The Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients (ICECAP) Trial
William J. Meurer1, Robert Silbergleit2, Romergryko Geocadin3, Sharon Yeatts4, Viswanathan Ramakrishnan4
1Departments of Emergency Medicine and Neurology, University of Michigan, 2University of Michigan, 3Johns Hopkins University School of Medicine, 4Medical University of South Carolina
Objective:
To characterize, in comatose survivors of cardiac arrest, the duration-response curve for hypothermia to determine the shortest cooling duration (target) that provides the maximal treatment effect, and whether the duration-response curve implies efficacy versus no cooling.
Background:
Delayed neurological death or disability is the most common outcome among comatose survivors of out-of-hospital cardiac arrest (OHCA). Therapeutic hypothermia (TH) is neuroprotective in animal models of hypoxic ischemic brain injury, and has demonstrated efficacy in some human indications. Clinical trials of TH in adults after OHCA have not consistently demonstrated improved outcomes. Efficacy may depend on implementation factors, including cooling duration and patient selection.
Design/Methods:
ICECAP was a multi-center randomized, response-adaptive, duration (dose) finding, clinical trial with blinded outcome assessment. We included two populations of adult comatose survivors of OHCA to determine the shortest cooling duration to 33°C that yielded the maximum treatment effect. The design used a statistical model of response as defined by the primary endpoint, a weighted 90-day modified Rankin Scale, across the treatment arms. For 200 enrollments, patients were equally randomized to 12, 24, or 48 h of therapeutic cooling. Following that, additional treatment arms between 6 and 72 h potentially opened, and patients were allocated within each initial cardiac rhythm type (shockable or non-shockable) by response-adaptive randomization. The maximum sample size was 1800.
Results:
After randomizing 1158 patients, the trial met a pre-specified stopping rule at a planned interim analysis. The 6-hour duration had a greater than 50% probability of being the target. The longest duration used was 48 hours; the prespecified model incorporating accumulating outcomes from the trial did not allocate to 60 or 72 hours. No safety issues were noted by the DSMB. Full results will be presented at the meeting.
Conclusions:
Longer durations of TH were not associated with improved neurological outcomes in the ICECAP trial.
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