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Introduction: In patients suspected of stroke or transient ischemic attack (TIA), rapid triaging is imperative to improve clinical outcomes. For this purpose, balance-eye-face-arm-speech-time (BEFAST) items are used in out-of-hours primary care (OHS-PC). We explored the risk of stroke and TIA among BEFAST positive patients calling to the OHS-PC, and assessed whether additional predictors could improve risk stratification., Methods: This is a cross-sectional study of retrospectively gathered routine care data from telephone triage tape-recordings of patients calling the OHS-PC with neurological deficit symptoms, classified as BEFAST positive. Four models-with the predictors age, sex, a history of cardiovascular or cerebrovascular disease, and cardiovascular risk factors-were fitted using logistic regression to predict the outcome stroke or TIA. Likelihood ratio testing was used to select the best model, which was subsequently internally validated., Results: The risk of stroke or TIA diagnosis was 52% among 1,289 BEFAST positive patients, median age 72 years, 56% female sex. Of patients with the outcome stroke/TIA, 24% received a low urgency allocation, while 92% had signs or symptoms when calling. Only the addition of age and sex improved predicting stroke or TIA (internally validated c-statistic 0.72, 95%CI 0.69-0.75). The predicted risk of stroke or TIA remained below 20% in those aged below 40. Females aged 70 or over and males aged 55 or over, had a predicted risk above 50%., Discussion: Urgency allocation appears to be suboptimal in BEFAST positive patients calling the OHS-PC. Risk stratification could be improved in this setting by adding age and sex., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 van Royen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: There is ambiguity whether frail patients with atrial fibrillation managed with vitamin K antagonists (VKAs) should be switched to a non-vitamin K oral anticoagulant (NOAC)., Methods: We conducted a pragmatic, multicenter, open-label, randomized controlled superiority trial. Older patients with atrial fibrillation living with frailty (≥75 years of age plus a Groningen Frailty Indicator score ≥3) were randomly assigned to switch from international normalized ratio-guided VKA treatment to an NOAC or to continued VKA treatment. Patients with a glomerular filtration rate <30 mL·min -1 ·1.73 m -2 or with valvular atrial fibrillation were excluded. Follow-up was 12 months. The cause-specific hazard ratio was calculated for occurrence of the primary outcome that was a major or clinically relevant nonmajor bleeding complication, whichever came first, accounting for death as a competing risk. Analyses followed the intention-to-treat principle. Secondary outcomes included thromboembolic events., Results: Between January 2018 and June 2022, a total of 2621 patients were screened for eligibility and 1330 patients were randomly assigned (mean age 83 years, median Groningen Frailty Indicator score 4). After randomization, 6 patients in the switch-to-NOAC arm and 1 patient in the continue-with-VKA arm were excluded due to the presence of exclusion criteria, leaving 662 patients switched from a VKA to an NOAC and 661 patients continued VKAs in the intention-to-treat population. After 163 primary outcome events (101 in the switch arm, 62 in the continue arm), the trial was stopped for futility according to a prespecified futility analysis. The hazard ratio for our primary outcome was 1.69 (95% CI, 1.23-2.32). The hazard ratio for thromboembolic events was 1.26 (95% CI, 0.60-2.61)., Conclusions: Switching international normalized ratio-guided VKA treatment to an NOAC in frail older patients with atrial fibrillation was associated with more bleeding complications compared with continuing VKA treatment, without an associated reduction in thromboembolic complications., Registration: URL: https://eudract.ema.europa.eu; Unique identifier: 2017-000393-11. URL: https://eudract.ema.europa.eu; Unique identifier: 6721 (FRAIL-AF study)., Competing Interests: Disclosures Dr Hemels reports payment for educational lectures from Bayer, BMS/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo. Dr Huisman reports payment to institution from Dutch Healthcare Fund, Dutch Heart Foundation, Bayer Health Care, Pfizer, and Leo Pharma. Dr Kruip reports payment to institution of unrestricted grants from Sobi, payment to institution of research grants from The Netherlands Organisation for Health Research and Development and The Netherlands Thrombosis Foundation, and payment to institution of speaker fees from Sobi, Roche, Dr Geersing reports payment to institution of unrestricted grants from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer, and Daiichi Sankyo. Dr Rutten reports payment to institution of unrestricted grants from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer, and Daiichi Sankyo.

Introduction: Integrated care is effective in reducing all-cause mortality in patients with atrial fibrillation (AF) in primary care, though time and resource intensive. The aim of the current study was to assess whether integrated care should be directed at all AF patients equally., Methods: The ALL-IN trial (n = 1,240 patients, median age 77 years) was a cluster-randomized trial in which primary care practices were randomized to provide integrated care or usual care to AF patients aged 65 years and older. Integrated care comprised of (i) anticoagulation monitoring, (ii) quarterly checkups and (iii) easy-access consultation with cardiologists. For the current analysis, cox proportional hazard analysis with all clinical variables from the CHA2DS2-VASc score was used to predict all-cause mortality in the ALL-IN trial. Subsequently, the hazard ratio and absolute risk reduction were plotted as a function of this predicted mortality risk to explore treatment heterogeneity., Results: Under usual care, after a median of 2 years follow-up the absolute risk of all-cause mortality in the highest-risk quarter was 31.0%, compared to 4.6% in the lowest-risk quarter. On the relative scale, there was no evidence of treatment heterogeneity (p for interaction = 0.90). However, there was substantial treatment heterogeneity on the absolute scale: risk reduction in the lowest risk- quarter of risk 3.3% (95% CI -0.4% - 7.0) compared to 12.0% (95% CI 2.7% - 22.0) in the highest risk quarter., Conclusion: While the relative degree of benefit from integrated AF care is similar in all patients, patients with a high all-cause mortality risk have a greater benefit on an absolute scale and should therefore be prioritized when implementing integrated care., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: G.J. Geersing, F.H. Rutten, and M.E.W. Hemels report unrestricted institutional grants for performing research in the field of atrial fibrillation from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo. I.C. van Gelder reports consultancy fees from Boston, BMS and Bayer to the institution, unrestricted research grants from the Netherlands Cardiovascular Research Initiative, unrestricted research grant from the European Union’s Horizon 2020 research and innovation programme under grant agreement: EHRA-PATHS (945260). M. Rienstra reports Consultancy fees from Bayer, Microport, InCarda Therapeutics to the institution, an unrestricted research grant from ZonMW and the Dutch Heart Foundation; DECISION project 848090001, unrestricted research grants from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation; RACE V (CVON 2014–9), RED-CVD (CVON2017-11), an unrestricted research grant from Top Sector Life Sciences & Health to the Dutch Heart Foundation (PPP Allowance; CVON-AI (2018B017)), and an unrestricted research grant from the European Union’s Horizon 2020 research and innovation programme under grant agreement; EHRA-PATHS (945260). S. van Doorn reports an unrestricted institutional grant for performing research in the field of stroke diagnosis from Stoffels-Hornstra. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Trinks-Roerdink et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Postmarketing observational studies report that a substantial percentage of patients with atrial fibrillation (AF) receive a reduced non-vitamin K antagonist oral anticoagulant (NOAC) dose without a clear indication. Recently, increasing evidence has become available to explore the clinical consequences of such off-label reduced dosing (OLRD). This study aims to systematically review and meta-analyse observational studies that report clinical outcomes associated with OLRD of NOACs compared with on-label non-reduced dosing (OLNRD) of NOACs in patients with AF., Methods and Analysis: We performed a systematic literature review and meta-analysis of observational studies reporting clinical outcomes in AF patients with OLRD of an NOAC compared with AF patients with OLNRD of an NOAC. Using random effects meta-analyses, we estimated the risk of stroke/thromboembolism, bleeding and all-cause mortality., Results: We included 19 studies with a total of 170 394 NOAC users. In these studies, the percentage of OLRD among patients with an indication for an on-label non-reduced NOAC dose ranged between 9% and 53%. 7 of these 19 studies met the predefined criteria for meta-analysis (n=80 725 patients). The pooled HR associated with OLRD of NOACs was 1.04 (95% CI 0.83 to 1.29; 95% prediction interval (PI) 0.60 to 1.79) for stroke/thromboembolism, 1.10 (95% CI 0.95 to 1.29; 95% PI 0.81 to 1.50) for bleeding and 1.22 (95% CI 0.81 to 1.84; 95% PI 0.55 to 2.70) for all-cause mortality., Conclusion: This meta-analysis shows no statistically significant increased risk of stroke/thromboembolism, nor a decreased bleeding risk, nor a difference in risk of all-cause mortality in patients with OLRD of NOACs. Future research may focus on differences between NOACs., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/. FR, MH and G-JG report unrestricted institutional grants for performing research in the field of atrial fibrillation from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo. CBG reports personal fees from Bayer Healthcare and Boston Scientific; grants and personal fees from Boehringer-Ingelheim, BMS Pfizer and Janssen; and grants from Daiichi-Sankyo during the conduct of the study; personal fees from AbbVie, Espero, Medscape, Medtronic, Merck, the National Institutes of Health, Novo Nordisk, Roche, Rho Pharmaceuticals, CeleCor, Correvio, Philips, Abiomed and Anthos Therapeutics; grants from Akros, AstraZeneca, the US Food and Drug Administration, Glaxo Smith Kline, Medtronic Foundation and Apple; and grants and personal fees from Novartis and The Medicines Company outside the submitted work. SvD reports an unrestricted research grant from Stoffels Hornstra. All other authors (LJ, RvM, CJvdD and AWH) declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear tohave influenced the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To investigate the effects of off-label non-vitamin K oral anticoagulant (NOAC) dose reduction compared with on-label standard dosing in atrial fibrillation (AF) patients in routine care., Methods: Population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink, comparing adults with non-valvular AF receiving an off-label reduced NOAC dose to patients receiving an on-label standard dose. Outcomes were ischaemic stroke, major/non-major bleeding and mortality. Inverse probability of treatment weighting and inverse probability of censoring weighting on the propensity score were applied to adjust for confounding and informative censoring., Results: Off-label dose reduction occurred in 2466 patients (8.0%), compared with 18 108 (58.5%) on-label standard-dose users. Median age was 80 years (interquartile range [IQR] 73.0-86.0) versus 72 years (IQR 66-78), respectively. Incidence rates were higher in the off-label dose reduction group compared to the on-label standard dose group, for ischaemic stroke (0.94 vs 0.70 per 100 person years), major bleeding (1.48 vs 0.83), non-major bleeding (6.78 vs 6.16) and mortality (10.12 vs 3.72). Adjusted analyses resulted in a hazard ratio of 0.95 (95% confidence interval [CI] 0.57-1.60) for ischaemic stroke, 0.88 (95% CI 0.57-1.35) for major bleeding, 0.81 (95% CI 0.67-0.98) for non-major bleeding and 1.34 (95% CI 1.12-1.61) for mortality., Conclusion: In this large population-based study, the hazards for ischaemic stroke and major bleeding were low, and similar in AF patients receiving an off-label reduced NOAC dose compared with on-label standard dose users, while non-major bleeding risk appeared to be lower and mortality risk higher. Caution towards prescribing an off-label reduced NOAC dose is therefore required., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Guidelines on atrial fibrillation (AF) recommend the CHA 2 DS 2 -VASc rule for anticoagulant decision-making, but underuse exists. We studied the impact of an automated decision support on stroke prevention in patients with AF in a cluster randomised trial in general practice., Methods: Intervention practices were provided with a CHA 2 DS 2 -VASc based anticoagulant treatment recommendation. Reference practices provided care as usual. The primary outcome was incidence of ischaemic stroke, transient ischaemic attack (TIA) and/or thromboembolism (TE). Secondary outcomes were bleeding and the proportion of patients on guideline recommended anticoagulant treatment., Results: In total, 1129 AF patients were included in the 19 intervention practices and 1226 AF patients in the 19 reference practices. The median age was 77 (interquartile range (IQR) 68-75) years, the median CHA 2 DS 2 -VASc score was 3.0 (IQR 2.0-5.0). Underuse of anticoagulants in patients with CHA 2 DS 2 -VASc score ≥ 2 was 6.6%. After a median follow-up of 2.7 years (IQR 2.3-3.0), the incidence rate per 100 person-years of ischaemic stroke/TIA/TE was 1.96 in the intervention group and 1.42 in the reference group (hazard ratio (HR) 1.3, 95% C.I. 0.8-2.1). No difference was observed in the rate of bleeding (0.79 versus 0.82), or in the underuse (7.2% versus 8.2%) or overuse (8.0% versus 7.9%) of anticoagulation., Conclusions: In this study in patients with AF in general practice, underuse of anticoagulants was relatively low. Providing practitioners with CHA 2 DS 2 -VASc based decision support did not result in a reduction in stroke incidence, affect bleeding risk or anticoagulant over- or underuse., (Copyright © 2018 Elsevier B.V. All rights reserved.)