Changes in nationwide in-hospital stroke care during the first four waves of COVID-19 in Germany.

Introduction: In the early stages of the global COVID-19 pandemic hospital admissions for acute ischemic stroke (AIS) decreased substantially. As health systems have become more experienced in dealing with the pandemic, and as the proportion of the population vaccinated rises, it is of interest to determine whether the prevalence of AIS hospitalization and outcomes from hospitalization have returned to normal. Patients and methods: In this observational, retrospective cohort study, we compared the prevalence and outcomes of AIS during the first four waves of the pandemic to corresponding pre-pandemic periods in 2019 using administrative data collected from a nationwide network of 76 hospitals that manages 7% of all in-hospital cases in Germany. Results: We included 25,821 AIS cases in the study period (2020/2021) and used 26,295 AIS cases as controls (2019). Compared to pre-pandemic numbers, mean daily AIS admissions decreased only during wave 1 (from 39.6 to 34.1; p < 0.01) and wave 2 (from 39.9 to 38.3; p = 0.03) and returned to normal levels during waves 3 and 4. AIS case fatality increased in wave 1 only (from 6.0% to 7.6%; p = 0.03). We observed a consistent decrease in the prevalences of arterial hypertension, diabetes, and obesity among AIS cases throughout the pandemic and no changes in rates of systemic thrombolysis, mechanical thrombectomy, or decompressive craniectomy. The rate of transfer to stroke units increased only during waves 2 (by 4.6%; p < 0.01) and 3 (by 3.0%; p < 0.01). The proportion of patients with coinciding SARS-CoV-2 and AIS was low, peaking at 3.4% in wave 2 and subsequently decreasing to 0.4% in wave 4. Conclusion: In Germany, the COVID-19 pandemic seems to have had a larger effect on nationwide in-hospital AIS care during the early pandemic stages, in which AIS case numbers decreased and case fatality rose. This may reflect a nationwide "learning curve" within health care systems in providing AIS care in times of a pandemic.

Patient-Centered Outcomes in a Randomized Trial Investigating a Multimodal Prevention Program After Transient Ischemic Attack or Minor Stroke: The INSPiRE-TMS Trial.

BACKGROUND: The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes. METHODS: In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up. RESULTS: Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5-43.5); 36.1 after 2 years (95% CI, 13.1-59.7) and 29.6 (95% CI, 2.0-57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03-1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96-1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95-1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up. CONCLUSIONS: Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01586702.

Delirium on stroke units: a prospective, multicentric quality-improvement project.

BACKGROUND: Post-stroke delirium (POD) in patients on stroke units (SU) is associated with an increased risk for complications and poorer clinical outcome. The objective was to reduce the severity of POD by implementing an interprofessional delirium-management. METHODS: Multicentric quality-improvement project on five SU implementing a delirium-management with pre/post-comparison. Primary outcome was severity of POD, assessed with the Nursing Delirium Screening Scale (Nu-DESC). Secondary outcome parameters were POD incidence, duration, modified Rankin Scale (mRS), length of stay in SU and hospital, mortality, and others. RESULTS: Out of a total of 799 patients, 59.4% (n = 475) could be included with 9.5% (n = 45) being delirious. Implementation of a delirium-management led to reduced POD severity; Nu-DESC median: pre: 3.5 (interquartile range 2.6-4.7) vs. post 3.0 (2.2-4.0), albeit not significant (p = 0.154). Other outcome parameters were not meaningful different. In the post-period, delirium-management could be delivered to 75% (n = 18) of delirious patients, and only 24 (53.3%) of delirious patients required pharmacological treatments. Patients with a more severe stroke and POD remained on their disability levels, compared to similar affected, non-delirious patients who improved. CONCLUSIONS: Implementation of delirium-management on SU is feasible and can be delivered to most patients, but with limited effects. Nursing interventions as first choice could be delivered to the majority of patients, and only the half required pharmacological treatments. Delirium-management may lead to reduced severity of POD but had only partial effects on duration of POD or length of stay. POD hampers rehabilitation, especially in patients with more severe stroke. REGISTRY: DRKS, DRKS00021436. Registered 04/17/2020, www.drks.de/DRKS00021436 .

Impact of the coronavirus disease 2019 pandemic on stroke teleconsultations in Germany in the first half of 2020.

BACKGROUND AND PURPOSE: The effects of the coronavirus disease 2019 (COVID-19) pandemic on telemedical care have not been described on a national level. Thus, we investigated the medical stroke treatment situation before, during, and after the first lockdown in Germany. METHODS: In this nationwide, multicenter study, data from 14 telemedical networks including 31 network centers and 155 spoke hospitals covering large parts of Germany were analyzed regarding patients' characteristics, stroke type/severity, and acute stroke treatment. A survey focusing on potential shortcomings of in-hospital and (telemedical) stroke care during the pandemic was conducted. RESULTS: Between January 2018 and June 2020, 67,033 telemedical consultations and 38,895 telemedical stroke consultations were conducted. A significant decline of telemedical (p < 0.001) and telemedical stroke consultations (p < 0.001) during the lockdown in March/April 2020 and a reciprocal increase after relaxation of COVID-19 measures in May/June 2020 were observed. Compared to 2018-2019, neither stroke patients' age (p = 0.38), gender (p = 0.44), nor severity of ischemic stroke (p = 0.32) differed in March/April 2020. Whereas the proportion of ischemic stroke patients for whom endovascular treatment (14.3% vs. 14.6%; p = 0.85) was recommended remained stable, there was a nonsignificant trend toward a lower proportion of recommendation of intravenous thrombolysis during the lockdown (19.0% vs. 22.1%; p = 0.052). Despite the majority of participating network centers treating patients with COVID-19, there were no relevant shortcomings reported regarding in-hospital stroke treatment or telemedical stroke care. CONCLUSIONS: Telemedical stroke care in Germany was able to provide full service despite the COVID-19 pandemic, but telemedical consultations declined abruptly during the lockdown period and normalized after relaxation of COVID-19 measures in Germany.

Reevaluation of risk factors for time to subsequent events after first stroke occurrence using a new weighted all-cause effect measure.

BACKGROUND: Risk diseases and risk factors for stroke include atrial fibrillation, hypertension, diabetes mellitus, smoking, and elevated LDL-cholesterol. Due to modern treatment options, the impact of these risk diseases on subsequent cardiovascular events or death after a first stroke is less clear and needs to be elucidated. We therefore aimed to get insights into the persistence of adverse prognostic effects of these risk diseases and risk factors on subsequent stroke or death events 1 year after the first stroke by using the new weighted all-cause hazard ratio. METHODS: This study evaluates the 1 year follow-up of 470 first ever stroke cases identified in the area of Ludwigshafen, Germany, with 23 deaths and 34 subsequent stroke events. For this purpose, the recently introduced "weighted all-cause hazard ratio" was used, which allows a weighting of the competing endpoints within a composite endpoint. Moreover, we extended this approach to allow an adjustment for covariates. RESULTS: None of these risk factors and risk diseases, most probably being treated after the first stroke, remained to be associated with a subsequent death or stroke [weighted hazard ratios (95% confidence interval) for diabetes mellitus, atrial fibrillation, high cholesterol, hypertension, and smoking are 0.4 (0.2-0.9), 0.8 (0.4-2.2), 1.3 (0.5-2.5), 1.2 (0.3-2.7), 1.6 (0.8-3.6), respectively]. However, when analyzed separately in terms of death and stroke, the risk factors and risk diseases under investigation affect the subsequent event rate to a variable degree. CONCLUSIONS: Using the new weighted hazard ratio, established risk factors and risk diseases for the occurrence of a first stroke do not remain to be significant predictors for subsequent events like death or recurrent stroke. It has been demonstrated that the new weighted hazard ratio can be used for a more adequate analysis of cardiovascular risk and disease progress. The results have to be confirmed within a larger study with more events.

Association of a Multigenetic Pro-Inflammatory Profile with Ischaemic Stroke.

OBJECTIVE: A multigenetic pro-inflammatory profile may increase stroke risk. We investigated whether a higher number of pro-inflammatory genetic variants are associated with ischaemic stroke risk and whether other risk factors further elevate this risk. METHODS: In a case-control study with 470 ischaemic stroke patients (cases) and 807 population controls, we investigated 23 haplotypes or alleles in 16 inflammatory genes (interleukin [IL]1A, IL1B, IL1 receptor antagonist, IL6, IL6 receptor, IL10, tumour necrosis factor-a; C-C motif chemokine ligand 2, C-C motif chemokine receptor 5, C-reactive protein (CRP), intercellular adhesion molecule 1, transforming growth factor ß1, E-Selectin, selenoprotein S, cluster determinant 14, histone deacetylase 9 [HDAC9]). We constructed an extended gene score (EGS) as the sum of all individual risk alleles and analysed its effect on stroke, just as its association and interaction with cardiovascular risk factors and infectious scores (IgG antibodies against 5 respectively IgA antibodies against 4 microbial antigens). RESULTS: Cases were less likely to carry the minor allele of IL10 rs1800872 and more likely to carry the HDAC9 allele rs11984041 and the pro-inflammatory haplotype of CRP, although the latter was not statistically significant in our study. Overall, cases tended to have more pro-inflammatory alleles and haplotypes than controls (mean ± SD 13.25 ± 2.25 and 13.04 ± 2.41, respectively). However, the EGS only slightly and not significantly increased the risk of stroke (OR 1.04, 95% CI 0.99-1.09). Its effect was neither associated with included risk factors nor with IgA and IgG infectious scores, and we found no significant interaction effects. CONCLUSION: A more pro-inflammatory genetic profile might increase stroke risk to some extent. This potential effect is most likely independent of established cardiovascular risk factors and the infectious burden of an individual.

Serum lipopolysaccharide neutralizing capacity in ischemic stroke.

INTRODUCTION: Periodontitis is associated with increased serum lipopolysaccharide (LPS) activity, which may be one mechanism linking periodontitis with the risk of cardiovascular diseases. As LPS-carrying proteins including lipoproteins modify LPS-activity, we investigated the determinants of serum LPS-neutralizing capacity (LPS-NC) in ischemic stroke. The association of LPS-NC and Aggregatibacter actinomycetemcomitans, a major microbial biomarker in periodontitis, was also investigated. MATERIALS AND METHODS: The assay to measure LPS-NC was set up by spiking serum samples with E. coli LPS. The LPS-NC, LPS-binding protein (LBP), soluble CD14 (sCD14), lipoprotein profiles, apo(lipoprotein) A-I, apoB, and phospholipid transfer protein (PLTP) activity, were determined in 98 ischemic stroke patients and 100 age- and sex-matched controls. Serum and saliva immune response to A. actinomycetemcomitans, its concentration in saliva, and serotype-distribution were examined. RESULTS: LPS-NC values ranged between 51-83% in the whole population. Although several of the LPS-NC determinants differed significantly between cases and controls (PLTP, sCD14, apoA-I, HDL-cholesterol), the levels did not (p = 0.056). The main determinants of LPS-NC were i) triglycerides (ß = -0.68, p<0.001), and ii) HDL cholesterol (0.260, <0.001), LDL cholesterol (-0.265, <0.001), PLTP (-0.196, 0.011), and IgG against A. actinomycetemcomitans (0.174, 0.011). Saliva A. actinomycetemcomitans concentration was higher [log mean (95% CI), 4.39 (2.35-8.19) vs. 10.7 (5.45-21) genomes/ml, p = 0.023) and serotype D more frequent (4 vs. 0%, p = 0.043) in cases than controls. Serotypeablity or serotypes did not, however, relate to the LPS-NC. CONCLUSION: Serum LPS-NC comprised low PLTP-activity, triglyceride and LDL cholesterol concentrations, as well as high HDL cholesterol and IgG against A. actinomycetemcomitans. The present findings let us to conclude that LPS-NC did not associate with stroke.

Pregnancy outcomes in anti-NMDA receptor encephalitis: Case series.

OBJECTIVE: To report the effects of anti-NMDA receptor (NMDAR) encephalitis in pregnant patients and their babies. METHODS: We studied a retrospective cohort of patients who developed anti-NMDAR encephalitis during pregnancy or became pregnant while recovering from the encephalitis. In addition, we reviewed the English literature between 2010 and 2019 related to this topic. RESULTS: We studied 11 patients; 6 developed anti-NMDAR encephalitis during pregnancy, and 5 became pregnant while recovering. There were no obstetrical complications, but 6 (55%) babies were premature. Ten newborns were healthy, and 1 (9%) developed transient respiratory distress. Nine infants had assessable follow-up (median 18 months; range, 7-96 months), and all showed normal development. We identified 21 cases in the English literature. Obstetrical complications occurred in 7 (33%) pregnancies. Two patients died of septic shock (1 baby successfully delivered), another 2 had miscarriages, and in 2, the pregnancy was terminated. Sixteen babies (76%) were delivered, 9 (56%) premature. At birth, 13/16 (81%) newborns were healthy, 2/16 (13%) had transient neurologic or respiratory symptoms, and 1 (6%) died of brain edema. Follow-up (median 12 months; range, 6-36 months) was reported for 8 children: 7 (88%) showed normal development and behavior, and 1 (13%) cortical dysplasia. Immunotherapy was used during pregnancy in 7 (64%) of our patients and 18 (86%) of the reported cases, including rituximab in 4 cases, without adverse effects. CONCLUSIONS: Patients who develop anti-NMDAR encephalitis during pregnancy or become pregnant during recovery often have obstetrical complications, but most of the newborns are healthy and appear to have normal development.

A support programme for secondary prevention in patients with transient ischaemic attack and minor stroke (INSPiRE-TMS): an open-label, randomised controlled trial.

BACKGROUND: Patients with recent stroke or transient ischaemic attack are at high risk for a further vascular event, possibly leading to permanent disability or death. Although evidence-based treatments for secondary prevention are available, many patients do not achieve recommended behavioural modifications and pharmaceutical prevention targets in the long-term. We aimed to investigate whether a support programme for enhanced secondary prevention can reduce the frequency of recurrent vascular events. METHODS: INSPiRE-TMS was an open-label, multicentre, international randomised controlled trial done at seven German hospitals with acute stroke units and a Danish stroke centre. Patients with non-disabling stroke or transient ischaemic attack within 2 weeks from study enrolment and at least one modifiable risk factor (ie, arterial hypertension, diabetes, atrial fibrillation, or smoking) were included. Computerised randomisation was used to allocate patients (1:1) either to the support programme in addition to conventional care or to conventional care alone. The support programme used feedback and motivational interviewing strategies with eight outpatient visits over 2 years aiming to improve adherence to secondary prevention targets. The primary outcome was the composite of major vascular events consisting of stroke, acute coronary syndrome, and vascular death, assessed in the intention-to-treat population (all patients who underwent randomisation, did not withdraw study participation, and had at least one follow-up). Outcomes were assessed at annual follow-ups using time-to-first-event analysis. All-cause death was monitored as a safety outcome. This trial is registered with ClinicalTrials.gov, NCT01586702. FINDINGS: From Aug 22, 2011, to Oct 30, 2017, we enrolled 2098 patients. Of those, 1048 (50·0%) were randomly assigned to the support programme group and 1050 (50·0%) patients were assigned to the conventional care group. 1030 (98·3%) patients in the support group and 1042 (99·2%) patients in the conventional care group were included in the intention-to-treat analysis. The mean age of analysed participants was 67·4 years and 700 (34%) were women. After a mean follow-up of 3·6 years, the primary outcome of major vascular events had occurred in 163 (15·8%) of 1030 patients of the support programme group and in 175 (16·8%) of 1042 patients of the conventional care group (hazard ratio [HR] 0·92, 95% CI 0·75-1·14). Total major vascular event numbers were 209 for the support programme group and 225 for the conventional care group (incidence rate ratio 0·93, 95% CI 0·77-1·12; p=0·46) and all-cause death occurred in 73 (7·1%) patients in the support programme group and 85 (8·2%) patients in the conventional care group (HR 0·85, 0·62-1·17). More patients in the support programme group achieved secondary prevention targets (eg, in 1-year-follow-up 52% vs 42% [p<0·0001] for blood pressure, 62% vs 54% [p=0·0010] for LDL, 33% vs 19% [p<0·0001] for physical activity, and 51% vs 34% [p=0·0010] for smoking cessation). INTERPRETATION: Provision of an intensified secondary prevention programme in patients with non-disabling stroke or transient ischaemic attack was associated with improved achievement of secondary prevention targets but did not lead to a significantly lower rate of major vascular events. Further research is needed to investigate the effects of support programmes in selected patients who do not achieve secondary prevention targets soon after discharge. FUNDING: German Federal Ministry of Education and Research, Pfizer, and German Stroke Foundation.

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.

Low self-reported sports activity before stroke predicts poor one-year-functional outcome after first-ever ischemic stroke in a population-based stroke register.

BACKGROUND: Physical activity (PA) is associated with lower risk of stroke. We tested the hypothesis that lack of pre-stroke PA is an independent predictor of poor outcome after first-ever ischemic stroke. METHODS: We assessed recent self-reported PA and other potential predictors for loss of functional independence - modified Rankin Scale (mRS) > 2 - one year after first-ever ischemic stroke in 1370 patients registered between 2006 and 2010 in the Ludwigshafen Stroke Study, a population-based stroke registry. RESULTS: After 1 year, 717 (52.3%) of patients lost their independence including 251 patients (18.3%) who had died. In multivariate logistic regression analysis lack of regular PA prior to stroke (Odds Ratio (OR) 1.7, Confidence Interval (CI) 1.1-2.5), independently predicted poor outcome together with higher age (65-74: OR 1.7; CI 1.1-2.8, 75-84 years: OR 3.3; CI 2.1-5.3; ≥85 years OR 14.5; CI 7.4-28.5), female sex (OR 1.5; CI 1.1-2.1), diabetes mellitus (OR 1.8; CI 1.3-2.5), stroke severity (OR 1.2; CI 1.1-1.2), probable atherothrombotic stroke etiology (OR 1.8; CI 1.1-2.8) and high leukocyte count (> 9.000/mm3; OR 1.4; CI 1.0-1.9) at admission. Subclassifying unknown stroke etiology, embolic stroke of unknown source (ESUS; n = 40, OR 2.2; CI 0.9-5.5) tended to be associated with loss of independence. CONCLUSION: In addition to previously reported factors, lack of PA prior to stroke as potential indicator of worse physical condition, high leukocyte count at admission as indicator of the inflammatory response and probable atherothrombotic stroke etiology might be independent predictors for non-functional independence in first-ever ischemic stroke.

Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and mechanical heart valves.

Aims: Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH. Methods and results: We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03). Conclusion: Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.

Serum matrix metalloproteinase-8, tissue inhibitor of metalloproteinase and myeloperoxidase in ischemic stroke.

BACKGROUND AND AIMS: Matrix metalloproteinase (MMP)-8 and myeloperoxidase (MPO) may contribute to cerebral damage in acute ischemic stroke. We tested the hypothesis that levels of MPO, MMP-8 and the ratio between MMP-8 and its regulator, tissue inhibitor of metalloproteinase (TIMP-1), are increased in acute ischemic stroke and its etiologic subgroups and they correlate with stroke severity. METHODS: In a cross-sectional case-control study, serum concentrations of MMP-8, MPO and TIMP-1 were assessed within 24 h after admission in 470 first-ever ischemic stroke patients and 809 age- and sex-matched controls, randomly selected from the population. Odds ratios (OR) per decade of log transformed dependent variables were calculated and adjusted for age, sex and vascular risk factors. RESULTS: Levels of MMP-8 (OR 4.9; 95% CI 3.4-7.2), MMP-8/TIMP-1 ratio (3.0; 2.2-4.1) and MPO (6.6; 4.0-11.0) were independently associated with ischemic stroke. MMP-8 levels differed between etiologic stroke subgroups (p = 0.019, ANOVA), with higher levels in cardioembolic stroke and stroke due to large vessel disease, and lower levels in microangiopathic stroke. MMP-8, MMP-8/TIMP-1 ratio and MPO (p < 0.001) concentrations showed positive associations with stroke severity independent of stroke etiology. CONCLUSIONS: Concentrations of serum neutrophil markers are increased after ischemic stroke and associate with stroke severity and etiology. The value of these biomarkers in diagnostics and prognostics is worth being evaluated.

Haemorrhagic Transformation after Ischaemic Stroke in Patients Taking Non-vitamin K Antagonist Oral Anticoagulants.

BACKGROUND AND PURPOSE: To evaluate the frequency and outcome of haemorrhagic transformation (HT) after ischaemic stroke in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). METHODS: Patients with stroke on treatment with a NOAC were prospectively enrolled in this multicentre observational study between February 2012 and 2015. Brain imaging at admission and follow-up imaging until day 7 were reviewed for HT. Functional outcome was assessed by the modified Rankin scale (mRS) before the index event, at discharge, and at 3-months. RESULTS: 231 patients without recanalisation therapy (no-RT), and 32 patients with RT were eligible for analysis. Any HT was present at admission in 9/231 no-RT patients (3.9%, 95% CI 2.0 to 7.3) and in none of the patients with RT. In patients with follow-up imaging (no-RT, n=129, and RT, n=32), HT was present in 14.0% (no-RT; 95% CI, 8.9 to 21.1), and 40.6% (RT, 95% CI, 25.5 to 57.8), respectively. After adjustment for stroke severity, this difference between the no-RT and RT groups became non-significant. Symptomatic ICH was observed in 1 patient per group. HT was not associated with unfavourable outcome (mRS 3-6) at 3-months in multivariable analysis. Resumption of OAC after stroke was delayed in patients with HT compared to those without (15 d [IQR, 5-26] vs. 1 d [0-4], P<0.001). CONCLUSIONS: The frequency and severity of HT after stroke on NOAC appears similar to previous reports for vitamin K antagonists and no anticoagulation. Whether asymptomatic HT should delay resumption of preventive anticoagulation requires further investigation.

Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design.

BACKGROUND: Worldwide, about 1.3 million annual ischaemic strokes (IS) occur in adults aged <50 years. Of these early-onset strokes, up to 50% can be regarded as cryptogenic or associated with conditions with poorly documented causality like patent foramen ovale and coagulopathies. KEY HYPOTHESES/AIMS: (1) Investigate transient triggers and clinical/sub-clinical chronic risk factors associated with cryptogenic IS in the young; (2) use cardiac imaging methods exceeding state-of-the-art to reveal novel sources for embolism; (3) search for covert thrombosis and haemostasis abnormalities; (4) discover new disease pathways using next-generation sequencing and RNA gene expression studies; (5) determine patient prognosis by use of phenotypic and genetic data; and (6) adapt systems medicine approach to investigate complex risk-factor interactions. DESIGN: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725) is a prospective multi-centre case-control study enrolling patients aged 18-49 years hospitalised due to first-ever imaging-proven IS of undetermined etiology. Patients are examined according to a standardised protocol and followed up for 10 years. Patients are 1:1 age- and sex-matched to stroke-free controls. Key study elements include centralised reading of echocardiography, electrocardiography, and neurovascular imaging, as well as blood samples for genetic, gene-expression, thrombosis and haemostasis and biomarker analysis. We aim to have 600 patient-control pairs enrolled by the end of 2018. SUMMARY: SECRETO is aiming to establish novel mechanisms and prognosis of cryptogenic IS in the young and will provide new directions for therapy development for these patients. First results are anticipated in 2019.

Coagulation Testing in Acute Ischemic Stroke Patients Taking Non-Vitamin K Antagonist Oral Anticoagulants.

BACKGROUND AND PURPOSE: In patients who present with acute ischemic stroke while on treatment with non-vitamin K antagonist oral anticoagulants (NOACs), coagulation testing is necessary to confirm the eligibility for thrombolytic therapy. We evaluated the current use of coagulation testing in routine clinical practice in patients who were on NOAC treatment at the time of acute ischemic stroke. METHODS: Prospective multicenter observational RASUNOA registry (Registry of Acute Stroke Under New Oral Anticoagulants; February 2012-2015). Results of locally performed nonspecific (international normalized ratio, activated partial thromboplastin time, and thrombin time) and specific (antifactor Xa tests, hemoclot assay) coagulation tests were documented. The implications of test results for thrombolysis decision-making were explored. RESULTS: In the 290 patients enrolled, nonspecific coagulation tests were performed in ≥95% and specific coagulation tests in 26.9% of patients. Normal values of activated partial thromboplastin time and international normalized ratio did not reliably rule out peak drug levels at the time of the diagnostic tests (false-negative rates 11%-44% [95% confidence interval 1%-69%]). Twelve percent of patients apparently failed to take the prescribed NOAC prior to the acute event. Only 5.7% (9/159) of patients in the 4.5-hour time window received thrombolysis, and NOAC treatment was documented as main reason for not administering thrombolysis in 52.7% (79/150) of patients. CONCLUSIONS: NOAC treatment currently poses a significant barrier to thrombolysis in ischemic stroke. Because nonspecific coagulation test results within normal range have a high false-negative rate for detection of relevant drug concentrations, rapid drug-specific tests for thrombolysis decision-making should be established. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01850797.

Association between infectious burden, socioeconomic status, and ischemic stroke.

BACKGROUND AND AIMS: Infectious diseases contribute to stroke risk, and are associated with socioeconomic status (SES). We tested the hypotheses that the aggregate burden of infections increases the risk of ischemic stroke (IS) and partly explains the association between low SES and ischemic stroke. METHODS: In a case-control study with 470 ischemic stroke patients and 809 age- and sex-matched controls, randomly selected from the population, antibodies against the periodontal microbial agents Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, against Chlamydia pneumonia, Mycoplasma pneumoniae (IgA and IgG), and CagA-positive Helicobacter pylori (IgG) were assessed. RESULTS: IgA seropositivity to two microbial agents was significantly associated with IS after adjustment for SES (OR 1.45 95% CI 1.01-2.08), but not in the fully adjusted model (OR 1.32 95% CI 0.86-2.02). By trend, cumulative IgA seropositivity was associated with stroke due to large vessel disease (LVD) after full adjustment (OR 1.88, 95% CI 0.96-3.69). Disadvantageous childhood SES was associated with higher cumulative seropositivity in univariable analyses, however, its strong impact on stroke risk was not influenced by seroepidemiological data in the multivariable model. The strong association between adulthood SES and stroke was rendered nonsignificant when factors of dental care were adjusted for. CONCLUSIONS: Infectious burden assessed with five microbial agents did not independently contribute to ischemic stroke consistently, but may contribute to stroke due to LVD. High infectious burden may not explain the association between childhood SES and stroke risk. Lifestyle factors that include dental negligence may contribute to the association between disadvantageous adulthood SES and stroke.

[Consensus statement: Management of oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation]. / Konsensuspapier: Schlaganfallprophylaxe bei Patienten mit nichtvalvulärem Vorhofflimmern.

With the introduction of edoxaban last year in Germany, four nonvitamin K antagonist oral anticoagulants are now available for stroke prevention in patients with nonvalvular atrial fibrillation. These novel oral anticoagulants (NOAC) represent an attractive new option compared to vitamin K antagonists (e.g., warfarin or phenprocoumon) due to simple use and fewer interactions with other drugs or food. Therefore, no INR monitoring and dosage adjustments are required for NOAC. The compelling clinical advantage of NOAC is the dramatic risk reduction of hemorhagic stroke and intracranial bleeding compared to current standard. In addition, total mortality is significantly reduced by 10 %. These effects are demonstrated for all four NOAC (dabigatran, rivaroxaban, apixaban and edoxaban). Therefore, current national and international guidelines recommend NOAC as the preferred option or at least as an attractive alternative compared to the former standard of vitamin K antagonists. The economic impact and reimbursement by Statutory Health Insurance (GKV) is of major importance for treatment in an outpatient setting. For apixaban and edoxaban, an additional benefit was granted by the institution of G­BA and IQWiG in this clinical setting, whereas dabigatran and rivaroxaban were not assessed due to market entrance prior to 2011 before the AMNOG procedure was initiated. The members of this consensus paper recommend NOAC as the preferred option for patients with nonvalvular atrial fibrillation who are currently not treated with anticoagulant drugs in spite of clear indication for anticoagulation. For new patients with nonvalvular fibrillation, it should be decided on an individual basis which treatment option is adequate for the patient with their respective comorbidities.

Socioeconomic Conditions in Childhood, Adolescence, and Adulthood and the Risk of Ischemic Stroke.

BACKGROUND AND PURPOSE: The association between socioeconomic status in adulthood and the risk of stroke is well established; however, the independent effects of socioeconomic conditions in different life phases are less understood. METHODS: Within a population-based stroke registry, we performed a case-control study with 470 ischemic stroke patients (cases) aged 18 to 80 years and 809 age- and sex-matched stroke-free controls, randomly selected from the population (study period October 2007 to April 2012). We assessed socioeconomic conditions in childhood, adolescence, and adulthood, and developed a socioeconomic risk score for each life period. RESULTS: Socioeconomic conditions were less favorable in cases regarding paternal profession, living conditions and estimated family income in childhood, school degree, and vocational training in adolescence, last profession, marital status and periods of unemployment in adulthood. Using tertiles of score values, low socioeconomic conditions during childhood (odds ratio 1.77; 95% confidence interval 1.20-2.60) and adulthood (odds ratio 1.74; 95% confidence interval 1.16-2.60) but not significantly during adolescence (odds ratio 1.64; 95% confidence interval 0.97-2.78) were associated with stroke risk after adjustment for risk factors and other life stages. Medical risk factors attenuated the effect of childhood conditions, and lifestyle factors reduced the effect of socioeconomic conditions in adolescence and adulthood. Unfavorable childhood socioeconomic conditions were particularly associated with large artery atherosclerotic stroke in adulthood (odds ratio 2.13; 95% confidence interval 1.24-3.67). CONCLUSIONS: This study supports the hypothesis that unfavorable childhood socioeconomic conditions are related to ischemic stroke risk, independent of established risk factors and socioeconomic status in adulthood, and fosters the idea that stroke prevention needs to begin early in life.