Abstract
BackgroundThe 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.MethodsThe 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).ResultsOf 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).ConclusionsTreatment 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.
Highlights
The sequential organ failure assessment score (SOFA) is increasingly used as an endpoint in intensive care randomized controlled trials (RCTs)
The SOFA score was recognized as a potential endpoint for randomized controlled trials (RCTs) when serially measured scores were found to be associated with mortality independent of admission score [2,3,4]
Most RCTs were performed in patients with severe sepsis or septic shock
Summary
The sequential organ failure assessment score (SOFA) is increasingly used as an endpoint in intensive care randomized controlled trials (RCTs). The SOFA score was recognized as a potential endpoint for randomized controlled trials (RCTs) when serially measured scores were found to be associated with mortality independent of admission score [2,3,4]. Due to its scalar nature, demonstrating a treatment effect on SOFA score requires a smaller sample size than demonstrating an effect on (dichotomous) mortality. This has led to increasing popularity of the SOFA score as a primary or secondary endpoint in RCTs. The SOFA score is an intrinsically informative endpoint because it can be used to evaluate the effects of treatment on organ dysfunction, a primary focus of intensive care. To extrapolate treatment effects from an intermediate outcome to a clinical outcome, effects of an intervention on the intermediate outcome (SOFA score) must reliably predict the overall effect on the clinical outcome (mortality) [6, 7]
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