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Background and Objectives: The antifibrinolytic agent tranexamic acid has been tested in intracerebral hemorrhage trials with overall neutral results. Ongoing contrast extravasation on CT angiography (spot sign) can identify individuals with ongoing bleeding who may benefit from anti-fibrinolytic therapy. We aimed to investigate the effect of tranexamic acid on hematoma growth in patients with spot signs treated within 4.5 hours of onset., Methods: We conducted a systematic review and individual patient meta-analysis, which we report according to the Preferred Reporting Items for Systematic Review and Meta-analyses of Individual Participant Data guidelines. PubMed and Embase were searched from inception to May 29, 2023, using the terms ((stroke) AND (randomised OR randomized) AND (tranexamic acid) AND (haemorrhage OR hemorrhage)). We included randomized trials comparing tranexamic acid with placebo in participants with primary intracerebral hemorrhage who had a spot sign and who had follow-up imaging within the required timeframe. Individual patient data were provided by each study and were integrated by the coordinating center. Data were pooled using a random-effects model. The primary endpoint was hematoma growth within 24 hours, defined as ≥33% relative or ≥6 mL absolute hematoma expansion compared with baseline, analyzed using mixed-effects-modified Poisson regression with robust standard errors, adjusted for baseline hematoma volume. Safety outcomes were mortality and major thromboembolic events within 90 days., Results: Of 197 studies identified, 3 were eligible, contributing 162 participants for the primary analysis (60 female and 102 male). Hematoma growth occurred in 36 of 74 (49%) participants treated with tranexamic acid, compared with 48 of 88 (55%) participants treated with placebo (adjusted risk ratio 0.86, 95% CI 0.84-0.89, p < 0.001). Adjusted median absolute hematoma growth was 1.60 mL (95% CI 0.77-2.43) lower with tranexamic acid vs placebo. No differences in functional outcome or safety were observed., Discussion: Tranexamic acid modestly reduced hematoma growth in patients with CT angiography spot signs treated within 4.5 hours of onset. Given the trials in the meta-analysis were individually neutral, these results require further validation before clinical application.

Background and Objectives: Clopidogrel-aspirin initiated within 72 hours of symptom onset is effective in patients with mild ischemic stroke or transient ischemic attack (TIA) in the Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial. Uncertainties remain about the duration of the treatment effect. This study aimed to assess duration of benefit and risk of clopidogrel-aspirin in these patients., Methods: The INSPIRES trial was a 2*2 factorial placebo-controlled randomized trial conducted in 222 hospitals in China. The 2 treatments did not interact and were evaluated separately. In this study, we performed secondary analyses based on antiplatelet treatment. All patients with mild stroke or TIA of presumed atherosclerotic cause within 72 hours of symptom onset enrolled in the trial were included. Patients were randomly assigned to receive clopidogrel-aspirin on days 1-21 followed by clopidogrel on days 22-90 or aspirin alone for 90 days. The primary efficacy outcome was major ischemic event which included the composite of ischemic stroke and nonhemorrhagic death. The primary safety outcome was moderate-to-severe bleeding. We estimated the risk difference between the 2 treatments for each stratified week., Results: All 6,100 patients in the trial were included (3,050 in each group). The mean age was 65 years, and 3,915 patients (64.2%) were men. Compared with aspirin alone, the reduction of major ischemic events by clopidogrel-aspirin mainly occurred in the first week (absolute risk reduction [ARR] 1.42%, 95% CI 0.53%-2.32%) and remained in the second week (ARR 0.49%, 95% CI 0.09%-0.90%) and the third week (ARR 0.29%, 95% CI -0.05% to 0.62%). Numerical higher risk of moderate-to-severe bleedings in the clopidogrel-aspirin group was observed in the first 3 weeks (absolute risk increase 0.05% [95% CI -0.10% to 0.20%], 0.10% [95% CI -0.09% to 0.29%], and 0.18% [95% CI -0.03% to 0.40%] in the first, second, and third weeks, respectively)., Conclusions: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, the net benefit of clopidogrel-aspirin initiated within 72 hours of symptom onset was pronounced in the first week and continued to a lesser degree in the following 2 weeks, outweighing the low, but ongoing hemorrhagic risk., Trial Registration Information: ClinicalTrials.gov Identifier: NCT03635749., Classification of Evidence: This study provides Class II evidence that among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, the net benefit of clopidogrel-aspirin initiated within 72 hours of symptom onset was pronounced in the first week and continued to a lesser degree in the following 2 weeks, outweighing the low but ongoing hemorrhagic risk.

Background and Objectives: The Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial showed that among Chinese patients with minor ischemic stroke or transient ischemic attack (TIA) who were carriers of CYP2C19 loss-of-function alleles, dual-antiplatelet therapy with ticagrelor-aspirin reduced the 90-day risk of stroke without increased severe or moderate bleeding compared with clopidogrel-aspirin. However, whether dual-antiplatelet therapy with ticagrelor was superior to clopidogrel beyond the 90 days of follow-up remained unclear. In this study, we reported 1-year follow-up outcomes of the CHANCE-2 trial., Methods: The CHANCE-2 trial is a randomized, double-blind, placebo-controlled trial at 202 centers in China. Patients with a minor stroke or TIA who carried CYP2C19 loss-of-function alleles were randomized within 24 hours after symptom onset, in a 1:1 ratio, to receive ticagrelor and placebo clopidogrel or to receive clopidogrel and placebo ticagrelor for 90 days; both groups received aspirin for the first 21 days. After day 90, treatment was as per the choice of the clinician and the patient., Results: Among 6,412 patients, the proportion of patients on ticagrelor plus aspirin, clopidogrel plus aspirin, ticagrelor alone, clopidogrel alone, aspirin alone, other antiplatelet, and no antiplatelet beyond month 3 to 1 year was 0.09%, 1.56%, 0.13%, 2.66%, 73.65%, 0.78%, and 21.13% in the ticagrelor-aspirin group and 0.03%, 1.63%, 0.19%, 2.60%, 72.83%, 0.66%, and 22.06% in the clopidogrel-aspirin group, respectively. The primary outcome of new stroke occurred in 252 patients (7.91%) in the ticagrelor-aspirin group and 310 patients (9.73%) in the clopidogrel-aspirin group by 1 year of follow-up (hazard ratio 0.80; 95% CI 0.68-0.95; p = 0.007); new stroke beyond 3 months to 1 year occurred in 61 patients (2.07%) and 67 patients (2.32%) ( p = 0.48), respectively. Primary safety outcome of severe or moderate bleeding occurred in 17 patients (0.53%) in the ticagrelor-aspirin group and 20 patients (0.63%) in the clopidogrel-aspirin group ( p = 0.61)., Discussion: For CYP2C19 loss-of-function allele carriers, early dual-antiplatelet therapy with ticagrelor is superior to clopidogrel at 1 year in reducing recurrent stroke., Trial Registration Information: URL: clinicaltrials.gov. Unique identifier: NCT04078737., Classification of Evidence: This study provides Class II evidence that for patients with minor stroke or TIA with TIACYP2C19 loss-of-function, ticagrelor plus aspirin for 21 days is superior to clopidogrel plus aspirin in reducing the 1-year risk of recurrent stroke.

Background and Objective: Genotype data of the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial showed that efficacy of clopidogrel aspirin depended on CYP2C19 genotype and risk profile. A stratification of patients who carried CYP2C19 loss-of-function (LOF) alleles according to the risk of recurrent stroke may be important for selecting optimal antiplatelet therapy. We aimed to compare the efficacy and safety of ticagrelor aspirin with clopidogrel aspirin in CYP2C19 LOF carriers with minor stroke or transient ischemic attack (TIA) stratified by risk profile., Methods: Data were obtained from Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial. Low-risk and high-risk profiles were defined by Essen Stroke Risk Score (ESRS) (<3 [low risk] and ≥3 [high risk], respectively)., Results: A total of 6,412 CYP2C19 LOF carriers were enrolled; ticagrelor aspirin was associated with a reduced risk of primary outcome (new stroke within 90-day follow-up) in patients at low risk (hazard ratio [HR], 0.65; 95% CI, 0.48-0.82), but not in those at high risk (HR, 0.97; 95% CI, 0.73-1.29), compared with clopidogrel aspirin ( p = 0.02 for interaction). Secondary outcomes generally went in the same direction as the primary outcome. The primary safety outcome of severe or moderate bleeding did not differ based on risk profile ( p = 0.24 for interaction), although the incidence of total bleeding was greater with ticagrelor aspirin than with clopidogrel aspirin among patients at low risk ( p < 0.01 for interaction). Analysis in the per-protocol population yielded similar results., Discussion: This post hoc analysis of CHANCE-2 trial showed that CYP2C19 LOF carriers with minor stroke or TIA at low risk of recurrent stroke received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin., Classification of Evidence: This study provides Class II evidence that CYP2C19 LOF carriers with minor stroke or TIA at low risk, but not at high risk, of recurrent stroke (by the ESRS) received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin., Trial Registration Information: URL: www., Clinicaltrials: gov. Unique identifier: NCT04078737., (© 2022 American Academy of Neurology.)

Objective: To assess the association of baseline imaging markers of cerebral small vessel disease (SVD) and brain frailty with clinical outcome after acute stroke in the Efficacy of Nitric Oxide in Stroke (ENOS) trial., Methods: ENOS randomized 4,011 patients with acute stroke (<48 hours of onset) to transdermal glyceryl trinitrate (GTN) or no GTN for 7 days. The primary outcome was functional outcome (modified Rankin Scale [mRS] score) at day 90. Cognition was assessed via telephone at day 90. Stroke syndrome was classified with the Oxfordshire Community Stroke Project classification. Brain imaging was adjudicated masked to clinical information and treatment and assessed SVD (leukoaraiosis, old lacunar infarcts/lacunes, atrophy) and brain frailty (leukoaraiosis, atrophy, old vascular lesions/infarcts). Analyses used ordinal logistic regression adjusted for prognostic variables., Results: In all participants and those with lacunar syndrome (LACS; 1,397, 34.8%), baseline CT imaging features of SVD and brain frailty were common and independently associated with unfavorable shifts in mRS score at day 90 (all participants: SVD score odds ratio [OR] 1.15, 95% confidence interval [CI] 1.07-1.24; brain frailty score OR 1.25, 95% CI 1.17-1.34; those with LACS: SVD score OR 1.30, 95% CI 1.15-1.47, brain frailty score OR 1.28, 95% CI 1.14-1.44). Brain frailty was associated with worse cognitive scores at 90 days in all participants and in those with LACS., Conclusions: Baseline imaging features of SVD and brain frailty were common in lacunar stroke and all stroke, predicted worse prognosis after all acute stroke with a stronger effect in lacunar stroke, and may aid future clinical decision-making., Identifier: ISRCTN99414122., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To study the early time course of major bleeding and its subtypes in patients with cerebral ischemia on dual and single antiplatelet therapy., Methods: We performed a post hoc analysis on individual patient data from 6 randomized clinical trials (Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events [CAPRIE], Second European Stroke Prevention Study [ESPS-2], Management of Atherothrombosis With Clopidogrel in High-Risk Patients [MATCH], Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA], European/Australasian Stroke Prevention in Reversible Ischaemia Trial [ESPRIT], and Prevention Regimen for Effectively Avoiding Second Strokes [PRoFESS]) including 45,195 patients with a TIA or noncardioembolic ischemic stroke. We studied incidence rates of bleeding per antiplatelet regimen stratified by time from randomization (≤30, 31-90, 91-180, 181-365, >365 days). We calculated incidence rates per trial and pooled estimates with random-effects meta-analysis. We performed Poisson regression to assess differences between time periods with adjustment for age and sex., Results: The incidence of major bleeding on aspirin plus clopidogrel and aspirin plus -dipyridamole was highest in the first 30 days, 5.8 and 4.9 per 100 person-years, respectively, and was significantly higher than at 31 to 90 days (rate ratio 1.98, 95% confidence interval 1.16-3.40 for aspirin plus clopidogrel; rate ratio 1.94, 95% confidence interval 1.24-3.03 for aspirin plus dipyridamole). Incidence rates on aspirin and clopidogrel monotherapy were 2.8 and 2.5 per 100 person-years, respectively, in the first 30 days, with no significant change over time. The time course was similar for gastrointestinal bleeds. There was no early excess of intracranial hemorrhage in patients on either dual or single antiplatelet therapy., Conclusion: Dual antiplatelet therapy is associated with high early risks of major and gastrointestinal bleeding that decline after the first month in trial cohorts., (© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To compare the prognostic accuracy of various acute stroke prognostic scales using a large, independent, clinical trials dataset., Methods: We directly compared 8 stroke prognostic scales, chosen based on focused literature review (Acute Stroke Registry and Analysis of Lausanne [ASTRAL]; iSCORE; iSCORE-revised; preadmission comorbidities, level of consciousness, age, and neurologic deficit [PLAN]; stroke subtype, Oxfordshire Community Stroke Project, age, and prestroke modified Rankin Scale [mRS] [SOAR]; modified SOAR; Stroke Prognosis Instrument 2 [SPI2]; and Totaled Health Risks in Vascular Events [THRIVE]) using individual patient-level data from a clinical trials archive (Virtual International Stroke Trials Archive [VISTA]). We calculated area under receiver operating characteristic curves (AUROC) for each scale against 90-day outcomes of mRS (dichotomized at mRS >2), Barthel Index (>85), and mortality. We performed 2 complementary analyses: the first limited to patients with complete data for all components of all scales (simultaneous) and the second using as many patients as possible for each individual scale (separate). We compared AUROCs and performed sensitivity analyses substituting extreme outcome values for missing data., Results: In total, 10,777 patients contributed to the analyses. Our simultaneous analyses suggested that ASTRAL had greatest prognostic accuracy for mRS, AUROC 0.78 (95% confidence interval [CI] 0.75-0.82), and SPI2 had poorest AUROC, 0.61 (95% CI 0.57-0.66). Our separate analyses confirmed these results: ASTRAL AUROC 0.79 (95% CI 0.78-0.80 and SPI2 AUROC 0.60 (95% CI 0.59-0.61). On formal comparative testing, there was a significant difference in modified Rankin Scale AUROC between ASTRAL and all other scales. Sensitivity analysis identified no evidence of systematic bias from missing data., Conclusions: Our comparative analyses confirm differences in the prognostic accuracy of stroke scales. However, even the best performing scale had prognostic accuracy that may not be sufficient as a basis for clinical decision-making., (© 2017 American Academy of Neurology.)

Objective: To develop and externally validate a prediction model for major bleeding in patients with a TIA or ischemic stroke on antiplatelet agents., Methods: We combined individual patient data from 6 randomized clinical trials (CAPRIE, ESPS-2, MATCH, CHARISMA, ESPRIT, and PRoFESS) investigating antiplatelet therapy after TIA or ischemic stroke. Cox regression analyses stratified by trial were performed to study the association between predictors and major bleeding. A risk prediction model was derived and validated in the PERFORM trial. Performance was assessed with the c statistic and calibration plots., Results: Major bleeding occurred in 1,530 of the 43,112 patients during 94,833 person-years of follow-up. The observed 3-year risk of major bleeding was 4.6% (95% confidence interval [CI] 4.4%-4.9%). Predictors were male sex, smoking, type of antiplatelet agents (aspirin-clopidogrel), outcome on modified Rankin Scale ≥3, prior stroke, high blood pressure, lower body mass index, elderly, Asian ethnicity, and diabetes (S 2 TOP-BLEED). The S 2 TOP-BLEED score had a c statistic of 0.63 (95% CI 0.60-0.64) and showed good calibration in the development data. Major bleeding risk ranged from 2% in patients aged 45-54 years without additional risk factors to more than 10% in patients aged 75-84 years with multiple risk factors. In external validation, the model had a c statistic of 0.61 (95% CI 0.59-0.63) and slightly underestimated major bleeding risk., Conclusions: The S 2 TOP-BLEED score can be used to estimate 3-year major bleeding risk in patients with a TIA or ischemic stroke who use antiplatelet agents, based on readily available characteristics. The discriminatory performance may be improved by identifying stronger predictors of major bleeding., (© 2017 American Academy of Neurology.)

Objective: To assess whether statin treatment before or after acute ischemic stroke (AIS) affects the risk of acute intracerebral hemorrhage (ICH), postacute ICH, and mortality within 90 days., Methods: Data were sought from the Virtual International Stroke Trials Archive, an international repository of clinical trials data. Using propensity score matching, we retrospectively compared patients with prior statin treatment and newly initiated statin within 3 days after AIS to patients without statin exposure. Outcomes of interest were acute symptomatic ICH (sICH), any acute ICH, postacute ICH, and mortality during follow-up of 3 months., Results: A total of 8,535 patients (mean age 70 years, 54% male, median baseline NIH Stroke Scale score 13) were analyzed. After propensity score matching, prior statin use was not strongly associated with sICH (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 0.83-2.14) or any ICH (adjusted OR 1.35, 95% CI 0.92-1.98). There was no evidence of an interaction between prior statin use and thrombolysis. New initiation of statins was not associated with postacute ICH (adjusted hazard ratio [HR] 1.60, 95% CI 0.70-3.65). There was a signal towards lower 90-day mortality in patients with prior statin use (adjusted HR 0.84, 95% CI 0.70-1.00) and especially early initiation of statins (adjusted HR 0.67, 95% CI 0.46-0.97)., Conclusions: Statin use prior to AIS was not associated with early hemorrhagic complications, irrespective of treatment with thrombolysis. New initiation of statin treatment early after AIS did not affect risk of postacute ICH, but might be associated with reduced mortality., (© 2016 American Academy of Neurology.)

The authors investigated whether the lack of effect of tirilazad on clinical outcome in patients with acute ischemic stroke is explained by failure of tirilazad to reduce infarct volume. Overall, tirilazad had no significant effect on infarct volume. In the subgroups of male patients and of those with a cortical infarct, tirilazad significantly reduced infarct volume. These effects were reduced to nonsignificant trends after adjustment for imbalances in baseline characteristics. In conclusion, early treatment of patients with tirilazad has no effect on infarct volume.