Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest: a statistical analysis plan
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Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest: a statistical analysis plan Janus Christian Jakobsen1,2,3* , Josef Dankiewicz4, Theis Lange5, Tobias Cronberg6, Gisela Lilja6, Helena Levin7, Jan Bělohlávek8, Clifton Callaway9, Alain Cariou10, David Erlinge4, Jan Hovdenes11, Michael Joannidis12, Per Nordberg13, Mauro Oddo14, Paolo Pelosi15,16, Hans Kirkegaard17, Glenn Eastwood18, Christian Rylander19, Manoj Saxena20, Christian Storm21,22, Fabio Silvio Taccone23, Matthew P. Wise24, Matt P. G. Morgan24, Paul Young25, Alistair Nichol26,27,28, Hans Friberg29, Susann Ullén30† and Niklas Nielsen31†
Abstract Background: To date, targeted temperature management (TTM) is the only neuroprotective intervention after resuscitation from cardiac arrest that is recommended by guidelines. The evidence on the effects of TTM is unclear. Methods/design: The Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2) trial is an international, multicentre, parallel group, investigator-initiated, randomised, superiority trial in which TTM with a target temperature of 33 °C after cardiac arrest will be compared with a strategy to maintain normothermia and active treatment of fever (≥ 37.8 °C). Prognosticators, outcome assessors, the steering group, the trial coordinating team, and trial statisticians will be blinded to treatment allocation. The primary outcome will be all-cause mortality at 180 days after randomisation. We estimate a 55% mortality in the targeted normothermia group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The secondary neurological outcome will be poor functional outcome (modified Rankin scale 4–6) at 180 days after cardiac arrest. In this paper, a detailed statistical analysis plan is presented, including a comprehensive description of the statistical analyses, handling of missing data, and assessments of underlying statistical assumptions. Final analyses will be conducted independently by two qualified statisticians following the present plan. Discussion: This SAP, which was prepared before completion of enrolment, should increase the validity of the TTM trial by mitigation of analysis-bias.
Related article: https://doi.org/10.1016/j.ahj.2019.06.012 * Correspondence: [email protected] Susann Ullén and Niklas Nielsen are shared the last authorship. 1 Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Tagensvej 22, Copenhagen, Denmark 2 Department of Cardiology, Holbæk Hospital, Holbæk, Denmark Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the
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