No influence of dabigatran anticoagulation on hemorrhagic transformation in an experimental model of ischemic stroke

Background: Dabigatran etexilate (DE) is a new oral direct thrombin inhibitor. Clinical trials point towards a favourable risk-to-benefit profile of DE compared to warfarin. In this study, we evaluated whether hemorrhagic transformation (HT) occurs after experimental stroke under DE treatment as we have shown for warfarin. Methods: 44 male C57BL/6 mice were pretreated orally with 37.5 mg/kg DE, 75 mg/kg DE or saline and diluted thrombin time (dTT) and DE plasma concentrations were monitored. Ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAO) for 1 h or 3 h. We assessed functional outcome and HT blood volume 24 h and 72 h after tMCAO. Results: After 1 h tMCAO, HT blood volume did not differ significantly between mice pretreated with DE 37.5 mg/kg and controls (1.5±0.5 µl vs. 1.8±0.5 µl, p>0.05). After 3 h tMCAO, DE-anticoagulated mice did also not show an increase in HT, neither at the dose of 37.5 mg/kg equivalent to anticoagulant treatment in the therapeutic range (1.3±0.9 µl vs. control 2.3±0.5 µl, p>0.05) nor at 75 mg/kg, clearly representing supratherapeutic anticoagulation (1.8±0.8 µl, p>0.05). Furthermore, no significant increase in HT under continued anticoagulation with DE 75 mg/kg could be found at 72 h after tMCAO for 1 h (1.7±0.9 µl vs. control 1.6±0.4 µl, p>0.05). Conclusion: Our experimental data suggest that DE does not significantly increase hemorrhagic transformation after transient focal cerebral ischemia in mice. From a translational viewpoint, this indicates that a continuation of DE anticoagulation in case of an ischemic stroke might be safe, but clearly, clinical data on this question are warranted

Evaluation of endovascular treatment for acute basilar occlusion in a state-wide prospective stroke registry

Context: Despite overwhelming evidence for endovascular therapy in anterior circulation ischemic stroke due to large-vessel occlusion, data regarding the treatment of acute basilar artery occlusion (BAO) are still equivocal. The BASICS trial failed to show an advantage of endovascular therapy (EVT) over best medical treatment (BMT). In contrast, data from the recently published BASILAR registry showed a better outcome in patients receiving EVT. Objective: The aim of the study was to investigate the safety and efficacy of EVT plus BMT vs. BMT alone in acute BAO. Methods: We analyzed the clinical course and short-term outcomes of patients with radiologically confirmed BAO dichotomized by BMT plus EVT or BMT only as documented in a state-wide prospective registry of consecutive patients hospitalized due to acute stroke. The primary endpoint was a favorable functional outcome (mRS 0–3) at hospital discharge assessed as common odds ratio using binary logistic regression. Secondary subgroup analyses and propensity score matching were added. Safety outcomes included mortality, the rate of intracerebral hemorrhages, and complications during hospitalization. Results: We included 403 patients with acute BAO (2017–2019). A total of 270 patients (67%) were treated with BMT plus EVT and 133 patients (33%) were treated with BMT only. A favorable outcome (mRS 0–3) was observed in 33.8% of the BMT and 26.7% of the BMT plus EVT group [OR.770, CI (0.50–1.2)]. Subgroup analyses for patients with a NIHSS score > 10 at admission to the hospital revealed a benefit from EVT [OR 3.05, CI (1.03–9.01)]. Conclusions: In this prospective, quasi population-based registry of patients hospitalized with acute BAO, BMT plus EVT was not superior to BMT alone. Nevertheless, our results suggest that severely affected BAO patients are more likely to benefit from EVT

Measuring patient safety climate in acute stroke therapy

Background: Treatment of acute stroke is highly time-dependent and performed by a multiprofessional, interdisciplinary team. Interface problems are expectable and issues relevant to patient safety are omnipresent. The Safety Attitudes Questionnaire (SAQ) is a validated and widely used instrument to measure patient safety climate. The objective of this study was to evaluate the SAQ for the first time in the context of acute stroke care. Methods: A survey was carried out during the STREAM trial (NCT 032282) at seven university hospitals in Germany from October 2017 to October 2018. The anonymous survey included 33 questions (5-point Likert scale, 1 = disagree to 5 = agree) and addressed the entire multiprofessional stroke team. Statistical analyses were used to examine psychometric properties as well as descriptive findings. Results: 164 questionnaires were completed yielding a response rate of 66.4%. 67.7% of respondents were physicians and 25.0% were nurses. Confirmatory Factor Analysis revealed that the original 6-factor structure fits the data adequately. The SAQ for acute stroke care showed strong internal consistency (α = 0.88). Exploratory analysis revealed differences in scores on the SAQ dimensions when comparing physicians to nurses and when comparing physicians according to their duration of professional experience. Conclusion: The SAQ is a helpful and well-applicable tool to measure patient safety in acute stroke care. In comparison to other high-risk fields in medicine, patient safety climate in acute stroke care seems to be on a similar level with the potential for further improvements. Trial registration: www.ClinicalTrials.gov Identifier: NCT032282

Divergence and Convergence of Sex‐Specific Time Trends in Ischemic Stroke: 10‐Year Analysis of a State‐Wide Registry in Germany

Background The incidence of ischemic stroke was previously expected to rise among countries with an aging population. Lately, several studies from developed countries have reported a decline in certain cohorts. Whether this applies to all sexes, however, is uncertain, with limited data on the temporal development in incidence, treatment, and recovery. Methods and Results We analyzed a prospective stroke inpatient quality‐assurance registry of the federal state of Hesse, Germany. Recruitment of all patients with a final diagnosis of ischemic stroke at hospital discharge (International Classification of Diseases, Tenth Revision [ICD‐10]: I63) is mandatory by law. Incidence rates were calculated based on census data of all inhabitants and stratified according to age. Between 2010 and 2019, there were 141 277 patients included, 73 770 (52.2%) male patients and 67 507 (47.8%) female patients. Overall, the incidence of ischemic stroke was 228 per 100 000 in 2010 and 226 per 100 000 in 2019 (−0.8%; odds ratio [OR], 0.99 [95% CI, 0.96–1.02]; P=0.50). For male patients, the incidence increased continuously from 236 per 100 000 to 245 per 100 000 (+3.8%); in female patients it decreased from 220 per 100 000 to 208 per 100 000 (−5.6%). After adjusting for age, the OR for ischemic stroke between male and female patients was 1.40 in 2010 (95% CI, 1.35–1.44; P<0.001) and 1.48 in 2019 (95% CI, 1.43–1.53; P<0.001). This development was most pronounced in male patients aged 45 to 59 years with an increase from 151 per 100 000 to 176 per 100 000. In this age group, male patients showed increasing rates of prior strokes and atrial fibrillation, surpassing the prevalence in female patients over time. After multivariable regression analysis, male patients had a lower modified Rankin Scale at discharge compared with female patients, but this difference has decreased since 2015 (common OR in 2010, 0.83 [95% CI, 0.78–0.88]; common OR in 2019, 0.90 [95% CI, 0.84–0.95]), which coincided with rising rates of endovascular treatment. Conclusions Over the past decade in the federal state of Hesse, the overall incidence of ischemic stroke has declined predominantly in the female population. In contrast, for male patients, the incidence has risen by about 4%, with a steeper increase of 16% in male patients aged 45 to 59 years, which might be related to increasing rates of recurrent strokes and atrial fibrillation in this cohort. This finding provides a cautionary tale for effective secondary prevention. Female patients were generally less likely to achieve a favorable outcome, but since the introduction of endovascular treatment, the outcome gap is decreasing

Reduction of Ischemic Stroke Associated Disability in the Population: A State-Wide Stroke Registry Analysis over a Decade

(Background): Effective prevention strategies and acute therapies have been established and distributed in recent years to reduce the global burden of stroke. However, beyond randomized clinical trials, limited data exist on the real-world impact of these measures. Our goal was to analyze whether the stroke-associated disability in the population decreased over time based on a state-wide stroke registry analysis. (Methods): Consecutive data from a state-wide inpatient stroke registry covering the entire federal state of Hesse, Germany, were obtained. The clinical data of 141,287 patients with ischemic stroke (ICD-10: I63) admitted between 2010 and 2019 were included. The primary outcome was the odds ratio for a change of modified Ranking Scale (mRS) at discharge over time, estimated by ordinary logistic regression and adjusted for age and sex. The secondary outcome was the odds ratio for a lower National Institutes of Health Stroke Scale (NIHSS) score at hospital admission. (Results): The absolute number of severely disabled (mRS 4–5) stroke patients at discharge decreased over time (2010: 3223 (equivalent to 53/100,000 population); 2019: 2429 [39/100,000 population]). The odds at hospital admission for a higher mRS at discharge decreased significantly by 3.7% per year (OR 0.963 (95% CI 0.960–0.966), p 15) at admission declined over time (2010: 1589 [26/100,000]; 2019: 1185 [19/100,000]; p p < 0.001). Trends were most prominent for patients aged 80 years and older and for patients with atrial fibrillation but absent in patients <60 years. (Conclusions): Stroke-associated disability in the population steadily decreased between 2010 and 2019. The improved prevention of severe strokes in elderly patients may be a major driver of this observation

Exploring contraindications for thrombolysis: risk of hemorrhagic transformation and neurological deterioration after thrombolysis in mice with recent ischemic stroke and hyperglycemia

(1) Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke is limited because of several contraindications. In routine clinical practice, patients with a recent stroke are typically not treated with rt-PA in case of a recurrent ischemic event. The same applies to its use in the context of pulmonary artery embolism and myocardial infarction with a recent stroke. In this translational study, we evaluated whether rt-PA treatment after experimental ischemic stroke with or without additional hyperglycemia increases the risk for hemorrhagic transformation (HT) and worsens functional outcome regarding the old infarct area. (2) In total, 72 male C57BL/6N mice were used. Ischemic stroke (index stroke) was induced by transient middle cerebral artery occlusion (tMCAO). Mice received either rt-PA or saline 24 h or 14 days after index stroke to determine whether a recent ischemic stroke predisposes to HT. In addition to otherwise healthy mice, hyperglycemic mice were analyzed to evaluate diabetes as a second risk factor for HT. Mice designated to develop hyperglycemia were pre-treated with streptozotocin. (3) The neurological outcome in rt-PA and saline-treated normoglycemic mice did not differ significantly, either at 24 h or at 14 days. In contrast, hyperglycemic mice treated with rt-PA had a significantly worse neurological outcome (at 24 h, p = 0.02; at 14 days, p = 0.03). At 24 h after rt-PA or saline treatment, HT scores differed significantly (p = 0.02) with the highest scores within hyperglycemic mice treated with rt-PA, where notably only small petechial hemorrhages could be detected. (4) Thrombolysis after recent ischemic stroke does not increase the risk for HT or worsen the functional outcome in otherwise healthy mice. However, hyperglycemia as a second risk factor leads to neurological deterioration after rt-PA treatment, which cannot be explained by an increase of HT alone. Direct neurotoxic effects of rt-PA may play a role

Outcome after Thrombectomy of Acute M1 and Carotid-T Occlusions with Involvement of the Corticospinal Tract in Postinterventional Imaging

Objectives: Until now, thrombectomy studies have provided little reliable information about the correlation between the infarct topography and clinical outcome of acute stroke patients with embolic large-vessel occlusions. Therefore, we aimed to analyze whether infarcts of the corticospinal tracts in the central white matter (CWM) or the internal capsule on postinterventional imaging controls are associated with poor clinical outcome after thrombectomy. Materials and Methods: We retrospectively analyzed imaging data from 70 patients who underwent endovascular thrombectomy for emergent middle cerebral artery or carotid-T occlusions. Inclusion criteria were postinterventional infarct demarcation in the regions of the internal capsule, caudate, lentiform nucleus, and CWM. Primary outcome was the mRS after 90 days and secondary endpoints were subgroup analyses regarding additional cortical infarction. Conclusions: In this exploratory study, we found no indication that infarcts in the course of the corticospinal tracts predict poor clinical outcome after successful thrombectomy in patients with embolic carotid-T or M1 occlusions. In our analysis, a significant number of patients showed a favorable 90 day outcome. Additional cortical infarcts may have a greater impact on the risk of an unfavorable outcome. Results: Good clinical outcome after 90 days (mRS 0&ndash;2) was shown in 36 out of 70 patients (51.4%), with excellent clinical outcome (mRS 0&ndash;1) in 23 patients (32.9%). Here, 58.6% patients lived at home without nursing service after 90 days. Patients with minimal additional cortical infarction in postinterventional imaging had a 75.6% better chance of excellent outcome

Coadministration of FTY720 and rt-PA in an experimental model of large hemispheric stroke–no influence on functional outcome and blood–brain barrier disruption

BACKGROUND: Systemic thrombolysis with recombinant tissue plasminogen activator (rt-PA) is the standard of acute stroke care. Its potential to increase the risk of secondary intracerebral hemorrhage, especially if administered late, has been ascribed to its proteolytic activity that has detrimental effects on blood-brain barrier (BBB) integrity after stroke. FTY720 has been shown to protect endothelial barriers in several disease models such as endotoxin-induced pulmonary edema and therefore is a promising candidate to counteract the deleterious effects of rt-PA. Besides that, every putative neuroprotectant that will be eventually forwarded into clinical trials should be tested in conjunction with rt-PA. METHODS: We subjected C57Bl/6 mice to 3 h filament-induced tMCAO and postoperatively randomized them into four groups (n = 18/group) who received the following treatments directly prior to reperfusion: 1) vehicle-treatment, 2) FTY720 1 mg/kg i.p., 3) rt-PA 10 mg/kg i.v. or 4) FTY720 and rt-PA as a combination therapy. We measured functional neurological outcome, BBB disruption by quantification of EB extravasation and MMP-9 activity by gelatin zymography. RESULTS: We observed a noticeable increase in mortality in the rt-PA/FTY720 cotreatment group (61%) as compared to the vehicle (33%), the FTY720 (39%) and the rt-PA group (44%). Overall, functional neurological outcome did not differ significantly between groups and FTY720 had no effect on rt-PA- and stroke-induced BBB disruption and MMP-9 activation. CONCLUSIONS: Our data show that FTY720 does not improve functional outcome and BBB integrity in large hemispheric infarctions, neither alone nor in conjunction with rt-PA. These findings stand in contrast to a recently published study that showed beneficial effects of FTY720 in combination with thrombolysis in a thrombotic model of MCAO leading to circumscript cortical infarctions. They might therefore represent a caveat that the coadministration of these two drugs might lead to excess mortality in the setting of a severe stroke

Predicting poststroke pneumonia in patients with anterior large vessel occlusion: a prospective, population-based stroke registry analysis

Objective: To assess predictive factors for poststroke pneumonia (PSP) in patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) of the anterior circulation, with special regard to the impact of intravenous thrombolysis (IVT) and endovascular treatment (EVT) on the risk of PSP. As a secondary goal, the validity of the A2DS2, PNEUMONIA, and ISAN scores in LVO will be determined. Methods: Analysis was based on consecutive data for the years 2017 to 2019 from the prospective inpatient stroke registry covering the entire federal state of Hesse, Germany, using the Kruskal-Wallis test and binary logistic regression. Results: Data from 4,281 patients with LVO were included in the analysis (54.8% female, median age = 78 years, range = 18–102), of whom 66.4% (n = 2,843) received recanalization therapy (RCT). In total, 19.4% (n = 832) of all LVO patients developed PSP. Development of PSP was associated with an increase in overall in-hospital mortality of 32.1% compared with LVO patients without PSP (16.4%; p < 0.001). Incidence of PSP was increased in 2132 patients with either EVT (n = 928; 25.9% PSP incidence) or combined EVT plus IVT (n = 1,204; 24.1%), compared with 2,149 patients with IVT alone (n = 711; 15.2%) or conservative treatment only (n = 1,438; 13.5%; p < 0.001). Multivariate analysis identified EVT (OR 1.5) and combined EVT plus IVT (OR 1.5) as significant independent risk factors for PSP. Furthermore, male sex (OR 1.9), age ≥ 65 years (OR 1.7), dysphagia (OR 3.2) as well as impaired consciousness at arrival (OR 1.7) and the comorbidities diabetes (OR 1.4) and atrial fibrillation (OR 1.3) were significantly associated risk factors (each p < 0.001). Minor stroke (NIHSS ≤ 4) was associated with a significant lower risk of PSP (OR 0.5). Performance of risk stratification scores varied between A2DS2 (96.1% sensitivity, 20.7% specificity), PNEUMONIA (78.2% sensitivity and 45.1% specificity) and ISAN score (98.0% sensitivity, 20.0% specificity). Conclusion: Nearly one in five stroke patients with LVO develops PSP during acute care. This risk of PSP is further increased if an EVT is performed. Other predictive factors are consistent with those previously described for all AIS patients. Available risk stratification scores proved to be sensitive tools in LVO patients but lack specificity

Large-vessel-occlusion in patients with previous ischemic stroke: an analysis of adherence to secondary preventive medication for different etiologies

Abstract Background Large vessel occlusion (LVO) is a severe condition that carries a high risk of morbidity and mortality, underscoring the importance of effective prevention strategies. This retrospective study aimed to analyze the intake of preventive medication at the time of hospitalization in a cohort of recurrent stroke patients presenting with acute LVO. Methods The study assessed the intake of either platelet aggregation inhibitors (PAI), oral anticoagulants (OAC) or statins at admission in patients with recurrent stroke and correlated it with the final classification of LVO. The frequency of those secondary preventive medication in recurrent stroke patients was defined as primary endpoint. The Modified Rankin Scale (mRS) at discharge was used as a functional outcome and defined as a secondary outcome measure. Results This study included 866 patients who were treated for LVO between 2016 and 2020, of whom 160 (18.5%) had a recurrent ischemic stroke. OAC (25.6% vs. 14.1%, p < 0.01), PAI (50.0% vs. 26.0%, p < 0.01), or statin therapy (50.6% vs. 20.8%, p < 0.01) at admission were significantly more frequent in recurrent stroke patients compared to patients with a first-time stroke. Concerning LVO etiology in recurrent stroke patients, OAC at admission was taken in 46.8% of cardioembolic LVO, whereas PAI and statin at admission in macroangiopathic LVO were administered to 40.0%; neither PAI nor OAC was taken in 26.0%, 28.3%, and 31.6% of cardioembolic, macroangiopathic, or cryptogenic strokes, respectively. Regardless of stroke recurrence or etiology, there was an increase in mRS at discharge. Conclusions Despite high-quality healthcare, this study suggested a significant proportion of patients with recurrent stroke who were either non-adherent or insufficiently adherent to secondary preventive medication. Given the disability associated with LVO, improving patients’ medication adherence and identifying unknown stroke causes are crucial for effective prevention strategies