Abstract: Early blood–brain barrier damage after acute ischemic stroke has previously been qualitatively linked to subsequent intracranial hemorrhage (ICH). In this quantitative study, it was investigated whether the amount of blood–brain barrier damage evident on pre–tissue-type plasminogen activator MRI scans was related to the degree of post–tissue-type plasminogen activator ICH in patients with acute ischemic stroke. Methods— Analysis was performed on a database of patients with acute ischemic stroke provided by the Stroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA) Imaging Investigators. Patients with perfusion-weighted imaging lesions 〉 10 mL and negative gradient-recalled echo imaging before intravenous tissue-type plasminogen activator were included. Postprocessing of the perfusion-weighted imaging source images was performed to estimate changes in blood–brain barrier permeability within the perfusion deficit relative to the unaffected hemisphere. Follow-up gradient-recalled echo images were reviewed for evidence of ICH and divided into 3 groups according to European Cooperative Acute Stroke Study (ECASS) criteria: no hemorrhage, hemorrhagic infarction, and parenchymal hematoma. Results— Seventy-five patients from the database met the inclusion criteria, 28 of whom experienced ICH, of which 19 were classified as hemorrhagic infarction and 9 were classified as parenchymal hematoma. The mean permeability (±SDs), expressed as an index of contrast leakage, was 17.0±8.8% in the no hemorrhage group, 19.4±4.0% in the hemorrhagic infarction group, and 24.6±4.5% in the parenchymal hematoma group. Permeability was significantly correlated with ICH grade in univariate ( P= 0.007) and multivariate ( P= 0.008) linear regression modeling. Conclusions— A perfusion-weighted imaging–derived index of blood–brain barrier damage measured before intravenous tissue-type plasminogen activator is given is associated with the severity of ICH after treatment in patients with acute ischemic stroke.

Abstract: Background: Venous thromboembolism (VTE) is common after hospitalization in acutely ill medical patients, yet extended thromboprophylaxis has not been widely implemented due to concerns about bleeding. The MARINER study (NCT02111564) compared thromboprophylaxis with rivaroxaban (10mg daily or 7.5mg daily in subjects with creatinine clearance 30- & lt;50ml/min at baseline) vs placebo for 45 days beyond hospital discharge to prevent symptomatic VTE in acutely ill medical patients while reducing bleeding events through patient selection (Spyropoulos AC et al NEJM 2018). Rivaroxaban did not significantly lower the composite of symptomatic VTE and VTE-related death but reduced symptomatic VTE (0.18% vs 0.42%, p=0.023). While major bleeding (MB) was infrequent in both study groups (0.28% vs 0.15% with rivaroxaban vs. placebo, p=0.124), there was more non-major clinically relevant bleeding (NMCRB) with rivaroxaban (1.42% vs 0.85%, HR 1.66, 95%CI 1.17-2.35, p=0.004). Although MB has been associated with increased mortality, the relationship between NMCRB and all-cause mortality (ACM) is not established. We hypothesized that subjects in the MARINER trial with MB but not those with NMCRB would be at an increased risk of ACM irrespective of treatment group. Methods: We evaluated all bleeding events in subjects taking at least one dose of study drug from randomization until 2 days after the last dose (safety population) and their association with ACM through the Day 75 visit in 3 mutually exclusive groups: (1) subjects with no MB or NMCRB; (2) subjects whose first event was NMCRB; and (3) subjects whose first event was MB. Subjects only developing minimal or trivial bleeding were grouped with those who had no bleeding. Using a Cox proportional hazards model that included the bleeding group variable and baseline covariates that were significantly associated with ACM at p & lt;0.05 (age, sex, history of VTE, history of anemia), we compared the risk of ACM in subjects with and without bleeding events. Results: The incidence of ACM among subjects who had a NMCRB was not increased over that in subjects without bleeding (2/136, 1.5% vs 218/11800, 1.8%, HR 0.41 95%CI 0.10, 1.67, p=0.213), while those experiencing MB had a higher incidence of death (4/26, 15.4% vs 218/11800, 1.8%, HR 3.43 95%CI 1.23, 9.54, p=0.018). Results of landmark analyses from the first bleeding event or end of treatment + 2 days to ACM for the three groups are displayed (Figure). Limitations: This analysis was post hoc and the MARINER trial excluded subjects at a high risk of bleeding. Conclusion: Although few subjects had MB events, those who did had an increased risk of ACM, while those who had NMCRB events did not. This suggests that the modest increase in NMCRB in trials of extended thromboprophylaxis may be an acceptable tradeoff to prevent VTE. Disclosures Spyropoulos: Janssen R & D, LLC: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Bayer Healthcare: Consultancy; Portola: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Ageno:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research support,travel support ; BMS Pfizer: Other: travel support; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Other: conference and travel support; Portola: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Aspen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: travel support. Albers:Janssen R & D, LLC: Consultancy; Bayer Healthcare: Consultancy. Elliott:Bayer Healthcare: Consultancy; University of Cincinnati: Honoraria; Spectrum Health: Honoraria; Janssen R & D, LLC: Consultancy. Halperin:Ortho-McNeil-Janssen: Consultancy; Johnson & Johnson: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; NIH: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy. Hiatt:Bayer Healthcare: Consultancy; NIH: Research Funding; Janssen R & D, LLD: Consultancy. Maynard:Janssen R & D, LLC: Consultancy. Steg:Novartis: Consultancy; Regeneron: Consultancy; Lilly: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Amarin: Consultancy; Servier: Consultancy, Research Funding; Merck: Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Research Funding; Janssen R & D, LLC: Consultancy, Research Funding; AstraZeneca: Consultancy. Weitz:Novartis: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bayer Healthcare: Consultancy, Honoraria; Janssen R & D, LLC: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Lu:Janssen R & D, LLC: Employment, Equity Ownership. Sugarmann:Janssen Research and Development LLC: Employment, Equity Ownership. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Raskob:Boehringer Ingelheim: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy, Honoraria; Tetherex: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Anthos: Consultancy; BMS: Consultancy, Honoraria; Janssen R & D, LLC: Consultancy, Honoraria; Portola: Consultancy; Novartis: Consultancy; Bayer Healthcare: Consultancy, Honoraria. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. OffLabel Disclosure: Rivaroxaban is a Factor Xa inhibitor. The study evaluated the efficacy and safety of rivaroxaban post-hospitalization in subjects with an acute medical illness as thromboprophylaxis for venous thromboembolism.

Abstract: The recent “Advanced Neuroimaging for Acute Stroke Treatment” meeting on September 7 and 8, 2007 in Washington DC, brought together stroke neurologists, neuroradiologists, emergency physicians, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), industry representatives, and members of the US Food and Drug Administration (FDA) to discuss the role of advanced neuroimaging in acute stroke treatment. The goals of the meeting were to assess state-of-the-art practice in terms of acute stroke imaging research and to propose specific recommendations regarding: (1) the standardization of perfusion and penumbral imaging techniques, (2) the validation of the accuracy and clinical utility of imaging markers of the ischemic penumbra, (3) the validation of imaging biomarkers relevant to clinical outcomes, and (4) the creation of a central repository to achieve these goals. The present article summarizes these recommendations and examines practical steps to achieve them.

Abstract: Background and Purpose— Epidemiological studies have found strong correlations between elevated plasma fibrinogen levels and both ischemic stroke incidence and stroke mortality. Little is known about the influence of fibrinogen levels on functional stroke outcome. Methods— Placebo data from the Stroke Treatment with Ancrod Trial (STAT) and European Stroke Treatment with Ancrod Trial (ESTAT) were analyzed. Fibrinogen levels were determined within 3 hours (STAT) or 6 hours (ESTAT) of stroke onset and at preset intervals throughout 5 days of intravenous infusions. Barthel Index scores at 90 days quantified functional outcomes. The association between initial fibrinogen levels and functional outcomes was evaluated using a multiple logistic regression analysis. Results— Fibrinogen levels increased gradually over the first 24 hours from a pretreatment median value of 340 mg/dL to a 24-hour median value of 376 mg/dL. In a univariate analysis, the proportion of patients with good functional outcome decreased with increasing quartiles of initial fibrinogen levels in both STAT (36.0% to 26.2%) and ESTAT (53.8% to 24.8%). In a multifactorial analysis, the same trend was observed. Patients with initial fibrinogen levels 〈 450 mg/dL had better outcomes in both studies; the difference (42.0% versus 21.6%) was significant in ESTAT ( P =0.0006), even when corrected for age and initial stroke severity. Conclusion— The independent association of higher initial fibrinogen levels with poor outcome needs to be verified using a larger acute stroke dataset. Even in the present small populations, the apparent association of these 2 variables suggests that treatments designed to reduce fibrinogen levels could potentially be important in treating acute ischemic stroke.

Abstract: Introduction: Intra-arterial therapy has become standard-of-care for stroke patients with large vessel occlusions presenting within 6 hours of symptom onset. Treatment effectiveness at later times is currently unknown. Using data from the CT Perfusion (CTP) to predict Response to recanalization in Ischemic Stroke Project (CRISP), we assessed the effect of time to treatment on the probability of good outcomes. Hypothesis: Symptom onset-to-reperfusion time is not associated with probability of favorable outcomes in patients with target mismatch who achieve reperfusion. Methods: All patients enrolled underwent baseline CTP. For this analysis, we included data from patients with target mismatch (ratio of Tmax 〉 6s lesion to core volume of 〉 1.8) who achieved endovascular reperfusion. We determined reperfusion status by early follow-up MRI or CTP, or final TICI score 2b-3 if early follow-up perfusion imaging is unavailable. We defined good functional outcome (GFO) as mRS 0-2 at day 90. We assessed the probability of good outcome as a function of onset-to-reperfusion time using logistic regression, with prespecified adjustment for age and baseline NIHSS. Results: Following intra-arterial intervention performed within 18 hours, 102 patients with target mismatch achieved reperfusion. Median onset-to-reperfusion time was 6.6 hours (IQR 5.2-9.5). In univariate analysis, onset-to-reperfusion time was not associated with GFO (p=0.19), whereas age and NIHSS were. Similarly, in multivariate analysis, age and NIHSS were associated with GFO, while onset-to-reperfusion time was not. The adjusted relative risk per hour of delay is 0.994 (95% CI 0.97-1.02). GFO was achieved in 71.4% of patients treated within 6 hours, and in 61.7% of patients treated after 6 hours. Conclusion: The lack of significant association between onset-to-reperfusion time and GFO, and the high proportion of patients achieving good outcomes at 6-18 hours, suggest that endovascular interventions may be beneficial beyond 6 hours with a CTP target mismatch profile, supporting randomized controlled trials of endovascular therapy in the extended time window in selected patients.

Abstract: This study aims to describe the relationship between computed tomographic (CT) perfusion (CTP)-to-reperfusion time and clinical and radiological outcomes, in a cohort of patients who achieve successful reperfusion for acute ischemic stroke. Methods— We included data from the CRISP (Computed Tomographic Perfusion to Predict Response in Ischemic Stroke Project) in which all patients underwent a baseline CTP scan before endovascular therapy. Patients were included if they had a mismatch on their baseline CTP scan and achieved successful endovascular reperfusion. Patients with mismatch were categorized into target mismatch and malignant mismatch profiles, according to the volume of their Tmax 〉 10s lesion volume (target mismatch, 〈 100 mL; malignant mismatch, 〉 100 mL). We investigated the impact of CTP-to-reperfusion times on probability of achieving functional independence (modified Rankin Scale, 0–2) at day 90 and radiographic outcomes at day 5. Results— Of 156 included patients, 108 (59%) had the target mismatch profile, and 48 (26%) had the malignant mismatch profile. In patients with the target mismatch profile, CTP-to-reperfusion time showed no association with functional independence ( P =0.84), whereas in patients with malignant mismatch profile, CTP-to-reperfusion time was strongly associated with lower probability of functional independence (odds ratio, 0.08; P =0.003). Compared with patients with target mismatch, those with the malignant mismatch profile had significantly more infarct growth (90 [49–166] versus 43 [18–81] mL; P =0.006) and larger final infarct volumes (110 [61–155] versus 48 [21–99] mL; P =0.001). Conclusions— Compared with target mismatch patients, those with the malignant profile experience faster infarct growth and a steeper decline in the odds of functional independence, with longer delays between baseline imaging and reperfusion. However, this does not exclude the possibility of treatment benefit in patients with a malignant profile.

Abstract: Background: We hypothesized that cerebral perfusion deficits are more severe in acute stroke patients with poor collaterals and that the severity would increase over time if reperfusion does not occur. Methods: This is a substudy of DEFUSE 2. Collaterals were assessed on conventional angiography and dichotomized as poor vs. good flow. DWI and PWI were performed before and within 12 hrs after endovascular therapy; PWI lesion volumes were determined using a Tmax 〉 6sec threshold. The hypoperfusion ratio (HR) was calculated by determining the proportion of the PWI lesion that had severe Tmax delay ( 〉 10sec). Acute lesion growth was defined as the difference between the baseline and follow-up DWI volume. Part 1: In patients with an ICA or M1 occlusion we compared the HR to the collateral score. An ROC curve assessed whether the HR predicts the collateral score. Part 2: Among patients who did not experience early reperfusion, the difference between the baseline and follow-up HR was assessed and correlated with early infarct growth. Results: Part 1: Fifty six patients were eligible. Poor collateral flow was associated with larger baseline PWI lesion volume, p=0.012 and a higher HR compared to patients with good flow [median HR 45% (IQR: 35-52%) vs. 34% (IQR 14-41), p=0.003]. A HR 〉 41% predicted poor collateral flow with an AUC=0.73 (sensitivity 65%, specificity 78%, p=0.003). Part 2: Thirty two patients who did not achieve reperfusion were included; PWI Tmax 〉 6sec lesions volumes at baseline and follow-up were similar (median volume 75 mL at both time points). The median HR at follow-up was significantly higher than baseline [46% IQR (34-65) vs. 40% (24-48), p=0.007; median difference = 13% (IQR: 3.5-17)]. Patients who had worsening of their HR between baseline and follow-up were more likely to experience early ischemic lesion growth (R=0.53, p=0.002). Conclusion: The size and severity of Tmax lesions are associated with angiographic collateral scores. Patients who have a high percentage of their PWI lesion comprised of severe Tmax delays are likely to have poor collaterals. When early reperfusion is not achieved, the severity of hypoperfusion progresses and this progression is associated with early infarct growth.

Abstract: We evaluate associations between the severity of magnetic resonance perfusion-weighted imaging abnormalities, as assessed by the hypoperfusion intensity ratio (HIR), on infarct progression and functional outcome in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2). Methods— Diffusion-weighted magnetic resonance imaging and perfusion-weighted imaging lesion volumes were determined with the RAPID software program. HIR was defined as the proportion of TMax 〉 6 s lesion volume with a Tmax 〉 10 s delay and was dichotomized based on its median value (0.4) into low versus high subgroups as well as quartiles. Final infarct volumes were assessed at day 5. Initial infarct growth velocity was calculated as the baseline diffusion-weighted imaging (DWI) lesion volume divided by the delay from symptom onset to baseline magnetic resonance imaging. Total Infarct growth was determined by the difference between final infarct and baseline DWI volumes. Collateral flow was assessed on conventional angiography and dichotomized into good and poor flow. Good functional outcome was defined as modified Rankin Scale ≤2 at 90 days. Results— Ninety-nine patients were included; baseline DWI, perfusion-weighted imaging, and final infarct volumes increased with HIR quartiles ( P 〈 0.01). A high HIR predicted poor collaterals with an area under the curve of 0.73. Initial infarct growth velocity and total infarct growth were greater among patients with a high HIR ( P 〈 0.001). After adjustment for age, DWI volume, and reperfusion, a low HIR was associated with good functional outcome: odds ratio=4.4 (95% CI, 1.3–14.3); P =0.014. Conclusions— HIR can be easily assessed on automatically processed perfusion maps and predicts the rate of collateral flow, infarct growth, and clinical outcome.