2018 科隆共识会议建议：肺疾病所致肺动脉高压

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Pulmonary hypertension due to lung diseases: Updated recommendations from the Cologne Consensus Conference 2018

 Horst Olschewski, Jürgen Behr, Hinrich Bremer, Martin Claussen, Philipp Douschan, Michael Halank, Matthias Held, Marius M. Hoeper, Stephan Holt, Hans Klose, Stephan Krüger, Tobias J. Lange, Frank Reichenberger, Dirk Skowasch, Silvia Ulrich, Heinrike Wilkens, Werner Seeger

PII: S0167-5273(18)34353-5 DOI: doi: 10.1016/j.ijcard.2018.08.043 Reference: IJCA 26859 To appear in: International Journal of Cardiology Received date: 9 August 2018 Accepted date: 10 August 2018

Please cite this article as: Horst Olschewski, Jürgen Behr, Hinrich Bremer, Martin Claussen, Philipp Douschan, Michael Halank, Matthias Held, Marius M. Hoeper, Stephan Holt, Hans Klose, Stephan Krüger, Tobias J. Lange, Frank Reichenberger, Dirk Skowasch, Silvia Ulrich, Heinrike Wilkens, Werner Seeger , Pulmonary hypertension due to lung diseases: Updated recommendations from the Cologne Consensus Conference 2018. Ijca (2018), doi: 10.1016/j.ijcard.2018.08.043

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## Pulmonary hypertension due to lung diseases: Updated recommendations from the Cologne Consensus Conference 2018

Horst Olschewski 1 , Jürgen Behr 2 , Hinrich Bremer 3 , Martin Claussen 4 , Philipp Douschan 1 , Michael Halank 5 , Matthias Held 6 , Marius M. Hoeper 7 , Stephan Holt 8 , Hans Klose 9 , Stephan Krüger 10 , Tobias J. Lange 11 , Frank Reichenberger 2 , Dirk Skowasch 12 , Silvia Ulrich 13 , Heinrike Wilkens 14 , Werner Seeger 15

1 Klinische Abteilung für Lungenkrankheiten, Universitätsklinik für Innere Medizin, Medizinische Universität Graz und Ludwig Boltzmann Institut für Lungengefäßforschung, Graz, Österreich. 2 Med Klinik und Poliklinik V und Asklepios Fachkliniken München-Gauting, Comprehensive Pneumology Center, Universität München, Mitglied des Deutschen Zentrums für Lungenforschung (DZL) 3 Schwarzwald-Baar Klinikum, Villingen-Schwenningen GmbH 4 Zentrum für Pneumologie und Thoraxchirurgie, LungenClinic Grosshansdorf GmbH, Member of the Deutsche Zentrum für Lungenforschung (DZL), Grosshansdorf 5 Medizinische Klinik I, Universitätsklinikum Carl Gustav Carus an der TU Dresden 6 Zentrum für pulmonale Hypertonie und Lungengefäßerkrankungen, Abteilung Innere Medizin, Missionsärztliche Klinik Würzburg 7 Klinik für Pneumologie, Medizinische Hochschule Hannover, Mitglied des Deutschen Zentrums für Lungenforschung (DZL), Hannover 8 Krankenhaus Bethanien Solingen, Pneumologisches Institut der Universität Köln 9 Sektion Pneumologie, II. Medizinische Klinik und Poliklinik, Onkologisches Zentrum, Universitätsklinikum Hamburg-Eppendorf 10 Klinik für Pneumologie, Kardiologie und Internistische Intensivmedizin, Florence Nightingale Krankenhaus, Düsseldorf und Klinik für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum Düsseldorf 11 Klinik und Poliklinik für Innere Medizin II, Uniklinik Regensburg 12 Sektion Pneumologie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn 13 Klinik für Pneumologie, Universitätsspital Zürich, Schweiz. 14 Innere Medizin V - Pneumologie, Allergologie, Beatmungs- und Umweltmedizin, Universitätsklinikum des Saarlandes, Homburg 15 Medizinische Klinik und Poliklinik II, Universities of Giessen and Marburg Lung Center (UGMLC), Mitglied des Deutschen Zentrums für Lungenforschung (DZL), Gießen

Word count : 3143 No. of references: 49 No. of figures : 0 No. of tables : 1

Address correspondence to: Prof. Dr. med. H. Olschewski Klinische Abteilung für Lungenkrankheiten Universitätsklinik für Innere Medizin, Medizinische Universität Graz Auenbruggerplatz 15 8036 Graz, Österreich Tel.: $+43$ (316) 385-12183 FAX: $+43$ (316) 385-13930 e-mail: horst.olschewski@medunigraz.at

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Summary

The 2015 European Guidelines on Pulmonary Hypertension did not only cover pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This ACCEPTED MANUSCRIPT

Word count summary:

Key words:

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## Clinical significance of pulmonary hypertension in patients with lung disease

At the 2013 World Symposium on Pulmonary Hypertension (PH) in Nice, a separate working group for PH due to lung disease was convened for the first time, and its findings were published in highimpact journals before the year was out [1]. The chapter on this topic in the 2015 ESC/ERS guidelines is based on these recommendations, although not before being further revised by the authors of the guidelines and approved by the respective medical societies: the European Society of Cardiology (ESC) and

Comments: the PH groups [3;4].

$(S v O_{2})$

condition causing PH [15]. The prevalence of PH in interstitial lung disease (ILD) correlates only weakly with the degree of restriction [16;17]. Patients with CPFE develop PH in 47-90% of cases [18- 21]. In these patients, the diffusing capacity of the lungs for carbon monoxide (DLCO) is severely restricted (in most cases to 20-45% of the predicted reference range), while lung volumes are normal or slightly changed and severe airway obstructions are absent. The mortality rate for this disease is high and is also strongly associated with pulmonary pressure [18;22;23].

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In some of these patients, abnormalities of the lung parenchyma seen on computed tomography (CT) scans are rather discrete, which makes it difficult to differentiate the disease from idiopathic pulmonary arterial hypertension (IPAH). A Dutch working group compared their IPAH patients who had a substantially decreased DLCO $\langle\llcorner45\%$ of the predicted reference range) with other IPAH patients [24]. The patients with the low DLCO were similar to the CPFE patients described in other publications in terms of their hemodynamics, age, proportion of males, and similarly high number of pack years. Some of them had pathological changes on high resolution CT scans, although they were not very pronounced. In these patients, in whom the low DLCO would constitute a global indicator of possible lung disease, PH could be referred to as “atypical PAH” or “PAH with pulmonary comorbidities”.

Definitions

The new terms ‘PH-COPD, PH-IPF, PH-CPFE’ and ‘severe PH-COPD, PH-IPF, PH-CPFE’ were coined in MANU the publication from the Nice working group and in the ESC/ERS guidelines [1;2]. ‘Non-severe’ disease refers to the respective lung diseases with an mPAP ≥25 mmHg, ‘severe’ disease to those with an mPAP ≥35 mmHg or an mPAP ≥25 mmHg and decreased cardiac output. The wording in the ESC/ERS guidelines is: ‘...in the presence of a low cardiac output (CI <2.5 L/min)’. Apparently what was meant was a CI <2.5 L/min/m 2 , as stated in the online version of the ESC/ERS guidelines [http://erj.ersjournals.com/content/46/6/1855]. In the Nice working group [1], the CI criterion in question was <2.0 L/min/m 2 . According to the consistent statements of the Nice working group and the ESC/ERS guidelines, PAH therapy should in principle be considered for patients with ‘severe PH due to lung disease’.

Comments: The change in the CI criterion from 2.0 to 2.5 L/min/m 2 increases the number of patients with lung disease who qualify as having ‘severe PH due to lung disease’. The reason for this is that very few patients with chronic lung disease have an mPAP >35 mmHg, but many have an mPAP ≥25 mmHg. On the other hand, patients with an mPAP between 25 and 35 mmHg rarely have a CI of <2.0 L/min/m 2 , but frequently have a CI between 2.0 and 2.5 L/min/m 2 . No reason was given for choosing the value of 2.5 L/min/m 2 , which makes it difficult to comprehend the underlying rationale. The criteria for severe PH due to lung disease in the paper published by the Nice working group [1] originally came from the 2010 Cologne Consensus Conference [25], some of the authors of which also worked on the current comments. Then, as now, the evidence for the criteria for ‘severe PH due to lung disease’ is weak. The aim of the criteria is to identify those patients who have a good chance of responding well to PAH therapy. The recent disappointing treatment outcomes from the RISE-IIP study (NCT 02 138 825) make this yet another in a long line of negative controlled studies in which Group 3 PH patients were enrolled without due consideration of the criteria for ‘severe PH’. Therefore,

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the 2016 Consensus Conference recommends going back to the original criteria for severe PH due to lung disease, which have also been taken up by and are being used by our American and French colleagues [26;27].

The criteria for severe PH due to lung disease are:

PAP >35 mmHg PAP ≥25 mmHg and CI <2.0 L/min/m

To make a diagnosis, at least two of these criteria must be met.

In practical terms this means that patients must have a clearly elevated PVR, either based on a high MANUSCRIPT mPAP or on a clearly reduced cardiac output or CI. This will ensure that PAH drugs, which as is generally known act primarily on PVR, will find a relevant target. This PVR criterion is supported by the research conducted by Corte and colleagues, and the findings from the ASPIRE study [12; 13].

The Nice working group [1] proposed specific criteria for differentiating between PH due to lung disease (Group 3 PH) and PAH (Group 1 PAH) with a concomitant but independent lung disease. The criteria listed for Group 1 PAH were:

1) normal or slightly decreased ventilatory function, which is defined as a forced expiratory volume in 1 second of >60% of the normal range for COPD and a vital capacity of ${>}70\%$ for IPF 2) absence of serious lung parenchymal changes on high resolution CT scans 3) predominantly circulatory limitation on physical exercise.

Comments: Unfortunately, the above Nice working group criteria were not included in the ESC/ERS guidelines, so the important and difficult process of differential diagnosis is still subject to the experience and judgment of the individual physician. Interestingly, the DLCO is therefore not taken into account despite it being known to have a high sensitivity for detection of parenchymal lung disease. There is a lack of clarity how patients with low DLCO but without extensive lung parenchymal pathologies on high resolution CT scans should be categorized. Therefore it is also difficult to state criteria for DLCO that suggest a distinct lung disease. Independent of this consideration, it should be noted here that a low DLCO is a strong predictor of an unfavorable prognosis, both in IPAH and in diastolic left heart failure with preserved ejection fraction (HFpEF) [24;28].

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Recommendations for management

The recommendations of the ESC/ERS Guidelines for PH due to lung disease [2] (Table 1) were all given evidence level C, which means that they are not based on controlled studies or meta-analyses. The recommendation classes range from I (unconditional recommendation) and IIa (strong recommendation for) to III (clear recommendation against). Comments on all six recommendations are given below.

1)

Comments:

2)

Comments:

3)

Comments:

4) Referral to a PH expert centre should be considered for patients with severe PH / severe RV failure for individualized treatment (IIa).

Comments: This statement should be viewed in the context of the definition of an ‘expert centre for PH’ (ESC/ERS Guidelines) and the definition of ‘severe PH due to lung disease’ (see above).

5) Right heart catheterization is not recommended for suspected PH in patients with lung disease, unless therapeutic consequences are anticipated, e.g.

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lung transplantation alternative diagnoses such as PAH/CTEPH, and/or potential enrolment in a clinical trial (III).

Comments: This statement implies that right heart catheterization should be performed only at an expert centre and nowhere else. The expert centre will check whether RHC is indicated. Among other things, this approach ensures that the expert centre does not have to repeat a

6)

Comments: an expert centre.

Comments: ACCEPTED MANUSCRIPT disease might benefit from targeted PH treatment, in particular prostanoids given via the inhaled route or orally administered PDE-5 inhibitors [33;34]. Although smaller case series have also suggested beneficial effects for riociguat [41,44,52], recently a phase IIb study of riociguat in patients with idiopathic interstitial pneumonia (IIP) and PH had to be terminated early for safety reasons. Even without a detailed analysis available, IIP represents a new contraindication for riociguat.

In randomized controlled trials, the endothelin receptor antagonist (ERA) ambrisentan led to more rapid progression in IPF patients, more side effects and increased mortality, without fundamentally

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improving the additional PH [35;36]. In fibrosing IIP, bosentan reduced neither the PVR nor the functional capacity after 16 weeks of treatment [37].

Currently, there are no specific treatment recommendations for CPFE. Potential treatments can be based on the recommendations for pulmonary fibrosis or pulmonary emphysema [38;39].

In patients with PH-COPD who meet the definition of ‘severe PH’ proposed above, there have been no large randomized controlled studies from Western countries investigating the efficacy of PAH

Future study concepts

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Comments: the potential indication of PAH drugs in patients with PH due to lung disease. The treatment has two main aims: to improve clinical symptoms, and to improve the course of the disease.

If vasodilatory PAH drugs, which are known to act primarily on PVR, are used as they have been in the past, the inclusion criteria should require a sufficiently high PVR. The Cologne Consensus Conference proposes the same criteria as for a ‘severe group 3 PH’ (see above). Patients with mild cardiac comorbidities should explicitly be included because there is a very high prevalence of heart disease in

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the typical patient population, although patients with overt pulmonary venous congestion (PAWP >15 mmHg) and a history of pulmonary edema should be excluded for safety reasons.

Given that mortality is very high in severe PH due to lung disease, it is recommended that cardiorespiratory mortality and death due to any cause be used, ideally as the primary endpoint. Patient-oriented treatment goals such as quality of life, oxygenation and exercise capacity should also be considered.

course.

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Comments: This recommendation is an important deviation from earlier conventions and may also be relevant for longitudinal catheterization studies of individual patients. If, for example, the zero point was placed at the 2/3 or 3/5 thoracic level during earlier examinations but is now placed at 1/2 thoracic level, the pressure readings will be around 2-3 mmHg higher. If the examination is not performed with the patient completely supine, the zero point should also be set at the level of the left atrium. Based on the ‘phlebostatic axis’ [48] a modified method (‘phlebostatic point’) is recommended, which can be used with the body in any position [46].

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The ESC/ERS guidelines leave it up to the investigator to decide whether to measure pulmonary pressures at the end of expiration or to take an average of several respiratory cycles.

Comments: The Cologne Consensus Conference working group recommends using only the second method for patients with obstructive lung disease. Rationale: in patients with severe obstructive lung disease, usually the ‘pressure at the end of expiration’ corresponds to the pressure in the last phase of active expiration and not the pressure at the end of the passive expiratory flow, where it can be ACCEPTED MANUSCRIPT

Table 1: Definitions and management of pulmonary hypertension due to chronic lung disease

| Underlying lung disease |mPAP | |---|---|

CI: cardiac index, COPD: chronic obstructive pulmonary disease, CPFE: combined pulmonary fibrosis and emphysema, $\mathsf{F E V}_{1}$ fibrosis, mPAP: mean pulmonary artery pressure, PAH: pulmonary arterial hypertension, PH: pulmonary hypertension, pred: predicted.

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Conflicts of interest / Author declarations:

HO: received fees for lectures and/or consulting and/or research support to institution from Actelion, Bayer, Belerophon, Boehringer, GSK, Menarini, MSD, Novartis, Pfizer, Roche JB: received fees for lectures and/or consulting and/or research support to institution from Actelion, Bayer, Boehringer, Gilead, GSK, Roche HB: received fees for lectures and/or consulting and/or research support to institution from Actelion, Bayer, GSK ACCEPTED MANUSCRIPT Actelion, GSK, Berlin Chemie Bayer, GSK, Pfizer Bayer, Pfizer, Novartis