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1.
Differences Between Anticoagulated Patients With Ischemic Stroke Versus Intracerebral Hemorrhage.
Schaub, F, Polymeris, AA, Schaedelin, S, Hert, L, Meya, L, Thilemann, S, Traenka, C, Wagner, B, Seiffge, D, Gensicke, H, et al
Journal of the American Heart Association. 2022;(1):e023345
Abstract
Background Data on the relative contribution of clinical and neuroimaging risk factors to acute ischemic stroke (AIS) versus intracerebral hemorrhage (ICH) occurring on oral anticoagulant treatment are scarce. Methods and Results Cross-sectional study was done on consecutive oral anticoagulant-treated patients presenting with AIS, transient ischemic attack (TIA), or ICH from the prospective observational NOACISP (Novel-Oral-Anticoagulants-In-Stroke-Patients)-Acute registry. We compared clinical and neuroimaging characteristics (small vessel disease markers and atherosclerosis) in ICH versus AIS/TIA (reference) using logistic regression. Among 734 patients presenting with stroke on oral anticoagulant treatment (404 [55%] direct oral anticoagulants, 330 [45%] vitamin K antagonists), 605 patients (82%) had AIS/TIA and 129 (18%) had ICH. Prior AIS/TIA, coronary artery disease, dyslipidemia, and worse renal function were associated with AIS/TIA (adjusted odds ratio [aOR] [95% CI] 0.51 [0.32-0.82], 0.48 [0.26-0.86], 0.55 [0.34-0.89], and 0.82 [0.75-0.90] per 10 mL/min). Prior ICH, older age, higher admission blood pressure, and statin treatment were associated with ICH (aOR [95% CI] 6.33 [2.87-14.04], 1.37 [1.04-1.81] per 10 years, 1.19 [1.10-1.29] per 10 mm Hg, and 1.81 [1.09-3.03]). Cerebral microbleeds and moderate-to-severe white matter hyperintensities contributed more to ICH (aOR [95% CI] 2.77 [1.34-6.18], and 2.62 [1.28-5.63]). Aortic arch, common and internal carotid artery atherosclerosis, and internal carotid artery stenosis ≥50% contributed more to AIS/TIA (aOR [95% CI] 0.54 [0.31-0.90], 0.29 [0.05-0.97], 0.48 [0.30-0.76], and 0.32 [0.13-0.67]). Conclusions In patients presenting with stroke on oral anticoagulant, AIS/TIA was 5 times more common than ICH. A high atherosclerotic burden (indicated by cardiovascular comorbidities and extracranial atherosclerosis) and prior AIS/TIA contributed more to AIS/TIA, while small vessel disease markers and prior ICH were stronger determinants for ICH. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02353585.
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Early Anticoagulation in Patients with Acute Ischemic Stroke Due to Atrial Fibrillation: A Systematic Review and Meta-Analysis.
Palaiodimou, L, Stefanou, MI, Katsanos, AH, Paciaroni, M, Sacco, S, De Marchis, GM, Shoamanesh, A, Malhotra, K, de Sousa, DA, Lambadiari, V, et al
Journal of clinical medicine. 2022;(17)
Abstract
Introduction: There is uncertainty regarding the optimal timing for initiation of oral anticoagulation in patients with acute ischemic stroke (AIS) due to atrial fibrillation (AF). Methods: We performed a systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) and prospective observational studies to assess the efficacy and safety of early anticoagulation in AF-related AIS (within 1 week versus 2 weeks). A second comparison was performed assessing the efficacy and safety of direct oral anticoagulants (DOACs) versus vitamin-K antagonists (VKAs) in the two early time windows. The outcomes of interest were IS recurrence, all-cause mortality, symptomatic intracerebral haemorrhage (sICH) and any ICH. Results: Eight eligible studies (6 observational, 2 RCTs) were identified, including 5616 patients with AF-related AIS who received early anticoagulation. Patients that received anticoagulants within the first week after index stroke had similar rate of recurrent IS, sICH and all-cause mortality compared to patients that received anticoagulation within two weeks (test for subgroup differences p = 0.1677; p = 0.8941; and p = 0.7786, respectively). When DOACs were compared to VKAs, there was a significant decline of IS recurrence in DOAC-treated patients compared to VKAs (RR: 0.65; 95%CI: 0.52-0.82), which was evident in both time windows of treatment initiation. DOACs were also associated with lower likelihood of sICH and all-cause mortality. Conclusions: Early initiation of anticoagulation within the first week may have a similar efficacy and safety profile compared to later anticoagulation (within two weeks), while DOACs seem more effective in terms of IS recurrence and survival compared to VKAs.
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Impact of Sodium Levels on Functional Outcomes in Patients With Stroke - A Swiss Stroke Registry Analysis.
Potasso, L, Refardt, J, De Marchis, GM, Wiencierz, A, Wright, PR, Wagner, B, Dittrich, T, Polymeris, AA, Gensicke, H, Bonati, LH, et al
The Journal of clinical endocrinology and metabolism. 2022;(2):e672-e680
Abstract
CONTEXT Correction of hyponatremia might represent an additional treatment for improving stroke patients' clinical outcomes. OBJECTIVE Admission hyponatremia is associated with worse clinical outcome in stroke patients, but whether normalization of hyponatremia improves outcome is unknown. We investigated whether normalization of hyponatremia affects patients' disability, mortality, and stroke recurrence within 3 months; length of hospitalization; and discharge destination. DESIGN This was a registry-based analysis of data collected between January 2016 and December 2018. We linked data from Swiss Stroke Registry (SSR) with electronic patients' records for extracting sodium values. SETTING We analyzed data of hospitalized patients treated at University Hospital of Basel. PATIENTS Stroke patients whose data and informed consent were available. MAIN OUTCOME MEASURE Modified Rankin Scale (mRS) score at 3 months. The tested hypothesis was formulated after SSR data collection but before linkage with electronic patients' records. RESULTS Of 1995 patients, 144 (7.2%) had hyponatremia on admission; 102 (70.8%) reached normonatremia, and 42 (29.2%) remained hyponatremic at discharge. An increase of initial sodium was associated with better functional outcome at 3 months (odds ratio [OR] 0.94; 95% CI, 0.90-0.99, for a shift to higher mRS per 1 mmol/L sodium increase). Compared with normonatremic patients, patients who remained hyponatremic at discharge had a worse functional outcome at 3 months (odds ratio 2.46; 95% CI, 1.20-5.03, for a shift to higher mRS). No effect was found on mortality, recurrence, or length of hospitalization. CONCLUSIONS In hospitalized acute stroke patients, persistent hyponatremia is associated with worse functional outcome. Whether active correction of hyponatremia improves outcome remains to be determined in prospective studies.
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New Avenues for Optimal Treatment of Atrial Fibrillation and Stroke Prevention.
De Marchis, GM, Sposato, LA, Kühne, M, Dittrich, TD, Bonati, LH, Fischer, U, Chaturvedi, S
Stroke. 2021;(4):1490-1499
Abstract
One in 3 individuals free of atrial fibrillation (AF) at index age 55 years is estimated to develop AF later in life. AF increases not only the risk of ischemic stroke but also of dementia, even in stroke-free patients. In this review, we address recent advances in the heart-brain interaction with focus on AF. Issues discussed are (1) the timing of direct oral anticoagulants start following an ischemic stroke; (2) the comparison of direct oral anticoagulants versus vitamin K antagonists in early secondary stroke prevention; (3) harms of bridging with heparin before direct oral anticoagulants; (4) importance of appropriate direct oral anticoagulants dosing; (5) screening for AF in high-risk populations, including the role of wearables; (6) left atrial appendage occlusion as an alternative to oral anticoagulation; (7) the role of early rhythm-control therapy; (8) effect of lifestyle interventions on AF; (9) AF as a risk factor for dementia. An interdisciplinary approach seems appropriate to address the complex challenges posed by AF.
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Direct Oral Anticoagulants after Ischemic Stroke: Which Patient? Which Drug? And How Early?
De Marchis, GM
Hamostaseologie. 2021;(1):31-34
Abstract
Direct oral anticoagulants (DOACs) are recommended over vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and ischemic stroke. The main advantage of DOAC over VKA is the lower rate of bleeding and mortality. This review covers challenges clinicians can encounter when treating patients with AF and ischemic stroke, including timing of DOAC start and ongoing randomized clinical trials, appropriate dosing, and available comparative evidence across DOACs. For patients without AF but with an ischemic stroke, the review outlines the role of DOACs. Finally, the risk of thrombotic events associated with specific DOAC reversal agents and DOAC pausing is reviewed.
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Challenges of treatment adherence with direct oral anticoagulants in pandemic.
Dittrich, T, Polymeris, A, De Marchis, GM
Current opinion in neurology. 2021;(1):38-44
Abstract
PURPOSE OF REVIEW Direct oral anticoagulants (DOAC) are crucial for the prevention of thromboembolic events in patients with nonvalvular atrial fibrillation. Drug adherence by the patient but also adherence to guidelines by the physician are suboptimal. This review highlights aspects of DOAC treatment during the coronavirus disease 2019 (COVID-19) pandemic and selected challenging scenarios. RECENT FINDINGS For patients with a newly diagnosed indication for oral anticoagulation, a new interim clinical guidance recommends starting DOAC instead of vitamin K antagonists if DOAC are not contraindicated. The goal is to reduce the potential exposure of patients to severe acute respiratory syndrome coronavirus during the routine coagulation monitoring visits. As COVID-19 can lead to kidney failure, we discuss the challenges of DOAC dosing in kidney failures. Finally, we discuss two common challenges - when to start a DOAC after an ischemic stroke linked to atrial fibrillation, and whether cerebral microbleeds, including their count, are per se a contraindication to DOAC. SUMMARY There are still open challenges regarding DOAC treatment on the patient and physician side, both related and unrelated to the pandemic.
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Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial.
Engelter, ST, Traenka, C, Gensicke, H, Schaedelin, SA, Luft, AR, Simonetti, BG, Fischer, U, Michel, P, Sirimarco, G, Kägi, G, et al
The Lancet. Neurology. 2021;(5):341-350
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Abstract
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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Oral Anticoagulants in Atrial Fibrillation Patients With Recent Stroke Who Are Dependent on the Daily Help of Others.
Meya, L, Polymeris, AA, Schaedelin, S, Schaub, F, Altersberger, VL, Traenka, C, Thilemann, S, Wagner, B, Fladt, J, Hert, L, et al
Stroke. 2021;(11):3472-3481
Abstract
BACKGROUND AND PURPOSE Data on the effectiveness and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in patients with stroke attributable to atrial fibrillation (AF) who were dependent on the daily help of others at hospital discharge are scarce. METHODS Based on prospectively obtained data from the observational Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-longterm registry from Basel, Switzerland, we compared the occurrence of the primary outcome—the composite of recurrent ischemic stroke, major bleeding, and all-cause death—among consecutive patients with AF-stroke treated with either VKAs or DOACs between patients dependent (defined as modified Rankin Scale score, 3–5) and patients independent at discharge. We used simple, adjusted, and weighted Cox proportional hazards regression to account for potential confounders. RESULTS We analyzed 801 patients (median age 80 years, 46% female), of whom 391 (49%) were dependent at discharge and 680 (85%) received DOACs. Over a total follow-up of 1216 patient-years, DOAC- compared to VKA-treated patients had a lower hazard for the composite outcome (hazard ratio [HR], 0.58 [95% CI, 0.42–0.81]), as did independent compared to dependent patients (HR, 0.54 [95% CI, 0.40–0.71]). There was no evidence that the effect of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome differed between dependent (HRdependent, 0.68 [95% CI, 0.45–1.01]) and independent patients (HRindependent, 0.44 [95% CI, 0.26–0.75]) in the simple model (Pinteraction=0.212). Adjusted (HRdependent, 0.74 [95% CI, 0.49–1.11] and HRindependent, 0.51 [95% CI, 0.30–0.87]; Pinteraction=0.284) and weighted models (HRdependent, 0.79 [95% CI, 0.48–1.31] and HRindependent, 0.46 [95% CI, 0.26–0.81]; Pinteraction=0.163) yielded concordant results. Secondary analyses focusing on the individual components of the composite outcome were consistent to the primary analyses. CONCLUSIONS The benefits of DOACs in patients with atrial fibrillation with a recent stroke were maintained among patients who were dependent on the help of others at discharge. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT03826927.
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Fatal intracranial haemorrhage occurring after oral anticoagulant treatment initiation for secondary stroke prevention in patients with atrial fibrillation.
Tsivgoulis, G, Katsanos, AH, Seiffge, DJ, Paciaroni, M, Wilson, D, Koga, M, Macha, K, Cappellari, M, Kallmünzer, B, Polymeris, AA, et al
European journal of neurology. 2020;(8):1612-1617
Abstract
BACKGROUND AND PURPOSE In this pooled analysis of seven multicentre cohorts potential differences were investigated in the incidence, characteristics and outcomes between intracranial haemorrhages (ICHs) associated with the use of non-vitamin K antagonist oral anticoagulants (NOAC-ICH) or with vitamin K antagonists (VKA-ICH) in ischaemic stroke patients after oral anticoagulant treatment initiation for atrial fibrillation (AF). METHODS Data from 4912 eligible AF patients who were admitted in a stroke unit with ischaemic stroke or transient ischaemic attack and who were treated with either VKAs or NOACs within 3 months post-stroke were included. Fatal ICH was defined as death occurring during the first 30 days after ICH onset. A meta-analysis of available observational studies reporting 30-day mortality rates from NOAC-ICH or VKA-ICH onset was additionally performed. RESULTS During 5970 patient-years of follow-up 71 participants had an ICH, of whom 20 were NOAC-ICH and 51 VKA-ICH. Patients in the two groups had comparable baseline characteristics, except for the higher prevalence of kidney disease in VKA-ICH patients. There was a non-significant higher number of fatal ICH in patients with VKAs (11 events per 3385 patient-years) than in those with NOACs (three events per 2623 patient-years; hazard ratio 0.32, 95% confidence interval 0.09-1.14). Three-month functional outcomes were similar (P > 0.2) in the two groups. The meta-analysis showed a lower 30-day mortality risk for patients with NOAC-ICH compared to VKA-ICH (relative risk 0.70, 95% confidence interval 0.51-0.95). CONCLUSIONS Non-vitamin K oral anticoagulants for intracranial haemorrhages and VKA-ICH occurring during secondary stroke prevention of AF patients have comparable baseline characteristics and outcomes except for the risk of fatal ICH within 30 days, which might be greater in VKA-ICH.
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Causes and Risk Factors of Cerebral Ischemic Events in Patients With Atrial Fibrillation Treated With Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention.
Paciaroni, M, Agnelli, G, Caso, V, Silvestrelli, G, Seiffge, DJ, Engelter, S, De Marchis, GM, Polymeris, A, Zedde, ML, Yaghi, S, et al
Stroke. 2019;(8):2168-2174
Abstract
Background and Purpose- Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non-vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods- Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results- Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95-5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63-9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83-3.16), and CHA2DS2-VASc score (OR, 1.72 for each point increase; 95% CI, 1.58-1.88) were associated with ischemic events. Among the CHA2DS2-VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33-0.61). Conclusions- In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA2DS2-VASc score were associated with increased risk of cerebrovascular events.