Cardiovascular risk factor assessment in late-onset seizures: A study protocol to assess the value of structured intervention.

OBJECTIVE: A growing body of evidence suggests patients with late-onset seizures are at an increased risk of stroke, but the potential for reducing cardiovascular morbidity through risk factor screening and management is unknown. We aim to determine whether individuals with new-onset unprovoked seizures after middle age should undergo vascular risk assessment. The long follow-up needed to assess stroke risk and the known benefit of vascular risk factor modification make a standard RCT logistically and ethically challenging. Instead, we propose and have developed a protocol for a cluster project assessing the effect of vascular risk factor screening in an intervention trial as well as a cohort study. METHODS: Participating neurology clinics will implement standard cardiovascular risk factor assessment into the routine evaluation for individuals aged ≥50 years attending their first specialized consultation after an unprovoked seizure, excluding those with progressive brain disease. The project has two interlinked components: a prospective single group trial, in which risk factor assessment is performed and subsequent management is followed for one year; and a register-based cohort study examining the long-term effects of the intervention on a system level by comparing patients attending initial consultations in the 2 years after start of the study, with patients seen in the four preceding years at the same clinics. ANALYSIS: The primary outcome of the intervention trial is the proportion of patients receiving subsequent pharmacological treatment. The primary outcome of the cohort study is the incidence of acute stroke in the Swedish Stroke Register. ETHICS AND DISSEMINATION: Swedish Ethical Review Authority approval (which is valid for 2 years only) will be sought when funding is obtained. The results will be disseminated through peer-reviewed scientific publications. REGISTRATION DETAILS: The study will be registered at clinicaltrials.gov. PLAIN LANGUAGE SUMMARY: A first seizure in a middle-aged or older person indicates a higher risk of stroke. It is not known whether investigating and treating blood pressure, blood cholesterol, or similar risk factors after a first seizure is an effective way to prevent stroke. A traditional clinical study would need too many patients and it would be unethical not to treat the control group. We have designed a study in which participating neurology departments change their practice to test and treat vascular risk factors. Patients are then compared to historic controls using registered data.

Large variations in atrial fibrillation screening practice after ischemic stroke and transient ischemic attack in Sweden: a survey study.

BACKGROUND: Atrial fibrillation (AF) screening after ischemic stroke or transient ischemic attack (TIA) is given high priority in clinical guidelines. However, patient selection, electrocardiogram (ECG) modality and screening duration remains undecided and current recommendations vary. METHODS: The aim of this study was to investigate the clinical practice of AF screening after ischemic stroke or TIA at Swedish stroke units. In collaboration with the stakeholders of the Swedish Stroke Register (Riksstroke) a digital survey was drafted, then tested and revised by three stroke consultants. The survey consisted of 17 multiple choice/ free text questions and was sent by e-mail to the medical directors at all stroke units in Sweden. RESULTS: All 72 stroke units in Sweden responded to the survey. Most stroke units reported that ≥ 75% of ischemic stroke (69/72 stroke units) or TIA patients (67/72 stroke units), without previously known AF, were screened for AF. Inpatient telemetry ECG was the method of first-choice in 81% of the units, but 7% reported lack of access. A variety of standard monitoring durations were used for inpatient telemetry ECG. The second most common choice was Holter ECG (17%), also with considerable variations in monitoring duration. Other AF screening modalities were used as a first-choice method (handheld and patch ECG) but less frequently. CONCLUSIONS: Clinical practice for AF screening after ischemic stroke or TIA differed between Swedish stroke units, both in choice of AF screening methods as well as in monitoring durations. There is an urgent need for evidence and evidence-based recommendations in this field. TRIAL REGISTRATION: Not applicable.

Multicentre, national, investigator-initiated, randomised, parallel-group, register-based superiority trial to compare extended ECG monitoring versus standard ECG monitoring in elderly patients with ischaemic stroke or transient ischaemic attack and the effect on stroke, death and intracerebral bleeding: the AF SPICE protocol.

INTRODUCTION: Atrial fibrillation (AF) is a major risk factor for ischaemic stroke and transient ischaemic attack (TIA), and AF detection can be challenged by asymptomatic and paroxysmal presentation. Long-term ECG monitoring after ischaemic stroke or TIA is recommended by all major societies in cardiology and cerebrovascular medicine as a secondary prophylactic measure. However, data on stroke reduction are lacking, and the recommendations show significant diversity. METHODS AND ANALYSIS: AF SPICE is a multicentre, national, investigator-initiated, randomised, parallel-group, register-based trial comparing extended ECG monitoring versus standard ECG monitoring in patients admitted with ischaemic stroke or TIA, with a composite endpoint of stroke, all-cause-mortality and intracerebral bleeding. Patients aged ≥70 years without previous AF will be randomised 1:1 to control (standard ECG monitoring) or intervention (extended ECG monitoring). In the control arm, patients will undergo 48±24 hours (ie, a range of 24-72 hours) of continuous ECG monitoring according to national recommendations. In the intervention arm, patients will undergo 14+14 days of continuous ECG monitoring 3 months apart using an ECG patch device, which will provide an easy-accessed, well-tolerated 14-day continuous ECG recording. All ECG patch recordings will be read in a core facility. In cases of AF detection, oral anticoagulation will be recommended if not contraindicated. A pilot phase has been concluded in 2022, which will transcend into the main trial during 2023-2026, including approximately 30 stroke units. The sample size was calculated to be 3262 patients. The primary outcome will be collected from register data during a 36-month follow-up. ETHICS AND DISSEMINATION: Ethical approval has been provided by the Swedish Ethical Review Authority, reference 2021-02770. The trial will be conducted according to the ethical principles of the Declaration of Helsinki and national regulatory standards. Positive results from the study have the potential for rapid dissemination in clinical practice. TRIAL REGISTRATION NUMBER: NCT05134454.

[Preventive treatment to avoid recurrence of stroke and TIA is effective]. / Förebyggande behandling efter ischemisk stroke/TIA har effekt.

Healthy living with physical activity, healthy eating habits, no smoking, and no alcohol overuse have an important role in primary and secondary stroke prevention. Further secondary prevention depends on type and cause of stroke or TIA. After intracerebral bleeding, ischemic stroke or TIA, preventive pharmacological therapies include antihypertensive drugs. After ischemic stroke or TIA, treatment with antithrombotics (oral anticoagulants or antiplatelets) and statins is recommended. In stroke due to unusual causes, the pharmacological preventive treatment described above may need modification. For symptomatic carotid stenosis, carotid surgery is recommended, preferably within the first 14 days after onset. A surgical preventive treatment is closure of patent foramen ovale in patients aged 18-60 years with ischemic stroke of unknown cause.

Plasma Neurofilament Light Chain Is Elevated after Transcatheter Aortic Valve Implantation.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is associated with a high incidence of new silent brain infarcts (SBIs) on postprocedural neuroimaging. A venous blood sample reflecting neuronal damage following TAVI could help identify patients with potential SBIs. We aimed to investigate if a biochemical marker of neuronal injury, neurofilament light chain (NFL), is elevated after TAVI. METHODS: In this observational study, NFL was measured in plasma from 31 patients before and after TAVI. Multivariable regression analysis was performed to investigate any effect of clinical- and procedure-related factors on differences in NFL levels before and after TAVI. RESULTS: Samples were collected 41 (14-81) days before and 44 (35-59) days after TAVI, median (interquartile range). Median age was 81 (77-84) years, and 35% were female. No patient had any overt procedure-related neurological complications. The geometric mean (95% confidence interval) of the NFL concentration was 30 (25-36) pg/mL before TAVI and 48 (39-61) pg/mL, after TAVI, p <0.001. None of the included variables in the multiple linear regression model were statistically significantly associated with the difference in levels before and after TAVI. CONCLUSIONS: NFL levels in plasma were higher after TAVI as compared with levels before, with a mean increase of 60% (18 pg/mL). Further studies including neuroimaging and cognitive outcomes are needed to understand the potential value of measuring NFL in relation to TAVI.

Early Versus Delayed Non-Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study.

BACKGROUND: There are no evidence-based recommendations on the optimal time point to initiate non-vitamin K antagonist oral anticoagulants (NOACs) after acute ischemic stroke in patients with atrial fibrillation. We aimed to investigate the efficacy and safety of early versus delayed initiation of NOAC in these patients. METHODS: TIMING (Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation) was a registry-based, randomized, noninferiority, open-label, blinded end-point study at 34 stroke units using the Swedish Stroke Register for enrollment and follow-up. Within 72 hours from stroke onset, patients were randomized to early (≤4 days) or delayed (5-10 days) NOAC initiation, with choice of NOAC at the investigators' discretion. The primary outcome was the composite of recurrent ischemic stroke, symptomatic intracerebral hemorrhage, or all-cause mortality at 90 days. The prespecified noninferiority margin was 3%. Secondary outcomes included the individual components of the primary outcome. RESULTS: Between April 2, 2017, and December 30, 2020, 888 patients were randomized to either early (n=450) or delayed (n=438) initiation of NOAC. No patient was lost to 90-day follow-up. Mean age was 78.3 years (SD, 9.9 years); 46.2% were women; 49.1% had previously known atrial fibrillation; and 17.5% prior stroke. The primary outcome occurred in 31 patients (6.89%) assigned to early initiation and in 38 patients (8.68%) assigned to delayed NOAC initiation (absolute risk difference, -1.79% [95% CI, -5.31% to 1.74%]; Pnoninferiority=0.004). Ischemic stroke rates were 3.11% and 4.57% (risk difference, -1.46% [95% CI, -3.98% to 1.07%]) and all-cause mortality rates were 4.67% and 5.71% (risk difference, -1.04% [95% CI, -3.96% to 1.88%]) in the early and delayed groups, respectively. No patient in either group experienced symptomatic intracerebral hemorrhage. CONCLUSIONS: Early initiation was noninferior to delayed start of NOAC after acute ischemic stroke in patients with atrial fibrillation. Numerically lower rates of ischemic stroke and death and the absence of symptomatic intracerebral hemorrhages implied that the early start of NOAC was safe and should be considered for acute secondary stroke prevention in patients eligible for NOAC treatment. REGISTRATION: URL: http://www. CLINICALTRIALS: gov; Unique identifier: NCT02961348.

Association Between Antiseizure Drug Monotherapy and Mortality for Patients With Poststroke Epilepsy.

Importance: There is little evidence to guide the choice of antiseizure medication (ASM) for patients with poststroke epilepsy. Theoretical concerns about detrimental effects of ASMs on survival exist. Enzyme-inducing drugs could interfere with secondary stroke prevention. The US Food and Drug Administration recently issued a safety announcement about the potential proarrhythmic properties of lamotrigine. Objective: To investigate whether mortality varies with specific ASMs among patients with poststroke epilepsy. Design, Setting, and Participants: A cohort study was conducted using individual-level data from linked registers on all adults in Sweden with acute stroke from July 1, 2005, to December 31, 2010, and subsequent onset of epilepsy before December 31, 2014. A total of 2577 patients receiving continuous ASM monotherapy were eligible for the study. Data were analyzed between May 27, 2019, and April 8, 2021. Exposures: The dispensed ASM (Anatomical Therapeutic Chemical code N03A) determined exposure status, and the first dispensation date marked the start of treatment. Main Outcomes and Measures: The primary outcome, all-cause death, was analyzed using Cox proportional hazards regression with carbamazepine as the reference. Cardiovascular death (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes I0-I99 as the underlying cause) was assessed using Fine-Gray competing risk regression models. Results: A total of 2577 patients (1400 men [54%]; median age, 78 years [IQR, 69-85 years]) were included. The adjusted hazard ratio of all-cause death compared with carbamazepine was 0.72 (95% CI, 0.60-0.86) for lamotrigine, 0.96 (95% CI, 0.80-1.15) for levetiracetam, 1.40 (95% CI, 1.23-1.59) for valproic acid, 1.16 (95% CI, 0.88-1.51) for phenytoin, and 1.16 (95% CI, 0.81-1.66) for oxcarbazepine. The adjusted hazard ratio of cardiovascular death compared with carbamazepine was 0.76 (95% CI, 0.61-0.95) for lamotrigine, 0.77 (95% CI, 0.60-0.99) for levetiracetam, 1.40 (95% CI, 1.19-1.64) for valproic acid, 1.02 (95% CI, 0.71-1.47) for phenytoin, and 0.71 (95% CI, 0.42-1.18) for oxcarbazepine. Conclusions and Relevance: This cohort study's findings suggest differences in survival between patients treated with different ASMs for poststroke epilepsy. Patients receiving lamotrigine monotherapy had significantly lower mortality compared with those receiving carbamazepine. The opposite applied to patients prescribed valproic acid, who had a higher risk of cardiovascular and all-cause death. Levetiracetam was associated with a reduced risk of cardiovascular death compared with carbamazepine, but there was no significant difference in overall mortality.

Sex Differences in Stroke Care and Outcome 2005-2018: Observations From the Swedish Stroke Register.

Background and Purpose: Previous studies of stroke management and outcome in Sweden have revealed differences between men and women. We aimed to analyze if differences in stroke incidence, care, and outcome have altered over time. Methods: All stroke events registered in the Swedish Stroke Register 2005 to 2018 were included. Background variables and treatment were collected during the acute hospital stay. Survival data were obtained from the national cause of death register by individual linkage. We used unadjusted proportions and estimated age-adjusted marginal means, using a generalized linear model, to present outcome. Results: We identified 335 183 stroke events and a decreasing incidence in men and women 2005 to 2018. Men were on average younger than women (73.3 versus 78.1 years) at stroke onset. The age-adjusted proportion of reperfusion therapy 2005 to 2018 increased more rapidly in women than in men (2.3%­15.1% in men versus 1.4%­16.9% in women), but in 2018, women still had a lower probability of receiving thrombolysis within 30 minutes. Among patients with atrial fibrillation, oral anticoagulants at discharge increased more rapidly in women (31.2%­78.6% in men versus 26.7%­81.9% in women). Statins remained higher in men (36.9%­83.7% in men versus 32.3%­81.2% in women). Men had better functional outcome and survival after stroke. After adjustment for women's higher age, more severe strokes, and background characteristics, the absolute difference in functional outcome was <1% and survival did not differ. Conclusions: Stroke incidence, care, and outcome show continuous improvements in Sweden, and previously reported differences between men and women become less evident. More severe strokes and older age in women at stroke onset are explanations to persisting differences.

Age in relation to comorbidity and outcome in patients with high-risk TIA or minor ischemic stroke: A Swedish national observational study.

INTRODUCTION: Recent trials report positive results for preventing vascular events with dual antiplatelet therapy (DAPT) in patients with high-risk TIA or minor ischemic stroke. We aimed to investigate this population regarding influence of age on vascular risk factors, hospital stay and mortality. PATIENTS AND METHODS: Data on patients aged 40-100 years with TIA or ischemic stroke in the Swedish Stroke Register during 2012-13 were linked with national registers. To identify patients with high-risk TIA (ABCD2 ≥6) or minor ischemic stroke (NIHSS ≤5) eligible for DAPT, we excluded patients with atrial fibrillation, anticoagulant use, prior major bleeding, or unknown stroke severity. FINDINGS: We identified 10,053 potential DAPT-candidates (mean age 72.6 years, 45.2% female, 16.4% with TIA). With advancing age, most vascular risk factors increased. Antiplatelet treatment increased from 31.9% before the event to 95.5% after discharge. Within 1 year following index event, the proportion of patients with ≥1 re-admission increased with age (29.2% in 40-64 year-olds; 47.2% in 85-100 year-olds). All-cause death per 100 person-years was 6.9 (95% CI 6.4-7.4) within 1 year, and highest in the first 30 days (15.2; 95% CI 12.8-18.2). For each year of increased age, the risk of death increased with 3.5% (p = 0.128) in patients 40-64 years and with 11.8% (p < 0.001) in those ≥85 years. CONCLUSIONS: While in theory representing a subset of patients with mild injury, our observational study highlights substantial use of health-care resources and high mortality rates among patients with high-risk TIA or minor ischemic stroke assumed eligible for DAPT.

Sex differences in stroke.

Sex disparities within the field of stroke, including subarachnoid hemorrhages (SAHs), have been in focus during the last 2 decades. It is clear that stroke incidence is higher in men, and also that men have their first stroke earlier than women. On the other hand, women have more severe strokes, mainly because cardioembolic strokes are more common in women. This leads to higher case fatality and worse functional outcome in women. It has often been pointed out that women more often have nontraditional stroke symptoms, and therefore may seek medical help later. After discharge from the hospital, female stroke survivors live alone in many cases and are dependent on external care. Therefore, these women frequently rate their quality of life (QoL) lower than men do. Female spouses more often provide help to their male stroke survivors than the reverse, and they accept a heavier burden. These caregivers are at high risk for depression, low QoL, and low psychologic wellbeing. SAH is a special form of stroke, often caused by a ruptured aneurysm. It is about 20% more common in women. The case fatality is high, but does not differ between the sexes.

Risk of stroke after new-onset seizures.

PURPOSE: Observational cohort studies have reported a potentially increased risk of stroke in patients with epileptic seizures. Whether late-onset seizures merit primary stroke prophylaxis is not known, and more information on stroke risk is needed for the planning of RCTs. We performed a case-control study based on Swedish national registers to quantify the risk of stroke after epileptic seizures. METHODS: Cases ≤100 years of age with a first-ever stroke 2001-2009 were identified through the Swedish Stroke Register, and stroke-free controls (matched for age and sex) were obtained from the Population Register. The National Patient Register provided information on diagnostic codes for seizures, epilepsy and comorbidities. 123 105 stroke cases and 250 506 controls were included. RESULTS: Epileptic seizures prior to index stroke date were detected in 1559 (1.27 %) cases and 1806 (0.72 %) controls, yielding an odds ratio (95 % confidence interval) for stroke of 1.77 (1.65-1.89). ORs were similar in men and women, but higher below the age of 75. An onset of seizures in the year preceding stroke date resulted in a higher risk for stroke (OR = 2.21, 95 % CI = 1.79-2.72) compared to when more than 5 years had passed since the first seizure (OR = 1.57, 95 % CI = 1.43-1.72). CONCLUSION: A history of epileptic seizures was associated with an increased risk of subsequent stroke. The risk seems to be particularly high in the first year following seizure diagnosis, which supports the notion that unexplained late-onset seizures may merit swift assessment of vascular risk profile. The nature of stroke prevention requires further study.

Statins as secondary preventives in patients with intracerebral hemorrhage.

BACKGROUND: Statins are important components of secondary stroke prevention, but there is a concern they may increase the risk of intracerebral hemorrhage. Although this risk may have been overestimated, there is still an open question whether statin therapy should be continued, or even initiated, in patients who have had a recent intracerebral hemorrhage. AIM: Our aim was to investigate the risk of statin use after an intracerebral hemorrhage with respect to recurrent intracerebral hemorrhage, stroke in general, and death. METHODS: This observational study was based on patients with a first intracerebral hemorrhage in 2004 through 2009. Clinical characteristics, index intracerebral hemorrhage, and recurrent intracerebral hemorrhages were identified by the Swedish Stroke Register; additional data on comorbidities and vital status were retrieved through record linkages to national registers. A propensity score for the likelihood of receiving statins at discharge was developed and used with other established risk factors in a multivariable analysis. RESULTS: Of 6082 intracerebral hemorrhage patients (mean age 69.6 years), 1097 (18%) were prescribed statins at discharge. During the follow-up (mean 3.1 years), 1434 (23.6%) deaths and 234 (3.8%) recurrent intracerebral hemorrhages were observed. Statin therapy was associated with a reduced risk of death (adjusted hazard ratio: 0.71; 95% confidence interval: 0.60-0.84) but not with the risk of recurrent intracerebral hemorrhage (adjusted hazard ratio: 0.82; 95% confidence interval: 0.55-1.22). CONCLUSIONS: This study provides some reassurance that statins may be safe to use, in at least some patients, after an intracerebral hemorrhage. In patients with intracerebral hemorrhage, statin use was associated with a reduced risk of death, without an increased risk of recurrent intracerebral hemorrhage.

Family history increases the risk of late seizures after stroke.

OBJECTIVE: To assess the association between a family history of epilepsy and risk of late poststroke seizures (LPS). METHODS: This register-based cohort study was based on adult patients from the Swedish Stroke Register (Riksstroke) with stroke from 2001 to 2012 and no prior epilepsy. LPS (>7 days after stroke) and epilepsy were ascertained in cases and in their first-degree biological relatives by cross-referencing Riksstroke, the Multi-Generation Register, and the National Patient Register. RESULTS: Of 86,550 patients with stroke, a family history of epilepsy was detected in 7,433 (8.6%), and LPS (>7 days after stroke) occurred in 7,307 (8.4%). The survival-adjusted risk of LPS was higher in patients with compared to those without a family history of epilepsy: 6.8% (95% confidence interval [CI] 6.2%-7.4%) vs 5.9% (95% CI 5.7%-6.1%) at 2 years and 9.5% (95% CI 8.7%-10.3%) vs 8.2% (95% CI 8.0%-8.4%) at 5 years. In a Cox model adjusted for age, sex, and stroke type, the hazard ratio (HR) for LPS in patients with stroke with ≥1 relative with epilepsy was 1.18 (95% CI 1.09-1.28). The increased HR remained significant with adjustments for stroke severity and in multiple sensitivity analyses. A higher risk for patients with stroke with >1 relative with epilepsy was also seen but was not significant in all Cox models. CONCLUSIONS: Although stroke characteristics remain the most important risk factors for LPS, having a first-degree relative with epilepsy also increases the risk in a multivariate analysis. The findings highlight the need for family history assessment in patients with stroke and the need for future studies on genetic vulnerability and environmental factors that may aid in the identification of at-risk individuals.

Retention rate of first antiepileptic drug in poststroke epilepsy: A nationwide study.

PURPOSE: To describe the retention rates of first antiepileptic drugs (AEDs) in patients with poststroke epilepsy on a nationwide scale. METHODS: The Swedish Stroke Register, which has 94% coverage and high-resolution data on stroke, comorbidities, and disability, was cross-referenced to the National Patient Register, Drug Register, and Cause-of-Death Register. Patients with onset of AED-treated epilepsy after stroke in 2005-2010 were included. An algorithm based on prescription renewal intervals was used to analyze treatment data until the end of 2014. RESULTS: A total of 4991 patients were included. First AEDs analyzed were carbamazepine (n = 2373), valproic acid (n = 943), levetiracetam (n = 555), lamotrigine (n = 519), phenytoin (n = 176), and oxcarbazepine (n = 89). The five-year retention rate was highest for lamotrigine (75%, 95%CI:70.4-79.4), followed by levetiracetam (69%, 95%CI:62.9-74.3), oxcarbazepine (68%, 95%CI:55.2-79.8), valproic acid (62%, 95%CI:57.8-66.4), carbamazepine (60%, 95%CI:57.6-62.4), and phenytoin (55%, 95%CI:45.2-64.0). There were minor differences in baseline characteristics with low levels of disability being slightly more common in patients treated with lamotrigine and levetiracetam. Atrial fibrillation and hypertension were more common in patients treated with levetiracetam, and atrial fibrillation was less common in patients treated with carbamazepine. In a Cox model adjusted for baseline characteristics, the risk of discontinuation was lower for lamotrigine (HR 0.53, 95%CI:0.43-0.67) and levetiracetam (HR 0.75, 95%CI:0.60-0.94) when compared to carbamazepine. CONCLUSIONS: Lamotrigine and levetiracetam have higher retention rates than carbamazepine in poststroke epilepsy. This is in agreement with existing small RCTs in this patient group.

Survival and incidence of cardiovascular diseases in participants in a long-distance ski race (Vasaloppet, Sweden) compared with the background population.

Aims: We studied the relationship between taking part in a long-distance ski race and incidence of cardiovascular diseases (CVDs) to address the hypothesis that lifestyle lowers the incidence. Methods and results: A cohort of 399 630 subjects in Sweden, half were skiers in the world's largest ski race, and half were non-skiers. Non-skiers were frequency matched for sex, age, and year of race. Individuals with severe diseases were excluded. The endpoints were death, myocardial infarction, or stroke. The subjects were followed up for a maximum of 21.8 years and median of 9.8 years. We identified 9399 death, myocardial infarction, or stroke events among non-skiers and 4784 among the Vasaloppet skiers. The adjusted hazard ratios (HRs) comparing skiers and non-skiers were 0.52 [95% confidence interval (CI) 0.49-0.54] for all-cause mortality, 0.56 (95% CI 0.52-0.60) for myocardial infarction and 0.63 (95% CI 0.58-0.67) for stroke and for all three outcomes 0.56 (95% CI 0.54-0.58). The results were consistent across subgroups: age, sex, family status, education, and race year. For skiers, a doubling of race time was associated with a higher age-adjusted risk of 19%, and male skiers had a doubled risk than female skiers, with a HR 2.06 (95% CI 1.89-2.41). The outcome analyses revealed no differences in risk of atrial fibrillation between skiers and non-skiers. Conclusion: This large cohort study provides additional support for the hypothesis that individuals with high level of physical activity representing a healthy lifestyle, as evident by their participation in a long-distance ski race, have a lower risk of CVD or death.

Timing of oral anticoagulant therapy in acute ischemic stroke with atrial fibrillation: study protocol for a registry-based randomised controlled trial.

BACKGROUND: Oral anticoagulation therapy is recommended for the prevention of recurrent ischemic stroke in patients with atrial fibrillation (AF). Current guidelines do not provide evidence-based recommendations on optimal time-point to start anticoagulation therapy after an acute ischemic stroke. Non-vitamin K antagonist oral anticoagulants (NOACs) may offer advantages compared to warfarin because of faster and more predictable onset of action and potentially a lower risk of intracerebral haemorrhage also in the acute phase after an ischemic stroke. The TIMING study aims to establish the efficacy and safety of early vs delayed initiation of NOACs in patients with acute ischemic stroke and AF. METHODS/DESIGN: The TIMING study is a national, investigator-led, registry-based, multicentre, open-label, randomised controlled study. The Swedish Stroke Register is used for enrolment, randomisation and follow-up of 3000 patients, who are randomised (1:1) within 72 h from ischemic stroke onset to either early (≤ 4 days) or delayed (≥ 5-10 days) start of NOAC therapy. The primary outcome is the composite of recurrent ischemic stroke, symptomatic intracerebral haemorrhage, or all-cause mortality within 90 days after randomisation. Secondary outcomes include: individual components of the primary outcome at 90 and 365 days; major haemorrhagic events; functional outcome by the modified Rankin Scale at 90 days; and health economics. In an optional biomarker sub-study, blood samples will be collected after randomisation from approximately half of the patients for central analysis of cardiovascular biomarkers after study completion. The study is funded by the Swedish Medical Research Council. Enrolment of patients started in April 2017. CONCLUSION: The TIMING study addresses the ongoing clinical dilemma of when to start NOAC after an acute ischemic stroke in patients with AF. By the inclusion of a randomisation module within the Swedish Stroke Register, the advantages of a prospective randomised study design are combined with the strengths of a national clinical quality register in allowing simplified enrolment and follow-up of study patients. In addition, the register adds the possibility of directly assessing the external validity of the study findings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02961348 . Registered on 8 November 2016.

To Treat or Not to Treat: Anticoagulants as Secondary Preventives to the Oldest Old With Atrial Fibrillation.

BACKGROUND AND PURPOSE: Anticoagulant treatment is effective for preventing recurrent ischemic strokes in patients who have atrial fibrillation. This benefit is paid by a small increase of hemorrhages. Anticoagulant-related hemorrhages seem to increase with age, but there are few studies showing whether the benefits of treatment persist in old age. METHODS: For this observational study, 4 different registers were used, among them Riksstroke, the Swedish Stroke Register. Patients who have had a recent ischemic stroke, were 80 to 100 years of age, and had atrial fibrillation, were included from 2006 through 2013. The patients were stratified into 3 age groups: 80 to 84, 85 to 89, and ≥90 years of age. Information on stroke severity, risk factors, drugs, and comorbidities was gathered from the registers. The patients were followed with respect to ischemic or hemorrhagic stroke, other hemorrhages, or death. RESULTS: Of all 23 356 patients with atrial fibrillation, 6361 (27%) used anticoagulants after an ischemic stroke. Anticoagulant treatment was associated with less recurrent ischemic stroke in all age groups. Hemorrhages increased most in the ≥90-year age group, but this did not offset the overall beneficial effect of the anticoagulant. Apart from age, no other cardiovascular risk factor or comorbidity was identified that influenced the risk of anticoagulant-associated hemorrhage. Drugs other than anticoagulants did not influence the incidence of major hemorrhage. CONCLUSIONS: Given the patient characteristics in this study, there is room for more patients to be treated with anticoagulants, without hemorrhages to prevail. In nonagenarians, hemorrhages increased somewhat more, but this did not affect the overall outcome in this age stratum.

Pre-stroke seizures: A nationwide register-based investigation.

PURPOSE: The relationship between cerebrovascular disease and seizures is clearly illustrated by poststroke epilepsy. Seizures can also be the first manifestation of cerebrovascular disease and case-control studies have demonstrated that seizures carry an increased risk of subsequent stroke. Thus, seizures could serve as a marker for vascular risk that merits intervention, but more data is needed before proper trials can be conducted. The occurrence of pre-stroke seizures has not been assessed on a national scale. We asked what proportion of strokes in middle-aged and elderly patients was preceded by seizures. METHODS: All patients over 60 years of age with first-ever stroke in 2005-2010 (n=92,596) were identified in the Swedish stroke register (Riksstroke) and cross-sectional data on a history of a first seizure or epilepsy diagnosis in the ten years preceding stroke were collected from national patient registers with mandatory reporting. RESULTS: 1372 patients (1.48%) had a first seizure or epilepsy diagnosis registered less than ten years prior to the index stroke. The mean latency between seizure and stroke was 1474days (SD 1029 days). CONCLUSIONS: Seizures or epilepsy preceded 1.48% of strokes in patients >60years of age. Based on recent national incidence figures, 5-20% of incident cases of seizures or epilepsy after 60 years of age could herald stroke, depending on age group. These proportions are of a magnitude that merit further study on how to reduce the risk of stroke in patients with late-onset seizures or epilepsy.

Cause of death in patients with poststroke epilepsy: Results from a nationwide cohort study.

The risk of death is increased for persons with epilepsy. The literature on causes of death in epilepsy is based mainly on cohorts with epilepsy of mixed aetiologies. For clinical purposes and improved understanding of mortality in different epilepsies, more information is needed on mortality in epilepsies of specific causes. In poststroke epilepsy (PSE), seizures occur in a setting of vascular disease and high mortality rates. The extent to which epilepsy contributes to mortality in this patient group is poorly understood. We therefore aimed to describe causes of death (COD) in PSE on a national scale. A previously identified cohort of 7740 patients with epilepsy or seizures after a stroke in 2005-2010 was investigated. A total of 4167 deaths occurred before the end of 2014. The standardized mortality ratio for the study cohort was 3.56 (95% CI: 3.45-3.67). The main underlying causes of death were disorders of the circulatory system (60%) followed by neoplasms (12%). Diseases of the nervous system were the sixth leading underlying COD (3%), and epilepsy or status epilepticus was considered the underlying COD in approximately a similar proportion of cases as neurodegenerative disorders (0.9% and 1.1%, respectively). Epilepsy was considered a contributing COD in 14% of cases. Our findings highlight the importance of optimal management of vascular morbidity in patients with PSE. The large proportion of patients with epilepsy as a contributing COD indicate the need of high ambitions also regarding the management of seizures in patients with PSE.

[Anticoagulants after acute ischemic stroke with atrial fibrillation]. / Antikoagulantia efter akut ischemisk stroke med förmaksflimmer - Frågan om rätt tidpunkt för insättning kräver randomiserad klinisk prövning.

Early or delayed onset of oral anticoagulant therapy in patients with acute ischemic stroke with atrial fibrillation is an unsolved issue. Retrospectively, 294 patient records at two hospitals were scrutinized according to a protocol consisting of 20 items regarding choice of therapy (warfarin or NOAC), time for onset of therapy, CT findings of bleeding, capacity to swallow, and occurrence of clinical deterioration during the acute phase. Out of 249 patients who survived the acute phase, 116 (47%) patients were given a new prescription of warfarin or NOAC at discharge, while 43 (17 %) continued with anticoagulant therapy already prescribed before the onset of stroke. The median value for new prescriptions in relation to stroke admission was 5 days. The pattern was similar for warfarin and NOAC. Patients in whom anticoagulant therapy was started early were characterized by good capacity to swallow and no signs of bleeding on initial CT. The question ¼early or delayed onset of oral anticoagulant therapy after acute ischemic stroke with atrial fibrillation« needs to be tested in a randomized clinical trial.