TY - JOUR
T1 - Association of N-Terminal Pro Brain Natriuretic Peptide and Long-Term Outcome in Patients with Pulmonary Arterial Hypertension
T2 - Insights from the Phase III GRIPHON Study
AU - Chin, Kelly M.
AU - Rubin, Lewis J.
AU - Channick, Richard
AU - Di Scala, Lilla
AU - Gaine, Sean
AU - Galiè, Nazzareno
AU - Ghofrani, Hossein Ardeschir
AU - Hoeper, Marius M.
AU - Lang, Irene M.
AU - McLaughlin, Vallerie V.
AU - Preiss, Ralph
AU - Simonneau, Gérald
AU - Sitbon, Olivier
AU - Tapson, Victor F.
N1 - Funding Information:
Dr Chin has served as a steering committee member for Actelion Pharmaceuticals Ltd; has received research grants from Actelion Pharmaceuticals Ltd, National Institutes of Health, Ironwood Pharmaceuticals, National Institutes of Health and SoniVie; has served on an advisory board for Bayer Healthcare (through UCSD) and Flowonix; has served as an adjudication committee member for Arena Pharmaceuticals; is Circulation Associate Editor for American Heart Association; and has received consultancy fees from Actelion Pharmaceuticals Ltd. Dr Rubin has served as a steering committee member for Ac-telion Pharmaceuticals Ltd; and has received consultancy fees from Actelion Pharmaceuticals Ltd, Arena Pharmaceuticals, GeNO Pharmaceuticals, Gilead, Karos Pharmaceuticals, Pfizer, and SoniVie Ltd. Dr Channick has served as a steering committee member for Actelion Pharmaceuticals Ltd; has served on an advisory board for Actelion Pharmaceuticals Ltd and Bayer; has received consultancy fees from Bayer and Arena Pharmaceuticals; and has received research grants from Actelion Pharmaceuticals Ltd and United Therapeutics. Dr Di Scala is an employee of Actelion Pharmaceuticals Ltd and in the past held stock/stock options for Actelion Pharmaceuticals Ltd and currently holds stock/ stock options in the parent company Johnson&Johnson. Dr Gaine has served as a steering committee member for Actelion Pharmaceuticals Ltd; has received speaker fees from Actelion Pharmaceuticals Ltd; has received advisory board fees from Actelion Pharmaceuticals Ltd, and Daiichi-Sankyo; and has served on a data and safety monitoring board for United Therapeutics. Dr Galiè is a steering committee member for Actelion Pharmaceuticals Ltd; has received grant support, personal fees, and nonfinancial support from Actelion Pharmaceuticals Ltd; and has received grant support and personal fees from Bayer Healthcare, Pfizer, and GlaxoSmithKline. Dr Ghofrani has served as a steering committee member for Actelion Pharmaceuticals Ltd; has received advisory board and speaker fees from Actelion Pharmaceuticals Ltd, Bayer, GlaxoSmith-Kline, Novartis, and Pfizer; has received consultancy fees from Actelion Pharmaceuticals Ltd, Bayer, Bellerophon Pulse Technologies, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Pfizer; and has received research grants from Actelion Pharmaceuticals Ltd and Deutsche Forschungsgemeinschaft. Dr Ho-eper has served as a steering committee member for Actelion Pharmaceuticals Ltd; has received speaker and consultancy fees from Actelion Pharmaceuticals Ltd, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer; and has received research grants from Actelion Pharmaceuticals Ltd. Dr Lang has served as a steering committee member for Actelion Pharmaceuticals Ltd; has received speaker fees from Actelion Pharmaceuticals Ltd, Merck Sharp & Dohme, and AOP Orphan Pharmaceuticals; and has received research grants from Actelion Pharmaceuticals Ltd and AOP Orphan Pharmaceuticals. Dr McLaughlin reports grants, personal fees and nonfinancial support from Actelion Pharmaceuticals Ltd and Bayer; grants from Eiger and SoniVie; and personal fees from United Therapeutics, Arena, Caremark, Medtronic, and Merck Sharp & Dohme. Dr Pre-iss is an employee of Actelion Pharmaceuticals Ltd and in the past held stock/ stock options for Actelion Pharmaceuticals Ltd and currently holds stock/stock options in the parent company Johnson&Johnson. Dr Simonneau has served as a steering committee member for and received research grants from Acte-lion Pharmaceuticals Ltd and Bayer; and has received speaker and consultancy fees from Actelion Pharmaceuticals Ltd, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer. Dr Sitbon has served as a steering committee member for Actelion Pharmaceuticals Ltd; has served as an advisory board member for and received research grants from Actelion Pharmaceuticals Ltd, Bayer, Glaxo-SmithKline, and Merck Sharp & Dohme; has received consultancy fees from Actelion Pharmaceuticals Ltd, Arena, Bayer, GlaxoSmithKline, and Merck Sharp & Dohme; has received speaker fees from Actelion Pharmaceuticals Ltd, Bayer, GlaxoSmithKline, and Merck Sharp & Dohme; has served on a scientific advisory board for Arena Pharmaceuticals and Gossamer Bio; and has received writing assistance from Actelion Pharmaceuticals Ltd and GlaxoSmithKline. Dr Tapson has served as a steering committee member for Actelion Pharmaceuticals Ltd, Bayer, and United Therapeutics; has received consultancy fees from Actelion Pharmaceuticals Ltd, Arena Pharmaceuticals, Bayer, Daiichi-Sankyo, EKOS/BTG, Gilead Sciences, Janssen, Reata, and United Therapeutics; has received research grants from Arena Pharmaceuticals, Arena, Bayer, EKOS/BTG, and Riata; has received speaker fees from Bayer, Gilead Sciences, and Janssen.
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/5/21
Y1 - 2019/5/21
N2 - Background: NT-proBNP (N-terminal pro brain natriuretic peptide) levels are included in the multiparametric risk assessment approach for pulmonary arterial hypertension (PAH) outlined in PAH guidelines. However, data supporting the use of NT-proBNP risk thresholds in assessing prognosis in PAH are limited. The GRIPHON trial (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial Hypertension) provides an opportunity to assess the prognostic value of NT-proBNP thresholds in a controlled clinical trial and to evaluate the response to selexipag according to these thresholds. Methods: The event-driven GRIPHON trial randomly assigned patients to selexipag or placebo. NT-proBNP was measured at regular intervals in GRIPHON. Here, patients were categorized post hoc into low, medium, and high NT-proBNP subgroups according to 2 independent sets of thresholds: (1) baseline tertiles: <271 ng/L; 271 to 1165 ng/L; >1165 ng/L; and (2) 2015 European Society of Cardiology/European Respiratory Society guidelines cutoffs: <300 ng/L; 300 to 1400 ng/L; >1400 ng/L. Hazard ratios (selexipag versus placebo) with 95% CIs were calculated for the primary end point (composite morbidity/mortality events) by NT-proBNP category at baseline using Cox proportional-hazards models, and at any time during the exposure period using a time-dependent Cox model. Results: With both thresholds, baseline and follow-up NT-proBNP categories were highly prognostic for future morbidity/mortality events during the study (P<0.0001). In the time-dependent analysis, the risk of experiencing a morbidity/mortality event was 92% and 83% lower in selexipag-treated patients with a low and medium NT-proBNP level, and 90% and 56% lower in placebo-treated patients with a low and medium NT-proBNP level, in comparison with patients with a high NT-proBNP level. Selexipag reduced the risk of morbidity/mortality events across all 3 NT-proBNP categories in both the baseline and time-dependent analyses, with a more pronounced treatment benefit of selexipag seen in the medium and low NT-proBNP subgroups (interaction P values 0.20 and 0.007 in the baseline and time-dependent analyses). Conclusions: These analyses further establish the prognostic relevance of NT-proBNP levels in PAH and provide first evidence for the association of NT-proBNP level and treatment response. Using 2 similar sets of thresholds, these analyses support the relevance of the low, medium, and high NT-proBNP categories as part of the multiparametric risk assessment approach outlined in the European Society of Cardiology/European Respiratory Society guidelines for the management of PAH patients.
AB - Background: NT-proBNP (N-terminal pro brain natriuretic peptide) levels are included in the multiparametric risk assessment approach for pulmonary arterial hypertension (PAH) outlined in PAH guidelines. However, data supporting the use of NT-proBNP risk thresholds in assessing prognosis in PAH are limited. The GRIPHON trial (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial Hypertension) provides an opportunity to assess the prognostic value of NT-proBNP thresholds in a controlled clinical trial and to evaluate the response to selexipag according to these thresholds. Methods: The event-driven GRIPHON trial randomly assigned patients to selexipag or placebo. NT-proBNP was measured at regular intervals in GRIPHON. Here, patients were categorized post hoc into low, medium, and high NT-proBNP subgroups according to 2 independent sets of thresholds: (1) baseline tertiles: <271 ng/L; 271 to 1165 ng/L; >1165 ng/L; and (2) 2015 European Society of Cardiology/European Respiratory Society guidelines cutoffs: <300 ng/L; 300 to 1400 ng/L; >1400 ng/L. Hazard ratios (selexipag versus placebo) with 95% CIs were calculated for the primary end point (composite morbidity/mortality events) by NT-proBNP category at baseline using Cox proportional-hazards models, and at any time during the exposure period using a time-dependent Cox model. Results: With both thresholds, baseline and follow-up NT-proBNP categories were highly prognostic for future morbidity/mortality events during the study (P<0.0001). In the time-dependent analysis, the risk of experiencing a morbidity/mortality event was 92% and 83% lower in selexipag-treated patients with a low and medium NT-proBNP level, and 90% and 56% lower in placebo-treated patients with a low and medium NT-proBNP level, in comparison with patients with a high NT-proBNP level. Selexipag reduced the risk of morbidity/mortality events across all 3 NT-proBNP categories in both the baseline and time-dependent analyses, with a more pronounced treatment benefit of selexipag seen in the medium and low NT-proBNP subgroups (interaction P values 0.20 and 0.007 in the baseline and time-dependent analyses). Conclusions: These analyses further establish the prognostic relevance of NT-proBNP levels in PAH and provide first evidence for the association of NT-proBNP level and treatment response. Using 2 similar sets of thresholds, these analyses support the relevance of the low, medium, and high NT-proBNP categories as part of the multiparametric risk assessment approach outlined in the European Society of Cardiology/European Respiratory Society guidelines for the management of PAH patients.
KW - brain natriuretic peptide
KW - hypertension, pulmonary
KW - prostacyclin receptor
KW - risk assessment
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UR - http://www.scopus.com/inward/citedby.url?scp=85066456441&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.118.039360
DO - 10.1161/CIRCULATIONAHA.118.039360
M3 - Article
C2 - 30982349
AN - SCOPUS:85066456441
VL - 139
SP - 2440
EP - 2450
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 21
ER -