Etiology, 3-Month Functional Outcome and Recurrent Events in Non-Traumatic Intracerebral Hemorrhage

BACKGROUND AND PURPOSE Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce. METHODS We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019). RESULTS We included 2,650 patients (mean±standard deviation age 72±14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and lower mortality (aOR, 0.64; 95% CI, 0.47 to 0.86; P=0.003). ICH due to antithrombotic therapy had higher mortality (aOR, 1.62; 95% CI, 1.01 to 2.61; P=0.045). Within 3 months, 4.2% of patients had cerebrovascular events. The rate of ischemic stroke was higher than that of recurrent ICH in all etiologies but CAA and unknown etiology. CAA had high odds of recurrent ICH (aOR, 3.38; 95% CI, 1.48 to 7.69; P=0.004) while the odds was lower in ICH due to hypertension (aOR, 0.42; 95% CI, 0.19 to 0.93; P=0.031). CONCLUSIONS Although hypertension is the leading etiology of ICH, other etiologies are frequent. One-third of ICH patients are functionally independent at 3 months. Except for patients with presumed CAA, the risk of ischemic stroke within 3 months of ICH was higher than the risk of recurrent hemorrhage

Chronic cerebral infarctions and white matter lesions link to long-term survival after a first ischemic event: A cohort study.

BACKGROUND AND PURPOSE To investigate the association of different phenotypes, count, and locations of chronic covert brain infarctions (CBI) with long-term mortality in patients with first-ever manifest acute ischemic stroke (AIS) or transient ischemic attack (TIA). Additionally, to analyze their potential interaction with white matter hyperintensities (WMH) and predictive value in addition to established mortality scores. METHODS Single-center cohort study including consecutive patients with first-ever AIS or TIA with available MRI imaging from January 2015 to December 2017. Blinded raters adjudicated CBI phenotypes and WMH (age-related white matter changes score) according to established definitions. We compared Cox regression models including prespecified established predictors of mortality using Harrell's C and likelihood ratio tests. RESULTS A total of 2236 patients (median [interquartile range] age: 71 [59-80] years, 43% female, National Institutes of Health Stroke Scale: 2 [1-6], median follow-up: 1436 days, 21% death during follow-up) were included. Increasing WMH (per point adjusted Hazard Ratio [aHR] = 1.29 [1.14-1.45]), but not CBI (aHR = 1.21 [0.99-1.49]), were independently associated with mortality. Neither CBI phenotype, count, nor location was associated with mortality and there was no multiplicative interaction between CBI and WMH (p > .1). As compared to patients without CBI or WMH, patients with moderate or severe WMH and additional CBI had the highest hazards of death (aHR = 1.62 [1.23-2.13]). The Cox regression model including CBI and WMH had a small but significant increment in Harrell's C when compared to the model including 14 clinical variables (0.831 vs. 0.827, p < .001). DISCUSSION WMH represent a strong surrogate biomarker of long-term mortality in first-ever manifest AIS or TIA patients. CBI phenotypes, count, and location seem less relevant. Incorporation of CBI and WMH slightly improves predictive capacity of established risk scores

Association of Chronic Covert Cerebral Infarctions and White Matter Hyperintensities With Atrial Fibrillation Detection on Post-Stroke Cardiac Rhythm Monitoring: A Cohort Study.

Background This study was conducted to explore the association of different phenotypes, count, and location of chronic covert brain infarctions (CBIs) with detection of atrial fibrillation (AF) on prolonged post-stroke cardiac rhythm monitoring (PCM). Methods and Results We conducted a cohort single-center study of consecutive first-ever ischemic stroke or transient ischemic attack patients undergoing PCM between January 2015 and December 2017. We blindly rated CBI phenotypes according to established definitions and white matter hyperintensities (WMHs) according to the age-related white matter changes rating scale. We used (multiple) regression models to assess the association of the imaging biomarkers and incident AF on PCM. A total of 795 patients (median [interquartile range]) aged 69 (57-78) years, 41% women, median National Institutes of Health Stroke Scale score 2 (0-5), median PCM duration 14 (7-14) days, and AF detection in 61 patients (7.7%) were included. On univariate analysis, WMHs (per point odds ratio, 1.35 [95% CI, 1.03-1.78]) but not CBIs (odds ratio, 0.90 [95% CI, 0.52-1.56]) were associated with AF detection. Neither CBI phenotype, count, nor location were associated with AF detection. After adjustment for age, hypertension, and stroke severity, neither increasing WMHs (per point adjusted odds ratio, 0.85 [95% CI, 0.60-1.20]) nor CBIs (adjusted odds ratio, 0.60 [95% CI, 0.33-1.09]) were independently associated with AF detection. Conclusions Although WMHs and CBIs represent surrogate biomarkers of vascular risk factors, neither WMHs nor CBIs, including their phenotypes, count, and location, were independently associated with AF detection on PCM. In patients with manifest ischemic stroke or transient ischemic attack, the presence of imaging biomarkers of chronic ischemic injury does not seem promising to further refine prediction tools for AF detection on PCM

Multivariable Prediction Model for Futile Recanalization Therapies in Patients With Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES Very poor outcome despite intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) occurs in about 1 of 4 patients with ischemic stroke and is associated with a high logistic and economic burden. We aimed to develop and validate a multivariable prognostic model to identify futile recanalization therapies (FRT) in patients undergoing those therapies. MATERIALS AND METHODS Patients from a prospectively collected observational registry of a single academic stroke center treated with MT and/or IVT were included. The dataset was split into a training (N=1808, 80%) and internal validation (N=453, 20%) cohort. We used gradient boosted decision tree machine-learning models after k-NN imputation of 32 variables available at admission to predict FRT defined as modified Rankin-Scale (mRS) 5-6 at 3 months. We report feature importance, ability for discrimination, calibration and decision curve analysis. RESULTS 2261 patients with a median (IQR) age 75 years (64-83), 46% female, median NIHSS 9 (4-17), 34% IVT alone, 41% MT alone, 25% bridging were included. Overall 539 (24%) had FRT, more often in MT alone (34%) as compared to IVT alone (11%). Feature importance identified clinical variables (stroke severity, age, active cancer, prestroke disability), laboratory values (glucose, CRP, creatinine), imaging biomarkers (white matter hyperintensities) and onset-to-admission time as the most important predictors. The final model was discriminatory for predicting 3-month FRT (AUC 0.87, 95% CI 0.87-0.88) and had good calibration (Brier 0.12, 0.11-0.12). Overall performance was moderate (F1-score 0.63 ± 0.004) and decision curve analyses suggested higher mean net benefit at lower thresholds of treatment (up to 0.8). CONCLUSIONS This FRT prediction model can help inform shared decision making and identify the most relevant features in the emergency setting. While it might be particularly useful in low resource healthcare settings, incorporation of further multifaceted variables is necessary to further increase the predictive performance

Yield of Echocardiography in Ischemic Stroke and Patients With Transient Ischemic Attack With Established Indications for Long-Term Direct Oral Anticoagulant Therapy: A Cross-Sectional Diagnostic Cohort Study.

Background We aimed to determine the diagnostic yield of transthoracic (TTE) and transesophageal echocardiography (TEE) in patients with ischemic stroke and transient ischemic attack with established indications for direct oral anticoagulants before the index event. Methods and Results This was a retrospective cohort study of consecutive patients with preceding established indications for long-term therapeutic direct oral anticoagulants presenting to a single comprehensive stroke center with ischemic stroke or transient ischemic attack. Choice of echocardiography modality was based on expert recommendations. The primary outcome was a composite of prespecified management-relevant high-risk findings adjudicated by an expert panel, based on TTE and TEE reports according to evidence-based recommendations. Explorative analyses were performed to identify biomarkers associated with the primary outcome. Of 424 patients included (median [interquartile range] age, 78 [70-84] years; 175 [41%] women; National Institutes of Health Stroke Scale, 4 [1-12]; 67% atrial fibrillation), 292 (69%) underwent echocardiography, while 132 (31%) did not. Modality was TTE in 191 (45%) and TEE in 101 (24%). Median time from index event to echocardiography was 2 (1-3) days. TTE identified 26 of 191 (14%) patients with 35 management-relevant pathologies. TEE identified 16 of 101(16%) patients with 20 management-relevant pathologies. Most management-relevant findings represented indicated coronary artery disease and valvular pathologies. In a further 3 of 191 (2%) patients with TTE and 4 of 101 (4%) patients with TEE, other relevant findings were identified. Variables associated with management-relevant high-risk pathologies included more severe stroke, diabetes, and laboratory biomarkers (NT-proBNP [N-terminal pro-B-type natriuretic peptide], C-reactive protein, d-dimer, and troponin levels). Conclusions In patients with established indications for long-term direct oral anticoagulant therapy and stroke who received echocardiography, both TTE and TEE identified a relevant and similar proportion of management-relevant high-risk pathologies and predictive biomarkers could help to guide diagnostic workup in such patients

Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (Pinteraction=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION URL: https://clinicaltrials.gov; Unique identifier: NCT02866838

Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial

BACKGROUND: Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS: We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS: Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (P$_{interaction}$=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS: In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH

Etiology, 3-Month Functional Outcome and Recurrent Events in Non-Traumatic Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce. METHODS We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019). RESULTS We included 2,650 patients (mean±standard deviation age 72±14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and lower mortality (aOR, 0.64; 95% CI, 0.47 to 0.86; P=0.003). ICH due to antithrombotic therapy had higher mortality (aOR, 1.62; 95% CI, 1.01 to 2.61; P=0.045). Within 3 months, 4.2% of patients had cerebrovascular events. The rate of ischemic stroke was higher than that of recurrent ICH in all etiologies but CAA and unknown etiology. CAA had high odds of recurrent ICH (aOR, 3.38; 95% CI, 1.48 to 7.69; P=0.004) while the odds was lower in ICH due to hypertension (aOR, 0.42; 95% CI, 0.19 to 0.93; P=0.031). CONCLUSIONS Although hypertension is the leading etiology of ICH, other etiologies are frequent. One-third of ICH patients are functionally independent at 3 months. Except for patients with presumed CAA, the risk of ischemic stroke within 3 months of ICH was higher than the risk of recurrent hemorrhage

Anticoagulation after stroke: persistent uncertainties.

PURPOSE OF REVIEW Direct oral anticoagulants (DOAC) are the mainstay of anticoagulant therapy for stroke prevention in patients with nonvalvular atrial fibrillation. Persistent uncertainties remain in different areas, and this review discusses current dilemmas based on selected studies. RECENT FINDINGS Optimal timing of DOAC initiation after a recent ischaemic stroke in patients with atrial fibrillation is currently unknown and subject of ongoing randomized controlled trials. Ischaemic stroke despite anticoagulant therapy in patients with atrial fibrillation is frequent, constitutes heterogeneous causes (competing stroke cause, medication error and cardioembolism despite anticoagulation) and optimal treatment is currently unknown. Thorough etiological work-up is justified. Recent randomized controlled trials found no beneficial effect of DOAC therapy in unselected patients with embolic stroke of undetermined source (ESUS). Currently ongoing trials targeting subgroup of ESUS patients with additional atrial cardiopathy will provide novel data. Cerebral mircobleeds combined in a novel risk score (MICON score) provide good predictive value to stratify the risk of intracranial haemorrhage in patients taking anticoagulants. Use of DOAC after intracerebral haemorrhage in patients with atrial fibrillation is subject of ongoing trials. SUMMARY There are still significant uncertainties in anticoagulant management in patients with stroke. Ongoing trials will soon provide novel data to improve management of these patients

Neuromonitoring Using Neurosonography and Pupillometry in A Weaning and Early Neurorehabilitation Unit.

BACKGROUND AND PURPOSE Long-term surveillance of intracranial pressure (ICP) in neurological/neurosurgical patients during ventilator weaning and early neurorehabilitation currently relies on clinical observation because neuroimaging is rarely readily available. In this prospective study, multimodal neurosonography and pupillometry are evaluated for follow-up monitoring. METHODS Sonographic neuromonitoring was used to noninvasively examine patients' ICP during weaning and early neurorehabilitation. It allowed assessments of third ventricle width, possible midline shift, middle cerebral artery flow velocities, and bilateral optic nerve sheath diameters. Quantitative pupillometry was used to determine pupil size and reactivity. Other neuroimaging findings, spinal tap ICP measurements, and clinical follow-up data served as controls. RESULTS Seventeen patients-11 suffering from intracranial hemorrhage, four from encephalopathies, and two from ischemic stroke-were examined for ICP changes by using neurosonography and pupillometry during a mean observation period of 21 days. In total, 354 of 980 analyses (36.1%) yielded pathological results. In 15 of 17 patients (88.2%), pathological values were found during follow-up without a clear clinical correlate. In two patients (11.8%), clinically relevant changes in ICP occurred and were identified using neurosonography. Abnormal pupillometry findings displayed a high predictive value for absent clinical improvement. CONCLUSION Multimodal neurosonography may be a noninvasive means for long-term ICP assessment, whereas pupillometry may only detect rapid ICP changes during acute neurointensive care. The study also illustrates common pitfalls in neuromonitoring in general, with large numbers of pathological albeit nonsignificant findings. Additional controlled studies should validate the influence of detected subtle changes in ICP on neurological outcome