SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis

Harm-Jan de Grooth, Irma L Geenen, Armand R Girbes, Jean-Louis Vincent, Jean-Jacques Parienti, Heleen M Oudemans-van Straaten, Harm-Jan de Grooth, Irma L Geenen, Armand R Girbes, Jean-Louis Vincent, Jean-Jacques Parienti, Heleen M Oudemans-van Straaten

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 I 2).

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, I 2 = 5%); the overall mortality effect explained by SOFA score (R 2) 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, I 2 = 12%) and explained 3% of the overall mortality effect (R 2). Delta SOFA was significantly associated with mortality (slope = 0.70 (95% CI 0.26; 1.14), p = 0.004, I 2 = 0%) and explained 32% of the overall mortality effect (R 2).

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.

Keywords: Critical care trials; Multiple organ failure; Sepsis; Surrogate endpoints.

Figures

Fig. 1
Fig. 1
Flowchart of the search strategy and included trials. SOFA sequential organ failure assessment, RCT randomized controlled trial
Fig. 2
Fig. 2
Included trials by publication year
Fig. 3
Fig. 3
Regression analyses of the relationship between the RCT treatment effects on mortality vs. (a) any SOFA endpoint, (b) Fixed-day SOFA, and (c) Delta SOFA. The size of the circle is proportional to the RCT sample size. RCTs in the green quadrants show agreement between SOFA and the effects on mortality (e.g. lower SOFA and lower mortality), while RCTs in the red quadrants show conflicting effects (lower SOFA but higher mortality or vice versa). Broken line significant association with residual heterogeneity; solid line significant association without residual heterogeneity. SOFA sequential organ failure assessment, RCT randomized controlled trial, OR odds ratio

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