Implications of Central Adjudication for the Primary Outcome in an International Randomized Trial

Background: Masked adjudication of trial outcomes that are subject to ascertainment bias increases the validity of reported treatment effects, but central adjudication is resource intensive and its influence on reported results is unclear. Research Question: What is the impact of adjudicating the primary efficacy outcome of clinically important upper gastrointestinal bleeding used in a stress ulcer prophylaxis trial? Study Design and Methods: This was a preplanned secondary analysis of the Re-Evaluating the Inhibition of Stress Erosions (REVISE) trial database. The REVISE trial compared daily pantoprazole with placebo in patients who were invasively ventilated. Sites submitted relevant clinical data for each gastrointestinal bleeding episode that were reviewed in duplicate by trained adjudicators masked to treatment allocation and site. Results: Adjudicators reviewed 271 possible bleeding events from 236 patients. Between adjudicator pairs, crude agreement about the presence or absence of clinically important upper gastrointestinal bleeding occurred for 233 of 236 patients (98.7%) of suspected events. One hundred nine patients were adjudicated as having a clinically important upper gastrointestinal bleed. The final analysis showed less bleeding among those receiving pantoprazole (hazard ratio, 0.30; 95% CI, 0.19-0.47; P < .001). Had the 182 patients with site-reported upper gastrointestinal events been used for analysis, the benefit of pantoprazole also would have been shown (hazard ratio, 0.42; 95% CI, 0.31-0.58; P < .001). Interpretation: Our results show that central adjudication of the trial outcome of clinically important upper gastrointestinal bleeding may generate more credible outcome ascertainment, but in our study, it reduced the overall event rate by 40%. If site-submitted events had been analyzed instead of adjudicated events, the trial effect size would have been similar, but qualitatively smaller. Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03374800; URL: www.clinicaltrials.gov