Marius M Hoeper

PH in pulmonary disease

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

Pulmonary Hypertension in Lung Disease

Emphysema

Pulmonary fibrosis

Combined pulmonaryfibrosis and emphysema

Epidemiology and impact of PH in lung disease

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

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

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

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

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

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

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

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

Cottin V et al. ERJ 2005; 26:586-93

n=61; 55% developed PH

PAPsyst < 45 mmHg

PAPsyst ≥ 45 mmHg

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 S et al. Chest 2007;131:657-63

2Shorr AF et al. Chest 2007;30:715-21

Echocardiography

Apical 4-chamberview

CW

-Dopple

r

Tricuspid regurgitationBernoulli: (Vmax² x 4)+RA-pressure=PASP

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%

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

Nathan SD et al. Resp Med 2008;102:1305-10

An optimal RVSP threshold for accurate diagnosis of PH could not be detected

ESC/ERS Guidelines 2009Recommendations 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 unclear1NOTT Group, Ann Intern Med 1980; 93: 391-8; 2MRC Group. Lancet 981; 1: 681-63Simonneau G. NEJM 1981; 304:1582-5

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

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-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

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

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.

ESC/ERS Guidelines 2009Recommendations for PH in lung disease

Nice, FranceFebruar 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 Schoolhoeper.marius@mh-hannover.de

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

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 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

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/orrisk factors for developing PH (lung disease, post PE)

ECG and BNP/NT-proBNP measurements

Refer for echocardiography PH unlikely

Both normalAny abnormalities

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

Morbidity-Mortality events in BUILD-IBosentan in patients with IPF

King T et al. Am J Respir Crit Care Med. 2008;177:75-81

Morbidity-Mortality events in BUILD-IIBosentan in patients with SSc-ILD

Seibold J et al. Arthritis Rheum. 2010;62:2101-8

Morbidity-Mortality events in BUILD-IIIBosentan 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=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

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

Nathan S et al. Chest 2007;2007:657-63

Data from 118 patients with IPF

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%

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

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

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

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 IPFDLCO <35%PH no criterion12 weeks

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