COMPERA 2.0: a refined four-stratum risk assessment model for pulmonary arterial hypertension

Marius M Hoeper, Christine Pausch, Karen M Olsson, Doerte Huscher, David Pittrow, Ekkehard Grünig, Gerd Staehler, Carmine Dario Vizza, Henning Gall, Oliver Distler, Christian Opitz, J Simon R Gibbs, Marion Delcroix, H Ardeschir Ghofrani, Da-Hee Park, Ralf Ewert, Harald Kaemmerer, Hans-Joachim Kabitz, Dirk Skowasch, Juergen Behr, Katrin Milger, Michael Halank, Heinrike Wilkens, Hans-Jürgen Seyfarth, Matthias Held, Daniel Dumitrescu, Iraklis Tsangaris, Anton Vonk-Noordegraaf, Silvia Ulrich, Hans Klose, Martin Claussen, Tobias J Lange, Stephan Rosenkranz, Marius M Hoeper, Christine Pausch, Karen M Olsson, Doerte Huscher, David Pittrow, Ekkehard Grünig, Gerd Staehler, Carmine Dario Vizza, Henning Gall, Oliver Distler, Christian Opitz, J Simon R Gibbs, Marion Delcroix, H Ardeschir Ghofrani, Da-Hee Park, Ralf Ewert, Harald Kaemmerer, Hans-Joachim Kabitz, Dirk Skowasch, Juergen Behr, Katrin Milger, Michael Halank, Heinrike Wilkens, Hans-Jürgen Seyfarth, Matthias Held, Daniel Dumitrescu, Iraklis Tsangaris, Anton Vonk-Noordegraaf, Silvia Ulrich, Hans Klose, Martin Claussen, Tobias J Lange, Stephan Rosenkranz

Abstract

Background: Risk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk.

Methods: We analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan-Meier analyses, log-rank testing and Cox proportional hazards models.

Results: Data from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk.

Conclusions: Modified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

Conflict of interest statement

Conflict of interest: M.M. Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD and Pfizer. Conflict of interest: C. Pausch has nothing to disclose. Conflict of interest: K.M. Olsson has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: D. Huscher has received travel compensation from Shire. Conflict of interest: D. Pittrow has received fees for consultations from Actelion, Amgen, Aspen, Bayer, Biogen, Boehringer Ingelheim, Daiichi Sankyo, MSD, Novartis, Sanofi-Genzyme, Takeda and Viatris. Conflict of interest: E. Grünig has received fees for lectures and/or consultations from Actelion, Bayer, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: G. Staehler has received honoraria for lectures and/or consultancy for Actelion, Bayer, GSK, Novartis and Pfizer. Conflict of interest: C.D. Vizza has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: H. Gall reports personal fees from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer and United Therapeutics. Conflict of interest: O. Distler has/had consultancy relationship and/or has received research funding from 4 D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, BMS, ChemoAb, EpiPharm, Ergonex, espeRare foundation, GSK, 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; and has a patent mir-29 for the treatment of systemic sclerosis licensed. Conflict of interest: C. Opitz has nothing to disclose. Conflict of interest: J.S.R. Gibbs has received fees for lectures and/or consultations from Acceleron, Actelion, Aerovate, Bayer, Complexia, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: 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. Conflict of interest: 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, GSK, Actelion, Lilly, Merck, Encysive and Ergonex; has 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). Conflict of interest: D-H. Park has nothing to disclose. Conflict of interest: R. Ewert has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Janssen, Lilly, MSD, Novartis, Pfizer and United Therapeutics. Conflict of interest: H. Kaemmerer has received honoraria for lectures and/or consultancy from Actelion, Bristol Myers Squibb and Janssen. Conflict of interest: H-J. Kabitz has received fees from Löwenstein Medical, Weinmann, Philips Respironics, ResMed, Vivisol, Sapio Life and Sanofi-Genzyme. Conflict of interest: D. Skowasch received fees for lectures and/or consulting and/or research support (paid to institution) from Actelion, Bayer, GSK, Janssen, MSD and Pfizer. Conflict of interest: J. Behr received grants from Actelion, Bayer, Biogen, Boehringer Ingelheim, Galapagos, Novartis, Roche and Sanofi/Genzyme. Conflict of interest: K. Milger has received fees from Actelion, AstraZeneca, GSK, Janssen, MSD, Novartis and Sanofi-Aventis. Conflict of interest: M. Halank has received speaker fees and honoraria for consultations from Acceleron, Actelion, AstraZeneca, Bayer, BerlinChemie, GSK, Janssen and Novartis. Conflict of interest: H. Wilkens received fees for lectures and/or consultations from Actelion, Bayer, Biotest, Boehringer, GSK, Janssen, Pfizer and Roche. Conflict of interest: H-J. Seyfarth has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Janssen and MSD. Conflict of interest: 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. Conflict of interest: D. Dumitrescu declares honoraria for lectures and/or consultancy from Actelion, AstraZeneca, Bayer, GSK, Janssen, MSD, Novartis, Pfizer, Servier and Vifor. Conflict of interest: I. Tsangaris has received fees from Actelion, Bayer, ELPEN, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: A. Vonk-Noordegraaf reports receiving fees for lectures and/or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. Conflict of interest: S. Ulrich reports personal fees from Actelion, Janssen and MSD outside the submitted work. Conflict of interest: H. Klose has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Janssen, MSD, Novartis, Pfizer and United Therapeutics. Conflict 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. Conflict of interest: T.J. Lange has received speaker fees and honoraria for consultation from Acceleron, Actelion, Bayer, GSK, Janssen-Cilag, MSD, Pfizer and United Therapeutics. Conflict of interest: S. Rosenkranz has received fees for lectures and/or consultations from Abbott, Acceleron, Actelion, Bayer, BMS, Gilead, GSK, Janssen, MSD, Novartis, Pfizer, United Therapeutics and Vifor; research grants to institution from AstraZeneca, Actelion, Bayer Janssen and Novartis.

Copyright ©The authors 2022.

Figures

FIGURE 1
FIGURE 1
Strengthening the Reporting of Observational Studies in Epidemiology diagram showing patient eligibility for analysis. #: more than one reason for exclusion could apply. COMPERA: Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension; PAH: pulmonary arterial hypertension; WHO FC: World Health Organization functional class; 6MWD: 6-min walk distance; BNP: brain natriuretic peptide; NT-proBNP: N-terminal pro-BNP; mPAP: mean pulmonary arterial pressure; PVR: pulmonary vascular resistance; PAWP: pulmonary arterial wedge pressure.
FIGURE 2
FIGURE 2
Kaplan–Meier survival curves based on the four risk strata obtained a) at baseline, b) at first follow-up.
FIGURE 3
FIGURE 3
Change in risk from baseline to first follow-up. Risk at baseline and at first follow-up and changes in risk are shown for a) the three-stratum model and b) the four-stratum model.
FIGURE 4
FIGURE 4
Mortality risk of patients who changed their risk category from baseline to follow-up with the three-stratum model. Mortality risk of patients who changed from baseline to follow-up with the three-stratum model a) from intermediate risk to other risk categories and b) from high risk to intermediate risk. Data for patients coming from low risk at baseline and those from patients coming from high risk and improving to low risk are not shown due to small numbers. All comparisons were made against patients who remained in their original risk category. Analyses were done with Cox proportional hazard models and depicted as hazard ratio (HR) and 95% confidence intervals.
FIGURE 5
FIGURE 5
Mortality risk of patients who changed their risk category from baseline to follow-up with the four-stratum model. Survival of patients who changed from baseline to follow-up with the four-stratum model a) from intermediate-low risk to other risk categories, b) from intermediate-high risk to other risk categories, c) from high risk to other risk categories and d) from intermediate-high or high risk combined to intermediate-low or low risk. Data for patients coming from low risk at baseline and those from patients coming from high risk and improving to low risk are not shown due to small numbers. All comparisons were made against patients who remained in their original risk category. Analyses were done with Cox proportional hazard models and depicted as hazard ratio (HR) and 95% confidence intervals.

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