Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension

Pulido, Tomás; Адзерихо, И. Э.; Channick, Richard N.; Delcroix, Marion; Galiè, Nazzareno; Ghofrani, Hossein Ardeschir; Jansa, Pavel; Jing, Zhi‐Cheng; Brun, Franck-Olivier Le; Mehta, Sanjay; Mittelholzer, Camilla; Perchenet, Loı̈c; Sastry, B.K.S.; Sitbon, Olivier; Souza, Rogério; Torbicki, Adam; Zeng, Xiaofeng; Rubin, Lewis J.; Simonneau, Gérald

doi:10.1056/nejmoa1213917

Cited by 1,233 publications

(1,288 citation statements)

References 27 publications

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“…Third, the worsening PAH component of the primary end-point, which contributed most to the study outcome, differs from that used in recent PAH studies [5,15,16] in that it was determined using the PGSA score as the initial step, with subsequent consideration of 6MWD and the need for additional PAH therapy. Although the PGSA has not been validated in PAH and is associated with some limitations (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…At that time, validated PAH-specific patient-reported outcome tools were unavailable. Following the third World Symposium on Pulmonary Hypertension, recommendations regarding composite end-points have evolved and this is reflected in the design of more recent PAH studies, which have employed composite primary end-points with more objective criteria for assessing disease progression [5,16].…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, this observation suggests that the evolution of inclusion/exclusion criteria in subsequent PAH trials, incorporating more stringent screening steps to minimise the enrolment of patients with confounding factors such as comorbidities, is warranted. The need for careful oversight of enrolled patients has been a key lesson from COMPASS-2 and has affected subsequent long-term event-driven trials in PAH [5,16].…”

Section: Discussionmentioning

confidence: 99%

“…Three major mechanistic pathways, the endothelin, prostacyclin and nitric oxide pathways, are known to be involved in the pathogenesis of PAH and therapies that target these pathways are available [1][2][3]. Combining agents that target more than one pathway is an attractive option for the treatment of PAH and may offer additional long-term benefits compared with monotherapy [4,5]. The proceedings from the third World Symposium on Pulmonary Hypertension state that, despite the lack of supporting trial data, combination therapy could be considered an option for patients deteriorating on monotherapy [6].…”

Section: Introductionmentioning

confidence: 99%

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Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension

et al. 2015

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The safety and efficacy of adding bosentan to sildenafil in pulmonary arterial hypertension (PAH) patients was investigated.In this prospective, double-blind, event-driven trial, symptomatic PAH patients receiving stable sildenafil (⩾20 mg three times daily) for ⩾3 months were randomised (1:1) to placebo or bosentan (125 mg twice daily). The composite primary end-point was the time to the first morbidity/mortality event, defined as all-cause death, hospitalisation for PAH worsening or intravenous prostanoid initiation, atrial septostomy, lung transplant, or PAH worsening. Secondary/exploratory end-points included change in 6-min walk distance and World Health Organization functional class at 16 weeks, change in N-terminal pro-brain natriuretic peptide (NT-proBNP) over time, and all-cause death.Overall, 334 PAH patients were randomised to placebo (n=175) or bosentan (n=159). A primary endpoint event occurred in 51.4% of patients randomised to placebo and 42.8% to bosentan (hazard ratio 0.83, 97.31% CI 0.58-1.19; p=0.2508). The mean between-treatment difference in 6-min walk distance at 16 weeks was +21.8 m (95% CI +5.9-37.8 m; p=0.0106). Except for NT-proBNP, no difference was observed for any other end-point. The safety profile of bosentan added to sildenafil was consistent with the known bosentan safety profile.In COMPASS-2, adding bosentan to stable sildenafil therapy was not superior to sildenafil monotherapy in delaying the time to the first morbidity/mortality event. @ERSpublications COMPASS-2: adding bosentan was not superior to sildenafil alone in delaying time to first morbidity/mortality event http://ow.ly/NiM65

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension

et al. 2015

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“…This finding highlights its important role as a clinical test, as it stands out for its practicability in daily routine. With the exception of the registration trial for macitentan, a new dual endothelin antagonist, the 6-MWT has been used as the primary end-point in registration trials for all PAH medications [23][24][25][26]. However, recent publications have criticised the application of the 6-MWT as a primary end-point, indicating that changes in 6-MWT might not reflect benefits in outcome, and proposed new end-points such as time to clinical worsening [27][28][29][30].…”

Section: Discussionmentioning

confidence: 99%

Novel biomarkers for risk stratification in pulmonary arterial hypertension

et al. 2016

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Risk stratification in pulmonary arterial hypertension (PAH) is paramount to identifying individuals at highest risk of death. So far, there are only limited parameters for prognostication in patients with PAH.95 patients with confirmed PAH were included in the present analysis and followed for a total of 4 years. Blood samples were analysed for serum levels of N-terminal pro-brain natriuretic peptide, highsensitivity troponin T (hsTnT), pro-atrial natriuretic peptide ( proANP), growth differentiation factor 15, soluble fms-like tyrosine kinase 1 and placental growth factor. 27 (28.4%) patients died during a follow-up of 4 years. Levels of all tested biomarkers, except for placental growth factor, were significantly elevated in nonsurvivors compared with survivors. Receiver operating characteristic analyses demonstrated that cardiac biomarkers had the highest power in predicting mortality. In particular, proANP exhibited the highest area under the curve, followed by N-terminal probrain natriuretic peptide and hsTnT. Furthermore, proANP and hsTnT added significant additive prognostic value to the established markers in categorical and continuous net reclassification index. Moreover, after Cox regression, proANP (hazard ratio (HR) 1.91), hsTnT (HR 1.41), echocardiographic right ventricular impairment (HR 1.30) and 6-min walk test (HR 0.97 per 10 m) remained the only significant parameters in prognostication of mortality.Our data suggest benefits of the implementation of proANP and hsTnT as additive biomarkers for risk stratification in patients with PAH. @ERSpublications The cardiac biomarkers proANP and hsTnT may be of use in the assessment of risk stratification in PAH patients http://ow.ly/RJFtn

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Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis

Investigators

2016

JAMA

109

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Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension

Abstract: Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.).

Cited by 1,233 publications

References 27 publications

Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension

Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension

Novel biomarkers for risk stratification in pulmonary arterial hypertension

Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis

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