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PH in pulmonary disease
Marius M Hoeper
Current classification of PAH (Nice 2013)
Group 1: PAH
Group 3: PH due to lung disease
Group 4: CTEPH
Group 5: Multifactorial mechanisms
Group 2: PH due to left heart disease
Simonneau G et al. J Amer Coll Cardiol 2013;62:D34-41
Pulmonary Hypertension in Lung Disease
Combined pulmonary
fibrosis and emphysema
Pulmonary fibrosis
Emphysema
Epidemiology and impact of PH in
lung disease
Pulmonary Hypertension in COPD
NETT: 120 patients with severe emphysema
PAPm > 20 mmHg in 91%
Mostly mild PH with PAPm < 30 mmHg
Scharf SM et al. Am J Resp Crit Care Med 2002; 166:314-22
Hemodynamics in COPD-PH
Average increase in PAPm 0,4 mmHg/year
Scharf SM et al. Am J Resp Crit Care Med 2002; 166:314-22
Kessler R et al. Am J Resp Crit Care Med 2001; 162:219-24
Some patients with COPD develop severe
(„out-of-proportion“) PH
n=215; candidates for LVRS or LTx
PAPm > 25 mmHg: 36.7%
PAPm > 35 mmHg: 9.8%
PAPm > 45 mmHg: 3,7%
Out of
Proportion ?
Thabut G et al. Chest 2005; 127:1531-6
Severe PH affects survival in patients with
COPD
Chaouat A et al. AJRCCM 2005; 172:189-94
Pulmonary hypertension in patients with
interstitial lung disease
Prevalence of PH in IPF depends on
diagnostic modality and population
Study
Cohort
Dx modality
% with PH
Nadrous
Random
Echo
84%
Agarwal
Random
Echo
36%
Gagermeier
Random
Echo
40.1%
Lettieri
LTx
RHC
31.6%
Hamada
Random
RHC
8.1%
Nathan
LTx
RHC
40.7%
Shorr
LTx
RHC
46.1%
Zisman
Random (mostly LTx)
RHC
39.3%
Zisman
Most LTx
RHC
32%
References in Hoeper MM et al. JACC 2009;54:S85-96
Prevalence of PH in patients with IPF
increases over time
100
90
80
70
60
50
40
30
20
10
0
PH defined as PAPm ≥25 mmHg
as determined by RHC
86,4%
38,6%
258 days
Baseline
Transplant
Nathan SD et al. Respiration 2008; 76:288-94
PH in patients with IPF is associated with a
reduced exercise capacity
n=454
500
n=79
p < 0.001
6 MWD (meters)
400
300
200
100
0
MPAP < 25
MPAP > 25
Lettieri et al. Chest 2006;129:746-52
Lederer et al. AJRCCM 2006;174:659-64
The presence of PH is associated with poor
survival in patients with IPF-PH
n=54
n=25
Lettieri CJ et al. Chest 129;746-752
Clinical characteristics of patients with
combined fibrosis and emphysema
Cottin V et al. ERJ 2005; 26:586-93
PH and survival in patients with CPFE
n=61; 55% developed PH
PAPsyst < 45 mmHg
PAPsyst ≥ 45 mmHg
Cottin V et al. ERJ 2005; 26:586-93
PH in lung disease is important!
How do we identify these patients?
When to suspect PH in patients with IPF?
 Degree of dyspnea worse than to be expected from
pulmonary function testing
 Worsening symptoms despite stable lung function
parameters
 Right ventricular strain on ECG
 Elevated BNP/NT-proBNP
 Very low DLCO (<30% pred.)1
 Unexpectedly low PaO2,2 especially in the presence of
hyperventilation (low PaCO2)
1Nathan
2Shorr
S et al. Chest 2007;131:657-63
AF et al. Chest 2007;30:715-21
Echocardiography
CW-Doppler
Apical 4-chamber
view
Tricuspid regurgitation
Bernoulli: (Vmax² x 4)+RA-pressure=PASP
Inaccurate estimation of PA pressure
by echo in patients with COPD
Doppler-pressure could be recorded in only 38% of all patients;
PV 68%, NPV 67%
Fisher MR et al. ERJ 2007; 30:914-21
Inaccurate estimation of PA pressure
by echo in patients with ILD
Inaccurate PAPsyst (difference >10 mmHg) in 60% of the patients
Nathan SD et al. Resp Med 2008;102:1305-10
Inaccurate estimation of PA pressure
by echo in patients with ILD
An optimal RVSP threshold for accurate diagnosis of PH could not be detected
Nathan SD et al. Resp Med 2008;102:1305-10
ESC/ERS Guidelines 2009
Recommendations for PH in lung disease
How to treat PH in lung disease?
Treating PH in patients with
chronic lung disease
 Treating lung disease has usually no effect on PH
 LTOT to maintain SaO2 >90% recommended1,2
 Vasodilators such as CCB lower PA pressure but
worsen gas exchange3
 Lung Tx may sometimes be the best option for
eligible patients with end-stage lung disease and PH
 The role of „PAH drugs“ remains unclear
1NOTT
Group, Ann Intern Med 1980; 93: 391-8; 2MRC Group. Lancet 981; 1: 681-6
3Simonneau G. NEJM 1981; 304:1582-5
Bosentan in patients with COPD
without severe PH
*
12 week, randomized, Placebo-controlled trial
 No improvement in exercise capacity
 No improvement in VO2max
 Significant deterioration in Pa,O2
 Significant deterioration in QoL (SF-36)
*Pts (n=30) suffered from severe COPD but mild pulmonary hypertension
Stolz D et al., ERJ 2008; 32:619-28
Eur Respir J. 2013;42:982-92
ERA trials in IPF-PH
Trial
Drug
Population
Trial result
BUILD-1
Bosentan
IPF
Negative1
BUILD-2
Bosentan
Scleroderma with
pulmonary fibrosis
Negative2
BUILD-3
Bosentan
IPF
Negative3
ARTEMIS-IPF
Ambrisentan
IPF
Negative4
ARTEMIS-PH
Ambrisentan
IPF with PH
Negative4
1KingTE
3King
et al. AJRCCM 2008;177:75-81; 2Seibold JR et al. Arthritis Rheum 2010;62:2101-8;
TE et al. AJRCCM 2011;184:92-9; 4unpublished
Higher rate of Morbidity/Mortality events
with Ambrisentan in ARTEMIS-IPF
Raghu G et al. Ann Intern Med 2013;158:641-9
STEP-IPF in Pulmonary Fibrosis
STEP-IPF Study group. New Engl J Med 2010;363:620-8
STEP-IPF: Primary endpoint missed - some
secondary endpoints met
Primary
endpoint
Secondary
endpoints
Parameter
Results
p-Value
Proportion of patients with ≥ 20%
increase in 6 mwt
10% (Sildenafil) vs
7% (Placebo)
0.39
Arterial oxygen saturation
Δ+1.22 favoring
sildenafil
0.05
DLCO (% pred value)
Δ+1.55 favoring
sildenafil
0.04
Shortness of breath
questionnaire
Δ-5.68 favoring
sildenafil
0.006
QoL (St. George Resp
Questionnaire)
Δ-4.08 favoring
sildenafil
0.01
Death and acute exacerbations
No significant
difference
n.s.
STEP-IPF Study group. New Engl J Med 2010;363:620-8
ESC/ERS Guidelines 2009
Recommendations for PH in lung disease
Nice, France
Februar 27-28, March 1, 2013
Seeger W et al. JACC 2013;62:D109-16
Take home messages
 PH (not PAH) is a common complication of chronic lung
disease
 The development of PH is associated with deterioration in
exercise capacity and poorer outcome
 ECG, NT-proBNP and echocardiography may help to
identify patients with PH
 There are no approved therapies for PH due to lung
disease
 Patients with severe PH („PAH-like phenotype“) and mild
lung disease may benefit from targeted therapies
Thanks a lot for your attention!
Marius M Hoeper, Hannover Medical School
[email protected]
Hoeper MM et al. J Am Coll Cardiol 2013;62:D42-50
1
Echocardiography
2
Heart or lung
disease?
3
CTEPH?
4
RHC +/- Angio
5
Classification
What is PH?

PAPm ≥25 mmHg at rest
What is PAH?
PAPm ≥25 mmHg at rest
 PAWP/LVEDP ≤15 mmHg
 PVR >3 Wood units (>240 dyn)
 Other causes of PH excluded (e.g., lung
disease, CTEPH)

PH in patients with lung disease is not PAH!
Data from the NETT Registry
National Emphysema Treatment Trial (Minai O et al. ATS 2010)
Patients with Emphysema; n=1,866
Echocardiography
PAPsyst ≤ 45 mmHg;
n=1,069 (57%)
PAPsyst > 45 mmHg;
n=797 (43%)
No further evaluation
of PH
Right heart catheter
PAPm ≥ 25 mmHg;
n = 302 (16%/38%), only 1 Pat >35 mmHg
18 pts (1%) qualified as severe PH
PH in other forms of ILD
Patients with SSc and ILD-PH have a worse
outcome than patients with SSc-PAH
Condliffe R et al. AJRCCM 2009;179:151-7
PH in Langerhans cell granulomatosis
Farthouk M et al. AJRCCM 2000;161:216-23
PH in Sarcoidosis
Baughman RP et al; Chest 2010:138:1078-85
How can the pulmonologist approach
possible pulmonary hypertension?
Dyspnoea of unknown cause and/or
risk factors for developing PH (lung disease, post PE)
ECG and BNP/NT-proBNP measurements
Any abnormalities
Refer for echocardiography
Both normal
PH unlikely
Diagnostic performance of BNP in chronic
lung disease
Patients with various chronic lung diseases, n=176
 AUC, 0.91
 Sensitivity, 0.85
 Specificity, 0.88
 PPV, 0.73
 NPV, 0.92
Leuchte H et al. AJRCCM 2006;173:744-50
Morbidity-Mortality events in BUILD-I
Bosentan in patients with IPF
King T et al. Am J Respir Crit Care Med. 2008;177:75-81
Morbidity-Mortality events in BUILD-II
Bosentan in patients with SSc-ILD
Seibold J et al. Arthritis Rheum. 2010;62:2101-8
Morbidity-Mortality events in BUILD-III
Bosentan in patients with IPF
King T et al. Am J Respir Crit Care Med. 2011;184:92-9
MUSIC trial with negative results*
Macitentan Use in Idiopathic Pulmonary Fibrosis Clinical Study
 Patients with IPF (no PH), n=178
 2:1 randomized, placebo controlled, double blind
 Macitentan 10 mg versus Placebo for 12 months
 Primary endpoint, change in VC, not met
 Liver enzyme elevations 3xULN (3.4%) same as with
placebo (5.1%)
 Favourable side-effect profile
Actelion press release 29.08.2011
STEP-IPF in Pulmonary Fibrosis
STEP-IPF Study group. New Engl J Med 2010;363:620-8
AHA/ACC Recommendations for PH
associated with chronic lung disease
McLaughlin VV et al. Circulation 2009;53:1573-619
Lack of correlation between PAPm and
lung function parameters
Data from 118 patients with IPF
Nathan S et al. Chest 2007;2007:657-63
Inaccurate estimation of PA pressure
by echo in patients with COPD
Low accuracy (52% inaccurate, i.e. difference > 10 mmHg),
48% misclassified as having PH; PV 52%, NPV 87%
Arcasoy SM et al. AJRCCM 2003; 167:735-40
Which patient(s) should we treat?
1
2
3
4
IPF
IPF
IPF
IPF
Age
60 years
60 years
60 years
60 years
TLC
80%
80%
80%
50%
PaCO2
32 mmHg
32 mmHg
32 mmHg
60 mmHg
PAPm
25 mmHg
30 mmHg
40 mmHg
40 mmHg
200 dyn
350 dyn
750 dyn
750 dyn
PVR
Hemodynamics in COPD-PH
PAH1
PH-COPD2
n = 123
n = 120
8±5
10 ± 6
PAPm (mmHg)
52 ± 10
26 ± 5
PCWP (mmHg)
7±3
14 ± 5
3,9 ± 1,2
5,2 ± 1,2
1,027 ± 443
193 ± 95
RAP (mmHg)
CO (l/min)
PVR (dynes)
1Hoeper
2Scharf
MM et al. ERJ 2005; 26:858-63
SM et al. AJRCCM 2002; 166:314-22
Severity of PH in patients with IPF
n=79
 PH is mostly mild in
patients with IPF
 PAPm <30 mmHg in
90% of pts
 5% of patients with IPF
have a PAPm >35
mmHg
Lettieri CJ et al. Chest 2006;129:746-752
Even mild PH is associated with decreased
survival rates in patients with IPF
PAPm < 17 mm Hg
(13 ± 2 mmHg, n = 37)
PAPm > 17 mm Hg
(21 ± 4 mmHg, n = 24)
Hamada et al Chest 2007; 131: 650-6
p < 0.001
PH is an independent predictor of death in
patients with COPD
PAPm < 25 mmHg
PAPm > 25 mmHg
p < 0.001
Oswald-Mammosser M et al. Chest 1995; 107:1193-8
Treating severe PH in patients with chronic
lung disease
 In general, treating PH with „PAH drugs“ is
discouraged in patients with lung disease
 A treatment trial may be justified in patients with
mild-to-moderate lung disease but severe PH
 No drug currently approved for PH in lung
disease!
Advanced IPF
DLCO <35%
PH no criterion
12 weeks
Causes of death in PAH and COPD
PAH
COPD
Right heart failure
Cardiovascular (MI, stroke)
Sudden death
Lung cancer
Septicemia
Exacerbations, pneumonia
Others
Other cancers
Others
PH is not a leading cause of death in COPD patients