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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
41 RHC, mPAP>25mmHg IPF, pretransplant (n=118)
Shorr AF:ERJ 2007:30:715
46
9
RHC, mPAP> 25mmHg
RHC, mPAP>40mmHg
IPF, pretransplant (n=2525)
Zisman DA:Resp Med 2007:101:2153
39 RHC, mPAP>25mmHg IPF, pretransplant (n=60)
Modrykamen AM:Resp Care 2010:55:584
43 RHC, mPAP>25mmHg IPF, pretransplant (n=58)
Minai OA:Resp Med 2012:106:1613
44
5
RHC, mPAP> 25mmHg
RHC, mPAP>40mmHg
IPF, pretransplant (n=124)
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
-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
Pathogenesis of PH in lung diseases
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
Pathogenesis of PH in lung diseases
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
Pathogenesis of PH in lung diseases
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
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!