Trial of Thrombectomy for Stroke with a Large Infarct of Unrestricted Size.

BACKGROUND: The use of thrombectomy in patients with acute stroke and a large infarct of unrestricted size has not been well studied. METHODS: We assigned, in a 1:1 ratio, patients with proximal cerebral vessel occlusion in the anterior circulation and a large infarct (as defined by an Alberta Stroke Program Early Computed Tomographic Score of ≤5; values range from 0 to 10) detected on magnetic resonance imaging or computed tomography within 6.5 hours after symptom onset to undergo endovascular thrombectomy and receive medical care (thrombectomy group) or to receive medical care alone (control group). The primary outcome was the score on the modified Rankin scale at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). The primary safety outcome was death from any cause at 90 days, and an ancillary safety outcome was symptomatic intracerebral hemorrhage. RESULTS: A total of 333 patients were assigned to either the thrombectomy group (166 patients) or the control group (167 patients); 9 were excluded from the analysis because of consent withdrawal or legal reasons. The trial was stopped early because results of similar trials favored thrombectomy. Approximately 35% of the patients received thrombolysis therapy. The median modified Rankin scale score at 90 days was 4 in the thrombectomy group and 6 in the control group (generalized odds ratio, 1.63; 95% confidence interval [CI], 1.29 to 2.06; P<0.001). Death from any cause at 90 days occurred in 36.1% of the patients in the thrombectomy group and in 55.5% of those in the control group (adjusted relative risk, 0.65; 95% CI, 0.50 to 0.84), and the percentage of patients with symptomatic intracerebral hemorrhage was 9.6% and 5.7%, respectively (adjusted relative risk, 1.73; 95% CI, 0.78 to 4.68). Eleven procedure-related complications occurred in the thrombectomy group. CONCLUSIONS: In patients with acute stroke and a large infarct of unrestricted size, thrombectomy plus medical care resulted in better functional outcomes and lower mortality than medical care alone but led to a higher incidence of symptomatic intracerebral hemorrhage. (Funded by Montpellier University Hospital; LASTE ClinicalTrials.gov number, NCT03811769.).

Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).

Trial of Endovascular Treatment of Acute Basilar-Artery Occlusion.

BACKGROUND: Data from trials investigating the effects and risks of endovascular thrombectomy for the treatment of stroke due to basilar-artery occlusion are limited. METHODS: We conducted a multicenter, prospective, randomized, controlled trial of endovascular thrombectomy for basilar-artery occlusion at 36 centers in China. Patients were assigned, in a 2:1 ratio, within 12 hours after the estimated time of basilar-artery occlusion to receive endovascular thrombectomy or best medical care (control). The primary outcome was good functional status, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]), at 90 days. Secondary outcomes included a modified Rankin scale score of 0 to 2, distribution across the modified Rankin scale score categories, and quality of life. Safety outcomes included symptomatic intracranial hemorrhage at 24 to 72 hours, 90-day mortality, and procedural complications. RESULTS: Of the 507 patients who underwent screening, 340 were in the intention-to-treat population, with 226 assigned to the thrombectomy group and 114 to the control group. Intravenous thrombolysis was used in 31% of the patients in the thrombectomy group and in 34% of those in the control group. Good functional status at 90 days occurred in 104 patients (46%) in the thrombectomy group and in 26 (23%) in the control group (adjusted rate ratio, 2.06; 95% confidence interval [CI], 1.46 to 2.91, P<0.001). Symptomatic intracranial hemorrhage occurred in 12 patients (5%) in the thrombectomy group and in none in the control group. Results for the secondary clinical and imaging outcomes were generally in the same direction as those for the primary outcome. Mortality at 90 days was 37% in the thrombectomy group and 55% in the control group (adjusted risk ratio, 0.66; 95% CI, 0.52 to 0.82). Procedural complications occurred in 14% of the patients in the thrombectomy group, including one death due to arterial perforation. CONCLUSIONS: In a trial involving Chinese patients with basilar-artery occlusion, approximately one third of whom received intravenous thrombolysis, endovascular thrombectomy within 12 hours after stroke onset led to better functional outcomes at 90 days than best medical care but was associated with procedural complications and intracerebral hemorrhage. (Funded by the Program for Innovative Research Team of the First Affiliated Hospital of USTC and others; ATTENTION ClinicalTrials.gov number, NCT04751708.).

Intravenous Thrombolysis before Complete Angiographic Reperfusion: Beyond Angiographic Assessment to Target Microvascular Obstruction?

OBJECTIVE: Recent data have suggested that ineffective tissue reperfusion despite successful angiographic reperfusion was partly responsible for unfavorable outcomes after endovascular therapy (EVT) and might be modulated by intravenous thrombolysis (IVT) use before EVT. To specifically decipher the effect played by IVT before EVT, we compared the clinical and safety outcomes of patients who experienced a complete reperfusion at the end of EVT according to IVT use before EVT. METHODS: The Endovascular Treatment in Ischemic Stroke (ETIS) registry is an ongoing, prospective, observational study at 21 centers that perform EVT in France. Patients were included if they had an anterior large vessel occlusion of the intracranial internal carotid artery or middle cerebral artery (M1/M2 segments) and complete reperfusion (expanded Thrombolysis in Cerebral Infarction score = 3) with EVT within 6 hours, between January 2015 and December 2021. The cohort was divided into two groups according to IVT use before EVT, and propensity score matching (PSM) was used to balance the two groups. Primary outcome was the shift in the degree of disability as measured by the modified Rankin Scale (mRS) at 90 days. Secondary outcomes included favorable outcome (mRS 0-2) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage and 90-day mortality. Outcomes were estimated with multivariate logistic models adjusted for age, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT Score, and time from symptom onset to puncture. RESULTS: Among 5,429 patients included in the ETIS registry, 1,093 were included in the study, including 651 patients with complete recanalization treated with IVT before EVT. After PSM, 488 patients treated with IVT before EVT were compared to 337 patients without IVT. In the matched cohort analysis, the IVT+EVT group had a favorable shift in the overall mRS score distribution (adjusted odds ratio [aOR] = 1.41, 95% confidence interval [CI] = 1.04-1.91, p = 0.023) and higher rates of favorable outcome (61.1% vs 48.7%, aOR = 1.49, 95% CI = 1.02-2.20, p = 0.041) at 90 days compared with the EVT alone group. Rates of symptomatic intracerebral hemorrhage were comparable between both groups (6.0% vs 4.3%, aOR = 1.16, 95% CI = 0.53-2.54, p = 0.709). INTERPRETATION: In clinical practice, even after complete angiographic reperfusion by EVT, prior IVT use improves clinical outcomes of patients without increasing bleeding risk. ANN NEUROL 2024;95:762-773.

Expansion of Telestroke Coverage in Community Hospitals: Unifying Stroke Care and Reducing Transfer Rate.

OBJECTIVE: Telestroke (TS) service has been shown to improve stroke diagnosis timing and accuracy, facilitate treatment decisions, and decrease interfacility transfers. Expanding TS service to inpatient units at the community hospital provides an opportunity to follow up on stroke patients and optimize medical management. This study examines the outcome of expanding TS coverage from acute emergency room triage to incorporate inpatient consultation. METHODS: We studied the effect of expanding TS to inpatient consultation service at 19 regional hospitals affiliated with Promedica Stroke Network. We analyzed data pre- and post-TS expansion. We reviewed changes in TS utilization, admission rate, thrombolytic therapy, patient transfer rate, and diagnosis accuracy. RESULTS: Between January 2018 and June 2022, a total of 9,756 patients were evaluated in our stroke network (4,705 in pre- and 5,051 in the post-TS expansion). In the post-TS expansion period, stroke patients' admission at the spoke hospital increased from 18/month to 40/month, and for TIA from 11/month to 16/month. TS cart use increased from 12% to 35.2%. Patient transfers to hub hospital decreased by 31%. TS service expansion did not affect intravenous thrombolytic therapy rate or door-to-needle time. There was no difference in length of stay or readmission rate, and the patients at the spoke hospitals had a higher rate of home discharge 57.38% compared with 52.58% at hub hospital. INTERPRETATION: Telestroke service expansion to inpatient units helped decrease transfers and retain patients in their communities, increased stroke and TIA diagnosis accuracy, and did not compromise patients' hospitalization or outcome. ANN NEUROL 2024;95:576-582.

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives.

Ischemic stroke (IS) poses a significant threat to global human health and life. In recent decades, we have witnessed unprecedented progresses against IS, including thrombolysis, thrombectomy, and a few medicines that can assist in reopening the blocked brain vessels or serve as standalone treatments for patients who are not eligible for thrombolysis/thrombectomy therapies. However, the narrow time windows of thrombolysis/thrombectomy, coupled with the risk of hemorrhagic transformation, as well as the lack of highly effective and safe medications, continue to present big challenges in the acute treatment and long-term recovery of IS. In the past 3 years, several excellent articles have reviewed pathophysiology of IS and therapeutic medicines for the treatment of IS based on the pathophysiology. Regretfully, there is no comprehensive overview to summarize all categories of anti-IS drugs/agents designed and synthesized based on molecular mechanisms of IS pathophysiology. From medicinal chemistry view of point, this article reviews a multitude of anti-IS drugs/agents, including small molecule compounds, natural products, peptides, and others, which have been developed based on the molecular mechanism of IS pathophysiology, such as excitotoxicity, oxidative/nitrosative stresses, cell death pathways, and neuroinflammation, and so forth. In addition, several emerging medicines and strategies, including nanomedicines, stem cell therapy and noncoding RNAs, which recently appeared for the treatment of IS, are shortly introduced. Finally, the perspectives on the associated challenges and future directions of anti-IS drugs/agents are briefly provided to move the field forward.

STREAM-2: Half-Dose Tenecteplase or Primary Percutaneous Coronary Intervention in Older Patients With ST-Segment-Elevation Myocardial Infarction: A Randomized, Open-Label Trial.

BACKGROUND: ST-segment-elevation myocardial infarction (STEMI) guidelines recommend pharmaco-invasive treatment if timely primary percutaneous coronary intervention (PCI) is unavailable. Full-dose tenecteplase is associated with an increased risk of intracranial hemorrhage in older patients. Whether pharmaco-invasive treatment with half-dose tenecteplase is effective and safe in older patients with STEMI is unknown. METHODS: STREAM-2 (Strategic Reperfusion in Elderly Patients Early After Myocardial Infarction) was an investigator-initiated, open-label, randomized, multicenter study. Patients ≥60 years of age with ≥2 mm ST-segment elevation in 2 contiguous leads, unable to undergo primary PCI within 1 hour, were randomly assigned (2:1) to half-dose tenecteplase followed by coronary angiography and PCI (if indicated) 6 to 24 hours after randomization, or to primary PCI. Efficacy end points of primary interest were ST resolution and the 30-day composite of death, shock, heart failure, or reinfarction. Safety assessments included stroke and nonintracranial bleeding. RESULTS: Patients were assigned to pharmaco-invasive treatment (n=401) or primary PCI (n=203). Median times from randomization to tenecteplase or sheath insertion were 10 and 81 minutes, respectively. After last angiography, 85.2% of patients undergoing pharmaco-invasive treatment and 78.4% of patients undergoing primary PCI had ≥50% resolution of ST-segment elevation; their residual median sums of ST deviations were 4.5 versus 5.5 mm, respectively. Thrombolysis In Myocardial Infarction flow grade 3 at last angiography was ≈87% in both groups. The composite clinical end point occurred in 12.8% (51/400) of patients undergoing pharmaco-invasive treatment and 13.3% (27/203) of patients undergoing primary PCI (relative risk, 0.96 [95% CI, 0.62-1.48]). Six intracranial hemorrhages occurred in the pharmaco-invasive arm (1.5%): 3 were protocol violations (excess anticoagulation in 2 and uncontrolled hypertension in 1). No intracranial bleeding occurred in the primary PCI arm. The incidence of major nonintracranial bleeding was low in both groups (<1.5%). CONCLUSIONS: Halving the dose of tenecteplase in a pharmaco-invasive strategy in this early-presenting, older STEMI population was associated with electrocardiographic changes that were at least comparable to those after primary PCI. Similar clinical efficacy and angiographic end points occurred in both treatment groups. The risk of intracranial hemorrhage was higher with half-dose tenecteplase than with primary PCI. If timely PCI is unavailable, this pharmaco-invasive strategy is a reasonable alternative, provided that contraindications to fibrinolysis are observed and excess anticoagulation is avoided. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02777580.

Shorter Door-to-Needle Times Are Associated With Better Outcomes After Intravenous Thrombolytic Therapy and Endovascular Thrombectomy for Acute Ischemic Stroke.

BACKGROUND: Existing data and clinical trials could not determine whether faster intravenous thrombolytic therapy (IVT) translates into better long-term functional outcomes after acute ischemic stroke among those treated with endovascular thrombectomy (EVT). Patient-level national data can provide the required large population to study the associations between earlier IVT, versus later, with longitudinal functional outcomes and mortality in patients receiving IVT+EVT combined treatment. METHODS: This cohort study included older US patients (age ≥65 years) who received IVT within 4.5 hours or EVT within 7 hours after acute ischemic stroke using the linked 2015 to 2018 Get With The Guidelines-Stroke and Medicare database (38 913 treated with IVT only and 3946 with IVT+EVT). Primary outcome was home time, a patient-prioritized functional outcome. Secondary outcomes included all-cause mortality in 1 year. Multivariate logistic regression and Cox proportional hazards models were used to evaluate the associations between door-to-needle (DTN) times and outcomes. RESULTS: Among patients treated with IVT+EVT, after adjusting for patient and hospital factors, including onset-to-EVT times, each 15-minute increase in DTN times for IVT was associated with significantly higher odds of zero home time in a year (never discharged to home) (adjusted odds ratio, 1.12 [95% CI, 1.06-1.19]), less home time among those discharged to home (adjusted odds ratio, 0.93 per 1% of 365 days [95% CI, 0.89-0.98]), and higher all-cause mortality (adjusted hazard ratio, 1.07 [95% CI, 1.02-1.11]). These associations were also statistically significant among patients treated with IVT but at a modest degree (adjusted odds ratio, 1.04 for zero home time, 0.96 per 1% home time for those discharged to home, and adjusted hazard ratio 1.03 for mortality). In the secondary analysis where the IVT+EVT group was compared with 3704 patients treated with EVT only, shorter DTN times (≤60, 45, and 30 minutes) achieved incrementally more home time in a year, and more modified Rankin Scale 0 to 2 at discharge (22.3%, 23.4%, and 25.0%, respectively) versus EVT only (16.4%, P<0.001 for each). The benefit dissipated with DTN>60 minutes. CONCLUSIONS: Among older patients with stroke treated with either IVT only or IVT+EVT, shorter DTN times are associated with better long-term functional outcomes and lower mortality. These findings support further efforts to accelerate thrombolytic administration in all eligible patients, including EVT candidates.

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.

Thrombolysis for Wake-Up Stroke Versus Non-Wake-Up Unwitnessed Stroke: EOS Individual Patient Data Meta-Analysis.

BACKGROUND: Stroke with unknown time of onset can be categorized into 2 groups; wake-up stroke (WUS) and unwitnessed stroke with an onset time unavailable for reasons other than wake-up (non-wake-up unwitnessed stroke, non-WUS). We aimed to assess potential differences in the efficacy and safety of intravenous thrombolysis (IVT) between these subgroups. METHODS: Patients with an unknown-onset stroke were evaluated using individual patient-level data of 2 randomized controlled trials (WAKE-UP [Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke], THAWS [Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg]) comparing IVT with placebo or standard treatment from the EOS (Evaluation of Unknown-Onset Stroke Thrombolysis trial) data set. A favorable outcome was prespecified as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. The IVT effect was compared between the treatment groups in the WUS and non-WUS with multivariable logistic regression analysis. RESULTS: Six hundred thirty-four patients from 2 trials were analyzed; 542 had WUS (191 women, 272 receiving alteplase), and 92 had non-WUS (42 women, 43 receiving alteplase). Overall, no significant interaction was noted between the mode of onset and treatment effect (P value for interaction=0.796). In patients with WUS, the frequencies of favorable outcomes were 54.8% and 45.5% in the IVT and control groups, respectively (adjusted odds ratio, 1.47 [95% CI, 1.01-2.16]). Death occurred in 4.0% and 1.9%, respectively (P=0.162), and symptomatic intracranial hemorrhage in 1.8% and 0.3%, respectively (P=0.194). In patients with non-WUS, no significant difference was observed in favorable outcomes relative to the control (37.2% versus 29.2%; adjusted odds ratio, 1.76 [0.58-5.37]). One death and one symptomatic intracranial hemorrhage were reported in the IVT group, but none in the control. CONCLUSIONS: There was no difference in the effect of IVT between patients with WUS and non-WUS. IVT showed a significant benefit in patients with WUS, while there was insufficient statistical power to detect a substantial benefit in the non-WUS subgroup. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: CRD42020166903.

Safety and Efficacy of Reduced-Dose Versus Full-Dose Alteplase for Acute Pulmonary Embolism: A Multicenter Observational Comparative Effectiveness Study.

OBJECTIVES: Systemic thrombolysis improves outcomes in patients with pulmonary embolism (PE) but is associated with the risk of hemorrhage. The data on efficacy and safety of reduced-dose alteplase are limited. The study objective was to compare the characteristics, outcomes, and complications of patients with PE treated with full- or reduced-dose alteplase regimens. DESIGN: Multicenter retrospective observational study. SETTING: Tertiary care hospital and 15 community and academic centers of a large healthcare system. PATIENTS: Hospitalized patients with PE treated with systemic alteplase. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pre- and post-alteplase hemodynamic and respiratory variables, patient outcomes, and complications were compared. Propensity score (PS) weighting was used to adjust for imbalances of baseline characteristics between reduced- and full-dose patients. Separate analyses were performed using the unweighted and weighted cohorts. Ninety-eight patients were treated with full-dose (100 mg) and 186 with reduced-dose (50 mg) regimens. Following alteplase, significant improvements in shock index, blood pressure, heart rate, respiratory rate, and supplemental oxygen requirements were observed in both groups. Hemorrhagic complications were lower with the reduced-dose compared with the full-dose regimen (13% vs. 24.5%, p = 0.014), and most were minor. Major extracranial hemorrhage occurred in 1.1% versus 6.1%, respectively ( p = 0.022). Complications were associated with supratherapeutic levels of heparin anticoagulation in 37.5% of cases and invasive procedures in 31.3% of cases. The differences in complications persisted after PS weighting (15.4% vs. 24.7%, p = 0.12 and 1.3% vs. 7.1%, p = 0.067), but did not reach statistical significance. There were no significant differences in mortality, discharge destination, ICU or hospital length of stay, or readmission after PS weighting. CONCLUSIONS: In a retrospective, PS-weighted observational study, when compared with the full-dose, reduced-dose alteplase results in similar outcomes but fewer hemorrhagic complications. Avoidance of excessive levels of anticoagulation or invasive procedures should be considered to further reduce complications.

Thrombectomy with or without Intravenous Thrombolytics in Basilar Artery Occlusion.

OBJECTIVE: Two randomized trials demonstrated the benefit of endovascular therapy (EVT) in patients suffering from a stroke due to a basilar artery occlusion (BAO). However, intravenous thrombolytic (IVT) use before EVT was low in these trials, questioning the added value of this treatment in this setting. We sought to investigate the efficacy and safety of EVT alone compared to IVT + EVT in stroke patients with a BAO. METHODS: We analyzed data from the Endovascular Treatment in Ischemic Stroke registry, a prospective, observational, multicenter study of acute ischemic stroke patients treated with EVT in 21 centers in France between 1 January 2015 and 31 December 2021. We included patients with BAO and/or intracranial vertebral artery occlusion and compared patients treated with EVT alone versus IVT + EVT after propensity score (PS) matching. Variables selected for the PS were pre-stroke mRS, dyslipidemia, diabetes, anticoagulation, admission mode, baseline NIHSS and ASPECTS, type of anesthesia, and time from symptom onset to puncture. Efficacy outcomes were good functional outcome (modified Rankin Scale [mRS] 0-3) and functional independence (mRS 0-2) at 90 days. Safety outcomes were symptomatic intracranial hemorrhages and all-cause mortality at 90 days. RESULTS: Among 385 patients, 243 (134 EVT alone and 109 IVT + EVT) were included after PS matching. There was no difference between EVT alone and IVT + EVT regarding good functional outcome (adjusted odd ratio [aOR] labeling = 1.27, 95% confidence interval [CI], 0.68-2.37, p = 0.45) and functional independence (aOR = 1.50, 95% CI, 0.79-2.85, p = 0.21). Symptomatic intracranial hemorrhage and all-cause mortality were also similar between the two groups (aOR = 0.42, 95% CI, 0.10-1.79, p = 0.24 and aOR = 0.56, 95% CI, 0.29-1.10, p = 0.09, respectively). INTERPRETATION: In this PS matching analysis, EVT alone seemed to lead to similar neurological recovery than IVT + EVT, with comparable safety profile. However, given our sample size and the observational nature of this study, further studies are needed to confirm these findings. ANN NEUROL 2023;94:596-604.

Thrombolytic tPA-induced hemorrhagic transformation of ischemic stroke is mediated by PKCß phosphorylation of occludin.

The current standard of care for moderate to severe ischemic stroke is thrombolytic therapy with tissue plasminogen activator (tPA). Treatment with tPA can significantly improve neurologic outcomes; however, thrombolytic therapy is associated with an increased risk of intracerebral hemorrhage (ICH). The risk of hemorrhage significantly limits the use of thrombolytic therapy, and identifying pathways induced by tPA that increase this risk could provide new therapeutic options to extend thrombolytic therapy to a wider patient population. Here, we investigate the role of protein kinase Cß (PKCß) phosphorylation of the tight junction protein occludin during ischemic stroke and its role in cerebrovascular permeability. We show that activation of this pathway by tPA is associated with an increased risk of ICH. Middle cerebral artery occlusion (MCAO) increased phosphorylation of occludin serine 490 (S490) in the ischemic penumbra in a tPA-dependent manner, as tPA-/- mice were significantly protected from MCAO-induced occludin phosphorylation. Intraventricular injection of tPA in the absence of ischemia was sufficient to induce occludin phosphorylation and vascular permeability in a PKCß-dependent manner. Blocking occludin phosphorylation, either by targeted expression of a non-phosphorylatable form of occludin (S490A) or by pharmacologic inhibition of PKCß, reduced MCAO-induced permeability and improved functional outcome. Furthermore, inhibiting PKCß after MCAO prevented ICH associated with delayed thrombolysis. These results show that PKCß phosphorylation of occludin is a downstream mediator of tPA-induced cerebrovascular permeability and suggest that PKCß inhibitors could improve stroke outcome and prevent ICH associated with delayed thrombolysis, potentially extending the window for thrombolytic therapy in stroke.

Catheter-based therapy for intermediate or high-risk pulmonary embolism is associated with lower in-hospital mortality in patients with cancer: Insights from the National Inpatient Sample.

BACKGROUND: Pulmonary embolism (PE) is a common complication among patients with cancer and is a significant contributor to morbidity and mortality. Catheter-based therapies (CBT), including catheter-directed thrombolysis (CDT) and mechanical thrombectomy, have been developed and are used in patients with intermediate or high-risk PE. However, there is a paucity of data on outcomes in patients with cancer as most clinical studies exclude this group of patients. AIMS: To characterize outcomes of patients with cancer admitted with intermediate or high-risk PE treated with CBT compared with no CBT. METHODS: Patients with an admission diagnosis of intermediate or high-risk PE and a history of cancer from October 2015 to December 2018 were identified using the National Inpatient Sample. Outcomes of interest were in-hospital death or cardiac arrest (CA) and major bleeding. Inverse probability treatment weighting (IPTW) was utilized to compare outcomes between patients treated with and without CBT. Variables that remained unbalanced after IPTW were adjusted using multivariable logistic regression. RESULTS: A total of 2084 unweighted admissions (10,420 weighted) for intermediate or high-risk PE and cancer were included, of which 136 (6.5%) were treated with CBT. After IPTW, CBT was associated with lower death or CA (aOR 0.54, 95% CI 0.46-0.64) but higher major bleeding (aOR 1.41, 95% CI 1.21-1.65). After stratifying by PE risk type, patients treated with CBT had lower risk of death or CA in both intermediate (aOR 0.52, 95% CI 0.36-0.75) and high-risk PE (aOR 0.48, 95% CI 0.33-0.53). However, patients with CBT were associated with increased risk of major bleeding in intermediate-risk PE (aOR 2.12, 95% CI 1.67-2.69) but not in those with high-risk PE (aOR 0.84, 95% CI 0.66-1.07). CONCLUSIONS: Among patients with cancer hospitalized with intermediate or high-risk PE, treatment with CBT was associated with lower risk of in-hospital death or CA but higher risk of bleeding. Prospective studies and inclusion of patients with cancer in randomized trials are warranted to confirm our findings.

Ultrasound-assisted endovascular thrombolysis versus large-bore thrombectomy in acute intermediate-high risk pulmonary embolism: The propensity-matched EKNARI cohort study.

BACKGROUND: Ultrasound-assisted thrombolysis (USAT) and large-bore-thrombectomy (LBT) are under investigation for the treatment of intermediate-high and high-risk pulmonary embolisms (PE). Comparative studies investigating both devices are scarce. AIMS: This study aimed to compare the safety and efficacy of the two most frequently used devices for treatment of acute PE. METHODS: This multicenter, retrospective study included 125 patients undergoing LBT or USAT for intermediate- or high-risk PE between 2019 and 2023. Nearest neighbor propensity matching with logistic regression was used to achieve balance on potential confounders. The primary outcome was the change in the right to left ventricular (RV/LV) ratio between baseline and 24 h. RESULTS: A total of 125 patients were included. After propensity score matching, 95 patients remained in the sample, of which 69 (73%) underwent USAT and 26 (27%) LBT. The RV/LV ratio decrease between baseline and 24 h was greater in the LBT than in the USAT group (adjusted between-group difference: -0.10, 95% CI: -0.16 to -0.04; p = 0.001). Both procedures were safe and adverse events occurred rarely (10% following USAT vs. 4% following LBT; p = 0.439). CONCLUSION: In acute intermediate-high and high-risk PE, both LBT and USAT were feasible and safe. The reduction in RV/LV ratio was greater following LBT than USAT. Further randomized controlled trials are needed to confirm these findings.

Advances in Acute Ischemic Stroke Therapy.

The treatment of acute ischemic stroke continues to advance. The mainstay of treatment remains intravenous thrombolysis with alteplase. Recent studies demonstrated that later treatment with alteplase is beneficial in patients selected with advanced imaging techniques. Tenecteplase has been evaluated as an alternative thrombolytic drug and evidence suggests that it is as least as effective as alteplase and may lyse large vessel clots more effectively. Endovascular therapy with mechanical thrombectomy has now been shown to be beneficial up to 24 hours after stroke onset in carefully selected patients with proximal, large vessel occlusions. Ongoing studies are evaluating the effectiveness of thrombectomy in patients with more distal vessel occlusions and patients with proximal large vessel occlusions with larger ischemic core volumes and also in patients with milder neurological deficits. Cytoprotection is another potential acute stroke therapy that has not demonstrated efficacy in prior clinical trials. It should be reconsidered as an adjunct to reperfusion and a variety of new clinical trials can be envisioned to evaluate the potential benefits of cytoprotection in patients before and after reperfusion.

Hyponatremia is associated with unfavorable outcomes after reperfusion treatment in acute ischemic stroke.

BACKGROUND AND PURPOSE: In patients with acute ischemic stroke, hyponatremia (plasma sodium < 136 mmol/L) is common and associated with unfavorable outcomes. However, data are limited for patients who underwent intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT). Therefore, our aim was to assess the impact of hyponatremia on postreperfusion outcomes. METHODS: We analyzed data of consecutive patients who presented with acute ischemic stroke and were treated with IVT and/or EVT at Isala Hospital, the Netherlands, in 2019 and 2020. The primary outcome measure was the adjusted common odds ratio (acOR) for a worse modified Rankin Scale (mRS) score at 3-month follow-up. Secondary outcomes included symptomatic intracranial hemorrhage, in-hospital mortality, infarct core, and penumbra volumes. RESULTS: Of the 680 patients (median age = 73 years, 49% female, median National Institutes of Health Stroke Scale = 5), 430 patients (63%) were treated with IVT, 120 patients (18%) with EVT, and 130 patients (19%) with both. Ninety-two patients (14%) were hyponatremic on admission. Hyponatremia was associated with a worse mRS score at 3 months (acOR = 1.76, 95% confidence interval [CI] = 1.12-2.76) and in-hospital mortality (aOR = 2.39, 95% CI = 1.23-4.67), but not with symptomatic intracranial hemorrhage (OR = 1.17, 95% CI = 0.39-3.47). Hyponatremia was also associated with a larger core (17.2 mL, 95% CI = 2.9-31.5) and core to penumbra ratio (55.0%, 95% CI = 7.1-102.9). CONCLUSIONS: Admission hyponatremia in patients with acute ischemic stroke treated with IVT and/or EVT was independently associated with unfavorable postreperfusion outcomes, a larger infarct core, and a larger core to penumbra ratio. Future studies should address whether correction of hyponatremia improves the prognosis.

Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes with Alteplase at 0.6 mg/kg in Clinical Practice: THAWS2 Study.

INTRODUCTION: The aim of this study was to determine the safety and efficacy of intravenous (IV) alteplase at 0.6 mg/kg for patients with acute wake-up or unclear-onset strokes in clinical practice. METHODS: This multicenter observational study enrolled acute ischemic stroke patients with last-known-well time >4.5 h who had mismatch between DWI and FLAIR and were treated with IV alteplase. The safety outcomes were symptomatic intracranial hemorrhage (sICH) after thrombolysis, all-cause deaths, and all adverse events. The efficacy outcomes were favorable outcome defined as an mRS score of 0-1 or recovery to the same mRS score as the premorbid score, complete independence defined as an mRS score of 0-1 at 90 days, and change in NIHSS at 24 h from baseline. RESULTS: Sixty-six patients (35 females; mean age, 74 ± 11 years; premorbid complete independence, 54 [82%]; median NIHSS on admission, 11) were enrolled at 15 hospitals. Two patients (3%) had sICH. Median NIHSS changed from 11 (IQR, 6.75-16.25) at baseline to 5 (3-12.25) at 24 h after alteplase initiation (change, -4.8 ± 8.1). At discharge, 31 patients (47%) had favorable outcome and 29 (44%) had complete independence. None died within 90 days. Twenty-three (35%) also underwent mechanical thrombectomy (no sICH, NIHSS change of -8.5 ± 7.3), of whom 11 (48%) were completely independent at discharge. CONCLUSIONS: In real-world clinical practice, IV alteplase for unclear-onset stroke patients with DWI-FLAIR mismatch provided safe and efficacious outcomes comparable to those in previous trials. Additional mechanical thrombectomy was performed safely in them.

Effect of Needle-To-Puncture Time on Reperfusion Outcome in Acute Ischemic Stroke.

INTRODUCTION: The aim of the study was to investigate the impact of time interval between start of intravenous thrombolysis (IVT) to start of endovascular thrombectomy (EVT) on stroke outcomes. METHODS: Data from the Quality Improvement and Clinical Research (QuICR) provincial stroke registry from Alberta, Canada, were used to identify stroke patients who received IVT and EVT from January 2015 to December 2019. We assessed the impact of the time interval between IVT bolus to EVT puncture (needle-to-puncture times [NPT]) on outcomes. Radiological outcomes included successful initial recanalization (revised Arterial Occlusive Lesion 2b-3), successful initial and final reperfusion (modified thrombolysis in cerebral infarction 2b-3). Clinical outcomes were 90-day modified Rankin Scale (mRS) and mortality. RESULTS: Of the 680 patients, 233 patients (median age: 73, 41% females) received IVT + EVT. Median NPT was 38 min (IQR, 24-60). Arrival during working hours was independently associated with shorter NPT (p < 0.001). Successful initial recanalization and initial and final reperfusion were observed in 12%, 10%, and 83% of patients, respectively. NPT was not associated with initial successful recanalization (OR 0.97 for every 10-min increase of NPT, 95% CI: 0.91-1.04), initial successful reperfusion (OR 1.01, 95% CI: 0.96-1.07), or final successful reperfusion (OR: 1.03, 95% CI: 0.97-1.08). Every 10-min delay in NPT was associated with lower odds of functional independence at 90 days (mRS ≤2; OR: 0.93; 95% CI, 0.88-0.97). Patients with shorter NPT (≤38 min) had lower 90-day mRS scores (median 1 vs. 3; OR: 0.54 [0.31-0.91]) and had lower mortality (6.1% vs. 21.2%; OR, 0.23 [0.10-0.57]) than the longer NPT group. CONCLUSION: Shorter NPT did not impact reperfusion outcomes but was associated with better clinical outcome.

Cost Effectiveness of Early Endovenous Thrombus Removal for Acute Iliofemoral Deep Vein Thrombosis in the United Kingdom.

OBJECTIVE: Early clot removal using endovascular intervention aims to reduce post-thrombotic syndrome (PTS) following iliofemoral deep venous thrombosis (DVT). This may reduce long term morbidity but incurs a higher initial cost. This study examined the cost effectiveness of catheter directed thrombolysis (CDT) and pharmacochemical thrombectomy (PMT) compared with oral anticoagulation (OAC) alone for treatment of acute iliofemoral DVT in the United Kingdom. METHODS: A combined decision tree (acute DVT complications) and Markov model (long term complications [PTS]) was used for decision analytic modelling with five states: no PTS, mild PTS, moderate PTS, severe PTS, and dead. All patients started with acute DVT. Patients who survived acute complications transitioned into the Markov model. Cycle time was six months. A healthcare payer perspective and lifetime horizon was used, adjusting for excess mortality due to history of thrombosis. Data for probabilities, transition probabilities, mortality, and utilities were obtained from the published literature. Cost data were obtained from UK NHS tariffs and published literature. Outcomes were mean lifetime cost, quality adjusted life years (QALYs), and cost effectiveness. RESULTS: Over a patient's lifetime, OAC was more costly (£37 206) than CDT (£32 043) and PMT (£36 288). Mean lifetime QALYs for OAC (12.9) were lower than CDT (13.5) and PMT (13.3). Therefore, in the incremental cost effectiveness analysis, both CDT and PMT were dominant: CDT was less costly (-£5 163) and more effective (+0.6 QALYs) than OAC, and PMT was also less costly (-£917) and more effective (+0.3 QALYs) than OAC. Results were robust to univariable sensitivity analyses, but probabilistic sensitivity analyses suggested considerable parameter uncertainty. CONCLUSION: Early interventional treatment of iliofemoral DVT is cost effective in the UK. Future clinical and epidemiological studies are needed to characterise parameter uncertainty. Further analysis of modern practice, alternative treatments, and optimised care models is warranted.