Time of Day, Outcome, and Response to Thrombolytic Therapy: The National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Trial Experience

Abstract

Circadian pattern for the onset of acute ischemic stroke has been described; however, data assessing an association between thrombolytic therapy efficacy and circadian rhythm are limited. We assessed the relationship between the time of stroke onset and neurologic outcomes after thrombolytic therapy for acute ischemic stroke in the National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator (rt-PA) Stroke Trial. We conducted exploratory, post hoc analysis of 624 patients in the NINDS rt-PA Stroke Trial. Variables assessed included presenting time of day (4- and 6-hour time blocks), outcome variables, stroke subtypes, treatment assignment, and biological markers. Outcome variables included 3-month mortality, clinical outcome at 3 months, intracranial hemorrhage (ICH), computed tomography lesion volume at 3 months, and deterioration at 24 hours. The distribution of patients in the time blocks was balanced between the rt-PA and placebo groups. There was not a clear circadian variation in the stroke onset time. There were no associations detected between stroke onset time and clinical outcome, computed tomography lesion volume, and asymptomatic hemorrhage. Patients treated with rt-PA whose stroke onset was between 0401 and 0800 hours had less symptomatic ICH, whereas those who received rt-PA between 0000 and 0400 hours had a 43% incidence of symptomatic ICH. Patients in the placebo group who had stroke onset between 1801 and 2400 hours had lower chances for neurologic deterioration. Patients who had a stroke between 0001 and 0400 hours had the highest fibrinogen concentrations. We did not find a circadian pattern to time of day of stroke onset in the patients included in the NINDS rt-PA Stroke Trial. The effect of rt-PA treatment on favorable outcome was independent of time of day of stroke onset. Patients who received rt-PA between 4 and 8 am were less likely to develop symptomatic ICH.