Publications by authors named "Stefan T Engelter"

135 Publications

Rivaroxaban versus aspirin for prevention of covert brain infarcts in patients with embolic stroke of undetermined source: NAVIGATE ESUS MRI substudy.

Int J Stroke 2021 Nov 18:17474930211058012. Epub 2021 Nov 18.

Population Health Research Institute, Hamilton Health Sciences, Hamilton, ON, Canada.

Background: Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown.

Aims: To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies.

Methods: At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression.

Results: Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52-1.7).

Conclusions: Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide. https://www.clinicaltrials.gov. Unique identifier: NCT02313909.
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http://dx.doi.org/10.1177/17474930211058012DOI Listing
November 2021

Oral Anticoagulants in the Oldest Old with Recent Stroke and Atrial Fibrillation.

Ann Neurol 2021 Nov 8. Epub 2021 Nov 8.

Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Perugia, Italy.

Objective: To investigate the safety and effectiveness of direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA) after recent stroke in patients with atrial fibrillation (AF) aged ≥85 years.

Methods: Individual patient data analysis from seven prospective stroke cohorts. We compared DOAC versus VKA treatment among patients with AF and recent stroke (<3 months) aged ≥85 versus <85 years. Primary outcome was the composite of recurrent stroke, intracranial hemorrhage (ICH) and all-cause death. We used simple, adjusted, and weighted Cox regression to account for confounders. We calculated the net benefit of DOAC versus VKA by balancing stroke reduction against the weighted ICH risk.

Results: In total, 5,984 of 6,267 (95.5%) patients were eligible for analysis. Of those, 1,380 (23%) were aged ≥85 years and 3,688 (62%) received a DOAC. During 6,874 patient-years follow-up, the impact of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome did not differ between patients aged ≥85 (HR  = 0.65, 95%-CI [0.52, 0.81]) and < 85 years (HR  = 0.79, 95%-CI [0.66, 0.95]) in simple (p  = 0.129), adjusted (p  = 0.094) or weighted (p  = 0.512) models. Analyses on recurrent stroke, ICH and death separately were consistent with the primary analysis, as were sensitivity analyses using age dichotomized at 90 years and as a continuous variable. DOAC had a similar net clinical benefit in patients aged ≥85 (+1.73 to +2.66) and < 85 years (+1.90 to +3.36 events/100 patient-years for ICH-weights 1.5 to 3.1).

Interpretation: The favorable profile of DOAC over VKA in patients with AF and recent stroke was maintained in the oldest old. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26267DOI Listing
November 2021

ESO guideline for the management of extracranial and intracranial artery dissection.

Eur Stroke J 2021 Sep 13;6(3):XXXIX-LXXXVIII. Epub 2021 Oct 13.

Department of Neurology, University of Utah, Salt Lake City, UT, USA.

The aim of the present European Stroke Organisation guideline is to provide clinically useful evidence-based recommendations on the management of extracranial artery dissection (EAD) and intracranial artery dissection (IAD). EAD and IAD represent leading causes of stroke in the young, but are uncommon in the general population, thus making it challenging to conduct clinical trials and large observational studies. The guidelines were prepared following the Standard Operational Procedure for European Stroke Organisation guidelines and according to GRADE methodology. Our four recommendations result from a thorough analysis of the literature comprising two randomized controlled trials (RCTs) comparing anticoagulants to antiplatelets in the acute phase of ischemic stroke and twenty-six comparative observational studies. In EAD patients with acute ischemic stroke, we recommend using intravenous thrombolysis (IVT) with alteplase within 4.5 hours of onset if standard inclusion/exclusion criteria are met, and mechanical thrombectomy in patients with large vessel occlusion of the anterior circulation. We further recommend early endovascular or surgical intervention for IAD patients with subarachnoid hemorrhage (SAH). Based on evidence from two phase 2 RCTs that have shown no difference between the benefits and risks of anticoagulants versus antiplatelets in the acute phase of symptomatic EAD, we strongly recommend that clinicians can prescribe either option. In post-acute EAD patients with residual stenosis or dissecting aneurysms and in symptomatic IAD patients with an intracranial dissecting aneurysm and isolated headache, there is insufficient data to provide a recommendation on the benefits and risks of endovascular/surgical treatment. Finally, nine expert consensus statements, adopted by 8 to 11 of the 11 experts involved, propose guidance for clinicians when the quality of evidence was too low to provide recommendations. Some of these pertain to the management of IAD (use of IVT, endovascular treatment, and antiplatelets versus anticoagulation in IAD with ischemic stroke and use of endovascular or surgical interventions for IAD with headache only). Other expert consensus statements address the use of direct anticoagulants and dual antiplatelet therapy in EAD-related cerebral ischemia, endovascular treatment of the EAD/IAD lesion, and multidisciplinary assessment of the best therapeutic approaches in specific situations.
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http://dx.doi.org/10.1177/23969873211046475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564160PMC
September 2021

Early versus late start of direct oral anticoagulants after acute ischaemic stroke linked to atrial fibrillation: an observational study and individual patient data pooled analysis.

J Neurol Neurosurg Psychiatry 2021 Oct 11. Epub 2021 Oct 11.

Stroke Research Center, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.

Objective: The optimal timing to start direct oral anticoagulants (DOACs) after an acute ischaemic stroke (AIS) related to atrial fibrillation (AF) remains unclear. We aimed to compare early (≤5 days of AIS) versus late (>5 days of AIS) DOAC-start.

Methods: This is an individual patient data pooled analysis of eight prospective European and Japanese cohort studies. We included patients with AIS related to non-valvular AF where a DOAC was started within 30 days. Primary endpoints were 30-day rates of recurrent AIS and ICH.

Results: A total of 2550 patients were included. DOACs were started early in 1362 (53%) patients, late in 1188 (47%). During 212 patient-years, 37 patients had a recurrent AIS (1.5%), 16 (43%) before a DOAC was started; 6 patients (0.2%) had an ICH, all after DOAC-start. In the early DOAC-start group, 23 patients (1.7%) suffered from a recurrent AIS, while 2 patients (0.1%) had an ICH. In the late DOAC-start group, 14 patients (1.2%) suffered from a recurrent AIS; 4 patients (0.3%) suffered from ICH. In the propensity score-adjusted comparison of late versus early DOAC-start groups, there was no statistically significant difference in the hazard of recurrent AIS (aHR=1.2, 95% CI 0.5 to 2.9, p=0.69), ICH (aHR=6.0, 95% CI 0.6 to 56.3, p=0.12) or any stroke.

Conclusions: Our results do not corroborate concerns that an early DOAC-start might excessively increase the risk of ICH. The sevenfold higher risk of recurrent AIS than ICH suggests that an early DOAC-start might be reasonable, supporting enrolment into randomised trials comparing an early versus late DOAC-start.
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http://dx.doi.org/10.1136/jnnp-2021-327236DOI Listing
October 2021

Cervical and intracranial artery dissections.

Ther Adv Neurol Disord 2021 12;14:17562864211037238. Epub 2021 Aug 12.

Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Petersgraben 4, Basel 4031, Switzerland.

This review summarizes recent therapeutic advances in cervical (CeAD) and intracranial artery dissection (IAD) research. Despite unproven benefits, but in the absence of any signal of harm, in patients, with acute ischemic stroke attributable to CeAD, intravenous thrombolysis and, in case of large-vessel occlusion, endovascular revascularization should be considered. Future research will clarify which patients benefit most from either treatment modality. For stroke prevention, the recently published randomized controlled TREAT-CAD study showed that, against the initial hypothesis, aspirin was not shown non-inferior to anticoagulation with vitamin K antagonists (VKAs). With the results of two randomized controlled trials (CADISS and TREAT-CAD) available now, the evidence to consider aspirin as the standard therapy of CeAD is weak. Further analyses might clarify whether the assumption supports, in particular, that patients presenting with cerebral ischemia, clinical or subclinical with magnetic resonance imaging surrogates, might benefit most from VKA treatment. In turn, it remains to be shown, whether in CeAD patients presenting with pure local symptoms and without hemodynamic compromise, antiplatelets are sufficient, and whether a dual antiplatelet therapy during the first weeks of treatment is recommendable. The observation that ischemic strokes occurred (or recurred) very early after CeAD diagnosis, consistently across randomized and observational studies, supports the recommendation to start antithrombotic treatment immediately, whatever antithrombotic agent is chosen in each individual case. The lack of a license for the use in CeAD patients and the paucity of data are still arguments against the use of direct oral anticoagulants in CeAD. Nevertheless, due to their beneficial safety and efficacy profile proven in atrial fibrillation, these agents are a worthwhile treatment option to be tested in further CeAD treatment trials. In IAD, the experience with the use of antithrombotic agents is limited. As the risk of suffering intracranial hemorrhage is higher in IAD than in CeAD, the use of antithrombotic therapy in IAD remains controversial.
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http://dx.doi.org/10.1177/17562864211037238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366117PMC
August 2021

Oral Anticoagulants in Atrial Fibrillation Patients With Recent Stroke Who Are Dependent on the Daily Help of Others.

Stroke 2021 Nov 27;52(11):3472-3481. Epub 2021 Jul 27.

Department of Neurology and Stroke Center (L.M., A.A.P., F.S., V.L.A., C.T., S.T., B.W., J.F., A.Z., T.D., U.F., N.P., G.M.D.M., H.G., L.H.B., P.A.L., S.T.E.), University Hospital Basel and University of Basel, Switzerland.

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.120.033862DOI Listing
November 2021

[Intracerebral haemorrhage - acute event and chronic disease].

Ther Umsch 2021 Aug;78(6):320-327

Klinik für Neurologie, Inselspital Universitätsspital Bern.

Intracerebral haemorrhage - acute event and chronic disease Intracerebral hemorrhage accounts for 10-15% of all strokes and approximately 1'500-2'000 patients per year in Switzerland. Acute treatment by multi-disciplinary experts at certified stroke units and stroke centers is important to provide optimal care. A simple ABC-care bundle (revert anticoagulation, control blood pressure, inform neurosurgeon) decreases poor outcome. Despite a high mortality, one third of patients are functionally independent after intracerebral hemorrhage contradicting widespread pessimism. About 80% of all intracerebral hemorrhage are attributable to different types of cerebral small vessel disease. Relative and absolute risks of recurrent hemorrhage and ischemic stroke differ significantly. Patients with intracerebral hemorrhage are vascular high-risk patients with chronic cerebrovascular disease. Long-term outpatient management should include neurovascular specialists to deal with important decisions (blood pressure management, antithrombotic therapy including anticoagulation, specialized neurorehabilitation to improve neurocognitive deficits, therapy of possible complications such as epilepsy) to provide optimal and individual care to patients. Currently ongoing randomized controlled trials will provide important results in the next years further improving treatment of intracerebral hemorrhage.
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http://dx.doi.org/10.1024/0040-5930/a001276DOI Listing
August 2021

Cervical Artery Dissection and Sports.

Front Neurol 2021 31;12:663830. Epub 2021 May 31.

Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.

Cervical artery dissection (CeAD) occurring in the context of sports is a matter of concern for CeAD patients. They seek advice on the role of sports in CeAD and on the safety of resuming sports after CeAD. The scarcity of studies and guidelines addressing these issues poses a challenge. We aimed at summarizing the current knowledge about CeAD and sports in order to provide an informed, comprehensive opinion for counseling CeAD patients. We took into account pathophysiological considerations, observations of cases reports, series, and registries, and conclusions by analogy from aortic dissection or inherited connective tissue syndromes. In summary, practicing active sports as the cause of CeAD seems uncommon. It seems recommendable to refrain from any kind of sports activities for at least 1 month, which can be extended in case of an unfavorable clinical or neurovascular course. We recommend starting with sport activities at low intensity-preferably with types of endurance sports-and to gradually increase the pace in an individually tailored manner, taking into circumstances of the occurrences of the CeAD in the individual patient (particularly in relation to sports), the meaning of sports activities for the individual well-being, the presence or absence of comorbidities and of neurological sequela, neurovascular findings, and whether there are signs of an underlying connective tissue alteration. Major limitations and several forms of bias are acknowledged. Still, in the absence of any better data, the summarized observations and considerations might help clinicians in advising and counseling patients with CeAD in clinical practice.
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http://dx.doi.org/10.3389/fneur.2021.663830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200565PMC
May 2021

Impact of the COVID-19 lockdown on the adherence of stroke patients to direct oral anticoagulants: a secondary analysis from the MAAESTRO study.

J Neurol 2021 Jun 3. Epub 2021 Jun 3.

Department of Neurology and Stroke Centre, University Hospital Basel and University of Basel, Basel, Switzerland.

Background: The negative impact of the COVID-19 outbreak on stroke care has been reported, but no data exist on the influence of the lockdown on medication adherence to antithrombotic treatment for stroke prevention. We present a comparison of electronic adherence data of stroke patients treated with direct oral anticoagulants (DOAC) prior to and during the COVID-19 lockdown in spring 2020 in Switzerland.

Methods: This is a secondary analysis using data from the ongoing MAAESTRO study, in which stroke patients with atrial fibrillation electronically monitor their adherence to DOAC treatment. Eligible patients for this analysis had at least four weeks of adherence data prior to and during the COVID-19 lockdown. Three adherence metrics (taking adherence, timing adherence, drug holidays) were calculated and compared descriptively.

Results: The analysis included eight patients (median age 81.5 years, IQR 74.8-84.5). Five patients had a pre-lockdown taking adherence over 90% (mean 96.8% ± 2.9), with no change during lockdown, high timing adherence in both periods and no drug holidays. The remaining three patients had pre-lockdown taking and timing adherence below 90%. Of those, two patients showed a moderate decline either in taking or timing adherence compared to pre-lockdown. One showed a substantial increase in taking and timing adherence during lockdown (both + 25.8%).

Conclusion: Our data suggest that a major disruption of social life (i.e., the imposed COVID-19 lockdown) is unlikely to relevantly affect the medication intake behaviour of patients with high pre-established adherence, but might have an impact in patients with previously suboptimal adherence.

Trial Registration Number: MAAESTRO: electronic Monitoring and improvement of Adherence to direct oral Anticoagulant treatment-a randomized crossover study of an Educational and reminder-based intervention in ischaemic STROke patients under polypharmacy, NCT03344146.
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http://dx.doi.org/10.1007/s00415-021-10631-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173508PMC
June 2021

Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial.

Lancet Neurol 2021 05 23;20(5):341-350. Epub 2021 Mar 23.

Department of Neurology and Stroke Centre, University Hospital Basel and University of Basel, Basel, Switzerland; Neurology and Neurorehabilitation, University Hospital for Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland.

Background: Cervical artery dissection is a major cause of stroke in young people (aged <50 years). Historically, clinicians have preferred using oral anticoagulation with vitamin K antagonists for patients with cervical artery dissection, although some current guidelines-based on available evidence from mostly observational studies-suggest using aspirin. If proven to be non-inferior to vitamin K antagonists, aspirin might be preferable, due to its ease of use and lower cost. We aimed to test the non-inferiority of aspirin to vitamin K antagonists in patients with cervical artery dissection.

Methods: We did a multicentre, randomised, open-label, non-inferiority trial in ten stroke centres across Switzerland, Germany, and Denmark. We randomly assigned (1:1) patients aged older than 18 years who had symptomatic, MRI-verified, cervical artery dissection within 2 weeks before enrolment, to receive either aspirin 300 mg once daily or a vitamin K antagonist (phenprocoumon, acenocoumarol, or warfarin; target international normalised ratio [INR] 2·0-3·0) for 90 days. Randomisation was computer-generated using an interactive web response system, with stratification according to participating site. Independent imaging core laboratory adjudicators were masked to treatment allocation, but investigators, patients, and clinical event adjudicators were aware of treatment allocation. The primary endpoint was a composite of clinical outcomes (stroke, major haemorrhage, or death) and MRI outcomes (new ischaemic or haemorrhagic brain lesions) in the per-protocol population, assessed at 14 days (clinical and MRI outcomes) and 90 days (clinical outcomes only) after commencing treatment. Non-inferiority of aspirin would be shown if the upper limit of the two-sided 95% CI of the absolute risk difference between groups was less than 12% (non-inferiority margin). This trial is registered with ClinicalTrials.gov, NCT02046460.

Findings: Between Sept 11, 2013, and Dec 21, 2018, we enrolled 194 patients; 100 (52%) were assigned to the aspirin group and 94 (48%) were assigned to the vitamin K antagonist group. The per-protocol population included 173 patients; 91 (53%) in the aspirin group and 82 (47%) in the vitamin K antagonist group. The primary endpoint occurred in 21 (23%) of 91 patients in the aspirin group and in 12 (15%) of 82 patients in the vitamin K antagonist group (absolute difference 8% [95% CI -4 to 21], non-inferiority p=0·55). Thus, non-inferiority of aspirin was not shown. Seven patients (8%) in the aspirin group and none in the vitamin K antagonist group had ischaemic strokes. One patient (1%) in the vitamin K antagonist group and none in the aspirin group had major extracranial haemorrhage. There were no deaths. Subclinical MRI outcomes were recorded in 14 patients (15%) in the aspirin group and in 11 patients (13%) in the vitamin K antagonist group. There were 19 adverse events in the aspirin group, and 26 in the vitamin K antagonist group.

Interpretation: Our findings did not show that aspirin was non-inferior to vitamin K antagonists in the treatment of cervical artery dissection.

Funding: Swiss National Science Foundation, Swiss Heart Foundation, Stroke Funds Basel, University Hospital Basel, University of Basel, Academic Society Basel.
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http://dx.doi.org/10.1016/S1474-4422(21)00044-2DOI Listing
May 2021

Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.

Lancet Neurol 2021 04 17;20(4):294-303. Epub 2021 Mar 17.

Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk.

Methods: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602.

Findings: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models.

Interpretation: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted.

Funding: British Heart Foundation and Stroke Association.
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http://dx.doi.org/10.1016/S1474-4422(21)00024-7DOI Listing
April 2021

A nomogram to predict unfavourable outcome in patients receiving oral anticoagulants for atrial fibrillation after stroke.

Eur Stroke J 2020 Dec 26;5(4):384-393. Epub 2020 Nov 26.

Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.

Introduction: It is unknown whether the type of treatment (direct oral anticoagulant versus vitamin K antagonist) and the time of treatment introduction (early versus late) may affect the functional outcome in stroke patients with atrial fibrillation. We aimed to develop and validate a nomogram model including direct oral anticoagulant/vitamin K antagonist and early/late oral anticoagulant introduction for predicting the probability of unfavourable outcome after stroke in atrial fibrillation-patients.

Patients And Methods: We conducted an individual patient data analysis of four prospective studies. Unfavourable functional outcome was defined as three-month modified Rankin Scale score 3 -6. To generate the nomogram, five independent predictors including age (<65 years, reference; 65--79; or 80), National Institutes of Health Stroke Scale score (0--5 points, reference; 6--15; 16--25; or >25), acute revascularisation treatments (yes, reference, or no), direct oral anticoagulant (reference) or vitamin K antagonist, and early (7 days, reference) or late (8--30) anticoagulant introduction entered into a final logistic regression model. The discriminative performance of the model was assessed by using the area under the receiver operating characteristic curve.

Results: A total of 2102 patients with complete data for generating the nomogram was randomly dichotomised into training ( = 1553) and test ( = 549) sets. The area under the receiver operating characteristic curve was 0.822 (95% confidence interval, CI: 0.800--0.844) in the training set and 0.803 (95% CI: 0.764--0.842) in the test set. The model was adequately calibrated (9.852;  = 0.276 for the Hosmer--Lemeshow test).

Discussion And Conclusion: Our nomogram is the first model including type of oral anticoagulant and time of treatment introduction to predict the probability of three-month unfavourable outcome in a large multicentre cohort of stroke patients with atrial fibrillation.
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http://dx.doi.org/10.1177/2396987320945840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856583PMC
December 2020

Tenecteplase in wake-up ischemic stroke trial: Protocol for a randomized-controlled trial.

Int J Stroke 2021 10 14;16(8):990-994. Epub 2021 Jan 14.

Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.

Background: Patients with wake-up ischemic stroke who have evidence of salvageable tissue on advanced imaging can benefit from intravenous thrombolysis. It is not known whether patients who do not fulfil such imaging criteria might benefit from treatment, but studies indicate that treatment based on non-contrast CT criteria may be safe. Tenecteplase has shown promising results in patients with acute ischemic stroke. The aim of the Tenecteplase in Wake-up Ischemic Stroke Trial (TWIST) is to compare the effect of thrombolytic treatment with tenecteplase and standard care versus standard care alone in patients with wake-up ischemic stroke selected by non-contrast CT.

Methods/design: TWIST is an international, investigator-initiated, multi-centre, prospective, randomized-controlled, open-label, blinded end-point trial of tenecteplase ( = 300) versus standard care ( = 300) in patients who wake up with an acute ischemic stroke and can be treated within 4.5 h upon awakening. Seventy-seven centres in 10 countries (Denmark, Estonia, Finland, Latvia, Lithuania, New Zealand, Norway, Sweden, Switzerland, and the United Kingdom) participate. The primary outcome is the modified Rankin Scale on the ordinal scale (0-6) at three months.

Discussion: TWIST aims to determine the effect and safety of thrombolytic treatment with tenecteplase in patients with wake-up ischemic stroke selected by non-contrast CT.

Trial Registration: ClinicalTrials.gov NCT03181360. EudraCT Number 2014-000096-80.
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http://dx.doi.org/10.1177/1747493020984073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554491PMC
October 2021

Insights Into Direct Oral Anticoagulant Therapy Implementation of Stroke Survivors with Atrial Fibrillation in an Ambulatory Setting.

J Stroke Cerebrovasc Dis 2021 Feb 14;30(2):105530. Epub 2020 Dec 14.

Pharmaceutical Care Research Group, Department of Pharmaceutical Sciences, University of Basel, Petersplatz 14, Postfach 2148, 4051 Basel, Switzerland, Tel: +41 61 207 14 26. Electronic address:

Objectives: To describe how stroke survivors with atrial fibrillation implement direct oral anticoagulant treatment and propose appropriate metrics to describe adherence.

Materials And Methods: Stroke patients with atrial fibrillation electronically recorded their self-administered direct oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) during a 6-month observation phase after hospitalisation for ischemic stroke. Taking and timing adherence, correct dosing days, drug holidays, time of the day and day of the week subsets, dose-to-dose intervals and longest intervals between two consecutive doses were calculated from electronic monitoring data to describe and discuss the implementation phase of adherence.

Results: Data from 41 patients were analysed. Median age was 77 (IQR = 69-84), 63.4% were male and the majority suffered a mild stroke (median NIHSS: 1). Mean taking and timing adherence exceeded 90%. Correct dosing occurred in 86.6% of the days. Seven patients (17.1%) had intake pauses of three or more consecutive days. Patients with twice-daily regimen (70.7%) had higher taking adherence in the morning than in the evening (94.4% versus 89.9%; p = 0.001). No therapy- or anamneses-related characteristic was associated with taking adherence.

Conclusions: Although adherence to direct oral anticoagulants of stroke patients with atrial fibrillation exceeded 90%, deviant intake patterns such as drug holidays and missed evening doses were common and raise concerns. Appropriate adherence metrics calculated from electronic monitoring data may guide healthcare professionals elucidating patient-tailored adherence-enhancing interventions. ClinicalTrials.gov registration number: NCT03344146.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105530DOI Listing
February 2021

Biomarkers and antithrombotic treatment in cervical artery dissection - Design of the TREAT-CAD randomised trial.

Eur Stroke J 2020 Sep 29;5(3):309-319. Epub 2020 Jun 29.

Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.

Introduction: The type of antithrombotic treatment in cervical artery dissection patients is still a matter of debate. Most physicians prefer anticoagulants over antiplatelet agents for stroke prevention. However, this approach is not evidence-based and antiplatelets might be as safe and as effective. The 'Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection' ('TREAT-CAD') trial (clinicaltrials.gov: NCT02046460) compares Aspirin to oral anticoagulants (vitamin K antagonists) with regard to efficacy and safety by using both clinical and imaging surrogate outcome measures. TREAT-CAD tests the hypothesis, that aspirin is as safe and effective as vitamin K antagonists.

Patients And Methods: TREAD-CAD is a rospective, andomised controlled, pen-labelled, multicentre, non-inferiority trial with linded assessment of outcome vents (PROBE-design). Key eligibility criteria are (i) clinical symptoms attributable to cervical artery dissection and (ii) verification of the cervical artery dissection diagnosis by established magnetic resonance imaging criteria. Patients are randomised to receive either Aspirin 300 mg daily or vitamin K antagonists for 90 days.

Results: Primary outcomes are assessed at 14 ± 10 days (magnetic resonance imaging and clinical examination) and at 90 ± 30 days (clinical examinations). The primary endpoint is a composite outcome measure - labelled erebrovascular schemia, major emorrhagic events or eath (CIHD) - and includes (i) occurrence of any stroke (including retinal infarction), (ii) new ischaemic lesions on diffusion-weighted magnetic resonance imaging, (iii) any major extracranial haemorrhage, (iv) any symptomatic intracranial haemorrhage, (v) any new haemorrhagic lesion visible on paramagnetic-susceptible sequences and (vi) death.

Discussion: After database closure, (i) central verification of cervical artery dissection diagnosis will be done by two experienced raters, (ii) adjudication of outcome events will be performed by independent adjudication committees, separately for clinical and imaging outcomes. The primary analysis will be done on the per protocol data set. The targeted sample size consists of 169 evaluable patients in the per protocol data set.

Conclusion: TREAT-CAD is testing the non-inferiority of Aspirin versus vitamin K antagonists treatment in patients with symptomatic cervical artery dissection by combined clinical and magnetic resonance imaging outcomes.
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http://dx.doi.org/10.1177/2396987320921151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538765PMC
September 2020

Serum Neurofilament Light Chain Is Associated with Incident Lacunes in Progressive Cerebral Small Vessel Disease.

J Stroke 2020 Sep 29;22(3):369-376. Epub 2020 Sep 29.

Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background And Purpose: Serum neurofilament light (NfL)-chain is a circulating marker for neuroaxonal injury and is also associated with severity of cerebral small vessel disease (SVD) cross-sectionally. Here we explored the association of serum-NfL with imaging and cognitive measures in SVD longitudinally.

Methods: From 503 subjects with SVD, baseline and follow-up magnetic resonance imaging (MRI) was available for 264 participants (follow-up 8.7±0.2 years). Baseline serum-NfL was measured by an ultrasensitive single-molecule-assay. SVD-MRI-markers including white matter hyperintensity (WMH)-volume, mean diffusivity (MD), lacunes, and microbleeds were assessed at both timepoints. Cognitive testing was performed in 336 participants, including SVD-related domains as well as global cognition and memory. Associations with NfL were assessed using linear regression analyses and analysis of covariance (ANCOVA).

Results: Serum-NfL was associated with baseline WMH-volume, MD-values and presence of lacunes and microbleeds. SVD-related MRI- and cognitive measures showed progression during follow-up. NfL-levels were associated with future MRI-markers of SVD, including WMH, MD and lacunes. For the latter, this association was independent of baseline lacunes. Furthermore, NfL was associated with incident lacunes during follow-up (P=0.040). NfL-levels were associated with future SVD-related cognitive impairment (processing speed: β=-0.159; 95% confidence interval [CI], -0.242 to -0.068; P=0.001; executive function β=-0.095; 95% CI, -0.170 to -0.007; P=0.033), adjusted for age, sex, education, and depression. Dementia-risk increased with higher NfL-levels (hazard ratio, 5.0; 95% CI, 2.6 to 9.4; P<0.001), however not after adjusting for age.

Conclusions: Longitudinally, serum-NfL is associated with markers of SVD, especially with incident lacunes, and future cognitive impairment affecting various domains. NfL may potentially serve as an additional marker for disease monitoring and outcome in SVD, potentially capturing both vascular and neurodegenerative processes in the elderly.
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http://dx.doi.org/10.5853/jos.2019.02845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568975PMC
September 2020

Effect of haemoglobin levels on outcome in intravenous thrombolysis-treated stroke patients.

Eur Stroke J 2020 Jun 13;5(2):138-147. Epub 2019 Nov 13.

Stroke Center and Department of Neurology, University Hospital Basel and University of Basel, Basel, Switzerland.

Introduction: Alterations in haemoglobin levels are frequent in stroke patients. The prognostic meaning of anaemia and polyglobulia on outcomes in patients treated with intravenous thrombolysis is ambiguous.

Patients And Methods: In this prospective multicentre, intravenous thrombolysis register-based study, we compared haemoglobin levels on hospital admission with three-month poor outcome (modified Rankin Scale 3-6), mortality and symptomatic intracranial haemorrhage (European Cooperative Acute Stroke Study II-criteria (ECASS-II-criteria)). Haemoglobin level was used as continuous and categorical variable distinguishing anaemia (female: <12 g/dl; male: <13 g/dl) and polyglobulia (female: >15.5 g/dl; male: >17 g/dl). Anaemia was subdivided into mild and moderate/severe (female/male: <11 g/dl). Normal haemoglobin level (female: 12.0-15.5 g/dl, male: 13.0-17.0 g/dl) served as reference group. Unadjusted and adjusted odds ratios with 95% confidence intervals were calculated with logistic regression models.

Results: Among 6866 intravenous thrombolysis-treated stroke patients, 5448 (79.3%) had normal haemoglobin level, 1232 (17.9%) anaemia - of those 903 (13.2%) had mild and 329 (4.8%) moderate/severe anaemia - and 186 (2.7%) polyglobulia. Anaemia was associated with poor outcome (OR 1.25 (1.05-1.48)) and mortality (OR 1.58 (1.27-1.95)). In anaemia subgroups, both mild and moderate/severe anaemia independently predicted poor outcome (OR 1.29 (1.07-1.55) and 1.48 (1.09-2.02)) and mortality (OR 1.45 (1.15-1.84) and OR 2.00 (1.46-2.75)). Each haemoglobin level decrease by 1 g/dl independently increased the risk of poor outcome (OR 1.07 (1.02-1.11)) and mortality (OR 1.08 (1.02-1.15)). Anaemia was not associated with occurrence of symptomatic intracranial haemorrhage. Polyglobulia did not change any outcome.

Discussion: The more severe the anaemia, the higher the probability of poor outcome and death. Severe anaemia might be a target for interventions in hyperacute stroke.

Conclusion: Anaemia on admission, but not polyglobulia, is a strong and independent predictor of poor outcome and mortality in intravenous thrombolysis-treated stroke patients.
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http://dx.doi.org/10.1177/2396987319889468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313367PMC
June 2020

Association of prestroke metformin use, stroke severity, and thrombolysis outcome.

Neurology 2020 07 29;95(4):e362-e373. Epub 2020 Jun 29.

From the Department of Neurology (L.P.W., R.W., A.R.L., S.W.), University Hospital Zurich; Epidemiology, Biostatistics and Prevention Institute, Department of Biostatistics (U.H., K.S.), University of Zurich, Switzerland; Department of Neurology (C.H., P.R.), University Hospital Heidelberg, Germany; Department of Neurology (S.C., N.M.-M., M.T.), University of Helsinki and Helsinki University Hospital, Finland; Department of Neurology and Center for Stroke Research (C.H.N., J.F.S., H.E.), Charité University Hospital, Berlin, Germany; Stroke Center and Neurology (A.A.P., C.T., H.G., S.T.E.), University Hospital Basel and University Basel; Department of Neurology (A.E., P.M.), University Hospital Lausanne; Department of Neurology (M.R.H., M.A.), Inselspital, Bern University Hospital, University of Bern, Switzerland; Department of Neurology and Stroke Center (A.Z.), IRCCS Istituto delle Scienze Neurologiche di Bologna, Maggiore Hospital; Stroke Unit (L.V.), Department of Neuroscience, S'Agostino-Estense Hospital, Modena University Hospital, Italy; Department of Neurology (J.M.C., A.E.G., P.N.), Amsterdam University Medical Centers (AUMC), Location AMC, University of Amsterdam, the Netherlands; Neurology Clinic Belgrade (V.P., D.R.J.), Clinical Centre of Serbia; Medical Faculty (D.R.J.), University of Belgrade, Serbia; Department of Neurology (Y.B., C.B.), University Hospital of Dijon, University of Burgundy; Department of Neurology (G.T., P.S.), Sainte-Anne Hospital, Paris, France; Department of Clinical and Experimental Sciences (A.P.), Neurology Clinic, University of Brescia; Stroke Unit (M.M.), ASST Spedali Civili, Brescia, Italy; Department of Neurology (D.L., S.G.), University Hospital of Lille, France; Department of Neurology (M.J.S., G.K.), St. Gallen Cantonal Hospital, Switzerland; Department of Neurology (T.T.), Sahlgrenska University Hospital; Department of Clinical Neurosciences (T.T.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden; and Neurorehabilitation Unit (S.T.E.), University Center for Medicine of Aging and Rehabilitation Basel, Felix Platter Hospital, University of Basel, Switzerland.

Objective: To evaluate whether pretreatment with metformin (MET) is associated with less stroke severity and better outcome after IV thrombolysis (IVT), we analyzed a cohort of 1,919 patients with stroke with type 2 diabetes mellitus in a multicenter exploratory analysis.

Methods: Data from patients with diabetes and ischemic stroke treated with IVT were collected within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration. We applied propensity score matching (PSM) to obtain balanced baseline characteristics of patients treated with and without MET.

Results: Of 1,919 patients with stroke with type 2 diabetes who underwent IVT, 757 (39%) had received MET before stroke (MET+), whereas 1,162 (61%) had not (MET-). MET+ patients were younger with a male preponderance. Hypercholesterolemia and pretreatment with statins, antiplatelets, or antihypertensives were more common in the MET+ group. After PSM, the 2 groups were well balanced with respect to demographic and clinical aspects. Stroke severity on admission (NIH Stroke Scale 10.0 ± 6.7 vs 11.3 ± 6.5), 3-month degree of independence on modified Rankin Scale (2 [interquartile range (IQR) 1.0-4.0] vs 3 [IQR 1.0-4.0]), as well as mortality (12.5% vs 18%) were significantly lower in the MET+ group. The frequency of symptomatic intracerebral hemorrhages did not differ between groups. HbA1c levels were well-balanced between the groups.

Conclusions: Patients with stroke and diabetes on treatment with MET receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests a protective effect of MET resulting in less severe strokes as well as beneficial thrombolysis outcome.
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http://dx.doi.org/10.1212/WNL.0000000000009951DOI Listing
July 2020

Prior Stroke in PFO Patients Is Associated With Both PFO-Related and -Unrelated Factors.

Front Neurol 2020 4;11:503. Epub 2020 Jun 4.

Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.

To identify factors associated with prior stroke at presentation in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO). We studied cross-sectional data from the International PFO Consortium Study (NCT00859885). Patients with first-ever stroke and those with prior stroke at baseline were analyzed for an association with PFO-related (right-to-left shunt at rest, atrial septal aneurysm, deep venous thrombosis, pulmonary embolism, and Valsalva maneuver) and PFO-unrelated factors (age, gender, BMI, hypertension, diabetes mellitus, hypercholesterolemia, smoking, migraine, coronary artery disease, aortic plaque). A multivariable analysis was used to adjust effect estimation for confounding, e.g., owing to the age-dependent definition of study groups in this cross-sectional study design. We identified 635 patients with first-ever and 53 patients with prior stroke. Age, BMI, hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and right-to-left shunt (RLS) at rest were significantly associated with prior stroke. Using a pre-specified multivariable logistic regression model, age (Odds Ratio 1.06), BMI (OR 1.06), hypercholesterolemia (OR 1.90) and RLS at rest (OR 1.88) were strongly associated with prior stroke.Based on these factors, we developed a nomogram to illustrate the strength of the relation of individual factors to prior stroke. In patients with CS and PFO, the likelihood of prior stroke is associated with both, PFO-related and PFO-unrelated factors.
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http://dx.doi.org/10.3389/fneur.2020.00503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289181PMC
June 2020

Clinical Usefulness of Serial Duplex Ultrasound in Cervical Artery Dissection Patients.

Cerebrovasc Dis 2020 14;49(2):206-215. Epub 2020 Apr 14.

Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.

Purpose: To study the clinical usefulness of serial color-coded duplex ultrasound (DUS) examinations in cervical artery dissection (CeAD) patients.

Methods: Single-center, CeAD registry-based re-review of serial, routine DUS exams in consecutive CeAD patients treated at the Stroke Center Basel, Switzerland (2009-2015). Two experienced raters reassessed all DUS for the occurrence of new arterial findings during follow-up, that is. (i) recanalization of the dissected artery (if occluded at baseline), (ii) delayed occlusion of a patent dissected artery, and (iii) recurrent CeAD. We studied whether these new arterial findings were associated with clinical symptoms.

Results: In 94 CeAD patients (n = 40 female [42.6%], median age 46 years [interquartile range (IQR) 36.2-53]), 506 DUS examinations were reviewed covering a median length of follow-up of 54.1 weeks (IQR 30.5-100.5). In total, 105 dissected arteries were detected, of which 27 (25.7%) were occluded. In 28/94 patients (29.8%), 31 new arterial findings were recorded, which were associated with clinical symptoms in 9/31 (30%) patients. Recanalization of occluded CeAD was observed in 22/27 (81.5%) arteries and occurred in 20/22 arteries within 3 months. In 4/22 patients (18.2%), recanalization was associated with clinical symptoms (ischemic events [n = 2], pure local symptoms [n = 2]). Delayed occlusions were observed in 4/78 (5.1%) dissected arteries patent at baseline. All were clinically asymptomatic and occurred within 14 days from baseline. Recurrent CeAD (all symptomatic) occurred in 5 previously non-dissected arteries.

Conclusion: In CeAD patients, follow-up DUS identified new arterial findings, of which several were associated with clinical symptoms: we found that about 1 of 5 recanalizations were associated with clinical symptoms, of whom half were ischemic symptoms. Further, delayed occlusions occurred in patients with no or mild stenosis at baseline and were asymptomatic. This study emphasizes the potential importance of repeated DUS in CeAD particularly in the early phase of up to 4 weeks.
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http://dx.doi.org/10.1159/000507485DOI Listing
September 2020

Small vessel disease is associated with an unfavourable outcome in stroke patients on oral anticoagulation.

Eur Stroke J 2020 Mar 12;5(1):63-72. Epub 2019 Nov 12.

Department of Neurology and Stroke Center, University Hospital and University of Basel, Switzerland.

Introduction: Cerebral small vessel disease is an important cause for both ischaemic stroke and intracranial haemorrhage. To date, knowledge on the impact of small vessel disease on the clinical course in stroke patients treated with oral anticoagulation for atrial fibrillation is limited.

Patients And Methods: Registry-based prospective observational study of 320 patients (aged 78.2 ± 9.2 years) treated with anticoagulation following atrial fibrillation stroke. Patients underwent standardised magnetic-resonance-imaging assessing measures of small vessel disease, including cerebral microbleeds and white matter hyperintensities. Median follow-up was 754 (interquartile range = [708-828]) days. Using adjusted logistic and Cox regression, we assessed the association of imaging measures with clinical outcome including recurrent ischaemic stroke, intracranial haemorrhage and death and assessed disability (modified Rankin Scale).

Results: Overall, recurrent ischaemic stroke was more common than intracranial haemorrhage (22 versus 8, respectively). Cerebral microbleeds were related to an increased risk of the composite endpoint (ischaemic stroke, intracranial haemorrhage, death: odds ratio (OR) 2.05, 95% confidence interval (CI) 1.27-3.31;  = 0.003), as were white matter hyperintensities (OR 2.00, 95%CI 1.23-3.27,  = 0.005). This was also true in time-to-event analysis (cerebral microbleeds: HR 2.31, 95%CI 1.39-3.52;  < 0.001; white matter hyperintensities: HR 1.99, 95%CI 1.20-3.17;  = 0.007). Both measures were associated with an increased risk for recurrent ischaemic stroke (cerebral microbleeds: HR 4.42, 95%CI 1.07-18.20;  = 0.04; white matter hyperintensities: HR 5.27, 95%CI 1.08-25.79,  = 0.04) and intracranial haemorrhage (cerebral microbleeds: HR 2.43, 95%CI 1.04-5.69;  = 0.04; white matter hyperintensities: HR 2.57, 95%CI 1.11-5.98,  = 0.03). Furthermore, confluent white matter hyperintensities were associated with increased disability (OR 4.03; 95%CI 2.16-7.52;  < 0.001) and mortality (HR 1.81, 95%CI 1.04-3.14,  = 0.04).

Discussion And Conclusion: In atrial fibrillation stroke patients treated with oral anticoagulation, small vessel disease is associated with an unfavourable outcome. The presence of microbleeds indicated a risk higher for recurrent ischaemic stroke than for intracranial haemorrhage.
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http://dx.doi.org/10.1177/2396987319888016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092732PMC
March 2020

Ischemic Stroke despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation.

Ann Neurol 2020 Feb 12. Epub 2020 Feb 12.

Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Perugia, Italy.

Objective: It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed.

Methods: We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OAC ) with those without prior oral anticoagulation (OAC ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OAC ) with those who continued the same anticoagulation as secondary prevention (OAC ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA DS -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OAC (n = 1,195) and OAC (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OAC was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OAC (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OAC (n = 585).

Interpretation: Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA DS -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group. ANN NEUROL 2020.
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http://dx.doi.org/10.1002/ana.25700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383617PMC
February 2020

Artery occlusion independently predicts unfavorable outcome in cervical artery dissection.

Neurology 2020 01 22;94(2):e170-e180. Epub 2019 Nov 22.

From the Department of Neurology and Stroke Center (C.T., G.M.D.M., A. Polymeris, H.G., L.H.B., S.T.E., P.L.), University Hospital Basel and University of Basel; Neurorehabilitation Unit (C.T., H.G., S.T.E.), University of Basel and University Center for Medicine of Aging and Rehabilitation, Felix Platter Hospital, Basel, Switzerland; Departments of Neurology (C.G.-G., M.K.) and Vascular and Endovascular Surgery (C.G.-G.), Heidelberg University Hospital, Germany; Department of Neurology (B.G.S., U.F., H.S., M.A.), University Hospital Bern; Ospedale San Giovanni (B.G.S.), Bellinzona, Switzerland; Department of Neurology (T.M.M., T.T.), Helsinki University Central Hospital, Finland; Department of Neurology (S.D.), Bordeaux University Hospital; Inserm U1219 (S.D.), Bordeaux; University of Bordeaux (S.D.), France; Department of Neurology (S.D.), Boston University School of Medicine, MA; Department of Clinical and Experimental Sciences (A.Pezzini.), Neurology Clinic, University of Brescia, Italy; Department of Neurology (J.J.M.), University of Utah, Salt Lake City; Departments of Neurology and Public Health Sciences (A.M.S., B.B.W.), University of Virginia Health System, Charlottesville; Univ-Lille (D.L.), Inserm U1171, CHU Lille, France; Neuro Center (R.B.), Clinic Hirslanden, Zurich, Switzerland; Stroke Unit and Division of Internal and Cardiovascular Medicine (V.C.), University of Perugia, Italy; Centre Hospitalier Universitaire Dijon Bourgogne (Y.B.), EA7460, Pathophysiology and Epidemiology of Cardio-Cerebro-Vascular Diseases, University of Burgundy, Dijon, France; Department of Neurology (H.S.), University Hospital of Zurich, Switzerland; Stroke Theme (V.T.), Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Cerebrovascular Unit Fondazione IRCCS Istituto Neurologico Carlo Besta (A.B.), Milan, Italy; Swiss National Accident Insurance Institution (T.B.), Lucerne, Switzerland; Normandie Université (E.T.), Université Caen Normandie, Inserm U1037, Department of Neurology, CHU Caen Normandie; Department of Neurology (E.T.), CH Sainte-Anne, University Paris Descartes, France; Department of Neurology (J.J.M.), Sanatorio Allende, Cordoba, Argentina; Department of Neurology (H.C.), Lariboisière Hospital, Paris, France; Department of Neurology (T.T.), Sahlgrenska University Hospital; and Department of Clinical Neuroscience Institute for Neuroscience and Physiology (T.T.), Sahlgrenska Academy at University of Gothenburg, Sweden.

Objective: To assess the impact of dissected artery occlusion (DAO) on functional outcome and complications in patients with cervical artery dissection (CeAD).

Methods: We analyzed combined individual patient data from 3 multicenter cohorts of consecutive patients with CeAD (the Cervical Artery Dissection and Ischemic Stroke Patients [CADISP]-Plus consortium dataset). Patients with data on DAO and functional outcome were included. We compared patients with DAO to those without DAO. Primary outcome was favorable functional outcome (i.e., modified Rankin Scale [mRS] score 0-1) measured 3-6 months from baseline. Secondary outcomes included delayed cerebral ischemia, major hemorrhage, recurrent CeAD, and death. We performed univariate and multivariable binary logistic regression analyses and calculated odds ratios (OR) with 95% confidence intervals (CI), with adjustment for potential confounders.

Results: Of 2,148 patients (median age 45 years [interquartile range (IQR) 38-52], 43.6% women), 728 (33.9%) had DAO. Patients with DAO more frequently presented with cerebral ischemia (84.6% vs 58.5%, < 0.001). Patients with DAO were less likely to have favorable outcome when compared to patients without DAO (mRS 0-1: 59.6% vs 80.1%, < 0.001). After adjustment for age, sex, and initial stroke severity, DAO was independently associated with less favorable outcome (mRS 0-1: OR 0.65, CI 0.50-0.84, = 0.001). Delayed cerebral ischemia occurred more frequently in patients with DAO than in patients without DAO (4.5% vs 2.9%, = 0.059).

Conclusion: DAO independently predicts less favorable functional outcome in patients with CeAD. Further research on vessel patency, collateral status and effects of revascularization therapies particularly in patients with DAO is warranted.
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http://dx.doi.org/10.1212/WNL.0000000000008654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988986PMC
January 2020

Reasons for Prehospital Delay in Acute Ischemic Stroke.

J Am Heart Assoc 2019 10 2;8(20):e013101. Epub 2019 Oct 2.

Department of Neurology University Hospital Basel Basel Switzerland.

Background Prehospital delay reduces the proportion of patients with stroke treated with recanalization therapies. We aimed to identify novel and modifiable risk factors for prehospital delay. Methods and Results We included patients with an ischemic stroke confirmed by diffusion-weighted magnetic resonance imaging, symptom onset within 24 hours and hospitalized in the Stroke Center of the University Hospital Basel, Switzerland. Trained study nurses interviewed patients and proxies along a standardized questionnaire. Prehospital delay was defined as >4.5 hours between stroke onset-or time point of wake-up-and admission. Overall, 336 patients were enrolled. Prehospital delay was observed in 140 patients (42%). The first healthcare professionals to be alarmed were family doctors for 29% of patients (97/336), and a quarter of these patients had a baseline National Institute of Health Stroke Scale score of 4 or higher. The main modifiable risk factor for prehospital delay was a face-to-face visit to the family doctor (adjusted odds ratio, 4.19; 95% CI, 1.85-9.46). Despite transport by emergency medical services being associated with less prehospital delay (adjusted odds ratio, 0.41; 95% CI, 0.24-0.71), a minority of patients (39%) who first called their family doctor were transported by emergency medical services to the hospital. The second risk factor was lack of awareness of stroke symptoms (adjusted odds ratio, 4.14; 95% CI, 2.36-7.24). Conclusions Almost 1 in 3 patients with a diffusion-weighted magnetic resonance imaging-confirmed ischemic stroke first called the family doctor practice. Face-to-face visits to the family doctor quadrupled the odds of prehospital delay. Efforts to reduce prehospital delay should address family doctors and their staffs as important partners in the prehospital pathway. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02798770.
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http://dx.doi.org/10.1161/JAHA.119.013101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818040PMC
October 2019

Stent Design, Restenosis and Recurrent Stroke After Carotid Artery Stenting in the International Carotid Stenting Study.

Stroke 2019 11 24;50(11):3013-3020. Epub 2019 Sep 24.

From the Department of Neurology and Stroke Center (M.D.M., S.T.E., P.A.L., L.H.B.).

Background and Purpose- Open-cell carotid artery stents are associated with a higher peri-procedural stroke risk than closed-cell stents. However, the effect of stent design on long-term durability of carotid artery stenting (CAS) is unknown. We compared the medium- to long-term risk of restenosis and ipsilateral stroke between patients treated with open-cell stents versus closed-cell stents in the ICSS (International Carotid Stenting Study). Methods- Patients with symptomatic carotid stenosis were randomized to CAS or endarterectomy and followed with duplex ultrasound for a median of 4.0 years. We analyzed data from patients with completed CAS procedures, known stent design, and available ultrasound follow-up. The primary outcome, moderate or higher restenosis (≥50%) was defined as a peak systolic velocity of >1.3 m/s on ultrasound or occlusion of the treated internal carotid artery and analyzed with interval-censored models. Results- Eight hundred fifty-five patients were allocated to CAS. Seven hundred fourteen patients with completed CAS and known stent design were included in the current analysis. Of these, 352 were treated with open-cell and 362 with closed-cell stents. Moderate or higher restenosis occurred significantly less frequently in patients treated with open-cell (n=113) than closed-cell stents (n=154; 5-year risks were 35.5% versus 46.0%; unadjusted hazard ratio, 0.68; 95% CI, 0.53-0.88). There was no significant difference in the risk of severe restenosis (≥70%) after open-cell stenting (n=27) versus closed-cell stenting (n=43; 5-year risks, 8.6% versus 12.7%; unadjusted hazard ratio, 0.63; 95% CI, 0.37-1.05). The risk of ipsilateral stroke beyond 30 days after treatment was similar with open-cell and closed-cell stents (hazard ratio, 0.78; 95% CI, 0.35-1.75). Conclusions- Moderate or higher restenosis after CAS occurred less frequently in patients treated with open-cell stents than closed-cell stents. However, both stent designs were equally effective at preventing recurrent stroke during follow-up. Clinical Trial Registration- URL: http://www.isrctn.com/. Unique identifier: ISRCTN25337470.
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http://dx.doi.org/10.1161/STROKEAHA.118.024076DOI Listing
November 2019

Meta-analysis of haematoma volume, haematoma expansion and mortality in intracerebral haemorrhage associated with oral anticoagulant use.

J Neurol 2019 Dec 20;266(12):3126-3135. Epub 2019 Sep 20.

Stroke Research Centre, Institute of Neurology, University College London, Russell Square House, 10 Russell Square, London, UK.

Objective: To obtain precise estimates of age, haematoma volume, secondary haematoma expansion (HE) and mortality for patients with intracerebral haemorrhage (ICH) taking oral anticoagulants [Vitamin K antagonists (VKA-ICH) or non-Vitamin K antagonist oral anticoagulants (NOAC-ICH)] and those not taking oral anticoagulants (non-OAC ICH) at ICH symptom onset.

Methods: We conducted a systematic review and meta-analysis of studies comparing VKA-ICH or NOAC-ICH or both with non-OAC ICH. Primary outcomes were haematoma volume (in ml), HE, and mortality (in-hospital and 3-month). We calculated odds ratios (ORs) using the Mantel-Haenszel random-effects method and corresponding 95% confidence intervals (95%CI) and determined the mean ICH volume difference.

Results: We identified 19 studies including data from 16,546 patients with VKA-ICH and 128,561 patients with non-OAC ICH. Only 2 studies reported data on 4943 patients with NOAC-ICH. Patients with VKA-ICH were significantly older than patients with non-OAC ICH (mean age difference: 5.55 years, 95%CI 4.03-7.07, p < 0.0001, I = 92%, p < 0.001). Haematoma volume was significantly larger in VKA-ICH with a mean difference of 9.66 ml (95%CI 6.24-13.07 ml, p < 0.00001; I = 42%, p = 0.05). HE occurred significantly more often in VKA-ICH (OR 2.96, 95%CI 1.74-4.97, p < 0.00001; I = 65%). VKA-ICH was associated with significantly higher in-hospital mortality (VKA-ICH: 32.8% vs. non-OAC ICH: 22.4%; OR 1.83, 95%CI 1.61-2.07, p < 0.00001, I = 20%, p = 0.27) and 3-month mortality (VKA-ICH: 47.1% vs. non-OAC ICH: 25.5%; OR 2.24, 95%CI 1.52-3.31, p < 0.00001, I = 71%, p = 0.001). We did not find sufficient data for a meta-analysis comparing NOAC-ICH and non-OAC-ICH.

Conclusion: This meta-analysis confirms, refines and expands findings from prior studies. We provide precise estimates of key prognostic factors and outcomes for VKA-ICH, which has larger haematoma volume, increased rate of HE and higher mortality compared to non-OAC ICH. There are insufficient data on NOACs.
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http://dx.doi.org/10.1007/s00415-019-09536-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851029PMC
December 2019

Intravenous thrombolysis for suspected ischemic stroke with seizure at onset.

Ann Neurol 2019 11 9;86(5):770-779. Epub 2019 Sep 9.

Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.

Objective: Seizure at onset (SaO) has been considered a relative contraindication for intravenous thrombolysis (IVT) in patients with acute ischemic stroke, although this appraisal is not evidence based. Here, we investigated the prognostic significance of SaO in patients treated with IVT for suspected ischemic stroke.

Methods: In this multicenter, IVT-registry-based study we assessed the association between SaO and symptomatic intracranial hemorrhage (sICH, European Cooperative Acute Stroke Study II definition), 3-month mortality, and 3-month functional outcome on the modified Rankin Scale (mRS) using unadjusted and adjusted logistic regression, coarsened exact matching, and inverse probability weighted analyses.

Results: Among 10,074 IVT-treated patients, 146 (1.5%) had SaO. SaO patients had significantly higher National Institutes of Health Stroke Scale score and glucose on admission, and more often female sex, prior stroke, and prior functional dependence than non-SaO patients. In unadjusted analysis, they had generally less favorable outcomes. After controlling for confounders in adjusted, matched, and weighted analyses, all associations between SaO and any of the outcomes disappeared, including sICH (odds ratio [OR] = 1.53 [95% confidence interval (CI) = 0.74-3.14], OR = 0.52 [95% CI = 0.13-2.16], OR = 0.68 [95% CI = 0.15-3.03], OR = 0.95 [95% CI = 0.39-2.32]), mortality (OR = 1.49 [95% CI = 1.00-2.24], OR = 0.98 [95% CI = 0.5-1.92], OR = 1.13 [95% CI = 0.55-2.33], OR = 1.17 [95% CI = 0.73-1.88]), and functional outcome (mRS ≥ 3/ordinal mRS: OR = 1.33 [95% CI = 0.96-1.84]/1.35 [95% CI = 1.01-1.81], OR = 0.78 [95% CI = 0.45-1.32]/0.78 [95% CI = 0.52-1.16], OR = 0.75 [95% CI = 0.43-1.32]/0.45 [95% CI = 0.10-2.06], OR = 0.87 [95% CI = 0.57-1.34]/1.00 [95% CI = 0.66-1.52]). These results were consistent regardless of whether patients had an eventual diagnosis of ischemic stroke (89/146) or stroke mimic (57/146 SaO patients).

Interpretation: SaO was not an independent predictor of poor prognosis. Withholding IVT from patients with assumed ischemic stroke presenting with SaO seems unjustified. ANN NEUROL 2019;86:770-779.
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http://dx.doi.org/10.1002/ana.25582DOI Listing
November 2019

Silent brain infarcts on diffusion-weighted imaging after carotid revascularisation: A surrogate outcome measure for procedural stroke? A systematic review and meta-analysis.

Eur Stroke J 2019 Jun 15;4(2):127-143. Epub 2019 Jan 15.

Stroke Center and Department of Neurology, University Hospital Basel and University of Basel, Basel, Switzerland.

Aim: To investigate whether lesions on diffusion-weighted imaging (DWI+) after carotid artery stenting (CAS) or endarterectomy (CEA) might provide a surrogate outcome measure for procedural stroke.

Materials And Methods: Systematic MedLine® database search with selection of all studies published up to the end of 2016 in which DWI scans were obtained before and within seven days after CAS or CEA. The correlation between the underlying log odds of stroke and of DWI+ across all treatment groups (i.e. CAS or CEA groups) from included studies was estimated using a bivariate random effects logistic regression model. Relative risks of DWI+ and stroke in studies comparing CAS vs. CEA were estimated using fixed-effect Mantel-Haenszel models.

Results: We included data of 4871 CAS and 2099 CEA procedures (85 studies). Across all treatment groups (CAS and CEA), the log odds for DWI+ was significantly associated with the log odds for clinically manifest stroke (correlation coefficient 0.61 (95% CI 0.27 to 0.87), p = 0.0012). Across all carotid artery stenting groups, the correlation coefficient was 0.19 (p = 0.074). There were too few CEA groups to reliably estimate a correlation coefficient in this subset alone. In 19 studies comparing CAS vs. CEA, the relative risks (95% confidence intervals) of DWI+ and stroke were 3.83 (3.17-4.63, p < 0.00001) and 2.38 (1.44-3.94, p = 0.0007), respectively.

Discussion: This systematic meta-analysis demonstrates a correlation between the occurrence of silent brain infarcts on diffusion-weighted imaging and the risk of clinically manifest stroke in carotid revascularisation procedures.

Conclusion: Our findings strengthen the evidence base for the use of DWI as a surrogate outcome measure for procedural stroke in carotid revascularisation procedures. Further randomised studies comparing treatment effects on DWI lesions and clinical stroke are needed to fully establish surrogacy.
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http://dx.doi.org/10.1177/2396987318824491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591767PMC
June 2019
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