Prevalence of bias attributable to composite outcome in clinical trials: a systematic review

ObjectiveTo investigate the prevalence of bias attributable to composite outcome (BACO) in clinical trials. Study design and settingWe searched PubMed for randomized clinical trials where the primary outcome was a binary composite that included all-cause mortality among its components from January 1, 2019, to December 31, 2020. For each trial, the BACO index was calculated to assess the correspondence between effects on the composite outcome and that on mortality. This systematic review was registered in PROSPERO (CRD42021229554). ResultsAfter screening 1,076 citations and 171 full-text articles, 91 studies were included from 13 different medical areas. The prevalence of significant or suggestive BACO among the 91 included articles was 25.2% (n=23), including 12 with p<0.005 and 11 with p between 0.005 and <0.05. We observed that in 17 (73.9%) of these 23 studies, the BACO index value was between zero and <1, indicating an underestimation of the effect. The other six studies showed negative values (26.1%), indicating an inversion of the association with mortality. None of the studies showed significant overestimation of the association attributable to the composite outcome. ConclusionThese findings highlight the need to predefine guidelines for interpreting effects on composite endpoints based on objective criteria such as the BACO index. What is new?O_ST_ABSKey FindingsC_ST_ABSO_LIThe study found that 25.2% of the included clinical trials exhibited significant or suggestive bias attributable to composite outcomes (BACO). C_LIO_LIIn 73.9% of these cases, the BACO index was less than 1, indicating an underestimation of the effect. 26.1% of the studies showed an inversion of the association with mortality. C_LIO_LINo significant overestimation of the association due to composite outcomes was observed. C_LI What This Adds to What Was Known?O_LIThis study contributes to the existing knowledge by quantifying the prevalence of bias attributable to composite outcomes in clinical trials. C_LIO_LIIt highlights that a significant proportion of trials may underestimate the effect or even show an inversion of the association with mortality when composite outcomes are used. C_LIO_LIThis finding emphasizes the need for careful consideration and objective criteria, like the BACO index, in the design and interpretation of clinical trials involving composite outcomes. C_LI What Is the Implication and What Should Change Now?O_LIResearchers and clinicians should be cautious about relying solely on composite outcomes without assessing the potential biases they introduce. C_LIO_LIThe study suggests a need for predefined guidelines and objective criteria, such as the BACO index, for interpreting the effects of composite outcomes. C_LI