Effects of simulated sample sizes on the mortality effect estimates in three randomized intensive care unit trials

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Background: Randomized 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. Methods: In 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. Results: The 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. Conclusions: In 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.

OriginalsprogEngelsk
TidsskriftActa Anaesthesiologica Scandinavica
Vol/bind64
Udgave nummer7
Sider (fra-til)976-981
Antal sider6
ISSN0001-5172
DOI
StatusUdgivet - 2020

Bibliografisk note

Funding Information:
There was no funding or commercial support for this study. Funding of the original trials: The 6S trial: Supported by grants from the Danish Research Council (271‐08‐0691 and 09‐066938), the Rigshospitalet Research Council, and the Scandinavian Society of Anesthesiology and Intensive Care Medicine (funded by the ACTA Foundation). The TRISS trial: Supported by a grant (09‐066938) from the Danish Strategic Research Council and by Copenhagen University Hospital, Rigshospitalet, the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (ACTA Foundation), and Ehrenreich's Foundation. The SUP‐ICU trial: Supported by Innovation Fund Denmark (4108‐00011A), Rigshospitalet, the Capital Region of Denmark, the Regions of Denmark, the Scandinavian Society of Anaesthesiology and Intensive Care Medicine, Ehrenreich's Foundation, the Aase and EjnarDanielsens Foundation, the Danish Society of Anesthesiology and Intensive Care Medicine, the Danish Medical Association and the European Society of Intensive Care Medicine.

Publisher Copyright:
© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd

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