1. Marius M Hoeper PH in pulmonary disease

2. 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

3. Pulmonary Hypertension in Lung Disease Emphysema Pulmonary fibrosis Combined pulmonary fibrosis and emphysema

4. Epidemiology and impact of PH in lung disease

5. 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

6. Hemodynamics in COPD-PH 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 Average increase in PAPm 0,4 mmHg/year

7. 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

8. Severe PH affects survival in patients with COPD Chaouat A et al. AJRCCM 2005; 172:189-94

9. Pulmonary hypertension in patients with interstitial lung disease

10. Prevalence of PH in IPF depends on diagnostic modality and population StudyCohortDx modality% with PH NadrousRandomEcho84% AgarwalRandomEcho36% GagermeierRandomEcho40.1% LettieriLTxRHC31.6% HamadaRandomRHC8.1% NathanLTxRHC40.7% ShorrLTxRHC46.1% ZismanRandom (mostly LTx)RHC39.3% ZismanMost LTxRHC32% References in Hoeper MM et al. JACC 2009;54:S85-96

11. Prevalence of PH in patients with IPF increases over time 258 days PH defined as PAPm ≥25 mmHg as determined by RHC Nathan SD et al. Respiration 2008; 76:288-94

12. PH in patients with IPF is associated with a reduced exercise capacity Lettieri et al. Chest 2006;129:746-52 Lederer et al. AJRCCM 2006;174:659-64 n=79 n=454

13. 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

15. Clinical characteristics of patients with combined fibrosis and emphysema Cottin V et al. ERJ 2005; 26:586-93

16. 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

17. PH in lung disease is important!

18. How do we identify these patients?

19. 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 PaO 2, 2 especially in the presence of hyperventilation (low PaCO 2 ) 1 Nathan S et al. Chest 2007;131:657-63 2 Shorr AF et al. Chest 2007;30:715-21

20. Echocardiography Apical 4-chamber view CW-Doppler Tricuspid regurgitation Bernoulli: (Vmax² x 4)+RA-pressure=PASP

21. 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%

22. 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

23. 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

24. ESC/ERS Guidelines 2009 Recommendations for PH in lung disease

25. How to treat PH in lung disease?

26. Treating PH in patients with chronic lung disease Treating lung disease has usually no effect on PH LTOT to maintain SaO 2 >90% recommended 1,2 Vasodilators such as CCB lower PA pressure but worsen gas exchange 3 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 1 NOTT Group, Ann Intern Med 1980; 93: 391-8; 2 MRC Group. Lancet 981; 1: 681-6 3 Simonneau G. NEJM 1981; 304:1582-5

27. Bosentan in patients with COPD without severe PH No improvement in exercise capacity No improvement in VO 2 max Significant deterioration in Pa,O 2 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

28. Eur Respir J. 2013;42:982-92

29. ERA trials in IPF-PH TrialDrugPopulationTrial result BUILD-1BosentanIPFNegative 1 BUILD-2Bosentan Scleroderma with pulmonary fibrosis Negative 2 BUILD-3BosentanIPFNegative 3 ARTEMIS-IPFAmbrisentanIPFNegative 4 ARTEMIS-PHAmbrisentanIPF with PHNegative 4 1 KingTE et al. AJRCCM 2008;177:75-81; 2 Seibold JR et al. Arthritis Rheum 2010;62:2101-8; 3 King TE et al. AJRCCM 2011;184:92-9; 4 unpublished

30. Higher rate of Morbidity/Mortality events with Ambrisentan in ARTEMIS-IPF Raghu G et al. Ann Intern Med 2013;158:641-9

31. STEP-IPF in Pulmonary Fibrosis STEP-IPF Study group. New Engl J Med 2010;363:620-8

32. STEP-IPF: Primary endpoint missed - some secondary endpoints met STEP-IPF Study group. New Engl J Med 2010;363:620-8 ParameterResultsp-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.

33. ESC/ERS Guidelines 2009 Recommendations for PH in lung disease

34. Nice, France Februar 27-28, March 1, 2013

35. Seeger W et al. JACC 2013;62:D109-16

36. 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

37. Thanks a lot for your attention! Marius M Hoeper, Hannover Medical School hoeper.marius@mh-hannover.de

38. Hoeper MM et al. J Am Coll Cardiol 2013;62:D42-50 1 1 Echocardiography 2 2 Heart or lung disease? 3 3 CTEPH? 4 4 RHC +/- Angio 5 5 Classification

39. What is PH? PAPm ≥25 mmHg at rest

40. 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!

41. 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

42. PH in other forms of ILD

43. Patients with SSc and ILD-PH have a worse outcome than patients with SSc-PAH Condliffe R et al. AJRCCM 2009;179:151-7

44. PH in Langerhans cell granulomatosis Farthouk M et al. AJRCCM 2000;161:216-23

45. PH in Sarcoidosis Baughman RP et al; Chest 2010:138:1078-85

46. 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 Refer for echocardiographyPH unlikely Both normal Any abnormalities

47. 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

48. 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

49. Morbidity-Mortality events in BUILD-II Bosentan in patients with SSc-ILD Seibold J et al. Arthritis Rheum. 2010;62:2101-8

50. 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

51. 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

52. STEP-IPF in Pulmonary Fibrosis STEP-IPF Study group. New Engl J Med 2010;363:620-8

53. AHA/ACC Recommendations for PH associated with chronic lung disease McLaughlin VV et al. Circulation 2009;53:1573-619

54. Lack of correlation between PAPm and lung function parameters Nathan S et al. Chest 2007;2007:657-63 Data from 118 patients with IPF

55. 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%

56. Which patient(s) should we treat? 1234 IPF Age60 years TLC80% 50% PaCO 2 32 mmHg 60 mmHg PAPm25 mmHg30 mmHg40 mmHg PVR200 dyn350 dyn750 dyn

57. Hemodynamics in COPD-PH 1 Hoeper MM et al. ERJ 2005; 26:858-63 2 Scharf SM et al. AJRCCM 2002; 166:314-22 PAH 1 PH-COPD 2 n = 123n = 120 RAP (mmHg)8 ± 510 ± 6 PAPm (mmHg)52 ± 1026 ± 5 PCWP (mmHg)7 ± 314 ± 5 CO (l/min)3,9 ± 1,25,2 ± 1,2 PVR (dynes)1,027 ± 443193 ± 95

58. 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

59. 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

60. 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

61. 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!

62. Advanced IPF DLCO <35% PH no criterion 12 weeks

63. 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