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Elevated pulmonary vascular resistance predicts mortality in COPD patients

Katarina Zeder, Alexander Avian, Gerhard Bachmaier, Philipp Douschan, Vasile Foris, Teresa Sassmann, Natascha Troester, Luka Brcic, Michael Fuchsjaeger, Leigh Matthew Marsh, Bradley A. Maron, Horst Olschewski, Gabor Kovacs
European Respiratory Journal 2021 58: 2100944; DOI: 10.1183/13993003.00944-2021
Katarina Zeder
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
2Division of Pulmonology, Dept of Internal Medicine, Medical University of Graz, Graz, Austria
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Alexander Avian
3Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
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Gerhard Bachmaier
3Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
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Philipp Douschan
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
2Division of Pulmonology, Dept of Internal Medicine, Medical University of Graz, Graz, Austria
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Vasile Foris
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
2Division of Pulmonology, Dept of Internal Medicine, Medical University of Graz, Graz, Austria
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Teresa Sassmann
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
2Division of Pulmonology, Dept of Internal Medicine, Medical University of Graz, Graz, Austria
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Natascha Troester
2Division of Pulmonology, Dept of Internal Medicine, Medical University of Graz, Graz, Austria
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Luka Brcic
4Dept of Pathology, Medical University of Graz, Graz, Austria
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Michael Fuchsjaeger
5Dept of Radiology, Medical University of Graz, Graz, Austria
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Leigh Matthew Marsh
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
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Bradley A. Maron
6Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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Horst Olschewski
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
2Division of Pulmonology, Dept of Internal Medicine, Medical University of Graz, Graz, Austria
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  • For correspondence: horst.olschewski@medunigraz.at
Gabor Kovacs
1Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
2Division of Pulmonology, Dept of Internal Medicine, Medical University of Graz, Graz, Austria
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Abstract

PVR >5 WU proved to be the strongest independent haemodynamic predictor of mortality in COPD patients. This threshold may best identify COPD patients with severe pulmonary vascular disease. https://bit.ly/3v4QE96

To the Editor:

COPD is frequently associated with mild to moderate pulmonary hypertension (PH). However, a small subset of patients develops severe PH, which is currently haemodynamically defined as mean pulmonary arterial pressure (mPAP) ≥35 mmHg, or mPAP ≥25 mmHg in combination with cardiac index <2.0 L·min−1·m−2 [1, 2]. These cut-offs are, however, arbitrary and mainly based on expert opinion. In this study we aimed to determine prognostically relevant haemodynamic thresholds for severe PH in COPD by using an unbiased approach.

We retrospectively analysed COPD patients with at least 1-year follow-up who underwent right heart catheterisation (RHC) and clinical evaluation at our clinic due to suspected PH between 2003 and 2018. RHC was performed in the supine position, with a mid-thoracic zero reference level, as previously described [3]. All data were included into a prospective local database (GRAPHIC (GRAz Pulmonary Hypertension In COPD) registry). Patients undergoing lung transplantation at any time (n=3) were excluded from this analysis. We performed Cox regression analysis, adjusting for age, sex and forced expiratory volume in 1 s (FEV1) with the primary outcome all-cause mortality. For identification of the best prognostic cut-offs, we searched for the lowest p-values. Continuous baseline characteristics of the groups according to the best cut-off were compared using independent t-tests or Mann–Whitney U-test, as appropriate. Continuous variables are described as mean±sd or median (interquartile range), as appropriate. The study was approved by the institutional ethics board (EK: 32–180 ex 19/20) of the Medical University Graz.

We included 139 COPD patients (age 68 (62–73) years; 55.4% male; mPAP 35 (27–43) mmHg; pulmonary vascular resistance (PVR) 4.3 (2.9–7.3) WU; FEV1 56±20% predicted). 72 patients (52%) died during a follow-up of 8.0 (3.8–11.7) years, with a median time to death of 3.0 (1.3–5.2) years. 61 (44%) patients received any PAH drug at any time-point.

Out of the examined haemodynamic parameters, after adjustment for age, sex and FEV1, PVR (HR 1.09, 95% CI 1.02–1.16; p=0.007) and mPAP (HR 1.03, 95% CI 1.01–1.05; p=0.001) were associated with survival, while pulmonary arterial wedge pressure (PAWP) and cardiac index were not (p=0.696 and p=0.171). Among all haemodynamic parameters, PVR >5.0 WU was the best prognostic cut-off (HR 2.59, 95% CI 1.58–4.27; p<0.001) (figure 1a). Patients with PVR >5.0 WU were more frequently males (p<0.001) and had a lower 6-min walk distance (254±112 versus 333±117 m; p<0.001), lower peak oxygen uptake (41±13 versus 61±23% predicted; p<0.001) and higher N-terminal pro brain natriuretic peptide (2288 (694–3634) versus 442 (160–1126) pg·mL−1; p<0.001) as compared to patients with PVR ≤5.0 WU.

FIGURE 1
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FIGURE 1

a) Multivariate Cox regression analysis by pulmonary vascular resistance (PVR) groups (cut-off: PVR >5.0 WU) accounting for age, sex and forced expiratory volume in 1 s (FEV1) (n=138; HR 2.59, 95% CI 1.58–4.27; p<0.001). b) Multivariate Cox regression analysis by mean pulmonary arterial pressure (mPAP) groups (cut-off: mPAP ≥33 mmHg) accounting for age, sex and FEV1 (n=139; HR 2.26, 95% CI 1.37–3.71; p=0.001). c) Univariate Cox regression analysis by mPAP and PVR groups with mPAP cut-off ≥33 mmHg and PVR cut-off >5.0 WU (n=138; p=0.001; reference category: mPAP <33 mmHg and PVR ≤5.0 WU (green curve); versus mPAP ≥33 mmHg and PVR ≤5.0 WU (yellow curve): HR 2.02, 95% CI 1.04–3.93; versus mPAP <33 mmHg and PVR >5.0 WU (orange curve): HR 3.45, 95% CI 1.25–9.52; versus mPAP ≥33 mmHg and PVR >5.0 WU (red curve): HR 3.35, 95% CI 1.95–6.06). For data in panels a and c, n=138 as pulmonary arterial wedge pressure and therefore PVR was not available in one patient.

For mPAP, the p-values for potential cut-off scores showed two equivalent minimal levels, the first at 33 mmHg (HR 2.26, 95% CI 1.37–3.71; p=0.001) (figure 1b) and the second at 45 mmHg (HR 2.44, 95% CI 1.43–4.16; p=0.001). Out of the patients with mPAP ≥33 mmHg, n=28 (36%) and n=49 (64%) had PVR ≤5.0 WU and >5.0 WU, respectively. A PVR >5.0 WU was associated with higher mPAP (46 (41–54) versus 36.5 (35–41.5); p<0.001), lower PAWP (10 (8–13) versus 13 (10–19); p=0.001) and higher FEV1 (58±19 versus 47±15; p=0.016). PVR >5.0 WU appeared to better identify subjects with a poor prognosis as compared to mPAP ≥33 mmHg (figure 1c). A PVR above 5.0 WU in the absence of mPAP ≥33 mmHg was rare (n=6 out of 138; 4.3%).

Our study, using an unbiased approach, confirmed that an elevated mPAP has a significant impact on the age-, gender- and FEV1-corrected prognosis of COPD patients. The identified threshold (≥33 mmHg) was very near to the recommended threshold in the current PH guidelines at 35 mmHg. This is also in line with previous studies [4–8]. However, the strongest predictor of prognosis in our study was PVR, with the best prognostic cut-off at 5.0 WU. This was true for the whole cohort and the subgroup with classic group 3 PH. The prognostic relevance of PVR is supported by recently published data from the COMPERA registry, revealing PVR as an independent predictor of mortality in over 370 COPD patients with PH [9].

PVR >5.0 WU may be considered an appropriate threshold to define severe PH in COPD due to the following reasons. First, PVR elevation is considered as major hallmark of pulmonary vascular disease, better reflecting the severity of pulmonary vascular remodelling than mPAP. Second, the clinical and haemodynamic characteristics of our patients with mPAP ≥33 mmHg and PVR >5.0 WU corresponded to the pulmonary vascular phenotype of COPD, with lower PAWP and less severe airway obstruction than other patients [10]. Third, patients presenting with mPAP ≥33 mmHg and PVR ≤5.0 WU rather represented a combination of pulmonary and left heart disease with some degree of pulmonary vasculopathy. Fourth, all currently available PAH drugs are strong pulmonary vasodilators, primarily acting on PVR. Therefore, it appears reasonable to consider severely elevated PVR as potential criterion for the indication of a PAH drug or at least as an inclusion criterion for future randomised controlled trials in group 3 PH [2].

It is often difficult to classify PH patients with COPD. The proceedings of the 6th World Symposium on PH [1] and the 2015 European Society of Cardiology/European Respiratory Society PH guidelines [2] provide some guidance regarding how to differentiate between patients with pulmonary arterial hypertension with COPD as comorbidity (group 1 PH) and patients with group 3 PH. Based on our data, PVR >5 WU may serve as a prognostic threshold independent of the PH classification, as long as the criteria for COPD are met.

As a limitation of our study, we included a relatively low number of patients; however, they were followed for a long time with a high number of events and sufficient statistical power. The single-centre retrospective design is another drawback. However, this may be compensated by the highly standardised clinical approach and the enrolment of all patients into a prospective registry. Nevertheless, further studies will be necessary to validate our findings in independent COPD cohorts.

In conclusion, by employing an unbiased approach, we identified PVR >5 WU as the strongest independent haemodynamic predictor of mortality in patients with COPD. A PVR >5 WU suggests the presence of severe pulmonary vascular disease and this was associated with less severe airflow obstruction and a relatively low pulmonary venous pressure, which is consistent with a pulmonary vascular phenotype of COPD.

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Acknowledgements

We thank Daniela Kleinschek for excellent assistance. We thank PH Austria Research Association and Self-Help Organization for their support.

Footnotes

  • This article has an editorial commentary: https://doi.org/10.1183/13993003.02008-2021

  • Author contributions: K. Zeder: study design and development, data analysis and interpretation, writing the paper, final approval of the submitted version. A. Avian and G. Bachmaier: statistical analysis, final approval of the submitted version. P. Douschan, V. Foris, T. Sassmann, N. Troester, L. Brcic, M. Fuchsjäger, L.M. Marsh and B.A. Maron: data interpretation, final approval of the submitted version. H. Olschewski: study design and development, data analysis and interpretation, final approval of the submitted version. G. Kovacs: study design and development, data analysis and interpretation, writing the paper, final approval of the submitted version. All authors contributed to the writing and editing of the manuscript.

  • Conflict of interest: K. Zeder has nothing to disclose.

  • Conflict of interest: A. Avian has nothing to disclose.

  • Conflict of interest: G. Bachmaier has nothing to disclose.

  • Conflict of interest: P. Douschan reports personal fees and non-financial support from Actelion and GSK, non-financial support from AstraZeneca, Bayer, MSD, Novartis, Teva and Boehringer Ingelheim, outside the submitted work.

  • Conflict of interest: V. Foris reports personal fees and non-financial support from Boehringer Ingelheim, GSK and MSD, non-financial support from Actelion, Chiesi, BMS and Menarini, outside the submitted work.

  • Conflict of interest: T. Sassmann has nothing to disclose.

  • Conflict of interest: N. Troester has nothing to disclose.

  • Conflict of interest: L. Brcic has nothing to disclose.

  • Conflict of interest: M. Fuchsjäger has nothing to disclose.

  • Conflict of interest: L.M. Marsh has nothing to disclose.

  • Conflict of interest: B.A. Maron has nothing to disclose.

  • Conflict of interest: H. Olschewski reports grants from Bayer, Unither Pharmaceuticals, Actelion Pharmaceuticals Ltd, Roche, Boehringer Ingelheim and Pfizer Inc., personal fees from Gilead Sciences Inc., Encysive Pharmaceuticals Ltd and Nebu-Tec, personal fees and non-financial support from Bayer, Unither Pharmaceuticals, Actelion Pharmaceuticals Ltd, Pfizer Inc., Eli Lilly, Novartis, AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, MSD and GSK, outside the submitted work.

  • Conflict of interest: G. Kovacs reports personal fees and non-financial support from Actelion, Janssen, Bayer, GSK, MSD, Boehringer Ingelheim, Novartis, Chiesi, Vitalaire, Ferrer and AOP, outside the submitted work.

  • Received February 25, 2021.
  • Accepted April 14, 2021.
  • Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
https://www.ersjournals.com/user-licence

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Elevated pulmonary vascular resistance predicts mortality in COPD patients
Katarina Zeder, Alexander Avian, Gerhard Bachmaier, Philipp Douschan, Vasile Foris, Teresa Sassmann, Natascha Troester, Luka Brcic, Michael Fuchsjaeger, Leigh Matthew Marsh, Bradley A. Maron, Horst Olschewski, Gabor Kovacs
European Respiratory Journal Aug 2021, 58 (2) 2100944; DOI: 10.1183/13993003.00944-2021

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Elevated pulmonary vascular resistance predicts mortality in COPD patients
Katarina Zeder, Alexander Avian, Gerhard Bachmaier, Philipp Douschan, Vasile Foris, Teresa Sassmann, Natascha Troester, Luka Brcic, Michael Fuchsjaeger, Leigh Matthew Marsh, Bradley A. Maron, Horst Olschewski, Gabor Kovacs
European Respiratory Journal Aug 2021, 58 (2) 2100944; DOI: 10.1183/13993003.00944-2021
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