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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%]; P noninferiority =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.

Background Endovascular thrombectomy (EVT) is standard of care for anterior circulation acute ischemic stroke (AIS) caused by large vessel occlusion (LVO), but data on nationwide performance in routine healthcare are sparse. The study aims were to describe EVT patients with LVO AIS, analyze mortality and functional outcome, and compare results with randomized controlled trials (RCTs). Methods Data from the Riksstroke and the Swedish Endovascular Treatment of Acute Stroke Registry (RSEVAS) on pre-stroke independent patients, with LVO AIS in 2017–2019, defined as occlusion of the intracranial internal carotid artery, or the M1 or M2 segments of the middle cerebral artery, and groin puncture Results In all, 1011/2560 of RSEVAS patients matched RCT inclusion criteria. Compared with RCT data, patients were older (73 vs. 68), fewer received intravenous thrombolysis (63.1% vs. 83%), and M2 occlusions were more common (24.5% vs. 8%). 90-day survival in RSEVAS was 85.3%, 42.8% achieved good outcome and 5% had symptomatic intracerebral hemorrhage (sICH). Corresponding outcomes in RCT data were 84.7% survival, 46% good outcome, and 4.4% sICH. Functional outcome was most favorable following M2 occlusions. Conclusions EVT patients from our large real-world national dataset differed from RCT patients in several baseline factors including distribution of vascular occlusion site. However, the overall outcome of EVT in our Swedish cohort appeared to well match the pivotal trial findings.

Objective: To evaluate whether estimates of risk of future cardiovascular events and death and established or unknown diabetes are significantly associated with calcified carotid artery atheromas (CCAAs) on panoramic radiographs (PRs). The main focus was on men and women without previous myocardial infarction (MI). Methods: The PAROKRANK (Periodontitis and its Relation to Coronary Artery Disease) study included patients with a first MI and matched control subjects. In this substudy, 738 patients (138 women) and 744 control subjects (144 women) with available PRs were assessed for CCAA. Cardiovascular risk estimates were determined according to the Framingham Risk Score (FRS) and Systematic COronary Risk Evaluation (SCORE). Established and previously unknown diabetes was also determined. Results: CCAA was detected on PRs in 206 control subjects (28%) and 251 patients (34%). FRS was significantly associated with CCAA among control subjects (P = .04) and patients (P = .001). SCORE was associated with CCAA among control subjects (P < .01) but not patients (P = .07). Among men, FRS and SCORE were associated with CCAA in both control subjects and patients. Diabetes was not significantly associated with CCAA after adjustments. Conclusions: Elevated cardiovascular risk scores were associated with CCAA on PRs among control subjects. Diabetes was not independently associated with CCAA, possibly owing to selection bias.

BackgroundEndovascular thrombectomy (EVT) for ischemic stroke (IS) beyond 6 hours has been proven effective in randomized controlled trials. We present data on implementation and outcomes for EVT beyond 6 hours in Sweden.MethodsWe included all cases of anterior circulation IS caused by occlusion of the intracranial carotid artery, and the M1 or M2 segment of the middle cerebral artery, registered in two nationwide quality registers for stroke in 2015–2020. Three groups were defined from onset-to-groin-puncture (OTG) time: early window (ResultsLate window EVT increased from 0.3% of all IS in 2015 to 1.8% in 2020, and from 17.4% of all anterior circulation EVTs in 2015 to 32.9% in 2020. Of 2199 patients, 76.9% (n=1690) were early window EVTs and 23.1% late window EVTs (n=509; 141 known onset, 368 LSW). Median age was 73 years, and 46.2% were female, with no differences between groups. Favorable outcome did not differ between groups (early window 42.4%, late window known onset 38.9%, late window LSW 37.3% (p=0.737)) and remained similar when adjusted for baseline differences. sICH rates did not differ (early window 4.0%, late window known onset 2.1%, late window LSW 4.9% (p=0.413)).ConclusionLate window EVTs have increased substantially over time, and currently account for one third of anterior circulation treatments. Early and late window patients had similar outcomes.

Objectives: The risk of cardiovascular disease is associated with the echo intensity of carotid plaques in ultrasound images and their cardiac cycle-induced intensity variations. In this study, we aimed to 1) explore the underlying origin of echo intensity variations by using simulations and 2) evaluate the association between the two-dimensional (2D) spatial distribution of these echo intensity variations and plaque vulnerability. Methods: First, we analyzed how out-of-plane motion and compression of simulated scattering spheres of different sizes affect the ultrasound echo intensity. Next, we propose a method to analyze the features of the 2D spatial distribution of interframe plaque echo intensity in carotid ultrasound image sequences and explore their associations with plaque vulnerability in experimental data. Results: The simulations showed that the magnitude of echo intensity changes was similar for both the out-of-plane motion and compression, but for scattering objects smaller than 1 mm radius, the out-of-plane motion dominated. In experimental data, maps of the 2D spatial distribution of the echo intensity variations had a low correlation with standard B-mode echo intensity distribution, indicating complementary information on plaque tissue composition. In addition, we found the existence of ∼1 mm diameter subregions with pronounced echo intensity variations associated with plaque vulnerability. Conclusions: The results indicate that out-of-plane motion contributes to intra-plaque regions of high echo intensity variation. The 2D echo intensity variation maps may provide complementary information for assessing plaque composition and vulnerability. Further studies are needed to verify this method's role in identifying vulnerable plaques and predicting cardiovascular disease risk.

Background Oral and pharyngeal swallowing dysfunction are common complications in acute stroke patients. This primary aim of this study was to determine whether oral neuromuscular training improves swallowing function in participants with swallowing dysfunction after stroke. A secondary aim was to assess how well results of the timed water-swallow test (TWST) correspond with swallowing dysfunction diagnosed by videofluoroscopy (VFS). Methods This was an intention-to-treat two-centre prospective randomized open-label study with blinded-evaluators (PROBE) design. At 4 weeks after stroke onset, participants with swallowing dysfunction were randomized to 5 weeks of continued orofacial sensory-vibration stimulation with an electric toothbrush or additional oral neuromuscular training with an oral device (Muppy®). Participants were examined with TWST, a lip-force test, and VFS before (baseline), after 5 weeks’ treatment (the end-of-treatment), and 12 months after treatment (follow-up). The baseline VFS results were compared with the TWST results. The primary endpoint was changes in swallowing rate assessed using TWST, from baseline to the end of training and from baseline to follow-up based on intention-to-treat analyses. The secondary endpoint was the corresponding changes in lip-force between baseline, the end of treatment, and follow-up. Results The participants were randomly assigned as controls (n = 20) or for intervention with oral neuromuscular training (n = 20). After treatment, both groups had improved significantly (intervention, P P = 0.001) in TWST but there was no significant between-group difference in swallowing rate. At the 12-month follow-up, the intervention group had improved further whereas the controls had deteriorated, and there were significant between-group differences in swallowing rate (P = 0.032) and lip force (P = 0.001). A TWST Conclusion The 5-week oral neuromuscular training improved swallowing function in participants with post-stroke dysphagia compared with the controls 12 months after intervention, but there was no between-group difference in improvement immediately after treatment. TWST results corresponded with VFS results, making TWST a feasible method for identifying persons with swallowing dysfunction after stroke. Larger randomized controlled trials are required to confirm our preliminary positive long-term results. Trial registration Retrospectively registered at ClinicalTrials.gov: NCT04164420. Registered on 15 November 2019.

Background: Studies have suggested that fluoxetine could improve neurological recovery after stroke. The Efficacy oF Fluoxetine—a randomisEd Controlled Trial in Stroke (EFFECTS) trial aimed to assess whether administration of oral fluoxetine for 6 months after acute stroke improves functional outcome. Methods: EFFECTS was an investigator-led, multicentre, randomised, placebo-controlled, double-blind, parallel group trial that enrolled patients aged 18 years or older between 2 and 15 days after stroke onset in 35 stroke and rehabilitation centres in Sweden. Eligible patients had a clinical diagnosis of ischaemic or intracerebral haemorrhage, brain imaging that was consistent with intracerebral haemorrhage or ischaemic stroke, and had at least one persisting focal neurological deficit. A web-based randomisation system that incorporated a minimisation algorithm was used to randomly assign (1:1) participants to receive oral fluoxetine 20 mg once daily or matching placebo capsules for 6 months. Patients, care providers, investigators, and outcomes assessors were masked to the allocation. The primary outcome was functional status, measured with the modified Rankin Scale (mRS) at 6 months, analysed in all patients with available mRS data at the 6-month follow-up; we did an ordinal analysis adjusted for the minimisation variables used in the randomisation. This trial is registered with EudraCT, 2011-006130-16; ISRCTN, 13020412; and ClinicalTrials.gov, NCT02683213. Findings: Between Oct 20, 2014, and June 28, 2019, 1500 patients were enrolled, of whom 750 were randomly assigned to fluoxetine and 750 were randomly assigned to placebo. At 6 months, mRS data were available for 737 (98%) patients in the fluoxetine group and 742 (99%) patients in the placebo group. There was no effect of fluoxetine on the primary outcome—distribution across mRS score categories—compared with placebo (adjusted common odds ratio 0·94 [95% CI 0·78 to 1·13]; p=0·42). The proportion of patients with a new diagnosis of depression was lower with fluoxetine than with placebo (54 [7%] patients vs 81 [11%] patients; difference −3·60% [–6·49 to −0·71]; p=0·015), but fluoxetine was associated with more bone fractures (28 [4%] vs 11 [2%]; difference 2·27% [0·66 to 3·87]; p=0·0058) and hyponatraemia (11 [1%] vs one [

This review describes the evolution of endovascular treatment for acute ischemic stroke, current state of the art, and the challenges for the next decade. The rapid development of endovascular thrombectomy (EVT), from the first attempts into standard of care on a global scale, is one of the major achievements in modern medicine. It was possible thanks to the establishment of a scientific framework for patient selection, assessment of stroke severity and outcome, technical development by dedicated physicians and the MedTech industry, including noninvasive imaging for patient selection, and radiological outcome evaluation. A series of randomized controlled trials on EVT in addition to intravenous thrombolytics, with overwhelmingly positive results for anterior circulation stroke within 6 h of onset regardless of patient characteristics with a number needed to treat of less than 3 for any positive shift in outcome, paved the way for a rapid introduction of EVT into clinical practice. Within the “extended” time window of 6–24 h, the effect has been even greater for patients with salvageable brain tissue according to perfusion imaging with a number needed to treat below 2. Even so, EVT is only available for a small portion of stroke patients, and successfully recanalized EVT patients do not always achieve excellent functional outcome. The major challenges in the years to come include rapid prehospital detection of stroke symptoms, adequate clinical and radiological diagnosis of severe ischemic stroke cases, enabling effective recanalization by EVT in dedicated angiosuites, followed by personalized post-EVT stroke care.

Objectives: Clinicians and researchers have addressed concerns about the negative impact of COVID-19 outbreaks on the ability of health care systems to provide timely assessment and acute therapies to patients with stroke. The aim of this study is to describe stroke care during the first wave of the COVID-19 pandemic compared to the same period the year before at an acute care hospital in Sweden. Materials and Methods: In this cohort study data were collected from March 1st to August 31st in 2019 and 2020 on all patients diagnosed with stroke and TIA and registered at Danderyd Hospital in the national quality registry (Riksstroke). Data were completed with information from the hospital record. Sweden had no lockdown during 2020. Results: During the study period in year 2019 there were 426 registered stroke patients at Danderyd hospital, compared to 403 registered stroke patients the same period during 2020 (p = 0.483). The number of minor stroke and TIA during the period in 2019 compared to 2020 were 468 versus 453 respectively (minor stroke p = 0.475 versus TIA p = 0.50). Conclusions: There were no difference in the number of patients diagnosed with stroke and TIA during the first wave of the COVID-19 pandemic.

Objective: Carotid stenosis is a major risk factor for stroke and surgical treatment is key in preventing recurrent ischaemic events. Previous randomised trials have demonstrated the net benefit of surgery for significant symptomatic carotid stenosis but, with present day medical treatment, there is limited evidence on the risk of late ipsilateral ischaemic stroke (IS) and its main risk factors. Method: Ipsilateral IS after the peri-operative period (

Atherosclerosis is an important cause of stroke and accumulating evidence suggests the existence of a possible shared pathophysiological process that may drive aging-related disease such as cardiovascular disease, stroke and dementia. The increased intimal permeability represents the substrate on which initial intimal thickening can promote the development of advanced atherosclerotic lesion. Traditional risk factors of cardiovascular disease (hypertension, diabetes mellitus, dyslipidemia, obesity, smoking and atrial fibrillation) have been associated with increased risk of development of vascular dementia and Alzheimer’s disease. Atherosclerotic plaques are composed of different elements including collagen, necrotic core, inflammatory cells and calcification. Recent advancement of imaging modalities, such as ultrasound, computed tomography and magnetic resonance imaging (MRI), can identify atherosclerosis at different stages of its development and differentiate plaque composition. Calcium can be easily identified using different imaging techniques and its amount is increased with advancing age. Atherosclerotic calcification in the coronary, carotid and intracranial arteries have been strongly associated with microstructural brain changes on brain MRI, dementia and Alzheimer’s disease. Subclinical arterial calcification in carotid and cerebral vessels could be present in asymptomatic patients and its presence could be used as a clue to initiate neuropsychological testing for dementia and also to initiate preventative and therapeutic strategies, because mid-life vascular risk factors control can prevent late-life dementia and stroke.

Background: The efficacy of early supported discharge (ESD) has not been tested in current stroke care setting, which provide relatively short hospital stays, access to hyper-acute therapies and early carotid stenosis interventions. This study aimed to compare patient-reported outcome measures (PROM) among patients with stroke that received modern stroke unit care with or without ESD. Methods: Observational study of 30,232 patients with first-ever stroke registered in the Riksstroke registry in Sweden, between 1 January 2010 and 31 December 2013. Patient characteristics were collected from the Riksstroke and Statistics Sweden databases. The primary outcome was satisfaction with the rehabilitation at 3 months after discharge. Secondary outcome were information about stroke provided, tiredness/fatigue, pain, dysthymia/ depression, general health status and dependence in activities of daily living (mobility, toileting and dressing) at 3 months after the stroke. We used separate multivariable logistic regression models for each PROM variable to analyze associations between PROMs and ESD/no ESD. Results: The ESD group comprised 1495 participants: the control group comprised 28,737 participants. Multivariable logistic regression models of PROMs showed that, compared to controls, the ESD group was more satisfied with rehabilitation after discharge (OR: 1.78, 95% CI: 1.17–2.49), experienced less dysthymia/depression (OR: 0.68, 95% 0.55–0.84) and showed more independence in mobility (OR: 1.50, 95% CI: 1.17–1.92), toileting (OR: 1.30, 95%CI: 1.05–1.61), and dressing (OR: 1.23, 95%CI: 1.02–1.48). Conclusion: In the setting of modern stroke unit care, ESD appeared to have positive effects on stroke rehabilitation, in the subacute phase. Originally included in thesis in manuscript form with title: "Effect of early supported discharge after stroke on patient reported outcome: observational study from the Swedish Riksstroke registry".

BACKGROUND: Primary prevention of cardiovascular disease often fails because of poor adherence among practitioners and individuals to prevention guidelines. We aimed to investigate whether ultrasou ...

IntroductionShortening the time from stroke onset to treatment increases the effectiveness of endovascular stroke therapies.AimThis study aimed to predict the modified Rankin Scale score at 90 days post-stroke (mRS-90d score) in patients with acute ischaemic stroke (AIS) with respect to four types of treatment: conservative therapy (CVT), intravenous thrombolysis only (IVT), mechanical thrombectomy only (MT) and pretreatment with IVT before MT (IVT+MT).Patients and methodsThis nationwide observational study included 124 484 confirmed cases of acute stroke in Sweden over 6 years (2012–2017). The associations between onset-to-treatment time (OTT), patient age and hospital admission National Institutes of Health Stroke Scale (NIHSS) score with the five-levelled mRS-90d score were retrospectively studied. A generalised linear model (GLM) was fitted to predict the mRS-90d scores for each patient group.ResultsThe fitted GLM for CVT patients is a function of age and NIHSS score. For IVT, MT and IVT+MT patients, GLMs additionally employed OTT variables. By reducing the mean OTTs by 15 min, the number needed-to-treat (NNT) for one patient to make a favourable one-step shift in the mRS was 30 for IVT, 48 for MT and 21 for IVT+MT.Discussion and conclusionThis study demonstrates linear associations of mRS-90d score with OTT for IVT, MT and IVT+MT, and shows in absolute effects measures that OTT reductions for IVT and/or MT produces substantial health gains for patients with AIS. Even moderate OTT reductions led to sharp drops in the NNT.

Background: Two out of three randomised controlled trials fail to meet their recruitment goals. Recruitment to EFFECTS, a trial of fluoxetine for stroke recovery was slower than anticipated. We aimed to evaluate an intervention to improve recruitment to EFFECTS.Methods: We performed a stepped wedge, cluster randomised trial embedded in the ongoing EFFECTS trial. The Enhancing Recruitment Using Teleconference and Commitment Contract (ERUTECC) comprised a structured teleconference with the study personnel and the head of department supplemented by a commitment contract. ERUTECC’s primary outcome was the number of patients recruited into EFFECTS per 60 days per site. We compared the recruitment 60 days before the intervention with 60 days after and considered at least a 20% increase to be a positive outcome. All centres started as controls and were followed by 60 days observation. The order in which the centres began was decided through block randomisation.Results: At randomisation, EFFECTS had 29 active centres. ERUTECC recruited 20 centres between 9th Nov 2017 and 30th June 2018, providing 80 site months of observation for the primary analysis.The inclusion rate was 1.9 patient/centre/60 days before the intervention and 2.1 patient/centre/60 days after the intervention, representing a 10% overall increase. However, the recruitment increased more than 20% the first 30 days after the intervention. We also noted that inclusion rate increased directly after the first contact with the centres, announcing a future telephone conference. Some centres changed their screening process, transferring the task from doctors to nurses.Conclusions: Although a teleconference with the study personnel and the head of department accompanied by a commitment contract did not increase recruitment to an RCT by more than 20%, 60 days post intervention, recruitment improved during the first month, especially at low-recruitment centres.Trial registration : The ERUTECC study was registered in the Northern Ireland Hub for Trials Methodology Research Studies Within a Trial Repository (SWAT58) 30 April 2017. https://www.qub.ac.uk/sites/TheNorthernIrelandNetworkforTrialsMethodologyResearch/SWATSWARInformation/Repositories/SWATStore/EFFECTS was retrospectively registered 2 February 2016 in ClinicalTrials.gov: NCT02683213.

Objective: This meta-analysis aims to compare the relationship between phenotypic manifestation of coronary and carotid atherosclerosis using available imaging techniques. Approach and Results: We searched all electronic databases until October 2020 for studies which reported relationship between carotid and coronary atherosclerosis. The primary end point was correlation between carotid intima-media thickness (CIMT) and carotid plaque features (calcification and lipid-rich necrotic core) with coronary artery disease (CAD). Secondary end points included carotid pathology that predicts CAD. Eighty-nine papers with 22 683 patients comparing carotid and coronary atherosclerosis were included in the analysis. CIMT was increased linearly with severity of CAD irrespective of its significance ( P P =0.003), and 2 versus multivessel disease ( P P P =0.03, P r =0.60, P r =0.49, P r =0.53, P r =0.61, P Conclusions: These results support the concept that atherosclerosis affects both carotid and coronary systems, although not always in identical phenotypic manner. These findings highlight the beneficial examination of carotid arteries whenever CAD is suspected.

Introduction: The modified Rankin scale (mRS) is the most common assessment tool for measuring overall functional outcome in stroke studies. The traditional way of using mRS face-to-face is time- and cost-consuming. The aim of this study was to test the validity of the Swedish translation of the simplified modified Rankin scale questionnaire (smRSq) as compared with the mRS assessed face-to-face 6 months after a stroke. Methods: Within the ongoing EFFECTS trial, smRSq was sent out to 108 consecutive stroke patients 6 months after a stroke. The majority, 90% (97/108), of the patients answered the questionnaire; for the remaining 10%, it was answered by the next of kin. The patients were assessed by face-to-face mRS by 7 certified healthcare professionals at 4 Swedish stroke centres. The primary outcome was assessed by Cohen’s kappa and weighted kappa. Results: There was good agreement between postal smRSq, answered by the patients, and the mRS face-to-face; Cohen’s kappa was 0.43 (CI 95% 0.31–0.55), weighted kappa was 0.64 (CI 95% 0.55–0.73), and Spearman rank correlation was 0.82 (p < 0.0001). In 55% (59/108), there was full agreement, and of the 49 patients not showing exact agreement, 44 patients differed by 1 grade and 5 patients had a difference of 2 grades. Discussion/Conclusion: Our results show good validity of the postal smRSq, answered by the patients, compared with the mRS carried out face-to-face at 6 months after a stroke. This result could help trialists in the future simplify study design and make multicentre trials and quality registers with a large number of patients more feasible and time-saving.

Background and aims Many patients with prior intracerebral haemorrhage have indications for antithrombotic treatment with antiplatelet or anticoagulant drugs for prevention of ischaemic events, but it is uncertain whether such treatment is beneficial after intracerebral haemorrhage. STudy of Antithrombotic Treatment after IntraCerebral Haemorrhage will assess (i) the effects of long-term antithrombotic treatment on the risk of recurrent intracerebral haemorrhage and occlusive vascular events after intracerebral haemorrhage and (ii) whether imaging findings, like cerebral microbleeds, modify these effects. Methods STudy of Antithrombotic Treatment after IntraCerebral Haemorrhage is a multicentre, randomised controlled, open trial of starting versus avoiding antithrombotic treatment after non-traumatic intracerebral haemorrhage, in patients with an indication for antithrombotic treatment. Participants with vascular disease as an indication for antiplatelet treatment are randomly allocated to antiplatelet treatment or no antithrombotic treatment. Participants with atrial fibrillation as an indication for anticoagulant treatment are randomly allocated to anticoagulant treatment or no anticoagulant treatment. Cerebral CT or MRI is performed before randomisation. Duration of follow-up is at least two years. The primary outcome is recurrent intracerebral haemorrhage. Secondary outcomes include occlusive vascular events and death. Assessment of clinical outcomes is performed blinded to treatment allocation. Target recruitment is 500 participants. Trial status: Recruitment to STudy of Antithrombotic Treatment after IntraCerebral Haemorrhage is on-going. On 30 April 2020, 44 participants had been enrolled in 31 participating hospitals. An individual patient–data meta-analysis is planned with similar randomised trials.

Studies have suggested that fluoxetine might improve neurological recovery after stroke, but the results remain inconclusive. The EFFECTS (Efficacy oF Fluoxetine – a randomisEd Controlled Trial in Stroke) reached its recruitment target of 1500 patients in June 2019. The purpose of this article is to present all amendments to the protocol and describe how we formed the EFFECTS trial collaboration in Sweden. Methods In this investigator-led, multicentre, parallel-group, randomised, placebo-controlled trial, we enrolled non-depressed stroke patients aged 18 years or older between 2 and 15 days after stroke onset. The patients had a clinical diagnosis of stroke (ischaemic or intracerebral haemorrhage) with persisting focal neurological deficits. Patients were randomised to fluoxetine 20 mg or matching placebo capsules once daily for 6 months. Results Seven amendments were made and included clarification of drug interaction between fluoxetine and metoprolol and the use of metoprolol for severe heart failure as an exclusion criterion, inclusion of data from central Swedish registries and the Swedish Stroke Register, changes in informed consent from patients, and clarification of design of some sub-studies. EFFECTS recruited 1500 patients at 35 centres in Sweden between 20 October 2014 and 28 June 2019. We plan to unblind the data in January 2020 and report the primary outcome in May 2020. Conclusion EFFECTS will provide data on the safety and efficacy of 6 months of treatment with fluoxetine after stroke in a Swedish health system setting. The data from EFFECTS will also contribute to an individual patient data meta-analysis. Trial registration EudraCT 2011-006130-16. Registered on 8 August 2014. ISRCTN, ISRCTN13020412. Registered on 19 December 2014. ClinicalTrials.gov: NCT02683213. Retrospectively registered on 2 February 2016.

Abstract Studies have suggested that fluoxetine might improve neurological recovery after stroke, but the results remain inconclusive. The EFFECTS (Efficacy oF Fluoxetine – a randomisEd Controlled Trial in Stroke) reached its recruitment target of 1500 patients in June 2019. The purpose of this article is to present all amendments to the protocol and describe how we formed the EFFECTS trial collaboration in Sweden. Methods In this investigator-led, multicentre, parallel-group, randomised, placebo-controlled trial, we enrolled non-depressed stroke patients aged 18 years or older between 2 and 15 days after stroke onset. The patients had a clinical diagnosis of stroke (ischaemic or intracerebral haemorrhage) with persisting focal neurological deficits. Patients were randomised to fluoxetine 20 mg or matching placebo capsules once daily for 6 months. Results Seven amendments were made and included clarification of drug interaction between fluoxetine and metoprolol and the use of metoprolol for severe heart failure as an exclusion criterion, inclusion of data from central Swedish registries and the Swedish Stroke Register, changes in informed consent from patients, and clarification of design of some sub-studies. EFFECTS recruited 1500 patients at 35 centres in Sweden between 20 October 2014 and 28 June 2019. We plan to unblind the data in January 2020 and report the primary outcome in May 2020. Conclusion EFFECTS will provide data on the safety and efficacy of 6 months of treatment with fluoxetine after stroke in a Swedish health system setting. The data from EFFECTS will also contribute to an individual patient data meta-analysis. Trial registration EudraCT 2011-006130-16. Registered on 8 August 2014. ISRCTN, ISRCTN13020412. Registered on 19 December 2014. ClinicalTrials.gov: NCT02683213. Retrospectively registered on 2 February 2016.

Objectives: The aim of this study was to map the vertical locations of calcified carotid plaques (CCPs), osseous anatomic structures, and calcified soft tissues in the area of the carotid artery, determine to what extent CCPs are superimposed on the cervical spine in coronal images, and analyze the differences between men and women. Study Design: Computed tomography angiography (CTA) scans of 79 patients were studied. CCPs were discovered in 152 of the total 158 neck sides. Evaluations were performed by using sagittal and coronal reformatted CTA images with maximum intensity projection. Results: Most of the calcified anatomic structures studied, including the carotid bifurcation, were found in close relationship to the level of the third and fourth cervical vertebrae. In the coronal view, all or most of the areas of the CCPs were superimposed on the cervical spine in 22 of 44 (50%) neck sides with CCP in women and in 37 of 108 (34.2%) in men (P = .070). Conclusions: The carotid bifurcation is in close proximity to various calcified anatomic structures. This should be taken into account when diagnosing CCPs in panoramic radiographs. In the coronal view, CCPs and the cervical spine are often superimposed; thus, coronal images are not recommended for confirmation of putative carotid calcifications diagnosed on the basis of panoramic radiographs.

Purpose Ultrasound examinations of atherosclerotic carotid plaques can be used to calculate risk markers associated with plaque vulnerability. Recent studies demonstrate significant inter-frame variability in risk markers. Here, we investigate risk marker variability in symptomatic plaques and its impact on reclassification of plaque vulnerability, as well as its association with the shape of the temporal variation over the cardiac cycle. Methods 56 patients with symptomatic carotid stenosis were included in this study. 88 plaques were identified and the plaque risk markers size (area), echogenicity (gray scale median, GSM) and heterogeneity (coarseness) were measured in all frames of ultrasound B-mode image sequences. Inter-frame variability was quantified using the coefficient of variation (CV). Results Inter-frame variabilities of the risk markers were area CV 5–8%; GSM CV 4–7%; coarseness CV 8–15% and was in general significantly lower in large as compared to smaller plaques. The variability in GSM risk marker caused a reclassification of vulnerability in 30 to 38% of the plaques. Temporal variations in GSM with a heart rate periodic or drift/trending pattern were found in smaller plaques (2), whereas random pattern was found in larger plaques. In addition, hypoechoic plaques (GSM Conclusions Risk marker variability causes substantial reclassification of plaque vulnerability in symptomatic patients. Inter-frame variation and its temporal pattern should be considered in the design of future studies related to risk markers.

Background Many randomised controlled trials (RCTs) fail to meet their recruitment goals in time. Trialists are advised to include study recruitment strategies within their trials. EFFECTS is a Swedish, academic-led RCT of fluoxetine for stroke recovery. The trial’s primary objective is to investigate whether 20 mg fluoxetine daily compared with placebo for 6 months after an acute stroke improves the patient’s functional outcome. The first patient was included on 20 October 2014 and, as of 31 August 2017, EFFECTS has included 810 of planned 1500 individuals. EFFECTS currently has 32 active centres. The primary objective of the ERUTECC (Enhancing Recruitment Using Teleconference and Commitment Contract) study is to investigate whether a structured teleconference re-visit with the study personnel at the centres, accompanied by a commitment contract, can enhance recruitment by 20% at 60 days post intervention, compared with 60 days pre-intervention, in an ongoing RCT. Methods ERUTECC is a randomised, stepped-wedge cluster trial embedded in EFFECTS. The plan is to start ERUTECC with a running-in period of September 2017. The first intervention is due in October 2017, and the study will continue for 12 months. We are planning to intervene at all active centres in EFFECTS, except the five top recruiting centres (n = 27). The rationale for not intervening at the top recruiting centres is that we believe they have reached their full potential and the intervention would be too weak for them. The hypothesis of this study is that a structured teleconference re-visit with the study personnel at the centres, accompanied by a commitment contract, can enhance recruitment by 20% 60 days post intervention, compared to 60 days pre-intervention, in an ongoing RCT. Discussion EFFECTS is a large, pragmatic RCT of stroke in Sweden. Results from the embedded ERUTECC study could probably be generalised to high-income Western countries, and is relevant to trial management and could improve trial management in the future. It might also be useful in clinical settings outside the field of stroke. Trial registrations The ERUTECC study was registered in the Northern Ireland Hub for Trials Methodology Research Studies Within a Trial repository (SWAT58) on 30 April 2017. ClinicalTrials.gov, ID: NCT02683213. Retrospectively registered on 2 February 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2367-8) contains supplementary material, which is available to authorized users.

Background Clinical risk factors of cardiovascular diseases (CVD) are related to atherosclerosis and cIMT and plaque are signs of early atherosclerosis. However, associations between risk factors and ultrasound variables are not fully established and comparison between studies is hampered by different imaging protocols. There is limited data regarding study population characteristics and ultrasound measurements differ regarding arterial bed, projections, and plaque definitions and inclusion Purpose 1/ To describe the distribution of asymptomatic atherosclerosis as assessed by carotid ultrasound in a middle-aged population at low/intermediate risk of CVD. 2/ To investigate the associations between clinical risk factors and a set of ultrasound variables Method Bilateral carotid ultrasound examinations were performed according to a standardized protocol in 3532 healthy VIPVIZA-participants with at least one conventional CVD risk factor. CIMT was measured in the distal far wall of CCA, 240o and 210o left and 150o and 120o right side, based on Meijer arch. For each angle, mean and max IMT was measured in a 10 mm segment. Plaques were identified according to the Mannheim consensus. Socio-economic data was also recorded. Associations between the risk factors and the set of ultrasound variables were quantified by a partial least squares (PLS) regression. A new compound ultrasound variable was computed, PLS UL, bya combining all IMT variables and plaque using the weights of the first PLS component. In a second step, to estimate how much risk factors explained the variability of the ultrasound results, associations between risk factors and both PLS UL and single cIMT variables and plaque were determined using step-wise linear regression modelling Results Mean age was 55.6 and 55.8 years among men and women (52.7% women), 13% were smokers in both sexes, and 50.8% and 39.3%, respectively, had carotid plaque. Mean of mean cIMT was 0.68 mm vs 0.64 mm (p All ultrasound variables had similar univariate associations with clinical risk factors, positive associations for all risk factors except physical activity, fruit and vegetable consumption, education and HDL-cholesterol. The strongest association between risk factors and ultrasound variables was found with PLS UL (R2=23%), compared to single cIMT variables (R2=14–18%) and plaque (R2=15%). The pattern was similar in both sexes with most risk factors shared between the sexes. The association with factors and PLS UL was stronger among 40-year olds (R2=22%) than among 50- and 60-year olds (R=12%) Conclusion A combination of ultrasound variables are stronger associated to CVD risk factors than plaque or a single CIMT measurement. The pattern is similar in men and women. These findings are relevant for development of a consensus for cIMT measurements Acknowledgement/Funding Västerbotten County Council, the Swedish Research Council, the Heart and Lung Foundation, the Swedish Society of Medicin, Carl Bennet Ltd, Sweden

Background Time delay from stroke onset to hospital arrival is an important obstacle to recanalization therapy. To increase knowledge about stroke symptoms and potentially reduce delayed hospital arrival, a 27-month national public information campaign was conducted in Sweden. Aim To assess the effects of a national stroke campaign in Sweden. Methods This nationwide study included 97,840 patients with acute stroke, admitted to hospital and registered in the Swedish Stroke Register from 1 October 2010 to 31 December 2014 (one year before the campaign started to one year after the campaign ended). End points were (1) proportion of patients arriving at hospital within 3 h of stroke onset and (2) the proportion Results During the campaign, both the proportion of patients arriving at hospital within 3 h (p Conclusion The Swedish National Stroke Campaign was associated with a sustained increase in the proportion of patients receiving recanalization therapy and a small but significant improvement in the proportion arriving at hospital within 3 h.

Objectives: this prospective, cluster randomised, controlled trial investigated the effect of oral neuromuscular training among older people in intermediate care with impaired swallowing. Methods: older people (≥65 years) with swallowing dysfunction were cluster randomised according to care units for 5 weeks of neuromuscular training of the orofacial and pharyngeal muscles or usual care. The primary endpoint was the change in swallowing rate (assessed with a timed water swallow test) from baseline to the end-of-treatment and 6 months post-treatment. The secondary endpoints were changes in signs of aspiration during the water swallow test, and swallowing-related quality of life (QOL). An intention-to-treat principle was followed, and mixed-effects models were used for data analysis with the clustered study design as a random factor. Results: in total, 385 participants from 36 intermediate care units were screened, and 116 participants were randomly assigned to oral neuromuscular training (intervention; n = 49) or usual care (controls; n = 67). At the end of treatment, the geometric mean of the swallowing rate in the intervention group had significantly improved 60% more than that of controls (P = 0.007). At 6 months post-treatment, the swallowing rate of the intervention group remained significantly better (P = 0.031). Signs of aspiration also significantly reduced in the intervention group compared with controls (P = 0.01). No significant between-group differences were found for swallowing-related QOL. Conclusions: oral neuromuscular training is a new promising swallowing rehabilitation method among older people in intermediate care with impaired swallowing. Trial registration: ClinicalTrials.gov: NCT02825927. Originally included in thesis in manuscript form.

Objectives: We investigated the associations between swallowing dysfunction, poor oral health and mortality among older people in intermediate care in Sweden. Methods: This prospective cohort study investigated 391 older people in 36 intermediate care units (clusters). Swallowing function was assessed with the timed water swallow test (TWST), and oral health with the revised oral assessment guide (ROAG) at baseline. Data were collected on age, sex, education level, multimorbidity, cognitive impairment, care dependency and body mass index (BMI). Time to mortality was recorded during the following year. The mixed effects Cox regression model with cluster as a random factor was used to estimate hazards ratios (HR) with 95% confidence intervals (CI). Results: The median age of the participants was 84 years (interquartile range [IQR]: 11), and 53.3% were females. Mortality within one year was 25.1%. In the adjusted model, swallowing dysfunction and poor oral health were both independently associated with mortality (adjusted HR [aHR]: 1.67, 95% CI 1.02‐2.75; P = .041 and aHR: 1.98, 95% CI 1.07‐3.65; P = .029, respectively). Participants with combined swallowing dysfunction and poor oral health showed the highest mortality (35.0%) and 2.6 (95% CI 1.15‐5.89; P = .022) times higher mortality risk than those with normal swallowing function and good oral health (13.0%). Conclusions: Swallowing dysfunction and poor oral health were identified as independent risk factors for mortality in older people in intermediate care. Although further studies are required to verify these findings, they suggest that systematic assessment of swallowing function and oral health status should be performed for care considerations. Originally included in thesis in manuscript form

Background In odontology, panoramic radiographs (PRs) are regularly performed. PRs depict the teeth and jaws as well as carotid artery calcifications (CACs). Patients with CACs on PRs have an increased risk of vascular events compared to healthy controls without CACs, but this association is often caused by more vascular events and risk factors at baseline. However, the risk of vascular events has only been analyzed based on the presence of CACs, and not their shape. Thus, this study determined if the shape of CACs in PRs affects the risk of future vascular events. Methods The study cohort included 117 consecutive patients with CACs in PRs and 121 age-matched controls without CACs. CAC shape in PRs was dichotomized into bilateral vessel-outlining CACs and other CAC shapes. Participants were followed prospectively for an endpoint of vascular events including myocardial infarction, stroke, and vascular death. Results Patients with bilateral vessel-outlining CACs had more previous vascular events than those with other CAC shapes and the healthy controls (p 2). The mean follow-up duration was 9.5 years. The endpoint was reached in 83 people. Patients with bilateral vessel-outlining CACs had a higher annual risk of vascular events (7.0%) than those with other CAC shapes (4.4%) and the controls (2.6%) (p Conclusions Findings of bilateral vessel-outlining CACs in PRs are independent risk markers for future vascular events.

OBJECTIVE: To evaluate the cost-effectiveness of adding endovascular thrombectomy to standard care in patients with acute ischemic stroke. METHODS: The cost-effectiveness analysis of endovascular thrombectomy in patients with acute ischemic stroke was based on a decision-analytic Markov model. Primary outcomes from ESCAPE, Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA), Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours (REVASCAT), and Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) along with data from published studies and registries were used in this analysis. We used a health care payer perspective and a lifelong time horizon to estimate costs and effects. RESULTS: The model showed that adding thrombectomy with stent retrievers to guideline-based care (including IV thrombolysis) resulted in a gain of 0.40 life-years and 0.99 quality-adjusted life-years along with a cost savings of approximately $221 per patient. The sensitivity analysis showed that the results were not sensitive to changes in uncertain parameters or assumptions. CONCLUSIONS: Adding endovascular treatment to standard care resulted in substantial clinical benefits at low costs. The results were consistent throughout irrespective of whether data from ESCAPE, EXTEND-IA, MR CLEAN, REVASCAT, or SWIFT PRIME were used in this model. Funding agencies: Dental and Pharmaceutical Benefits Agency