Hyperacute treatment initiation in neuroprotective agent stroke trials

Background: Late treatment start may be an important cause for the repeated failure of neuroprotective agents in acute ischemic stroke trials. Animal models suggest the optimal therapeutic window for neuroprotective intervention is the first 1 to 3 hours after ischemia onset. No prior study has analyzed the frequency of treatment initiation within the first 1, 2, and 3 hours in human neuroprotective stroke clinical trials. Methods: A total of 30 phase 3 neuroprotective trials published in English between 1990 and 2001 were identified by systematic literature review. A 1-page, 4-field data questionnaire was mailed to the principal investigators of identified trials, asking them to specify the number of patients enrolled in their trial or trials within the following epochs: 0 to 60, 61 to 120, 121 to 180, and 181 to 360 minutes. Results: A total of 6 trials, enrolling 5345 patients, provided detailed data. In all, 4 trials, enrolling 4166 patients, used a maximum permitted time enrollment window of less than 6 hours, whereas two trials allowed enrollment beyond 6 hours. Across all trials, the number and proportion of patients enrolled in early time epochs were: 0 to 60 minutes, 10 (0.2%); 61 to 120 minutes, 66 (1.2%); 121 to 180 minutes, 340 (6.3%); and 181 to 360 minutes, 3723 (69.7%). Even in trials with less than 6-hour time windows, fewer than 2% of patients received study agent within 2 hours of onset. Conclusions: Only a very small proportion of patients in recent neuroprotective acute stroke trials have been enrolled in hyperacute, under 3-hour time epochs, when treatment effect is likely to be most substantial. New treatment delivery and trial design strategies are suggested that could accelerate agent initiation in neuroprotective treatment trials.