Ability of patients with acute ischemic stroke to recall given information on intravenous thrombolysis: Results of a prospective multicenter study.

Introduction: Intravenous thrombolysis (IVT) is an on label treatment for selected patients with acute ischemic stroke (AIS). As major bleeding or allergic shock may occur, the need to ensure patients' informed consent for IVT is a matter of debate. Patients and methods: Prospective investigator-initiated multi-center observational study to assess the ability of AIS patients to recall information, provided by a physician during a standardized educational talk (SET) on IVT use. The recall of 20 pre-defined items was assessed in AIS after 60-90 min (n = 93) or 23-25 h (n = 40) after SET. About 40 patients with subacute stroke, 40 non-stroke patients, and 23 relatives of AIS patients served as controls, and were surveyed 60-90 min after SET. Results: Within 60-90 min after SET, AIS patients (median age 70 years, 31% female, median NIHSS score on admission 3 points) who were considered capable to provide informed consent recalled 55% (IQR 40%-66.7%) of the provided SET items. In multivariable linear regression analysis recapitulation by AIS patients was associated with their educational level (ß = 6.497, p < 0.001), self-reported excitement level (ß = 1.879, p = 0.011) and NIHSS score on admission (ß = -1.186, p = 0.001). Patients with subacute stroke (70 years, 40% female, median NIHSS = 2) recalled 70% (IQR 55.7%-83.6%), non-stroke patients (75 years, 40% female) 70% (IQR 60%-78.7%), and AIS relatives (58 years, 83% female) 70% (IQR 60%-85%). Compared to subacute stroke patients, AIS patients less often recalled the frequency of IVT-related bleeding (21% vs 43%), allergic shock (15% vs 39%), and bleeding-related morbidity and mortality (44% vs 78%). AIS patients recalled 50% (IQR 42.3%-67.5%) of the provided items 23-25 h after SET. Conclusion: AIS patients eligible for IVT remember about half of all SET-items after 60-90 min or 23-25 h, respectively. The fact that the recapitulation of IVT-associated risks is particularly poor should be given special consideration.

Coping Strategies and Posttraumatic Growth Following Transient Ischemic Attack: A Qualitative Study.

A transient ischemic attack (TIA) is defined as a temporary neurological dysfunction due to focal brain ischemia. We aimed to identify common coping strategies and the possible occurrence of posttraumatic growth in TIA patients. Semistructured interviews were conducted with TIA patients three months after TIA. We asked the participants about possible changes in the aftermath of their TIA and their way of coping with said changes. All interviews were tape-recorded and subsequently transcribed verbatim. Thematic content analysis was performed to identify main categories and themes. Seventeen patients with a median age of 66 years completed the semistructured interviews. Qualitative content analysis revealed 332 single codes, from which the three main categories "impairments as a consequence of TIA", "coping strategies" and "posttraumatic growth" were generated. The main categories were further subdivided into seven categories and thirty-six themes. TIA patients may suffer from various physical impairments, which also involve medication side effects. Activating resources on the one hand, and avoiding negative thoughts and feelings on the other hand, were identified to be the relevant coping strategies in TIA patients. Posttraumatic growth seems to be a common phenomenon after TIA, which may have important implications for treatment and rehabilitation.

Echocardiography in acute stroke patients: a nationwide analysis in departments with certified stroke units in Germany.

BACKGROUND: Echocardiography is highly relevant in patients with ischemic stroke or TIA. Utilization of routine echocardiographic examinations [transthoracic (TTE) or transesophageal (TEE)] on stroke units remains however unknown. To representatively examine echocardiographic rates on stroke units in Germany and to evaluate structural factors that may influence the decision to conduct echocardiography. METHODS: A nationwide analysis was performed by using certification audit data of all primary and comprehensive stroke centers (pSC and cSC) in Germany. RESULTS: Structural and organizational requirements of 310 departments (cSCs: 42.6%) were extracted. Median TTE rate was 63.3% (IQR 39.3-80.8), median TEE rate 21.3% (IQR 16.4-29.5). A cardiological department on site was present in 74.2%, and they were associated with higher TEE rates. TTE rates decreased with increasing numbers of patients (p = 0.026). Likewise, TEE rates decreased with increasing numbers of patients (p = 0.006), mediated by departments with cSCs (p = 0.008 for cSCs vs p = 0.230 for pSCs). TTE rates were far more inhomogeneously distributed than TEE rates and higher in pSCs (p = 0.011). Overall, 12.9% of centers did not perform any echocardiographic examination in at least 50% of all stroke patients. CONCLUSION: More detailed recommendations regarding echocardiography should be included in future guidelines. Moreover, evaluating the impact of echocardiographic examinations on long-term prognosis in stroke patients should be focus of further evaluations.

Association of stroke lesion shape with newly detected atrial fibrillation - Results from the MonDAFIS study.

Paroxysmal Atrial fibrillation (AF) is often clinically silent and may be missed by the usual diagnostic workup after ischemic stroke. We aimed to determine whether shape characteristics of ischemic stroke lesions can be used to predict AF in stroke patients without known AF at baseline. Lesion shape quantification on brain MRI was performed in selected patients from the intervention arm of the Impact of standardized MONitoring for Detection of Atrial Fibrillation in Ischemic Stroke (MonDAFIS) study, which included patients with ischemic stroke or TIA without prior AF. Multiple morphologic parameters were calculated based on lesion segmentation in acute brain MRI data. Multivariate logistic models were used to test the association of lesion morphology, clinical parameters, and AF. A stepwise elimination regression was conducted to identify the most important variables. A total of 755 patients were included. Patients with AF detected within 2 years after stroke (n = 86) had a larger overall oriented bounding box (OBB) volume (p = 0.003) and a higher number of brain lesion components (p = 0.008) than patients without AF. In the multivariate model, OBB volume (OR 1.72, 95%CI 1.29-2.35, p < 0.001), age (OR 2.13, 95%CI 1.52-3.06, p < 0.001), and female sex (OR 2.45, 95%CI 1.41-4.31, p = 0.002) were independently associated with detected AF. Ischemic lesions in patients with detected AF after stroke presented with a more dispersed infarct pattern and a higher number of lesion components. Together with clinical characteristics, these lesion shape characteristics may help in guiding prolonged cardiac monitoring after stroke.

Low Exposure to Direct Oral Anticoagulants Is Associated with Ischemic Stroke and Its Severity.

BACKGROUND AND PURPOSE: In acute stroke patients, plasma concentrations of direct oral anticoagulants (DOAC) at hospital admission only poorly mirror DOAC exposure or the coagulation status at the time of the event. Here, we evaluated whether DOAC exposure and DOAC plasma concentration at the time of transient ischemic attacks (TIA) and ischemic strokes correlate with their likelihood of occurrence. METHODS: Prospectively, consecutive DOAC patients with acute ischemic stroke or TIA were included. Admission DOAC plasma concentrations were measured by ultraperformance liquid chromatography- tandem mass spectrometry. Individual DOAC exposure (area under the curve) and DOAC concentrations at event onset were derived from population pharmacokinetic analyses. RESULTS: DOAC exposure was successfully modeled in 211 patients (ischemic stroke 74.4%, TIA 25.6%). Compared to published values, 63.0% had relatively lower DOAC exposure and they more often received lower DOAC doses than recommended (odds ratio [OR], 2.125; 95% confidence interval [CI], 1.039 to 4.560; P=0.044). These patients more likely suffered ischemic strokes than TIA (OR, 2.411; 95% CI, 1.254 to 4.638; P=0.008) and their strokes were more severe (slope, 3.161; 95% CI, 0.741 to 5.58; P=0.011). Low relative DOAC concentrations at event onset were likewise associated with ischemic strokes (OR, 4.123; 95% CI, 1.834 to 9.268; P=0.001), but not to stroke severity (P=0.272). DOAC exposure had a higher explanatory value for stroke severity than concentrations at event. CONCLUSIONS: Low DOAC exposure is strongly associated to ischemic stroke and its severity. By monitoring DOAC plasma concentrations, patients prone to ischemic stroke might be identified.

The Impact of Post-contrast Acute Kidney Injury on In-hospital Mortality After Endovascular Thrombectomy in Patients With Acute Ischemic Stroke.

Background and Purpose: Clinical outcome and mortality after endovascular thrombectomy (EVT) in patients with ischemic stroke are commonly assessed after 3 months. In patients with acute kidney injury (AKI), unfavorable results for 3-month mortality have been reported. However, data on the in-hospital mortality after EVT in this population are sparse. In the present study, we assessed whether AKI impacts in-hospital and 3-month mortality in patients undergoing EVT. Materials and Methods: From a prospectively recruiting database, consecutive acute ischemic stroke patients receiving EVT between 2010 and 2018 due to acute large vessel occlusion were included. Post-contrast AKI (PC-AKI) was defined as an increase of baseline creatinine of ≥0.5 mg/dL or >25% within 48 h after the first measurement at admission. Adjusting for potential confounders, associations between PC-AKI and mortality after stroke were tested in univariate and multivariate logistic regression models. Results: One thousand one hundred sixty-nine patients were included; 166 of them (14.2%) died during the acute hospital stay. Criteria for PC-AKI were met by 29 patients (2.5%). Presence of PC-AKI was associated with a significantly higher risk of in-hospital mortality in multivariate analysis [odds ratio (OR) = 2.87, 95% confidence interval (CI) = 1.16-7.13, p = 0.023]. Furthermore, factors associated with in-hospital mortality encompassed higher age (OR = 1.03, 95% CI = 1.01-1.04, p = 0.002), stroke severity (OR = 1.05, 95% CI = 1.03-1.08, p < 0.001), symptomatic intracerebral hemorrhage (OR = 3.20, 95% CI = 1.69-6.04, p < 0.001), posterior circulation stroke (OR = 2.85, 95% CI = 1.72-4.71, p < 0.001), and failed recanalization (OR = 2.00, 95% CI = 1.35-3.00, p = 0.001). Conclusion: PC-AKI is rare after EVT but represents an important risk factor for in-hospital mortality and for mortality within 3 months after hospital discharge. Preventing PC-AKI after EVT may represent an important and potentially lifesaving effort in future daily clinical practice.

Does Chronic Kidney Disease Have an Impact on the Use of Oral Anticoagulants after Stroke? An Observational Follow-Up Study.

INTRODUCTION: Chronic kidney disease is common in patients with acute ischemic stroke. We investigated whether chronic kidney disease has an impact on anticoagulation treatment recommendations after ischemic stroke or transient ischemic attack (TIA) related with atrial fibrillation (AF). MATERIALS AND METHODS: We extracted treatment-related data concerning stroke/TIA patients with AF and available estimated glomerular filtration rates (eGFR) from a monocentric prospective German stroke registry. Chronic kidney disease was defined as eGFR <60 mL/min/1.73 m2. Using uni- and multivariate logistic regression analyses, we investigated whether chronic kidney disease was associated with a lower probability to be treated with anticoagulation early after stroke. RESULTS: A total of 273 patients entered the analysis. In 242 AF patients (88.6%), oral anticoagulation was recommended after stroke. In multivariate logistic regression analysis, chronic kidney disease was not identified as an independent factor for the decision against anticoagulation (OR 1.63, 95% CI: 0.50-5.31, p = 0.421); only increasing age (OR 1.10, 95% CI: 1.00-1.21, p = 0.061) and a modified Rankin Scale >3 at discharge (OR 3.41, 95% CI: 0.88-13.24, p = 0.077) showed a nonsignificant trend for the decision to omit anticoagulation. A total of 155 of 167 patients (92.8%) were still anticoagulated at follow-up. A total of 44 patients with chronic kidney disease completed follow-up, and of those, 37 were still anticoagulated (84%). In patients without chronic kidney disease, 118/167 (70.7%) had continued anticoagulation (p = 0.310). CONCLUSION: Our results show that chronic kidney disease was not the main factor in the decision to withhold oral anticoagulation in patients with recent stroke/TIA and AF.

Expert opinion paper on cardiac imaging after ischemic stroke.

This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.

Thunderclap Headache: A Primary Symptom of a Steroid-Responsive Encephalopathy with Autoimmune Thyroiditis.

Thunderclap headache is frequently associated with serious intracranial vascular disorders and a usual reason for emergency department admissions. Association of thunderclap headaches with autoimmune disorders, such as steroid-responsive encephalopathy with autoimmune thyroiditis (SREAT), is highly unusual. Here, we report a patient who presented with high-intensity headache of abrupt onset. Cerebrospinal fluid (CSF) analysis revealed moderate lymphocytic pleocytosis without evidence of infectious, neoplastic, or metabolic causes. Brain magnetic resonance imaging showed no specific pathologies, and examinations for neuronal antibodies in serum and CSF were negative. The medical history revealed that seven years before, an episode of an aseptic meningoencephalitis with remarkable response to steroids was present. Finally, increased levels of serum anti-TPO antibodies were identified, and against the background of a previous steroid-responsive aseptic meningoencephalitis, diagnosis of SREAT was highly probable. Methylprednisolone therapy was initiated, and the patient recovered completely. In particular, because most SREAT patients respond very well to steroids, this case underlines the importance of taking SREAT into consideration during the assessment of a high-intensity headache of abrupt onset.

Systematic monitoring for detection of atrial fibrillation in patients with acute ischaemic stroke (MonDAFIS): a randomised, open-label, multicentre study.

BACKGROUND: Systematic electrocardiogram (ECG) monitoring improves detection of covert atrial fibrillation in stroke survivors but the effect on secondary prevention is unknown. We aimed to assess the effect of systematic ECG monitoring of patients in hospital on the rate of oral anticoagulant use after 12 months. METHODS: In this investigator-initiated, randomised, open-label, parallel-group multicentre study with masked endpoint adjudication, we recruited patients aged at least 18 years with acute ischaemic stroke or transient ischaemic attack without known atrial fibrillation in 38 certified stroke units in Germany. Patients were randomly assigned (1:1) to usual diagnostic procedures for atrial fibrillation detection (control group) or additional Holter-ECG recording for up to 7 days in hospital (intervention group). Patients were stratified by centre using a random permuted block design. The primary outcome was the proportion of patients on oral anticoagulants at 12 months after the index event in the intention-to-treat population. Secondary outcomes included the number of patients with newly diagnosed atrial fibrillation in hospital and the composite of recurrent stroke, major bleeding, myocardial infarction, or death after 6 months, 12 months, and 24 months. This trial was registered with ClinicalTrials.gov, NCT02204267, and is completed and closed for participants. FINDINGS: Between Dec 9, 2014, and Sept 11, 2017, 3465 patients were randomly assigned, 1735 (50·1%) to the intervention group and 1730 (49·9%) to the control group. Oral anticoagulation status was available in 2920 (84·3%) patients at 12 months (1484 [50·8%] in the intervention group and 1436 [49·2%] in the control group). For the primary outcome, at 12 months, 203 (13·7%) of 1484 patients in the intervention group versus 169 (11·8%) of 1436 in the control group were on oral anticoagulants (odds ratio [OR] 1·2 [95% CI 0·9-1·5]; p=0·13). Atrial fibrillation was newly detected in patients in hospital in 97 (5·8%) of 1714 in the intervention group versus 68 (4·0%) of 1717 in the control group (hazard ratio [HR] 1·4 [95% CI 1·0-2·0]; p=0·024). The composite of cardiovascular outcomes and death did not differ between patients randomly assigned to the intervention group versus the control group at 24 months (232 [13·5%] of 1714 vs 249 [14·5%] of 1717; HR 0·9 [0·8-1·1]; p=0·43). Skin reactions due to study ECG electrodes were reported in 56 (3·3%) patients in the intervention group. All-cause death occured in 73 (4·3%) patients in the intervention group and in 103 (6·0%) patients in the control group (OR 0·7 [0·5-0·9]). INTERPRETATION: Systematic core centrally reviewed ECG monitoring is feasible and increases the detection rate of atrial fibrillation in unselected patients hospitalised with acute ischaemic stroke or transient ischaemic attack, if added to usual diagnostic care in certified German stroke units. However, we found no effect of systematic ECG monitoring on the rate of oral anticoagulant use after 12 months and further efforts are needed to improve secondary stroke prevention. FUNDING: Bayer Vital. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Prophylactic anticoagulation in patients with glioblastoma or brain metastases and atrial fibrillation: an increased risk for intracranial hemorrhage?

PURPOSE: Patients with glioblastoma (GBM) or brain metastases (MET) and atrial fibrillation (AF) might be at an increased risk of intracranial hemorrhage (ICH) due to anticoagulation (AC). Our aim was to assess this risk. METHODS: Our institution's database (from 2005 to 2017) was screened for patients with GBM or MET and AF with an indication for AC according to their CHA2DS2VASc stroke risk score (≥ 2). Required follow-up was at least 3 months. AC was either performed with heparins, phenprocoumon or non-Vitamin K antagonist oral anticoagulants. Applying the propensity score approach, patient cohorts (matched according to primary tumor, age, sex) were generated (GBM [or MET] with AF ± AC, GBM [or MET] without AF/AC, no GBM [or MET] but AF on AC). ICH was defined as clinical deterioration caused by new blood on imaging. A log rank test was performed to compare the risk for ICH between the three groups. RESULTS: In total, 104 patients were identified of which 49 with GBM (37% on AC) and 37 with MET (46% on AC) were successfully matched. Median follow up was 8.6 and 7.2 months, respectively. ICH occurred in 10.2% of GBM + AF and 12.2% GBM-AF, whereas 8% of patients with AF on AC suffered ICH (p = 0.076). 13.5% of patients with MET + AF had ICHs, in the controls it was 16% for MET-AF and 8% for AF on AC (p = 0.11). CONCLUSION: AC did not seem to influence the incidence of ICH in patients with glioblastoma or brain metastases within follow up of just under 9 months.

Prothrombin complex concentrate for vitamin K antagonist reversal in traumatic intracranial hemorrhage.

OBJECTIVE: Administration of prothrombin complex concentrate (PCC) is recommended for vitamin K antagonist (VKA) reversal in patients with severe bleeding complications. However, there are only limited data available on its use for VKA reversal in patients with traumatic intracranial hemorrhage (ICH). METHODS: Data from all anticoagulated patients referred to our hospital for treatment of traumatic ICH and who received PCC for anticoagulation reversal were retrospectively analysed with specific focus on bleeding and thromboembolic complications during the further in-hospital course. RESULTS: A total of 142 patients were included in the present study. The median age was 78 years (Interquartile range [IQR]: 72-84) and the median Glasgow Coma Scale (GCS) score on admission was 12 (IQR: 7-14). Median International Normalized Ratio (INR) on admission was 2.5 [IQR: 2.0-3.3] and decreased to 1.2 [IQR: 1.1-1.3] following administration of a median dose of 2000 I.U. PCC [IQR: 1500-2625]. The in-hospital mortality rate was 13% and the median GCS of survivors at discharge was 14 [IQR: 12-15]. Thromboembolic events after PCC administration occurred in 4 patients (2.8%). The overall one-year mortality rate in this patient cohort was 49%. CONCLUSIONS: PCC administration rapidly normalises INR and facilitates urgent neurosurgical procedures in anticoagulated patients with traumatic ICH.

Predictors of posttraumatic stress following transient ischemic attack: An observational cohort study.

OBJECTIVE: Transient ischemic attack (TIA) has been reported to be frequently followed by symptoms of post-TIA posttraumatic stress disorder (post-TIA PTSD). Risk factors for post-TIA PTSD remain largely unknown. We aimed to identify predictors of post-TIA PTSD development to enable post-TIA PTSD risk assessment and inform future development of treatment and prevention interventions. METHOD: TIA patients were examined twice for this observational cohort study. Symptoms of post-TIA PTSD, depression and anxiety were assessed shortly after TIA during in-hospital stay (T1) and three months after TIA (T2). The impact of known general PTSD risk factors (psychiatric history, peritraumatic dissociation, social support), psychological resilience factors (sense of coherence, mindfulness, attachment style) and TIA characteristics (affected circulatory territory, symptom type and duration) at T1 on post-TIA PTSD symptom severity at T2 was tested using hierarchical multiple linear regression. RESULTS: Sixty-one patients (83.6%) completed the study at T2. Fifteen patients (24.6%) were classified as post-TIA PTSD⊕ at T2. In multiple linear regression analysis, age, sex, psychiatric history, peritraumatic dissociation and social support together explained 39.9% of variance of post-TIA posttraumatic stress symptom severity. Sense of coherence and mindfulness explained further 17.8% of variance. Clinical TIA characteristics were not associated with post-TIA PTSD. CONCLUSIONS: Post-TIA PTSD is a common phenomenon. General PTSD risk factors can be applied for post-TIA PTSD risk assessment. Sense of coherence and mindfulness are promising target variables for post-TIA PTSD treatment and prevention interventions.

Association of Surgical Hematoma Evacuation vs Conservative Treatment With Functional Outcome in Patients With Cerebellar Intracerebral Hemorrhage.

Importance: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established. Objective: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH. Design, Setting, and Participants: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015). Exposure: Surgical hematoma evacuation vs conservative treatment. Main Outcomes and Measures: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH. Results: Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02). Conclusions and Relevance: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.

Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways.

BACKGROUND: Apixaban effectively lowers the risk of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Systemic exposure to a given apixaban dose depends on multiple clearance pathways. Though routine quantification of direct oral anticoagulants (DOACs) in neurological emergency situations has not been widely established, suspected associations of DOAC peak concentrations with bleeding events and DOAC trough concentrations with efficacy and safety suggest that such information might support clinical decision making. CASE PRESENTATION: We describe the case of a 75 year-old woman with atrial fibrillation maintained on apixaban who was admitted due to suspected acute stroke. Clinical work-up did not confirm ischemic or hemorrhagic stroke but routine quantification of apixaban revealed an excessively high apixaban plasma concentration (~ 3 h after the last drug intake: 1100 ng/ml (expected range: 91-321 ng/ml); ~ 12 h after drug intake: 900 ng/ml (expected range: 41-230 ng/ml)) and a substantially prolonged elimination half-life (~ 31 h). The corresponding apixaban concentration-to-dose ratio was 9900 (ng/ml)/(mg/kg/d) and 8100 (ng/ml)/(mg/kg/d), respectively (expected range: 249-463 (ng/ml)/(mg/kg/d)). Renal function was only moderately impaired (creatinine 1.36 mg/dl (0.5-1.1 mg/dl), creatinine clearance 40 ml/min). Genotype analyses revealed that the patient was a CYP3A5*3/*3 non-expressor, a heterozygous carrier of the ABCG2 c.421C/A alleles, and a homozygous carrier of ABCB1 c.2677 T/T and ABCB1 c.3435 T/T. In the absence of known drug interactions explaining apixaban clearance impairment, excessive apixaban concentrations were most probably caused by moderate renal impairment combined with multiple functional polymorphisms of apixaban clearance pathways. CONCLUSIONS: This case suggests that concurrent genetic polymorphisms can impair multiple apixaban elimination pathways and thus substantially increase its exposure.

Rationale and design of the Registry of Acute Stroke Under Novel Oral Anticoagulants-prime (RASUNOA-prime).

BACKGROUND: Anticoagulation with vitamin K antagonists and non-vitamin K antagonists oral anticoagulants (NOAC) is effective in stroke prevention in patients with atrial fibrillation. However, anticoagulation also poses a major challenge for emergency treatment of patients suffering ischaemic stroke or intracerebral haemorrhage. AIM: The registry RASUNOA-prime is designed to describe current patterns of emergency management, clinical course and outcome of patients with atrial fibrillation experiencing an acute ischaemic stroke or intracerebral haemorrhage under different anticoagulation schemes prior to stroke (NOAC, vitamin K antagonists or no anticoagulation). METHODS AND DESIGN: RASUNOA-prime (ClinicalTrials.gov, NCT02533960) is a prospective, investigator-initiated, multicentre, observational cohort study aiming to recruit 3000 patients with acute ischaemic stroke and atrial fibrillation, and 1000 patients with acute intracerebral haemorrhage and atrial fibrillation with different anticoagulation schemes pre-stroke. It is a non-interventional triple-armed study aiming at a balanced inclusion of ischaemic stroke and intracerebral haemorrhage patients according to the different anticoagulation schemes. Patients will be followed up for clinical course, management and outcome up to three months after the event. Findings in ischaemic stroke and intracerebral haemorrhage patients on NOAC will be compared with patients taking vitamin K antagonists or no anticoagulant pre-stroke. STUDY OUTCOMES: Primary endpoint for ischaemic stroke patients: occurrence of symptomatic intracerebral haemorrhage, for intracerebral haemorrhage patients: occurrence of secondary haematoma expansion. Secondary endpoints include assessment of coagulation, use of thrombolysis and/or mechanical thrombectomy, occurrence of complications, implementation of secondary prevention. SUMMARY: Describing the current patterns of early management as well as outcome of stroke patients with atrial fibrillation will help guide physicians to develop recommendations for emergency treatment of stroke patients under different anticoagulation schemes.

Characteristics in Non-Vitamin K Antagonist Oral Anticoagulant-Related Intracerebral Hemorrhage.

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage.

OBJECTIVE: To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH. METHODS: Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC. RESULTS: IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04-1.93) vs non-LDSH: 1.32 (0.33-3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38-4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4-6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04-0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11-0.78); p=0.014) were significantly associated with fewer IHC. CONCLUSIONS: Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.

Renal Impairment Is Associated with Intracerebral Hemorrhage after Mechanical Thrombectomy in Vertebrobasilar Stroke.

BACKGROUND AND PURPOSE: Renal dysfunction (RD) is overall associated with unfavorable functional outcome and higher risk of mortality after acute ischemic stroke. Associations between RD and outcome in patients with acute vertebrobasilar stroke treated with thrombectomy have not been evaluated so far. MATERIALS AND METHODS: Consecutive patients with vertebrobasilar stroke treated with mechanical thrombectomy between October 2010 and July 2017 at our center were analyzed. RD was defined as glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 at admission. Endpoints were (I) poor clinical outcome (modified Rankin Scale > 2) at 3 months, (II) 3-month mortality, and (III) intracerebral hemorrhage (ICH) after treatment. RESULTS: Overall, 106 patients were included. Median age was 73.0 years (interquartile range 62.0-80.0), and RD was present in 20.8%. Multivariate analysis revealed that RD was associated with a higher risk for any ICH (OR 3.54; 95% CI 1.09-11.49; p = 0.035). Stroke severity at onset predicted poor clinical outcome (OR 1.08; 95% CI 1.03-1.14; p = 0.003). Neither low GFR nor any ICH, but stroke severity (OR 1.08; 95% CI 1.03-1.14; p = 0.002) and poor recanalization results (OR 11.38; 95% CI 2.01-64.41; p = 0.006) were associated with a higher risk for mortality. CONCLUSIONS: Patients with RD and acute vertebrobasilar stroke should be thoroughly monitored to prevent ICH after thrombectomy. Our results support performing mechanical thrombectomy in acute stroke patients with large vessel occlusions of the posterior circulation, irrespective of their renal function.

Management of Patients with Acute Subdural Hemorrhage During Treatment with Direct Oral Anticoagulants.

BACKGROUND: Anticoagulation therapy is a major risk factor for unfavorable patient outcomes following (traumatic) intracranial hemorrhage. Direct oral anticoagulants (DOAC) are increasingly used for the prevention and treatment of thromboembolic diseases. Data on patients treated for acute subdural hemorrhage (SDH) during anticoagulation therapy with DOAC are limited. METHODS: We analyzed the medical records of consecutive patients treated at our institution for acute SDH during anticoagulation therapy with DOAC or vitamin K antagonists (VKA) during a period of 30 months. Patient characteristics such as results of imaging and laboratory studies, treatment modalities and short-term patient outcomes were included. RESULTS: A total of 128 patients with preadmission DOAC (n = 65) or VKA (n = 63) intake were compared. The overall 30-day mortality rate of this patient cohort was 27%, and it did not differ between patients with DOAC or VKA intake (26% vs. 27%; p = 1.000). Similarly, the rates of neurosurgical intervention (65%) and intracranial re-hemorrhage (18%) were comparable. Prothrombin complex concentrates were administered more frequently in patients with VKA intake than in patients with DOAC intake (90% vs. 58%; p < 0.0001). DOAC treatment in patients with acute SDH did not increase in-hospital and 30-day mortality rates compared to VKA treatment. CONCLUSIONS: These findings support the favorable safety profile of DOAC in patients, even in the setting of intracranial hemorrhage. However, the availability of specific antidotes to DOAC may further improve the management of these patients.