Targeting Fibrinolytic Inhibition for Venous Thromboembolism Treatment: Overview of an Emerging Therapeutic Approach.

Venous thrombosis and pulmonary embolism (venous thromboembolism) are important causes of morbidity and mortality worldwide. In patients with venous thromboembolism, thrombi obstruct blood vessels and resist physiological dissolution (fibrinolysis), which can be life threatening and cause chronic complications. Plasminogen activator therapy, which was developed >50 years ago, is effective in dissolving thrombi but has unacceptable bleeding risks. Safe dissolution of thrombi in patients with venous thromboembolism has been elusive despite multiple innovations in plasminogen activator design and catheter-based therapy. Evidence now suggests that fibrinolysis is rigidly controlled by endogenous fibrinolysis inhibitors, including α2-antiplasmin, plasminogen activator inhibitor-1, and thrombin-activable fibrinolysis inhibitor. Elevated levels of these fibrinolysis inhibitors are associated with an increased risk of venous thromboembolism in humans. New therapeutic paradigms suggest that accelerated and effective fibrinolysis may be achieved safely by therapeutically targeting these fibrinolytic inhibitors in venous thromboembolism. In this article, we discuss the role of fibrinolytic components in venous thromboembolism and the current status of research and development targeting fibrinolysis inhibitors.

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.

How Clot Composition Influences Fibrinolysis in the Acute Phase of Stroke: A Proteomic Study of Cerebral Thrombi.

BACKGROUND: The dramatic clinical improvement offered by mechanical thrombectomy raised questions about the relevance of prior intravenous thrombolysis in large-vessel occlusion strokes. Hence, studying intravenous thrombolysis susceptibility and its dependence on thrombus composition is crucial. We used an observational proteomic study of whole thrombi retrieved by mechanical thrombectomy to identify factors associated with fibrin content and fibrinolytic activity (FA). METHODS: In 104 stroke patients, the thrombi proteome was established by mass spectrometry coupled to liquid chromatography. FA was estimated in clots both outside (FAout) by measuring D-dimer levels at the blood-thrombus interface and inside (FAin) by evaluating the ratio of fibrinogen α to its plasmin-cleaved forms using proteomics coupled with protein electrophoresis. The factors associated with fibrin content, FAin, and FAout were determined by intravenous thrombolysis-adjusted linear regression. RESULTS: FAout (P<0.0001) and FAin (P=0.0147) were driven by recombinant tissue-type plasminogen activator (r-tPA) administration (47/104) and thrombus composition. Indeed, FAout was greater with fibrin-rich than erythrocyte-rich thrombi, presumably because of more (r)tPA substrates. Thus, FAout was increased with cardioembolic thrombi (72/104), which are rich in fibrin (P=0.0300). Opposite results were found inside the thrombus, suggesting that (r)tPA penetrability was hampered by the density of the fibrinous cap. Moreover, blood cells had a strong impact on thrombus structure and susceptibility to (r)tPA. Indeed, fibrin content was negatively associated with erythrocyte-specific proteins in the thrombus, admission hematocrit (P=0.0139), and hemoglobin level (P=0.0080), which underlines the key role of erythrocytes in thrombus composition. Also, an increased number of neutrophils impaired FAout (P=0.0225), which suggests that their aggregation around the thrombus prevented the (r)tPA attack. Only FAout was significantly associated with reduced thrombus weight (P=0.0310), increased recanalization rate (P=0.0150), good clinical outcome (P=0.0480), and reduced mortality (P=0.0080). CONCLUSIONS: Proteomics can offer new insights into the close relationship between thrombus composition and susceptibility to fibrinolysis, paving the way for new adjuvant therapies.

Intravenous Thrombolysis Before Endovascular Treatment in Posterior Circulation Occlusions: A MR CLEAN Registry Study.

BACKGROUND: The effectiveness of intravenous thrombolysis (IVT) before endovascular treatment (EVT) has been investigated in randomized trials and meta-analyses. These studies mainly concerned anterior circulation occlusions. We aimed to investigate clinical, technical, and safety outcomes of IVT before EVT in posterior circulation occlusions in a nationwide registry. METHODS: Patients were included from the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), a nationwide, prospective, multicenter registry of patients with acute ischemic stroke due to a large intracranial vessel occlusion receiving EVT between 2014 and 2019. All patients with a posterior circulation occlusion were included. Primary outcome was a shift toward better functional outcome on the modified Rankin Scale at 90 days. Secondary outcomes were favorable functional outcome (modified Rankin Scale scores, 0-3), occurrence of symptomatic intracranial hemorrhages, successful reperfusion (extended Thrombolysis in Cerebral Ischemia ≥2B), first-attempt successful reperfusion, and mortality at 90 days. Regression analyses with adjustments based on univariable analyses and literature were applied. RESULTS: A total of 248 patients were included, who received either IVT (n=125) or no IVT (n=123) before EVT. Results show no differences in a shift on the modified Rankin Scale (adjusted common odds ratio, 1.04 [95% CI, 0.61-1.76]). Although symptomatic intracranial hemorrhages occurred more often in the IVT group (4.8% versus 2.4%), regression analysis did not show a significant difference (adjusted odds ratio, 1.65 [95% CI, 0.33-8.35]). Successful reperfusion, favorable functional outcome, first-attempt successful reperfusion, and mortality did not differ between patients treated with and without IVT. CONCLUSIONS: We found no significant differences in clinical, technical, and safety outcomes between patients with a large vessel occlusion in the posterior circulation treated with or without IVT before EVT. Our results are in line with the literature on the anterior circulation.

Emerging Adjuvant Thrombolytic Therapies for Acute Ischemic Stroke Reperfusion.

Thrombolytic therapies for acute ischemic stroke are widely available but only result in recanalization early enough, to be therapeutically useful, in 10% to 30% of cases. This large gap in treatment effectiveness could be filled by novel therapies that can increase the effectiveness of thrombus clearance without significantly increasing the risk of harm. This focused update will describe the current state of emerging adjuvant treatments for acute ischemic stroke reperfusion. We focus on new treatments that are designed to (1) target different components that make up a stroke thrombus, (2) enhance endogenous fibrinolytic systems, (3) reduce stagnant blood flow, and (4) improve recanalization of distal thrombi and postendovascular thrombectomy.

Outcomes of Bridging Intravenous Thrombolysis Versus Endovascular Therapy Alone in Late-Window Acute Ischemic Stroke.

BACKGROUND: Studies comparing bridging intravenous thrombolysis (IVT) with direct endovascular therapy (EVT) in patients with acute ischemic stroke who present late are limited. We aimed to compare the clinical outcomes and safety of bridging IVT in patients with acute ischemic stroke due to anterior circulation large vessel occlusion who underwent EVT 6 to 24 hours after time last known well. METHODS: We enrolled patients with anterior circulation large vessel occlusion stroke and a National Institutes of Health Stroke Scale score of ≥6 from 20 centers across 10 countries in the multicenter retrospective CLEAR study (CT for Late Endovascular Reperfusion) between January 2014 and May 2022. We used inverse probability of treatment weighting modeling adjusted for clinical and imaging confounders to compare functional outcomes, reperfusion success, symptomatic intracranial hemorrhage, and mortality between EVT patients with and without prior IVT. RESULTS: Of 5098 patients screened for eligibility, we included 2749 patients, of whom 549 received bridging IVT before EVT. The timing of IVT was not recorded. Witnessed stroke onset and transfer rates were higher in the bridging IVT group (25% versus 12% and 77% versus 55%, respectively, P value for both <0.0001), and time intervals between stroke onset and treatment were shorter (time last known well-start of EVT median 560 minutes [interquartile range, 432-791] versus 724 minutes [interquartile range, 544-912]; P<0.0001). After adjustment for confounders, there was no difference in functional outcome at 3 months (adjusted common odds ratio for modified Rankin Scale shift, 1.03 [95% CI, 0.89-1.19]; P=0.72) or successful reperfusion (adjusted odds ratio, 1.19 [95% CI, 0.81-1.75]; P=0.39). There were no safety concerns associated with bridging IVT versus direct EVT (symptomatic intracranial hemorrhage: adjusted odds ratio, 0.75 [95% CI, 0.38-1.48]; P=0.40; mortality: adjusted odds ratio, 1.14 [95% CI, 0.89-1.46]; P=0.31). Results were unchanged when the analysis was limited to patients who received IVT >6 hours after last known well. CONCLUSIONS: In patients with an anterior circulation large vessel occlusion stroke who underwent EVT 6 to 24 hours from last known well, bridging IVT was not associated with a difference in outcomes compared with direct EVT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04096248.

Comparing Outcomes of Thrombectomy Versus Intravenous Thrombolysis Based on Middle Cerebral Artery M2 Occlusion Features.

BACKGROUND: Current evidence provides limited support for the superiority of endovascular thrombectomy (EVT) in patients with M2 segment middle cerebral artery occlusion. We aim to investigate whether imaging features of M2 segment occlusion impact the effectiveness of EVT. METHODS: We conducted a retrospective cohort study from January 2017 to January 2022, drawing data from the CASE II registry (Computer-Based Online Database of Acute Stroke Patients for Stroke Management Quality Evaluation), which specifically documented patients with acute ischemic stroke presenting with M2 segment occlusion undergoing reperfusion therapy. Patients were stratified into the intravenous thrombolysis (IVT) group (IVT alone) and EVT group (IVT plus EVT or EVT alone). The primary outcome was a modified Rankin Scale score 0 to 2 at 90 days. Secondary outcomes included additional thresholds and distribution of modified Rankin Scale scores, 24-hour recanalization, early neurological deterioration, and relevant complications during hospitalization. Safety outcomes encompassed intracranial hemorrhagic events at 24 hours and mortality at 90 days. Binary logistic regression analyses with propensity score matching were used. Subgroup analyses were performed based on the anatomic site of occlusion, including right versus left, proximal versus distal, dominant/co-dominant versus nondominant, single versus double/triple branch(es), and anterior versus central/posterior branch. RESULTS: Among 734 patients (43.3% were females; median age, 73 years) with M2 segment occlusion, 342 (46.6%) were in the EVT group. Propensity score matching analysis revealed no statistical difference in the primary outcome (odds ratio, 0.860 [95% CI, 0.611-1.209]; P=0.385) between the EVT group and IVT group. However, EVT was associated with a higher incidence of subarachnoid hemorrhage (odds ratio, 6.655 [95% CI, 1.487-29.788]; P=0.004) and pneumonia (odds ratio, 2.015 [95% CI, 1.364-2.977]; P<0.001). Subgroup analyses indicated that patients in the IVT group achieved better outcomes when presenting with right, distal, or nondominant branch occlusion (Pall interaction<0.05). CONCLUSIONS: Our study showed similar efficiency of EVT versus IVT alone in acute M2 segment middle cerebral artery occlusion. This suggested that only specific patient subpopulations might have a potentially higher benefit of EVT over IVT alone. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04487340.

Arterial Recanalization During Interhospital Transfer for Thrombectomy.

BACKGROUND: Patients with acute ischemic stroke harboring a large vessel occlusion admitted to nonendovascular-capable centers often require interhospital transfer for thrombectomy. We evaluated the incidence and predictors of arterial recanalization during transfer, as well as the relationship between interhospital recanalization and clinical outcomes. METHODS: We analyzed data from 2 cohorts of patients with an anterior circulation large vessel occlusion transferred for consideration of thrombectomy to a comprehensive center, with arterial imaging at the referring hospital and on comprehensive stroke center arrival. Interhospital recanalization was determined by comparison of the baseline and posttransfer arterial imaging and was defined as revised arterial occlusive lesion (rAOL) score 2b to 3. Pretransfer variables independently associated with interhospital recanalization were studied using multivariable logistic regression analysis. RESULTS: Of the 520 included patients (Montpellier, France, n=237; Stanford, United States, n=283), 111 (21%) experienced interhospital recanalization (partial [rAOL=2b] in 77% and complete [rAOL=3] in 23%). Pretransfer variables independently associated with recanalization were intravenous thrombolysis (adjusted odds ratio, 6.8 [95% CI, 4.0-11.6]), more distal occlusions (intracranial carotid occlusion as reference: adjusted odds ratio, 2.0 [95% CI, 0.9-4.5] for proximal first segment of the middle cerebral artery, 5.1 [95% CI, 2.3-11.5] for distal first segment of the middle cerebral artery, and 5.0 [95% CI, 2.1-11.8] for second segment of the middle cerebral artery), and smaller clot burden (clot burden score 0-4 as reference: adjusted odds ratio, 3.4 [95% CI, 1.5-7.6] for 5-7 and 5.6 [95% CI, 2.4-12.7] for 8-9). Recanalization on arrival at the comprehensive center was associated with less interhospital infarct growth (rAOL, 0-2a: 11.6 mL; rAOL, 2b: 2.2 mL; rAOL, 3: 0.6 mL; Ptrend<0.001) and greater interhospital National Institutes of Health Stroke Scale score improvement (0 versus -5 versus -6; Ptrend<0.001). Interhospital recanalization was associated with reduced 3-month disability (adjusted common odds ratio, 2.51 [95% CI, 1.68-3.77]) with greater benefit from complete than partial recanalization. CONCLUSIONS: Recanalization is frequently observed during interhospital transfer for thrombectomy and is strongly associated with favorable outcomes, even when partial. Broadening thrombolysis indications in primary centers, and developing therapies that increase recanalization during transfer, will likely improve clinical outcomes.

Perfusion Abnormalities on 24-Hour Perfusion Imaging in Patients With Complete Endovascular Reperfusion.

BACKGROUND: Perfusion abnormalities in the infarct and salvaged penumbra have been proposed as a potential reason for poor clinical outcome (modified Rankin Scale score >2) despite complete angiographic reperfusion (Thrombolysis in Cerebral Infarction [TICI3]). In this study, we aimed to identify different microvascular perfusion patterns and their association with clinical outcomes among TICI3 patients. METHODS: University Hospital Bern's stroke registry of all patients between February 2015 and December 2021. Macrovascular reperfusion was graded using the TICI scale. Microvascular reperfusion status was evaluated within the infarct area on cerebral blood volume and cerebral blood flow perfusion maps obtained 24-hour postintervention. Primary outcome was functional independence (90-day modified Rankin Scale score 0-2) evaluated with the logistic regression analysis adjusted for age, sex, and 24-hour infarct volume from follow-up imaging. RESULTS: Based on microvascular perfusion findings, the entire cohort (N=248) was stratified into one of the 4 clusters: (1) normoperfusion (no perfusion abnormalities; n=143/248); (2) hyperperfusion (hyperperfusion on both cerebral blood volume and cerebral blood flow; n=54/248); (3) hypoperfusion (hypoperfusion on both cerebral blood volume and cerebral blood flow; n=14/248); and (4) mixed (discrepant findings, eg, cerebral blood volume hypoperfusion and cerebral blood flow hyperperfusion; n=37/248). Compared with the normoperfusion cluster, patients in the hypoperfusion cluster were less likely to achieve functional independence (adjusted odds ratio, 0.3 [95% CI, 0.1-0.9]), while patients in the hyperperfusion cluster tended to have better outcomes (adjusted odds ratio, 3.3 [95% CI, 1.3-8.8]). CONCLUSIONS: In around half of TICI3 patients, perfusion abnormalities on the microvascular level can be observed. Microvascular hypoperfusion, despite complete macrovascular reperfusion, is rare but may explain the poor clinical course among some TICI3 patients, while a detrimental effect of hyperperfusion after reperfusion could not be confirmed.

Endovascular Treatment of Medium Vessel Occlusion Stroke.

Approximately one-third of acute ischemic strokes with an identifiable vessel occlusion are caused by medium vessel occlusion (MeVO), that is, nonlarge vessel occlusions that are potentially amenable to endovascular treatment (EVT). Management of patients with MeVO is challenging in many ways: detecting MeVOs can be challenging, particularly for inexperienced physicians, and in busy clinical routine, MeVOs, therefore, remain sometimes undiagnosed. While the clinical course of MeVO stroke with medical management, including intravenous thrombolysis, is by no means, benign, it is more favorable compared with large vessel occlusion. At the same time, EVT complication rates are higher, and thus, the marginal benefit of EVT beyond best medical management is expected to be smaller and more challenging to detect if it were present. Several randomized controlled trials are currently underway to investigate whether and to what degree patients with MeVO may benefit from EVT and will soon provide robust data for evidence-based MeVO EVT decision-making. In this review, we discuss different ways of defining MeVOs, strategies to optimize MeVO detection on imaging, and considerations for EVT decision-making in the setting of MeVO stroke. We discuss the technical challenges related to MeVO EVT and conclude with an overview of currently ongoing MeVO EVT trials.

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.

R-tPA Resistance Is Specific for Platelet-Rich Stroke Thrombi and Can Be Overcome by Targeting Nonfibrin Components.

BACKGROUND: Resistance to r-tPA (recombinant tissue-type plasminogen activator) is a well-known but poorly understood phenomenon that hampers successful recanalization in patients with acute ischemic stroke. Using clinically relevant thrombi from patients with acute ischemic stroke, we investigated if and how thrombus composition impacts r-tPA-mediated lysis. In addition, we explored strategies to overcome r-tPA resistance. METHODS: Thrombi were split into 2 parts, 1 of which was used for thrombolysis and the other for detailed histological analysis. Thrombolysis was performed in normal human plasma using r-tPA alone, using r-tPA in combination with DNase-1 or using r-tPA in combination with N,N'-diacetyl-l-cystine. Thrombus lysis was calculated as the percentage of residual thrombus weight compared with its initial weight and the degree of lysis was linked to thrombus composition determined via histology. RESULTS: Interestingly, we found that the efficacy of r-tPA-mediated thrombolysis was strongly correlated with the composition of the thrombi. Thrombi containing high amounts of red blood cells and low amounts of DNA and von Willebrand Factor were efficiently degraded by r-tPA, whereas thrombi containing low amounts of red blood cells and higher amounts of DNA and von Willebrand Factor were resistant to r-tPA. Importantly, combination of r-tPA with DNase-1 or N,N'-diacetyl-l-cystine significantly and specifically improved the lysis of these r-tPA-resistant thrombi. CONCLUSIONS: Using patient thrombus material, our results for the first time show that the composition of stroke thrombi largely determines their susceptibility to r-tPA-mediated thrombolysis. Red blood cell-poor thrombi have a specific resistance to r-tPA, which can be overcome by targeting nonfibrin components using DNase-1 or N,N'-diacetyl-l-cystine.

Rural Hospital Performance in Guideline-Recommended Ischemic Stroke Thrombolysis, Secondary Prevention, and Outcomes.

BACKGROUND: Existing data suggested a rural-urban disparity in thrombolytic utilization for ischemic stroke. Here, we examined the use of guideline-recommended stroke care and outcomes in rural hospitals to identify targets for improvement. METHODS: This retrospective cohort study included patients (aged ≥18 years) treated for acute ischemic stroke at Get With The Guidelines-Stroke hospitals from 2017 to 2019. Multivariable mixed-effect logistic regression was used to compare thrombolysis rates, speed of treatment, secondary stroke prevention metrics, and outcomes after adjusting for patient- and hospital-level characteristics and stroke severity. RESULTS: Among the 1 127 607 patients admitted to Get With The Guidelines-Stroke hospitals in 2017 to 2019, 692 839 patients met the inclusion criteria. Patients who presented within 4.5 hours were less likely to receive thrombolysis in rural stroke centers compared with urban stroke centers (31.7% versus 43.5%; adjusted odds ratio [aOR], 0.72 [95% CI, 0.68-0.76]) but exceeded rural nonstroke centers (22.1%; aOR, 1.26 [95% CI, 1.15-1.37]). Rural stroke centers were less likely than urban stroke centers to achieve door-to-needle times of ≤45 minutes (33% versus 44.7%; aOR, 0.86 [95% CI, 0.76-0.96]) but more likely than rural nonstroke centers (aOR, 1.24 [95% CI, 1.04-1.49]). For secondary stroke prevention metrics, rural stroke centers were comparable to urban stroke centers but exceeded rural nonstroke centers (aOR of 1.66, 1.94, 2.44, 1.5, and 1.72, for antithrombotics within 48 hours of admission, antithrombotics at discharge, anticoagulation for atrial fibrillation/flutter, statin treatment, and smoking cessation, respectively). In-hospital mortality was similar between rural and urban stroke centers (aOR, 1.11 [95% CI, 0.99-1.24]) or nonstroke centers (aOR, 1.00 [95% CI, 0.84-1.18]). CONCLUSIONS: Rural hospitals had lower thrombolysis utilization and slower treatment times than urban hospitals. Rural stroke centers provided comparable secondary stroke prevention treatment to urban stroke centers and exceeded rural nonstroke centers. These results reveal important opportunities and specific targets for rural health equity interventions.

David G. Sherman Lecture: Improving Stroke Diagnosis and Treatment-A Journey Toward the End of Time.

In the 2024 David G. Sherman Lecture, Steven J. Warach, illustrating with examples from his research, walks through the history of magnetic resonance imaging in acute stroke from the 1990s and early 2000s with the introduction, validation, and application of diffusion-weighted imaging, penumbral imaging (the diffusion-perfusion mismatch), and other imaging markers of the acute stroke pathology into routine clinical practice and stroke trials. The adaptation of diffusion-weighted imaging for clinical scanners in the acute hospital setting began a revolution in ischemic stroke diagnosis as the presence, location, and size of ischemic lesions could now be visualized at the earliest times after stroke onset when computed tomography and conventional magnetic resonance imaging still appeared normal. In combination with perfusion magnetic resonance imaging, diffusion-weighted imaging made imaging of the ischemic penumbra a practical reality for routine clinical use and feasible for integration as a selection tool into clinical trials. It was apparent from the initial use of diffusion-perfusion imaging in acute stroke that many patients had persistence of penumbra as late as 24 hours after stroke onset although the probability of penumbra decreased over time. The therapeutic time window for ischemic stroke selected by clinical and temporal criteria reflected the decreased proportion of patients with the therapeutic target over time rather than the absence of the penumbral target in all patients at later times. This work provided the empirical and conceptual framework for the shift toward selection and evaluation of patients for acute stroke therapies based on direct observation of the target pathology and away from the exclusive dependence on clinical and temporal surrogates to infer the presence of stroke therapeutic targets, a shift that has expanded the indications for acute reperfusion therapies over the last 10 years.

Lack of Interactions Between Alteplase/Tenecteplase and the Adenosine A1R/A3R Agonist AST-004.

BACKGROUND: AST-004, a small molecule agonist of the adenosine A1 and A3 receptors, is a potential cerebroprotectant for patients with acute stroke and is currently in clinical trials. Drug-drug interactions are critically important to assess in the context of acute stroke care. Lytic therapy with tPA (tissue-type plasminogen activator)-induced plasmin formation (alteplase) is the only available pharmacotherapy for acute stroke. Consequently, it is imperative to evaluate potential interactions between AST-004 and tPAs such as alteplase and tenecteplase. METHODS: The interactions between AST-004 and tPAs were evaluated in 3 ways in preparation for AST-004 phase II trials. First, the metabolic stability of AST-004 was determined in the presence of alteplase and plasmin. Second, the potential for AST-004 to influence the thrombolytic efficacy of alteplase and tenecteplase was evaluated with an in vitro assay system utilizing a fluorogenic substrate of plasmin. Finally, the potential for AST-004 to influence the thrombolytic efficacy of alteplase was also determined with an in vitro thrombolysis assay of human blood thrombi. RESULTS: Neither alteplase nor plasmin affected the stability of AST-004 in vitro. In 2 different in vitro systems, AST-004 had no effect on the ability of alteplase or tenecteplase to generate plasmin, and AST-004 had no effect on the thrombolytic efficacy of alteplase to lyse blood clots in human blood. CONCLUSIONS: These studies indicate that there will be no interactions between AST-004 and tPAs such as alteplase or tenecteplase in patients with stroke undergoing thrombolytic therapy.

Safety and Efficacy of Reteplase Versus Alteplase for Acute Ischemic Stroke: A Phase 2 Randomized Controlled Trial.

BACKGROUND: Reteplase is a more affordable new-generation thrombolytic with a prolonged half-life. We aimed to determine the safety dose range of reteplase for patients with acute ischemic stroke within 4.5 hours of onset. METHODS: This is a multicenter, prospective, randomized controlled, open-label, blinded-end point phase 2 clinical trial. Patients with acute ischemic stroke aged between 18 and 80 years who were eligible for standard intravenous thrombolysis were enrolled from 17 centers in China and randomly assigned (1:1:1) to receive intravenous reteplase 12+12 mg, intravenous reteplase 18+18 mg, or intravenous alteplase 0.9 mg/kg. The primary safety outcome was symptomatic intracranial hemorrhage (SITS definition) within 36 hours. The primary efficacy outcome was the proportion of patients with the National Institutes of Health Stroke Scale score of no more than 1 or a decrease of at least 4 points from the baseline at 14 days after thrombolysis. RESULTS: Between August 2019 and May 2021, 180 patients were randomly assigned to reteplase 12+12 mg (n=61), reteplase 18+18 mg (n=67), or alteplase (n=52). Four patients did not receive the study agent. Symptomatic intracranial hemorrhage occurred in 3 of 60 (5.0%) in the reteplase 12+12 mg group, 1 of 66 (1.5%) in the reteplase 18+18 mg group, and 1 of 50 (2.0%) in the alteplase group (P=0.53). The primary efficacy outcome in the modified intention-to-treat population occurred in 45 of 60 (75.0%) in the reteplase 12+12 mg group (odds ratio, 0.85 [95% CI, 0.35-2.06]), 48 of 66 (72.7%) in the reteplase 18+18 mg group (odds ratio, 0.75 [95% CI, 0.32-1.78]), and 39 of 50 (78.0%) in alteplase group. CONCLUSIONS: Reteplase was well tolerated in patients with acute ischemic stroke within 4.5 hours of onset in China with a similar efficacy profile to alteplase. The efficacy and appropriate dosage of reteplase for patients with acute ischemic stroke need prospective validation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04028518.

A systematic review and meta-analysis on the outcomes of carotid endarterectomy after intravenous thrombolysis for acute ischemic stroke.

BACKGROUND: Intravenous thrombolysis (IVT) is the mainstay of treatment for patients presenting with acute ischemic stroke, whereas carotid endarterectomy (CEA) is indicated in patients with symptomatic carotid stenosis. However, the impact of prior IVT on the outcomes of CEA (IVT-CEA) is not clear. The aim of this study was to determine whether IVT may create additional stroke and death risk for CEA, compared with CEA performed in the absence of a history of recent IVT, and to determine the optimal timing for CEA after IVT. METHODS: We conducted a systematic review and meta-analysis of studies comparing the outcomes of IVT-CEA vs CEA, using the Medline, Embase, and Cochrane databases. RESULTS: We included 11 retrospective comparative studies, in which 135,644 patients underwent CEA and 2070 underwent IVT-CEA. The pooled rate of perioperative stroke was 4.2% in the IVT-CEA group and 1.3% in the CEA group (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.12-1.58; P = .21), with a high heterogenicity (I2 = 93%). The rate of stroke/death was 5.9% in patients undergoing IVT-CEA 1.9% in those receiving CEA only (OR, 0.42; 95% CI, 0.15-1.14; I2 = 92%; P = .09); after exclusion of studies including TIA as presenting symptom, stroke/death risk was 3.6% in IVT-CEA and 3.0% in CEA (OR, 1.42; 95% CI, 0.80-2.53; I2 = 50%; P = .11). The risk of stoke decreased with a delay in the performance of CEA (P = .268). Using results of the metaregression, the calculated delay of CEA that allows for a <6% risk was 4.6 days. Compared with CEA, patients undergoing IVT-CEA had a significantly higher risk of intracranial hemorrhage (2.5% vs 0.1%; OR, 0.11; 95% CI, 0.06-0.21; I2 = 28%; P < .001) and neck hematoma requiring reintervention (3.6% vs 2.3%; OR, 0.61; 95% CI, 0.43-0.85; I2 = 0%; P = .003). CONCLUSIONS: In patients presenting with an acute ischemic stroke, CEA can be safely performed after a prior endovenous thrombolysis, maintaining a stroke/death risk of <6%. After IVT, CEA should be deferred for ≥5 days to minimize the risk for intracranial hemorrhage and neck bleeding.

Deep learning-based white matter lesion volume on CT is associated with outcome after acute ischemic stroke.

BACKGROUND: Intravenous thrombolysis (IVT) before endovascular treatment (EVT) for acute ischemic stroke might induce intracerebral hemorrhages which could negatively affect patient outcomes. Measuring white matter lesions size using deep learning (DL-WML) might help safely guide IVT administration. We aimed to develop, validate, and evaluate a DL-WML volume on CT compared to the Fazekas scale (WML-Faz) as a risk factor and IVT effect modifier in patients receiving EVT directly after IVT. METHODS: We developed a deep-learning model for WML segmentation on CT and validated with internal and external test sets. In a post hoc analysis of the MR CLEAN No-IV trial, we associated DL-WML volume and WML-Faz with symptomatic-intracerebral hemorrhage (sICH) and 90-day functional outcome according to the modified Rankin Scale (mRS). We used multiplicative interaction terms between WML measures and IVT administration to evaluate IVT treatment effect modification. Regression models were used to report unadjusted and adjusted common odds ratios (cOR/acOR). RESULTS: In total, 516 patients from the MR CLEAN No-IV trial (male/female, 291/225; age median, 71 [IQR, 62-79]) were analyzed. Both DL-WML volume and WML-Faz are associated with sICH (DL-WML volume acOR, 1.78 [95%CI, 1.17; 2.70]; WML-Faz acOR, 1.53 95%CI [1.02; 2.31]) and mRS (DL-WML volume acOR, 0.70 [95%CI, 0.55; 0.87], WML-Faz acOR, 0.73 [95%CI 0.60; 0.88]). Only in the unadjusted IVT effect modification analysis WML-Faz was associated with more sICH if IVT was given (p = 0.046). Neither WML measure was associated with worse mRS if IVT was given. CONCLUSION: DL-WML volume and WML-Faz had a similar relationship with functional outcome and sICH. Although more sICH might occur in patients with more severe WML-Faz receiving IVT, no worse functional outcome was observed. CLINICAL RELEVANCE STATEMENT: White matter lesion severity on baseline CT in acute ischemic stroke patients has a similar predictive value if measured with deep learning or the Fazekas scale. Safe administration of intravenous thrombolysis using white matter lesion severity should be further studied. KEY POINTS: White matter damage is a predisposing risk factor for intracranial hemorrhage in patients with acute ischemic stroke but remains difficult to measure on CT. White matter lesion volume on CT measured with deep learning had a similar association with symptomatic intracerebral hemorrhages and worse functional outcome as the Fazekas scale. A patient-level meta-analysis is required to study the benefit of white matter lesion severity-based selection for intravenous thrombolysis before endovascular treatment.

Radiomics using non-contrast CT to predict hemorrhagic transformation risk in stroke patients undergoing revascularization.

OBJECTIVES: This study explores whether textural features from initial non-contrast CT scans of infarcted brain tissue are linked to hemorrhagic transformation susceptibility. MATERIALS AND METHODS: Stroke patients undergoing thrombolysis or thrombectomy from Jan 2012 to Jan 2022 were analyzed retrospectively. Hemorrhagic transformation was defined using follow-up magnetic resonance imaging. A total of 94 radiomic features were extracted from the infarcted tissue on initial NCCT scans. Patients were divided into training and test sets (7:3 ratio). Two models were developed with fivefold cross-validation: one incorporating first-order and textural radiomic features, and another using only textural radiomic features. A clinical model was also constructed using logistic regression with clinical variables, and test set validation was performed. RESULTS: Among 362 patients, 218 had hemorrhagic transformations. The LightGBM model with all radiomics features had the best performance, with an area under the receiver operating characteristic curve (AUROC) of 0.986 (95% confidence interval [CI], 0.971-1.000) on the test dataset. The ExtraTrees model performed best when textural features were employed, with an AUROC of 0.845 (95% CI, 0.774-0.916). Minimum, maximum, and ten percentile values were significant predictors of hemorrhagic transformation. The clinical model showed an AUROC of 0.544 (95% CI, 0.431-0.658). The performance of the radiomics models was significantly better than that of the clinical model on the test dataset (p < 0.001). CONCLUSIONS: The radiomics model can predict hemorrhagic transformation using NCCT in stroke patients. Low Hounsfield unit was a strong predictor of hemorrhagic transformation, while textural features alone can predict hemorrhagic transformation. CLINICAL RELEVANCE STATEMENT: Using radiomic features extracted from initial non-contrast computed tomography, early prediction of hemorrhagic transformation has the potential to improve patient care and outcomes by aiding in personalized treatment decision-making and early identification of at-risk patients. KEY POINTS: • Predicting hemorrhagic transformation following thrombolysis in stroke is challenging since multiple factors are associated. • Radiomics features of infarcted tissue on initial non-contrast CT are associated with hemorrhagic transformation. • Textural features on non-contrast CT are associated with the frailty of the infarcted tissue.

Association between PAI-1 4G/5G genotype and residual thrombus in acute mesenteric venous thrombosis.

OBJECTIVE: Plasminogen activator inhibitor-1 (PAI-1) is the most important inhibitor of plasminogen activator. The functional 4G/5G polymorphism of the gene coding for PAI-1 may affect PAI-1 plasmatic activity, influencing the imbalance between coagulation and fibrinolysis cascades. In this study, we investigated the association between the PAI-1 4G/5G genotype and the development and residual thrombus of acute primary mesenteric venous thrombosis (MVT). METHODS: The clinical data of 34 patients who underwent acute primary MVT were retrospectively reviewed. Fluorescence in situ hybridization was used to determine if patients had the 4G/5G polymorphism in the promoter of the PAI-1 gene. Patients were stratified according to the genotype of PAI-1. RESULTS: 11 patients (32.3%) were homozygous for the 4G genotype, 23 patients (67.6%) were non-homozygous for the 4G genotype (5G/5G). The extent of thrombosis was not correlated with the PAI-4G/5G polymorphism. After a mean follow-up of 16.6 ± 10.4 months, the 4G/4G genotype had a significantly larger thrombus burden (p < 0.05). 54% of patients in the 4G/4G genotype group had no lessening in the degree of mesenteric venous thrombosis, significantly higher than other patients (4G/5G + 5G/5G genotypes) (p < 0.05). CONCLUSION: The PAI-1 4G/4G predicts residual thrombus of mesenteric veins after the acute phase.