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Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2) : A randomized clinical trial—Rationale and design

Dankiewicz, Josef LU ; Cronberg, Tobias LU ; Lilja, Gisela LU ; Jakobsen, Janus Christian ; Bělohlávek, Jan ; Callaway, Clifton ; Cariou, Alain ; Eastwood, Glenn ; Erlinge, David LU and Hovdenes, Jan , et al. (2019) In American Heart Journal 217. p.23-31
Abstract

Background: Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. Methods: The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of... (More)

Background: Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. Methods: The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. Sedation will be mandatory for all patients throughout the intervention period. The clinical team involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention. Prognosticators, outcome-assessors, the steering group, the trial coordinating team, and trial statistician will be blinded. The primary outcome will be all-cause mortality at 180 days after randomization. We estimate a 55% mortality in the control 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 main secondary neurological outcome will be poor functional outcome (modified Rankin Scale 4–6) at 180 days after arrest. Discussion: The TTM2-trial will compare hypothermia to 33°C with normothermia and early treatment of fever (≥37.8°C) after out-of-hospital cardiac arrest.

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@article{3c94b1eb-7adf-42a9-8593-6eee601b7d92,
  abstract     = {<p>Background: Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. Methods: The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. Sedation will be mandatory for all patients throughout the intervention period. The clinical team involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention. Prognosticators, outcome-assessors, the steering group, the trial coordinating team, and trial statistician will be blinded. The primary outcome will be all-cause mortality at 180 days after randomization. We estimate a 55% mortality in the control 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 main secondary neurological outcome will be poor functional outcome (modified Rankin Scale 4–6) at 180 days after arrest. Discussion: The TTM2-trial will compare hypothermia to 33°C with normothermia and early treatment of fever (≥37.8°C) after out-of-hospital cardiac arrest.</p>},
  author       = {Dankiewicz, Josef and Cronberg, Tobias and Lilja, Gisela and Jakobsen, Janus Christian and Bělohlávek, Jan and Callaway, Clifton and Cariou, Alain and Eastwood, Glenn and Erlinge, David and Hovdenes, Jan and Joannidis, Michael and Kirkegaard, Hans and Kuiper, Michael and Levin, Helena and Morgan, Matt P.G. and Nichol, Alistair D. and Nordberg, Per and Oddo, Mauro and Pelosi, Paolo and Rylander, Christian and Saxena, Manoj and Storm, Christian and Taccone, Fabio and Ullén, Susann and Wise, Matthew P. and Young, Paul and Friberg, Hans and Nielsen, Niklas},
  issn         = {0002-8703},
  language     = {eng},
  pages        = {23--31},
  publisher    = {Mosby},
  series       = {American Heart Journal},
  title        = {Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2) : A randomized clinical trial—Rationale and design},
  url          = {http://dx.doi.org/10.1016/j.ahj.2019.06.012},
  doi          = {10.1016/j.ahj.2019.06.012},
  volume       = {217},
  year         = {2019},
}