Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2)

Abstract

Background and purpose: Therapeutic hypothermia is a potent neuroprotectant approved for cerebral protection after neonatal hypoxia-ischemia and cardiac arrest. Therapeutic hypothermia for acute ischemic stroke is safe and feasible in pilot trials. We designed a study protocol to provide safer, faster therapeutic hypothermia in stroke patients.

Methods: Safety procedures and 4°C saline infusions for faster cooling were added to the ICTuS trial (Intravascular Cooling in the Treatment of Stroke) protocol. A femoral venous intravascular cooling catheter after intravenous recombinant tissue-type plasminogen activator in eligible patients provided 24 hours cooling followed by a 12-hour rewarm. Serial safety assessments and imaging were performed. The primary end point was 3-month modified Rankin score 0,1.

Results: Of the intended 1600 subjects, 120 were enrolled before the study was stopped. Randomly, 63 were to receive hypothermia plus antishivering treatment and 57 normothermia. Compared with previous studies, cooling rates were improved with a cold saline bolus, without fluid overload. The intention-to-treat primary outcome of 90-day modified Rankin Score 0,1 occurred in 33% hypothermia and 38% normothermia subjects, odds ratio (95% confidence interval) of 0.81 (0.36-1.85). Serious adverse events occurred equally. Mortality was 15.9% hypothermia and 8.8% normothermia subjects, odds ratio (95% confidence interval) of 1.95 (0.56-7.79). Pneumonia occurred in 19% hypothermia versus 10.5% in normothermia subjects, odds ratio (95% confidence interval) of 1.99 (0.63-6.98).

Conclusions: Intravascular therapeutic hypothermia was confirmed to be safe and feasible in recombinant tissue-type plasminogen activator-treated acute ischemic stroke patients. Protocol changes designed to reduce pneumonia risk appeared to fail, although the sample is small.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01123161.

Keywords: hypothermia; intention to treat analysis; ischemic stroke; neuroprotection; pneumonia; stroke; therapeutics.

Figure 1. CONSORT flow diagram

The flow of patients into the trial is summarized according to CONSORT guidelines. Patients could be excluded for more than one reason. A total of 3 patients were lost to follow up, 2 NT and 1HY. However, the HY patient was available by telephone, and for the 3 month mRS (primary endpoint) only, a score was recorded.

Figure 2. Key Trial Milestones

Time from arrival in the Emergency Department (ED) to key milestone events is summarized with box plots. Out of 63 ITT HY patients, no data was collected in 9 “early responder” patients; one patient crossed over from HY to NT; so the plots summarize data from the remaining 53 ITT HY patients. Each line represents the median, each box represents the upper and lower quartile, and whiskers are 1. 5* interquartile distance (IQD) from the quartile (upper, and lower, respectively). Outliers are shown as open circles. Bolus = time to rt-PA bolus. Saline = time to initiation of saline bolus. Cath = time to skin puncture for intravascular cooling catheter insertion. Cool = time to initiate cooling (start the cooling console) after successful catheter insertion. Target = time to first temperature in target range (<34 °C) or lowest temperature achieved if target was never reached.

Figure 3. Vital Signs Throughout the Duration of Cooling and Rewarming

At each time point the ITT population mean and 95% confidence intervals using standard errors is shown for each variable. Systolic blood pressure (Panel A) and oxygen saturation (Panel C) were not statistically different between groups. Respiratory rate (Panel B) was significantly suppressed in the hypothermia group (Wilcoxon Rank Sum test P<0.01). Core body temperature (Panel D) was rapidly and significantly reduced (Wilcoxon Rank Sum test P<0.01).