Utilization of a Supraglottic Airway Device for Airway Rescue and Tamponade of an Oropharyngeal Hemorrhage After Systemic Thrombolysis for an Acute Ischemic Stroke: A Case Report.

A 39-year-old man presented for mechanical thrombectomy after receiving systemic tissue plasminogen activator (tPA) for a basilar artery occlusion. The anesthesiology team was initially unable to intubate the patient due to oropharyngeal bleeding and a large epiglottis. Two-handed, 2-provider mask ventilation with an oral airway proved difficult. The team successfully placed a supraglottic airway (SGA) through which an oral endotracheal tube (ETT) was advanced over a fiberoptic bronchoscope into the trachea. The SGA remained overnight with the cuff inflated to tamponade the bleeding. The ETT was exchanged over an airway exchange catheter on postoperative day 1 without further airway complications.

Risk Factors Associated With Exclusion of Obese Patients Ischemic Stroke With a History of Smoking From Thrombolysis Therapy.

The objective of this study is to determine risk factors that may contribute to exclusion decision from recombinant tissue plasminogen activator (rtPA) in patients with acute ischemic stroke (AIS) with a combined current or history of smoking and obesity. This study was conducted on data from 5469 patients with AIS collected from a regional stroke registry. Risk factors associated with inclusion or exclusion from rtPA were determined using multivariate logistic regression analysis. The adjusted odds ratios and 95% confidence interval for each risk factor were used to predict the increasing odds of an association of a specific risk factor with exclusion from rtPA. In the adjusted analysis, obese patients with AIS with a history of smoking (current and previous) excluded from rtPA were more likely to present with carotid artery stenosis (OR = 0.069, 95% CI 0.011-0.442), diabetes (OR = 0.604, 95% CI 0.366-0.997), higher total cholesterol (OR = 0.975, 95% CI 0.956-0.995), and history of alcohol use (OR = 0.438, 95% CI 0.232-0.828). Higher NIHSS score (OR = 1.051, 95% CI 1.017-1.086), higher triglycerides (OR = 1.004, 95% CI 1.001-1.006), and higher high-density lipoprotein (OR = 1.028, 95% CI 1.000-1.057) were associated with the inclusion for rtPA. Our findings reveal specific risk factors that contribute to the exclusion of patients with AIS with a combined effect of smoking and obesity from rtPA. These findings suggest the need to develop management strategies to improve the use of rtPA for obese patients with AIS with a history of smoking.

What does cognitive screening reveal about early cognitive performance following endovascular clot retrieval and intravenous thrombolysis in acute ischaemic stroke?

Background Little is known regarding cognitive outcomes following treatment with endovascular clot retrieval (ECR) and intravenous tissue plasminogen activator (t-PA). We aimed to determine if there were any differences on a measure of cognitive screening between patients treated with ECR, t-PA, and those who were managed conservatively. Methods The medical records of ischaemic stroke patients admitted to Monash Medical Centre between January 2019 and December 2019 were retrospectively reviewed. Information extracted from medical records included age, sex, National Institutes of Health Stroke Scale at presentation, location of occlusion, treatment type, medical history, and cognitive screening performance measured by the Montreal Cognitive Assessment (MoCA). Results Eighty-two patients met the inclusion criteria (mean age = 66.5 ± 13.9; 49 male, 33 female). Patients treated with ECR performed significantly better on the MoCA (n = 36, 24.1 ± 4.3) compared to those who were managed conservatively (n = 26, 20.7 ± 5.5). Performance for patients treated with t-PA (n = 20, 23.9 ± 3.5) fell between the ECR and conservative management groups, but they did not significantly differ from either. Conclusion Our retrospective chart review found that ischaemic stroke patients treated with ECR appear to perform better on cognitive screening compared to patients who are managed conservatively. We also found that patients treated with ECR and t-PA appear to have similar cognitive screening performances in the acute stages following ischaemic stroke, although this finding is likely to have been impacted by group differences in stroke characteristics and may reflect the possibility that the ECR group performed better than expected based on their stroke severity.

Predictors of the unfavorable outcomes in acute ischemic stroke patients treated with alteplase, a multi-center randomized trial.

Worldwide, stroke is a leading cause of long-term disability in adults. Alteplase is the only approved treatment for acute ischemic stroke (AIS) and results in an improvement in a third of treated patients. We evaluated the post-stroke unfavourable outcome predictors in alteplase-treated patients from Egypt and Saudi Arabia. We assessed the effect of different risk factors on AIS outcomes after alteplase in Egypt and Saudi Arabia. Our study included 592 AIS alteplase-treated patients. The relationship between risk factors, clinical presentation, and imaging features was evaluated to predict factors associated with poor outcomes. An mRS score of three or more was used to define poor outcomes. Poor outcome was seen in 136 patients (23%), and Patients with unfavourable effects had significantly higher admission hyperglycaemia, a higher percentage of diabetes mellitus, cardioembolic stroke, and a lower percentage of small vessel stroke. Patients with higher baseline NIHSS score (OR 1.39; 95% CI 1.12-1.71; P = 0.003), admission hyperglycaemia (OR 13.12; 95% CI 3.37-51.1; P < 0.001), and post-alteplase intracerebral haemorrhage (OR 7.41; 95% CI 1.69-32.43; P = 0.008) independently predicted unfavourable outcomes at three months. In AIS patients treated with alteplase, similar to reports from other regions, in patients from Egypt and Saudi Arabia also reveal that higher NIHSS, higher serum blood sugar, and post-alteplase intracerebral haemorrhage were the predictors of unfavourable outcomes three months after ischemic stroke.Trial registration: (clinicaltrials.gov NCT06058884), retrospectively registered on 28/09/2023.

Preoperative co-application of bevacizumab and tissue plasminogen activator in vitrectomy for proliferative diabetic retinopathy.

PURPOSE: To investigate the clinical benefits of the co-application of bevacizumab and tissue plasminogen activator as adjuncts in the surgical treatment of proliferative diabetic retinopathy. METHODS: Patients who underwent vitrectomy for proliferative dia-betic retinopathy complications were preoperatively given in-travitreal injection with either bevacizumab and tissue plasminogen activator (Group 1) or bevacizumab alone (Group 2). Primary outcomes were surgery time and number of intraoperative iatrogenic retinal breaks. Secondary outcomes included changes in the best-corrected visual acuity and postoperative complications at 3 months postoperatively. RESULTS: The mean surgery time in Group 1 (52.95 ± 5.90 min) was significantly shorter than that in Group 2 (79.61 ± 12.63 min) (p<0.001). The mean number of iatrogenic retinal breaks was 0.50 ± 0.59 (0-2) in Group 1 and 2.00 ± 0.83 (0-3) in Group 2 (p<0.001). The best-corrected visual acuity significantly improved in both groups (p<0.001). One eye in each group developed retinal detachment. CONCLUSION: Preoperative co-application of bevacizumab and tissue plasminogen activator as adjuncts in the surgical treatment of proliferative diabetic retinopathy shortens the surgery time and reduces the number of intraoperative iatrogenic retinal breaks.

Intravenous Alteplase Versus Best Medical Therapy for Patients With Minor Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: The efficacy of thrombolysis (IVT) in minor stroke (National Institutes of Health Stroke Scale score, 0-5) remains inconclusive. The aim of this study is to compare the effectiveness and safety of IVT with best medical therapy (BMT) by means of a systematic review and meta-analysis of randomized controlled trials and observational studies. METHODS: We searched the PubMed, Embase, Cochrane Library, and Web of Science databases to obtain articles related to IVT in minor stroke from inception until August 10, 2023. The primary outcome was an excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days. The associations were calculated for the overall and preformulated subgroups by using the odds ratios (ORs). This study was registered with PROSPERO (CRD42023445856). RESULTS: A total of 20 high-quality studies, comprised of 13 397 patients with acute minor ischemic stroke, were included. There were no significant differences observed in the modified Rankin Scale scores of 0 to 1 (OR, 1.10 [95% CI, 0.89-1.37]) and 0 to 2 (OR, 1.16 [95% CI, 0.95-1.43]), mortality rates (OR, 0.67 [95% CI, 0.39-1.15]), recurrent stroke (OR, 0.89 [95% CI, 0.57-1.38]), and recurrent ischemic stroke (OR, 1.09 [95% CI, 0.68-1.73]) between the IVT and BMT group. There were differences between the IVT group and the BMT group in terms of early neurological deterioration (OR, 1.81 [95% CI, 1.17-2.80]), symptomatic intracranial hemorrhage (OR, 7.48 [95% CI, 3.55-15.76]), and hemorrhagic transformation (OR, 4.73 [95% CI, 2.40-9.34]). Comparison of modified Rankin Scale score of 0 to 1 remained unchanged in subgroup patients with nondisabling deficits or compared with those using antiplatelets. CONCLUSIONS: These findings indicate that IVT does not yield significant improvement in the functional prognosis of patients with acute minor ischemic stroke. Additionally, it is associated with an increased risk of symptomatic intracranial hemorrhage when compared with the BMT. Moreover, IVT may not have superiority over BMT in patients with nondisabling deficits or those using antiplatelets.

Retinal arterial and vein occlusion: is surgery ever indicated?

PURPOSE OF REVIEW: To highlight the recent progression in surgical treatments for central retinal vein occlusion (CRVO) and central retinal artery occlusion (CRAO). RECENT FINDINGS: Anti-VEGF treatment, accepted as a primary treatment for CRVO, is unable to effectively treat all types of the diseases. Regarding CRAO, there are not any accepted therapies available. There have however been recent innovations in surgery, such as utilizing robotics-assisted tools in cannulation procedures for central retinal artery occlusion, or micro-cystotomy for refractory macular edema resulting from ischemic CRVO. SUMMARY: Refractory macular edema due to CRVO can be treated with aspiration of the fluid found inside the large cysts often seen in edema. The success rate of micro-cystotomy has been reported at 78% in eyes with refractory macular edema. Recent studies have shown that cannulation with tissue plasminogen activator (tPA) is effective for eyes with CRAO due to thrombus.Recent cannulation or micro-cystotomy procedures can be enhanced with the use of robotic tools which allow us to perform this difficult procedure more easily. Newly developed technology, and consequent developments in surgical procedures, will allow us to deal with unmet needs for retinal vessel occlusive diseases.

Thrombus migration in emergent M1 middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Thrombus migration (TM) is a well-established phenomenon in patients with intracranial vessel occlusion, particularly in those who receive alteplase. However, the relationship between TM, reperfusion success, and clinic-radiological outcomes is still being determined. This study aimed to describe the various outcomes in the event of TM in patients with M1 middle cerebral artery (M1 MCA) occlusion. MATERIALS AND METHODS: The study involved a retrospective analysis of patients undergoing endovascular thrombectomy (EVT) due to M1 MCA occlusion from two tertiary centers between January 2015 and December 2020. The proximal positions of thrombi were measured using a curve tool on CT or MR angiography before EVT. Subsequently, measurements were taken on angiographic imaging. Patients were grouped based on the amount of difference between the two measurements: growth (≤ - 10 mm), stability (> -10 mm and ≤ 10 mm), migration (> 10 mm), and resolution. RESULTS: A total of 463 patients (266 [57%] females, median 76 [interquartile range IQR: 65-83] years) were analyzed. Of them, 106 (22.8%) expressed any degree of TM. In multivariate ordinal regression analysis, the alteplase was significantly associated with TM (t = 2.192, p = 0.028), as was the greater interval from first imaging to angiography (t = 2.574, p = 0.010). In multivariate logistical regression analysis, the good clinical outcome measured by the modified Rankin scale (0-2) was not associated with TM status. CONCLUSIONS: Thrombus migration within the M1 MCA segment occurs in almost a quarter of patients, is associated with alteplase administration, and is mainly irrelevant to radiological and clinical outcome.

The expression of ProBDNF and its high affinity receptor P75NTR in the neurons of emotion-related brain regions of post-stroke depression rats.

OBJECTIVE: To investigate the expression of the precursor of brain-derived neurotrophic factor (proBDNF) and its high-affinity receptor p75NTR in neurons of emotion-related brain areas (prefrontal cortex, hippocampus, and amygdala) in rats with post-stroke depression (PSD), and to explore the expression levels of proBDNF and p75NTR in neurons of emotion-related brain areas by injecting tissue plasminogen activator (t-PA) into the lateral ventricle of PSD rats, this significantly improved the stress-induced depression-like behavior,thus further validating the above results. METHODS: Rats were randomly divided into four groups: a normal control group (n = 8), a depression group (n = 8), a stroke group (n = 8), and a PSD group (n = 8). The rat model of stroke was established by thread embolism, and the PSD animal model was induced by chronic unpredictable mild stress (CUMS) and solitary feeding. Behavioral tests were conducted, including weight measurement, open field tests, and sucrose preference tests. Immunofluorescence double labeling was used to detect the expression of proBDNF and p75NTR in neurons of emotion-related brain regions in the PSD rat model. Four weeks after CUMS treatment, the PSD group was selected. Rats were infused with t-PA (3 µg dissolved in 6 µL saline, Boehringer Ingelheim), proBDNF (3 µg dissolved in 6 µL saline, Abcam), or equal-volume NS once per day for 7 consecutive days using the syringe pump connecting to injection needles. After 7 days of continuous administration, animal behavior was assessed through scoring, and the expression of proBDNF and p75NTR in the emotion-related brain regions of the PSD rat model was detected using immunofluorescence double labeling. RESULTS: Compared with the normal control group and the stroke group, the body weight, sucrose water consumption, and vertical movement distance in the PSD group were significantly lower (P < 0.05). In contrast, when compared with the proBDNF injection group and saline injection group, the weight, sucrose water consumption, field horizontal movement, and vertical movement distance of the t-PA injection group significantly increased after PSD lateral ventricle intubation.Double immunofluorescence revealed a higher neuronal expression of proBDNF as well as p75NTR in the prefrontal cortex and hippocampus of PSD rats compared to control animals (P < 0.05). In the amygdala, the expression levels of proBDNF and P75NTR were significantly reduced in the PSD group compared to the control group (P < 0.05). The results of the expression levels of proBDNF and P75NTR in the emotion-related brain regions of PSD rats injected with t-PA showed that proBDNF and P75NTR was significantly reduced in the prefrontal cortex, hippocampus, and amygdala of PSD rats compared to those of the NS and proBDNF groups (P < 0.05). CONCLUSIONS: The increased expression of the brain-derived neurotrophic factor precursor proBDNF and its receptor p75NTR in neurons of emotion-related brain regions may play an important role in the pathogenesis of PSD.t-PA reduced the expression of proBDNF and its receptor p75NTR in neurons emotion-related brain regions and significantly improved the stress-induced depression-like behavior. Therefore, it is reasonable to assume that exogenous injection of t-PA may alleviate the depressive symptoms of PSD patients.Reducing the expression of proBDNF by injecting t-PA may provide a novel therapeutic approach for the treatment of stress-related mood disorders.

Effect of Clot Burden Score on Safety and Efficacy of Intravenous Alteplase Prior to Mechanical Thrombectomy in Acute Ischemic Stroke: A Subgroup Analysis of a Randomized Phase 3 Trial.

BACKGROUND AND PURPOSE: Whether thrombus burden in acute ischemic stroke modify the effect of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) remains uncertain. We aim to investigate the treatment effect of stratified clot burden score (CBS) on the efficacy and safety of direct versus bridging MT. MATERIALS AND METHODS: This is an exploratory subgroup analysis of a randomized trial evaluating the effect of CBS on clinical outcome in the DIRECT-MT trial. CBS was divided into 3 groups (0-3, 4-6, and 7-10) based on preoperative CTA, where higher scores indicated a lower clot burden. We report the adjusted common odds ratio for a shift toward better outcomes on the mRS after thrombectomy alone compared with combination treatment by stratified CBS groups. RESULTS: No modification effect of mRS distribution was observed by CBS subgroups (CBS 0-3: adjusted common ratio odds 1.519 [95% CI, 0.928-2.486]; 4-6: 0.924 [0.635-1.345]; 7-10: 1.040 [0.481-2.247]). Patients with CBS 4-6 had a higher rate of early reperfusion (adjusted OR (aOR), 0.3 [95% CI, 0.1-0.9]), final reperfusion (aOR 0.5 [95% CI, 0.3-0.9]), and fewer thrombectomy attempts (aOR 0.4 [95% CI, 0.1-0.7]). Patients with CBS 7-10 had a higher rate of asymptomatic intracranial hemorrhage (14.9% versus 36.8%, P = .0197) for bridging MT. No significant difference was observed in other safety outcomes by trichotomized CBS. CONCLUSIONS: The subgroup analysis of DIRECT-MT suggested that thrombus burden did not alter the treatment effect of IVT before MT on functional outcomes in CBS subgroups.

Magnetically powered microwheel thrombolysis of occlusive thrombi in zebrafish.

Tissue plasminogen activator (tPA) is the only FDA-approved treatment for ischemic stroke but carries significant risks, including major hemorrhage. Additional options are needed, especially in small vessel thrombi which account for ~25% of ischemic strokes. We have previously shown that tPA-functionalized colloidal microparticles can be assembled into microwheels (µwheels) and manipulated under the control of applied magnetic fields to enable rapid thrombolysis of fibrin gels in microfluidic models of thrombosis. Transparent zebrafish larvae have a highly conserved coagulation cascade that enables studies of hemostasis and thrombosis in the context of intact vasculature, clotting factors, and blood cells. Here, we show that tPA-functionalized µwheels can perform rapid and targeted recanalization in vivo. This effect requires both tPA and µwheels, as minimal to no recanalization is achieved with tPA alone, µwheels alone, or tPA-functionalized microparticles in the absence of a magnetic field. We evaluated tPA-functionalized µwheels in CRISPR-generated plasminogen (plg) heterozygous and homozygous mutants and confirmed that tPA-functionalized µwheels are dose-dependent on plasminogen for lysis. We have found that magnetically powered µwheels as a targeted tPA delivery system are dramatically more efficient at plasmin-mediated thrombolysis than systemic delivery in vivo. Further development of this system in fish and mammalian models could enable a less invasive strategy for alleviating ischemia that is safer than directed thrombectomy or systemic infusion of tPA.

In silico study of combination thrombolytic therapy with alteplase and mutant pro-urokinase for fibrinolysis in ischemic stroke.

The synergistic advantage of combining tissue plasminogen activator (tPA) with pro-urokinase (proUK) for thrombolysis has been demonstrated in several in vitro experiments, and a single site proUK mutant (m-proUK) has been developed for better stability in plasma. Based on these studies, combination thrombolytic therapy with intravenous tPA and m-proUK has been suggested as a promising treatment for patients with ischemic stroke. This paper evaluates the efficacy and safety of the dual therapy by computational simulations of pharmacokinetics and pharmacodynamics coupled with a local fibrinolysis model. Seven dose regimens are simulated and compared with the standard intravenous tPA monotherapy. Our simulation results provide more insights into the complementary reaction mechanisms of tPA and m-proUK during clot lysis and demonstrate that the dual therapy can achieve a similar recanalization time (about 50 min) to tPA monotherapy, while keeping the circulating fibrinogen level within a normal range. Specifically, our results show that for all dual therapies with a 5 mg tPA bolus, the plasma concentration of fibrinogen remains stable at around 7.5 µM after a slow depletion over 50 min, whereas a rapid depletion of circulating fibrinogen (to 5 µM) is observed with the standard tPA therapy, indicating the potential advantage of dual therapy in reducing the risk of intracranial hemorrhage. Through simulations of varying dose combinations, it has been found that increasing tPA bolus can significantly affect fibrinogen level but only moderately improves recanalization time. Conversely, m-proUK doses and infusion duration exhibit a mild impact on fibrinogen level but significantly affect recanalization time. Therefore, future optimization of dose regimen should focus on limiting the tPA bolus while adjusting m-proUK dosage and infusion rate. Such adjustments could potentially maximize the therapeutic advantages of this combination therapy for ischemic stroke treatment.

Association Between Hematoma Volume and Risk of Subsequent Ischemic Stroke: A MISTIE III and ATACH-2 Analysis.

BACKGROUND: Nontraumatic intracerebral hemorrhage (ICH) is independently associated with a long-term increased risk of major arterial ischemic events. While the relationship between ICH location and ischemic risk has been studied, whether hematoma volume influences this risk is poorly understood. METHODS: We pooled individual patient data from the MISTIE III (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase 3) and the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) trials. The exposure was hematoma volume, treated as a continuous measure in the primary analysis, and dichotomized by the median in the secondary analyses. The outcome was a symptomatic, clinically overt ischemic stroke, adjudicated centrally within each trial. We evaluated the association between hematoma volume and the risk of an ischemic stroke using Cox regression analyses after adjustment for demographics, vascular comorbidities, and ICH characteristics. RESULTS: Of 1470 patients with ICH, the mean age was 61.7 (SD, 12.8) years, and 574 (38.3%) were female. The median hematoma volume was 17.3 mL (interquartile range, 7.2-35.7). During a median follow-up of 107 days (interquartile range, 91-140), a total of 30 ischemic strokes occurred, of which 22 were in patients with a median ICH volume of ≥17.3 mL and a cumulative incidence of 4.6% (95% CI, 3.1-7.1). Among patients with a median ICH volume <17.3 mL, there were 8 ischemic strokes with a cumulative incidence of 3.1% (95% CI, 1.7-6.0). In primary analyses using adjusted Cox regression models, ICH volume was associated with an increased risk of ischemic stroke (hazard ratio, 1.02 per mL increase [95% CI, 1.01-1.04]). In secondary analyses, ICH volume of ≥17.3 mL was associated with an increased risk of ischemic stroke (hazard ratio, 2.5 [95% CI, 1.1-7.2]), compared with those with an ICH volume <17.3 mL. CONCLUSIONS: In a heterogeneous cohort of patients with ICH, initial hematoma volume was associated with a heightened short-term risk of ischemic stroke.

Intravenous Tirofiban Versus Alteplase Before Endovascular Treatment in Acute Ischemic Stroke: A Pooled Analysis of the DEVT and RESCUE BT Trials.

BACKGROUND: The present study aimed to evaluate the efficacy and safety of intravenous tirofiban versus alteplase before endovascular treatment (EVT) in acute ischemic stroke patients with intracranial large vessel occlusion. METHODS: This was a post hoc analysis using data from 2 multicenter, randomized trials: the DEVT trial (Direct Endovascular Treatment for Large Vessel Occlusion Stroke) from May 2018 to May 2020 and the RESCUE BT trial (Intravenous Tirofiban Before Endovascular Thrombectomy for Acute Ischemic Stroke) from October 2018 to October 2021. Patients with acute intracranial large vessel occlusion within 4.5 hours from last known well were dichotomized into 2 groups: tirofiban plus EVT versus alteplase bridging with EVT. The primary outcome was functional independence (modified Rankin Scale score of 0-2) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage and 3-month mortality. Multivariable logistic regression (adjusting for baseline systolic blood pressure, occlusion site, onset-to-puncture time, anesthesia, and first choice of EVT) and propensity score overlap weighting (balance in demographic covariates, stroke characteristics, and initial management between groups) were performed. RESULTS: One-hundred and eighteen alteplase-treated patients in the DEVT trial and 98 tirofiban-treated patients in the RESCUE BT trial were included (median age, 70 years; 115 [53.2%] men). The rate of functional independence was 60.2% in the tirofiban group compared with 46.6% in the alteplase group (adjusted odds ratio, 1.25 [95% CI, 0.60-2.63]). Compared with alteplase, tirofiban was not associated with increased risk of symptomatic intracranial hemorrhage (6.8% versus 9.2%; P=0.51) and mortality (17.8% versus 19.4%; P=0.76). The propensity score overlap weighting analyses showed consistent outcomes. CONCLUSIONS: Among patients with intracranial large vessel occlusion within 4.5 hours of onset, tirofiban plus EVT was comparable to alteplase bridging with EVT regarding the efficacy and safety outcomes. These findings should be interpreted as preliminary and require confirmation in a randomized trial. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifiers: ChiCTR-IOR-17013568 and ChiCTR-INR-17014167.

Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection.

BACKGROUND: Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage. RESULTS: The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P = 0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively. CONCLUSIONS: Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by Genentech; TIMELESS ClinicalTrials.gov number, NCT03785678.).