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Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock

Pierre-François Laterre 1, 2 Scott Berry Allan Blemings 3 Jan Carlsen Bruno Francois 4 Todd Graves Karsten Jacobsen 3 Roger Lewis 5, 6 Steven Opal 7 Anders Perner 8 Peter Pickkers 9 James Russell 10 Nis Windeløv 3 Donald Yealy 11 Pierre Asfar 12 Morten Bestle Grégoire Muller 13 Cédric Bruel 14 Noëlle Brule 15 Johan Decruyenaere 16 Alain-Michel Dive 2 Thierry Dugernier Kenneth Krell Jean-Yves Lefrant 17, 18 Bruno Megarbane 19, 20 Emmanuelle Mercier 21 Jean-Paul Mira 22 Jean-Pierre Quenot 23 Bodil Steen Rasmussen Hans-Christian Thorsen-Meyer 8 Margot Vander Laenen 24 Marianne Lauridsen Vang Philippe Vignon 4 Isabelle Vinatier 25 Sine Wichmann Xavier Wittebole 1, 2 Anne Louise Kjolbye 3 Derek Angus 26
Abstract : Importance: Norepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects. Objective: To test whether selepressin improves outcome in septic shock. Design, setting, and participants: An adaptive phase 2b/3 randomized clinical trial comprising 2 parts that included adult patients (n = 868) with septic shock requiring more than 5 μg/min of norepinephrine. Part 1 used a Bayesian algorithm to adjust randomization probabilities to alternative selepressin dosing regimens and to trigger transition to part 2, which would compare the best-performing regimen with placebo. The trial was conducted between July 2015 and August 2017 in 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States, and follow-up was completed by May 2018. Interventions: Random assignment to 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, and 3.5 ng/kg/min; n = 585) or to placebo (n = 283), all administered as continuous infusions titrated according to hemodynamic parameters. Main outcomes and measures: Primary end point was ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) of commencing study drug. Key secondary end points were 90-day mortality, kidney replacement therapy-free days, and ICU-free days. Results: Among 868 randomized patients, 828 received study drug (mean age, 66.3 years; 341 [41.2%] women) and comprised the primary analysis cohort, of whom 562 received 1 of 3 selepressin regimens, 266 received placebo, and 817 (98.7%) completed the trial. The trial was stopped for futility at the end of part 1. Median study drug duration was 37.8 hours (IQR, 17.8-72.4). There were no significant differences in the primary end point (ventilator- and vasopressor-free days: 15.0 vs 14.5 in the selepressin and placebo groups; difference, 0.6 [95% CI, -1.3 to 2.4]; P = .30) or key secondary end points (90-day mortality, 40.6% vs 39.4%; difference, 1.1% [95% CI, -6.5% to 8.8%]; P = .77; kidney replacement therapy-free days: 18.5 vs 18.2; difference, 0.3 [95% CI, -2.1 to 2.6]; P = .85; ICU-free days: 12.6 vs 12.2; difference, 0.5 [95% CI, -1.2 to 2.2]; P = .41). Adverse event rates included cardiac arrhythmias (27.9% vs 25.2% of patients), cardiac ischemia (6.6% vs 5.6%), mesenteric ischemia (3.2% vs 2.6%), and peripheral ischemia (2.3% vs 2.3%). Conclusions and relevance: Among patients with septic shock receiving norepinephrine, administration of selepressin, compared with placebo, did not result in improvement in vasopressor- and ventilator-free days within 30 days. Further research would be needed to evaluate the potential role of selepressin for other patient-centered outcomes in septic shock. Trial registration: ClinicalTrials.gov Identifier: NCT02508649.
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https://hal.umontpellier.fr/hal-02793704
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Soumis le : vendredi 5 juin 2020 - 10:04:24
Dernière modification le : mercredi 19 août 2020 - 11:19:08

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Pierre-François Laterre, Scott Berry, Allan Blemings, Jan Carlsen, Bruno Francois, et al.. Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock. JAMA Cardiology, American Medical Association 2019, 322 (15), pp.1476-1485. ⟨10.1001/jama.2019.14607⟩. ⟨hal-02793704⟩

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