less dyspnea, improved QoL,

improved gas exchange

Uncontrolled proof-of

concept trial, 18/22 patients

completed the study

Conclusion:

• Riociguat safe

• Slight decrease in SaO2

• Increase in SmvO2

• Slight increase in 6MWd

RISE: A randomized, double-blind, placebo-controlled phase II

study to investigate the efficacy and safety of riociguat (0.5 mg, 1.0

mg, 1.5 mg, 2.0 mg and 2.5 mg TID) in patients with symptomatic

PH associated with idiopathic interstitial pneumonias (IIP).

Participates in randomized-controlled trial

on Riociguat in pulmonary fibrosis

• 6 minute walk distance: 350 → 430 m

• WHO functional class: III → II

• Lung function: stable

• Exacerbations: none

Friday, 6th of May 2016:

Telephone to stop study medication

RISE-StudieBerlin, May 12th, 2016 – Following the recommendation of an independent

Data Monitoring Committee (DMC), Bayer is terminating its Phase II study

investigating riociguat in patients with pulmonary hypertension associated

with idiopathic interstitial pneumonias (PH-IIP) with immediate effect. In

the ongoing review of the data, the Drug Monitoring Committee observed

that patients receiving riociguat were at a possible increased risk for

death and other serious adverse events as compared to patients in the

placebo group. The DMC did not identify any specific cause or common

feature among the patients who died except that many appeared to have

more serious and advanced underlying lung disease than the study

population as a whole. The patients in this trial will be continuously monitored

for safety immediately after stopping treatment and for a period of at least

four months.

Follow-up after stop Riociguat

• Dyspnea increases: WHO FC II → III

• 6 min. walk decreases: 430 m → 330 m

• No exacerbation

to study responsibles:

No possibility to get Riociguat back

• Start off-label Tadalafil

• 4 weeks later he is back to class II, walk-distance

increased, patient feels better

A 63 year old saleswoman with

COPD GOLD IV

• Stopped smoking 5 years ago, 42 PY

• Increasing dyspnea NYHA FC III-IV

• Reduced daily activity, but still works in a office

• 6 minute walk 420m

Therapy

• Longterm oxygen therapy since 6 month

• Inhalers and diuretics

A 57 year old saleswoman with

COPD GOLD IV

• Lung-function:

– GOLD IV, RV/TLC 72%, DLCO 23%

• Echocardiography:

– tricuspid pressure gradient 45 mmHg

• Right heart catheterisation:

– mPAP 33mmHg, Wedge 12mmHg, CO 2.9 l/min/kg, PVR 4 WU

Pulmonary hypertension may be

prevalent in most lung diseases

Galie ERJ/EHJ 2015

Prevalence of PH in COPDAuthor Year N Design FEV1 PaO2

(mmHg)

DLCO(%pred)

mPAP(mmHg)

CI (l/min/m2)

PVR(WU)

PH criteria Prevalence of

PH (%)

Burrows 1972 50 Prosp. 37% FCV NR 81 26 2.5 5.8 >25mmHg 20

Weitzenblum 1981 175 Prosp. 40% FVC 63 NR 20 3.5 NR >20mmHg 35

Weitzenblum 1984 93 Prosp. 41% FVC 66 NR 19 3.6 NR >20mmHg 34

Osswald-

Mammosser

1991 84 Prosp.

LTOT

36% FVC 52 NR 27 NR NR >20mmHg 77

Scharf 2002 120 Retro.

NETT

27% pred. 66 27 26 2.9 2.4 >20mmHg 90

Thabut 2005 215 Retro.

LVRS

24% pred. 62 NR 27 3 A 4.7 >25mmHg 50

Anderson 2012 409 Retro.

LTPL

23% pred. 63 25 24 3.2 3.5 B >25mmHg 36

Cuttica 2012 4930 Retro.

LTPL

22% pred. NR NR 25 NR NR >25mmHg 30

Mykland Hilde 2013 95 Outpa-

tiens

46/32%

No/PH

NR 57/36

No/PH

18/29

No/PH

5.2/5.6C

No/PH

2/3.3

No/PH

>25mmHg 5 / 27 / 53

II / III / IV

A = PVR index, B = patients with PH, C= cardiac output

Prevalence of PH in COPD

Thabut et al., Chest 2005;127:1531-1536: n=247, FEV1 24%, TLC 128%, RV 260%,

mean mPAP 27 mmHg, 14% mPAP>35mmHg

3.7 %9.8 %

A distinct disease?

Clinical relevance of PH in Lung

diseases• Survival↓

– worse hemodynamics - worse prognosis

• Clinical severity↑

• Exercise capacity↓

• Exacerbation rate ↑

• Hospitalisations ↑

Swiss-PH-registry on PH-lung

• Worst WHO class

• Worst exercise capacity

• Worst hemodynamics

• Worst event-free survival

PAH

PH-Lung

CTEPH

Pathogenesis of PH in lung diseases

Traditional:

• Hypoxic pulmonary vasoconstriction (HPV) → Remodeling

of the vessel wall

• Compression of pulmonary arterioles/capillaries by lung

hyperinflation, thrombosis, fibrosis

• Acidosis, hypercapnia, hyperviscosity (polycytemia),

hypervolemia


But:

• PH in COPD only weekly correlates with airflow obstruction

• PH in pulmonary fibrosis weakly correlates with FVC

• PH in OSA weakly correlates with apnea

Weitzenblum et al., Am Rev Respir Dis 130:993-8, 1984, Weitzenblum et al, Thorax 1981,

Scharf et al, NETT, AJRCCM 2002, Ulrich et al, Respiration 2010


MAB against alpha smooth muscle actin Orcein stain (elastic fibers)

Intima thickening

Barbera et al, ERJ 21;892-905: 2003

Comparable histology as in PAH


Other potential influence factors:

• Endothelial Dysfunction

• Genetic predisposition

• Inflammation

• Cigarette smoke

PAH- ♂ significantly more smokers thanCTEPH and healthy (85 vs. 58%, p<.01)

PAH smokers more PY

PAH non-smokers had more second-handsmoke exposure

PAH smokers diagnosed at lower age

Treatment of PH in Lung

diseases

Prospective trials PAH-Therapy in COPDAuthor/Year Drug Method/time N Characteristics Outcome +/-

Holverda Pul Phar

Ther 2008

Sildenafil Observational, RHC (acute) 18 GOLD II-IV, only 5 PH Exercise capacity

mPAP ↓

-

+

Rietema ERJ 2008 Sildenafil Observational, 12 weeks 15 GOLD II-IV, 9 PH SV by MRI & exercise -

Stolz ERJ 2008 Bosentan RCT 30 GOLD III-IV, no RHC, PH? 6MWD -

Valerio 2009 Bosentan Controlled, 18 month 32 GOLD II-IV, with PH mPAP & others +

Blanco

AJRCCM 2010

Sildenafil 20

& 40 mg

Acute, RHC, exercise 11

&

9

FEV1 35±10%

mPAP 27±10mmHg

mPAP ↓ rest &

exercise (mmHg).

PaO2 ↓

6 & 11

Only rest

Blanco

ERJ 2013

Sildenafil 20 RCT, 3 month, added to

Rehabilitation !

60 Mild PH-GOLD, Rehabilitation 6MWD + 0m (to

Placebo!)

-

Rao 2011 (Indian

Journal)

Sildenafil RCT, 12 weeks 37 mPAP 53 mmHg, GOLD? 6MWD + 190 m!

mPAP -12mmHg

+

Karakitsos Int J

Cardiol 2012

Sildenafil Observational, ICU 12 On dobutamine in exacerbation, no

RHC PH?

Stop dobutamine in 3-6

days

7+

5 -

Rafiei 2012 Sildenafil RCT, ICU 40 Exacerbation, no RHC PH? Weaning facilitated +

Lederer COPD 2012 Sildenafil RCT, cross over, 4 week 9 GOLD II-IV, no PH 6MWT & VO2max - & -

Blanco ERJ 2013 Sildenafil RCT, during Rehab 3 month GOLD III-IV, mPAP>25 mmHg at

RHC

Endurance in constant

load test

-

Treatment with pulmonary vasodilators in

PH in lung diseases?

Underlying lung disease mPAP < 25 mmHg mPAP 25 – 35 mmHg mPAP ≥ 35 mmHg

Mild lung disease:COPD FEV1 ≥60%

DPLD FVC ≥70%

No gross parenchymal or

airway abnormalities on CT

No PH

No PAH-treatment

recommended

Classifiaction uncertain –

PAH?

No PAH-treatment studies

May meet IPAH-criteria

Refer to center with

expertise in PAH

Relevant lung disease:COPD FEV1 < 60%

DPLD FVC < 70%

Combined pulmonary fibrosis

emphysema on CT

No PH

No PAH-treatment

recommended

PH-COPD, PH-IPF, PH-

CPFE

No data support PAH-

treatment

Severe PH-COPD, PH-IPF,

PH-CPFE

Refer to a center with

expertise in PH and lung

disease. Poor prognosis.

Individualized therapy.

Adapted from Seeger, JACC 2013

PH and Lung volume reduction

mPAP mmHg

CO l/min

Wedge mmHg

CI l/min/kg

Pilot-study:

5/6 Emphysema-Patients with PH

improved their hemodynamics after

endoscopic valvue therapy

Therapy of PH in lung diseases –

still a far way to go!

Pulmonary Hypertension in Lung diseases - a case-based ...

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