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Marius M Hoeper
PH in pulmonary disease
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Current classification of PAH (Nice 2013)
Simonneau G et al. J Amer Coll Cardiol 2013;62:D34-41
Group 1: PAH
Group 2: PH due to left heart disease
Group 3: PH due to lung disease
Group 4: CTEPH
Group 5: Multifactorial mechanisms
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Pulmonary Hypertension in Lung Disease
Emphysema
Pulmonary fibrosis
Combined pulmonaryfibrosis and emphysema
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Epidemiology and impact of PH in lung disease
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Pulmonary Hypertension in COPD
NETT: 120 patients with severe emphysemaPAPm > 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
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Hemodynamics in COPD-PH
Scharf SM et al. Am J Resp Crit Care Med 2002; 166:314-22Kessler R et al. Am J Resp Crit Care Med 2001; 162:219-24
Average increase in PAPm 0,4 mmHg/year
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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 ofProportion ?
Thabut G et al. Chest 2005; 127:1531-6
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Severe PH affects survival in patients with COPD
Chaouat A et al. AJRCCM 2005; 172:189-94
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Pulmonary hypertension in patients with interstitial lung disease
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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
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Prevalence of PH in patients with IPF increases over time
Baseline Transplant0
10
20
30
40
50
60
70
80
90
100
38,6%
86,4%
258 days
PH defined as PAPm ≥25 mmHgas determined by RHC
Nathan SD et al. Respiration 2008; 76:288-94
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PH in patients with IPF is associated with a reduced exercise capacity
6 M
WD
(met
ers)
0
100
200
300
400
500
MPAP < 25 MPAP > 25
p < 0.001
Lettieri et al. Chest 2006;129:746-52
Lederer et al. AJRCCM 2006;174:659-64
n=79
n=454
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The presence of PH is associated with poor survival in patients with IPF-PH
Lettieri CJ et al. Chest 129;746-752
n=54
n=25
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Clinical characteristics of patients with combined fibrosis and emphysema
Cottin V et al. ERJ 2005; 26:586-93
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PH and survival in patients with CPFE
Cottin V et al. ERJ 2005; 26:586-93
n=61; 55% developed PH
PAPsyst < 45 mmHg
PAPsyst ≥ 45 mmHg
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PH in lung disease is important!
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How do we identify these patients?
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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 S et al. Chest 2007;131:657-63
2Shorr AF et al. Chest 2007;30:715-21
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Echocardiography
Apical 4-chamberview
CW
-Dopple
r
Tricuspid regurgitationBernoulli: (Vmax² x 4)+RA-pressure=PASP
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Inaccurate estimation of PA pressure by echo in patients with COPD
Fisher MR et al. ERJ 2007; 30:914-21
Doppler-pressure could be recorded in only 38% of all patients;PV 68%, NPV 67%
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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
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Inaccurate estimation of PA pressure by echo in patients with ILD
Nathan SD et al. Resp Med 2008;102:1305-10
An optimal RVSP threshold for accurate diagnosis of PH could not be detected
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ESC/ERS Guidelines 2009Recommendations for PH in lung disease
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How to treat PH in lung disease?
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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 unclear1NOTT Group, Ann Intern Med 1980; 93: 391-8; 2MRC Group. Lancet 981; 1: 681-63Simonneau G. NEJM 1981; 304:1582-5
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Bosentan in patients with COPD without severe PH
No improvement in exercise capacityNo improvement in VO2max
Significant deterioration in Pa,O2
Significant deterioration in QoL (SF-36)
Stolz D et al., ERJ 2008; 32:619-28
12 week, randomized, Placebo-controlled trial*
*Pts (n=30) suffered from severe COPD but mild pulmonary hypertension
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Eur Respir J. 2013;42:982-92
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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-IPFAmbrisent
an IPF Negative4
ARTEMIS-PHAmbrisent
an IPF with PH Negative41KingTE et al. AJRCCM 2008;177:75-81; 2Seibold JR et al. Arthritis Rheum 2010;62:2101-8; 3King TE et al. AJRCCM 2011;184:92-9; 4unpublished
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Higher rate of Morbidity/Mortality events with Ambrisentan in ARTEMIS-IPF
Raghu G et al. Ann Intern Med 2013;158:641-9
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STEP-IPF in Pulmonary Fibrosis
STEP-IPF Study group. New Engl J Med 2010;363:620-8
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STEP-IPF: Primary endpoint missed - some secondary endpoints met
STEP-IPF Study group. New Engl J Med 2010;363:620-8
Parameter Results p-Value
Primary endpoint
Proportion of patients with ≥ 20% increase in 6 mwt
10% (Sildenafil) vs 7% (Placebo) 0.39
Secondary endpoints
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.
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ESC/ERS Guidelines 2009Recommendations for PH in lung disease
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Nice, FranceFebruar 27-28, March 1, 2013
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Seeger W et al. JACC 2013;62:D109-16
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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
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Hoeper MM et al. J Am Coll Cardiol 2013;62:D42-50
1 Echocardiography
2Heart or lung disease?
3 CTEPH?
4 RHC +/- Angio
5 Classification
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What is PH?
PAPm ≥25 mmHg at rest
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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!
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Data from the NETT RegistryNational 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 evaluationof PH
Right heart catheter
PAPm ≥ 25 mmHg;n = 302 (16%/38%), only 1 Pat >35 mmHg
18 pts (1%) qualified as severe PH
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PH in other forms of ILD
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Patients with SSc and ILD-PH have a worse outcome than patients with SSc-PAH
Condliffe R et al. AJRCCM 2009;179:151-7
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PH in Langerhans cell granulomatosis
Farthouk M et al. AJRCCM 2000;161:216-23
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PH in Sarcoidosis
Baughman RP et al; Chest 2010:138:1078-85
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How can the pulmonologist approach possible pulmonary hypertension?
Dyspnoea of unknown cause and/orrisk factors for developing PH (lung disease, post PE)
ECG and BNP/NT-proBNP measurements
Refer for echocardiography PH unlikely
Both normalAny abnormalities
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Diagnostic performance of BNP in chronic lung disease
Patients with various chronic lung diseases, n=176
AUC, 0.91Sensitivity, 0.85Specificity, 0.88PPV, 0.73NPV, 0.92
Leuchte H et al. AJRCCM 2006;173:744-50
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Morbidity-Mortality events in BUILD-IBosentan in patients with IPF
King T et al. Am J Respir Crit Care Med. 2008;177:75-81
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Morbidity-Mortality events in BUILD-IIBosentan in patients with SSc-ILD
Seibold J et al. Arthritis Rheum. 2010;62:2101-8
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Morbidity-Mortality events in BUILD-IIIBosentan in patients with IPF
King T et al. Am J Respir Crit Care Med. 2011;184:92-9
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MUSIC trial with negative results*Macitentan Use in Idiopathic Pulmonary Fibrosis Clinical Study
Patients with IPF (no PH), n=1782:1 randomized, placebo controlled, double
blindMacitentan 10 mg versus Placebo for 12
monthsPrimary endpoint, change in VC, not metLiver enzyme elevations 3xULN (3.4%)
same as with placebo (5.1%)Favourable side-effect profile
Actelion press release 29.08.2011
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STEP-IPF in Pulmonary Fibrosis
STEP-IPF Study group. New Engl J Med 2010;363:620-8
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AHA/ACC Recommendations for PH associated with chronic lung disease
McLaughlin VV et al. Circulation 2009;53:1573-619
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Lack of correlation between PAPm and lung function parameters
Nathan S et al. Chest 2007;2007:657-63
Data from 118 patients with IPF
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Inaccurate estimation of PA pressure by echo in patients with COPD
Arcasoy SM et al. AJRCCM 2003; 167:735-40
Low accuracy (52% inaccurate, i.e. difference > 10 mmHg), 48% misclassified as having PH; PV 52%, NPV 87%
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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
PVR 200 dyn 350 dyn 750 dyn 750 dyn
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Hemodynamics in COPD-PH
1Hoeper MM et al. ERJ 2005; 26:858-632Scharf SM et al. AJRCCM 2002; 166:314-22
PAH1 PH-COPD2
n = 123 n = 120
RAP (mmHg) 8 ± 5 10 ± 6
PAPm (mmHg) 52 ± 10 26 ± 5
PCWP (mmHg) 7 ± 3 14 ± 5
CO (l/min) 3,9 ± 1,2 5,2 ± 1,2
PVR (dynes) 1,027 ± 443 193 ± 95
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Severity of PH in patients with IPF
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
n=79
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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
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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
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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!
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Advanced IPFDLCO <35%PH no criterion12 weeks
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Causes of death in PAH and COPD
PH is not a leading cause of death in COPD patients
PAH
Right heart failure
Sudden death
Septicemia
Others
COPD
Cardiovascular (MI, stroke)
Lung cancer
Exacerbations, pneumonia
Other cancers
Others