selexipag and Pulmonary-Arterial-Hypertension

Despite the availability of treatments for all subgroups of pulmonary hypertension (PH), the prognosis for PH remains poor. This systematic review and meta-analysis aimed to determine the efficacy and safety of selexipag in patients with PH. A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials (RCTs) on treatment of PH with selexipag, compared with placebo or blank, were reviewed. Studies were pooled to weighted mean differences (WMDs) and risk ratios (RRs), with 95% confidence intervals (CIs). Selexipag was safe and significantly improved hospitalization for worsening of PH, WHO FC, mPAP, NT-proBNP, and cardiac index in patients with PH. Selexipag should be considered in patients with pulmonary arterial hypertension or chronic thromboembolic PH.

Topics: Acetamides; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Randomized Controlled Trials as Topic

The comparative efficacy between riociguat and selexipag in patients with pulmonary arterial hypertension (PAH) has never been described in literature. Our aim was to prepare indirect treatment comparison (ITC) to evaluate the cost-effectiveness of riociguat in Czechia.. A systematic literature review identified two relevant trials with comparable endpoints to inform a Bucher ITC of relative and absolute effects. Given the comparable efficacy of riociguat and selexipag, a cost-minimization analysis (CMA) was conducted.. A Bucher ITC provided evidence for the comparable relative efficacy of riociguat defined as the odds of unimproved functional class III 0.761 (95% CI 0.372 to 1.558; p = 0.455) compared to selexipag and a comparable absolute efficacy defined as a difference in the 6-minute walking distance of 10.560 meters (95% CI -10.692 to 31.812; p = 0.330). The CMA identified riociguat as the cost-saving therapy.. Switching to riociguat represents the cost-saving therapy for PAH patients who were inadequately compensated with the PDE5i+ERA therapy. Consequently, riociguat has been introduced to the list of reimbursed medicines in Czechia from October 2021. Based on two global trials, we prepared the first indirect treatment comparison followed with CMA of these therapies that may improve future decision-making for PAH indications.

Topics: Antihypertensive Agents; Costs and Cost Analysis; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension

: Pulmonary arterial hypertension (PAH) is a rare pulmonary vasculopathy. This review focuses on selexipag, a prostacyclin receptor agonist validated for the treatment of PAH.. We review the structure, mechanisms of action, pharmacokinetics, and pharmacodynamics of selexipag. Clinical efficacy and tolerability are discussed using the main clinical trial published for selexipag (GRIPHON) and its post-hoc analysis.. Selexipag should be added as a triple oral combination therapy in case of insufficient response to oral combination therapy with endothelin receptor antagonist and phosphodiesterase 5 inhibitor. However, selexipag should not replace parenteral prostacyclin in high-risk patients.

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Humans; Pulmonary Arterial Hypertension; Pyrazines

Pulmonary veno-occlusive disease (PVOD) is a rare condition with poor prognosis, and lung transplantation is recommended as the only curative therapy. The role of pulmonary arterial hypertension targeted therapy in PVOD remains controversial, and long-term effects of targeted therapy have been rarely reported. This study aims to retrospectively evaluate the role of targeted therapy in PVOD patients and the long-term outcome.. PVOD patients with good responses to targeted therapies were analyzed, and data pre- and post- targeted therapies were compared. An overview of the effects of targeted therapies on PVOD patients was also conducted.. Five genetically or histologically confirmed PVOD patients received targeted therapies and showed good responses. Their mean pulmonary arterial pressure by right heart catheterization was 62.0 ± 11.7 mmHg. Two receiving monotherapy got stabilized, and three receiving sequential combination therapy got improved, cardiac function and exercise capacity significantly improved after treatments. No pulmonary edema occurred. The mean time from the first targeted therapy to the last follow up was 39.3 months, and the longest was 9 years. A systematic review regarding the effects of targeted therapies on PVOD patients indicated majorities of patients got hemodynamics or 6-min walk distance improved, and 26.7% patients developed pulmonary edema. The interval from targeted drugs use to death ranged from 71 min to over 4 years.. Cautious use of targeted therapy could safely and effectively improve or stabilize hemodynamics and exercise capacity of some patients without any complications. PVOD patients could live longer than expected.

Topics: Acetamides; Adult; Anticoagulants; Antihypertensive Agents; Cardiac Catheterization; Disease Progression; Diuretics; Drug Therapy, Combination; Echocardiography, Doppler; Endothelin Receptor Antagonists; Enzyme Activators; Exercise Tolerance; Female; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Prostaglandins; Pulmonary Arterial Hypertension; Pulmonary Diffusing Capacity; Pulmonary Edema; Pulmonary Veno-Occlusive Disease; Pyrazines; Pyrazoles; Pyrimidines; Retrospective Studies; Walk Test

Reduced daily life physical activity (DLPA) in pulmonary arterial hypertension (PAH) contributes to a poor quality of life.. Can actigraphy be used to assess changes in DLPA in patients with PAH receiving selexipag or placebo?. Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension (TRACE) was a prospective, multicenter, randomized, placebo-controlled, double-blind, exploratory phase 4 study enrolling patients with PAH in World Health Organization functional class II/III, receiving stable endothelin receptor antagonist with/without phosphodiesterase type 5 inhibitor background therapy. Primary end points were change from baseline to Week 24 in actigraphy-assessed DLPA (recorded by using an accelerometer), including daily time spent in nonsedentary physical activity (NSPA), daily time spent in moderate to vigorous physical activity (MVPA), daily volume of activity, and daily number of steps.. At baseline, patients (N = 108) were prevalent, on stable background PAH therapy, and at low risk of disease progression. Patients showed high compliance with wear of the accelerometer throughout the study. From baseline to Week 24, mean daily time spent in NSPA increased by 1.1 min and decreased by 16.7 min in the selexipag and placebo groups (treatment difference [95% CI], 17.8 [-6.0, 41.6] min); mean time spent in MVPA increased by 0.3 min and was reduced by 2.0 min in the selexipag and placebo groups (treatment difference [95% CI], 2.3 [-10.8, 15.4] min); and mean number of daily steps decreased by 0.3 and 201.9 in the selexipag and placebo groups (treatment difference [95% CI], 201.6 [-243.0, 646.2]).. TRACE enrolled a prevalent population on background therapy and at low risk of disease progression. Changes in DLPA were small and highly variable, with no statistically significant differences between treatment groups. This patient-centric study was the first randomized trial in PAH to capture high-quality actigraphy data and to describe DLPA in terms of mean/median and variability, which may inform the design of future studies.. ClinicalTrials.gov; No.: NCT03078907; URL: www.. gov.

Topics: Actigraphy; Antihypertensive Agents; Disease Progression; Exercise; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Prospective Studies; Pulmonary Arterial Hypertension; Quality of Life

In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag.. Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019.. Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan-Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively.. These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen.. ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306.

Topics: Acetamides; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyrazines

The number of pulmonary arterial hypertension (PAH) patients with comorbidities is increasing and there are limited data on response to PAH-targeted therapies in this population. These post hoc analyses explored the effect of selexipag in PAH patients with cardiovascular comorbidities in the GRIPHON study.. Selexipag reduces the risk of a morbidity/mortality event vs. placebo irrespective of patient comorbidity status, suggesting that comorbidity status does not influence the treatment effect of selexipag.

Topics: Acetamides; Antihypertensive Agents; Comorbidity; Double-Blind Method; Heart Failure; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyrazines

In pulmonary arterial hypertension (PAH), there are no data comparing initial triple oral therapy with initial double oral therapy.. TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension; NCT02558231), a multicenter, double-blind, randomized phase 3b study, evaluated initial triple (macitentan, tadalafil, and selexipag) versus initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH.. Efficacy was assessed until the last patient randomized completed week 26 (end of main observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week 26.. Patients were assigned to initial triple (n = 123) or initial double therapy (n = 124). At week 26, both treatment strategies reduced PVR compared with baseline (by 54% and 52%), with no significant difference between groups (ratio of geometric means: 0.96; 95% confidence interval: 0.86-1.07; P = 0.42). Six-minute walk distance and N-terminal pro-brain natriuretic peptide improved by week 26, with no difference between groups. Risk for disease progression (to end of main observation period) was reduced with initial triple versus initial double therapy (hazard ratio: 0.59; 95% confidence interval: 0.32-1.09). Most common adverse events with initial triple therapy included headache, diarrhea, and nausea. By the end of the main observation period, 2 patients in the initial triple and 9 in the initial double therapy groups had died.. In patients with newly diagnosed PAH, both treatment strategies markedly reduced PVR by week 26, with no significant difference between groups (primary endpoint not met). Exploratory analyses suggested a possible signal for improved long-term outcomes with initial triple versus initial double oral therapy.

Topics: Acetamides; Adult; Aged; Antihypertensive Agents; Double-Blind Method; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pyrazines; Pyrimidines; Sulfonamides; Tadalafil

The oral IP receptor agonist selexipag is approved for the long-term treatment of pulmonary arterial hypertension (PAH). Treatment interruptions should be avoided due to the progressive nature of the disease. An intravenous (IV) formulation of selexipag was developed to provide a treatment option for short-term interruptions to oral selexipag. In this prospective, multicenter, open-label study, the safety, tolerability, and pharmacokinetics of temporarily switching between oral and IV selexipag were investigated (NCT03187678, ClinicalTrials.gov).. PAH patients receiving stable oral selexipag doses were enrolled. Following three consecutive IV selexipag infusions patients resumed oral selexipag. Corresponding IV and oral doses were selected to achieve comparable exposure to the active metabolite of selexipag. Safety outcomes were monitored throughout, and pharmacokinetic samples were obtained after oral and IV administration.. All 20 patients completed the study. Fifteen patients had adverse events (AEs), most were mild, and none resulted in discontinuation. Headache was the most common AE throughout the study (four patients). Three serious AEs occurred in two patients with underlying comorbidities when oral dosing had resumed. There were no changes in WHO functional class for any patient and no clinically symptomatic changes in blood pressure were observed. Comparable exposure to the active metabolite of selexipag was demonstrated following corresponding oral and IV selexipag doses.. Temporarily switching between corresponding doses of oral and IV selexipag was well-tolerated with no unexpected safety findings and comparable exposure to the active metabolite. Treatment with IV selexipag is a feasible option to bridge temporary oral selexipag treatment interruptions.

Topics: Acetamides; Administration, Intravenous; Administration, Oral; Aged; Antihypertensive Agents; Cross-Over Studies; Drug Administration Routes; Female; Headache; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Arterial Hypertension; Pyrazines

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 (PGI. 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.

Topics: Acetamides; Adult; Antihypertensive Agents; Disease Progression; Double-Blind Method; Female; Follow-Up Studies; Global Health; Humans; Male; Middle Aged; Morbidity; Prognosis; Pulmonary Arterial Hypertension; Pulmonary Wedge Pressure; Pyrazines; Survival Rate

Topics: Acetamides; Adult; Aged; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pulmonary Arterial Hypertension; Pyrazines; Pyrimidines; Severity of Illness Index; Sulfonamides; Tadalafil; Treatment Outcome; Vascular Resistance

A long-term trial showed that the oral prostacyclin (PGl. Patients receiving non-prostanoid oral PAH therapy and inhaled treprostinil at stable doses, in World Health Organization Functional Class II/III, with 6-minute walk distance ≥ 300 meters were enrolled. The 16-week main treatment period included downtitration of inhaled treprostinil over 8 weeks and parallel uptitration of selexipag over 12 weeks. Sustained treatment transition at Week 16 was defined as (1) receiving selexipag at Week 16; (2) no selexipag interruption(s) totaling ≥ 8 days; and (3) no inhaled treprostinil or other prostanoids after Week 8. Clinical parameters and patient-reported treatment satisfaction outcomes were assessed at Week 16.. All 34 enrolled patients completed the study. At Week 16, 32 patients (94.1%) had stopped inhaled treprostinil and were receiving selexipag. Twenty-eight patients (82.4%) met all criteria for sustained treatment transition. During the study, 3 patients discontinued selexipag due to adverse events. Overall, most adverse events were typical of prostanoid therapies and started during the uptitration phase. In general, patients remained clinically stable throughout treatment and reported improved convenience.. Transition to oral selexipag from inhaled treprostinil in PAH patients was successful and well tolerated in most patients, and associated with greater convenience.. NCT02471183.

Topics: Acetamides; Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Substitution; Drug Tolerance; Epoprostenol; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prodrugs; Prospective Studies; Pulmonary Arterial Hypertension; Pulmonary Wedge Pressure; Pyrazines; Treatment Outcome

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 [PGI. 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.. 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).. 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.. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01106014.

Topics: Acetamides; Adolescent; Adult; Aged; Antihypertensive Agents; Arterial Pressure; Biomarkers; Double-Blind Method; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Pulmonary Arterial Hypertension; Pulmonary Artery; Pyrazines; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Young Adult

This study aimed to investigate the safety, tolerability, and efficacy of selexipag in children and young adults with idiopathic and heritable pulmonary arterial hypertension.. This retrospective cohort study included clinical data from five children and six young adults with pulmonary arterial hypertension receiving selexipag as add-on therapy or as a transition from beraprost sodium or epoprostenol infusion therapy. Clinical efficacy was evaluated by measuring improvement in clinical variables from baseline, including hemodynamic parameters.. Of the 11 patients, 6 were switched from beraprost sodium to selexipag and one paediatric patient transitioned from epoprostenol to selexipag. The median maintenance dose of selexipag in children was 80 μg/kg/day. In nine patients undergoing repeat catheterisation, statistically significant improvements were observed after the initiation of selexipag in terms of mean pulmonary arterial pressure (p < 0.01), pulmonary vascular resistance index (p < 0.05), and cardiac index (p < 0.01). None of the patients had clinical worsening after selexipag during follow-up, but one young adult patient discontinued treatment due to severe headache. The most common side effect profiles were headache, nausea, abdominal pain, jaw pain, myalgia, and diarrhoea.. Selexipag may have a favourable safety profile and potential efficacy in children and young adults with pulmonary arterial hypertension.

Topics: Antihypertensive Agents; Child; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Retrospective Studies; Treatment Outcome; Young Adult

Topics: Acetamides; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyrazines

Intravenous (i.v.) prostacyclin is the cornerstone treatment in high-risk pulmonary arterial hypertension (PAH) patients. Selexipag is an orally available prostacyclin receptor agonist. Limited data are available regarding the feasibility of transitioning from i.v. epoprostenol to selexipag. A 50-year-old woman with idiopathic PAH was diagnosed in a World Health Organization (WHO) Functional Class (FC) IV. She improved with upfront triple combination therapy, including i.v. epoprostenol. Over 2 years of follow-up, the patient remained at low risk and expressed strong preference towards oral therapies. After careful risk-benefit clinical consideration, she was transitioned from i.v. epoprostenol to selexipag. Selexipag was started at dosage of 200 μg twice daily (b.i.d.) and titrated up to 1600 μg b.i.d. over 8 weeks (up-titration of 200 μg b.i.d. every week). Simultaneously, i.v. epoprostenol was down-titrated 3.0 ng/kg/min every week from a dosage of 27.5 ng/kg/min. The transition occurred under strict medical surveillance and was well tolerated. One year after discontinuation of epoprostenol, the patient remains in WHO FC I and has no signs of clinical deterioration. Although not generalizable to most PAH patients, this case highlights that a carefully planned transition from epoprostenol to selexipag is feasible in selected low-risk patients within a shared medical decision-making framework.

Topics: Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Middle Aged; Pulmonary Arterial Hypertension

Oral treprostinil and selexipag are drugs targeting the prostacyclin pathway and are approved for treatment of pulmonary arterial hypertension (PAH). In the setting of unsatisfactory clinical response or tolerability issues while on selexipag, there is little data on clinical benefit, safety, or strategies on transitioning to oral treprostinil. Using prospective data from the ADAPT registry, we aimed to evaluate clinical outcomes, safety, and transition strategies in ten patients with PAH transitioning from selexipag to oral treprostinil.. ADAPT was a prospective, real-world, multicenter, United States-based registry of patients with PAH newly started on oral treprostinil, with a cohort of patients (n = 10) transitioning from selexipag to oral treprostinil. PAH variables of interest were collected from standard-of-care clinic visits. Clinical improvement was defined by modified REPLACE criterion, and risk was assessed by REVEAL Lite 2 from baseline to last follow-up. Real world transition strategies were recorded. Healthcare utilization or worsening PAH was evaluated within 30 days of transitions.. Seven patients transitioned due to worsening PAH or lack of efficacy on selexipag, and three patients transitioned due to tolerability issues. Based on the modified REPLACE criterion, five patients demonstrated clinical improvement after transition from selexipag to oral treprostinil. Using REVEAL Lite 2 to assess risk, three patients improved and five patients maintained risk category from baseline to last follow-up. All transitions occurred in an outpatient setting either as abrupt stop/start or cross-titration, without parenteral treprostinil bridging.. Transition from selexipag to oral treprostinil was safe, performed without parenteral prostacyclin bridging, and resulted in clinical and categorical risk improvements in some patients.

Topics: Administration, Oral; Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Prospective Studies; Pulmonary Arterial Hypertension; Registries

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases.

Topics: Acetamides; Adult; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Lupus Erythematosus, Systemic; Pulmonary Arterial Hypertension; Pyrazines; Quality of Life

Optimizing an individual dose with careful management of adverse events (AEs) is essential in the treatment with selexipag approved for pulmonary arterial hypertension (PAH). This study aims to identify real-world practice patterns and AE characteristics of selexipag.. This multicenter, longitudinal, observational study included Korean patients with PAH who initiated with selexipag and were followed up to 24 weeks. The dose-titration pattern, AE incidences by dosing and time course, recovery pattern from AEs, and relationship between doses and AE incidences were evaluated.. Data for 113 patients were included in the analysis. The individual maintenance dose ranged between 200 and 3,200 µg/day. More often AEs were occurred in the titration phase than maintenance phase. There was no significant difference in AE incidences according to the distribution of titration and maintenance doses. The four most common AEs were diarrhea, headache, nausea/vomiting, and myalgia without showing a dose-dependent trend in either frequency or severity. The recovery rates were between 65.0% and 76.9% with a median time to recovery of 15-70 days (range, 2-233).. Our finding that AE incidence did not increase with increasing dose of selexipag would provide supportive real-world evidence on the management of optimal dose and safety.

Topics: Acetamides; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Republic of Korea

Pulmonary arterial hypertension is a progressive, debilitating condition characterized by increased resistance in the pulmonary arterial circulation. Current treatments for pulmonary arterial hypertension include endothelin receptor antagonists such as bosentan, sitaxentan, ambrisentan, macitentan, and oral prostacyclin receptor agonists such as selexipag. Endothelin receptor antagonists have been associated with liver injury, while hepatotoxicity was not reported for selexipag. Although genetic variability has been indisputably associated with variability in drug response, no study has been designed until now to assess its effects on the pharmacokinetics of endothelin receptor antagonists or selexipag.. We report the case of a 58-year-old female Caucasian patient with a dramatic increase in plasma levels of transaminases after treatment with macitentan and selexipag, drugs whose risk of causing liver injury has so far been considered limited. After therapy discontinuation, plasma levels of transaminases returned to baseline, thus suggesting a role of these drugs in the observed hepatotoxicity. After pharmacological counseling, we decided to introduce ambrisentan for the patient's treatment. After 7 months of treatment, no liver injury has been reported. To evaluate the role of genetic factors in the observed hepatotoxicity, we genotyped the patient for single-nucleotide polymorphisms previously associated with macitentan, ambrisentan, or selexipag metabolism. We found a genetic profile associated with a poor metabolizer (PM) phenotype for CYP2C8 and CYP2C9, key enzymes for elimination of both macitentan and selexipag. The reported results suggest that an allelic profile associated with low activity for CYP2C8 and CYP2C9 enzyme could be a potential risk factor for macitentan and selexipag-induced liver injury and could provide a possible marker for early identification of subjects at higher risk of developing hepatotoxicity.. A multidisciplinary approach based on clinical evaluation, as well as pharmacological counseling and evaluation of the patient's genetic profile, might be useful for identification of patients with a high chance of drug-induced liver injury, avoiding unnecessary risks in therapy selection and prescription.

Topics: Bosentan; Counseling; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C9; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Middle Aged; Pulmonary Arterial Hypertension; Receptors, Epoprostenol; Transaminases

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary vascular resistance that can lead to right ventricular failure and death. The use of medications that affect the prostacyclin pathway is an important treatment strategy in PAH. Inhaled iloprost is a prostacyclin analogue, and selexipag is an oral, non-prostanoid, prostacyclin IP receptor agonist. Data are limited on transitioning patients from inhaled iloprost to selexipag. In this case report, we describe the successful transition of a 57-year-old female with heritable PAH from inhaled iloprost to selexipag over 8 weeks in an out-patient setting. After initiation of selexipag, the patient's inhaled iloprost dose was gradually reduced and eventually discontinued. The patient tolerated the transition well with stable symptoms, 6-minute walk distance, and pulmonary hemodynamics. Additional studies are needed to better define the comparative efficacy and safety of inhaled iloprost and selexipag.

Topics: Acetamides; Antihypertensive Agents; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Pulmonary Arterial Hypertension; Pyrazines

Selexipag is a selective oral prostacyclin receptor agonist indicated for pulmonary arterial hypertension (PAH) treatment. SelexiPag: tHe usErs dRug rEgistry (SPHERE) (NCT03278002) is collecting data from selexipag-treated patients in real-world clinical practice to elucidate and describe the clinical characteristics, outcomes, and dosing/titration regimens of patients treated with selexipag in routine clinical practice.. SPHERE is a United States (US)-based, ongoing, multicenter, prospective observational study (target N = 800). This study enrolls patients who are either newly initiated on selexipag (≤60 days before enrollment) or were previously receiving selexipag with documentation of dose titration at study enrollment. Data collection for the study occurs at routine clinic visits. In this paper, we report on the first 500 patients enrolled.. Median follow-up was 17.8 months; 77.6% of patients completed the planned 18 months follow-up, and 22.4% discontinued early from the study. At diagnosis, 94.8% of patients had PAH (World Health Organization [WHO] Group 1), most commonly idiopathic (49.2%) and connective tissue disease associated (26.4%). Most patients (72.4%) initiated selexipag more than 60 days before enrollment. At initiation, 31.0% of patients had WHO functional class (FC) II disease, and 49.6% had WHO FC II or III disease. In addition, 55.0% of patients were receiving double therapy (most commonly an endothelin receptor antagonist plus phosphodiesterase type 5 inhibitor [42.3%]), whereas 30.6% were receiving monotherapy. Despite most patients already receiving PAH-specific therapy, at selexipag initiation, 67.2% (336 of 500) were at intermediate risk, and 9.6% (48 of 500) were at high risk of 1-year mortality. Risk scores remained stable in ∼55% of patients and improved in ∼20% at the end of the study. In total, 72.2% of patients had at least 1 adverse event (AE), and 37.6% reported a serious AE. The median selexipag maintenance dose was 1,200 µg twice daily (interquartile range: 800-1,600 µg twice daily).. Real-world, US-based patients with PAH initiating selexipag typically have WHO FC II/III disease and are at intermediate risk, despite receiving PAH-specific treatment. Selexipag was prescribed as part of a combination regimen in most patients. The study identified no unexpected adverse effects.

Topics: Acetamides; Aged; Antihypertensive Agents; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Prospective Studies; Pulmonary Arterial Hypertension; Pulmonary Wedge Pressure; Pyrazines; Receptors, Prostaglandin; Treatment Outcome; United States

Eisenmenger syndrome is a multisystem disorder and the most severe form of pulmonary arterial hypertension in adult congenital heart disease. Pulmonary arterial hypertension represents a fatal disease, characterized by increased pulmonary vascular resistance, right heart failure, and death. Although therapeutic management has rapidly advanced in recent years, these patients were not included in randomized controlled trials for specific pulmonary arterial hypertension drugs, except for bosentan. However, in clinical practice we apply treatment strategies combining drugs targeting multiple pathobiological pathways. We present 3 patients with Eisenmenger syndrome and their improvement after starting treatment with selexipag, an oral selective IP prostacyclin receptor agonist.

Topics: Acetamides; Adult; Antihypertensive Agents; Eisenmenger Complex; Female; Humans; Middle Aged; Pulmonary Arterial Hypertension; Pyrazines; Receptors, Epoprostenol

Parenteral prostacyclin therapies remain first-line therapy for patients with pulmonary arterial hypertension (PAH) with class IV symptoms. In selected patients who have been clinically stabilized, switching to selexipag, a chemically distinct prostacyclin receptor agonist, may alleviate risks associated with long-term parenteral therapy. We report our experience with transition of patients from parenteral prostacyclin therapy to selexipag. From January 2016 to July 2017, patients with PAH at the Duke University Pulmonary Vascular Disease Center with functional class II symptoms on stable parenteral prostacyclin therapy were offered the opportunity to transition to selexipag. A standardized protocol was developed to guide titration of therapies. Patients underwent pre- and post-transition assessments of hemodynamics, echocardiography, laboratory biomarkers, and functional status. We studied 14 patients with PAH (11 women; median age 53 years) in total. Overall, 13 patients tolerated the switch to selexipag and remained on the drug at study completion, and 1 patient passed away due to progressive liver failure. Surrogate markers including NT-proBNP, 6MWD, RV function, and TAPSE, and right heart catheterization hemodynamics were similar before and after transition. The transition from parenteral prostanoid therapy to oral selexipag was overall well-tolerated in patients with stable PAH and functional class II symptoms. Finally, doses of selexipag up to 3200 μg twice daily were well-tolerated in patients who had been treated with prior parenteral prostacyclins.

Topics: Acetamides; Antihypertensive Agents; Arterial Pressure; Drug Substitution; Feasibility Studies; Female; Humans; Infusions, Parenteral; Male; Middle Aged; Prospective Studies; Prostaglandins I; Pulmonary Arterial Hypertension; Pulmonary Artery; Pyrazines; Receptors, Epoprostenol; Time Factors; Treatment Outcome

Topics: Acetamides; Antihypertensive Agents; Epoprostenol; Humans; Pulmonary Arterial Hypertension; Pyrazines

NTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A. PAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar-Kyoto rats. Animals were assigned into groups: 1. 'No MCT'; 2. 'MCT Only'; 3. MCT + NTP42 (0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT.. From haemodynamic assessments, NTP42 reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standard-of-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover, NTP42 was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals.. These findings suggest that NTP42 and antagonism of the TP signalling pathway have a relevant role in alleviating the pathophysiology of PAH, representing a novel therapeutic target with marked benefits over existing standard-of-care therapies.

Topics: Acetamides; Animals; Antihypertensive Agents; Disease Models, Animal; Heart Ventricles; Hemodynamics; Humans; Hypertrophy, Right Ventricular; Male; Monocrotaline; Pulmonary Arterial Hypertension; Pulmonary Artery; Pyrazines; Rats; Rats, Inbred WKY; Receptors, Thromboxane; Sildenafil Citrate; Vascular Remodeling

Topics: Acetamides; Consensus; Epoprostenol; Humans; Prostaglandins I; Pulmonary Arterial Hypertension; Pyrazines

The European Pediatric Pulmonary Vascular Disease Network (EPPVDN) investigated the safety and efficacy of add-on selexipag, an oral prostacyclin receptor agonist approved for pulmonary arterial hypertension (PAH) in adults, in the largest, exploratory pediatric cohort to date.. This is a prospective observational study of 15 consecutive children with PAH, treated with oral add-on selexipag at 3 centers. Most patients underwent cardiac catheterizations at baseline and median of 8 months follow-up. All patients had clinical, echocardiographic, and N-terminal pro b-type natriuretic peptide studies, including the EPPVDN pediatric pulmonary hypertension (PH) risk score.. There was no death during the use of selexipag. Two of 15 patients ultimately underwent lung transplantation. One patient with heritable PAH died on intravenous treprostinil (off selexipag). The mean right atrial pressure, the ratio of pulmonary arterial pressure (PAP) to systemic arterial pressure (SAP) (mean PAP/mean SAP, diastolic PAP/diastolic SAP: -17%), and transpulmonary pressure gradients (TPG) (mean TPG: -17%; p < 0.01; diastolic TPG: -6 mm Hg; p < 0.05) were improved after the therapy (n = 10). Selexipag therapy was associated with a better right ventricular systolic function (tricuspid annular plane systolic excursion: +14.5%; p < 0.01) and functional class. Improvement was seen in non-invasive and combined invasive/non-invasive PH risk scores (lower risk: +18%-22%, higher risk: -35%-37%; p < 0.05). Overall, the efficacy of selexipag was variable, often with a better response in less sick patients.. Oral selexipag use in children with PAH is well tolerated and safe when closely monitored. Add-on selexipag therapy improved several outcome-relevant variables in about 50% of patients and prevented disease progression in additional 27% of patients. The novel EPPVDN pediatric PH risk score indicated these drug effects properly, can be useful in clinical follow-up, and should be validated in larger prospective studies.

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Blood Pressure; Child; Female; Humans; Male; Prodrugs; Prospective Studies; Pulmonary Arterial Hypertension; Pulmonary Artery; Pyrazines; Treatment Outcome

Aim To present an own experience in using a medication selexipag in patients with pulmonary arterial hypertension (PAH) included into the V. A. Almazov National Medical Research Center registry and participating in the GRIPHON and GRIPHON OL clinical studies.Material and methods 26 patients with PAH were included into this study since 2010: 20 patients with idiopathic PAH, 4 patients with PAH associated with systemic scleroderma, and 2 patients with corrected congenital heart defects. At the time of randomization, 19 patients had been receiving therapy with phosphodiesterase type 5 inhibitors for at least one month. Among the patients treated with selexipag (n=14), 4 patients reached a high individual maintenance dose (1200-1600 µg b.i.d.), 4 patients reached a medium dose (600-1000 µg b.i.d.), and 6 patients reached a low dose (200-400 µg b.i.d.).Results The selexipag therapy exerted a positive effect on secondary endpoints, specifically, on changes in the functional class of pulmonary hypertension, serum concentration of NT-proBNP, and physical working capacity of patients. Adverse events associated with the selexipag treatment, which resulted in termination of study participation, were observed in one patient.Conclusion To achieve the main goal of drug therapy, low risk of death with selexipag it is critical to observe the titration schedule and to aim at reaching the highest individual maintenance dose.

Topics: Acetamides; Humans; Pulmonary Arterial Hypertension; Pyrazines

Topics: Acetamides; Antihypertensive Agents; Humans; Pulmonary Arterial Hypertension; Pyrazines; Rosacea

Topics: Acetamides; Adolescent; Antihypertensive Agents; Asymptomatic Diseases; Bone Morphogenetic Protein Receptors, Type II; Cardiac Catheterization; Disease Progression; Dyspnea; Echocardiography; Exercise Tolerance; Female; Genetic Testing; Heterozygote; Humans; Male; Phenylpropionates; Pulmonary Arterial Hypertension; Pyrazines; Pyridazines; Sildenafil Citrate; Syncope; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by a progressive increase in pulmonary artery pressure due to an increase in vessel tone and occlusion of vessels. The endogenous vasodilator prostacyclin and its analogs are used as therapeutic agents for PAH. However, their pharmacological effects on occlusive vascular remodeling have not been elucidated yet. Selexipag is a recently approved, orally available and selective prostacyclin receptor agonist with a non-prostanoid structure. In this study, we investigated the pharmacological effects of selexipag on the pathology of chronic severe PAH in Sprague-Dawley and Fischer rat models in which PAH was induced by a combination of injection with the vascular endothelial growth factor receptor antagonist Sugen 5416 and exposure to hypoxia (SuHx). Oral administration of selexipag for three weeks significantly improved right ventricular systolic pressure and right ventricular (RV) hypertrophy in Sprague-Dawley SuHx rats. Selexipag attenuated the proportion of lung vessels with occlusive lesions and the medial wall thickness of lung arteries, corresponding to decreased numbers of Ki-67-positive cells and a reduced expression of collagen type 1 in remodeled vessels. Administration of selexipag to Fischer rats with SuHx-induced PAH reduced RV hypertrophy and mortality caused by RV failure. These effects were probably based on the potent prostacyclin receptor agonistic effect of selexipag on pulmonary vessels. Selexipag has been approved and is used in the clinical treatment of PAH worldwide. It is thought that these beneficial effects of prostacyclin receptor agonists on multiple aspects of PAH pathology contribute to the clinical outcomes in patients with PAH.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetamides; Animals; Cell Proliferation; Collagen Type I; Disease Models, Animal; Heart Ventricles; Hemodynamics; Hypertrophy, Right Ventricular; Hypoxia; Indoles; Lung; Male; Pulmonary Arterial Hypertension; Pyrazines; Pyrroles; Rats, Sprague-Dawley; Receptors, Epoprostenol; Systole; Vascular Remodeling

Epoprostenol, a synthetic prostaglandin I2 (PGI. After treating an index case of thyroid dysfunction occurring after initiation of epoprostenol, we reviewed our databases of PAH patients treated with epoprostenol, treprostinil or selexipag to identify the occurrence of this association.. We identified six cases of thyroid dysfunction in our cohort: five after initiation of an intravenous prostacyclin (epoprostenol) and one after initiation of an oral prostacyclin receptor agonist (selexipag). Four of the patients presented with hyperthyroidism and two with a large autoimmune goiter. Graves' disease was seen in three patients, Hashimoto's disease in two patients and thyrotoxicosis in one patient.. Therapy with medications targeting the prostacyclin pathway is a potential risk factor for the development of symptomatic thyroid disease.

Topics: Acetamides; Adult; Aged; Antihypertensive Agents; Epoprostenol; Female; Goiter; Graves Disease; Hashimoto Disease; Humans; Hyperthyroidism; Male; Pulmonary Arterial Hypertension; Pyrazines; Thyroiditis, Autoimmune; Thyrotoxicosis

Topics: Acetamides; Antihypertensive Agents; Drug Substitution; Drug Therapy, Combination; Epoprostenol; Female; Humans; Infusion Pumps; Middle Aged; Phenylpropionates; Pulmonary Arterial Hypertension; Pyrazines; Pyridazines; Sildenafil Citrate; Tadalafil; Vasodilator Agents

Topics: Acetamides; Antihypertensive Agents; Drug Substitution; Epoprostenol; Equipment Design; Female; Humans; Middle Aged; Monitoring, Physiologic; Prodrugs; Pulmonary Arterial Hypertension; Pulmonary Artery; Pulmonary Wedge Pressure; Pyrazines; Remote Sensing Technology

Patients with pulmonary arterial hypertension (PAH) and distal chronic thromboembolic pulmonary hypertension (CTEPH) who still reveal risk factors of worse prognosis on double combination therapy may benefit from add-on therapy with the novel oral selective prostacyclin receptor agonist selexipag.. We reviewed all patients with PAH/distal CTEPH in the Zurich cohort who received selexipag as add-on to oral combination therapy and retrieved New York Heart Association (NYHA) functional class, 6-min walk distance (6MWD), NT-pro-BNP, quality of life questionnaires (CAMPHOR and EuroQoL), tricuspid pressure gradient (TPG) by echocardiography and cardiopulmonary exercise test parameters (power output and oxygen uptake).. Twenty-three patients with PAH/CTEPH (20/3), 14 females, median (quartiles) age 56 (46; 66) years received an oral triple therapy containing selexipag at a median dose of 2000 (1600; 3100) mcg during 221 (113; 359) days. The following parameters were stabilized from baseline to last FU: 6MWD (440 (420; 490) to 464 (420; 526) m), NYHA class (three to two), NT-pro-BNP (326 (167; 1725) to 568 (135; 1856)  ng/l), TPG, power output, and oxygen uptake. Quality of life reflected by the CAMPHOR and EuroQoL improved.. Early initiation of triple oral combination therapy including selexipag in PAH/CTEPH with intermediate risk factor profile may help to stabilize functional class, exercise performance, and pulmonary hemodynamics in a real-life setting and potentially improves quality of life. Whether these beneficial effects can be truly attributed to the addition of selexipag should be addressed in future randomized controlled trials.

Topics: Acetamides; Aged; Antihypertensive Agents; Chronic Disease; Cohort Studies; Drug Therapy, Combination; Echocardiography; Endothelin Receptor Antagonists; Enzyme Activators; Exercise Test; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen Consumption; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pulmonary Embolism; Pyrazines; Quality of Life; Retrospective Studies; Soluble Guanylyl Cyclase; Tricuspid Valve; Walk Test

Selexipag is an enteral, selective prostacyclin IP receptor agonist approved for pulmonary hypertension in adults. There are few reports of its use in children and none in infants. We report the first transition of an infant (11.5 months, 8.6 kg) from intravenous treprostinil (40 ng/kg/minute) to enteral selexipag (400 mcg twice daily) with a good response and no adverse effects.

Topics: Acetamides; Administration, Intravenous; Administration, Oral; Antihypertensive Agents; Echocardiography; Enteral Nutrition; Epoprostenol; Humans; Infant, Newborn; Infusions, Intravenous; Male; Pulmonary Arterial Hypertension; Pulmonary Wedge Pressure; Pyrazines; Receptors, Prostaglandin