title: Designing phase 3 sepsis trials: application of learned experiences from critical care trials in acute heart failure.
abstract: Substantial attention and resources have been directed to improving outcomes of patients with critical illnesses, in particular sepsis, but all recent clinical trials testing various interventions or strategies have failed to detect a robust benefit on mortality. Acute heart failure is also a critical illness, and although the underlying etiologies differ, acute heart failure and sepsis are critical care illnesses that have a high mortality in which clinical trials have been difficult to conduct and have not yielded effective treatments. Both conditions represent a syndrome that is often difficult to define with a wide variation in patient characteristics, presentation, and standard management across institutions. Referring to past experiences and lessons learned in acute heart failure may be informative and help frame research in the area of sepsis. Academic heart failure investigators and industry have worked closely with regulators for many years to transition acute heart failure trials away from relying on dyspnea assessments and all-cause mortality as the primary measures of efficacy, and recent trials have been designed to assess novel clinical composite endpoints assessing organ dysfunction and mortality while still assessing all-cause mortality as a separate measure of safety. Applying the lessons learned in acute heart failure trials to severe sepsis and septic shock trials might be useful to advance the field. Novel endpoints beyond all-cause mortality should be considered for future sepsis trials.
authors.affiliation: University Paris Diderot, Sorbonne Paris Cité, Paris, France ; U942 Inserm, APHP, Paris, France ; APHP, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint Louis-Lariboisière, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mebazaa
authors.affiliation: Department of Critical Care Medicine, St. Luc University Hospital, Université Catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Pierre François
authors.initials: PF
authors.lastname: Laterre
authors.affiliation: Center for Heart Lung Innovation and the Division of Critical Care Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.affiliation: Adrenomed AG, Hennigsdorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergmann
authors.affiliation: Università di Milano, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Gattinoni
authors.affiliation: Département d'Anesthésie - Réanimation - SMUR, Hôpitaux Universitaires Saint Louis - Lariboisière, INSERM - UMR 942, Assistance Publique - Hôpitaux de Paris, Université Paris Diderot, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Gayat
authors.affiliation: Division of Epidemiology, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Harhay
authors.affiliation: Adrenomed AG, Hennigsdorf, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartmann
authors.affiliation: Adrenomed AG, Hennigsdorf, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Hein
authors.affiliation: Ferring Pharmaceuticals, Copenhagen, Denmark.
authors.forename: Anne Louise
authors.initials: AL
authors.lastname: Kjolbye
authors.affiliation: Department of Anesthesiology, Critical Care and Burn Unit, St. Louis Hospital, University Paris 7 Denis Diderot, UMR-S942, Inserm, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Legrand
authors.affiliation: Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, CA USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Lewis
authors.affiliation: Department of Surgery, Interdepartmental Division of Critical Care Medicine, University of Toronto, St. Michael's Hospital, Toronto, Ontario Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Marshall
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Marx
authors.affiliation: Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Radermacher
authors.affiliation: Adrenomed AG, Hennigsdorf, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Schroedter
authors.affiliation: Adrenomed AG, Hennigsdorf, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Scigalla
authors.affiliation: Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC USA.
authors.forename: Wendy Gattis
authors.initials: WG
authors.lastname: Stough
authors.affiliation: Adrenomed AG, Hennigsdorf, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Struck
authors.affiliation: Clinical Department and Laboratory of Intensive Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
authors.affiliation: Department of Cardiology, Cumhuriyet University Faculty of Medicine, Sivas, Turkey.
authors.forename: Mehmet Birhan
authors.initials: MB
authors.lastname: Yilmaz
authors.affiliation: CRISMA Center, Department of Critical Care Medicine, McGowan Institute for Regnerative Medicine, Clinical and Translational Science Institute, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA USA ; Department of Health Policy and Management, McGowan Institute for Regnerative Medicine, Clinical and Translational Science Institute, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA USA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
keywords: Clinical trials as topic; Heart failure; Mortality; Multiple organ failure; Sepsis