Tenecteplase versus alteplase for large vessel occlusion recanalization (T-FLAVOR): Trial protocol

Background Tenecteplase has higher fibrin specificity with a longer half-life and the potential to achieve higher rates of recanalization than alteplase. A critical limitation of tenecteplase is no commercial use in Japan and no experience with its administration to Japanese patients. Hypothesis Tenecteplase is superior to alteplase in achieving recanalization on the initial angiogram when administered ≤4.5-hour of stroke onset in patients planned for mechanical thrombectomy (MT) in Japan where alteplase at the unique dose of 0.6mg/kg is officially used. Methods The Tenecteplase versus alteplase For LArge Vessel Occlusion Recanalization (T-FLAVOR) trial is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, masked-endpoint, superiority study. Eligibility criteria include acute ischemic stroke with pre-stroke modified Rankin Scale score ≤3 and large vessel occlusion (internal carotid artery, middle cerebral artery, or basilar artery) eligible for intravenous thrombolysis ≤4.5-hour and MT ≤6-hour of stroke onset. After completing the safety confirmation phase involving three patients who received non-masked tenecteplase (0.25 mg/kg), 220 patients will be randomized to two groups (1:1), intravenous alteplase (0.6mg/kg, n = 110) or tenecteplase (0.25mg/kg, n = 110), prior to MT. Outcomes In the safety confirmation phase, the primary outcome is symptomatic intracranial hemorrhage (sICH) ≤24-36-hour. In the randomized, comparative phase, the primary efficacy outcome is substantial angiographic reperfusion (mTICI grade 2b/2c/3) or absence of retrievable thrombus on the initial angiogram. The primary safety outcome is sICH ≤24-36-hour and 90-day mortality. Discussion T-FLAVOR may help determine if tenecteplase should be recommended as a routine clinical strategy before MT for Japanese stroke patients. Trial registration jRCTs051210055

Genetic Factors, Brain Atrophy, and Response to Rehabilitation Therapy After Stroke

Objective Patients show substantial differences in response to rehabilitation therapy after stroke. We hypothesized that specific genetic profiles might explain some of this variance and, secondarily, that genetic factors are related to cerebral atrophy post-stroke. Methods The phase 3 ICARE study examined response to motor rehabilitation therapies. In 216 ICARE enrollees, DNA was analyzed for presence of the BDNF val66met and the ApoE ε4 polymorphism. The relationship of polymorphism status to 12-month change in motor status (Wolf Motor Function Test, WMFT) was examined. Neuroimaging data were also evaluated (n=127). Results Subjects were 61±13 years old (mean±SD) and enrolled 43±22 days post-stroke; 19.7% were BDNF val66met carriers and 29.8% ApoE ε4 carriers. Carrier status for each polymorphism was not associated with WMFT, either at baseline or over 12 months of follow-up. Neuroimaging, acquired 5±11 days post-stroke, showed that BDNF val66met polymorphism carriers had a 1.34-greater degree of cerebral atrophy compared to non-carriers (P=.01). Post hoc analysis found that age of stroke onset was 4.6 years younger in subjects with the ApoE ε4 polymorphism (P=.02). Conclusion Neither the val66met BDNF nor ApoE ε4 polymorphism explained inter-subject differences in response to rehabilitation therapy. The BDNF val66met polymorphism was associated with cerebral atrophy at baseline, echoing findings in healthy subjects, and suggesting an endophenotype. The ApoE ε4 polymorphism was associated with younger age at stroke onset, echoing findings in Alzheimer’s disease and suggesting a common biology. Genetic associations provide insights useful to understanding the biology of outcomes after stroke.

Subjective and Objective Assessments of Executive Functioning among Persons 10 years after Stroke Onset

Aim: This study aimed to investigate executive functioning (EF) among patients 10 years after stroke onset through comparing subjective patients’ and informants’ perceptions as well as objective neuropsychological assessments (NPAs). Materials and Method: One month prior to the neuropsychological assessment, 36 patients and their informants completed the Behaviour Rating Inventory of Executive Function - Adult Version (Brief-A) around 10 years after stroke onset. The patients’ EF was assessed with verbal fluency (FAS), backward Digit span backward and Trail making test (TMT)-B. Results: We found no significant differences between patient and informant ratings on EF on a group level, but more patients reported clinically significant executive dysfunctions (T > 65) than their informants. Only poor to slight agreements were observed between the patient and informant ratings of the BRIEF-A. Digit span backward was the only executive test that demonstrated significant improvement of EF 10 years post-stroke in the cohort. Neither patient nor informant ratings on EF showed any significant association with objective EF test performance. Conclusions: Mismatch patient-informant agreement on perceived executive dysfunction showed no clear association with EF test performance in this study. This may indicate the complexity of EF among persons with stroke at chronic phase.

Trajectories of Functional Health Following Stroke: The Role of Social Resources

Stroke is one of the major causes of disability in old age. Predictors for the functional prognosis have been studied, but the role of social resources in recovery has not studied as much. We examined whether social resources available before and after stroke onset improved functional prognoses. Data was derived from longitudinal data collected between 1987 and 2006 from Japanese adults aged 60 years and older. We identified 396 people who had experienced their self- or proxy-reported first stroke during follow-up (age at stroke onset: M = 76.0, SD = 6.9; 74.2% women). Functional health was measured by self- or proxy-reported activities of daily living. Social resources were indexed as residential status, contact with non-coresident children, social participation, and perceived support. Analyses were adjusted for age at stroke onset, gender, and education. A multiphase growth model showed that functional health typically deteriorated surrounding stroke and gradually declined thereafter. There were also individual differences in the trajectories of functional health. Individuals who more frequently participated in social groups prior to stroke and those who came to participate more frequently thereafter exhibited less functional decline immediately following stroke. Our findings indicate that social participation plays a protective role against adverse prognoses following stroke regardless of when individuals start participating. Inclusive communities would enable older adults to remain independent. Our study was limited in that crucial information about stroke, such as objective measures of initial severity, was not available and that individuals with more severe stroke may have dropped out after the onset.

Estimating nocturnal stroke onset times by magnetic resonance imaging in the WAKE-UP trial

Background Fluid-attenuated inversion recovery (FLAIR) sequences have gained a role to guide treatment of patients with unknown time of stroke symptom onset. Evolution of signal intensities in FLAIR is associated with time since stroke onset with continuous linear increases. Aims Estimating symptom onset during night-sleep in patients from the WAKE-UP trial based on relative signal intensities FLAIR (FLAIR-rSI) from acute stroke lesions an independent dataset (PRE-FLAIR study). Methods FLAIR-rSI was quantified in stroke lesions in PRE-FLAIR and WAKE-UP. The PRE-FLAIR study was a multicenter observational trial establishing FLAIR as a surrogate parameter for time since stroke onset. WAKE-UP was a randomized controlled trial that revealed a benefit for alteplase in patients selected based on a DWI-FLAIR mismatch. Stroke onset times were recorded in PRE-FLAIR and used to fit a linear regression model with FLAIR-rSI, adjusted for patient age and lesion volume. The model was applied to FLAIR-rSI of stroke lesions to estimate onset times in those patients enrolled in WAKE-UP who had symptom onset during night-sleep. Results FLAIR-rSI was quantified in 399 patients from PRE-FLAIR. Linear regression indicated a significant association of age ( p = 0.001), lesion volume ( p = 0.005) and FLAIR-rSI ( p < 0.001) with time since symptom onset (adjusted R2 = 0.179). In 813 patients from WAKE-UP, distribution of times of last seen well, symptom recognition and MRI examination were recorded. Median times of last seen well were 1 h before midnight (IQR 2.4 h) and symptom recognition 7 h after midnight (IRQ 2.2 h). Based on the FLAIR-rSI profiles, we estimated median stroke onset 6.1 h after midnight (IQR 2.7 h). Conclusion Nocturnal strokes during night-sleep may predominantly occur during the early morning hours. Our results are in line with evidence of characteristic diurnal patterns of cardiovascular events.

Relationship between the Corticospinal and Corticocerebellar Tracts and Their Role in Upper Extremity Motor Recovery in Stroke Patients

The corticospinal tract (CST) and corticocerebellar tract (CCT) are both involved in the upper extremity (UE) function after stroke. Understanding the relationship between the tracts and their functions can contribute to developing patient-specific rehabilitative strategies. Seventy ischemic stroke patients who underwent diffusion tensor imaging (DTI) two weeks after the stroke onset and motor function assessments two weeks and three months after the stroke onset were included in this study. To obtain the CST and CCT integrity, the functional anisotropy (FA) values of both tracts were extracted from the DTI data. Linear regression was used to identify the relationship and predictive accuracy. The CST FA data had predictive values, but CCT FA did not. There were interaction effects between the CST and CCT FA values (p = 0.011). The CCT was significantly associated with high CST FA but not low CST FA. When the CST or CCT FA were applied to patients depending on the CST status, the stratified model showed higher predictive accuracy (R2 = 0.380) than that of the CST-only model (R2 = 0.320). In this study, the conditional role of CCT depending on CST status was identified in terms of UE recovery in stroke patients. This result could provide useful information about individualized rehabilitative strategies in stroke patients.

Glymphatic Dysfunction in Patients With Ischemic Stroke

Objectives: Rodent experiments have provided some insight into the changes of glymphatic function in ischemic stroke. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) method offers an opportunity for the noninvasive investigation of the glymphatic system in patients with ischemic stroke. We aimed to investigate the changes of glymphatic function in ischemic stroke and the factors associated with the changes.Materials and Methods: A total of 50 patients (mean age 56.7 years; 30 men) and 44 normal subjects (mean age 53.3 years; 23 men) who had preoperative diffusion-tensor imaging for calculation of the analysis along the perivascular space (ALPS) index were retrospectively included. Information collected from each patient included sex, age, time since stroke onset, infarct location, hemorrhagic change, infarct volume, infarct apparent diffusion coefficient (ADC), infarct fractional anisotropy (FA), and ALPS index of both hemispheres. Interhemispheric differences in ALPS index (infarct side vs. contralateral normal side) were assessed with a paired t-test in all patients. ALPS index was normalized by calculating ALPS ratios (right-to-left and left-to-right) for comparisons between patients and normal subjects. Comparisons of ALPS ratios between patients and normal subjects were performed using analysis of covariance with adjustments for age and sex. Linear regression analyses were performed to identify factors associated with the ALPS index.Results: In patients, the mean ALPS index ipsilateral to infarct was 1.162 ± 0.126, significantly lower (P &lt; 0.001) than that of the contralateral side (1.335 ± 0.160). The right-to-left ALPS index ratio of patients with right cerebral infarct was 0.84 ± 0.08, significantly lower (P &lt; 0.001) than that of normal subjects (0.95 ± 0.07). The left-to-right ALPS ratio of patients with left cerebral infarct was 0.92 ± 0.09, significantly (P &lt; 0.001) lower than that of normal subjects (1.05 ± 0.08). On multiple linear regression analysis, time since stroke onset (β = 0.794, P &lt; 0.001) was the only factor associated with the ALPS index.Conclusion: The ALPS index showed lower values in ischemic stroke suggesting impaired glymphatic function. Following initial impairment, the ALPS index increased with the time since stroke onset, which is suggestive of glymphatic function recovery.

Drip-and-Ship for Thrombectomy Treatment in Patients With Acute Ischemic Stroke Leads to Inferior Clinical Outcomes in a Stroke Network Covering Vast Rural Areas Compared to Direct Admission to a Comprehensive Stroke Center

Introduction: Organizing regional stroke care considering thrombolysis as well as mechanical thrombectomy (MTE) remains challenging in light of a wide range of regional population distribution. To compare outcomes of patients in a stroke network covering vast rural areas in southwestern Germany who underwent MTE via direct admission to a single comprehensive stroke center [CSC; mothership (MS)] with those of patients transferred from primary stroke centers [PSCs; drip-and-ship (DS)], we undertook this analysis of consecutive stroke patients with MTE.Materials and Methods: Patients who underwent MTE at the CSC between January 2013 and December 2016 were included in the analysis. The primary outcome measure was 90-day functional independence [modified Rankin score (mRS) 0–2]. Secondary outcome measures included time from stroke onset to recanalization/end of MTE, angiographic outcomes, and mortality rates.Results: Three hundred and thirty-two consecutive patients were included (MS 222 and DS 110). Median age was 74 in both arms of the study, and there was no significant difference in baseline National Institutes of Health Stroke Scale scores (median MS 15 vs. 16 DS). Intravenous (IV) thrombolysis (IVT) rates differed significantly (55% MS vs. 70% DS, p = 0.008). Time from stroke onset to recanalization/end of MTE was 112 min shorter in the MS group (median 230 vs. 342 min, p &lt; 0.001). Successful recanalization [thrombolysis in cerebral infarction (TICI) 2b-3] was achieved in 72% of patients in the MS group and 73% in the DS group. There was a significant difference in 90-day functional independence (37% MS vs. 24% DS, p = 0.017), whereas no significant differences were observed for mortality rates at 90 days (MS 22% vs. DS 17%, p = 0.306).Discussion: Our data suggest that patients who had an acute ischemic stroke admitted directly to a CSC may have better 90-day outcomes than those transferred secondarily for thrombectomy from a PSC.

Off-label-dosing of non-vitamin K-dependent oral antagonists in AF patients before and after stroke: results of the prospective multicenter Berlin Atrial Fibrillation Registry

Aims We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke. Methods The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke. Results At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA2DS2-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05–7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04–10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24–9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01–0.47, P < 0.01; n = 56], CHA2DS2-VASc score [OR per point 1.47, 95% CI 1.08–2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28–2.84, P < 0.01]. Conclusion At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge. Clinical trial registration NCT02306824.

CT Hypoperfusion–Hypodensity Mismatch to Identify Patients With Acute Ischemic Stroke Within 4.5 Hours of Symptom Onset

ObjectiveTo test the hypothesis that CT hypoperfusion-hypodensity mismatch identifies patients with ischemic stroke within 4.5 hours of symptom onset.MethodsWe therefore performed the “retrospective multicenter hypoperfusion-hypodensity mismatch for the identification of patients with stroke within 4.5 hours study” of patients with acute ischemic stroke and known time of symptom onset. The predictive values of hypoperfusion-hypodensity mismatch for the identification of patients with symptom onset within 4.5 hours were the main outcome measure.ResultsOf 666 patients, 548 (82.3 %) had multimodal CT within 4.5 hours and 118 (17.7%) beyond. Hypoperfusion-hypodensity mismatch was visible in 516 (94.2%) patients with symptom onset within and in 30 (25.4%) patients beyond 4.5 hours. CT hypoperfusion-hypodensity mismatch identified patients within 4.5 hours of stroke onset with 94.2% (95% CI: 91.9-95.8%) sensitivity, 74.6% (95% CI: 66.0-81.6%) specificity, 94.5% (95% CI: 92.3-96.1%) positive predictive value, and 73.3% (95% CI: 64.8-80.4%) negative predictive value. Interobserver agreement for hypoperfusion-hypodensity mismatch was substantial (κ=0.61, 95% CI 0.53-0.69).ConclusionsIn conclusion, patients with acute ischemic stroke with absence of a hypodensity on native CT within the hypoperfused core lesion on perfusion CT (hypoperfusion-hypodensity mismatch) are likely to be within the time window of thrombolysis. Applying this method may guide the decision to use thrombolysis in patients with unknown time of stroke onset.Classification of EvidenceThis study provides Class III evidence that CT hypoperfusion-hypodensity mismatch identifies patients with stroke within 4.5 hours of onset.