Time of Day, Outcome, and Response to Thrombolytic Therapy: The National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Trial Experience
Received 5 January 2009; received in revised form 4 March 2009; accepted 9 March 2009.
Objective
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.
Methods
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 24hours.
Results
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 0800hours had less symptomatic ICH, whereas those who received rt-PA between 0000 and 0400hours had a 43% incidence of symptomatic ICH. Patients in the placebo group who had stroke onset between 1801 and 2400hours had lower chances for neurologic deterioration. Patients who had a stroke between 0001 and 0400hours had the highest fibrinogen concentrations.
Conclusions
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.
∗Department of Pharmacy Practice, Wayne State University, Detroit, Michigan
†Department of Neurology, Wayne State University, Detroit, Michigan
‡Department of Neurological Surgery, Wayne State University, Detroit, Michigan
§Department of Biostatistics, Medical University of South Carolina, Charleston
//Department of Neurology, Emory University School of Medicine, Atlanta, Georgia
¶Department of Neurosciences, University of California, San Diego
#Department of Neurology, The Mount Sinai School of Medicine, New York, New York
∗∗Mount Sinai Stroke Center, The Mount Sinai School of Medicine, New York, New York
Address correspondence to Denise H. Rhoney, PharmD, Departments of Pharmacy Practice and Neurology, Wayne State University, 259 Mack Ave, Detroit, MI 48201.
Supported by the National Institute of Neurological Disorders and Stroke (N01-NS-02383, N01-NS-02374, N01-NS-02377, N01-NS-02381, N01-NS-02379, N01-NS-02373, N01-NS-02378, N01-NS-02376, N01-NS-02380, K24N543992, and R01-NS-38905).
ABSTRACT