Reduced dose direct oral anticoagulants compared with warfarin with high time in therapeutic range in nonvalvular atrial fibrillation.

Direct oral anticoagulants (DOACs) used in nonvalvular atrial fibrillation (NVAF) are dose-reduced in elderly and patients with impaired renal function. Only reduced dose dabigatran is concluded as having similar stroke risk reduction and lower risk of major bleeding than warfarin in the pivotal studies. In clinical practice, reduced dose is prescribed more often than expected making this an important issue. The objective of this study was to compare effectiveness and safety between reduced dose DOACs and high TTR warfarin treatment (TTR ≥ 70%) in NVAF. A Swedish anticoagulation registry was used in identifying eligible patients from July 2011 to December 2017. The study cohort consisted of 40,564 patients with newly initiated DOAC (apixaban, dabigatran, or rivaroxaban) (11,083 patients) or warfarin treatment (29,481 patients) after exclusion of 374,135 patients due to not being warfarin or DOAC naïve, not being prescribed reduced dose, having previous mechanical heart valve (MHV), or being under 18 years old. The median durations of follow up were 365, 419, 432 and 473 days for apixaban, dabigatran, rivaroxaban and warfarin, respectively. Warfarin TTR identified from Auricula was 70.0%. Endpoints (stroke and major bleeding) and baseline characteristics were collected from hospital administrative registers using ICD-10 codes. Cohorts were compared using weighted adjusted Cox regression after full optimal matching based on propensity scores. DOACs are associated with lower risk of major bleeding (HR with 95% CI) 0.85 (0.78-0.93), intracranial bleeding HR 0.64 (0.51-0.80), hemorrhagic stroke HR 0.68 (0.50-0.92), gastrointestinal bleeding HR 0.81 (0.69-0.96) and all-cause stroke HR 0.87 (0.76-0.99), than warfarin. Apixaban and dabigatran are associated with lower risk of major bleeding, HR 0.70 (0.63-0.78) and HR 0.80 (0.69-0.94), and rivaroxaban is associated with lower risk of ischemic stroke, HR 0.73 (0.59-0.96), with higher major bleeding risk, HR 1.31 (1.15-1.48), compared to warfarin. Apixaban is associated with higher all-cause mortality compared to warfarin, HR 1.12 (1.03-1.21). DOACs are associated with lower risk of major bleeding and all-cause stroke, than high quality warfarin treatment, with exception of rivaroxaban that carried higher risk of major bleeding and lower risk of stroke or systemic embolism. In this large observational registry-based NVAF cohort, DOACs are preferred treatment in patients with indication for DOAC dose reduction, even in a high TTR setting.

Value of treatment by comprehensive stroke services for the reduction of critical gaps in acute stroke care in Europe.

Stroke is the second leading cause of death and dependency in Europe and costs the European Union more than €30bn, yet significant gaps in the patient pathway remain and the cost-effectiveness of comprehensive stroke care to meet these needs is unknown. The European Brain Council Value of Treatment Initiative combined patient representatives, stroke experts, neurological societies and literature review to identify unmet needs in the patient pathway according to Rotterdam methodology. The cost-effectiveness of comprehensive stroke services was determined by a Markov model, using UK cost data as an exemplar and efficacy data for prevention of death and dependency from published systematic reviews and trials, expressing effectiveness as quality-adjusted life-years (QALYs). Model outcomes included total costs, total QALYs, incremental costs, incremental QALYs and the incremental cost-effectiveness ratio (ICER). Key unmet needs in the stroke patient pathway included inadequate treatment of atrial fibrillation (AF), access to neurorehabilitation and implementation of comprehensive stroke services. In the Markov model, full implementation of comprehensive stroke services was associated with a 9.8% absolute reduction in risk of death of dependency, at an intervention cost of £9566 versus £6640 for standard care, and long-term care costs of £35 169 per 5.1251 QALYS vs. £32 347.40 per 4.5853 QALYs, resulting in an ICER of £5227.89. Results were robust in one-way and probabilistic sensitivity analyses. Implementation of comprehensive stroke services is a cost-effective approach to meet unmet needs in the stroke patient pathway, to improve acute stroke care and support better treatment of AF and access to neurorehabilitation.

Is carotid imaging underused in patients with transient ischemic attack or ischemic stroke? A Swedish Stroke Register (Riksstroke) study.

BACKGROUND AND AIM: Carotid artery stenosis is one of the major causes of transient ischemic attack (TIA) and acute ischemic stroke (IS), and carotid surgery and stenting are used to reduce the risk of ipsilateral IS. However, the adherence to the recommendation of carotid imaging in clinical practice has not been well studied. We analyzed proportions of carotid imaging and determinants for its non-use in patients with TIA and IS with respect to baseline demographics, risk factors, hospital characteristics, and geographical region. PATIENTS AND METHODS: Hospital-based data on TIA and IS events, registered from July 2011 to June 2013, were obtained from the Swedish Stroke Register (Riksstroke). Carotid imaging diagnostics included carotid Doppler ultrasound and computed tomography angiography. RESULTS: Carotid imaging was performed in 70% (10 545/15 021) of patients with TIA and 54% (23 772/44 075) of patients with IS. The most significant independent determinants for not undergoing carotid imaging were, in patients with TIA: age ≥85 year (odds ratio (OR), 7.3; 95% confidence interval (CI), 6.4-8.4) and a history of stroke (OR, 2.3; 95% CI, 2.1-2.5); and in patients with IS: age ≥85 year (OR, 9.8; 95% CI, 9.0-10.6), age 75-84 year (OR, 2.5; 95% CI, 2.3-2.7), and reduced level of consciousness at admission (OR, 3.4; 95% CI, 3.1-3.6). Care at a University hospital and in a stroke unit increased the likelihood of carotid imaging. There were substantial regional variations regarding proportions of carotid imaging. CONCLUSION: Carotid imaging appears to be underused in patients with TIA and IS. Opportunities of secondary stroke prevention with carotid interventions are likely missed.

Secondary prevention and lifestyle indices after stroke in a long-term perspective.

OBJECTIVES: To describe the long-term perspective regarding prevalence of risk factors, secondary stroke prevention, and lifestyle indices after stroke. METHODS: From a population-based one-year cohort (n = 416), we performed an observational study of 145 survivors at 16 months and 10 years after stroke (age 27-97 years) regarding secondary prevention including reaching acceptable treatment goals; nutritional status with focus on underweight; and the lifestyle indices: living situation, level of dependence, and self-assessed health condition. RESULTS: Ten years after stroke, 50% of the subjects with hypertension diagnosis and 55% of those without hypertension diagnosis were within the blood pressure goal <140/90 compared with 32% (P = .008) and 37% (N.S.) at 16 months. Acceptable HbA1c levels among subjects with diabetes mellitus diagnosis increased from 35% to 45% (N.S.). Among those without diabetes diagnosis, satisfactory HbA1c levels decreased from 98% to 79% (P < .001). Underweight increased from 9% to 17% (P = .019). Among patients with cerebral infarction, the prevalence of atrial fibrillation increased from 22% to 29% (P = .004), and treatment with oral anticoagulants from 75% to 78% (N.S.). Acceptable LDL cholesterol levels increased from 59% to 80% (P = .033) among subjects on lipid lowering treatment, and from 18% to 40% among untreated (P = .010). At 10 years, 90% still lived in their own home. Health condition was reported as good/very good/excellent by 65%. Age, female sex, and living situation were associated with intensity of secondary prevention measures and underweight. CONCLUSIONS: The proportion of individuals within treatment goals improved over time, but secondary prevention still needed additional consideration 10 years after stroke.

Management of acute ischaemic stroke in patients with dementia.

An estimated 10% of stroke patients have an underlying dementia. As a consequence, health professionals often face the challenge of managing patients with dementia presenting with an acute stroke. Patients with dementia are less likely to receive thrombolysis (0.56-10% vs. 1-16% thrombolysis rates in the general population), be admitted to a stroke unit or receive some types of care. Anticoagulation for secondary stroke prevention is sometimes withheld, despite dementia not being listed as an exclusion criterion in current guidelines. Studies in this population are scarce, and results have been contradictory. Three observational studies have examined intravenous thrombolysis for treatment of acute ischaemic stroke in patients with dementia. In the two largest matched case-control studies, there were no significant differences between patients with and without dementia in the risks of intracerebral haemorrhage or mortality. The risk of intracerebral haemorrhage ranged between 14% and 19% for patients with dementia. Studies of other interventions for stroke are lacking for this population. Patients with dementia are less likely to be discharged home compared with controls (19% vs. 41%) and more likely to be disabled (64% vs. 59%) or die during hospitalization (22% vs. 11%). The aim of this review was to summarize current knowledge about the management of ischaemic stroke in patients with pre-existing dementia, including organizational aspects of stroke care, intravenous thrombolysis, access to stroke unit care and use of supportive treatment. Evidence to support anticoagulation for secondary prevention of stroke in patients with atrial fibrillation and antiplatelet therapy in nonembolic stroke will be discussed, as well as rehabilitation and how these factors influence patient outcomes. Finally, ethical issues, knowledge gaps and pathways for future research will be considered.

Transient ischemic attack and ischemic stroke patients with or without prior stroke.

OBJECTIVES: A history of stroke is common in patients with transient ischemic attack (TIA) and ischemic stroke (IS), but there are few reports characterizing this group of patients. We aimed to compare characteristics, risk factors, and secondary preventive treatment in patients with TIA or IS with vs without a history of stroke. METHODS: Hospital-based data on TIA and IS events, registered from July 2011 to June 2013, were obtained from the Swedish Stroke Register (Riksstroke). Previous stroke was not specified as hemorrhagic or ischemic. RESULTS: A history of stroke was present in 19.3% (2892/15012) of TIA and 24.6% (10853/44169) of IS patients. Patients with prior stroke were older, more often male, and more likely to have atrial fibrillation (AF) (TIA: 27.4% vs 16.4%; IS: 36.1% vs 28.0%), hypertension (TIA: 77.5% vs 56.4%; IS: 74.2% vs 59.0%), and diabetes mellitus (TIA: 22.2% vs 14.2%; IS: 26.3% vs 19.5%) compared with those without (all differences P<.0001). At discharge, patients with prior stroke were more often treated with antihypertensive drugs than those without, whereas proportions treated with statins were similar in both groups. Patients with AF and prior stroke were less often treated with oral anticoagulant (OAC) medication than those without prior stroke. CONCLUSIONS: Both in TIA and IS, vascular risk factors were more common in patients with a history of stroke compared with those without. In contrast to other secondary preventive medications, OAC treatment in the presence of AF was underutilized in patients with a history of stroke.

Socioeconomic factors' effect on return to work after first stroke.

OBJECTIVE: The objective of this nationwide study was to analyze how functional status and socioeconomic status affect return to work (RTW) among younger patients with first-time stroke in a Sweden. MATERIAL AND METHODS: This register-based cohort study included employed patients aged 25-55 with first-time stroke between 2008 and 2011 and primary outcome was RTW within 1 year after stroke. Data regarding functional status and employment status were retrieved from the Swedish Stroke Register, Riksstroke, and socioeconomic data (income, education, and country of birth) from Statistics Sweden. RESULTS: We included 2539 patients who had answered the question on RTW, and 1880 (74.0%) had RTW within 12 months. Patients with low income (69.9% in lowest income group vs 79.9% in highest group, P<.001), patients born in countries outside the Nordic countries (Sweden 75.5%, Nordic countries 74.3%, European countries 61.7%, other countries 57.3%, P<.001), and the youngest patients (25-34, 63.1%; 35-44, 75.9%; 45-55, 74.3%; P=.008) were less likely to RTW. Pain, low mood, and answering the questionnaire with help were more common in low socioeconomic groups, and when adjusting for these variables, together with age and sex, income and country of birth were no longer independent predictors for RTW. CONCLUSION: Patients with low socioeconomic status less often RTW 1 year after stroke.Impaired functional status after stroke is more common in patients with lower socioeconomic status and mediates socioeconomic differences in RTW. Improvement of functional status should be targeted to facilitate RTW among stroke patients with low socioeconomic status.

Impact of the Swedish National Stroke Campaign on stroke awareness.

BACKGROUND: Time delay from stroke onset to arrival in hospital is an important obstacle to widespread reperfusion therapy. To increase knowledge about stroke, and potentially decrease this delay, a 27-month national public information campaign was carried out in Sweden. AIMS: To assess the effects of a national stroke campaign in Sweden. METHODS: The variables used to measure campaign effects were knowledge of the AKUT test [a Swedish equivalent of the FAST (Face-Arm-Speech-Time)] test and intent to call 112 (emergency telephone number) . Telephone interviews were carried out with 1500 randomly selected people in Sweden at eight points in time: before, three times during, immediately after, and nine, 13 and 21 months after the campaign. RESULTS: Before the campaign, 4% could recall the meaning of some or all keywords in the AKUT test, compared with 23% during and directly after the campaign, and 14% 21 months later. Corresponding figures were 15%, 51%, and 50% for those remembering the term AKUT and 65%, 76%, and 73% for intent to call 112 when observing or experiencing stroke symptoms. During the course of the campaign, improvement of stroke knowledge was similar among men and women, but the absolute level of knowledge for both items was higher for women at all time points. CONCLUSION: The nationwide campaign substantially increased knowledge about the AKUT test and intention to call 112 when experiencing or observing stroke symptoms, but knowledge declined post-intervention. Repeated public information therefore appears essential to sustain knowledge gains.

Cognitive function in stroke survivors: A 10-year follow-up study.

OBJECTIVES: Post-stroke cognitive impairment (PSCI) has considerable impact on patients and society. However, long-term studies on PSCI are scarce and may be influenced by assessment methods and selection bias. We aimed to (i) assess the prevalence of long-term PSCI; (ii) compare two common cognitive assessment instruments; and (iii) compare cognitive function of long-term stroke survivors with non-stroke persons. METHODS: Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were administered to 10-year survivors from a population-based cohort of first-ever stroke patients included in the Lund Stroke Register, Sweden, in 2001-2002. PSCI was defined as MMSE<27 and/or MoCA<25 and severe cognitive impairment as MMSE<23. Age- and sex-matched non-stroke control subjects who had performed MMSE (but not MoCA) were recruited from the longitudinal population study "Good Ageing in Skåne." The odds of having cognitive impairment for stroke survivors compared to controls were examined with logistic regression analyses adjusting for education. RESULTS: Of 145 stroke survivors after 10 years, 127 participated. MMSE showed PSCI in 46%, whereas MoCA displayed PSCI in 61%. Among the stroke survivors with MoCA<25, 35% had MMSE≥27 (P<.001). The odds of having severe cognitive impairment defined as MMSE<23 were higher among the stroke survivors compared to 354 controls (education-adjusted; OR=2.5; P=.004). CONCLUSIONS: Post-stroke cognitive impairment was prevalent among 10-year stroke survivors, and the odds of having severe cognitive impairment were higher among the stroke survivors compared to non-stroke persons. The burden of long-term PSCI might have been underestimated previously, and MoCA may be more suitable than MMSE to detect long-term PSCI.

Exome array analysis of ischaemic stroke: results from a southern Swedish study.

BACKGROUND AND PURPOSE: Genome-wide association (GWA) studies have identified a few risk loci for ischaemic stroke, but these variants explain only a small part of the genetic contribution to the disease. Coding variants associated with amino acid substitutions or premature termination of protein synthesis could have a large effect on disease risk. We performed an exome array analysis for ischaemic stroke. METHODS: Patients with ischaemic stroke (n = 2385) and control subjects (n = 6077) from three Swedish studies were genotyped with the Illumina HumanOmniExpressExome BeadChip. Single-variant association analysis and gene-based tests were performed of exome variants with minor allele frequency of < 5%. A separate GWA analysis was also performed, based on 700 000 genotyped common markers and subsequent imputation. RESULTS: No exome variant or gene was significantly associated with all ischaemic stroke after Bonferroni correction (all P > 1.8 × 10-6 for single-variant and >4.15 × 10-6 for gene-based analysis). The strongest association in single-variant analysis was found for a missense variant in the DNAH11 gene (rs143362381; P = 5.01 × 10-6 ). In gene-based tests, the strongest association was for the ZBTB20 gene (P = 7.9 × 10-5 ). The GWA analysis showed that the sample was homogenous (median genomic inflation factor = 1.006). No genome-wide significant association with overall ischaemic stroke risk was found. However, previously reported associations for the PITX2 and ZFHX3 gene loci with cardioembolic stroke subtype were replicated (P = 7 × 10-15 and 6 × 10-3 ). CONCLUSIONS: This exome array analysis did not identify any single variants or genes reaching the pre-defined significance level for association with ischaemic stroke. Further studies on exome variants should be performed in even larger, well-defined and subtyped samples.

Frequency and predictors of acute ischaemic lesions on brain magnetic resonance imaging in young patients with a clinical diagnosis of transient ischaemic attack.

BACKGROUND AND PURPOSE: Acute lesions in patients with transient ischaemic attack (TIA) are important as they are associated with increased risk for recurrence. Characteristics associated with acute lesions in young TIA patients were therefore investigated. METHODS: The sifap1 study prospectively recruited a multinational European cohort (n = 5023) of patients aged 18-55 years with acute cerebrovascular event. The detection of acute ischaemic lesions was based on diffusion-weighted imaging (DWI). The frequency of DWI lesions was assessed in 829 TIA patients who met the criteria of symptom duration <24 h and their association with demographic, clinical and imaging variables was analysed. RESULTS: The median age was 46 years (interquartile range 40-51 years); 45% of the patients were female. In 121 patients (15%) ≥1 acute DWI lesion was detected. In 92 patients, DWI lesions were found in the anterior circulation, mostly located in cortical-subcortical areas (n = 63). Factors associated with DWI lesions in multiple regression analysis were left hemispheric presenting symptoms [odds ratio (OR) 1.92, 95% confidence interval (CI) 1.27-2.91], dysarthria (OR 2.17, 95% CI 1.38-3.43) and old brain infarctions on MRI (territories of the middle and posterior cerebral artery: OR 2.43, 95% CI 1.42-4.15; OR 2.41, 95% CI 1.02-5.69, respectively). CONCLUSIONS: In young patients with a clinical TIA 15% demonstrated acute DWI lesions on brain MRI, with an event pattern highly suggestive of an embolic origin. Except for the association with previous infarctions there was no clear clinical predictor for acute ischaemic lesions, which indicates the need to obtain MRI in young individuals with TIA.

Proximity of brain infarcts to regions of endogenous neurogenesis and involvement of striatum in ischaemic stroke.

BACKGROUND AND PURPOSE: Clinical stroke trials with stem cell-based approaches aiming for trophic actions, modulation of inflammation and neuroprotection are ongoing. However, experimental studies also suggest that neuronal replacement by grafted neural stem cells (NSCs) and possibly by endogenous NSCs from the subventricular zone (SVZ) may restore function in the stroke-damaged striatum. To evaluate the potential clinical impact of these findings, we analyzed the spatial relationship of infarcts to the SVZ and the proportion of individuals with striatal lesions in a consecutive series of ischaemic stroke patients. METHODS: Patients aged 20-75 years with first-ever ischaemic stroke underwent DW-MRI of the brain within 4 days after stroke onset. We analyzed location, size, number of acute focal ischaemic abnormalities and their spatial relationship to the SVZ. Stroke severity was assessed using NIH Stroke Scale (NIHSS). RESULTS: Of 108 included patients, the distance from the nearest margin of the infarct(s) to the SVZ was ≤2 mm in 51/102 patients with visible ischaemic lesions on DW-MRI. Twenty-four patients had involvement of striatum. Eight of these had predominantly striatal lesions, that is >50% of the total ischaemic lesion volume was located in caudate nucleus and/or putamen. These 8 patients had a median NIHSS of 3. CONCLUSIONS: Many stroke patients have infarcts located close to the SVZ, providing some supportive evidence that optimized endogenous neurogenesis may have therapeutic potential. However, predominantly striatal infarcts are rare and tend to give mild neurological deficits, indicating that striatum should not be the primary target for neuronal replacement efforts in humans.

Are 25 SNPs from the CARDIoGRAM study associated with ischaemic stroke?

BACKGROUND AND PURPOSE: The Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Study (CARDIoGRAM) reported 25 single-nucleotide polymorphisms (SNPs) on 15 chromosomes to be associated with coronary artery disease (CAD) risk. Because common vascular risk factors are shared between CAD and ischaemic stroke (IS), these SNPs may also be related to IS overall or one or more of its pathogenetic subtypes. METHODS: We performed a candidate gene study comprising 3986 patients with IS and 2459 control subjects. The 25 CAD-associated SNPs reported by CARDIoGRAM were examined by allelic association analysis including logistic regression. Weighted and unweighted genetic risk scores (GRSs) were also compiled and likewise analysed against IS. We furthermore considered the IS main subtypes large-vessel disease (LVD), small-vessel disease and cardioembolic stroke [according to Trial of Org 10172 in Acute Stroke Treatment (TOAST)] separately. RESULTS: SNP rs4977574 on chromosome 9p21.3 was associated with overall IS [odds ratio (OR) = 1.12; 95% confidence interval (CI): 1.04-1.20; P = 0.002] as well as LVD (OR = 1.36; 95% CI: 1.13-1.64; P = 0.001). No other SNP was significantly associated with IS or any of its main subtypes. Analogously, the GRSs did not show any noticeable effect. CONCLUSIONS: Besides the previously reported association with SNPs on chromosome 9p21, this study did not detect any significant association between IS and CAD-susceptible genetic variants. Also, GRSs compiled from these variants did not predict IS or any pathogenetic IS subtype, despite a total sample size of 6445 participants.

Time delay between symptom and surgery in patients with carotid artery stenosis.

OBJECTIVES: Many severe strokes are preceded by warning signs such as a transient ischemic attack or stroke with minor deficits. Carotid endarterectomy (CEA) of a symptomatic carotid artery stenosis can prevent future strokes, but should be performed within 2 weeks after the initial symptom to maximize the benefit. The aim of this study was to determine the time delays between symptom and CEA. METHODS: We performed a single center observational retrospective study at a tertiary stroke center. A total of 142 carotids in 139 patients with symptomatic stenoses between 2002 and 2006 were included. The main outcome measure was time between qualifying cerebrovascular symptom and CEA. RESULTS: The median time between symptom and CEA was 26 days. The longest delays were between the last diagnostic examination and carotid conference, and between carotid conference and surgery. The median time was shorter for those who received emergency medical care (median 21 days) and for those who were admitted immediately to hospital (median 20 days). CONCLUSIONS: The time between symptom and surgery is often longer than desirable. There are several measures to improve the chain of procedures for patients with carotid artery stenosis. These may include omitting the formal carotid conference for uncomplicated cases and minimizing waiting time for surgery.

Comparison of 90-day case-fatality after ischemic stroke between two different stroke outcome registries using propensity score matching analysis.

BACKGROUND: It has not been clarified whether the disparity in ischemic stroke outcome between populations is caused by ethnic and geographic differences or by variations in case mix. Propensity score matching (PSM) analysis can overcome some analytical problems but is rarely used in stroke outcome research. This study was to compare the ischemic stroke case-fatality between two PSM cohorts of Sweden and Korea. METHODS: Prognostic variables related to baseline characteristics and stroke care were included in our PSM model. Then, we selected 7675 Swedish and 1220 Korean patients with ischemic stroke from each stroke registers and performed one-to-one matching based on propensity scores of each patient. RESULTS: After PSM, all measured variables were well balanced in 1163 matched subjects, and the 90-day case-fatality was identical 6.2% (HR 0.997, 95%CI 0.905-1.099) in Sweden and Korea. CONCLUSIONS: No difference is found in the 90-day case-fatality in propensity score-matched Swedish and Korean patients with ischemic stroke.

European Stroke Organisation (ESO) standard operating procedure for the preparation and publishing of guidelines.

The first European Stroke Organization (ESO) standard operating procedure (SOP) published in 2015 aimed at the implementation the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to provide evidence-based guidelines for stroke management. This second ESO-SOP is aiming at further increase of the practicability of ESO guidelines and its technical implications. Authors comprised of the members of the ESO guideline Board and ESO Executive Committee. The final document was agreed on by several internal reviews. The second SOP comprises of the following aspects: rational for the SOP, the introduction of expert consensus statements, types of guideline documents, structures involved and detailed description of the guideline preparation process, handling of financial and intellectual conflicts of interest (CoI), involvement of ESO members in the guideline process, review process, authorship and publication policy, updating of guidelines, cooperation with other societies, and dealing with falsified data. This second SOP supersedes the first SOP published in 2015.

The molecular basis of thrombolysis and its clinical application in stroke.

The rationale for thrombolysis, the most promising pharmacological approach in acute ischaemic stroke, is centred on the principal cause of most ischaemic strokes: the thrombus that occludes the cerebral artery, and renders part of the brain ischaemic. The occluding thrombus is bound together within fibrin. Fibrinolysis acts by activation of plasminogen to plasmin; plasmin splits fibrinogen and fibrin and lyses the clot, which then allows reperfusion of the ischaemic brain. Thrombolytic agents include streptokinase (SK) and recombinant tissue-type plasminogen activator (rt-PA) amongst others under test or development. SK is nonfibrin-specific, has a longer half-life than tissue-type plasminogen activator (t-PA), prevents re-occlusion and is degraded enzymatically in the circulation. rt-PA is more fibrin-specific and clot-dissolving, and is metabolized during the first passage in the liver. In animal models of ischaemic stroke, the effects of rt-PA are remarkably consistent with the effects seen in human clinical trials. For clinical application, some outcome data from the Cochrane Database of Systematic Reviews which includes all randomized evidence available on thrombolysis in man were used. Trials included tested urokinase, SK, rt-PA, pro-urokinase, or desmoteplase. The chief immediate hazard of thrombolytic therapy is fatal intracranial bleeding. However, despite the risk, the human trial data suggest the immediate hazards and the apparent substantial scope for net benefit of thrombolytic therapy given up to 6 h of acute ischaemic stroke. So far the fibrin-specific rt-PA is the only agent to be approved for use in stroke. This may be due to its short half-life and its absence of any specific amount of circulating fibrinogen degradation products, thereby leaving platelet function intact. The short half-life does not leave rt-PA without danger for haemorrhage after the infusion. Due to its fibrin-specificity, it can persist within a fibrin-rich clot for one or more days. The molecular mechanisms with regards to fibrin-specificity in thrombolytic agents should, if further studied, be addressed in within-trial comparisons. rt-PA has antigenic properties and although their long-term clinical relevance is unclear there should be surveillance for allergic reactions in relation to treatment. Although rt-PA is approved for use in selected patients, there is scope for benefit in a much wider variety of patients. A number of trials are underway to assess which additional patients - beyond the age and time limits of the current approval - might benefit, and how best to identify them.

Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and Rivaroxaban in atrial fibrillation.

INTRODUCTION: Direct oral anticoagulants (DOACs) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, with a lower risk of major hemorrhage, in patients with non-valvular atrial fibrillation (NVAF). We sought to investigate whether effectiveness and safety differs among apixaban, rivaroxaban and dabigatran. MATERIALS AND METHODS: Patients with newly initiated DOAC treatment were identified from the Swedish anticoagulation quality registry, ranging from January 1, 2013 to December 31, 2015. Patients were assigned to apixaban, dabigatran or rivaroxaban cohorts based on initiated DOAC and dose (standard or reduced). Baseline characteristics and endpoints were retrieved from validated Swedish quality registers and the National Patient Registry. Cohorts were matched using full optimal matching and directly compared. RESULTS: A total of 25,843 NVAF patients were included. Patients treated with standard dose apixaban or dabigatran had lower risk of major bleeding than patients treated with rivaroxaban, HR 0.69 (95% CI 0.54-0.88) and HR 0.64 (95% CI 0.48-0.87). Regarding reduced dose, patients treated with apixaban had lower risk of major bleeding than those treated with dabigatran or rivaroxaban, HR 0.62 (95% CI 0.44-0.88) and HR 0.45 (95% CI 0.33-0.61). In reduced dose, patients treated with dabigatran had the lowest all-cause mortality. No differences in effectiveness were found. CONCLUSIONS: In this large real-world NVAF cohort, direct comparisons show a favorable bleeding risk profile for dabigatran and apixaban in standard dose, and for apixaban in reduced dose. No differences in effectiveness were found. This study confirms previous indirect DOAC comparisons. Further studies are needed.

Stroke unit care revisited: who benefits the most? A cohort study of 105,043 patients in Riks-Stroke, the Swedish Stroke Register.

BACKGROUND: Treatment at stroke units is superior to treatment at other types of wards. The objective of the present study is to determine the effect size of stroke unit care in subgroups of patients with stroke. This information might be useful in a formal priority setting. METHODS: All acute strokes reported to the Swedish Stroke Register from 2001 through 2005 were followed until January 2007. The subgroups were age (18-64, 65-74, 75-84, 85+ years and above), sex (male, female), stroke subtype (intracerebral haemorrhage, cerebral infarction and unspecified stroke) and level of consciousness (conscious, reduced, unconscious). Cox proportional hazards and logistic regression analyses were used to estimate the risk for death, institutional living or dependency. RESULTS: 105,043 patients were registered at 86 hospitals. 79,689 patients (76%) were treated in stroke units and 25,354 patients (24%) in other types of wards. Stroke unit care was associated with better long-term survival in all subgroups. The best relative effect was seen among the following subgroups: age 18-64 years (hazard ratio (HR) for death 0.53; 0.49 to 0.58), intracerebral haemorrhage (HR 0.61; 0.58 to 0.65) and unconsciousness (HR 0.70; 0.66 to 0.75). Stroke unit care was also associated with reduced risk for death or institutional living after 3 months. CONCLUSIONS: Stroke unit care was associated with better long-term survival in all subgroups, but younger patients, patients with intracerebral haemorrhage and patients who were unconscious had the best relative effect and may be given the highest priority to this form of care.

Tumefactive demyelinating disease treated with decompressive craniectomy.

BACKGROUND: Tumefactive demyelinating disease (TDD) is a rare primary demyelinating disease with diagnostic and therapeutic challenges. METHODS AND RESULTS: We report a 50-year old woman with TDD successfully treated with decompressive craniectomy and corticosteroids. The patient presented with seizures, subacute progressive hemispheric syndrome, and a tumourlike abnormality on MRI. Demyelinating disease was initially considered unlikely. Due to a rapidly evolving herniation syndrome hemicraniectomy was performed. Outcome was favourable with only very mild neurological deficits 6 weeks later. CONCLUSION: TDD should be considered as a differential diagnosis in tumour-like presentations, and appears to have distinctive neuroimaging features. In the advent of treatement failure from high dose corticosteroids and plasmapheresis and development of severe mass effect, decompressive hemicraniectomy is an important treatment option.