title: SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis.
abstract: BACKGROUND
  The sequential organ failure assessment score (SOFA) is increasingly used as an endpoint in intensive care randomized controlled trials (RCTs). Although serially measured SOFA is independently associated with mortality in observational cohorts, the association between treatment effects on SOFA vs. effects on mortality has not yet been quantified in RCTs. The aim of this study was to quantify the relationship between SOFA and mortality in RCTs and to identify which SOFA derivative best reflects between-group mortality differences.
  
  
  METHODS
  The review protocol was prospectively registered (Prospero CRD42016034014). We performed a literature search (up to May 1, 2016) for RCTs reporting both SOFA and mortality, and analyzed between-group differences in these outcomes. Treatment effects on SOFA and mortality were calculated as the between-group SOFA standardized difference and log odds ratio (OR), respectively. We used random-effects meta-regression to (1) quantify the linear relationship between RCT treatment effects on mortality (logOR) and SOFA (i.e. responsiveness) and (2) quantify residual heterogeneity (i.e. consistency, expressed as I2).
  
  
  RESULTS
  Of 110 eligible RCTs, 87 qualified for analysis. Using all RCTs, SOFA was significantly associated with mortality (slope = 0.49 (95% CI 0.17; 0.82), p = 0.006, I2= 5%); the overall mortality effect explained by SOFA score (R2) was 9%. Fifty-eight RCTs used Fixed-day SOFA as an endpoint (i.e. the score on a fixed day after randomization), 25 studies used Delta SOFA as an endpoint (i.e. the trajectory from baseline score) and 15 studies used other SOFA derivatives as an endpoint. Fixed-day SOFA was not significantly associated with mortality (slope = 0.35 (95% CI -0.04; 0.75), p = 0.08, I2= 12%) and explained 3% of the overall mortality effect (R2). Delta SOFA was significantly associated with mortality (slope = 0.70 (95% CI 0.26; 1.14), p = 0.004, I2= 0%) and explained 32% of the overall mortality effect (R2).
  
  
  CONCLUSIONS
  Treatment effects on Delta SOFA appear to be reliably and consistently associated with mortality in RCTs. Fixed-day SOFA was the most frequently reported outcome among the reviewed RCTs, but was not significantly associated with mortality. Based on this study, we recommend using Delta SOFA rather than Fixed-day SOFA as an endpoint in future RCTs.
authors.affiliation: Department of Intensive Care, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. h.degrooth@vumc.nl.
authors.forename: Harm-Jan
authors.identifier: http://orcid.org/0000-0002-7499-076X
authors.initials: HJ
authors.lastname: de Grooth
authors.affiliation: Department of Intensive Care, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Irma L
authors.initials: IL
authors.lastname: Geenen
authors.affiliation: Department of Intensive Care, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Armand R
authors.initials: AR
authors.lastname: Girbes
authors.affiliation: Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vincent
authors.affiliation: Unité de Biostatistique et de Recherche Clinique, Centre Hospitalier Universitaire de Caen, Caen, France.|EA4655 « Risques microbiens », Faculté de Médecine, Université de Caen Normandie, Caen, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Parienti
authors.affiliation: Department of Intensive Care, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Heleen M
authors.initials: HM
authors.lastname: Oudemans-van Straaten
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D017052:Hospital Mortality / Q000639:trends*; D006801:Humans; D007362:Intensive Care Units / Q000458:organization & administration / Q000639:trends; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D063305:Organ Dysfunction Scores; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D016896:Treatment Outcome
keywords: Critical care trials; Multiple organ failure; Sepsis; Surrogate endpoints