RationaleBecause of lack of information regarding timing of stroke, patients who suffer stroke during sleep are generally ineligible for intravenous thrombolysis, although many of these patients could potentially recover with this treatment. Magnetic resonance image findings with positive diffusion-weighted imaging and no marked parenchymal hyperintensity on fluid-attenuated inversion recovery (negative pattern) can identify acute ischemic stroke patients within 4·5 h from symptom onset.AimsThe THrombolysis for Acute Wake-up and unclear-onset Strokes with alteplase at 0·6 mg/kg trial aims to determine the efficacy and safety of intravenous thrombolysis with alteplase at 0·6 mg/kg body weight, the approved dose for Japanese stroke patients, using magnetic resonance image-based selection in ischemic stroke patients with unclear time of symptom onset, and compare findings with standard treatment.DesignThis is an investigator-initiated, multicenter, prospective, randomized, open-treatment, blinded-end-point clinical trial. The design is similar to the Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke trial. Patients with unclear-onset time of stroke symptoms beyond 4·5 h and within 12 h after the time of the last-known-well period and within 4·5 h after symptom recognition, who showed a negative fluid-attenuated inversion recovery pattern, are randomized to either intravenous thrombolysis or standard treatment.Study outcomesThe primary efficacy end-point is modified Rankin Scale 0–1 at 90 days. The safety outcome measures are symptomatic intracranial hemorrhage at 22–36 h, and major bleeding and mortality at 90 days.DiscussionThis trial may help determine if low-dose alteplase at 0·6 mg/kg should be recommended as a routine clinical strategy for ischemic stroke patients with unclear-onset time.
Background and Purpose: We determined to identify patients with unknown onset stroke who could have favorable 90-day outcomes after low-dose thrombolysis from the THAWS (Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg) database. Methods: This was a subanalysis of an investigator-initiated, multicenter, randomized, open-label, blinded–end point trial. Patients with stroke with a time last-known-well >4.5 hours who showed a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg intravenously or standard medical treatment. The patients were dichotomized by ischemic core size or National Institutes of Health Stroke Scale score, and the effects of assigned treatments were compared in each group. The efficacy outcome was favorable outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. Results: The median DWI-Alberta Stroke Program Early CT Score (ASPECTS) was 9, and the median ischemic core volume was 2.5 mL. Both favorable outcome (47.1% versus 48.3%) and any intracranial hemorrhage (26% versus 14%) at 22 to 36 hours were comparable between the 68 thrombolyzed patients and the 58 control patients. There was a significant treatment-by-cohort interaction for favorable outcome between dichotomized patients by ASPECTS on DWI ( P =0.026) and core volume ( P =0.035). Favorable outcome was more common in the alteplase group than in the control group in patients with DWI-ASPECTS 5 to 8 (RR, 4.75 [95% CI, 1.33–30.2]), although not in patients with DWI-ASPECTS 9 to 10. Favorable outcome tended to be more common in the alteplase group than in the control group in patients with core volume >6.4 mL (RR, 6.15 [95% CI, 0.87–43.64]), although not in patients with volume ≤6.4 mL. The frequency of any intracranial hemorrhage did not differ significantly between the 2 treatment groups in any dichotomized patients. Conclusions: Patients developing unknown onset stroke with DWI-ASPECTS 5 to 8 showed favorable outcomes more commonly after low-dose thrombolysis than after standard treatment. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT02002325. URL: https://www.umin.ac.jp/ctr ; Unique Identifier: UMIN000011630.
Background and Purpose: In Japan, four non-vitamin K antagonist oral anticoagulants (NOACs) became available in clinical use for prevention of stroke in patients with non-valvular atrial fibrillation (NVAF) between 2011 through 2014. The aim of this study is to determine underlying characteristics and ischemic stroke/TIA features of patients taking NOACs or warfarin, a vitamin K antagonist (VKA) prior to stroke/TIA. Methods: We enrolled oral anticoagulant (OAC) users for NVAF, who were admitted to our stroke center for acute ischemic stroke/TIA between March 2011 and June 2015 (ClinicalTrials.gov Identifier: NCT02251665). Results: 381 OAC users who developed stroke/TIA were studied. Of these, 63 patients took NOACs [23 women, 77±9 years, dabigatran in 33 (7 taking higher dosage between two official ones), rivaroxaban in 22 (5), apixaban in 8 (3), edoxaban in none] and 318 took VKA (143 women, 79±8 years). There were no significant differences between NOACs users and VKA users in sex, age, CHADS2 score (median 3[IQR 2-4] vs. 3 [2-4]), history of ischemic stroke/TIA (57% vs. 51%) and prior antiplatelet use (25% vs. 24%). Admission NIHSS score tended to be lower (3 [1-15] vs. 7 [2-20], p=0.076) and discharge NIHSS score was lower (1[0-5] vs 3[1-13], p=0.032) in NOACs users. Discharge mRS (2 [1-4] vs. 3 [1-4]) and mortality during hospitalization (5% vs. 4%) were similar between two groups. A different point was timing of stroke/TIA after initiating OAC ; 6% of NOAC users developed events within 14 days and 32% within 3 months, whereas 4% and 7% of VKA users did, respectively (p<0.001). Congestive heart failure tended to be more common in NOACs users developing events within 3 months than those developing events later (43% vs. 19%, p=0.070). Conclusions: NOACs users tended to show milder neurological deficits than VKA users during acute hospitalization of ischemic stroke/TIA, although discharge mRS was similar. NOACs users often developed stroke/TIA within the initial 3 months after initiating OAC, particularly between 14 days and 3 months. One would take special care of ischemic events during early months after initiating NOACs.
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