Relationship Between Time From Diagnosis and Morbidity/Mortality in Pulmonary Arterial Hypertension

Abstract

BackgroundEarly 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 QuestionHow does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH?Study Design and MethodsThe 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.ResultsTime 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).InterpretationIn 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 RegistryClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov 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. How does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH? 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. 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). 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. ClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov FOR EDITORIAL COMMENT, SEE PAGE 25Pulmonary arterial hypertension (PAH) is a progressive disease with no available cure.1Humbert M. Guignabert C. Bonnet S. et al.Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives.Eur Respir J. 2019; 53: 1801887Crossref PubMed Scopus (373) Google Scholar Currently, therapies for PAH target 3 well-characterized pathways implicated in disease pathogenesis: the endothelin, nitric oxide, and prostacyclin pathways.2Galiè N. Humbert M. Vachiery J.L. et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Respir J. 2015; 46: 903-975Crossref PubMed Scopus (1735) Google Scholar Initiation of combination therapy, with an endothelin receptor antagonist and a phosphodiesterase type 5 inhibitor, is recommended by the European Society of Cardiology/European Respiratory Society guidelines2Galiè N. Humbert M. Vachiery J.L. et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Respir J. 2015; 46: 903-975Crossref PubMed Scopus (1735) Google Scholar,3Galiè N. Humbert M. Vachiéry J.L. et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Heart J. 2016; 37: 67-119Crossref PubMed Scopus (3365) Google Scholar and the proceedings from the 6th World Symposium on Pulmonary Hypertension4Galiè N. Channick R.N. Frantz R.P. et al.Risk stratification and medical therapy of pulmonary arterial hypertension.Eur Respir J. 2019; 53: 1801889Crossref PubMed Scopus (307) Google Scholar for patients with a low- or intermediate-risk status at diagnosis. Initial use of IV prostacyclin is recommended for high-risk patients with severe disease.2Galiè N. Humbert M. Vachiery J.L. et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Respir J. 2015; 46: 903-975Crossref PubMed Scopus (1735) Google Scholar, 3Galiè N. Humbert M. Vachiéry J.L. et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Heart J. 2016; 37: 67-119Crossref PubMed Scopus (3365) Google Scholar, 4Galiè N. Channick R.N. Frantz R.P. et al.Risk stratification and medical therapy of pulmonary arterial hypertension.Eur Respir J. 2019; 53: 1801889Crossref PubMed Scopus (307) Google Scholar FOR EDITORIAL COMMENT, SEE PAGE 25 The benefits of prostacyclin pathway agents5Simonneau G. Barst R.J. Galiè N. et al.Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial.Am J Respir Crit Care Med. 2002; 165: 800-804Crossref PubMed Scopus (1190) Google Scholar, 6Olsson K.M. Richter M.J. Kamp J.C. et al.Intravenous treprostinil as an add-on therapy in patients with pulmonary arterial hypertension.J Heart Lung Transplant. 2019; 38: 748-756Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 7Sitbon O. Channick R. Chin K.M. et al.Selexipag for the treatment of pulmonary arterial hypertension.N Engl J Med. 2015; 373: 2522-2533Crossref PubMed Scopus (503) Google Scholar are well documented, yet administration often is delayed, and a significant proportion of patients never receive a drug targeting this pathway.8Del Pozo R. Hernandez Gonzalez I. Escribano-Subías P. The prostacyclin pathway in pulmonary arterial hypertension: a clinical review.Expert Rev Respir Med. 2017; 11: 491-503Crossref PubMed Scopus (34) Google Scholar,9Farber H.W. Miller D.P. Meltzer L.A. et al.Treatment of patients with pulmonary arterial hypertension at the time of death or deterioration to functional class IV: insights from the REVEAL Registry.J Heart Lung Transplant. 2013; 32: 1114-1122Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Key factors delaying the use of prostacyclin and prostacyclin analogs include their adverse event profile, the need for titration to an individualized dose, and for some agents, the complexity of their administration.8Del Pozo R. Hernandez Gonzalez I. Escribano-Subías P. The prostacyclin pathway in pulmonary arterial hypertension: a clinical review.Expert Rev Respir Med. 2017; 11: 491-503Crossref PubMed Scopus (34) Google Scholar In addition, studies examining early treatment with these therapies are limited.6Olsson K.M. Richter M.J. Kamp J.C. et al.Intravenous treprostinil as an add-on therapy in patients with pulmonary arterial hypertension.J Heart Lung Transplant. 2019; 38: 748-756Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar,10Sitbon O. Jaïs X. Savale L. et al.Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study.Eur Respir J. 2014; 43: 1691-1697Crossref PubMed Scopus (234) Google Scholar,11Badagliacca R. Pezzuto B. Poscia R. et al.Prognostic factors in severe pulmonary hypertension patients who need parenteral prostanoid therapy: the impact of late referral.J Heart Lung Transplant. 2012; 31: 364-372Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Selexipag, a selective prostacyclin receptor agonist,7Sitbon O. Channick R. Chin K.M. et al.Selexipag for the treatment of pulmonary arterial hypertension.N Engl J Med. 2015; 373: 2522-2533Crossref PubMed Scopus (503) Google Scholar provides an opportunity for early targeting of the prostacyclin pathway with an orally available medication. Herein, we further evaluated its optimal use as part of the PAH treatment armamentarium. The Prostacyclin (PGI2) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON) study was a long-term, event-driven, randomized, placebo-controlled, phase III trial evaluating selexipag use in 1,156 PAH patients.7Sitbon O. Channick R. Chin K.M. et al.Selexipag for the treatment of pulmonary arterial hypertension.N Engl J Med. 2015; 373: 2522-2533Crossref PubMed Scopus (503) Google Scholar The study demonstrated a statistically significant 40% reduction in the risk of a primary composite outcome of morbidity and mortality (P < .001) with selexipag compared with placebo.7Sitbon O. Channick R. Chin K.M. et al.Selexipag for the treatment of pulmonary arterial hypertension.N Engl J Med. 2015; 373: 2522-2533Crossref PubMed Scopus (503) Google Scholar These post hoc analyses of the GRIPHON study investigated associations of time from PAH diagnosis with morbidity/mortality and with the response to treatment with selexipag. The data sharing policy of the sponsor is available at https://www.janssen.com/clinical-trials/transparency. As noted on this website, requests for access to the study data can be submitted through the Yale Open Data Access Project site at https://yoda.yale.edu. PAH patients with a diagnosis confirmed by right heart catheterization 18 to 75 years of age and with a pulmonary vascular resistance of ≥ 400 dyn·s·cm-5 were eligible for inclusion in the GRIPHON study.7Sitbon O. Channick R. Chin K.M. et al.Selexipag for the treatment of pulmonary arterial hypertension.N Engl J Med. 2015; 373: 2522-2533Crossref PubMed Scopus (503) Google Scholar At screening, patients were required to have a 6-min walk distance of 50 to 450 m and to be treatment naïve or receiving a phosphodiesterase type 5 inhibitor, endothelin receptor antagonist, or both at stable doses for at least 3 months before randomization. Patients receiving a prostacyclin analog were not eligible. All patients provided written informed consent before participation. The GRIPHON study (ClinicalTrials.gov Identifier: NCT01106014) was a global, double-blind, randomized, placebo-controlled, event-driven phase III study assessing the safety and efficacy of selexipag in patients with PAH. Patients were randomized 1:1 to receive selexipag or placebo twice daily. The study drug was titrated over a 12-week period, with patients reaching their individualized maintenance dose ranging between 200 and 1600 μg twice daily. Patients continued to receive double-blind treatment until a primary end point event was experienced, until of the study or until the end of the reaching the of primary end point events = the end of the study was The trial to the in the of with from or The primary composite end point in the GRIPHON study was the time from to the morbidity or mortality event to the end of the double-blind treatment events were as disease progression or of PAH in initiation of parenteral prostanoid therapy or long-term therapy, or the need for or progression was as a ≥ in 6-min walk distance from was confirmed by a on a with a in World functional class for patients in at or the need for PAH therapy patients in at All end point events were by a All randomized patients in the GRIPHON study were categorized post hoc to their time from PAH diagnosis to of study using a was on the in time from diagnosis was to vs PAH M. O. et in and of patients with pulmonary arterial hypertension.Eur Respir J. PubMed Scopus Google Scholar, G. Channick R.N. M. et and with pulmonary arterial hypertension: from Respir J. 2015; 46: PubMed Scopus Google Scholar, P. I. M. et in pulmonary hypertension in insights from the Respir J. 2012; PubMed Scopus Google Scholar, P. J. et and long-term of pulmonary arterial hypertension in the a of a Med. 2014; PubMed Scopus Google Scholar, Barst R.J. et in patients with primary pulmonary from a Med. PubMed Scopus Google Scholar and on the of the European Society of Cardiology/European Respiratory Society to have a to 6 months N. Humbert M. Vachiery J.L. et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Respir J. 2015; 46: 903-975Crossref PubMed Scopus (1735) Google Scholar,3Galiè N. Humbert M. Vachiéry J.L. et al.2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Heart J. 2016; 37: 67-119Crossref PubMed Scopus (3365) Google Scholar Time from diagnosis was on the of the right heart time from diagnosis of ≤ 6 months was to newly diagnosed patients treated earlier with with treatment as patients with a time from diagnosis of > 6 months before selexipag hoc analyses of the GRIPHON study primary composite end point or mortality were for patients to time from diagnosis at of ≤ 6 months or > 6 were for were to the impact of time from diagnosis at on the risk of a primary end point event the treatment and Hazard ratios with were calculated using Cox proportional hazard models. 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Chin K.M. et al.Selexipag for the treatment of pulmonary arterial hypertension.N Engl J Med. 2015; 373: 2522-2533Crossref PubMed Scopus (503) Google Scholar with diagnosed ≤ 6 months and diagnosed > 6 months from As in newly diagnosed patients 6 were than with a longer time from diagnosis 6 age years vs In addition, newly diagnosed patients were more to be in than patients with a longer time from diagnosis was in to time from with a proportion of newly diagnosed patients from and compared with patients with a longer time from of were from and from proportion of patients with a longer time from diagnosis were receiving therapy than newly diagnosed vs to Time PAH Diagnosis at 6 6 = PAH with with heart or walk PAH therapy and ≤ 6 for placebo = selexipag = > 6 for placebo = selexipag = are as or or not to of = endothelin receptor = PAH = pulmonary arterial = phosphodiesterase = World functional ≤ 6 for placebo = selexipag = > 6 for placebo = selexipag = Open in a Data are as or or not to of = endothelin receptor = PAH = pulmonary arterial = phosphodiesterase = World functional In the placebo to the end of double-blind of newly diagnosed patients a morbidity or mortality event compared with of patients diagnosed for a longer The at CI, of newly diagnosed patients in the placebo were event compared with CI, of patients with a longer time from diagnosis The of patients who a morbidity or mortality event in the selexipag was for with a or longer time from diagnosis and At CI, of newly diagnosed selexipag patients were compared with CI, of selexipag patients with a longer time from diagnosis In with from the GRIPHON O. 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Chin K.M. et al.Selexipag for the treatment of pulmonary arterial hypertension.N Engl J Med. 2015; 373: 2522-2533Crossref PubMed Scopus (503) Google Scholar for PAH and disease progression were the primary end point with the this was of time from diagnosis or treatment to PAH and to Time PAH Diagnosis at 6 = 6 = = = = = with morbidity or mortality morbidity or mortality event for PAH prostanoid therapy or PAH in need for or are as morbidity or mortality events to end of double-blind treatment are PAH = pulmonary arterial Open in a Data are as morbidity or mortality events to end of double-blind treatment are PAH = pulmonary arterial In the time from diagnosis was prognostic of morbidity/mortality events (P = Cox The prognostic of time from diagnosis was not on age (P = for or on the of at (P = for and no was for an of PAH therapy (P = for interaction). were in analyses were for Compared with placebo selexipag reduced the risk of morbidity/mortality by in newly diagnosed patients (hazard ratio, 0.45 [95% CI, and by in patients with a longer time from diagnosis (hazard ratio, 0.74 [95% CI, The P value a more pronounced treatment effect in newly diagnosed patients. In an to for the impact of in PAH therapy use at an for this was and a for the treatment effect was have to the P value of were in analyses were for of patients with a time from diagnosis of ≤ 6 months and > 6 months were in the low- and and and maintenance dose and time in the placebo was in newly diagnosed patients compared with in patients with a longer time from diagnosis. to selexipag was in both the newly diagnosed patients and with a longer time from diagnosis and In of selexipag and of newly diagnosed placebo patients compared with of selexipag and of placebo patients with a longer time from diagnosis. The of patients who of an adverse event and the of patients at least adverse event were between treatment and were not by time from diagnosis to the end of the study, in the newly diagnosed selexipag patients and placebo patients had in patients with a longer time from selexipag patients and placebo patients had and to Time PAH Diagnosis at the patients randomly assigned to placebo, not receive the study drug and were from the safety and a dose of of selexipag and was assigned to the selexipag for the safety 6 = 6 = = = = = of adverse with ≥ adverse with ≥ adverse with ≥ adverse event to study drug before the end of the study in patients a primary end point morbidity or mortality event with before the study drug end provided for events in ≥ of patients in by in the patients treated earlier with selexipag. in in are as Data for the safety PAH = pulmonary arterial the patients randomly assigned to placebo, not receive the study drug and were from the safety and a dose of of selexipag and was assigned to the selexipag for the safety study drug before the end of the study in patients a primary end point morbidity or mortality event with before the study drug end provided for events in ≥ of patients in by in the patients treated earlier with selexipag. Open in a Data are as Data for the safety PAH = pulmonary arterial The of these post hoc analyses from the randomized controlled GRIPHON trial newly diagnosed PAH patients have a worse prognosis than with a longer time from diagnosis. study selexipag reduced the risk of a morbidity or mortality event composite end both in patients with a time from diagnosis of ≤ 6 months and of > 6 months compared with placebo, with a more pronounced effect in newly diagnosed patients. These the benefits of early of an prostacyclin pathway to a treatment The prognostic value of time from diagnosis for disease progression demonstrated in these analyses is with data and from the with an Receptor in Pulmonary Arterial Hypertension to M. O. et in and of patients with pulmonary arterial hypertension.Eur Respir J. PubMed Scopus Google G. Channick R.N. 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