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Temporal trends in pulmonary arterial hypertension: results
from the COMPERA registry
Marius M. Hoeper
1,2
, Christine Pausch
3
, Ekkehard Grünig
2,4
, Gerd Staehler
5
, Doerte Huscher
6
,
David Pittrow
3,7
, Karen M. Olsson
1,2
, Carmine Dario Vizza
8
, Henning Gall
2,9
, Oliver Distler
10
,
Christian Opitz
11
, J. Simon R. Gibbs
12
, Marion Delcroix
13
, H. Ardeschir Ghofrani
2,9,14
,
Stephan Rosenkranz
15
, Da-Hee Park
1
, Ralf Ewert
16
, Harald Kaemmerer
17
, Tobias J. Lange
18
,
Hans-Joachim Kabitz
19
, Dirk Skowasch
20
, Andris Skride
21
, Martin Claussen
22
, Juergen Behr
23,24,25
,
Katrin Milger
24,25
, Michael Halank
26
, Heinrike Wilkens
27
, Hans-Jürgen Seyfarth
28
, Matthias Held
29
,
Daniel Dumitrescu
30
, Iraklis Tsangaris
31
, Anton Vonk-Noordegraaf
32
, Silvia Ulrich
33
and Hans Klose
34
1
Dept of Respiratory Medicine, Hannover Medical School, Hannover, Germany.
2
Member of the German Center for Lung Research
(DZL), Hannover, Germany.
3
GWT-TUD GmbH, Epidemiological Centre, Dresden, Germany.
4
Centre for Pulmonary Hypertension,
Thoraxclinic Heidelberg GmbH at Heidelberg University Hospital, Heidelberg, Germany.
5
Lungenklinik, Löwenstein, Germany.
6
Institute
of Biometry and Clinical Epidemiology, Charité-Universitätsmedizin, Berlin, Germany.
7
Institute for Clinical Pharmacology, Medical
Faculty, Technical University, Dresden, Germany.
8
Dept of Cardiovascular and Respiratory Diseases, Sapienza, University of Rome,
Rome, Italy.
9
Dept of Internal Medicine, Justus Liebig University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC),
Giessen, Germany.
10
Dept of Rheumatology, University Hospital, Zurich, Switzerland.
11
Dept of Cardiology, DRK Kliniken Berlin
Westend, Berlin, Germany.
12
Dept of Cardiology, National Heart and Lung Institute, Imperial College London, London, UK.
13
Clinical
Dept of Respiratory Diseases, University Hospitals of Leuven and Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE),
Dept of Chronic Diseases and Metabolism (CHROMETA), KU Leuven –University of Leuven, Leuven, Belgium.
14
Dept of Medicine,
Imperial College London, London, UK.
15
Clinic III for Internal Medicine (Cardiology) and Center for Molecular Medicine (CMMC), and
the Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany.
16
Dept of Respiratory Medicine, Ernst
Moritz Arndt University Greifswald, Greifswald, Germany.
17
Deutsches Herzzentrum München, Klinik für Angeborene Herzfehler und
Kinder Kardiologie, TU München, Munich, Germany.
18
Dept of Internal Medicine II, University Medical Center Regensburg, Regensburg,
Germany.
19
Medizinische Klinik II, Gemeinnützige Krankenhausbetriebsgesellschaft Konstanz mbH, Konstanz, Germany.
20
Medizinische
Klinik und Poliklinik II, Innere Medizin –Kardiologie/Pneumologie, Universitätsklinikum Bonn, Bonn, Germany.
21
VSIA Pauls Stradins
Clinical University Hospital, Riga Stradins University, Riga, Latvia.
22
Fachabteilung Pneumologie, LungenClinic Grosshansdorf,
Grosshansdorf, Germany.
23
Comprehensive Pneumology Center, Lungen Forschungsambulanz, Helmholtz Zentrum, Munich, Germany.
24
Dept of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany.
25
Member of the German Center for Lung Research (DZL), Munich, Germany.
26
Medizinische Klinik und Poliklinik I,
Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany.
27
Klinik für Innere Medizin V,
Pneumologie, Universitätsklinikum des Saarlandes, Homburg, Germany.
28
Medizinische Klinik und Poliklinik II, Abteilung für
Pneumologie, Universitätsklinikum Leipzig, Leipzig, Germany.
29
Dept of Internal Medicine, Respiratory Medicine and Ventilatory
Support, Medical Mission Hospital, Central Clinic Würzburg, Würzburg, Germany.
30
Clinic for General and Interventional Cardiology
and Angiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Bad Oeynhausen, Germany.
31
2nd Critical Care Dept,
Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
32
Dept of Pulmonary Medicine,
Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
33
Clinic of
Pulmonology, University and University Hospital of Zurich, Zurich, Switzerland.
34
Dept of Respiratory Medicine, Eppendorf University
Hospital, Hamburg, Germany.
Corresponding author: Marius M. Hoeper (hoeper.marius@mh-hannover.de)
Shareable abstract (@ERSpublications)
In this analysis of temporal trends in PAH treatment patterns and survival in 2010–2019, this study
found an increase in the use of targeted combination therapies but only a slight, nonsignificant
trend towards improved survival 3 years after diagnosis https://bit.ly/3FExlK5
Cite this article as: Hoeper MM, Pausch C, Grünig E, et al. Temporal trends in pulmonary arterial
hypertension: results from the COMPERA registry. Eur Respir J 2022; 59: 2102024 [DOI: 10.1183/
13993003.02024-2021].
Abstract
Background Since 2015, the European pulmonary hypertension guidelines recommend the use of
combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear
Copyright ©The authors 2022.
https://doi.org/10.1183/13993003.02024-2021 Eur Respir J 2022; 59: 2102024
EUROPEAN RESPIRATORY JOURNAL
ORIGINAL RESEARCH ARTICLE
M.M. HOEPER ET AL.
to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved
long-term survival.
Methods We analysed data from COMPERA, a large European pulmonary hypertension registry, to assess
temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH
between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data
comparing the periods 2010–2014 and 2015–2019.
Results A total of 2531 patients were included. The use of early combination therapy (within 3 months
after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients
diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after
diagnosis increased from 27.7% to 46.3%. When comparing the 2010–2014 and 2015–2019 periods,
1-year survival estimates were similar (89.0% (95% CI 87.2–90.9%) and 90.8% (95% CI 89.3–92.4%),
respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates
(67.8% (95% CI 65.0–70.8%) and 70.5% (95% CI 67.8–73.4%), respectively).
Conclusions The use of combination therapy increased from 2010 to 2019, but most patients still received
monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to
determine if the observed trend suggesting improved 3-year survival rates can be confirmed.
Introduction
The term pulmonary arterial hypertension (PAH) describes a potentially fatal pulmonary vasculopathy
characterised by a progressive increase in pulmonary vascular resistance (PVR) that may lead to right-sided
heart failure. The most common form of PAH is idiopathic (IPAH), but there are also heritable (HPAH)
and drug-associated (DPAH) forms as well as disease manifestation associated with various conditions,
such as connective tissue disease (CTD), HIV infection, portal (porto-pulmonary) hypertension and
congenital heart disease (CHD) [1].
Before targeted treatments became available, the outlook for patients with PAH was grim. A US registry
study published in 1991 found a median survival of patients with IPAH (at that time called primary
pulmonary hypertension) of 2.8 years after diagnosis [2]. Over the ensuing 30 years, various treatments
have been developed which improve haemodynamics, exercise tolerance and worsening-free survival [3].
Life expectancy of patients with PAH has also increased, with median survival after diagnosis now
exceeding 5 years [4–6]. However, for most of the currently approved therapies, no effect on mortality has
been demonstrated in randomised clinical trials (except for i.v. epoprostenol, which improved survival in a
randomised, open-label study done at a time when no other treatments were available) [7–11].
Over the years, with more PAH drugs becoming available, treatment strategies have evolved. In the 2004
European pulmonary hypertension guidelines, monotherapy was recommended for almost all patients and
all disease stages, with combination therapy receiving a “may be considered”recommendation as a last
resort [12]. In the 2009 European pulmonary hypertension guidelines, initial monotherapy remained the
recommended strategy for most patients, with initial combination therapy to be considered for patients
presenting in World Health Organization Functional Class IV and sequential combination therapy in case
of an insufficient response to monotherapy [13]. In 2015, the results of the AMBITION (Ambrisentan and
Tadalafil in Patients with Pulmonary Arterial Hypertension) study were published showing markedly better
treatment outcomes in terms of exercise tolerance and disease progression with initial combination therapy
with ambrisentan (an endothelin receptor antagonist (ERA)) and tadalafil (a phosphodiesterase-5 inhibitor
(PDE5i)) compared with monotherapy with these compounds [8]. Like other studies in the field,
AMBITION was not designed to detect and did not show a survival benefit at the end of the study [8, 11].
Still, the revised European pulmonary hypertension guidelines published in 2015 recommended for the
first time to use initial combination therapy in most patients with newly diagnosed PAH [14, 15].
Concurrently with the evolution of PAH therapies, there have been changes in patient phenotypes,
particularly in countries with an ageing population. While the disease was originally seen mostly in young,
otherwise healthy females, a diagnosis of PAH is nowadays made predominantly in male and female
patients of older age. In several recent registries, median age at PAH diagnosis was >60 years and many of
the older patients presented with numerous cardiopulmonary comorbidities [6, 16–19]. Such patients were
not well represented in the clinical trials that led to the approval of PAH medications. The aforementioned
AMBITION study had a small (n=105) subset of older (mean age 62 years) patients with multiple
comorbidities that were analysed separately and in whom no clear benefit from combination therapy could
be demonstrated [20]. According to registry data, older patients, compared with younger patients, tend to
be treated less aggressively, respond less well to PAH medications, have a higher likelihood to discontinue
their PAH medications and have a higher mortality risk [5, 6, 17, 21].
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This article has an editorial
commentary:
https://doi.org/10.1183/
13993003.00390-2022
Received: 21 July 2021
Accepted: 5 Oct 2021
https://doi.org/10.1183/13993003.02024-2021 2
EUROPEAN RESPIRATORY JOURNAL ORIGINAL RESEARCH ARTICLE | M.M. HOEPER ET AL.
It is unclear how the introduction of new treatments and new treatment strategies for PAH and the
demographic changes observed in this patient population have affected treatment patterns and survival over
time. Here, we present data from COMPERA (Comparative, Prospective Registry of Newly Initiated
Therapies for Pulmonary Hypertension). The objective of the present analysis was to describe temporal
trends in treatment patterns and survival of patients diagnosed with PAH between 2010 and 2019, i.e. over
a 10-year period.
Methods
Database
Details of COMPERA (www.COMPERA.org; ClinicalTrials.gov: NCT01347216) have been reported
previously [6, 22]. In brief, COMPERA is an ongoing web-based pulmonary hypertension registry
launched in 2007 that prospectively collects baseline, follow-up and outcome data of patients who receive
targeted therapies for pulmonary hypertension. Originally, COMPERA was initiated as a registry for
patients with PAH who were treated with ERA, but in June 2009, COMPERA evolved into a
comprehensive pulmonary hypertension registry enrolling patients with all forms of pulmonary
hypertension who receive medical therapy with any drug approved for PAH. Centres must enter their
patients within 6 months after the pulmonary hypertension diagnosis to ensure inclusion of newly
diagnosed patients. Pulmonary hypertension centres from various European countries participate (Austria,
Belgium, Germany, Greece, Hungary, Italy, Latvia, Lithuania, Netherlands, Slovakia, Switzerland and the
UK), with ∼80% of the enrolled patients coming from German pulmonary hypertension centres.
COMPERA has been approved by the ethics committees of all participating centres and all patients
provide written, informed consent prior to inclusion.
Patients
For the present analysis, patients were selected from the COMPERA database by the following criteria:
1) treatment-naïve patients aged ⩾18 years newly diagnosed with any form of PAH between 1 January
2010 and 31 December 2019, 2) at least one follow-up available, and 3) resting mean pulmonary arterial
pressure ⩾25 mmHg and mean pulmonary arterial wedge pressure ⩽15 mmHg at baseline. Patients with
suspected or confirmed pulmonary veno-occlusive disease or pulmonary capillary haemangiomatosis were
excluded, as were patients with other forms of pulmonary hypertension.
Statistical analyses
This was a post hoc analysis of prospectively collected variables. Continuous data are presented as mean
with standard deviation or as median (interquartile range). Categorical data are presented as number
(percentage). The dataset as of 1 September 2021 was analysed. Annualised data on the use of
monotherapy and combination therapy within 3 months after diagnosis, also termed early combination
therapy in this article, and after 1 year (±6 months) were shown based on the year of diagnosis.
Ascertainment of vital status was done by on-site visits or phone calls to the patients or their caregivers.
Patients who underwent lung transplantation and patients who were lost to follow-up were censored at the
date of the last contact. Survival was evaluated using Kaplan–Meier analysis and the log-rank test.
Estimated survival probability at 1 and 3 years was shown with 95% confidence intervals for each year of
diagnosis. All trends were visualised in figures without formal statistical testing. The 1-year survival
analyses were performed for all patients diagnosed between 2010 and 2019, while the 3-year survival
analysis was done only for patients diagnosed between 2010 and 2018. All analyses were done for the
entire cohort, for subgroups of patients divided by age (<65 versus ⩾65 years), for subgroups of patients
with I/H/D-PAH and CTD-PAH, and for a subgroup of patients with I/H/D-PAH who had no
comorbidities and a diffusing capacity of the lung for carbon monoxide (D
LCO
) >45% predicted [23, 24].
In addition, we compared the cumulative survival rates of patients diagnosed between 2010 and 2014 with
those of patients diagnosed between 2015 and 2019.
All statistical analyses were performed using R version 3.5.2 (www.r-project.org).
Results
Patient characteristics, treatment and survival of the entire cohort
A total of 2531 patients were included in the present analysis (figure 1). The patients’baseline
characteristics, including those of the subgroups of patients with I/H/D-PAH and CTD-PAH, are shown in
table 1. The baseline characteristics of the patient cohorts <65 years (n=1031 (40.7%)), ⩾65 years (n=1500
(59.3%)), and I/H/D-PAH without comorbidities and D
LCO
>45% predicted (n=128 (5.1%)) are shown in
supplementary table S1a–c. The annualised baseline characteristics did not suggest temporal trends in
patient demographics or disease severity over time (supplementary table S2 and supplementary figure S1).
https://doi.org/10.1183/13993003.02024-2021 3
EUROPEAN RESPIRATORY JOURNAL ORIGINAL RESEARCH ARTICLE | M.M. HOEPER ET AL.
The use of PAH medications, cumulated over the entire enrolment period, is shown in table 2 for the entire group
and in supplementary table S3a–e for the subgroups. Overall, 19.6% of the patients received combination therapy
within 3 months after diagnosis, 42.9% after 1 year and 49.8% after 3 years. In patients who received
combination therapy, ERA and PDE5i were used in about two-thirds of the cases. Other combination therapies
were used less frequently, and triple combination therapy including i.v. or s.c. prostacyclin analogues (PCAs) was
used in 0.9% of the patients at entry and in 3.5% of the patients during follow-up. The median dosages of PAH
medications at 3 months and 1 year are shown in supplementary table S4.
The median follow-up was 2.8 years for the entire cohort, and 3.3 and 2.5 years, respectively, for the subgroups
of patients aged <65 and ⩾65 years. A total of 978 (38.6%) patients died during the observation period, 29
(1.1%) underwent lung transplantation and 160 (6.3%) were lost to follow-up. The Kaplan–Meier estimated
survival curves are shown in figure 2. The estimated survival rates of the entire cohort were 90.0% after 1 year,
69.2% after 3 years and 55.3% after 5 years. Patients with HIV-PAH and CHD-PAH had a better survival than
patients with other forms of PAH, whereas patients with CTD-PAH had the worst outcome. The survival
estimates for the cohorts of patients in the subgroups are shown in supplementary figure S2a–c.
Temporal trends in PAH therapy
The annualised trends for the use of combination therapy within 3 months after diagnosis and after 1 year
are shown in figure 3. In the entire cohort, the use of early combination therapy increased from 10.0% in
patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The steepest
increase in the use of early combination therapy was seen between 2014 and 2015. The proportion of
patients who received combination therapy 1 year after diagnosis increased from 27.7% to 46.3% (figure 3a).
In the subgroup of patients with PAH who were aged <65 years at the time of diagnosis, the use of early
combination therapy increased from 13.6% to 41.8% and the use of combination therapy 1 year after
diagnosis increased from 28.2% to 65.9% during the observation period (figure 3b).
In the subgroup of patients with PAH who were aged ⩾65 years at the time of diagnosis, combination
therapy was given less frequently than in the younger cohort. The use of combination therapy increased
from 7.9% to 15.5% after 3 months and from 27.3% to 34.3% after 1 year (figure 3c).
Temporal trends in the use of combination therapy in the subgroups of patients with I/H/D-PAH,
CTD-PAH, and I/H/D-PAH without comorbidities and D
LCO
>45% predicted were in line with the
changes in the whole group (supplementary figure S3a–c).
Excluded:
#
4975 patients with a diagnosis other than PAH
3611 patients not diagnosed in 2010–2019
2349 not incident patients
995 patients not fulfilling mPAP ≥25 mmHg
2638 patients not fulfilling PAWP ≤15 mmHg
229 patients aged <18 years at baseline
Patients in the COMPERA registry
n=10 910
Excluded:
153 patients without follow-up visit(s)
Adult, incident PAH patients
diagnosed in 2010–2019
with mPAP ≥25 mmHg and
PAWP ≤15 mmHg
n=2684
Eligible patients
n=2531
FIGURE 1 STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) diagram showing
eligibility for analysis. PAH: pulmonary arterial hypertension; mPAP: mean pulmonary arterial pressure; PAWP:
pulmonary arterial wedge pressure.
#
: more than one reason for exclusion could apply.
https://doi.org/10.1183/13993003.02024-2021 4
EUROPEAN RESPIRATORY JOURNAL ORIGINAL RESEARCH ARTICLE | M.M. HOEPER ET AL.
Survival over time
Temporal trends in 1- and 3-year survival are shown in figure 4. In the entire cohort, the 1-year survival
rates varied between 82.3% (95% CI 77.4–87.5%) and 93.3% (95% CI 90.3–96.4%), with no clear
improvement over time (figure 4a). The annualised 3-year survival rates of the entire cohort ranged
between 65.0% (95% CI 58.8–71.8%) and 75.3% (95% CI 69.9–81.2%); here, a slight trend towards
improvement cannot be excluded (figure 4a).
TABLE 1 Baseline characteristics of patients newly diagnosed with pulmonary arterial hypertension (PAH) between 2010 and 2019
All PAH I/H/D-PAH CTD-PAH CHD-PAH HIV-PAH POPH
Patients 2531 (100) 1698 (67.1) 536 (21.2) 128 (5.1) 24 (0.9) 145 (5.7)
Age, years 64.6±15.8 65.9±15.9 66.3±13.1 50.6±18.1 45.8±12.1 57.8±11.7
Female 1609 (63.6) 1016 (59.8) 434 (81.0) 84 (65.6) 11 (45.8) 64 (44.1)
BMI, kg·m
−2
28.0±6.1 28.4±6.1 26.7±5.4 26.3±6.5 27.6±8.2 29.6±6.2
WHO FC
I 15 (0.6) 7 (0.4) 2 (0.4) 4 (3.5) 1 (4.2) 1 (0.7)
II 373 (15.7) 244 (15.3) 78 (15.4) 26 (22.8) 6 (25.0) 19 (13.8)
III 1675 (70.4) 1117 (69.9) 369 (73.1) 73 (64.0) 14 (58.3) 102 (73.9)
IV 315 (13.2) 229 (14.3) 56 (11.1) 11 (9.6) 3 (12.5) 16 (11.6)
6MWD, m 297.1±127.1 297.4±127.3 278.4±124.2 344.6±112.9 366.0±146.7 310.7±129.1
Pulmonary function
TLC, % pred 89.6±17.4 91.7±16.4 84.0±18.8 84.0±15.2 88.7±11.5 94.7±16.9
FVC, % pred 80.1±20.3 80.4±20.0 80.0±21.5 70.2±18.5 85.5±10.6 82.5±19.1
FEV
1
, % pred 76.4±19.8 76.5±20.0 76.9±19.6 66.0±16.9 85.0±15.3 78.8±19.6
D
LCO
, % pred 50.5±21.7 52.1±22.6 42.6±17.0 65.8±18.9 47.0±17.5 57.9±17.8
P
aO
2
, mmHg 65.0±12.3 64.5±12.6 65.2±12.0 66.0±10.1 69.8±19.3 68.9±10.8
P
aCO
2
, mmHg 35.1±6.5 35.6±6.4 34.3±6.8 35.9±6.0 35.2±1.3 33.0±5.9
Smoking history
Current 96 (6.9) 76 (6.6) 5 (3.3) 3 (10.0) 0 (0.0) 12 (25.5)
Former 594 (43.0) 490 (42.6) 66 (43.7) 13 (43.3) 2 (50.0) 23 (48.9)
Never 693 (50.1) 585 (50.8) 80 (53.0) 14 (46.7) 2 (50.0) 12 (25.5)
Pack-years
#
30.0 (15.0–40.0) 30.0 (15.0–45.0) 20.0 (10.0–30.0) 12.5 (10.0–28.8) NA (NA–NA) 20.0 (20.0–37.5)
Comorbid conditions
Obesity
¶
810 (32.7) 589 (35.1) 120 (23.7) 34 (26.6) 6 (28.6) 61 (42.4)
Hypertension 1329 (60.7) 1007 (65.6) 225 (56.0) 36 (32.4) 7 (46.7) 54 (43.2)
Coronary heart
disease
554 (26.1) 435 (29.0) 89 (23.2) 10 (9.3) 1 (6.7) 19 (15.8)
Diabetes mellitus 590 (27.2) 489 (32.1) 61 (15.5) 18 (16.2) 0 (0.0) 22 (17.5)
Haemodynamics
RAP, mmHg 8.3±4.8 8.3±4.7 7.8±4.9 8.6±5.5 8.3±4.1 9.8±5.3
mPAP, mmHg 44.2±12.9 44.3±12.7 41.3±11.5 50.8±19.1 47.0±11.4 47.4±10.8
PAWP, mmHg 9.5±3.4 9.5±3.3 9.3±3.4 9.6±3.6 7.9±3.0 9.7±3.5
CI, L·min
−1
·m
−2
2.3±0.8 2.2±0.8 2.4±0.8 2.8±1.2 2.3±1.0 2.7±1.1
PVR, dyn·s·cm
−5
742.7±402.4 764.8±412.5 675.5±353.8 789.4±511.0 871.2±348.3 669.7±321.6
PVR, WU 9.3±5.0 9.6±5.2 8.4±4.4 9.9±6.4 10.9±4.4 8.4±4.0
S
vO
2
, % 62.8±8.6 62.3±8.5 63.5±8.7 65.4±10.1 57.2±7.7 64.5±7.5
Laboratory findings
Creatinine, µmol·L
−1
101.7±55.3 106.1±60.2 95.3±41.9 86.5±50.9 83.0±24.6 89.1±33.9
Uric acid, µmol·L
−1
436.6±151.6 443.1±146.5 430.2±154.1 393.6±188.6 383.3±123.1 424.8±161.6
Bilirubin, µmol·L
−1
15.6±14.2 14.7±11.8 12.9±12.2 16.5±21.6 32.0±34.6 29.5±20.0
NT-proBNP, pg·mL
−1
1454 (480–3341) 1574 (566–3498) 1504 (432–3430) 513 (262–1163) 1212 (209–2542) 848 (233–2128)
BNP, pg·mL
−1
206 (94–497) 200 (102–462) 231 (78–636) 154 (62–315) 175 (150–201) 240 (143–454)
Risk
Low 246 (9.8) 153 (9.1) 49 (9.2) 22 (17.6) 6 (25.0) 16 (11.0)
Intermediate 1698 (67.6) 1144 (67.8) 349 (65.8) 91 (72.8) 15 (62.5) 99 (68.3)
High 568 (22.6) 391 (23.2) 132 (24.9) 12 (9.6) 3 (12.5) 30 (20.7)
Data are presented as n (%), mean±SD or median (interquartile range). I/D/H: idiopathic/drug-associated/heritable; CTD: connective tissue disease;
CHD: congenital heart disease; POPH: porto-pulmonary hypertension; BMI: body mass index; WHO FC: World Health Organization Functional Class;
6MWD: 6-min walk distance; TLC: total lung capacity; FVC: forced vital capacity; FEV
1
: forced expiratory volume in 1 s; D
LCO
: diffusing capacity of the
lung for carbon monoxide; P
aO
2
: arterial oxygen tension; P
aCO
2
: arterial carbon dioxide tension; RAP: right atrial pressure; mPAP: mean pulmonary
arterial pressure; PAWP: pulmonary arterial wedge pressure; CI: cardiac index; PVR: pulmonary vascular resistance; S
vO
2
: mixed venous oxygen
saturation; NT-proBNP: N-terminal fragment of pro-brain natriuretic peptide; BNP: brain natriuretic peptide.
#
: if current or former smoker;
¶
: BMI ⩾30 kg·m
−2
.
https://doi.org/10.1183/13993003.02024-2021 5
EUROPEAN RESPIRATORY JOURNAL ORIGINAL RESEARCH ARTICLE | M.M. HOEPER ET AL.
TABLE 2 Use of drugs to treat pulmonary arterial hypertension (PAH) within 3 months and 1, 2 and 3 years
(±6 months) after diagnosis
3 months
(n=2375)
1 year
(n=2136)
2 years
(n=1727)
3 years
(n=1299)
No therapy 8 (0.3) 73 (3.4) 61 (3.5) 48 (3.7)
Monotherapy 1901 (80.0) 1146 (53.7) 841 (48.7) 604 (46.5)
ERA 401 (21.1) 223 (19.5) 145 (17.2) 99 (16.4)
PDE5i 1375 (72.3) 851 (74.3) 642 (76.3) 467 (77.3)
sGC 63 (3.3) 40 (3.5) 31 (3.7) 23 (3.8)
PCA 6 (0.3) 3 (0.3) 1 (0.1) 1 (0.2)
PCA oral or inhaled
#
1 (16.7) 2 (66.7) 1 (100.0) 0 (0.0)
PCA i.v. or s.c.
¶
5 (83.3) 1 (33.3) 0 (0.0) 1 (100.0)
CCB 51 (2.7) 29 (2.5) 22 (2.6) 14 (2.3)
Other PAH treatment 5 (0.3) 0 (0.0) 0 (0.0) 0 (0.0)
Combination therapy 466 (19.6) 917 (42.9) 825 (47.8) 647 (49.8)
ERA+PDE5i 320 (68.7) 619 (67.5) 539 (65.3) 400 (61.8)
Other than ERA+PDE5i 146 (31.3) 298 (32.5) 286 (34.7) 247 (38.2)
ERA+PDE5i+PCA 33 (22.6) 106 (35.6) 110 (38.5) 104 (42.1)
Triple combination therapy including i.v. or s.c. PCA
+
21 (14.4) 44 (14.8) 47 (16.4) 45 (18.2)
Data are presented as n (%); percentages refer to subgroups only, if applicable. ERA: endothelin receptor
antagonist; PDE5i: phosphodiesterase-5 inhibitor; sGC: soluble guanylate cyclase stimulator; PCA: prostacyclin
analogue; CCB: calcium channel blocker.
#
: selexipag, iloprost inhaled, treprostinil inhaled, beraprost;
¶
: epoprostenol, iloprost i.v., treprostinil i.v./s.c.;
+
: all triple combination therapies that include i.v. or s.c. PCA
therapy.
At risk, n:
All 2531 2076 1596 1174 859 598 417 265 167 94
HIV-PAH 24 19 17 14 10 7 7 7 7 6
CHD-PAH 128 116 100 83 65 49 36 22 15 8
I/H/D-PAH 1698 1418 1094 798 588 409 298 191 117 64
POPH 145 116 85 66 49 30 16 9 6 3
CTD-PAH 536 407 300 213 147 103 60 36 22 13
1.00
0.75
0.50
0.25
0.00
0
Time, years
Survival probability
1 2 3 4 5 6 7 8 9
All
HIV-PAH
CHD-PAH
I/H/D-PAH
POPH
CTD-PAH
FIGURE 2 Kaplan–Meier survival estimates overall and by pulmonary arterial hypertension (PAH) subtype. CHD:
congenital heart disease; POPH: porto-pulmonary hypertension; I/H/D: idiopathic/heritable/drug-associated;
CTD: connective tissue disease.
https://doi.org/10.1183/13993003.02024-2021 6
EUROPEAN RESPIRATORY JOURNAL ORIGINAL RESEARCH ARTICLE | M.M. HOEPER ET AL.
100
75
50
25
0
Patients, %
b)
3 months
1 year
13.6
28.2
65.9
5.9
85.2
1.2
2010
3 months
1 year
20.5
45.3
54.7
0.0
79.5
0.0
2011
3 months
1 year
22.2
63.3
34.2
2.5
75.3
2.5
2012
3 months
1 year
21.6
50.4
46.9
2.7
78.4
0.0
2013
3 months
1 year
16.8
62.7
36.3
1.0
82.2
0.9
2014
3 months
1 year
34.2
56.2
43.8
0.0
64.0
1.8
2015
3 months
1 year
44.4
66.3
30.4
3.3
55.6
0.0
2016
3 months
1 year
28.8
59.4
36.2
4.3
71.2
0.0
2017
3 months
1 year
46.0
59.5
35.7
4.8
54.0
0.0
2018
3 months
1 year
41.8
65.9
31.8
2.3
58.2
0.0
2019
100
75
50
25
0
Patients, %
c)
3 months
1 year
7.9
27.3
64.0
8.6
91.4
0.7
2010
3 months
1 year
10.9
31.6
66.3
2.0
89.1
0.0
2011
3 months
1 year
9.0
33.6
61.7
4.7
91.0
0.0
2012
3 months
1 year
7.0
20.5
73.1
6.4
93.0
0.0
2013
3 months
1 year
4.1
38.8
59.2
1.9
95.9
0.0
2014
3 months
1 year
17.3
38.3
56.4
5.3
82.7
0.0
2015
3 months
1 year
15.5
34.5
61.5
4.0
84.5
0.0
2016
3 months
1 year
18.6
35.8
62.0
2.2
81.4
0.0
2017
3 months
1 year
16.1
36.0
59.2
4.8
83.2
0.6
2018
3 months
1 year
15.5
34.3
65.0
0.7
84.5
0.0
2019
100
75
50
25
0
Patients, %
a)
Combination therapy Monotherapy No therapy
3 months
1 year
10.0
27.7
64.7
7.6
89.1
0.9
2010
3 months
1 year
15.1
37.6
61.3
84.9
0.0
2011
3 months
1 year
14.6
46.2
50.0
3.8
84.4
1.0
2012
3 months
1 year
15.1
38.2
57.6
4.2
84.9
0.0
2013
3 months
1 year
10.0
50.7
47.8
1.5
89.5
0.4
2014
3 months
1 year
24.6
46.5
50.6
2.9
74.6
0.8
2015
3 months
1 year
25.5
45.5
50.8
3.8
74.5
0.0
2016
3 months
1 year
21.8
43.7
53.4
2.9
78.2
0.0
2017
3 months
1 year
27.8
45.5
49.8
4.8
71.8
0.4
2018
3 months
1 year
25.0
46.3
52.4
1.3
75.0
0.0
2019
1.2
FIGURE 3 Temporal trends in the use of initial combination therapy and combination therapy 1 year after
pulmonary arterial hypertension diagnosis in a) the entire cohort, and in the subgroups of patients aged
b) <65 years and c) ⩾65 years.
https://doi.org/10.1183/13993003.02024-2021 7
EUROPEAN RESPIRATORY JOURNAL ORIGINAL RESEARCH ARTICLE | M.M. HOEPER ET AL.
100
1 year 3 years
a)
b)
c)
80
Estimated survival probability, %
60
2010
219
150 124 123 123 136 155 169 140 54
171 173 167 209 229 250 227 226 205
82
65 62 62 76 74 78 66 49 28
77 77 100 106 111 92 77 94 77
137
85 62 61 47 62 77 103 91 26
94 96 67 103 118 158 150 132 128
2011 2012 2013 2014 2015
Year of PAH diagnosis
2016 2017 2018 2019
2010 2011 2012 2013 2014 2015
Year of PAH diagnosis
2016 2017 2018 2019
2010 2011 2012 2013 2014 2015
Year of PAH diagnosis
2016 2017 2018 2019
100
80
Estimated survival probability, %
60
100
80
Estimated survival probability, %
60
FIGURE 4 Annualised survival rates (95% CI) at 1 and 3 years after pulmonary arterial hypertension (PAH)
diagnosis in a) the entire cohort, and in the subgroups of patients aged b) <65 years and c) ⩾65 years. The
black and red numbers indicate the numbers of patients available for the annualised 1- and 3-year survival
rates, respectively.
https://doi.org/10.1183/13993003.02024-2021 8
EUROPEAN RESPIRATORY JOURNAL ORIGINAL RESEARCH ARTICLE | M.M. HOEPER ET AL.
In the patients who were aged <65 years at the time of diagnosis, the annualised 1-year survival estimates
varied between 87.7% (95% CI 82.1–93.8%) and 100.0% (95% CI 100.0–100.0%), and the 3-year
survival estimates ranged between 72.0% (95% CI 64.2–80.8%) and 87.3% (95% CI 80.3–95.0%) (figure
4b), also suggesting a possible improvement over time.
In the patients who were aged ⩾65 years at the time of diagnosis, the annualised 1-year survival estimates
varied between 75.3% (95% CI 67.3–84.5%) and 92.1% (95% CI 88.1–96.1%), and the 3-year survival
estimates ranged between 55.1% (95% CI 47.6–63.9%) and 71.7% (95% CI 64.9–79.3%) (figure 4c). In
both cohorts, there were fluctuations over time and no clear trend in the 1-year survival estimates, whereas
there was a possible increase in the 3-year survival estimates. Similar trends were observed in the
subgroups of patients with I/H/D-PAH and CTD-PAH (supplementary figure S4a and b).
The cumulative 1- and 3-year survival rates of patients diagnosed with PAH between 2010 and 2014 and
between 2015 and 2019 are shown in table 3. In this analysis, the 1-year survival of the entire cohort did
not differ between the two time periods, whereas the 3-year survival did improve slightly (albeit with
overlapping 95% confidence intervals). A similar pattern was seen in all subgroups.
Discussion
In the present study, we assessed the COMPERA database to describe temporal trends in treatment
strategies and survival of patients newly diagnosed with PAH between 2010 and 2019, i.e. over a 10-year
period. During this time, we observed an increase in the use of oral combination therapies, especially in
younger patients. While survival at 1 year after diagnosis did not improve over time, a slight improvement
in 3-year survival rates is possible, but unproven.
Although the use of combination therapy increased over time, it remained unexpectedly low. The steepest
increase in the use of early combination therapy was seen between 2014 and 2015, presumably resulting
from the publication of the AMBITION study, which showed that patients with PAH who received initial
combination therapy with an ERA and a PDE5i had more pronounced clinical improvement and fewer
clinical worsening events than patients receiving initial monotherapy [8]. Still, even at the end of the
observation period, early combination therapy was used in only 25% of the patients in the entire cohort
and in <50% of the patients who were aged <65 years at the time of diagnosis. In the subgroup of patients
who were aged ⩾65 years at the time of diagnosis, combination therapy was used much less frequently
than in younger patients, both initially and 1 year after diagnosis.
The reasons for the relatively infrequent use of combination therapies are unclear. Safety concerns may
play a role. However, in the AMBITION study, initial combination therapy was well tolerated and there
were no more premature study drug discontinuations with initial combination therapy than with
monotherapy [8]. In addition, several other large-scale studies have demonstrated the safety and efficacy of
various sequential combination therapies [9, 10]. However, neither these studies nor meta-analyses have
shown a survival advantage with the use of combination therapies over monotherapies [8–11, 25], which
may discourage physicians from a broader utilisation of combination therapies.
In the present series, older patients with PAH had more comorbidities, were less likely to receive
combination therapy and had a higher mortality risk than younger patients, similar to what has been
TABLE 3 Estimated survival probability at 1 and 3 years in patients diagnosed with pulmonary arterial hypertension (PAH) between 2010 and 2014
and between 2015 and 2019
2010–2014 2015–2019
1-year survival 3-year survival 1-year survival 3-year survival
Entire cohort 89.0 (87.2–90.9) 67.8 (65.0–70.8) 90.8 (89.3–92.4) 70.5 (67.8–73.4)
Patients aged <65 years 93.3 (91.1–95.5) 80.0 (76.4–83.8) 96.0 (94.3–97.8) 83.4 (79.7–87.2)
Patients aged ⩾65 years 85.5 (82.8–88.4) 58.1 (54.2–62.3) 87.7 (85.5–90.0) 63.1 (59.5–66.9)
I/H/D-PAH 90.2 (88.0–92.5) 69.4 (66.0–73.0) 90.8 (89.0–92.7) 70.4 (67.1–73.8)
CTD-PAH 85.3 (81.0–89.9) 57.4 (51.3–64.3) 88.2 (84.3–92.2) 67.1 (60.9–74.0)
I/H/D-PAH with no comorbidities and D
LCO
>45% predicted 90.7 (82.4–99.8) 86.0 (76.2–97.0) 97.5 (94.2–100.0) 90.1 (82.6–98.2)
Data are presented as mean % (95% CI). I/H/D: idiopathic/heritable/drug-associated; CTD: connective tissue disease; D
LCO
: diffusing capacity of the
lung for carbon monoxide.
https://doi.org/10.1183/13993003.02024-2021 9
EUROPEAN RESPIRATORY JOURNAL ORIGINAL RESEARCH ARTICLE | M.M. HOEPER ET AL.
observed in other PAH registries [16–18]. With older patients having a higher mortality risk, one might
expect that combination therapy would be used more frequently than in younger patients, whereas the
opposite is being observed. We have reported previously that the less frequent use of combination
therapies in elderly patients results not only from a lower initiation rate but also from a higher likelihood of
drug discontinuations [6, 21]. Physicians seem to be less confident with the use of combination therapy in
older patients with PAH and multiple comorbidities. This may be related, at least in part, to the fact that
such patients were under-represented in the pivotal trials that have been conducted in this area. Clinical
inertia, i.e. recognition of a problem, but failure to act, a phenomenon well known in other disease areas
[26], may also play a role. Prospective studies are underway to further explore the reasons for withholding
combination therapy in patients with PAH.
Although we cannot exclude a slight increase in the 3-year survival rates over time, we were surprised to
find no clearer signal, not even in younger patients, which we had expected to see with the increasing use
of combination therapies. Several reasons may apply. First, although the use of combination therapy
increased over time, most patients received monotherapy, so that any effect of combination therapy on
survival might have been diluted. Second, the drugs mainly used to treat PAH in the present series were
already available in 2010, i.e. when this analysis was started. The only drugs that were newly introduced in
Europe during the observation period were macitentan, an ERA [9], selexipag, a prostacyclin receptor
agonist [10], and riociguat, a stimulator of soluble guanylate cyclase [27]. For all three compounds,
improvement in event-free survival, but not overall survival, has been demonstrated [9, 10, 27]. The
concept of a goal-oriented use of combination therapy was already introduced in 2005 [28] and had
probably been adopted by many pulmonary hypertension centres in 2010, i.e. the onset of the observation
period of the present study. This and the observation that clinical studies using combination therapies have
consistently shown an improvement in event-free survival, but not in overall survival [8–10], may suggest
that treatment escalation at the time of a clinical worsening event might delay further clinical worsening
and death in some patients. If this is the case, early combination therapy would be expected to affect
overall survival to a lesser extent than time to clinical worsening.
Our findings corroborate those of BOUCLY et al. [5] who recently analysed initial treatment strategies and
long-term outcomes from the French Pulmonary Hypertension Registry and found no differences in
survival of patients who received initial monotherapy or initial oral combination therapy (except for a small
but statistically significant survival difference in patients at intermediate risk). Of note, in the French series,
the only treatment strategy that was associated with a long-term survival benefit was initial triple
combination therapy including ERA, PDE5i and i.v. or s.c. PCAs [5]. This treatment strategy was used in
∼5% of the patients in the French series but in <1% of the patients in our present series, indicating that
initial triple combination therapy including i.v. or s.c. prostacyclin cannot yet be considered standard of
care. However, as two large registry studies based on 1611 patients [5] and 2531 patients (our study) now
independently suggest that initial or early oral combination therapy may not necessarily be associated with
a long-term survival benefit over oral monotherapy, it becomes increasingly important to further explore
the effects of initial triple combination therapy including i.v. or s.c. PCAs on long-term outcome. In
addition, future studies exploring treatment strategies in PAH should be designed to show potential
survival differences.
It is important to note that our observations should not discourage physicians from using initial or early
oral combination therapy in patients with PAH. This treatment strategy is recommended by current
guidelines based on prospective randomised controlled trials showing meaningful improvements in several
clinically important end-points [3, 8, 15]. Given the post hoc nature of our study as well as the study by
BOUCLY et al. [5], our findings should be considered hypothesis generating and we need prospective studies
to compare the effects of various initial treatment strategies on long-term survival. Registry-based
pragmatic trials that have been used successfully in other disease areas [29] may be considered to approach
this fundamentally important question.
Our study has strengths and limitations. Strengths include the large sample size and the relatively constant
number of newly enrolled patients throughout the study period. The main limitations are those inherent to
registries, including the post hoc analysis and the potential of missing or wrongly entered data. To
minimise such risks, COMPERA uses several preventive strategies including automated plausibility
checks, regular queries of implausible entries and independent on-site monitoring with source data
verification. Moreover, dividing the age groups at 65 years for the subgroup analyses was arbitrary,
although this threshold is often used to define old age. In the setting of PAH, this threshold may be of
limited value as previous studies have shown differences in treatment patterns, treatment response and
survival in patients with PAH aged 18–45 years and those aged 46–64 years [16].
https://doi.org/10.1183/13993003.02024-2021 10
EUROPEAN RESPIRATORY JOURNAL ORIGINAL RESEARCH ARTICLE | M.M. HOEPER ET AL.
In summary, the present analysis of the COMPERA database showed that there was an increase in the use
of oral combination therapy over the 10-year period between 2010 and 2019, but about half of the patients
were still receiving monotherapy 1 year after diagnosis. While 1-year survival rates did not change over
time, there was a slight improvement in 3-year survival rates which was, however, not statistically
significant. It will be an important future task to find out if a more proactive use of combination therapy
including i.v. or s.c. PCAs translates into better long-term survival in patients with PAH.
Acknowledgements: The authors are indebted to the COMPERA investigators and their co-workers.
Conflicts of interest: M.M. Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion,
Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. C. Pausch has no disclosures. E. Grünig has received fees for
lectures and/or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer and United
Therapeutics. G. Staehler has received honoraria for lectures and/or consultancy for Actelion, Bayer,
GlaxoSmithKline, Novartis and Pfizer. D. Huscher has received consulting fees from Actelion. D. Pittrow has
received fees for consultations from Actelion, Amgen, Aspen, Bayer, Biogen, Boehringer Ingelheim, Daiichi Sankyo,
Sanofi, Takeda and Viatris. K.M. Olsson has received fees for lectures and/or consultations from Acceleron,
Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer and United Therapeutics. C.D. Vizza has received fees for
lectures and/or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer and United
Therapeutics. H. Gall reports personal fees from Actelion, AstraZeneca, Bayer, BMS, GlaxoSmithKline,
Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer and United Therapeutics. O. Distler has/had consultancy
relationship and/or has received research funding from 4D Science, Actelion, Active Biotec, Bayer, Biogen Idec,
Boehringer Ingelheim Pharma, BMS, ChemoAb, EpiPharm, Ergonex, EspeRare Foundation, GlaxoSmithKline,
Genentech/Roche, Inventiva, Janssen, Lilly, medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi,
Serodapharm and Sinoxa, in the area of potential treatments of scleroderma and its complications including PAH;
in addition, the author has a patent “mir-29 for the treatment of systemic sclerosis”licensed. C. Opitz has received
speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Lilly, Novartis and Pfizer.
J.S.R. Gibbs has received fees for lectures and/or consultations from Acceleron, Actelion, Aerovate, Bayer, Complexia,
Janssen, MSD, Pfizer and United Therapeutics. M. Delcroix reports research grants from Actelion/J&J, speaker and
consultant fees from Bayer, MSD, Acceleron, AOP and Daiichi Sankyo, outside the submitted work; and is holder of
the Janssen Chair for Pulmonary Hypertension at the KU Leuven. H.A. Ghofrani has received honoraria for
consultations and/or speaking at conferences from Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Lilly
and Novartis; is member of advisory boards for Acceleron, Bayer HealthCare AG, Pfizer, GlaxoSmithKline, Actelion,
Lilly, Merck, Encysive and Ergonex; and has also received governmental grants from the German Research
Foundation (DFG), Excellence Cluster Cardiopulmonary Research (ECCPS), State Government of Hessen (LOEWE)
and the German Ministry for Education and Research (BMBF). S. Rosenkranz has received fees for lectures and/or
consultations from Abbott, Acceleron, Actelion, Bayer, BMS, Gilead, GlaxoSmithKline, Janssen, MSD, Novartis,
Pfizer, United Therapeutics and Vifor; research grants to institution from AstraZeneca, Actelion, Bayer Janssen and
Novartis. D-H. Park has nothing to disclose. R. Ewert has received speaker fees and honoraria for consultations
from Actelion, Bayer, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer and United Therapeutics. H. Kaemmerer
has received honoraria for lectures and/or consultancy from Actelion, BMS and Janssen. T.J. Lange has received
speaker fees and honoraria for consultation from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen-Cilag, MSD,
Pfizer and United Therapeutics. H-J. Kabitz has received fees from Löwenstein Medical, Weinmann, Philips
Respironics, ResMed, Vivisol, Sapio Life and Sanofi-Genzyme. D. Skowasch received fees for lectures and/or
consulting and/or research support to institution from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer.
A. Skride reports no conflicts of interest. M. Claussen reports honoraria for lectures from Boehringer Ingelheim
Pharma GmbH and Roche Pharma, and for serving on advisory boards from Boehringer Ingelheim. J. Behr
received grants from Actelion, Bayer, Biogen, Boehringer Ingelheim, Galapagos, Novartis, Roche and Sanofi/
Genzyme. K. Milger has received fees from Actelion, AstraZeneca, GlaxoSmithKline, Janssen, MSD, Novartis and
Sanofi-Aventis. M. Halank has received speaker fees and honoraria for consultations from Acceleron, Actelion,
AstraZeneca, Bayer, BerlinChemie, GlaxoSmithKline, Janssen and Novartis. H. Wilkens received personal fees from
Actelion, Bayer, Biotest, Boehringer, GlaxoSmithKline, Janssen, Pfizer and Roche. H-J. Seyfarth has received
speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen and MSD. M. Held has
received speaker fees and honoraria for consultations from Actelion, Bayer, Boehringer Ingelheim Pharma,
GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Nycomed, Roche and Servier. D. Dumitrescu declares honoraria
for lectures and/or consultancy from Actelion, AstraZeneca, Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer
and Servier. I. Tsangaris has received fees from Actelion, Bayer, ELPEN, GlaxoSmithKline, Janssen, MSD, Pfizer and
United Therapeutics. A. Vonk-Noordegraaf reports receiving fees for lectures and/or consultations from Actelion,
Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. S. Ulrich reports personal fees from Actelion, Janssen and MSD
outside the submitted work. H. Klose has received speaker fees and honoraria for consultations from Actelion,
Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer and United Therapeutics.
https://doi.org/10.1183/13993003.02024-2021 11
EUROPEAN RESPIRATORY JOURNAL ORIGINAL RESEARCH ARTICLE | M.M. HOEPER ET AL.
Support statement: This work was supported by the German Center for Lung Research (DZL). COMPERA is funded
by unrestricted grants from Acceleron, Bayer, GlaxoSmithKline, Janssen and OMT. These companies were not
involved in data analysis or the writing of the manuscript.
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