Dataset Information

Incident and prevalent cohorts with pulmonary arterial hypertension: insight from SERAPHIN.

ABSTRACT: In SERAPHIN, a long-term, randomised, controlled trial (NCT00660179) in pulmonary arterial hypertension (PAH), macitentan significantly reduced the risk of morbidity/mortality and PAH-related death/hospitalisation. We evaluated disease progression and the effect of macitentan in treatment-naïve incident and prevalent cohorts.Patients allocated to placebo, or macitentan 3?mg or 10?mg were classified by time from diagnosis to enrolment as incident (?6?months; n=110) or prevalent (>6?months; n=157). The risk of morbidity/mortality and PAH-related death/hospitalisation was determined using Cox regression.The risk of morbidity/mortality (Kaplan-Meier estimates at month 12: 54.4% versus 26.7%; p=0.006) and PAH-related death/hospitalisation (Kaplan-Meier estimates at month 12: 47.3% versus 19.9%; p=0.006) were significantly higher for incident versus prevalent patients receiving placebo, respectively. There was no significant difference in the risk of all-cause death between incident and prevalent cohorts (p=0.587). Macitentan 10?mg significantly reduced the risk of morbidity/mortality and PAH-related death/hospitalisation versus placebo in incident and prevalent cohorts.Incident patients had a higher risk for PAH progression compared with prevalent patients but not a higher risk of death. Macitentan delayed disease progression in both incident and prevalent PAH patients.

SUBMITTER: Simonneau G

PROVIDER: S-EPMC4664609 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Incident and prevalent cohorts with pulmonary arterial hypertension: insight from SERAPHIN.

Simonneau Gérald G Channick Richard N RN Delcroix Marion M Galiè Nazzareno N Ghofrani Hossein-Ardeschir HA Jansa Pavel P Le Brun Franck-Olivier FO Mehta Sanjay S Perchenet Loic L Pulido Tomás T Sastry B K S BK Sitbon Olivier O Souza Rogério R Torbicki Adam A Rubin Lewis J LJ

The European respiratory journal 20151022 6

In SERAPHIN, a long-term, randomised, controlled trial (NCT00660179) in pulmonary arterial hypertension (PAH), macitentan significantly reduced the risk of morbidity/mortality and PAH-related death/hospitalisation. We evaluated disease progression and the effect of macitentan in treatment-naïve incident and prevalent cohorts.Patients allocated to placebo, or macitentan 3 mg or 10 mg were classified by time from diagnosis to enrolment as incident (≤6 months; n=110) or prevalent (>6 months; n=157) ...[more]

PMID: 26493786

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Project description:IntroductionEvaluating overall survival in randomized controlled trials (RCTs) can often be confounded by bias introduced by treatment switching. SERAPHIN was a large RCT that evaluated the effects of long-term treatment with the endothelin receptor antagonist macitentan in patients with pulmonary arterial hypertension. In an intent-to-treat (ITT) analysis, a non-significant decrease in the risk of all-cause mortality up to study closure was reported with macitentan 10 mg versus placebo. As patients could switch treatment when experiencing symptoms of disease progression, this analysis attempts to adjust for the confounding effects on overall survival.MethodsThe inverse probability of censoring weighted (IPCW) and rank-preserving structural failure time (RPSFT) models were used to estimate the treatment effect on overall mortality had there been no treatment switching in SERAPHIN. Time to all-cause death was evaluated up to study closure. Treatment switching was defined as patients in the placebo group switching to open-label macitentan 10 mg, and patients in the macitentan 10 mg group prematurely discontinuing macitentan.ResultsBy study closure, 73.2% (183/250) of patients in the placebo group had switched to macitentan 10 mg. Among these patients, exposure time to macitentan 10 mg represented 28.2% of total study treatment exposure (cumulative exposure 134.6 patient-years). At study closure, 24.8% (60/242) of patients in the macitentan 10 mg group were not receiving open-label macitentan; mean time not receiving macitentan was 44.3 weeks. The adjusted hazard ratios (HR) for overall survival using the IPCW and RPSFT methods were lower (HR 0.42, 95% confidence interval [CI] 0.22, 0.81; p = 0.009, and HR 0.33, 95% CI 0.04, 2.83, respectively) than the ITT unadjusted HR (0.80, 95% CI 0.51, 1.24).ConclusionThese results from the current analyses indicate that in SERAPHIN, the standard ITT analysis was confounded by treatment switching resulting in an underestimation of the benefit of macitentan 10 mg on overall survival. By adjusting for switching, the IPCW and RPSFT models estimated a 58% and 67% reduction in risk of mortality, respectively, with macitentan 10 mg versus placebo.Trial registrationClinicalTrials.gov identifier: NCT00660179.

Project description:IntroductionIn SERAPHIN, a long-term, event-driven, double-blind randomised controlled trial in pulmonary arterial hypertension (PAH), macitentan 10 mg significantly reduced the risk of morbidity/mortality compared with placebo. Its open-label extension study (SERAPHIN OL) further assessed long-term safety and tolerability of macitentan 10 mg in PAH patients.MethodsPatients in SERAPHIN who completed the double-blind treatment period or experienced a morbidity event during the study could enter SERAPHIN OL. Patients received macitentan 10 mg once daily, and safety and survival were assessed until end of treatment (+ 28 days). Two overlapping sets were analysed for safety: (1) all patients in SERAPHIN OL (OL safety set); (2) patients randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Survival was evaluated as an exploratory endpoint in the latter set.ResultsOf 742 patients randomised in SERAPHIN, 550 (74.1%) entered SERAPHIN OL (OL safety set); 242 patients were randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Median (min, max) exposure to macitentan 10 mg was 40.1 (0.1, 130.5) months (2074.7 patient-years; OL safety set) and 54.7 (0.1, 141.3) months (1151.0 patient-years; long-term safety/survival set). Safety in both analysis sets was comparable to the known safety profile of macitentan. Kaplan-Meier survival estimates (95% CI) at 1, 5, 7 and 9 years were 95.0% (91.3, 97.1), 73.3% (66.6, 78.9), 62.6% (54.6, 69.6) and 52.7% (43.6, 61.0), respectively (long-term safety/survival set; median follow-up: 5.9 years).ConclusionsThis analysis provides the longest follow-up for safety and survival published to date for any PAH therapy. The safety profile of macitentan 10 mg over this extensive treatment period was in line with that observed in SERAPHIN. As the majority of patients were receiving other PAH therapy at macitentan initiation, our study provides additional insight into the long-term safety of macitentan, including as part of combination therapy.Trial registrationClinicalTrials.gov Identifiers: NCT00660179 and NCT00667823.

Dataset Information

Incident and prevalent cohorts with pulmonary arterial hypertension: insight from SERAPHIN.

Publications

Incident and prevalent cohorts with pulmonary arterial hypertension: insight from SERAPHIN.

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