Safety of intravenous thrombolysis in stroke of unknown time of onset: A systematic review and meta-analysis.

The safety of intravenous tissue plasminogen activator (IV-tPA) in patients with stroke of unknown time of onset (SUTO) was unclear and mostly concerned. We sought to investigate the safety in terms of symptomatic intracranial hemorrhage (sICH) and death in SUTO patients treated with IV-tPA. We searched PubMed and EMBASE from inception to 2 December 2020 for eligible studies reporting IV-tPA in SUTO patients compared to conservative medical therapy, or to stroke of known onset time (SKOT) treated with IV-tPA within standard time window. We pooled relative risk (RR) with 95% confidence interval (95%CI) with random-effects model. Twenty-four studies were included, enrolling 77,398 patients. SUTO patients with IV-tPA had higher incidence of sICH than that in SUTO patients without IV-tPA (3.8% versus 0.96%; RR = 3.75, 95%CI: 2.69-5.22) but comparable to that in SKOT patients with IV-tPA (3.8% versus 4.1%; RR = 1.16, 95%CI: 0.94-1.44). There was no significant difference in death risk in SUTO patients with IV-tPA versus SUTO patients without IV-tPA (RR = 1.34, 95%CI: 0.60-3.01) and versus SKOT patients with IV-tPA (RR = 1.19, 95%CI: 0.95-1.50). Compared with SUTO patients without IV-tPA, SUTO patients with IV-tPA had higher likelihood of favorable functional outcome (adjusted RR = 1.28, 95%CI: 1.03-1.60) and functional independence (adjusted RR = 1.95, 95%CI: 1.24-3.06), comparable to that in SKOT patients with IV-tPA in favorable functional outcome (adjusted RR = 0.67, 95%CI: 0.38-1.20) and functional independence (adjusted RR = 0.84, 95%CI: 0.59-1.18). SUTO patients could be treated safely and effectively with IV-tPA under the guidance of imaging evaluation.

Intravenous Thrombolysis Guided by Perfusion CT with Alteplase in >4.5 Hours from Stroke Onset.

INTRODUCTION: The benefit of intravenous thrombolysis (IVT) in wake-up stroke (WUS), stroke of unknown time of onset (SUKO), or when time exceeds 4.5 h from last-seen-normal (LSN) guided by CT perfusion (CTP) or MRI has been recently suggested. However, there is limited information of IVT in those patients in real-world studies. OBJECTIVE: Our aim was to evaluate safety and efficacy of IVT selected by CTP in patients with WUS, SUKO, or stroke of time onset beyond 4.5 h. MATERIAL AND METHODS: We studied a prospective cohort of patients who underwent IVT from January 2010 to December 2017. Two groups were defined: standard of care group (SC) included patients with time onset <4.5 h and CTP group included patients with WUS, SUKO, or onset beyond >4.5 h from LSN with penumbra area in CTP. We evaluated baseline characteristics, functional outcomes according to modified Rankin Scale (mRS) at discharge and at 90 days, and intracranial hemorrhages rates. RESULTS: 657 patients were studied: 604 (92%) were treated in the SC group and 53 (8%) in the CTP group. The mean NIHSS score was 9.8 in the CTP group versus 13 in the SC group (p = 0.001). Seventeen patients in the CTP group (32.1%) received bridging therapy with mechanical thrombectomy (MT). Last time seen well-to-needle time was 538 versus 155 min (p < 0.001). The incidence of symptomatic intracranial hemorrhage was equal in both groups (3.8 vs. 3.8%, p = 1). Good functional outcome (mRS < 2) was achieved in both groups (72 vs. 60.4%, p = 0.107). CONCLUSIONS: IVT in patients with WUS, SUKO, or stroke beyond >4.5 h from LSN, with salvageable brain tissue on CTP, seems to be safe and has similar functional outcomes at 90 days to the standard therapeutic window, even when combined with MT.

Management of a wake-up stroke.

Current national guidelines advocate intravenous thrombolysis to treat patients with acute ischaemic stroke presenting within 4.5 hours from symptom onset, and thrombectomy for patients with anterior circulation ischaemic stroke from large vessel occlusion presenting within 6 hours from onset. However, a substantial group of patients presents with acute ischaemic stroke beyond these time windows or has an unknown time of onset. Recent studies are set to revolutionise treatment for these patients. Using MRI diffusion/FLAIR (fluid-attenuated inversion recovery) mismatch, it is possible to identify patients within 4.5 hours from onset and safely deliver thrombolysis. Using CT perfusion imaging, it is possible to identify subjects with a middle cerebral artery syndrome who have an extensive area of ischaemic brain but as yet have only a small area of infarction who may benefit from urgent thrombectomy in up to 24 hours. Here, we highlight the recent advances in late window stroke treatment and their potential contribution to clinical practice.

A Stroke Registry Data on the Use of Intravenous Recombinant Tissue Plasminogen Activator in Stroke of Unknown Time of Onset.

BACKGROUND: Stroke of unknown time of onset (SUTO) constitutes one fifth of all ischemic stroke admissions, and routine use of intravenous recombinant tissue plasminogen activator (IV rtPA) is recommended only in patients with a symptom onset time of less than 4.5 hours. There are limited data on clinical outcome in patients with SUTO versus patients with symptoms onset less than 4.5 hours from onset time. We hypothesized that efficacy and safety outcomes of IV rtPA therapy in selected SUTO patients are comparable to those with known onset time. METHODS: We compared 90 days' modified Rankin Scale (mRS), rates of symptomatic intracerebral hemorrhage (sICH), in-hospital mortality, and death due to sICH between 3 groups treated with IV rtPA: SUTO, 3 hours or less, and 3.0-4.5 hours from prospective patient admissions between April 1, 2012, and July 31, 2013. RESULTS: There were 65 participants in the SUTO group, 186 in the 3 hours or less group, and 51 in the 3.0-4.5 hours group. In-hospital mortality rates were 14.5%, 13.5%, and 11.8%, respectively. sICH risks were 1.5%, 1.6%, and 5.8%, and death rates due to sICH were 0%, 1.1%, and 1.9%, respectively. Ninety days' odds of excellent clinical outcome (mRS score 0-1) were not different between the SUTO group (odds ratio [OR] 1.14, 95% confidence interval [CI]: .63-2.10), the 3 hours or less group (OR .87, 95% CI: .48-1.60), and the 3.0-4.5 hours group (OR .79, 95% CI: .48-1.60) (P = .82). CONCLUSION: Thrombolytic therapy outcome in SUTO is not different from in-license use in our patient population. There is an urgent need to include this patient group in ongoing randomized multicenter trials.

The efficacy and safety of alteplase treatment in patients with acute ischemic stroke with unknown time of onset: -Real world data.

INTRODUCTION: Treatment with alteplase for acute ischemic stroke patients with an unknown time of onset is safe and effective. However, clinical trials have some selection bias. The purpose of this study was to clarify the efficacy and safety of alteplase treatment in patients with unknown time of onset in a real-world clinical setting. METHODS: We included consecutive patients with acute ischemic stroke visited within 4.5 h of onset or symptom recognition. We divided patients into two groups: onset clear group (C-group) and unknown time of onset group (U-group). We treated patients with an unknown time of onset if the DWI-FLAIR mismatch was positive. We calculated the prevalence of alteplase treatment in each group and compared prognosis between the two groups. RESULTS: Six hundred thirty-two patients arrived within 4.5 h of onset or symptom recognition. Of these, 446 patients (71 %) were in the C-group and 186 (29 %) in the U group. Alteplase treatment was performed in 35 % of patients in the C group and in 18 % in the U group (p < 0.001). Favorable outcomes at 90 days in patients treated with alteplase were comparable between the C group (52 %) and the U group (53 %) (p = 0.887). All hemorrhagic complications, including non-symptomatic hemorrhagic transformation, occurred in 11 of 157 patients (7 %) in the C-group and one of 34 patients (3 %) in the U-group (p = 0.696). CONCLUSION: In a real-world clinical setting, alteplase treatment was performed safe in 18% of patients with an unknown time of stroke onset based on patient selection using the DWI-FLAIR mismatch.

The Impact of Time to Reperfusion on Recanalization Rates and Outcome After Mechanical Thrombectomy: A Single Center Experience.

Background: Timely and effective recanalization to salvage the penumbra is the main determinant of outcome in acute ischemic strokes. Randomized controlled trials on late window mechanical thrombectomy (MT) have proved its safety and efficacy upto 24 h after stroke onset. We looked at the impact of time to reperfusion on vessel recanalization rates and short-term outcome in patients undergoing MT for large vessel occlusion. Methods: The clinical, imaging, and outcome of all patients undergoing MT upto 24 h from last seen normal was extracted from a prospectively maintained ischemic stroke database from January 2012 till September 2019. Results: There were 145 patients with a mean (SD) age of 58.2 (±14) years. Of them, 28 had wake up/unknown time of onset stroke and 9 presented beyond >360 min. There were 23 vertebrobasilar strokes. Median National Institute of Health Stroke scale score (NIHSS) at admission was 16.4 (Inter quartile range (IQR) 12-21). CT-Alberta Stroke program early CT score (CT-ASPECTS) was excellent (8-10) in 39 (31.6%) and fair (5-7) in 77 (63.6%) patients in anterior circulation strokes. About 25% underwent bridging therapy. Recanalization rates did not differ between those presenting early (<6 h) versus wake up strokes and late presenting patients (81.79% vs 71.9%). Symptomatic Intracerebral hemorrhage (ICH) occurred in 5%. At 3 months, excellent outcome (modified rankin scale <2) was observed in 28.9%. While Admission NIHSS remained strong predictor of poor outcome at 3 months, delay in presentation did not impact MT outcome (37.5% vs 45.79% and P = 0.460). Conclusions: The recanalization rates were similar in patients irrespective of the time to reperfusion from stroke onset. The functional outcome was not inferior in late presenters selected by advanced imaging.

Outcome of multimodal MRI-guided intravenous thrombolysis in patients with stroke with unknown time of onset.

OBJECTIVE: Intravenous tissue plasminogen activator (tPA) is the standard therapy for patients with acute ischaemic stroke (AIS) within 4.5 hours of onset. Recent trials have expanded the endovascular treatment window to 24 hours. We investigated the efficacy and safety of using multimodal MRI to guide intravenous tPA treatment for patients with AIS of unknown time of onset (UTO). METHODS: Data on patients with AIS with UTO and within 4.5 hours of onset were reviewed. Data elements collected and analysed included: demographics, National Institutes of Health Stroke Scale (NIHSS) score at baseline and 2 hours, 24 hours, 7 days after thrombolysis and before discharge, the modified Rankin Scale (mRS) score at 3 months after discharge, imaging findings and any adverse event. RESULTS: Forty-two patients with UTO and 62 in control group treated within 4.5 hours of onset were treated with intravenous tPA. The NIHSS scores after thrombolysis and/or before discharge in UTO group were significantly improved compared with the baseline (p<0.05). Between the two groups, no significant differences in NIHSS score were observed (p>0.05). Utilising the non-inferiority test, to compare mRS scores (0-2) at 3 months between the two groups, the difference was 5.2% (92% CI, OR 0.196). Patients in the UTO group had mRS scores of 0-2, which were non-inferior to the control group. Their incidence of adverse events was similar. CONCLUSIONS: Utilising multimodal MRI to guide intravenous only thrombolysis for patients with AIS with UTO was safe and effective. In those patients with AIS between 6 and 24 hours of time of onset but without large arterial occlusion, intravenous thrombolysis could be considered an option.