Code ICH: A Call to Action.

Intracerebral hemorrhage is the most serious type of stroke, leading to high rates of severe disability and mortality. Hematoma expansion is an independent predictor of poor functional outcome and is a compelling target for intervention. For decades, randomized trials aimed at decreasing hematoma expansion through single interventions have failed to meet their primary outcomes of statistically significant improvement in neurological outcomes. A wide range of evidence suggests that ultra-early bundled care, with multiple simultaneous interventions in the acute phase, offers the best hope of limiting hematoma expansion and improving functional recovery. Patients with intracerebral hemorrhage who fail to receive early aggressive care have worse outcomes, suggesting that an important treatment opportunity exists. This consensus statement puts forth a call to action to establish a protocol for Code ICH, similar to current strategies used for the management of acute ischemic stroke, through which early intervention, bundled care, and time-based metrics have substantially improved neurological outcomes. Based on current evidence, we advocate for the widespread adoption of an early bundle of care for patients with intracerebral hemorrhage focused on time-based metrics for blood pressure control and emergency reversal of anticoagulation, with the goal of optimizing the benefit of these already widely used interventions. We hope Code ICH will endure as a structural platform for continued innovation, standardization of best practices, and ongoing quality improvement for years to come.

Exploring Hematoma Expansion Shift With Recombinant Factor VIIa: A Pooled Analysis of 4 Randomized Controlled Trials.

BACKGROUND: Hematoma expansion shift (HES) analysis can be used to assess the biological effect of a hemostatic therapy for intracerebral hemorrhage. In this study, we applied HES analysis to individual patient data from 4 randomized controlled trials evaluating rFVIIa (recombinant factor VIIa) 80 µg/kg to placebo. METHODS: We generated polychotomous strata of HES using absolute growth thresholds (≤0/<6/≥6 mL) and quintiles of percent volume change. The relationship between treatment and HES was assessed using proportional odds models. Differences in subgroups based on baseline volume (≥ or <20 mL), and time from symptom onset to treatment (≤ or >2 hours) were explored with testing for interactions. RESULTS: The primary analysis included 721 patients. At 24 hours, 36% (134/369) of rFVIIa-treated patients exhibited no hematoma expansion as compared with 25% of placebo (88/352)-treated patients. Significant expansion (≥6 mL) was reduced by 10% in those treated with rFVIIa-(adjusted common odds ratio [acOR], 0.57 [95% CI, 0.43-0.75]). An examination of percent change similarly showed a shift across the spectrum of expansion (acOR, 0.61 [95% CI, 0.47-0.80]). In both groups, mild-to-moderate expansion was observed in 38% to 47% of patients, depending on the threshold used. Differences in absolute HES between the rFVIIa and placebo groups were more pronounced in patients with baseline hemorrhage volumes ≥20 mL (acOR, 0.48 [95% CI, 0.30-0.76] versus <20 mL: acOR, 0.67 [95% CI, 0.47-0.95]; Pinteraction=0.02). No treatment interaction in patients treated within 2 or after 2 hours from onset was observed (acOR, 0.42 [95% CI, 0.19-0.91 versus >2 hours: acOR, 0.59 [95% CI, 0.44-0.79]; Pinteraction=0.30). CONCLUSIONS: The association between rFVIIa and hematoma growth arrest is most pronounced in patients with larger baseline volumes but is evident across the full spectrum of treated patients.

Haemostatic therapies for stroke due to acute, spontaneous intracerebral haemorrhage.

BACKGROUND: Outcome after acute spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume. ICH expansion occurs in about 20% of people with acute ICH. Early haemostatic therapy might improve outcome by limiting ICH expansion. This is an update of a Cochrane Review first published in 2006, and last updated in 2018. OBJECTIVES: To examine 1. the effects of individual classes of haemostatic therapies, compared with placebo or open control, in adults with acute spontaneous ICH, and 2. the effects of each class of haemostatic therapy according to the use and type of antithrombotic drug before ICH onset. SEARCH METHODS: We searched the Cochrane Stroke Trials Register, CENTRAL (2022, Issue 8), MEDLINE Ovid, and Embase Ovid on 12 September 2022. To identify further published, ongoing, and unpublished randomised controlled trials (RCTs), we scanned bibliographies of relevant articles and searched international registers of RCTs in September 2022. SELECTION CRITERIA: We included RCTs of any haemostatic intervention (i.e. procoagulant treatments such as clotting factor concentrates, antifibrinolytic drugs, platelet transfusion, or agents to reverse the action of antithrombotic drugs) for acute spontaneous ICH, compared with placebo, open control, or an active comparator. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was death/dependence (modified Rankin Scale (mRS) 4 to 6) by day 90. Secondary outcomes were ICH expansion on brain imaging after 24 hours, all serious adverse events, thromboembolic adverse events, death from any cause, quality of life, mood, cognitive function, Barthel Index score, and death or dependence measured on the Extended Glasgow Outcome Scale by day 90. MAIN RESULTS: We included 20 RCTs involving 4652 participants: nine RCTs of recombinant activated factor VII (rFVIIa) versus placebo/open control (1549 participants), eight RCTs of antifibrinolytic drugs versus placebo/open control (2866 participants), one RCT of platelet transfusion versus open control (190 participants), and two RCTs of prothrombin complex concentrates (PCC) versus fresh frozen plasma (FFP) (47 participants). Four (20%) RCTs were at low risk of bias in all criteria. For rFVIIa versus placebo/open control for spontaneous ICH with or without surgery there was little to no difference in death/dependence by day 90 (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.05; 7 RCTs, 1454 participants; low-certainty evidence). We found little to no difference in ICH expansion between groups (RR 0.81, 95% CI 0.56 to 1.16; 4 RCTs, 220 participants; low-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 0.81, 95% CI 0.30 to 2.22; 2 RCTs, 87 participants; very low-certainty evidence; death from any cause: RR 0.78, 95% CI 0.56 to 1.08; 8 RCTs, 1544 participants; moderate-certainty evidence). For antifibrinolytic drugs versus placebo/open control for spontaneous ICH, there was no difference in death/dependence by day 90 (RR 1.00, 95% CI 0.93 to 1.07; 5 RCTs, 2683 participants; high-certainty evidence). We found a slight reduction in ICH expansion with antifibrinolytic drugs for spontaneous ICH compared to placebo/open control (RR 0.86, 95% CI 0.76 to 0.96; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.02, 95% CI 0.75 to 1.39; 4 RCTs, 2599 participants; high-certainty evidence; death from any cause: RR 1.02, 95% CI 0.89 to 1.18; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in quality of life, mood, or cognitive function (quality of life: mean difference (MD) 0, 95% CI -0.03 to 0.03; 2 RCTs, 2349 participants; mood: MD 0.30, 95% CI -1.98 to 2.57; 2 RCTs, 2349 participants; cognitive function: MD -0.37, 95% CI -1.40 to 0.66; 1 RCTs, 2325 participants; all high-certainty evidence). Platelet transfusion likely increases death/dependence by day 90 compared to open control for antiplatelet-associated ICH (RR 1.29, 95% CI 1.04 to 1.61; 1 RCT, 190 participants; moderate-certainty evidence). We found little to no difference in ICH expansion between groups (RR 1.32, 95% CI 0.91 to 1.92; 1 RCT, 153 participants; moderate-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.46, 95% CI 0.98 to 2.16; 1 RCT, 190 participants; death from any cause: RR 1.42, 95% CI 0.88 to 2.28; 1 RCT, 190 participants; both moderate-certainty evidence). For PCC versus FFP for anticoagulant-associated ICH, the evidence was very uncertain about the effect on death/dependence by day 90, ICH expansion, all serious adverse events, and death from any cause between groups (death/dependence by day 90: RR 1.21, 95% CI 0.76 to 1.90; 1 RCT, 37 participants; ICH expansion: RR 0.54, 95% CI 0.23 to 1.22; 1 RCT, 36 participants; all serious adverse events: RR 0.27, 95% CI 0.02 to 3.74; 1 RCT, 5 participants; death from any cause: RR 0.49, 95% CI 0.16 to 1.56; 2 RCTs, 42 participants; all very low-certainty evidence). AUTHORS' CONCLUSIONS: In this updated Cochrane Review including 20 RCTs involving 4652 participants, rFVIIa likely results in little to no difference in reducing death or dependence after spontaneous ICH with or without surgery; antifibrinolytic drugs result in little to no difference in reducing death or dependence after spontaneous ICH, but result in a slight reduction in ICH expansion within 24 hours; platelet transfusion likely increases death or dependence after antiplatelet-associated ICH; and the evidence is very uncertain about the effect of PCC compared to FFP on death or dependence after anticoagulant-associated ICH. Thirteen RCTs are ongoing and are likely to increase the certainty of the estimates of treatment effect.

Early Deterioration, Hematoma Expansion, and Outcomes in Deep Versus Lobar Intracerebral Hemorrhage: The FAST Trial.

BACKGROUND: In patients with intracerebral hemorrhage (ICH), it is unclear whether early neurological deterioration, hematoma expansion (HE), and outcome vary by supratentorial ICH location (deep versus lobar). Herein, we assessed these relationships in a clinical trial cohort that underwent brain imaging early after symptom onset. We hypothesized that HE would occur more frequently, and outcome would be worse in patients with deep ICH. METHODS: We performed a post hoc analysis of the FAST (Factor-VII-for-Acute-Hemorrhagic-Stroke-Treatment) trial including all patients with supratentorial hemorrhage. Enrolled patients underwent brain imaging within 3 hours of symptom onset and 24 hours after randomization. Multivariable regression was used to test the association between ICH location and 3 outcomes: HE (increase of ≥33% or 6mL), early neurological deterioration (decrease in Glasgow Coma Scale score ≥2 points or increase in National Institutes of Health Stroke Scale ≥4 points within 24 hours of admission), and 90-day outcome (modified Rankin Scale). RESULTS: Of 841 FAST trial patients, we included 728 (mean age 64 years, 38% women) with supratentorial hemorrhages (deep n=623, lobar n=105). HE (44 versus 27%, P=0.001) and early neurological deterioration (31 versus 17%, P=0.001) were more common in lobar hemorrhages. Deep hemorrhages were smaller than lobar hemorrhages at baseline (12 versus 35mL, P<0.001) and 24 hours (14 versus 38mL, P<0.001). Unadjusted 90-day outcome was worse in lobar compared with deep ICH (median modified Rankin Scale score 5 versus 4, P=0.03). However, when adjusting for variables included in the ICH score including ICH volume, deep location was associated with worse and lobar location with better outcome (odds ratio lobar location, 0.58 [95% CI, 0.38-0.89]; P=0.01). CONCLUSIONS: In this secondary analysis of randomized trial patients, lobar ICH location was associated with larger ICH volume, more HE and early neurological deterioration, and worse outcome than deep ICH. After adjustment for prognostic variables, however, deep ICH was associated with worse outcome, likely due to their proximity to eloquent brain structures.

Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage.

BACKGROUND: We evaluated the effect of persistent hyperglycemia on outcomes in 1000 patients with intracerebral hemorrhage enrolled within 4.5 hours of symptom onset. METHODS: We defined moderate and severe hyperglycemia based on serum glucose levels ≥140 mg/dL-<180 and ≥180 mg/dL, respectively, measured at baseline, 24, 48, and 72 hours. Persistent hyperglycemia was defined by 2 consecutive (24 hours apart) serum glucose levels. We evaluated the relationship between moderate and severe hyperglycemia and death or disability (defined by modified Rankin Scale score of 4-6) at 90 days in the overall cohort and in groups defined by preexisting diabetes. RESULTS: In the multivariate analysis, both moderate (odds ratio, 1.8 [95% CI, 1.1-2.8]) and severe (odds ratio, 1.8 [95% CI, 1.2-2.7]) hyperglycemia were associated with higher 90-day death or disability after adjusting for Glasgow Coma Scale score, hematoma volume, presence or absence of intraventricular hemorrhage, hyperlipidemia, cigarette smoking, and hypertension (no interaction between hyperglycemia and preexisting diabetes, P=0.996). Among the patients without preexisting diabetes, both moderate (odds ratio, 1.8 [95% CI, 1.0-3.2]) and severe (odds ratio, 2.0 [95% CI, 1.1-3.7]) hyperglycemia were associated with 90-day death or disability after adjusting for above mentioned potential confounders. Among the patients with preexisting diabetes, moderate and severe hyperglycemia were not associated with 90-day death or disability. CONCLUSIONS: Persistent hyperglycemia, either moderate or severe, increased the risk of death or disability in nondiabetic patients with intracerebral hemorrhage. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01176565.

Early Hyperchloremia is Independently Associated with Death or Disability in Patients with Intracerebral Hemorrhage.

BACKGROUND: On the basis of increased mortality associated with hyperchloremia among critically ill patients, we investigated the effect of occurrence of early hyperchloremia on death or disability at 90 days in patients with intracerebral hemorrhage (ICH). METHODS: We analyzed the data from Antihypertensive Treatment of Cerebral Hemorrhage 2 trial, which recruited patients with spontaneous ICH within 4.5 h of symptom onset. Patients with increased serum chloride levels (110 mmol/L or greater) at either baseline or 24, 48, or 72 h after randomization were identified. We further graded hyperchloremia into one occurrence or two or more occurrences within the first 72 h. Two logistic regression analyses were performed to determine the effects of hyperchloremia on (1) death within 90 days and (2) death or disability at 90 days after adjustment for potential confounders. RESULTS: Among the total of 1,000 patients analyzed, hyperchloremia within 72 h was seen in 114 patients with one occurrence and in 154 patients with two or more occurrences. Patients with one occurrence of hyperchloremia (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-5.5) and those with two or more occurrences (OR 2.6, 95% CI 1.3-5.0) had significantly higher odds of death within 90 days after adjustment for age, race and ethnicity, National Institutes of Health Stroke Scale score strata, hematoma volume, presence or absence of intraventricular hemorrhage, cigarette smoking, previous stroke, and maximum hourly dose of nicardipine. Patients with two or more occurrences of hyperchloremia (OR 3.4, 95% CI 2.1-5.6) had significantly higher odds of death or disability at 90 days compared with patients without hyperchloremia after adjustment for the abovementioned potential confounders. CONCLUSIONS: The independent association between hyperchloremia and death or disability at 90 days suggests that avoidance of hyperchloremia may reduce the observed death or disability in patients with ICH. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01176565.

Association of Serum IL-6 (Interleukin 6) With Functional Outcome After Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVES: IL-6 (interleukin 6) is a proinflammatory cytokine and an established biomarker in acute brain injury. We sought to determine whether admission IL-6 levels are associated with severity and functional outcome after spontaneous intracerebral hemorrhage (ICH). METHODS: We performed an exploratory analysis of the recombinant activated FAST trial (Factor VII for Acute ICH). Patients with admission serum IL-6 levels were included. Regression analyses were used to assess the associations between IL-6 and 90-day modified Rankin Scale. In secondary analyses, we used linear regression to evaluate the association between IL-6 and baseline ICH and perihematomal edema volumes. RESULTS: Of 841 enrolled patients, we included 552 (66%) with available admission IL-6 levels (mean age 64 [SD 13], female sex 203 [37%]). IL-6 was associated with poor outcome (modified Rankin Scale, 4-6; per additional 1 ng/L, odds ratio, 1.30 [95% CI, 1.04-1.63]; P=0.02) after adjustment for known predictors of outcome after ICH and treatment group. IL-6 was associated with ICH volume after adjustment for age, sex, and ICH location, and this association was modified by location (multivariable interaction, P=0.002), with a stronger association seen in lobar (ß, 12.51 [95% CI, 6.47-18.55], P<0.001) versus nonlobar (ß 5.32 [95% CI, 3.36-7.28], P<0.001) location. IL-6 was associated with perihematomal edema volume after adjustment for age, sex, ICH volume, and ICH location (ß 1.22 [95% CI, 0.15-2.29], P=0.03). Treatment group was not associated with IL-6 levels or outcome. CONCLUSIONS: In the FAST trial population, higher admission IL-6 levels were associated with worse 90-day functional outcome and larger ICH and perihematomal edema volumes.

Clinical Outcome After Endovascular Thrombectomy in 3 Triage Concepts: A Prospective, Observational Study (NEUROSQUAD).

BACKGROUND AND PURPOSE: NEUROSQUAD (Stroke Treatment: Quality and Efficacy in Different Referral Systems) is a prospective, observational, bicenter study comparing 3 triage pathways in endovascular stroke treatment: mothership, drip and ship (DS), and transferring a neurointerventionalist to a remote hospital for thrombectomy (drive the doctor [DD]). METHODS: Patients with anterior circulation stroke and premorbid modified Rankin Scale (mRS) score 0-3 who underwent thrombectomy within 24 hours after stroke onset were included. Primary outcome measure was good clinical outcome defined as 90-day mRS score 0-2 or clinical recovery to the status before stroke onset (ie, equal premorbid mRS and 90-day mRS). Secondary outcome measures were successful reperfusion, National Institutes of Health Stroke Scale at discharge, and mRS shift. RESULTS: In total, 360 patients were included in this study, of whom 111 patients (30.8%) were in the mothership group, 204 patients (56.7%) were in the DS group, and 45 patients (12.5%) were in the DD group. Good clinical outcome was achieved similarly in all three groups (mothership, 45.9%; DS, 43.1%; DD, 40.0%; P=0.778). Likewise, frequency of successful reperfusion was similar in all three groups (mothership, 86.5%; DS, 85.3%; DD, 82.2%; P=0.714). There was no significant difference among the groups regarding the National Institutes of Health Stroke Scale at discharge (P=0.115) and mRS shift (P=0.342). In the multivariate analysis, triage concept was not an independent predictor of good outcome (unadjusted odds ratio, 0.89 [CI, 0.64-1.23]; P=0.479). CONCLUSIONS: Our data suggest that clinical outcome after thrombectomy is similar in mothership, DS, and DD. Hence, DD can be a valuable triage option in acute stroke treatment.

Tranexamic Acid for Prevention of Hematoma Expansion in Intracerebral Hemorrhage Patients With or Without Spot Sign.

BACKGROUND AND PURPOSE: The computed tomography angiography or contrast-enhanced computed tomography based spot sign has been proposed as a biomarker for identifying on-going hematoma expansion in patients with acute intracerebral hemorrhage. We investigated, if spot-sign positive participants benefit more from tranexamic acid versus placebo as compared to spot-sign negative participants. METHODS: TICH-2 trial (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) was a randomized, placebo-controlled clinical trial recruiting acutely hospitalized participants with intracerebral hemorrhage within 8 hours after symptom onset. Local investigators randomized participants to 2 grams of intravenous tranexamic acid or matching placebo (1:1). All participants underwent computed tomography scan on admission and on day 2 (24±12 hours) after randomization. In this sub group analysis, we included all participants from the main trial population with imaging allowing adjudication of spot sign status. RESULTS: Of the 2325 TICH-2 participants, 254 (10.9%) had imaging allowing for spot-sign adjudication. Of these participants, 64 (25.2%) were spot-sign positive. Median (interquartile range) time from symptom onset to administration of the intervention was 225.0 (169.0 to 310.0) minutes. The adjusted percent difference in absolute day-2 hematoma volume between participants allocated to tranexamic versus placebo was 3.7% (95% CI, -12.8% to 23.4%) for spot-sign positive and 1.7% (95% CI, -8.4% to 12.8%) for spot-sign negative participants (Pheterogenity=0.85). No difference was observed in significant hematoma progression (dichotomous composite outcome) between participants allocated to tranexamic versus placebo among spot-sign positive (odds ratio, 0.85 [95% CI, 0.29 to 2.46]) and negative (odds ratio, 0.77 [95% CI, 0.41 to 1.45]) participants (Pheterogenity=0.88). CONCLUSIONS: Data from the TICH-2 trial do not support that admission spot sign status modifies the treatment effect of tranexamic acid versus placebo in patients with acute intracerebral hemorrhage. The results might have been affected by low statistical power as well as treatment delay. Registration: URL: http://www.controlled-trials.com; Unique identifier: ISRCTN93732214.

The Story of Intracerebral Hemorrhage: From Recalcitrant to Treatable Disease.

This invited special report is based on an award presentation at the World Stroke Organization/European Stroke Organization Conference in November of 2020 outlining progress in the acute management of intracerebral hemorrhage (ICH) over the past 35 years. ICH is the second most common and the deadliest type of stroke for which there is no scientifically proven medical or surgical treatment. Prospective studies from the 1990s onward have demonstrated that most growth of spontaneous ICH occurs within the first 2 to 3 hours and that growth of ICH and resulting volumes of ICH and intraventricular hemorrhage are modifiable factors that can improve outcome. Trials focusing on early treatment of elevated blood pressure have suggested a target systolic blood pressure of 140 mm Hg, but none of the trials were positive by their primary end point. Hemostatic agents to decrease bleeding in spontaneous ICH have included desmopressin, tranexamic acid, and rFVIIa (recombinant factor VIIa) without clear benefit, and platelet infusions which were associated with harm. Hemostatic agents delivered within the first several hours have the greatest impact on growth of ICH and potentially on outcome. No large Phase III surgical ICH trial has been positive by primary end point, but pooled analyses suggest that earlier ICH removal is more likely to be beneficial. Recent trials emphasize maximization of clot removal and minimizing brain injury from the surgical approach. The future of ICH therapy must focus on delivery of medical and surgical therapies as soon as possible if we are to improve outcomes.

Systolic Blood Pressure Reduction and Acute Kidney Injury in Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: We determined the rates and predictors of acute kidney injury (AKI) and renal adverse events (AEs), and effects of AKI and renal AEs on death or disability in patients with intracerebral hemorrhage. METHODS: We analyzed data from a multicenter trial which randomized 1000 intracerebral hemorrhage patients with initial systolic blood pressure ≥180 mm Hg to intensive (goal 110-139 mm Hg) over standard (goal 140-179 mm Hg) systolic blood pressure reduction within 4.5 hours of symptom onset. AKI was identified by serial assessment of daily serum creatinine for 3 days post randomization. RESULTS: AKI and renal AEs were observed in 149 patients (14.9%) and 65 patients (6.5%) among 1000 patients, respectively. In multivariate analysis, the higher baseline serum creatinine (≥110 µmol/L) was associated with AKI (odds ratio 2.4 [95% CI, 1.2-4.5]) and renal AEs (odds ratio 3.1 [95% CI, 1.2-8.1]). Higher area under the curve for intravenous nicardipine dose was associated with AKI (odds ratio 1.003 [95% CI, 1.001-1.005]) and renal AEs (odds ratio 1.003 [95% CI, 1.001-1.006]). There was a higher risk to death (relative risk 2.6 [95% CI, 1.6-4.2]) and death or disability (relative risk 1.5 [95% CI, 1.3-1.8]) at 90 days in patients with AKI but not in those with renal AEs. CONCLUSIONS: Intracerebral hemorrhage patients with higher baseline serum creatinine and those receiving higher doses of nicardipine were at higher risk for AKI and renal AEs. Occurrence of AKI was associated higher rates of death or disability at 3 months. Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT01176565.

Time Metrics to Endovascular Thrombectomy in 3 Triage Concepts: A Prospective, Observational Study (NEUROSQUAD).

Background and Purpose- NEUROSQUAD (Stroke Treatment: Quality and Efficacy in Different Referral Systems) is a prospective, observational, bi-center study comparing 3 triage pathways in endovascular stroke treatment: mothership (MS), drip and ship (DS) and transferring a neurointerventionalist to a remote hospital for thrombectomy (drive the doctor [DD]). Methods- Between February and October 2018, all stroke patients undergoing thrombectomy at 2 university hospitals and 2 associated remote hospitals were included. Primary outcome measures were time from onset to groin puncture and time from imaging to groin puncture. Secondary outcome measures were time from onset to imaging and time from onset to thrombolysis. Results- In total, 440 patients were included (mothership 32.3%, DS 55.9%, DD 11.8%). Median time from onset to groin puncture (168 minutes) and time from imaging to groin puncture (51 minutes) were the shortest in the mothership group. Time from onset to groin puncture (DD median 225 versus DS median 300 minutes; P=0.001) and time from imaging to groin puncture (DD median 118 versus DS median 172 minutes; P<0.001) were shorter in the DD group compared with DS. Time from onset to imaging was similar among mothership, DS, and DD (P=0.363). In patients receiving thrombolysis, time from onset to needle was similar among the groups (P=0.620). Conclusions- The NEUROSQUAD study adds evidence that DD may be a feasible alternative to DS, leading to shorter delay between symptom onset and groin puncture. Both are time-wise inferior compared with mothership, though.

Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.

BACKGROUND: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. METHODS: We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. RESULTS: A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. CONCLUSIONS: In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .).

Clinical Outcomes Depending on Acute Blood Pressure After Cerebral Hemorrhage.

OBJECTIVE: To determine the association between clinical outcomes and acute systolic blood pressure (SBP) levels achieved after intracerebral hemorrhage (ICH). METHODS: Eligible patients who were randomized to the ATACH-2 (Antihypertensive Treatment in Intracerebral Hemorrhage 2) trial (ClinicalTrials.gov: NCT01176565) were divided into 5 groups by 10-mmHg strata of average hourly minimum SBP (<120, 120-130, 130-140, 140-150, and ≥ 150 mmHg) during 2 to 24 hours after randomization. Outcomes included: 90-day modified Rankin Scale (mRS) 4 to 6; hematoma expansion, defined as an increase ≥6 ml from baseline to 24-hour computed tomography; and cardiorenal adverse events within 7 days. RESULTS: Of the 1,000 subjects in ATACH-2, 995 with available SBP data were included in the analyses. The proportion of mRS 4 to 6 was 37.5, 36.0, 42.8, 38.6, and 38.0%, respectively. For the "140 to 150" group relative to the "120 to 130," the odds ratio (OR), adjusting for sex, race, age, onset-to-randomization time, baseline National Institutes of Health Stroke Scale score, hematoma volume, and hematoma location, was 1.62 (95% confidence interval [CI], 1.02-2.58). Hematoma expansion was identified in 16.9, 13.7, 21.4, 18.5, and 26.4%, respectively. The 140 to 150 (OR, 1.80; 95% CI, 1.05-3.09) and "≥150" (1.98; 1.12-3.51) showed a higher frequency of expansion than the 120 to 130 group. Cardiorenal events occurred in 13.6, 16.6, 11.5, 8.1, and 8.2%, respectively. The 140 to 150 (0.43; 0.19-0.88) and ≥ 150 (0.44; 0.18-0.96) showed a lower frequency of the events than the 120 to 130. INTERPRETATION: Beneficial effects of lowering and maintaining SBP at 120 to 130 mmHg during the first 24 hours on clinical outcomes by suppressing hematoma expansion was somewhat offset by cardiorenal complications. ANN NEUROL 2019;85:105-113.

Management of acute ischemic stroke in patients with COVID-19 infection: Insights from an international panel.

OBJECTIVE: To present guidance for clinicians caring for adult patients with acuteischemic stroke with confirmed or suspected COVID-19 infection. METHODS: The summary was prepared after review of systematic literature reviews,reference to previously published stroke guidelines, personal files, and expert opinionby members from 18 countries. RESULTS: The document includes practice implications for evaluation of stroke patientswith caution for stroke team members to avoid COVID-19 exposure, during clinicalevaluation and conduction of imaging and laboratory procedures with specialconsiderations of intravenous thrombolysis and mechanical thrombectomy in strokepatients with suspected or confirmed COVID-19 infection. RESULTS: Conclusions-The summary is expected to guide clinicians caring for adult patientswith acute ischemic stroke who are suspected of, or confirmed, with COVID-19infection.

Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage.

BACKGROUND: Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage. METHODS: We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments. RESULTS: Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, P=0.002). CONCLUSIONS: The treatment of participants with intracerebral hemorrhage to achieve a target systolic blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg. (Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center; ATACH-2 ClinicalTrials.gov number, NCT01176565 .).

Idarucizumab for Reversal of Dabigatran in Early/Emergency Surgeries: A Case Series.

BACKGROUND: Idarucizumab is a humanized, monoclonal antibody fragment used specifically to reverse the anticoagulant effects of dabigatran. CASE REPORTS: We discuss 4 cases of patients who were treated with idarucizumab to reverse dabigatran before early/emergency surgery. Two of the patients had subdural hematomas, 1 had a splenic laceration, and 1 had Fournier gangrene. All patients received 5 g of idarucizumab before surgery. Intraoperative blood loss in all patients was normal, no adverse events were reported, and the patients recovered normally. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The case reports presented provide detailed, practical, real-world experience beyond that reported in other case reports and the Reversal Effects of Idarucizumab on Active Dabigatran study. This can help guide clinicians on how idarucizumab can reverse the anticoagulant effect of dabigatran in emergency situations, including patients with subdural hematoma. Our experience suggests that idarucizumab may be a safe and effective antidote to the effects of dabigatran in real-life bleeding situations involving early or emergency surgeries.

Closure of Patent Foramen Ovale Versus Medical Therapy in Patients With Cryptogenic Stroke or Transient Ischemic Attack: Updated Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Previous systematic reviews and meta-analyses compared the efficacy and safety of patent foramen ovale (PFO) closure versus medical treatment in patients with cryptogenic stroke or transient ischemic attack (TIA). Recently, new evidence from randomized trials became available. METHODS: We searched PubMed until September 24, 2017, for trials comparing PFO closure with medical treatment in patients with cryptogenic stroke/TIA using the items: stroke or cerebrovascular accident or TIA and patent foramen ovale or paradoxical embolism and trial or study. RESULTS: Among 851 identified articles, 5 were eligible. In 3627 patients with 3.7-year mean follow-up, there was significant difference in ischemic stroke recurrence (0.53 versus 1.1 per 100 patient-years, respectively; odds ratio [OR], 0.43; 95% confidence intervals (CI), 0.21-0.90; relative risk reduction, 50.5%; absolute risk reduction, 2.11%; and number needed to treat to prevent 1 event, 46.5 for 3.7 years). There was no significant difference in TIAs (0.78 versus 0.98 per 100 patient-years, respectively; OR, 0.80; 95% CI, 0.53-1.19) and all-cause mortality (0.18 versus 0.23 per 100 patient-years, respectively; OR, 0.73; 95% CI, 0.34-1.56). New-onset atrial fibrillation occurred more frequently in the PFO closure arm (1.3 versus 0.25 per 100 patient-years, respectively; OR, 5.15; 95% CI, 2.18-12.15) and resolved in 72% of cases within 45 days, whereas rates of myocardial infarction (0.12 versus 0.09 per 100 patient-years, respectively; OR, 1.22; 95% CI, 0.25-5.91) and any serious adverse events (7.3 versus 7.3 per 100 patient-years, respectively; OR, 1.07; 95% CI, 0.92-1.25) were similar. CONCLUSIONS: In patients with cryptogenic stroke/TIA and PFO who have their PFO closed, ischemic stroke recurrence is less frequent compared with patients receiving medical treatment. Atrial fibrillation is more frequent but mostly transient. There is no difference in TIA, all-cause mortality, or myocardial infarction.

Idarucizumab for Dabigatran Reversal.

BACKGROUND: Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran. METHODS: We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis. RESULTS: This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated. CONCLUSIONS: Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).

Prothrombin Complex Concentrates for Perioperative Vitamin K Antagonist and Non-vitamin K Anticoagulant Reversal.

Vitamin K antagonist therapy is associated with an increased bleeding risk, and clinicians often reverse anticoagulation in patients who require emergency surgical procedures. Current guidelines for rapid anticoagulation reversal for emergency surgery recommend four-factor prothrombin complex concentrate and vitamin K coadministration. The authors reviewed the current evidence on prothrombin complex concentrate treatment for vitamin K antagonist reversal in the perioperative setting, focusing on comparative studies and in the context of intracranial hemorrhage and cardiac surgery. The authors searched Cochrane Library and PubMed between January 2008 and December 2017 and retrieved 423 English-language papers, which they then screened for relevance to the perioperative setting; they identified 36 papers to include in this review. Prothrombin complex concentrate therapy was consistently shown to reduce international normalized ratio rapidly and control bleeding effectively. In comparative studies with plasma, prothrombin complex concentrate use was associated with a greater proportion of patients achieving target international normalized ratios rapidly, with improved hemostasis. No differences in thromboembolic event rates were seen between prothrombin complex concentrate and plasma, with prothrombin complex concentrate also demonstrating a lower risk of fluid overload events. Overall, the studies the authors reviewed support current recommendations favoring prothrombin complex concentrate therapy in patients requiring vitamin K antagonist reversal before emergency surgery.