• Andreas Kofoed, Anders Perner, Søren Marker, Nicolai Haase, Lars B Holst, and MøllerMorten HylanderMH0000-0002-6378-9673Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.Centre for Research in Intensive Care (CRIC), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark..
• Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
• Acta Anaesthesiol Scand. 2020 Aug 1; 64 (7): 976-981.

BackgroundRandomized clinical trials (RCTs) are occasionally stopped prematurely before reaching their planned sample sizes. It has been suggested that early stopped RCTs are associated with under- and overestimation of the effect estimates. We simulated the effect of hypothetical premature stopping of three large RCTs done in the intensive care unit (ICU) setting.MethodsIn this post hoc study, we simulated the impact of stopping trials early by calculating mortality effect estimates continuously after the inclusion of each individual patient in three large RCTs, that is the 6S trial on hydroxyethyl starch vs Ringer's acetate in sepsis in ICU, the TRISS trial on lower vs higher haemoglobin threshold for transfusion in septic shock in ICU and the SUP-ICU trial on pantoprazole in patients at risk for gastrointestinal bleeding in the ICU.ResultsThe three trials included a total of 5087 patients; 798 from the 6S trial, 998 from the TRISS trial and 3291 patients from the SUP-ICU trial. The premature mortality effect estimates showed considerable fluctuations until at least 20%-30% of the sample size was included. The premature estimates became stable after inclusion of 205 patients (26% of the final sample size) in the 6S trial, 133 patients(13%) in the TRISS trial and 1926 patients(59%) in the SUP-ICU trial.ConclusionsIn this post hoc study of three international RCTs within intensive care, we found that the simulated interim mortality effect estimates showed considerable fluctuations until at least 20%-30% of the sample size was included, but remained instable until the final sample sizes had been included. Thus, this study illustrates the necessity for cautious interpretations of prematurely stopped trials.© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

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