Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage.

One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials.

Intracerebral Hemorrhage and Coronavirus Disease 2019 in a Cohort of 282,718 Hospitalized Patients.

BACKGROUND: To identify whether the risk of intracerebral hemorrhage is higher in patients with coronavirus disease 2019 (COVID-19), we compared the risk factors, comorbidities, and outcomes in patients intracerebral hemorrhage and COVID-19 and those without COVID-19. METHODS: We analyzed the data from the Cerner deidentified COVID-19 data set derived from 62 health care facilities. The data set included patients with an emergency department or inpatient encounter with discharge diagnoses codes that could be associated with suspicion of or exposure to COVID-19 or confirmed COVID-19. RESULTS: There were a total of 154 (0.2%) and 667 (0.3%) patients with intracerebral hemorrhage among 85,645 patients with COVID-19 and 197,073 patients without COVID-19, respectively. In the multivariate model, there was a lower risk of intracerebral hemorrhage in patients with COVID-19 (odds ratio 0.5; 95% confidence interval 0.5-0.6; p < .0001) after adjustment for sex, age strata, race/ethnicity, hypertension, diabetes mellitus, nicotine dependence/tobacco use, hyperlipidemia, atrial fibrillation, congestive heart failure, long-term anticoagulant use, and alcohol abuse. The proportions of patients who developed pneumonia (58.4% versus 22.5%; p < .0001), acute kidney injury (48.7% versus 31.0%; p < .0001), acute myocardial infarction (11% versus 6.4%; p = .048), sepsis (41.6% versus 22.5%; p < .0001), and respiratory failure (61.7% versus 42.3%; p < .0001) were significantly higher among patients with intracerebral hemorrhage and COVID-19 compared with those without COVID-19. The in-hospital mortality among patients with intracerebral hemorrhage and COVID-19 was significantly higher compared with that among those without COVID-19 (40.3% versus 19.0%; p < .0001). CONCLUSIONS: Our analysis does not suggest that rates of intracerebral hemorrhage are higher in patients with COVID-19. The higher mortality in patients with intracerebral hemorrhage and COVID-19 compared with those without COVID-19 is likely mediated by higher frequency of comorbidities and adverse in-hospital events.

Yield of ASPECTS and Collateral CTA Selection for Mechanical Thrombectomy within 6-24 hours from Symptom Onset in a Hub and Spoke System.

BACKGROUND: Recent extended window trials support the benefit of mechanical thrombectomy in anterior circulation large vessel occlusions with clinical-radiographic dissociation. Using trial imaging criteria, 6% were found eligible for MT in the EW in a hub-and-spoke system. We examined the eligibility and outcomes in consecutive extended window-mechanical thrombectomy patients using more pragmatic selection criteria. METHODS: We retrospectively analyzed single-institution data of anterior circulation large vessel occlusions patients presenting between 6-24 h who underwent mechanical thrombectomy based on a priori determined criteria including non-contrast CT head ASPECTS ≥ 6 and/or CTA collateral scores ASITN/SIR 2-4. Primary outcomes consisted of post-mechanical thrombectomy TICI 2b-3 and 3-month modified Rankin scores; safety outcomes consisted of in-hospital mortality and symptomatic intracerebral hemorrhage. RESULTS: 767 consecutive acute ischemic strokes patients presented within the 6-24 hour window, and of these 48 (6%) anterior circulation large vessel occlusions patients underwent mechanical thrombectomy. In this cohort the mean age was 63±17 years, 56% were male, the median NIHSS was 16 [IQR 10-19], the median ASPECTS was 9 (IQR 8-10), and 79% (n=38) had good CTA collaterals. Occlusions were primarily M1 MCA (46%), with 29% tandem occlusions. Successful recanalization (mTICI 2b or 3) was achieved in 73% (n=35), while 6% (n=3) of patients developed symptomatic intracerebral hemorrhage. In-hospital mortality was 25% (n=12) while 40% (n=19) achieved 3-month modified Rankin Scores 0-2. CONCLUSIONS: Our data suggest the use of pragmatic imaging approach of ASPECTS ≥6 with CTA collateral grade in extended time window which is already established in most hospitals.

Utilization and Outcomes of Acute Revascularization Treatments in Ischemic Stroke Patients with SARS-CoV-2 Infection.

OBJECTIVES: Acute ischemic stroke patients with severe acute respiratory syndrome coronavirus maybe candidates for acute revascularization treatments (intravenous thrombolysis and/or mechanical thrombectomy). MATERIALS AND METHODS: We analyzed the data from 62 healthcare facilities to determine the odds of receiving acute revascularization treatments in severe acute respiratory syndrome coronavirus infected patients and determined the odds of composite of death and non-routine discharge with severe acute respiratory syndrome coronavirus infected and non-infected patients undergoing acute revascularization treatments after adjusting for potential confounders. RESULTS: Acute ischemic stroke patients with severe acute respiratory syndrome coronavirus infection were significantly less likely to receive acute revascularization treatments (odds ratio 0.6, 95% confidence interval 0.5-0.8, p = 0.0001). Among ischemic stroke patients who received acute revascularization treatments, severe acute respiratory syndrome coronavirus infection was associated with increased odds of death or non-routine discharge (odds ratio 3.0, 95% confidence interval 1.8-5.1). The higher odds death or non-routine discharge (odds ratio 2.1, 95% confidence interval 1.9-2.3) with severe acute respiratory syndrome coronavirus infection were observed in all ischemic stroke patients without any modifying effect of acute revascularization treatments (interaction term for death (p = 0.9) or death or non-routine discharge (p = 0.2). CONCLUSIONS: Patients with acute ischemic stroke with severe acute respiratory syndrome coronavirus infection were significantly less likely to receive acute revascularization treatments. Severe acute respiratory syndrome coronavirus infection was associated with a significantly higher rate of death or non-routine discharge among acute ischemic stroke patients receiving revascularization treatments.

Admission Neutrophil-to-Lymphocyte Ratio as a Prognostic Biomarker of Outcomes in Large Vessel Occlusion Strokes.

Background and Purpose- The purpose of this study is to evaluate the relationship between neutrophil-to-lymphocyte ratio (NLR) at admission with safety and efficacy outcomes in acute stroke patients with large vessel occlusion after mechanical thrombectomy. Methods- Consecutive large vessel occlusion patients treated with mechanical thrombectomy during a 4-year period were evaluated. Outcome measures included symptomatic intracranial hemorrhage, 3-month mortality, successful reperfusion (modified Thrombolysis in Cerebral Infarction score of 2b/3), and 3-month functional independence (modified Rankin Scale scores of 0-2). Results- A total of 293 large vessel occlusion patients underwent mechanical thrombectomy (median admission NLR, 3.5; interquartile range [IQR], 1.7-6.8). In initial univariable analyses, higher median admission NLR values were documented in patients with symptomatic intracranial hemorrhage (8.5; IQR, 4.7-11.3) versus (3.9; IQR, 1.9-6.5); P<0.001 and individuals who were dead at 3-months (5.4; IQR, 2.8-9.6) versus (4.0; IQR, 1.8-6.4); P=0.004. Lower NLR values were recorded in patients with 3-month functional independence (3.7; IQR, 1.7-6.5) versus (4.3; IQR, 2.6-8.3); P=0.039. After adjustment for potential confounders, a 1-point increase in NLR was independently associated with higher odds of symptomatic intracranial hemorrhage (odds ratio, 1.11; 95% CI, 1.03-1.20; P=0.006) and 3-month mortality (odds ratio, 1.08; 95% CI, 1.01-1.16; P=0.014). Conclusions- Higher admission NLR is an independent predictor of symptomatic intracranial hemorrhage and 3-month mortality in large vessel occlusion patients treated with mechanical thrombectomy, and it may identify a target group for testing adjunctive anti-inflammatory therapies.

Hemicraniectomy for Malignant Middle Cerebral Artery Syndrome: A Review of Functional Outcomes in Two High-Volume Stroke Centers.

BACKGROUND AND PURPOSE: Despite recent landmark randomized controlled trials showing significant benefits for hemicraniectomy (HCT) compared with medical therapy (MT) in patients with malignant middle cerebral artery infarction (MMCAI), HCT rates have not substantially increased in the United States. We sought to evaluate early outcomes in patients with MMCAI who were treated with HCT (cases) in comparison to patients treated with MT due to the perception of procedural futility by families (controls). METHODS: We retrospectively evaluated consecutive patients with acute MMCAI treated in 2 tertiary care centers during a 7-year period. Pretreatment National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) at 3 months were documented. Functional independence (FI) and survival without severe disability (SWSD) were defined as mRS of 0-2 and 0-4, respectively. RESULTS: A total of 66 patients (37 cases and 29 controls) fulfilled the study inclusion criteria (mean age 59 ± 15 years, 52% men, median admission NIHSS score: 19 points [interquartile range {IQR}: 16-22]). Cases were younger (51 ± 11 versus 68 ± 13 years; P < .001) and tended to have lower median admission NIHSS than controls (18 [IQR:16-20] versus 20 [IQR:18-23]; P = .072). The rates of FI and SWSD at 3 months were higher in cases than controls (16% versus 0% [P = .031] and 62% versus 0% [P < .001]), while 3-month mortality was lower (24% versus 77%; P < .001). Multivariable Cox regression analyses adjusting for potential confounders identified HCT as the most important predictor of lower risk of 3-month mortality (hazard ratio: .02, 95% confidence interval: .01-0.10; P < .001). CONCLUSIONS: HCT is a critical and effective therapy for patients with MMCAI but cannot provide a guarantee of functional recovery.

Hemicraniectomy versus Conservative Treatment in Large Hemispheric Ischemic Stroke Patients: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Several small trials have inconclusively evaluated the effect of hemicraniectomy in reducing death and disability in acute ischemic stroke patients with large hemispheric infarctions. We compared the effects of hemicraniectomy on death and disability with conservative treatment in patients with large hemispheric infarctions. METHODS: We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) using random-effects models from 7 randomized trials that compared hemicraniectomy with conservative treatment in acute ischemic stroke patients. The primary end point was a favorable outcome defined by modified Rankin Scale grades of 0 (no symptoms), 1 (no significant disability), 2 (slight disability), and 3 (moderate disability) at 6-12 months post randomization. RESULTS: Of the 341 total subjects randomized, the proportion of subjects who achieved a favorable outcome was significantly greater among those randomized to hemicraniectomy than among those randomized to conservative treatment (OR 2.04, 95% CI 1.03-4.03, P = .04). Survival was also significantly greater among those randomized to hemicraniectomy (OR 5.56, 95% CI 3.40-9.08, P < .001) than among those randomized to conservative treatment. There was a trend toward higher odds of favorable outcome among those randomized to hemicraniectomy than among those randomized to conservative treatment in trials that permitted recruitment of patients aged 60 years or older (303 subjects analyzed; OR 1.87, 95% CI .91-3.86, P = .09). CONCLUSIONS: Compared with conservative treatment, the odds of achieving a favorable outcome at 6 months is approximately 2-folds higher with hemicraniectomy in patients with large hemispheric infarctions.

Cost-effectiveness analysis of endovascular treatment with or without intravenous thrombolysis in acute ischemic stroke.

OBJECTIVE: Intravenous (IV) recombinant tissue plasminogen activator (r-tPA) may not provide additional benefit in terms of functional outcomes in patients with acute ischemic stroke (AIS) who undergo endovascular treatment (EVT). In this context, the cost-effectiveness of EVT alone compared with its application following IV r-tPA has not been evaluated. METHODS: The authors determined the average rates of death or disability in each of the two treatment groups from four randomized clinical trials that enrolled patients with AIS within 4.5 hours of symptom onset and randomly assigned patients to EVT alone and IV r-tPA and EVT. By using three sources derived from previous studies, the authors determined the cost of IV r-tPA, cost of staff time for administration, cost of the EVT, cost of hospital stay, costs of supported discharge and community care, and cost of posthospitalization care and disability. They then assessed the cost-effectiveness of EVT alone using a decision tree for the 1st year after AIS and a Markov model with a 10-year horizon, including probabilistic assessment by Monte Carlo simulations. RESULTS: The 1-year cost was higher with IV r-tPA and EVT compared with EVT alone (incremental cost ranging between $3554 and $13,788 per patient). The mean incremental cost-effectiveness ratios (ICERs) were -$1589, -$78,327, and -$15,471 per quality-adjusted life-year gained for cost sources 1, 2, and 3, respectively, for EVT alone compared with IV r-tPA and EVT at 10 years. The ceiling ICER (willingness to pay) for a probability of 100% that EVT alone was more cost-effective ranged between $25,000 and $100,000 in the three models. CONCLUSIONS: EVT alone appears to be more cost-effective compared with EVT and IV r-tPA for the treatment of AIS patients presenting within 4.5 hours of symptom onset.

Endovascular Thrombectomy With or Without Intravenous Thrombolysis: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: We performed this meta-analysis of randomized clinical trials to compare the outcomes in patients treated with endovascular thrombectomy who receive prior intravenous thrombolysis with those who do not receive such treatment. Recently, one randomized trial reported outcomes to address this issue, so timely update of meta-analysis is needed to determine the value of administering intravenous thrombolysis before endovascular thrombectomy. MATERIALS AND METHODS: Four randomized clinical trials are included in our meta-analysis. We calculated pooled odds ratios and 95% CIs using random-effects models. The primary efficacy endpoint was a favorable outcome defined by a modified Rankin Scale score of 0 (no symptoms), 1 (no significant disability), or 2 (slight disability) at 90 days post-randomization. Secondary endpoints analyzed were any intracerebral hemorrhage, symptomatic intracerebral hemorrhage, and mortality. RESULTS: Of the 1633 patients randomized, the proportion of patients who achieved a favorable outcome was similar between endovascular thrombectomy alone and combined approach with intravenous thrombolysis and endovascular thrombectomy (1631 patients analyzed; odds ratio 1.02; CI 0.84-1.25; p = 0.83). Risk of any intracerebral hemorrhage was significantly lower among those randomized to endovascular thrombectomy alone (1633 patients analyzed; odds ratio 0.75; CI 0.57-0.99; p = 0.04). Rates of symptomatic intracerebral hemorrhage (p = 0.36) and mortality (p = 0.62) were not significantly different between the two groups. CONCLUSIONS: Compared with endovascular thrombectomy preceded by intravenous thrombolysis, endovascular thrombectomy resulted in similar rates of favorable outcome with a lower rate of intracerebral hemorrhage. A large phase 3 trial is required to conclusively demonstrate equivalency of both approaches to guide future practice.

Intra-arterial injection of lidocaine into middle meningeal artery to treat intractable headaches and severe migraine.

BACKGROUND AND PURPOSE: We report the results of intra-arterial injection of lidocaine in the middle meningeal artery in patients with intractable headache or status migrainosus. METHODS: We treated four patients with intra-arterial lidocaine (2 mg/ml) in doses up to 50 mg in each middle meningeal artery via a microcatheter bilaterally (except in one patient). In two patients with intractable headache, the daily maximum intensity of headache (graded by 11-point numeric rating scale) was recorded for 7 days postprocedure. In two patients with status migrainosus, migraine-related disability 3 months prior and after treatment using MIDAS (Migraine Disability Assessment) questionnaire was recorded. RESULTS: Intra-arterial lidocaine reduced the headache intensity from 8/10 and 10/10 to 0/10 in the two patients with intractable headaches for 2 days (day 0 and day 1) postprocedure. Despite recurrence of headache on day 2, the intensity was less than preprocedure intensity up to the last day recorded (by 3 and 2 points on day 7). In the two patients with status migrainosus, there was immediate reduction in headache intensity following intra-arterial lidocaine. The post treatment 3-month MIDAS score was lower in both patients compared with pretreatment 3-month score; 3 versus 30 and 55 versus 90. Severe disability preprocedure by MIDAS was reduced to little or no disability postprocedure in one patient. CONCLUSIONS: Intra-arterial lidocaine resulted in amelioration of headache in patients with intractable headache and those with status migrainosus with improvement lasting longer than the short half-life of lidocaine possibly related to central desensitization.

Subarachnoid Hemorrhage and COVID-19: An Analysis of 282,718 Patients.

BACKGROUND: Intracranial hemorrhage (including subarachnoid hemorrhage [SAH]) has been reported in 0.3%-1.2% of patients with coronavirus disease 2019 (COVID-19). However, no study has evaluated the risk of SAH in patients with COVID-19. METHODS: We analyzed data from 62 health care facilities using the Cerner de-identified COVID-19 dataset. RESULTS: There were 86 (0.1%) and 376 (0.2%) patients with SAH among 85,645 patients with COVID-19 and 197,073 patients without COVID-19, respectively. In the multivariate model, there was a lower risk of SAH in patients with COVID-19 (odds ratio 0.5, 95% confidence interval 0.4-0.7, P < 0.0001) after adjusting for sex, age strata, race/ethnicity, hypertension, and nicotine dependence/tobacco use. The proportions of patients who developed pneumonia (58.1% vs. 21.3%, P < 0.0001), acute kidney injury (43% vs. 27.7%, P = 0.0005), septic shock (44.2% vs. 20.7%, P < 0.0001), and respiratory failure (64.0% vs. 39.1%, P < 0.0001) were significantly higher among patients with SAH and COVID-19 compared with patients without COVID-19. The in-hospital mortality among patients with SAH and COVID-19 was significantly higher compared with patients without COVID-19 (31.4% vs. 12.2%, P < 0.0001). CONCLUSIONS: The risk of SAH was not increased in patients with COVID-19. The higher mortality in patients with SAH and COVID-19 compared with patients without COVID-19 is likely mediated by higher frequency of systemic comorbidities.

The Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis Trial: Reanalysis Using the FDA "On Label" Criteria.

BACKGROUND AND PURPOSE: Due to higher rates of 1-month stroke and death with Wingspan intracranial stent placement observed in SAMMPRIS, the Food and Drug Administration (FDA) announced a more limited indication for Wingspan stent. METHODS: We compared the results of intracranial stent placement with best medical treatment in patients recruited in SAMMPRIS who met the new "on label" criteria with those who were categorized as "off label." The primary endpoint was any stroke or death occurring within 30 days of enrollment, or an ischemic stroke in the territory of the symptomatic intracranial artery from day 31 after study entry to completion of follow-up. RESULTS: A total of 31 (7%) among 451 recruited patients met the "on label" criteria. The relative risk of primary endpoint was lower in "on label" patients treated with stent placement compared with best medical treatment (relative risk .61, 95% confidence interval .2-1.7) but higher in "off label" patients (relative risk 1.81, 95% confidence interval 1.2-2.6). Primary endpoint was seen in 20% and 23.4% of patients treated with stent placement in "on label" and "off label" patients, respectively. Primary endpoint was seen in 25% and 14.2% of patients treated with best medical treatment in "on label" and "off label" patients, respectively. CONCLUSION: The new FDA "on label" criteria may identify a small group of people, who may benefit from intracranial stent placement due to higher risk of primary endpoint in those treated with best medical treatment.

Intravenous thrombolysis pretreatment and other predictors of infarct in a new previously unaffected territory (INT) in ELVO strokes treated with mechanical thrombectomy.

INTRODUCTION: One uncommon complication of mechanical thrombectomy (MT) is an infarct in a new previously unaffected territory (infarct in new territory (INT)). OBJECTIVE: To evaluate the predictors of INT with special focus on intravenous thrombolysis(IVT)pretreatmentbefore MT. METHODS: Consecutive patients with emergent large vessel occlusion (ELVO) treated with MT during a 5-year period were evaluated. INT was defined using standardized methodology proposed by ESCAPE investigators. The predictors of INT and its impact on outcomes were investigated. RESULTS: A total of 419 consecutive patients with ELVO received MT (mean age 64±15 years, 50% men, median baseline National Institutes of Health Stroke Scale score 16 points (IQR 11-20), 69% pretreated with IVT). The incidence of INT was lower in patients treated with combination therapy (IVTandMT) than in patients treated with MT alone, respectively (10% vs 20%; p=0.011). The INT group had more patients with posterior circulation occlusions than the group without INT (28% vs 10%, respectively; p<0.001). The rates of 3-month functional independence were lower in patients with INT (30% vs 50%; p=0.007). IVT pretreatment was not independently related to INT (OR=0.75; 95% CI 0.32 to 1.76), and INT did not emerge as an independent predictor of 3-month functional independence (OR=0.69; 95% CI 0.29 to 1.62) on multivariable logistic regression models. Location of posterior circulation occlusion was independently associated with a higher odds of INT (OR=3.33; 95% CI 1.43 to 7.69; p=0.005). CONCLUSIONS: IVT pretreatment is not independently associated with a lower likelihood of INT in patients with ELVO treated with MT. Patients with ELVO with posterior circulation occlusion are more likely to have INT after MT.

Medical Management vs Mechanical Thrombectomy for Mild Strokes: An International Multicenter Study and Systematic Review and Meta-analysis.

Importance: The benefit of mechanical thrombectomy (MT) in patients with stroke presenting with mild deficits (National Institutes of Health Stroke Scale [NIHSS] score <6) owing to emergency large-vessel occlusion (ELVO) remains uncertain. Objective: To assess the outcomes of patients with mild-deficits ELVO (mELVO) treated with MT vs best medical management (bMM). Data Sources: We retrospectively pooled patients with mELVO during a 5-year period from 16 centers. A meta-analysis of studies reporting efficacy and safety outcomes with MT or bMM among patients with mELVO was also conducted. Data were analyzed between 2013 and 2017. Study Selection: We identified studies that enrolled patients with stroke (within 24 hours of symptom onset) with mELVO treated with MT or bMM. Main Outcomes and Measures: Efficacy outcomes included 3-month favorable functional outcome and 3-month functional independence that were defined as modified Rankin Scale scores of 0 to 1 and 0 to 2, respectively. Safety outcomes included 3-month mortality and symptomatic and asymptomatic intracranial hemorrhage (ICH). Results: We evaluated a total of 251 patients with mELVO who were treated with MT (n = 138; 65 women; mean age, 65.2 years; median NIHSS score, 4; interquartile range [IQR], 3-5) or bMM (n = 113; 51 women; mean age, 64.8; median NIHSS score, 3; interquartile range [IQR], 2-4). The rate of asymptomatic ICH was lower in bMM (4.6% vs 17.5%; P = .002), while the rate of 3-month FI (after imputation of missing follow-up evaluations) was lower in MT (77.4% vs 88.5%; P = .02). The 2 groups did not differ in any other efficacy or safety outcomes. In multivariable analyses, MT was associated with higher odds of asymptomatic ICH (odds ratio [OR], 11.07; 95% CI, 1.31-93.53; P = .03). In the meta-analysis of 4 studies (843 patients), MT was associated with higher odds of symptomatic ICH in unadjusted analyses (OR, 5.52; 95% CI, 1.91-15.49; P = .002; I2 = 0%). This association did not retain its significance in adjusted analyses including 2 studies (OR, 2.06; 95% CI, 0.49-8.63; P = .32; I2 = 0%). The meta-analysis did not document any other independent associations between treatment groups and safety or efficacy outcomes. Conclusions and Relevance: Our multicenter study coupled with the meta-analysis suggests similar outcomes of MT and bMM in patients with stroke with mELVO, but no conclusions about treatment effect can be made. The clinical equipoise can further be resolved by a randomized clinical trial.

Oral anticoagulation in patients with chronic kidney disease: A systematic review and meta-analysis.

OBJECTIVE: Data regarding the efficacy and safety of warfarin and non-vitamin K antagonist oral anticoagulant (NOAC) among patients with chronic kidney disease (CKD) remain scarce. METHODS: Systematic review and meta-analysis of studies involving patients with CKD treated with oral anticoagulants were conducted to evaluate the following outcomes: ischemic stroke, intracerebral hemorrhage (ICH), combined ischemic and hemorrhagic stroke (strokecombined), stroke or systemic embolism, mortality, and major bleeding events. CKD was defined based on creatinine clearance (CrCl) ranging from mild (CrCl: 60-89 mL/min), moderate (CrCl: 30-59 mL/min), to severe (CrCl: 15-29 mL/min). RESULTS: Fifteen studies (7 comparing NOAC vs warfarin and 8 comparing warfarin vs no anticoagulant) were identified comprising 78,053 patients. Warfarin (vs no anticoagulant) was associated with reduced risk of ischemic stroke (risk ratio [RR] = 0.68; 95% confidence interval [CI] 0.55-0.84]) and mortality (RR = 0.70; 95% CI 0.62-0.78). In comparison to warfarin, NOAC use lowered the risk of ICH (RR = 0.43; 95% CI 0.33-0.56), strokecombined (RR = 0.83; 95% CI 0.72-0.96), stroke or systemic embolism (RR = 0.73; 95% CI 0.62-0.85), and major bleeding (RR = 0.77; 95% CI 0.66-0.90). In adjusted analyses, warfarin use (vs no anticoagulant) was associated with reduced mortality (HRadj = 0.68; 95% CI 0.61-0.76), whereas NOAC (vs warfarin) use reduced the risk of ICH (HRadj = 0.39; 95% CI 0.30-0.50) and stroke or systemic embolism (HRadj = 0.75; 95% CI 0.65-0.88). Our sensitivity analyses comparing different NOACs exhibited that factor Xa inhibitors (compared to warfarin) consistently reduced strokecombined (RR = 0.84; 95% CI 0.73-0.96), mortality (RR = 0.84; 95% CI 0.70-1.00), ICH (RR = 0.45; 95% CI 0.24-0.85), and major bleeding (RR = 0.76; 95% CI 0.64-0.91). CONCLUSIONS: Among patients with CKD treated with oral anticoagulants, NOACs present with a more favorable safety and efficacy profile for various cardiovascular outcomes.

Current evidence for anesthesia management during endovascular stroke therapy: updated systematic review and meta-analysis.

INTRODUCTION: Debate continues about the optimal anesthetic management for patients undergoing endovascular treatment (ET) of acute ischemic stroke due to emergent large vessel occlusion. OBJECTIVE: To compare, using current evidence, the clinical outcomes and procedural characteristics among patients undergoing general anesthesia (GA) and local or monitored anesthesia (non-GA). METHODS: We performed a systematic review and meta-analysis of all available studies that involved the use of stent retrievers for ET (stentriever group). Additionally, we included studies that were published in 2015 and later, and compared the clinical outcomes among the studies using stentrievers or no stentrievers (pre-stentriever group). Outcome variables included functional independence (FI; modified Rankin Scale scores of 0-2), symptomatic hemorrhage, mortality, procedure duration, and vascular and respiratory complications. We calculated pooled odds ratios and 95% CIs using random-effects models. RESULTS: Sixteen studies (three randomized controlled clinical trials (RCTs) and 13 non-randomized studies) were identified comprising 5836 patients. Although non-GA was associated with higher odds of 3-month FI (OR=1.57; 95% CI 1.17 to 2.10; P=0.003) and lower odds of 3-month mortality (OR=0.62; 95% CI 0.47 to 0.82; P=0.0006, substantial heterogeneity was noted across included trials. Sensitivity analyses of RCTs showed that non-GA was inversely associated with FI (OR=0.55; 95% CI 0.34 to 0.89; P=0.01; I2=15%), while no association was noted with mortality (OR=1.36; 95% CI 0.79 to 2.34; P=0.27; I2=0%). CONCLUSION: Our updated meta-analysis demonstrates favorable results with non-GA, probably owing to inclusion of non-randomized studies. Recent single-center RCTs indicate that GA is associated with higher odds of FI at 3 months, while other outcomes are similar between the two groups.

Mechanical thrombectomy outcomes in large vessel stroke with high international normalized ratio.

OBJECTIVE: Evaluating the safety and efficacy of mechanical thrombectomy (MT) in acute stroke patients due to emergent large vessel occlusion (ELVO) with high international-normalized-ratio (INR). METHODS: Consecutive ELVO patients treated with MT were evaluated from two centers. Outcome measures included symptomatic-intracranial-hemorrhage(sICH), three-month mortality, successful reperfusion(SR), and 3-month functional-independence(FI; mRS-scores of 0-2). Additionally, a meta-analysis of available cohort studies was performed to evaluate safety and efficacy of MT in ELVO patients with high INR. RESULTS: A total of 315 ELVO patients were evaluated. Of those 10 patients had INR >1.7 [mean age 63.5 ±â€¯15, median NIHSS-score: 17 points (IQR 14-22)],and remaining 305 ELVO patients had INR ≤ 1.7 ([mean age 62 ±â€¯14.4, median NIHSS-score: 17 points (IQR 12-21)]. Patients with high INR did not differ in terms of sICH (10.0% vs. 6.9%; p = .706), 3-month mortality (20.0% vs. 24.2%; p = .762), SR (88.9% vs. 69.4%; p = .209) and 3-month FI (50% vs. 49.3%; p = .762) compared to the rest. Meta-analysis of available studies (n = 5) showed that high INR was not related to sICH (OR: 0.94, 95%CI: 0.42-2.07; p = .88), 3-month mortality (OR: 1.07, 95%CI: CI 0.72-1.60; p = .73) and 3-month FI (OR: 0.69, 95%CI: 0.34-1.40; p = .30). CONCLUSIONS: MT can be performed safely and effectively in ELVO patients with high INR.

Impact of pretreatment with intravenous thrombolysis on reperfusion status in acute strokes treated with mechanical thrombectomy.

INTRODUCTION: We sought to evaluate the impact of pretreatment with intravenous thrombolysis (IVT) on the rate and speed of successful reperfusion (SR) in patients with emergent large vessel occlusion (ELVO) treated with mechanical thrombectomy (MT) in a high-volume tertiary care stroke center. METHODS: Consecutive patients with ELVO treated with MT were evaluated. Outcomes were compared between patients who underwent combined IVT and MT (IVT+MT) and those treated with direct MT (dMT). The elapsed time between groin puncture to beginning of reperfusion (GPTBRT) and the numbers of device passes required to achieve SR were also documented. RESULTS: A total of 287 and 132 patients were treated with IVT+MT and dMT, respectively. The IVT+MT group had higher SR (73.8% vs 62.9%; p=0.023) and 3-month functional independence (modified Rankin Scale score 0-2;51.6% vs 38.2%; p=0.008) rates. The median GPTBRT was shorter in the IVT+MT group (48 (IQR 33-70) vs 70 (IQR 44-98) min; p<0.001). Among patients who achieved SR (n=292), the median number of required device passes was lower in the IVT+MT subgroup (1 (IQR 1-1) vs 2 (IQR 1-2); p<0.001), while the rate of patients requiring ≤2 device passes was higher (98% vs 77%; p<0.001). IVT+MT was independently related to higher odds of SR (OR 1.64; 95% CI 1.03 to 2.61; p=0.036) and shorter GPTBRT (unstandardized linear regression coefficient -20.39; 95% CI -27.56 to -13.22; p<0.001) on multivariable analyses adjusting for potential confounders. Among patients with SR, IVT+MT was independently associated with a higher likelihood of ≤2 device passes (OR 14.63; 95% CI 4.46 to 48.00; p<0.001). CONCLUSIONS: IVT pretreatment appears to increase the rates of SR and shortens the duration of the endovascular procedure by requiring fewer device passes in patients with ELVO treated with MT.

Therapeutic Benefit of Cilostazol in Patients with Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized and Nonrandomized Studies.

OBJECTIVE: To assess the effectiveness of cilostazol, a selective inhibitor of phosphodiesterase type III, in preventing cerebral ischemia related to cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). METHODS: A total of six clinical studies met the inclusion criteria and were included in the meta-analysis. We calculated pooled risk ratios (RR) and 95% confidence intervals (CI) using random-effects models. The primary endpoint was cerebral ischemia related to vasospasm. Secondary endpoints were angiographic vasospasm, new cerebral infarct, mortality, and death or disability at the final follow-up. RESULTS: A total of 136 (22%) of 618 subjects (38 and 98 assigned to cilostazol and control treatments, respectively) with SAH developed cerebral ischemia related to vasospasm. The risk of cerebral ischemia related to vasospasm was significantly lower in subjects assigned to cilostazol treatment (RR 0.43; 95% CI 0.31-0.60; p< 0.001). The risks of angiographic vasospasm (RR 0.67, 95% CI 0.54-0.84, p< 0.001 ) and new cerebral infarct (RR 0.37, 95% CI 0.24-0.57, p< 0.001) were significantly lower in subjects assigned to cilostazol treatment. There was a significantly lower rate of death or disability in subjects assigned to cilostazol treatment at follow-up (PR 0.55, 95% 0.39-0.78, p = 0.001). CONCLUSION: The reduction in rates of cerebral ischemia related to vasospasm and death or disability at follow-up support further evaluation of oral cilostazol in patients with aneurysmal SAH in a large randomized clinical trial.