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.

Rates and Impact of Serious Adverse Events after Endovascular Thrombectomy among Large Vessel Occlusion Stroke Patients.

OBJECTIVE: Complications or serious adverse events (SAEs) are common in the treatment of patients with large vessel occlusion stroke. There has been limited study of the impact of SAEs for patients after endovascular thrombectomy (EVT). The goal of this study was to characterize the rates and clinical impact of SAEs following EVT. METHODS: A post hoc analysis was performed using pooled databases of the "DEVT" and "RESCUE BT" trials. SAEs were designated as symptomatic intracranial hemorrhage, brain herniation or craniectomy, respiratory failure, circulatory failure, pneumonia, deep venous thrombosis, and systemic bleeding. The primary endpoint was functional independence (modified Rankin scale score 0-2 within 90 days). Logistic regression analysis was used to determine the predictors and associations between SAEs and outcomes. RESULTS: Of 1,182 enrolled patients, 402 (34%) had a procedural complication and 745 (63%) had 1,404 SAE occurrences with 4.65% in-hospital mortality. The three most frequent SAEs were pneumonia (620, 52.5%), systemic bleeding (174, 14.7%), and respiratory failure (173, 14.6%). Pneumonia, systemic bleeding, or deep venous thrombosis was less life-threatening. Patients with advanced age (adjusted odds ratio, 1.28 [95% confidence interval, 1.14-1.43]), higher NIHSS (1.09 [1.06-1.11]), occlusion site (middle cerebral artery-M1 vs. internal carotid artery [ICA]: 0.75 [0.53-1.04]; M2 vs. ICA: 1.30 [0.80-2.12]), longer procedure time (1.01 [1.00-1.01]), and unsuccessful vessel recanalization (1.79 [1.06-2.94]) were more likely to experience SAEs. Compared with no SAE, patients with SAEs had lower odds of functional independence (0.46 [0.40-0.54]). CONCLUSIONS: Overall, SAEs diagnosed following thrombectomy in patients with stroke were common (more than 60%) and associated with functional dependence. Patients with advanced age, higher NIHSS, longer procedure time, and failed recanalization were more likely to experience SAEs. There was no statistical difference in the risk of SAEs among patients with M1 and M2 occluded compared with those ICA occluded. An understanding of the prevalence and predictors of SAEs could alert clinicians to the estimated risk of an SAE for a patient after EVT.

Decompressive craniectomy for patients with malignant infarction of the middle cerebral artery: A pooled analysis of two randomized controlled trials.

BACKGROUND: Decompressive craniectomy (DC) reduces mortality without increasing the risk of very severe disability among patients with life-threatening massive cerebral infarction. However, its efficacy was demonstrated before the era of endovascular thrombectomy trials. It remains uncertain whether DC improves the prognosis of patients with malignant middle cerebral artery (MCA) infarction receiving endovascular therapy. METHODS: We pooled data from two trials (DEVT and RESCUE BT studies in China) and patients with malignant MCA infarction were included to assess outcomes and heterogeneity of DC therapy effect. Patients with herniation were dichotomized into DC and conservative groups according to their treatment strategy. The primary outcome was the rate of mortality at 90 days. Secondary outcomes included disability level at 90 days as measured by the modified Rankin Scale score (mRS) and quality-of-life score. The associations of DC with clinical outcomes were performed using multivariable logistic regression. RESULTS: Of 98 patients with herniation, 37 received DC surgery and 61 received conservative treatment. The median (interquartile range) was 70 (62-76) years and 40.8% of the patients were women. The mortality rate at 90 days was 59.5% in the DC group compared with 85.2% in the conservative group (adjusted odds ratio, 0.31 [95% confidence interval (CI), 0.10-0.94]; P=0.04). There were 21.6% of patients in the DC group and 6.6% in the conservative group who had a mRS score of 4 (moderately severe disability); and 10.8% and 4.9%, respectively, had a score of 5 (severe disability). The quality-of-life score was higher in the DC group (0.00 [0.00-0.14] vs 0.00 [0.00-0.00], P=0.004), but DC treatment was not associated with better quality-of-life score in multivariable analyses (adjusted ß Coefficient, 0.02 [95% CI, -0.08-0.11]; p=0.75). CONCLUSIONS: DC was associated with decreased mortality among patients with malignant MCA infarction who received endovascular therapy. The majority of survivors remained moderately severe disability and required improvement on quality of life. CLINICAL TRIAL REGISTRATION: The DEVT trial: http://www.chictr.org. Identifier, ChiCTR-IOR-17013568. The RESCUE BT trial: URL: http://www.chictr.org. Identifier, ChiCTR-INR-17014167.

Efficacy and safety of tirofiban combined with endovascular therapy for basilar artery occlusion stroke due to large artery atherosclerosis.

BACKGROUND: This study aimed to evaluate the efficacy and safety of adjuvant tirofiban in patients with acute basilar artery occlusion due to large-artery atherosclerotic (LAA) receiving endovascular therapy (EVT). METHODS: This was a non-randomized, multicenter study using data from the Endovascular Treatment for Acute BASILAR Artery Occlusion (BASILAR) registry. Patients with acute basilar artery occlusion due to LAA within 24h of symptom onset who underwent EVT were included. Patients were divided into tirofiban and non-tirofiban groups according to whether tirofiban was used. The primary outcome was the ordinal modified Rankin scale score at 90 days. Safety outcomes were mortality within 90 days and symptomatic intracranial hemorrhage (sICH) within 48 h. RESULTS: A total of 417 patients were included, of whom 275 patients were in the tirofiban group and 142 patients in the non-tirofiban group. Compared with patients in the non-tirofiban group, patients in the tirofiban group were associated with a favorable shift in functional outcome at 90 days (6[4-6] vs 5 [2-6]; adjusted common OR, 2.51; 95 % CI, 1.64-3.83). The mortality was lower in the tirofiban group than the non-tirofiban group (40.7 % vs 58.5 %; adjusted OR, 0.35; 95 % CI, 0.21-0.56). The rate of sICH was 12.2 % in the non-tirofiban group and 5.2 % in the tirofiban group (adjusted OR, 0.37; 95 % CI, 0.17-0.80; P = 0.012). CONCLUSION: Tirofiban plus EVT might improve functional outcomes with a good safety for patients with acute basilar artery occlusion due to LAA. The results need to be confirmed in a randomized trial.

Effect of Imaging Selection Paradigms on Endovascular Thrombectomy Outcomes in Patients With Acute Ischemic Stroke.

BACKGROUND: The effect of imaging selection paradigms on endovascular thrombectomy outcomes in patients with acute ischemic stroke with large vessel occlusion remains uncertain. The study aimed to assess the effect of basic imaging (noncontrast computed tomography with or without computed tomographic angiography) versus advanced imaging (magnetic resonance imaging or computed tomography perfusion) on clinical outcomes following thrombectomy in patients with stroke with large vessel occlusion in the early and extended windows using a pooled analysis of patient-level data from 2 pivotal randomized clinical trials done in China. METHODS: This post hoc analysis used data from 1182 patients included in 2 multicenter, randomized controlled trials in China that evaluated adjunct therapies to endovascular treatment for acute ischemic stroke (Direct Endovascular Treatment for Large Artery Anterior Circulation Stroke performed from May 20, 2018, through May 2, 2020, and Intravenous Tirofiban Before Endovascular Treatment in Stroke from October 10, 2018, through October 31, 2021). Patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery (M1/M2 segments) were categorized according to baseline imaging modality (basic versus advanced) as well as treatment time window (early, 0-6 hours versus extended, 6-24 hours from last known well to puncture). The primary outcome was the proportion of patients with functional independence (modified Rankin Scale score of 0-2) at 90 days. Multivariable Poisson regression analysis was performed to determine the association between imaging selection modality and outcomes after endovascular treatment at each time windows. RESULTS: A total of 1182 patients were included in this cohort analysis, with 648 in the early (471 with basic imaging versus 177 advanced imaging) and 534 in the extended (222 basic imaging versus 312 advanced imaging) time window. There were no differences in 90-day functional independence between the advanced and basic imaging groups in either time windows (early window: adjusted relative risk, 0.99 [95% CI, 0.84-1.16]; P=0.91; extended window: adjusted relative risk, 1.00 [95% CI, 0.84-1.20]; P=0.97). CONCLUSIONS: In this post hoc analysis of 2 randomized clinical trial pooled data involving patients with large vessel occlusion stroke, an association between imaging selection modality and clinical or safety outcomes for patients undergoing thrombectomy in either the early or extended windows was not detected. Our study adds to the growing body of literature on simpler imaging paradigms to assess thrombectomy eligibility across both the early and extended time windows. REGISTRATION: URL: http://www.chictr.org.cn; Unique identifiers: ChiCTR-IOR-17013568 and ChiCTR-INR-17014167.

Association of Intravenous Tirofiban with Functional Outcomes in Acute Ischemic Stroke Patients with Acute Basilar Artery Occlusion Receiving Endovascular Thrombectomy.

INTRODUCTION: The aim of this study was to test the hypothesis that intravenous tirofiban improves functional outcomes without promoting the risk of intracranial hemorrhage (ICH) in stroke secondary to basilar artery occlusion (BAO) receiving endovascular thrombectomy. METHODS: Patients with acute BAO stroke who were treated with endovascular thrombectomy and had tirofiban treatment information were derived from "BASILAR": a nationwide, prospective registry. All eligible patients were divided into tirofiban and no-tirofiban groups according to whether tirofiban was used intravenously. The primary endpoint was the 90-day severity of disability as assessed by the modified Rankin scale score. Safety outcomes were the frequency of ICH and mortality. RESULTS: Of 645 patients included in this cohort, 363 were in the tirofiban group and 282 were in the no-tirofiban group. Thrombectomy with intravenous tirofiban reduced the 90-day disability level over the range of the modified Rankin scale (adjusted common odds ratio, 2.08; 95% confidence interval (CI), 1.45-2.97; p < 0.001). The 90-day mortality of patients in the tirofiban group was lower than that in the no-tirofiban group (41.6% vs. 52.1%; adjusted hazard ratio, 0.60; 95% CI, 0.47-0.77; p < 0.001). The frequency of any ICH (6.7% vs. 13.7%; p = 0.004) and symptomatic ICH (4.8% vs. 10.1%; p = 0.01) in the tirofiban group was significantly lower than that in the no-tirofiban group. CONCLUSIONS: In patients with acute BAO stroke who underwent endovascular treatment, intravenous tirofiban might be associated with favorable outcome, reduced mortality, and a decreased frequency of ICH.

Drug-Coated Balloon Angioplasty of Infrapopliteal Lesions in Chronic Limb-Threatening Ischemia: Six-month Outcomes of PRIME-WIFI.

PURPOSE: To evaluate 6-month outcomes of drug-coated balloon (DCB) angioplasty of infrapopliteal lesions in patients with chronic limb-threatening ischemia (CLTI). METHODS: We analyzed 6-month follow-up data from the 10-center PRIME-WIFI prospective registry on 300 consecutive patients (33.000% female) with CLTI who underwent DCB angioplasty for infrapopliteal arterial lesions. The primary outcome was freedom from major adverse event (MAE), a composite of major amputation, all-cause death, and clinically-driven target limb reintervention (CD-TLR). Secondary outcomes included amputation-free survival (AFS), freedom from each primary outcome component, primary sustained clinical improvement, and quality of life (QOL) score. Independent risk factors of MAE were determined using Cox proportional hazards regression analysis. RESULTS: A total of 409 infrapopliteal lesions in 312 limbs were treated with DCB, with 54.167% of the limbs being treated for isolated infrapopliteal lesions. By Kaplan-Meier analysis, at 6 months post- procedure (follow-up rate, 85.000%), freedom from MAE was 86.353%; AFS was 90.318%; and freedom from major amputation, all-cause death, and CD-TLR were 96.429%, 93.480%, and 95.079%, respectively. At 6-month follow-up, 83.590% of patients showed primary sustained clinical improvement, and QOL score (4.902±1.388) improved compared with that before procedure (2.327±1.109; p<0.001). Chronic renal insufficiency, chronic obstructive pulmonary disease, Rutherford grade, and postoperative infrapopliteal runoff score were independent risk factors for MAE within 6 months. CONCLUSION: In CLTI, DCB angioplasty of infrapopliteal lesions yields acceptable early efficacy and safety. CLINICAL IMPACT: This study evaluated the 6-month outcomes of DCB angioplasty in infrapopliteal lesions in CLTI patients by analyzing multicenter prospective data, showing that infrapopliteal DCB angioplasty can be performed with acceptable freedom from MAE rate, amputation-free survival rate, freedom from major amputation rate, survival rate, and freedom from CD-TLR rate. No patient experienced DCB-related intraoperative distal embolism. Chronic renal insufficiency, chronic obstructive pulmonary disease, Rutherford grade and postoperative infrapopliteal runoff score were independent risk factors for MAE within 6 months. Comparative real-world studies are needed.

One-Year Outcome After Endovascular Treatment for Acute Basilar Artery Occlusion.

BACKGROUND AND PURPOSE: The BASILAR registry, a nationwide prospective nonrandomized study conducted in China, enrolled consecutive patients with acute basilar artery occlusion receiving endovascular treatment or conventional-treatment from January 2014 to May 2019. This article aimed to report the results of clinical follow-up at one year among these patients. METHODS: The primary outcome was the modified Rankin Scale at one year, assessed as a common odds ratio using ordinal logistic regression analysis adjusted for prespecified prognostic factors. Secondary outcomes included the modified Rankin Scale-based outcome group at one year (0-1, 0-2, or 0-3) and all-cause death. RESULTS: Of the 829 patients enrolled in the original BASILAR registry, one-year data were available for 785 patients (94.7%). The distribution of outcomes on the modified Rankin Scale favored endovascular treatment over conventional-treatment (adjusted common odds ratio, 4.50 [95% CI, 2.81-7.29]; P<0.001). The cumulative one-year mortality rate was 54.6% in the endovascular treatment group versus 83.5% in the conventional-treatment group (adjusted odds ratio, 4.36 [95% CI, 2.69-7.29]; P<0.001). CONCLUSIONS: The beneficial effect of endovascular treatment on functional outcome at one year in patients with acute basilar artery occlusion is similar to that reported at 90 days in the original study. REGISTRATION: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1800014759.

Effect of Intravenous Tirofiban vs Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke: The RESCUE BT Randomized Clinical Trial.

Importance: Tirofiban is a highly selective nonpeptide antagonist of glycoprotein IIb/IIIa receptor, which reversibly inhibits platelet aggregation. It remains uncertain whether intravenous tirofiban is effective to improve functional outcomes for patients with large vessel occlusion ischemic stroke undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of intravenous tirofiban before endovascular thrombectomy for acute ischemic stroke secondary to large vessel occlusion. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 55 hospitals in China, enrolling 948 patients with stroke and proximal intracranial large vessel occlusion presenting within 24 hours of time last known well. Recruitment took place between October 10, 2018, and October 31, 2021, with final follow-up on January 15, 2022. Interventions: Participants received intravenous tirofiban (n = 463) or placebo (n = 485) prior to endovascular thrombectomy. Main Outcomes and Measures: The primary outcome was disability level at 90 days as measured by overall distribution of the modified Rankin Scale scores from 0 (no symptoms) to 6 (death). The primary safety outcome was the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 948 patients randomized (mean age, 67 years; 391 [41.2%] women), 948 (100%) completed the trial. The median (IQR) 90-day modified Rankin Scale score in the tirofiban group vs placebo group was 3 (1-4) vs 3 (1-4). The adjusted common odds ratio for a lower level of disability with tirofiban vs placebo was 1.08 (95% CI, 0.86-1.36). Incidence of symptomatic intracranial hemorrhage was 9.7% in the tirofiban group vs 6.4% in the placebo group (difference, 3.3% [95% CI, -0.2% to 6.8%]). Conclusions and Relevance: Among patients with large vessel occlusion acute ischemic stroke undergoing endovascular thrombectomy, treatment with intravenous tirofiban, compared with placebo, before endovascular therapy resulted in no significant difference in disability severity at 90 days. The findings do not support use of intravenous tirofiban before endovascular thrombectomy for acute ischemic stroke. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR-IOR-17014167.

Values of Baseline Posterior Circulation Acute Stroke Prognosis Early Computed Tomography Score for Treatment Decision of Acute Basilar Artery Occlusion.

BACKGROUND AND PURPOSE: This study aimed to analyze the impact of baseline posterior circulation Acute Stroke Prognosis Early Computed Tomography Score (pc-ASPECTS) on the efficacy and safety of endovascular therapy (EVT) for patients with acute basilar artery occlusion. METHODS: The BASILAR was a nationwide prospective registry of consecutive patients with a symptomatic and radiologically confirmed acute basilar artery occlusion within 24 hours of symptom onset. We estimated the effect of standard medical therapy alone (SMT group) versus SMT plus EVT (EVT group) for patients with documented pc-ASPECTS on noncontrast CT, both as a categorical (0-4 versus 5-7 versus 8-10) and as a continuous variable. The primary outcomes included favorable functional outcomes (modified Rankin Scale ≤3) at 90 days and mortality within 90 days. RESULTS: In total, 823 cases were included: 468 with pc-ASPECTS 8 to 10 (SMT: 71; EVT: 397), 317 with pc-ASPECTS 5 to 7 (SMT: 85; EVT: 232), and 38 with pc-ASPECTS 0 to 4 (SMT: 13; EVT: 25). EVT was associated with higher rate of favorable outcomes (adjusted relative risk with 95% CI, 4.35 [1.30-14.48] and 3.20 [1.68-6.09]; respectively) and lower mortality (60.8% versus 77.6%, P=0.005 and 35.0% versus 66.2%, P<0.001; respectively) than SMT in the pc-ASPECTS 5 to 7 and 8 to 10 subgroups. Continuous benefit curves also showed the superior efficacy and safety of EVT over SMT in patients with pc-ASPECTS ≥5. Furthermore, the prognostic effect of onset to puncture time on favorable outcome with EVT was not significant after adjustment for pc-ASPECTS (adjusted odds ratio, 0.98 [95% CI, 0.94-1.02]). CONCLUSIONS: Patients of basilar artery occlusion with pc-ASPECTS ≥5 could benefit from EVT. The baseline pc-ASPECTS appears more important for decision making and predicting prognosis than time to EVT. Registration: URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1800014759.

One-Year Clinical Outcome and Risk Factor Analysis of Directional Atherectomy Followed With Drug-Coated Balloon for Femoropopliteal Artery Disease.

PURPOSE: This study investigated the 1-year clinical outcomes of directional atherectomy combined with drug-coated balloon (DA + DCB) in femoropopliteal artery disease (FPAD) from real-world experience. MATERIALS AND METHODS: A retrospective study was conducted of patients treated between July 2016 and June 2019 using DA + DCB for FPAD. Patients' demographics, comorbidities, clinical characteristics and outcomes, and angiography and duplex ultrasound findings were analyzed. The 6-month and 1-year primary patency, primary assisted patency, secondary patency, and freedom from clinically-driven target lesion revascularization (CD-TLR) were evaluated. Univariate and multivariate analyses were performed to identify risk factors of primary patency loss or CD-TLR. RESULTS: Seventy-nine consecutive patients (83 lesions, mean age 70.9 years, 52 men) were included. Twenty-seven limbs had lifestyle-limiting claudication and 56 limbs had critical limb ischemia. There were 73 and 10 limbs with de novo lesion and in-stent restenosis, respectively. The mean lesion length of all the patients was 22.1 cm. The mean length of chronic total occlusions (CTOs) was 8.3 cm. Severe calcification was found in 32.5% cases. The 1-year primary patency rate was 80.8% and freedom from CD-TLR was 92.2%. The bailout stenting rate was 2.4%. Patients with CTO >10 cm had significantly lower 1-year primary patency rate and freedom from CD-TLR than did patients with CTO ≤10 cm. Total length of CTO (stratified as ≤5 cm, 5-10 cm, >10 cm) was identified as an independent risk factor of 1-year primary patency loss and CD-TLR. CONCLUSION: DA + DCB appears to be a safe and effective endovascular therapy to treat FPAD in real-world clinical practice, with a promising 1-year patency rate with a low rate of bailout stenting.

Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke: The DEVT Randomized Clinical Trial.

Importance: For patients with large vessel occlusion strokes, it is unknown whether endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment (standard treatment) can achieve similar functional outcomes. Objective: To investigate whether endovascular thrombectomy alone is noninferior to intravenous alteplase followed by endovascular thrombectomy for achieving functional independence at 90 days among patients with large vessel occlusion stroke. Design, Setting, and Participants: Multicenter, randomized, noninferiority trial conducted at 33 stroke centers in China. Patients (n = 234) were 18 years or older with proximal anterior circulation intracranial occlusion strokes within 4.5 hours from symptoms onset and eligible for intravenous thrombolysis. Enrollment took place from May 20, 2018, to May 2, 2020. Patients were enrolled and followed up for 90 days (final follow-up was July 22, 2020). Interventions: A total of 116 patients were randomized to the endovascular thrombectomy alone group and 118 patients to combined intravenous thrombolysis and endovascular thrombectomy group. Main Outcomes and Measures: The primary end point was the proportion of patients achieving functional independence at 90 days (defined as score 0-2 on the modified Rankin Scale; range, 0 [no symptoms] to 6 [death]). The noninferiority margin was -10%. Safety outcomes included the incidence of symptomatic intracerebral hemorrhage within 48 hours and 90-day mortality. Results: The trial was stopped early because of efficacy when 234 of a planned 970 patients had undergone randomization. All 234 patients who were randomized (mean age, 68 years; 102 women [43.6%]) completed the trial. At the 90-day follow-up, 63 patients (54.3%) in the endovascular thrombectomy alone group vs 55 (46.6%) in the combined treatment group achieved functional independence at the 90-day follow-up (difference, 7.7%, 1-sided 97.5% CI, -5.1% to ∞)P for noninferiority = .003). No significant between-group differences were detected in symptomatic intracerebral hemorrhage (6.1% vs 6.8%; difference, -0.8%; 95% CI, -7.1% to 5.6%) and 90-day mortality (17.2% vs 17.8%; difference, -0.5%; 95% CI, -10.3% to 9.2%). Conclusions and Relevance: Among patients with ischemic stroke due to proximal anterior circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared with intravenous alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence. These findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IOR-17013568.

miR-21 induces endothelial progenitor cells proliferation and angiogenesis via targeting FASLG and is a potential prognostic marker in deep venous thrombosis.

BACKGROUND: Deep venous thrombosis (DVT) of lower extremities is a common thrombotic disease, occurring either in isolation or as a complication of other diseases or procedures. MiR-21 is one of important microRNAs which play critical role in various cellular function. This study aim to determine the effect of miR-21 on endothelial progenitor cells (EPCs) and its role in predicting prognosis of DVT. METHODS: EPCs was isolated from DVT models and control subjects. miR-21 expression was confirmed by RT-PCR. Potential target mRNA was predicted by bioinformatics analysis. EPCs biological functions were examined by CCK-8 and tube formation assay. Besides, miR-21 expression was determined in DVT patients to investigate the correlation between miR-21 expression and prognosis of DVT. Cox proportional hazard regression analyses were also performed to reveal the risk factors associated with prognosis. RESULTS: Here, we found miR-21 was downregulated in EPCs of DVT model rats. Increased miR-21 expression promoted proliferation and angiogenesis of EPCs. Moreover, we demonstrated that FASLG was a target of miR-21 and revealed that FASLG knockdown inhibited function of EPCs. Upregulation of miR-21 led to thrombus resolution in a rat model of venous thrombosis. In addition, lower expression level of miR-21 in DVT patients was associated with an increase of recurrent DVT and post thrombotic syndrome (PTS). Furthermore, Cox proportional hazard regression analyses demonstrated miR-21 expression level as an independent predictor of recurrence of DVT. CONCLUSIONS: Our data revealed a role of miR-21 in regulating biological function of EPCs and could be a predictor for recurrent DVT or PTS.

Long-term follow-up of the stenting across the iliocaval confluence in patients with iliac venous lesions.

Stent implantation is the common treatment method for iliac vein (IV) occlusion. IV stents usually enter into the inferior vena cava (IVC) to partially or completely cover the contralateral IV, but it is still uncertain whether this can increase the risk of thrombosis in the contralateral IV. The purpose of this study was to investigate the effect of the stent position on the bilateral IVs patency. A total of 261 patients with symptomatic IV lesions, including 177 patients with non-thrombotic iliac vein lesions (NIVLs) and 84 patients with thrombotic iliac vein lesions (TIVLs), were implanted with IV stents between July 2007 and June 2017. The data of these patients were retrospectively studied. The follow-up time was 6-114 months, and the median time was 62 months. A total of 183 cases had stenting into the IVC for more than 5 mm. The incidence of thrombosis in the contralateral IV was only 0.55% (1/183). A total of 17 short- and long-term cumulative cases had ipsilateral thrombosis on the stent side. There was no significant difference between the incidence of patients (8.79%, 7/78) with stenting into the IVC for less than 5 mm and those with more than 5 mm (5.46%, 10/183, P = 0.287). However, in the TIVLs group, the incidence of ipsilateral thrombosis between stenting positions less than 5 mm (29.6%, 8/27) and those more than 5 mm (8.77%, 5/57) was significantly different (P = 0.022). Stent implantation for NIVLs had an excellent long-term patency rate; the primary patency rate and the assisted primary patency rate were 97.7% and 100%, respectively. The entry of IV stents into the IVC was safe and had a very low incidence of thrombosis in the contralateral vein. Stenting less into the IVC increased the incidence of thrombosis in the ipsilateral vein, especially among thrombotic cases. Treatment of NIVLs using stent implantation had a better long-term patency rate. This principle plays an important guiding role in the endovascular therapy of IV lesions.

Long-Term Outcome of Catheter-Directed Thrombolysis in Pregnancy-Related Venous Thrombosis.

BACKGROUND Venous thromboembolism (VT) is a leading cause of maternal mortality and morbidity worldwide. Catheter-directed thrombolysis (CDT) is an effective and safe treatment modality for VT patients. However, the long-term outcome of CDT in pregnancy-related venous thrombosis are unclear. The aim of this study was to assess long-term results of pregnancy-related VT patients. MATERIAL AND METHODS We reviewed 41 pregnancy-related deep venous thrombosis (DVT) patients who underwent CDT from February 2008 to May 2015. Clinical data, including demographic variables, disease location, vascular risk factors, treatment regimen, interventional procedure and complications, were collected retrospectively. Clinical and color-duplex ultrasonography were performed to monitor venous patency during follow-up. Post-thrombotic syndrome (PTS) was assessed with the Villalta scale and quality of life (QOL) was evaluated by the VEINES-QOL/Sym questionnaire. RESULTS Twenty-three patients underwent spontaneous abortion or induced abortion within 3 months before DVT, and 18 patients had DVT during the first 3 months after delivery. Technical success was achieved in all patients. Grade III (complete) lysis was obtained in 15 patients and grade II (partial) lysis was obtained in 21 patients. The follow-up period was 3 years. Twenty-eight patients had venous patency at 3-year follow-up; 36.6% of patients developed mild or moderate PTS (Villalta score 5-14) and 4.8% with severe PTS (Villalta score ≥15). VEINES-QOL/Sym scores were 55.24±7.35 and 53.25±6.65, respectively. CONCLUSIONS Catheter-directed thrombolysis is a reliable and safe treatment modality for postnatal or abortion patients with DVT. CDT can reduce the incidence rate of PTS and increase the quality of life.

Resveratrol Improves Endothelial Progenitor Cell Function through miR-138 by Targeting Focal Adhesion Kinase (FAK) and Promotes Thrombus Resolution In Vivo.

BACKGROUND Endothelial progenitor cells (EPCs) were found to be a potential therapeutic choice for low extremity deep vein thrombosis. The aim of our research was to investigate the effect of resveratrol (RSV) on EPCs that may promote thrombus resolution and its potential pathway. MATERIAL AND METHODS EPCs were pretreated with RSV and migration; angiogenesis were evaluated ex vivo. Expression of miR-138 and focal adhesion kinase (FAK) was also tested. A murine model of venous thrombosis was developed as an in vivo model. The effects of RSV treatment on mice with inferior venous thrombosis were evaluated. RESULTS We found that RSV increased EPCs migration and tube formation ex vivo. RSV significantly inhibited miR-138 expression. Moreover, we demonstrated that FAK was a target of miR-138 and revealed that FAK knockdown downregulated migration and angiogenesis of RSV-treated EPCs. In addition, RSV-induced EPCs promoted thrombus resolution in a murine model of venous thrombosis. CONCLUSIONS We found the first evidence that intravenous injection of RSV-treated EPCs enhanced thrombus resolution in vivo. RSV exerted its role by reducing miR-138 expression and therefore upregulated FAK.

Opposite roles of bradykinin B1 and B2 receptors during cerebral ischaemia-reperfusion injury in experimental diabetic rats.

Bradykinin receptors play important roles in cerebral ischaemia-reperfusion (I/R) injury of non-diabetics. Their functions in diabetics, however, have not been studied. In this study, we hypothesized that bradykinin 1 receptor (B1R) and bradykinin 2 receptor (B2R) would be upregulated and participate in the regulation of diabetic ischaemic stroke. To investigate this, we first evaluated B1R and B2R expression at different time points after I/R in non-diabetic and diabetic rats (Sprague-Dawley) by using real-time quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence. Then, pharmacological inhibitors were separately administered via the tail vein to analyse their effects on cerebral ischaemia in diabetics. Both receptors were significantly upregulated after cerebral I/R in non-diabetic and diabetic rats. B1R expression in diabetic rats increased in a sharper manner than in non-diabetic rats, whereas B2R expression increased to the same level during the early stage of reperfusion but later became lower. Interestingly, the upregulated B1R was expressed in astrocytes, whereas B2R was mainly located in neurons in the ischaemic penumbra. Functional studies showed that inhibition of B1R significantly reduced infarct volume, neurological deficits, cell apoptosis, and neuron degeneration, probably by attenuating blood-brain barrier (BBB) disruption and post-ischaemic inflammation, at 24 h after reperfusion. In contrast, B2R antagonist had opposite effects, and exacerbated BBB penetrability and tissue inflammation. These findings suggest that B1R and B2R have detrimental and beneficial effects, respectively in diabetic cerebral ischaemia, which might open new avenues for the treatment of ischaemic stroke in diabetic patients through selective pharmacological blockade or activation.

Human urine kininogenase attenuates balloon-induced intimal hyperplasia in rabbit carotid artery through transforming growth factor ß1/Smad2/3 signaling pathway.

OBJECTIVE: Effective treatments against restenosis after percutaneous transluminal angioplasty and stenting are largely lacking. Human tissue kallikrein gene transfer has been shown to be able to attenuate neointima formation induced by balloon catheter. As a tissue kallikrein in vivo, human urinary kininogenase (HUK) is widely used to prevent ischemia-reperfusion injury. However, the effects of HUK on neointima formation have not been explored. We therefore investigated whether HUK could alleviate balloon catheter-induced intimal hyperplasia in rabbits fed with high-fat diets. METHODS: The effects of HUK on neointima and atherosclerosis formation were analyzed by hematoxylin-eosin staining and immunohistochemical staining in balloon-injured carotid arteries of rabbits. Local inflammatory response was evaluated by detecting the gene expression of tumor necrosis factor α and interleukin 1ß with real-time quantitative polymerase chain reaction plus the invasion of macrophages with immunohistochemical staining. Western blotting was employed to investigate the effects of HUK on activities of endothelial nitric oxide synthase (eNOS), transforming growth factor ß1 (TGF-ß1), and Smad signaling pathway. The long-term effect of HUK on intimal hyperplasia of the injured carotid artery was assessed by angiography. RESULTS: Quantitative image analysis showed that intravenous administration of HUK for 14 days significantly decreased the intimal areas and intima area/media area ratios (day 14, 54% decrease in intimal area and 58% decrease in intima area/media area ratios; day 28, 63% and 85%). Significant decreases were also noted in macrophage foam cell-positive area after 7-day or 14-day administration of HUK (day 7, 69% decrease in intimal area and 78% decrease in media area; day 14, 79% and 60%; day 28, 68% and 44%). Actin staining for smooth muscle cells in neointima at 2 months showed similar results (vascular smooth muscle cell-positive area of neointima, 28.21% ± 5.58% vs 43.78% ± 8.36%; P < .05). Real-time quantitative polymerase chain reaction or Western blot analysis showed that HUK reduced expression of tumor necrosis factor α, interleukin 1ß, TGF-ß1, and p-Smad2/3 but increased the expression of p-eNOS. Angiography analysis showed that 14-day administration of HUK significantly decreased the degree of stenosis (26.8% ± 7.1% vs 47.9% ± 5.7%; P < .01) at 2 months after balloon injury. CONCLUSIONS: Our results indicate that HUK is able to attenuate atherosclerosis formation and to inhibit intimal hyperplasia by downregulating TGF-ß1 expression and Smad2/3 phosphorylation, upregulating eNOS activity. HUK may be a potential therapeutic agent to prevent stenosis after vascular injury.

Human Albumin Improves Long-Term Behavioral Sequelae After Subarachnoid Hemorrhage Through Neurovascular Remodeling.

OBJECTIVE: Subarachnoid hemorrhage results in significant long-lasting neurologic sequelae. Here, we investigated whether human albumin improves long-term outcomes in experimental subarachnoid hemorrhage and whether neurovascular remodeling is involved in the protection of albumin. DESIGN: Laboratory investigation. SETTING: Hospital research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Rats underwent subarachnoid hemorrhage by endovascular perforation. Albumin of either 0.63 or 1.25 g/kg was injected IV immediately after the surgery. Modified Garcia test, beam-walking test, novel object recognition, and Morris water maze were employed to determine the behavioral deficits. The effects of albumin on early neurovascular dysfunction and chronic synaptic plasticity were also studied. MEASUREMENTS AND MAIN RESULTS: Both doses of albumin significantly improved the sensorimotor scores (F = 31.277; p = 0.001) and cognitive performance (F = 7.982; p = 0.001 in novel object recognition test; and F = 3.431; p = 0.026 in the latency analysis of Morris water maze test) for at least 40 days after subarachnoid hemorrhage. There were remarkable microvasculature hypoperfusion, intracranial pressure rise, early vasoconstriction, neural apoptosis, and degeneration in subarachnoid hemorrhage rats, with albumin significantly attenuating such neurovascular dysfunction. Furthermore, albumin markedly prevented blood-brain barrier disruption, as indicated by less blood-brain barrier leakage, preserved blood-brain barrier-related proteins, and dampened gelatinase activities. The expressions of key synaptic elements were up-regulated with albumin supplementation in both acute and chronic phases. Accordingly, a higher dendritic spine density was observed in the prefrontal and hippocampal areas of albumin-treated subarachnoid hemorrhage animals. CONCLUSIONS: Albumin at low-to-moderate doses markedly improves long-term neurobehavioral sequelae after subarachnoid hemorrhage, which may involve an integrated process of neurovascular remodeling.

Endovascular treatments for cerebral venous sinus thrombosis.

Cerebral venous sinus thrombosis (CVST) is an uncommon but potentially fatal condition. CVST usually occurs young adults with a female predominance. The current mainstay for treating CVST is anticoagulation with heparin. However, more aggressive interventions, endovascular treatment as an example, may be indicated in selected patients who are non-responsive to heparin and other anticoagulants. Endovascular approaches include catheter-based local chemical thrombolysis, balloon angioplasty and mechanical thrombectomy, all of which may rapidly recanalize the occluded venous sinus, restore the blood flow, reduce the increased intracranial pressure, and subsequently relieve the corresponding symptoms. However, as an invasive strategy, endovascular procedures per se may cause complications, such as intracranial hemorrhage, vessel dissection and pulmonary embolization, which may substantially decrease the benefit-risk ratio of the treatment. Due to the rareness of the condition and the limited indication of this invasive strategy, safety and efficacy of endovascular procedures in treating CVST are less feasible to be evaluated in large randomized clinical trails. Therefore, the evidences for justifying this treatment strategy are largely derived from case reports, cohort studies and clinical observations.