Abstract
Background: Early initiation of pulmonary arterial hypertension (PAH) therapies is associated with improved long-term outcomes, yet data on the early use of prostacyclin pathway agents are limited. In these post hoc analyses of the Prostacyclin (PGI2) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON) study, the largest randomized controlled trial for PAH to date, the prognostic value of time from diagnosis and its impact on treatment response were examined. Research Question: How does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH? Study Design and Methods: The GRIPHON study randomly assigned 1,156 patients with PAH to selexipag or placebo treatment. Patients were categorized post hoc into a time from diagnosis of ≤ 6 months and > 6 months at randomization. Hazard ratios (selexipag vs placebo) were calculated for the primary end point of morbidity/mortality by time from diagnosis using Cox proportional hazard models. Results: Time from diagnosis was ≤ 6 months in 34.9% and > 6 months in 65.1% of patients. Time from diagnosis was prognostic of morbidity/mortality, with newly diagnosed patients having a poorer long-term outcome than patients diagnosed for longer. Compared with placebo, selexipag reduced the risk of morbidity/mortality in patients with a time from diagnosis of ≤ 6 months and > 6 months, with a more pronounced effect in newly diagnosed patients (hazard ratio, 0.45 [95% CI, 0.33-0.63] and 0.74 [95% CI, 0.57-0.96], respectively; P = .0219 for interaction). Interpretation: In the GRIPHON study, newly diagnosed PAH patients had a worse prognosis than patients with a longer time from diagnosis. The benefit of selexipag treatment on disease progression was more pronounced in patients treated earlier than in patients treated later. Trial Registry: ClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov
| Original language | English (US) |
|---|---|
| Pages (from-to) | 277-286 |
| Number of pages | 10 |
| Journal | CHEST |
| Volume | 160 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 2021 |
Keywords
- pulmonary arterial hypertension
- selexipag
- time from diagnosis
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine
- Cardiology and Cardiovascular Medicine
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In: CHEST, Vol. 160, No. 1, 07.2021, p. 277-286.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Relationship Between Time From Diagnosis and Morbidity/Mortality in Pulmonary Arterial Hypertension
T2 - Results From the Phase III GRIPHON Study
AU - Gaine, Sean
AU - Sitbon, Olivier
AU - Channick, Richard N.
AU - Chin, Kelly M.
AU - Sauter, Rafael
AU - Galiè, Nazzareno
AU - Hoeper, Marius M.
AU - McLaughlin, Vallerie V.
AU - Preiss, Ralph
AU - Rubin, Lewis J.
AU - Simonneau, Gérald
AU - Tapson, Victor
AU - Ghofrani, Hossein Ardeschir
AU - Lang, Irene
N1 - Funding Information: Other contributions: The authors thank the patients and the investigators for their contribution to the study. Medical writing support was provided by Carly Taylor of nspm, Ltd. (Meggen, Switzerland), and Iain Haslam of eluSCIdate, Ltd. (Meggen, Switzerland), and was funded by Actelion Pharmaceuticals, Ltd., Switzerland a Janssen Pharmaceutical Company of Johnson & Johnson . Funding Information: Financial/nonfinancial disclosures: The authors have reported to CHEST the following: S. G. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson, has received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, has received advisory board fees from Janssen Pharmaceutical Companies of Johnson & Johnson and Daiichi-Sankyo, and has served on a data and safety monitoring board for United Therapeutics. O. S. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has served as an advisory board member for and received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, and Merck Sharp & Dohme; has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Arena, Bayer, GlaxoSmithKline, and Merck Sharp & Dohme; has received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, 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 Janssen Pharmaceutical Companies of Johnson & Johnson and GlaxoSmithKline. R. N. C. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson, has served on an advisory board for Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer, has received consultancy fees from Bayer and Arena Pharmaceuticals, and has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson and United Therapeutics. K. M. C. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson, the National Institutes of Health, Ironwood Pharmaceuticals, and SoniVie Ltd.; 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 the American Heart Association; and has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson. R. S. is an employee of Actelion Pharmaceuticals, Ltd. N. G. is a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received grant support, personal fees, and non-financial support from Janssen Pharmaceutical Companies of Johnson & Johnson; and has received grant support and personal fees from Bayer Healthcare, Pfizer, and GlaxoSmithKline. M. M. H. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received speaker and consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer; and has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson. V. V. M. reports grants, personal fees, and nonfinancial support from Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer; grants from Eiger and SoniVie Ltd.; and personal fees from United Therapeutics, Arena, Caremark, Medtronic, and Merck Sharp & Dohme. R. P. is an employee of Actelion Pharmaceuticals, Ltd., in the past held stock/stock options for Actelion Pharmaceuticals, Ltd., and currently holds stock/stock options in the parent company Johnson & Johnson. L. J. R. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson and has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Arena Pharmaceuticals, GENO Pharmaceuticals, Gilead, Karos Pharmaceuticals, Pfizer, and SoniVie, Ltd. G. S. has served as a steering committee member for and received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer and has received speaker and consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer. V. T. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, and United Therapeutics; has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, 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; and has received speaker fees from Bayer, Gilead Sciences, and Janssen. H.-A. G. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received advisory board and speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Novartis, and Pfizer; has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, Bellerophon Pulse Technologies, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Pfizer; and has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson and Deutsche Forschungsgemeinschaft. I. L. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Merck Sharp & Dohme, and AOP Orphan Pharmaceuticals; and has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson and AOP Orphan Pharmaceuticals. Funding Information: FUNDING/SUPPORT: This study was funded by Actelion Pharmaceuticals , Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson. Funding Information: FUNDING/SUPPORT: This study was funded by Actelion Pharmaceuticals, Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson.Author contributions: S. G. is the guarantor of the manuscript and takes responsibility for the content of the manuscript, including the data and analysis. S. G. O. S. R. N. C. K. M. C. N. G. M. M. H. V. V. M. L. J. R. G. S. V. T. H.-A. G. and I. L. (members of the study steering committee) contributed to the conception and design of the study in collaboration with the funders and were involved in the collection and interpretation of the data. R. S. was involved in the statistical analyses. S. G. R. S. and R. P. were involved in development of the first draft of the manuscript, with medical writing assistance funded by the sponsor and provided by eluSCIdate Ltd. All authors had access to the data, reviewed and edited the manuscript, approved the final draft, and were involved in the decision to submit the manuscript for publication. All authors vouch for the accuracy and completeness of the analyses and for the fidelity of this report to the study protocol. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: S. G. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson, has received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, has received advisory board fees from Janssen Pharmaceutical Companies of Johnson & Johnson and Daiichi-Sankyo, and has served on a data and safety monitoring board for United Therapeutics. O. S. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has served as an advisory board member for and received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, and Merck Sharp & Dohme; has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Arena, Bayer, GlaxoSmithKline, and Merck Sharp & Dohme; has received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, 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 Janssen Pharmaceutical Companies of Johnson & Johnson and GlaxoSmithKline. R. N. C. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson, has served on an advisory board for Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer, has received consultancy fees from Bayer and Arena Pharmaceuticals, and has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson and United Therapeutics. K. M. C. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson, the National Institutes of Health, Ironwood Pharmaceuticals, and SoniVie Ltd.; 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 the American Heart Association; and has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson. R. S. is an employee of Actelion Pharmaceuticals, Ltd. N. G. is a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received grant support, personal fees, and non-financial support from Janssen Pharmaceutical Companies of Johnson & Johnson; and has received grant support and personal fees from Bayer Healthcare, Pfizer, and GlaxoSmithKline. M. M. H. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received speaker and consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer; and has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson. V. V. M. reports grants, personal fees, and nonfinancial support from Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer; grants from Eiger and SoniVie Ltd.; and personal fees from United Therapeutics, Arena, Caremark, Medtronic, and Merck Sharp & Dohme. R. P. is an employee of Actelion Pharmaceuticals, Ltd. in the past held stock/stock options for Actelion Pharmaceuticals, Ltd. and currently holds stock/stock options in the parent company Johnson & Johnson. L. J. R. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson and has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Arena Pharmaceuticals, GENO Pharmaceuticals, Gilead, Karos Pharmaceuticals, Pfizer, and SoniVie, Ltd. G. S. has served as a steering committee member for and received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer and has received speaker and consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer. V. T. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, and United Therapeutics; has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, 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; and has received speaker fees from Bayer, Gilead Sciences, and Janssen. H.-A. G. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received advisory board and speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Novartis, and Pfizer; has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, Bellerophon Pulse Technologies, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Pfizer; and has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson and Deutsche Forschungsgemeinschaft. I. L. has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Merck Sharp & Dohme, and AOP Orphan Pharmaceuticals; and has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson and AOP Orphan Pharmaceuticals. Role of sponsors: Actelion Pharmaceuticals Ltd. a Janssen Pharmaceutical Company of Johnson & Johnson, funded the study and participated in the design of the study, data analysis, interpretation, and preparation of the manuscript. Other contributions: The authors thank the patients and the investigators for their contribution to the study. Medical writing support was provided by Carly Taylor of nspm, Ltd. (Meggen, Switzerland), and Iain Haslam of eluSCIdate, Ltd. (Meggen, Switzerland), and was funded by Actelion Pharmaceuticals, Ltd. Switzerland a Janssen Pharmaceutical Company of Johnson & Johnson. Additional information: The e-Tables and e-Appendixes can be found in the Supplemental Materials section of the online article. Publisher Copyright: © 2021 The Authors
PY - 2021/7
Y1 - 2021/7
N2 - Background: Early initiation of pulmonary arterial hypertension (PAH) therapies is associated with improved long-term outcomes, yet data on the early use of prostacyclin pathway agents are limited. In these post hoc analyses of the Prostacyclin (PGI2) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON) study, the largest randomized controlled trial for PAH to date, the prognostic value of time from diagnosis and its impact on treatment response were examined. Research Question: How does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH? Study Design and Methods: The GRIPHON study randomly assigned 1,156 patients with PAH to selexipag or placebo treatment. Patients were categorized post hoc into a time from diagnosis of ≤ 6 months and > 6 months at randomization. Hazard ratios (selexipag vs placebo) were calculated for the primary end point of morbidity/mortality by time from diagnosis using Cox proportional hazard models. Results: Time from diagnosis was ≤ 6 months in 34.9% and > 6 months in 65.1% of patients. Time from diagnosis was prognostic of morbidity/mortality, with newly diagnosed patients having a poorer long-term outcome than patients diagnosed for longer. Compared with placebo, selexipag reduced the risk of morbidity/mortality in patients with a time from diagnosis of ≤ 6 months and > 6 months, with a more pronounced effect in newly diagnosed patients (hazard ratio, 0.45 [95% CI, 0.33-0.63] and 0.74 [95% CI, 0.57-0.96], respectively; P = .0219 for interaction). Interpretation: In the GRIPHON study, newly diagnosed PAH patients had a worse prognosis than patients with a longer time from diagnosis. The benefit of selexipag treatment on disease progression was more pronounced in patients treated earlier than in patients treated later. Trial Registry: ClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov
AB - Background: Early initiation of pulmonary arterial hypertension (PAH) therapies is associated with improved long-term outcomes, yet data on the early use of prostacyclin pathway agents are limited. In these post hoc analyses of the Prostacyclin (PGI2) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON) study, the largest randomized controlled trial for PAH to date, the prognostic value of time from diagnosis and its impact on treatment response were examined. Research Question: How does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH? Study Design and Methods: The GRIPHON study randomly assigned 1,156 patients with PAH to selexipag or placebo treatment. Patients were categorized post hoc into a time from diagnosis of ≤ 6 months and > 6 months at randomization. Hazard ratios (selexipag vs placebo) were calculated for the primary end point of morbidity/mortality by time from diagnosis using Cox proportional hazard models. Results: Time from diagnosis was ≤ 6 months in 34.9% and > 6 months in 65.1% of patients. Time from diagnosis was prognostic of morbidity/mortality, with newly diagnosed patients having a poorer long-term outcome than patients diagnosed for longer. Compared with placebo, selexipag reduced the risk of morbidity/mortality in patients with a time from diagnosis of ≤ 6 months and > 6 months, with a more pronounced effect in newly diagnosed patients (hazard ratio, 0.45 [95% CI, 0.33-0.63] and 0.74 [95% CI, 0.57-0.96], respectively; P = .0219 for interaction). Interpretation: In the GRIPHON study, newly diagnosed PAH patients had a worse prognosis than patients with a longer time from diagnosis. The benefit of selexipag treatment on disease progression was more pronounced in patients treated earlier than in patients treated later. Trial Registry: ClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov
KW - pulmonary arterial hypertension
KW - selexipag
KW - time from diagnosis
UR - http://www.scopus.com/inward/record.url?scp=85108231592&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108231592&partnerID=8YFLogxK
U2 - 10.1016/j.chest.2021.01.066
DO - 10.1016/j.chest.2021.01.066
M3 - Article
C2 - 33545163
AN - SCOPUS:85108231592
SN - 0012-3692
VL - 160
SP - 277
EP - 286
JO - Diseases of the chest
JF - Diseases of the chest
IS - 1
ER -