Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection: The STOP-CAD Study.

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45-1.12]; P=0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28-2.24]; P=0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35-5.45]; P=0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53-20.13]; P=0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18-0.88]; Pinteraction=0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

Ultrasonographic Vasospasm and Outcome of Posterior Reversible Encephalopathy and Cerebral Vasoconstriction Syndromes.

PURPOSE: Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) are often complicated by vasospasm and ischemia. Monitoring with transcranial color-coded Doppler (TCCD) could be useful, but its role is not established. We studied the incidence of ultrasonographic vasospasm (uVSP) in PRES/RCVS and its relationship with ischemic lesions and clinical outcome. MATERIALS AND METHODS: We conducted a multicenter retrospective study of all patients with PRES/RCVS from 2008 to 2020 who underwent TCCD and magnetic resonance imaging (MRI). TCCD exams were analyzed for uVSP. Diffusion-weighted MRI was analyzed for positive lesions (DWI-positive). Functional outcome was assessed by modified Rankin scale (mRS) at 90 days. The associations with outcomes were determined by logistic regression. RESULTS: We included 80 patients (mean age of 46 (standard deviation, 17) years; 66% females; 41 with PRES, 28 with RCVS and 11 with overlap phenotype). uVSP was detected in 25 (31%) patients. DWI-positive lesions were more often detected in uVSP-positive than uVSP-negative patients (36% vs. 15%; adjusted odds ratio [aOR] 4.05 [95% CI 1.06 - 15.5], P=0.04). DWI-positive lesions were independently associated with worse functional prognosis (mRS 2-6, 43% vs. 10%; aOR, 10 [95% CI 2.6 - 43], P<0.01). Having additional uVSP further increased the odds of a worse outcome (P interaction=0.03). CONCLUSION: Ultrasonographic vasospasm was detected in a third of patients with PRES/RCVS and was associated with brain ischemic lesions. TCCD bedside monitoring can help to stratify patients at risk for cerebral ischemia, a strong predictor of functional outcome.

Single-phase CT angiography predicts ASPECTS decay and may help determine when to repeat CT before thrombectomy.

OBJETIVES: Time is relative in large-vessel occlusion acute ischemic stroke (LVO-AIS). We aimed to evaluate the rate of inter-hospital ASPECTS decay in patients transferred from a primary (PSC) to a comprehensive stroke center (CSC); and to identify patients that should repeat computed tomography (CT) before thrombectomy. MATERIALS AND METHODS: This was a retrospective cohort study of consecutive anterior circulation LVO-AIS transferred patients. The rate of ASPECTS decay was defined as (PSC-ASPECTS - CSC-ASPECTS)/hours elapsed between scans. Single-phase CT angiography (CTA) at the PSC was used to classify the collateral score. We compared patients with futile versus useful CT scan re-evaluation. RESULTS: We included 663 patients, of whom 245 (37.0%) repeated CT at a CSC. The median rate of ASPECTS decay was 0.4/h (0.0-0.9). Patients excluded from thrombectomy after a CT scan repeat (n=64) had a median ASPECTS decay rate of 1.18/h (0.83-1.61). Patients with absent collateral circulation had a median rate of 1.51(0.65-2.19). The collateral score was an independent predictor of the ASPECTS decay rate (aß = -0.35; 95%CI -0.45 - -0.19, p<0.001). Age (aOR: 1.04 95% CI 1.02-1.07, p<0.001), NIHSS (aOR: 1.11 95% CI 1.06-1.15, p<0.001), PSC ASPECTS (aOR: 0.74 95% CI 0.60-0.91, p=0.006) and the CTA collateral score (aOR: 0.14 95% CI 0.08-0.22, p<0.001) were independent predictors of the usefulness of a CT scan repeat. CONCLUSIONS: The rate of ASPECTS decay can be predicted by the CTA collateral score, helping in the selection of patients that would benefit from repeating a CT assessment on arrival at the CSC.

Cerebrovascular Dissemination in Time and Space as a Predictor of Cardioembolism.

BACKGROUND: Cardioembolism has tendency to recur and cause lesions in distinct cerebrovascular territories. Using the imaging characteristics of cerebral lesions to determine dissemination in time and space (DTS) is a concept already used in other neurologic conditions; however, it has never been applied as a diagnostic tool in ischemic stroke etiology. AIM: This study aimed to assess DTS as a diagnostic marker of cardioembolism. METHODS: We enrolled consecutive patients with acute ischemic stroke of various etiologies admitted in a cerebrovascular disease nursery from a university hospital in a retrospective cohort study. We excluded patients with coexisting etiologies, incomplete study, or without an acute vascular lesion on computed tomography scan. Lacunar infarctions were not considered. Cerebrovascular territory was divided into right anterior, left anterior, and posterior. Localization of the acute vascular lesion(s), existence of previous vascular lesions, and their respective areas were analyzed. The presence of dissemination in time, space, or DTS was determined. RESULTS: We included 661 patients (mean age: 74.05 years (SD: 13.01)). Cardioembolism was the etiology with most DTS (30.47% of cardioembolic strokes); DT occurred more frequently within the atherosclerotic subtype (9.88%); DS was more prevalent within the arterial dissection group (3.33%). There was a statistically significant difference in stroke etiology between patients with DTS and patients without dissemination (P < .001). DTS had 81.67% specificity, 30.47% sensitivity, 66.67% positive predictive value, and 49.40% negative predictive value for the identification of cardioembolism. CONCLUSION: DTS is a specific diagnostic predictor of cardioembolic stroke and may be helpful in guiding etiologic investigation.

Early Mobilization Decision after an Acute Ischemic Stroke: Protocol for an Umbrella Review.

INTRODUCTION: Stroke is considered one of the greatest public health challenges worldwide, with the ischemic subtype being the most prevalent. Various acute stroke clinical guidelines recommend early rehabilitation interventions, including very early mobilization. However, despite the studies conducted in recent years regarding when to initiate mobilization after an acute stroke, there are few systematic and personalized protocols based on the factors for which patient mobilization should ideally be performed. We aim to conduct an umbrella review of systematic reviews and meta-analyses to study the early mobilization decision after an acute ischemic stroke in comparison with conventional care and correlate the different approaches with patient clinical outcomes. METHODS AND ANALYSIS: We will perform a systematic search on PubMed/MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Epistemonikos and Web of Science Core Collection databases. Retrieved studies will be independently reviewed by two authors and any discrepancies will be resolved by consensus or with a third reviewer. Reviewers will extract the data and assess the risk of bias in the selected studies. We will use the 16-item Assessment of Multiple Systematic Reviews 2 (AMSTAR2) checklist as the critical appraisal tool to assess cumulative evidence and risk of bias of the different studies. This will be the first umbrella review that compares early mobilization approaches in post-acute ischemic stroke. This study may help to define the optimal early mobilization strategy in stroke patients. PROSPERO registration number: CRD42023430494.

Acute management of cerebral venous thrombosis: Indications, technique, and outcome of endovascular treatment in two high-volume centers.

INTRODUCTION: After several uncontrolled studies and one randomized clinical trial, there is still uncertainty regarding the role of endovascular treatment (EVT) in cerebral venous thrombosis (CVT). This study aims to describe and assess different acute management strategies in the treatment of CVT. METHODS: We performed a retrospective analysis of an international two-center registry of CVT patients admitted since 2019. Good outcome was defined as a return to baseline modified Rankin scale at three months. We described and compared EVT versus no-EVT patients. RESULTS: We included 61 patients. Only one did not receive systemic anticoagulation. EVT was performed in 13/61 (20%) of the cases, with a median time from diagnosis to puncture of 4.5 h (1.25-28.5). EVT patients had a higher median baseline NIHSS [6 (IQR 2-17) vs 0 (0-2.7), p = 0.002)] and a higher incidence of intracerebral hemorrhage (53.8% vs 20.3%, p = 0.03). Recanalization was achieved in 10/13 (77%) patients. Thrombectomy was performed in every case with angioplasty in 7 out of 12 patients and stenting in 3 cases. No postprocedural complication was reported. An improvement of the median NIHSS from baseline to discharge [6 (2-17) vs 1(0-3.75); p < 0.001] was observed in EVT group. A total of 31/60 patients (50.8%) had good outcomes. Adjusting to NIHSS and ICH, EVT had a non-significant increase in the odds of a good outcome [aOR 1.42 (95%CI 0.73-2.8, p = 0.307)]. CONCLUSIONS: EVT in combination with anticoagulation was safe in acute treatment of CVT as suggested by NIHSS improvement. Selected patients may benefit from this treatment.

Intravenous Thrombolysis in Patients With Cervical Artery Dissection: A Secondary Analysis of the STOP-CAD Study.

OBJECTIVES: Cervical artery dissection (CeAD) accounts for 25% of ischemic strokes in young adults. This study evaluated the benefits and harms of intravenous thrombolysis (IVT) in patients presenting with spontaneous CeAD and acute ischemic stroke symptoms. METHODS: This analysis used data from the retrospective STOP-CAD study and included patients with spontaneous CeAD who presented within 1 day of acute ischemic stroke symptoms. Patients were dichotomized into those who received IVT and those managed without IVT. We assessed the association between IVT and 90-day functional independence (modified Rankin Scale scores 0-2) and the incidence of symptomatic intracranial hemorrhage (ICH, defined as ICH causing new or worsening neurologic symptoms within 72 hours after CeAD diagnosis). RESULTS: This study included 1,653 patients from the original STOP-CAD cohort of 4,023. The median age was 49 years, and 35.1% were women; 512 (31.0%) received IVT. IVT was associated with 90-day functional independence (adjusted odds ratio [aOR] = 1.67, 95% CI 1.23-2.28, p = 0.001), but not with symptomatic ICH (aOR = 1.52, 95% CI 0.79-2.92, p = 0.215). DISCUSSION: In patients with spontaneous CeAD and suspected ischemic stroke, IVT improved functional outcomes, without increasing symptomatic ICH risk. These findings support current guideline recommendations to consider thrombolysis for otherwise eligible patients with CeAD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that IVT significantly increases the probability of 90-day functional independence in patients with CeAD.

The Twitter factor: How does Twitter impact #Stroke journals and citation rates?

BACKGROUND: Twitter is a social media platform popularly used by health practitioners, a trend that has been followed by medical journals. The impact of Twitter in bibliometrics of stroke-related literature is yet to be determined. AIMS: We aimed to qualitatively assess the usage of Twitter by stroke journals and study the relationship between Twitter activity and citation rates of stroke articles. METHODS: We used Journal Citation Reports to identify stroke journals. We collected the 2021 Impact Factor (IF) and the top 50 articles contributing to each journal IF. Relevant metrics were collected through Twitonomy, Altmetric, and Web of Science. The association between Twitter activity and citation rates was tested by a negative binomial regression model adjusted to journal's IF. A bivariate correlation and a log-linear regression model adjusted to journal's IF tested the relationship between number of tweets, tweeters, and the number of citations. RESULTS: We collected 450 articles across nine stroke-dedicated journals, five of which had a Twitter account. Only 95 (21%) articles had no Twitter mentions. The median number of citations in articles with versus without Twitter activity was 19 (10-39) versus 11(7-17) (P < 0.001). Twitter activity was associated with higher citation rates controlling for the IF (odds ratio (OR): 2.7, 95% confidence interval (CI) 2.12-3.38, P < 0.001). We found number of tweets to be predicted by the number of citations controlling for the IF (B = 0.33, 95% CI 0.29-0.40, ß = 0.54, P < 0.001). CONCLUSIONS: Tweeted stroke articles tend to have higher citation rates which can be predicted by the number of tweets.

Diagnostic accuracy of CT angiography and CT perfusion imaging for detecting distal medium vessel occlusions: Protocol for a systematic review and meta-analysis.

BACKGROUND: Distal medium vessel occlusions (DMVOs) represent 25-40% of all acute ischemic strokes (AIS). DMVO clinical syndromes are heterogenous, but as eloquent brain regions are frequently involved, they are often disabling. Since current intravenous fibrinolytic therapies may fail to recanalize up to two-thirds of DMVOs, endovascular treatment is progressively being considered in this setting. Nevertheless, the optimal imaging method for diagnosis remains to be defined. Stroke centers that use computed tomography as a routine stroke imaging approach rely on either isolated computed tomography angiography (CTA) or combined perfusion (CTP) studies. Despite a simplified non-CTP-dependent approach seeming reasonable for large vessel occlusion AIS diagnosis, CTP may still hold advantages for DMVOs workup. Therefore, this systematic review aims to compare the diagnostic performance of CTA and CTP in detecting DMVOs. METHODS: We will perform a systematic search in PubMed, EMBASE, Web of Science Core Collection, and Cochrane Central Register of Controlled Trials. In addition, grey literature and ClinicalTrials.gov will be scanned. We will include any type of study that presents data on the diagnostic accuracy of CTA and/or CTP for detecting DMVOs. Two authors will independently review retrieved studies, and any discrepancies will be resolved by consensus or with a third reviewer. Reviewers will extract the data and assess the risk of bias in the selected studies. Data will be combined in a quantitative meta-analysis following the guidelines provided by the Cochrane Handbook for Systematic Reviews of Interventions. We will assess cumulative evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. DISCUSSION: This will be the first systematic review and meta-analysis that compares two different imaging approaches for detecting DMVOs. This study may help to define optimal acute ischemic stroke imaging work-up. TRIAL REGISTRATION: PROSPERO registration: CRD42022344006.

CTA and CTP for Detecting Distal Medium Vessel Occlusions: A Systematic Review and Meta-analysis.

BACKGROUND: The optimal imaging method for detecting distal medium vessel occlusions (DMVOs) remains undefined. PURPOSE: The objective of this study is to compare the diagnostic performance of CTA with CTP in detecting DMVOs. DATA SOURCES: We searched PubMed, EMBASE, Web of Science Core Collection, and Cochrane Central Register of Controlled Trials up to March 31, 2023 (PROSPERO: CRD42022344006). STUDY SELECTION: A total of 12 studies reporting accuracy values of CTA and/or CTP were included, comprising 2607 patients with 479 cases (18.3%) of DMVOs. DATA ANALYSIS: Pooled sensitivity and specificity of both imaging methods were compared using a random-effects model. Subgroup analyses were performed based on the technique used in CTA (multi or single-phase) and the subtype of DMVOs (M2-only vs. M2 and other DMVOs). We applied Quality Assessment of Diagnostic Accuracy (QUADAS-2) tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) quality assessment criteria. DATA SYNTHESIS: CTA demonstrated significantly lower sensitivity compared to CTP in detecting DMVOs [0.74, 95%CI (0.63-0.82) vs. 0.89, 95% CI (0.82-0.93), P < 0.01]. When subgrouped into single-phase and multi-phase CTA, multi-phase CTA exhibited higher sensitivity for DMVO detection than single-phase CTA [0.91, 95%CI (0.85-0.94) vs. 0.64, 95%CI (0.56-0.71), P < .01], while reaching similar levels to CTP. The sensitivity of single-phase CTA substantially decreased when extending from M2 to other non-M2 DMVOs [0.74, 95%CI (0.63-0.83) vs. 0.61, 0.95%CI (0.53-0.68), P = .02]. LIMITATIONS: We identified an overall high risk of bias and low quality of evidence, attributable to the design and reference standards of most studies. CONCLUSIONS: Our findings highlight a significantly lower sensitivity of single-phase CTA compared to multi-phase CTA and CTP in diagnosing DMVOs.

Reconsidering the role of blood-brain barrier in Alzheimer's disease: From delivery to target.

The existence of a selective blood-brain barrier (BBB) and neurovascular coupling are two unique central nervous system vasculature features that result in an intimate relationship between neurons, glia, and blood vessels. This leads to a significant pathophysiological overlap between neurodegenerative and cerebrovascular diseases. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease whose pathogenesis is still to be unveiled but has mostly been explored under the light of the amyloid-cascade hypothesis. Either as a trigger, bystander, or consequence of neurodegeneration, vascular dysfunction is an early component of the pathological conundrum of AD. The anatomical and functional substrate of this neurovascular degeneration is the BBB, a dynamic and semi-permeable interface between blood and the central nervous system that has consistently been shown to be defective. Several molecular and genetic changes have been demonstrated to mediate vascular dysfunction and BBB disruption in AD. The isoform ε4 of Apolipoprotein E is at the same time the strongest genetic risk factor for AD and a known promoter of BBB dysfunction. Low-density lipoprotein receptor-related protein 1 (LRP-1), P-glycoprotein, and receptor for advanced glycation end products (RAGE) are examples of BBB transporters implicated in its pathogenesis due to their role in the trafficking of amyloid-ß. This disease is currently devoid of strategies that change the natural course of this burdening illness. This unsuccess may partly be explained by our misunderstanding of the disease pathogenesis and our inability to develop drugs that are effectively delivered to the brain. BBB may represent a therapeutic opportunity as a target itself or as a therapeutic vehicle. In this review, we aim to explore the role of BBB in the pathogenesis of AD including the genetic background and detail how it can be targeted in future therapeutic research.

The evolution of blood-brain barrier permeability changes after stroke and its implications on clinical outcome: A systematic review and meta-analysis.

BACKGROUND: Blood-brain barrier permeability (BBBp) is a key process involved in ischemic stroke pathophysiology. However, there is a lack of consensus on how BBBp evolves after the ischemia injury, and its clinical relevance at different timepoints post stroke. AIMS: The main objective of this study is to assess BBBp evolution through stroke phases and its implications on patient outcomes. METHODS: We screened PubMed/MEDLINE, Embase, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials up to 31 December 2021. We included research quantitatively using neuroimaging to assess BBBp in stroke patients. BBBp in the different phases was evaluated by a random-effect model based on the standardized mean difference (SMD) between the ipsilateral and contralateral sides of the brain. We performed a subgroup analysis on clinical outcome, reperfusion treatment, haemorrhagic transformation, and imaging method. RESULTS: We identified 3761 studies, of which 22 (1592 patients and 1787 evaluations) were included in our study. Overall, 17 studies reported BBBp for the hyperacute phase, 8 for the acute, 5 for the subacute, and 2 for the chronic phase. All phases were associated with increased BBBp: 0.74 (0.48-0.99), 1.68 (0.94-2.42), 1.98 (0.96-3.00), and 1.00 (0.45-1.55), respectively. An increase in BBBp was associated with hemorrhagic transformation in the hyperacute phase and with improved functional outcomes in the late subacute phase. CONCLUSION: BBBp is persistently increased after stroke, peaking in the acute and subacute phases. The degree of BBBp influences patient outcomes depending on stroke phase. Our findings support the clinical relevance of BBBp dynamics in stroke care.

Therapeutic Nanoparticles for the Different Phases of Ischemic Stroke.

Stroke represents the second leading cause of mortality and morbidity worldwide. Ischemic strokes are the most prevalent type of stroke, and they are characterized by a series of pathological events prompted by an arterial occlusion that leads to a heterogeneous pathophysiological response through different hemodynamic phases, namely the hyperacute, acute, subacute, and chronic phases. Stroke treatment is highly reliant on recanalization therapies, which are limited to only a subset of patients due to their narrow therapeutic window; hence, there is a huge need for new stroke treatments. Nonetheless, the vast majority of promising treatments are not effective in the clinical setting due to their inability to cross the blood-brain barrier and reach the brain. In this context, nanotechnology-based approaches such as nanoparticle drug delivery emerge as the most promising option. In this review, we will discuss the current status of nanotechnology in the setting of stroke, focusing on the diverse available nanoparticle approaches targeted to the different pathological and physiological repair mechanisms involved in each of the stroke phases.

Pathophysiology of Blood-Brain Barrier Permeability Throughout the Different Stages of Ischemic Stroke and Its Implication on Hemorrhagic Transformation and Recovery.

The blood-brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting the brain from unwanted compounds, but its impairment is involved in a vast number of pathological conditions. Disruption of the BBB and increase in its permeability are key in the development of several neurological diseases and have been extensively studied in stroke. Ischemic stroke is the most prevalent type of stroke and is characterized by a myriad of pathological events triggered by an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). BBB permeability seems to follow a multiphasic pattern throughout the different stroke stages that have been associated with distinct biological substrates. In the hyperacute stage, sudden hypoxia damages the BBB, leading to cytotoxic edema and increased permeability; in the acute stage, the neuroinflammatory response aggravates the BBB injury, leading to higher permeability and a consequent risk of HT that can be motivated by reperfusion therapy; in the subacute stage (1-3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky BBB, but this permeability has been associated with improved clinical recovery. In the chronic stage (>6 weeks), an increase of BBB restoration factors leads the barrier to start decreasing its permeability. Nonetheless, permeability will persist to some degree several weeks after injury. Understanding the mechanisms behind BBB dysregulation and HT pathophysiology could potentially help guide acute stroke care decisions and the development of new therapeutic targets; however, effective translation into clinical practice is still lacking. In this review, we will address the different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery.

Misdosing of Non-Vitamin K Antagonist Oral Anticoagulants in Primary Care.

PURPOSE: Prescription patterns of non-vitamin K antagonist oral anticoagulants (NOACs) are unknown among primary care physicians, where most patients with nonvalvular atrial fibrillation (NVAF) are diagnosed and followed up. The goal of this study was to evaluate overdosing and underdosing of NOACs in patients with NVAF followed up in primary care and determine their clinical predictors. METHODS: This multicenter cross-sectional study included all patients with NVAF followed up in 13 primary care units in the center region of Portugal. Patients receiving antithrombotic regimens other than NOACs and patients with missing data were excluded. FINDINGS: The study included 858 patients with NVAF on an NOAC regimen. Overall, 30.3% were prescribed an off-label dosage (25.4% with infratherapeutic dosing [ITD] and 4.9% with supratherapeutic dosing). Chronic kidney disease (odds ratio, 14.0; 95% CI, 5.4-36.5; P < 0.001) and female sex (odds ratio, 2.6; 95% CI, 1.2-5.7; P < 0.001) were independent predictors of supratherapeutic dosing. We also found a significant effect of chronic kidney disease on ITD (odds ratio, 0.22; 95% CI, 0.258-0.678; P < 0.001). IMPLICATIONS: In primary care, NOACs are frequently prescribed with unadjusted dosages, generally infratherapeutic. Attention should be paid to women and patients with chronic kidney disease.