Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial.

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.

• Authors: Pierre-Francois Laterre, Scott M Berry, Allan Blemings, Jan E Carlsen, Bruno François, Todd Graves, Karsten Jacobsen, Roger J Lewis, Steven M Opal, Anders Perner, Peter Pickkers, James A Russell, Nis A Windeløv, Donald M Yealy, Pierre Asfar, Morten H Bestle, Grégoire Muller, Cédric Bruel, Noëlle Brulé, Johan Decruyenaere, Alain-Michel Dive, Thierry Dugernier, Kenneth Krell, Jean-Yves Lefrant, Bruno Megarbane, Emmanuelle Mercier, Jean-Paul Mira, Jean-Pierre Quenot, Bodil Steen Rasmussen, Hans-Christian Thorsen-Meyer, Margot Vander Laenen, Marianne Lauridsen Vang, Philippe Vignon, Isabelle Vinatier, Sine Wichmann, Xavier Wittebole, Anne Louise Kjølbye, Derek C Angus, SEPSIS-ACT Investigators
• Journal: JAMA (JAMA) Vol. 322 Issue 15 Pg. 1476-1485 (Oct 15 2019) ISSN: 1538-3598 [Electronic] United States
• PMID: 31577035 (Publication Type: Journal Article)