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. 2022 Jun 30;59(6):2102419.
doi: 10.1183/13993003.02419-2021. Print 2022 Jun.

External validation of a refined four-stratum risk assessment score from the French pulmonary hypertension registry

Athénaïs Boucly  1   2   3   4 , Jason Weatherald  5   4 , Laurent Savale  1   2   3 , Pascal de Groote  6 , Vincent Cottin  7 , Grégoire Prévot  8 , Ari Chaouat  9 , François Picard  10 , Delphine Horeau-Langlard  11 , Arnaud Bourdin  12 , Etienne-Marie Jutant  1   2   3   13 , Antoine Beurnier  1   2   3 , Mitja Jevnikar  1   2   3 , Xavier Jaïs  1   2   3 , Gérald Simonneau  1   2   3 , David Montani  1   2   3 , Olivier Sitbon  1   2   3   4 , Marc Humbert  14   2   3   4
Affiliations

External validation of a refined four-stratum risk assessment score from the French pulmonary hypertension registry

Athénaïs Boucly et al. Eur Respir J. .

Abstract

Introduction: Contemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators.

Methods: We evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan-Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches.

Results: At baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk.

Conclusions: The four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach.

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Conflict of interest statement

Conflict of interest: A. Boucly reports personal fees from Actelion, Bayer and Merck, outside the submitted work. Conflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc., grants, personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees from Novartis, outside the submitted work. Conflict of interest: L. Savale reports personal fees from Actelion, personal fees from MSD, grants and personal fees from GSK, outside the submitted work. Conflict of interest: P. de Groote reports consulting fees from Actelion, Janssen, MSD, Novartis, Servier, Boehringer Ingelheim, Abbott, Boston, AstraZeneca, Bayer; lecture honoraria from Abbott, Vifor, MSD, Servier, Novartis, AstraZeneca, Actelion, Janssen, Medtronic; outside the submitted work. Conflict of interest: V. Cottin reports advisory board fees and non-financial support from Actelion, advisory board fees from Bayer/MSD, outside the submitted work. Conflict of interest: G. Prévot reports personal fees from Actelion and GSK, outside the submitted work. Conflict of interest: A. Chaouat reports consulting fees from GSK, Actelion and Bayer, outside the submitted work. Conflict of interest: F. Picard has nothing to disclose. Conflict of interest: D. Horeau-Langlard reports grants from Acceleron, outside the submitted work. Conflict of interest: A. Bourdin reports grants from AstraZeneca and Boehringer Ingelheim; consulting fees from AstraZeneca, GSK, Novartis, Boehringer Ingelheim, Chiesi, Sanofi Regeneron, Amgen; lecture honoraria from AstraZeneca, GSK, Novartis, Boehringer Ingelheim, Chiesi, Sanofi Regeneron, Roche; travel support from Boehringer Ingelheim, Chiesi, Sanofi Regeneron, AstraZeneca, GSK, Roche; participation on advisory boards at AB science, AstraZeneca, GSK, Sanofi Regeneron, Novartis, Acceleron; and acted as investigator in clinical trials for Vertex, Abbvie, Galapagos, Fibrogen, Nuvaira, PulmonX, Gossamer, Acceleron; outside the submitted work. Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: M. Jevnikar has nothing to disclose. Conflict of interest: X. Jais reports grants from Bayer, Janssen and Merck; lecture honoraria from Janssen and Merck; outside the submitted work. Conflict of interest: G. Simonneau reports grants and personal fees from Janssen (formerly Actelion), Bayer and MSD; personal fees from Acceleron, outside the submitted work. Conflict of interest: D. Montani reports grants from Acceleron, Janssen and Merck; steering committee fees from Acceleron; lecture honoraria from Bayer, Janssen and Merck; outside the submitted work. Conflict of interest: O. Sitbon reports grants from Acceleron, Janssen, GSK and MSD; steering committee fees from Gossamer Bio, Janssen and MSD; lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD; advisory board participation at Acceleron, Janssen and MSD; outside the submitted work. Conflict of interest: M. Humbert reports grants, steering committee consulting fees, and advisory board participation from Acceleron, Janssen and Merck; lecture honoraria from AOP, Janssen and Merck; steering committee participation at United Therapeutics; outside the submitted work.

Figures

FIGURE 1
FIGURE 1
Study flow diagram. PAH: pulmonary arterial hypertension; PVOD: pulmonary veno-occlusive disease; CHD: congenital heart disease; WHO FC: World Health Organization functional class; 6MWD: 6-min walk distance; BNP: brain natriuretic peptide; NT-proBNP: N-terminal pro-BNP. #: more than one reason for exclusion could apply.
FIGURE 2
FIGURE 2
Survival according to a three-stratum strategy a) at diagnosis and b) after first reassessment. Survival according to the four-stratum risk assessment strategy c) after diagnosis and d) after first reassessment. Log rank test p<0.001 for all models.
FIGURE 3
FIGURE 3
Sankey diagrams showing changes in risk status using the a) three-stratum method and b) four-stratum method. Sankey diagrams are a visualisation technique to display flows. Each panel shows the flow of patients between risk strata (nodes) from baseline to first reassessment. The width of each band is weighted to the proportion of patients who had a given risk trajectory.
FIGURE 4
FIGURE 4
Overall survival according to changes in risk strata between baseline and first reassessment. Log rank test p<0.001.
FIGURE 5
FIGURE 5
Survival according to change in risk strata for patients who were a) low risk at baseline, b) intermediate-low risk at baseline, c) intermediate-high risk at baseline and d) high risk at baseline. Log-rank test p<0.001 for each panel.
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