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In this work, we describe an easy, simple, and cost-effective method to assess the proteolytic activity of snake venoms. The method is based on measuring the hydrolytic halo formed by gelatin radial hydrolysis following the incubation of venoms on a solid gelatin-agarose plate. Venoms from Bothrops (B.) alternatus, B. diporus, B. neuwiedi, B. jararaca, B. jararacussu, Crotalus atrox, and Trimeresurus albolabris were tested. A dose-response relationship was observed for each venom tested, with proteolytic capacity values, determined as GD (gelatinolytic dose, the dose causing a 15 mm hydrolytic halo) ranging from 21 to 222 μg. A correlation between hydrolysis and hemorrhagic activity in rat skin (minimal hemorrhagic dose) was found, with an r 2 value of 0.8774 (p < 0.0001). The venoms' hydrolytic activity was significantly, though not completely, inhibited by EDTA. This methodology was also deployed to assess venom neutralization by antivenoms on the hydrolytic activity of the different venoms, demonstrating its usefulness in evaluating antivenom neutralizing capacity. The method presented is simple, cheap and useful for preliminary screening of venom proteolytic activity and its inhibition and may also predict gross differences in hemorrhagic activity, contributing to the reduction of the number of animals used for these determinations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Abstract: Current guidelines for treating vaccine-induced immune thrombotic thrombocytopenia (VITT) recommend nonheparin anticoagulants and IV immunoglobulin (IVIg). However, the efficacy of these treatments remains uncertain due to case studies involving small patient numbers, confounding factors (eg, concurrent treatments), and a lack of animal studies. A recent study proposed danaparoid and heparin as potential VITT therapies because of their ability to disrupt VITT IgG-platelet factor 4 (PF4) binding. Here, we examined the effects of various anticoagulants (including unfractionated [UF] heparin, danaparoid, bivalirudin, fondaparinux, and argatroban), IVIg, and the FcγRIIa receptor-blocking antibody, IV.3. Our investigation focused on VITT IgG-PF4 binding, platelet activation, thrombocytopenia, and thrombosis. Danaparoid, at therapeutic doses, was the sole anticoagulant that reduced VITT IgG-PF4 binding, verified by affinity-purified anti-PF4 VITT IgG. Although danaparoid and high-dose UF heparin (10 U/mL) inhibited platelet activation, none of the anticoagulants significantly affected thrombocytopenia in our VITT animal model and all prolonged bleeding time. IVIg and all anticoagulants except UF heparin protected the VITT mice from thrombosis. Direct FcγRIIa receptor inhibition with IV.3 antibody is an effective approach for managing both thrombosis and thrombocytopenia in the VITT mouse model. Our results underscore the necessity of animal model investigations to inform and better guide clinicians on treatment choices. This study provides compelling evidence for the development of FcγRIIa receptor blockers to prevent thrombosis in VITT and other FcγRIIa-related inflammatory disorders., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The Direct Oral Anticoagulant (DOAC) Score can predict bleeding risk in patients with atrial fibrillation taking DOACs; however, it lacks external validation. Therefore, this study aimed to assess the association between the DOAC Score and bleeding events in patients with atrial fibrillation who underwent transcatheter aortic valve replacement., Methods and Results: This retrospective multicenter cohort study included patients with atrial fibrillation who underwent transcatheter aortic valve replacement, as registered in a Japanese multicenter registry. The primary end point was the incidence of bleeding. Patients were categorized based on their DOAC Score: low and moderate- (≤7 points), high- (8-9 points), and very high-risk (≥10 points) groups. Among 1230 patients (mean age 84.6±5.1 years; 457 men), 465 (37.8%) received a vitamin K antagonist, and the remaining patients received DOACs. The low and moderate-, high-, and very high-risk groups included 380 (30.1%), 497 (40.4%), and 353 patients (28.7%), respectively. The 3-year cumulative incidence of all bleeding events was significantly different among the 3 groups (low and moderate risk: 6.6%, high risk: 6.9%, and very high risk: 14.0%; P <0.01). Multivariable Cox regression analysis revealed that significant increments in the DOAC Score were associated with a risk of all bleeding events at 3 years in the overall cohort (hazard ratio [HR], 1.22 [95% CI, 1.08-1.38]; P <0.01), in the DOAC cohort (HR, 1.20 [95% CI, 1.01-1.42]; P =0.04), and in the vitamin K antagonist cohort (HR, 1.25 [95% CI, 1.04-1.50]; P =0.02)., Conclusions: The DOAC Score was significantly associated with bleeding events in patients with atrial fibrillation after transcatheter aortic valve replacement, aiding in clinical decision-making for anticoagulant management., Registration: URL: https://center6.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000023585; Unique identifier: UMIN000020423.

Background: Anticoagulation in atrial fibrillation (AF) increases the risk of major bleeding. No predictive model has hitherto provided estimates of the absolute risk for individual patients., Aim: To predict the individual 1-year risk of major bleeding in patients with AF taking anticoagulants and evaluate the importance of individual risk factors., Design: A nationwide register-based cohort study., Participants: Danish patients with first-time non-valvular AF who redeemed anticoagulants within 7 days after diagnosis., Method: The individual absolute risk of major bleeding was estimated from a logistic regression model (the Calculator of Absolute Bleeding Risk/CABS model) utilising the same risk factors as HAS-BLED, except allowing non-linear age effects, and allowing effect modification of all factors according to history of bleeding. The logistic regression was assessed in term of discrimination using the Area Under the ROC curve (AUC) and calibration., Results: Among 76,102 patients with AF redeeming anticoagulants, 2,406 suffered a major bleeding within 1 year. History of bleeding was the strongest predictor, and age significantly modified the risk. The CABS model superseded HAS-BLED score with regards to discrimination (AUC 0.646 vs 0.615, p<0.001) and calibrated well. A typical male patient was 70-years old without any risk factors and he had a 1-year bleeding risk of 1.4% (1.2; 1.6) while a typical female patient was 73-years old, had hypertension and a 1-year bleeding risk of 2.2% (1.9;2.6)., Conclusion: We propose CABS as a tool for prediction of individual absolute risks of major bleeding in patients with AF taking anticoagulant. The predicted absolute risk can be used for patient counselling., Competing Interests: CTP is supported by grants from Novo Nordic and Bayer. All other authors declared no conflict of interest. There was no funding for the study., (Copyright: © 2024 Toft-Petersen 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: COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment., Methods: This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration., Findings: Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB., Conclusion: A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events., Competing Interests: Competing interests: Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☒The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Casey O’Connell: consulting fee from AbbVie Inc. Advisory Board Janice Liebler: Grants or contracts from Immunexpress, St. Michaels Hospital, Toronto, Canada, CDC Foundation No conflict of interest for other authors., (Copyright: © 2024 Bhoopat L et al.)

The OCEANIC-AF trial was terminated early due to inferiority of asundexian compared with apixaban for the prevention of stroke and systemic embolism in patients with atrial fibrillation. 1 However, the promisingly low bleeding rates support continued exploration of factor XIa inhibitors. Future efforts should focus on achieving greater factor XIa inhibition and identifying patient populations that may benefit most from these therapies., Competing Interests: Declaration of interests L.P. served as an investigator in the OCEANIC-AF trial and serves as an investigator in the OCEANIC-STROKE trial. G.T. served as a local principal investigator in the OCEANIC-AF trial and serves as a national principal investigator in the OCEANIC-STROKE trial. He also serves on the Steering Committee of the OCEANIC-STROKE trial., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Venom-induced hemorrhage analysis usually is performed by Minimum Hemorrhagic Dose (MHD), however a similar method can be used to compare venoms with fewer laboratory animals. Our work compared the MHD of five different venoms, with the size of hemorrhagic spot, finding good correlations in the results. Considering the 3Rs principle, we propose the use of the hemorrhagic spot method to compare hemorrhagic activity of snake venoms, rather than using the MHD method, since the first one needs 5 times less animals than the other., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Obesity and underweight are a growing health problem worldwide and a challenge for clinicians concerning antithrombotic therapy, due to the associated risks of thrombosis and/or bleeding. This clinical consensus statement updates a previous one published in 2018, by reviewing the most recent evidence on antithrombotic drugs based on body size categories according to the World Health Organization classification. The document focuses mostly on individuals at the extremes of body weight, i.e. underweight and moderate-to-morbid obesity, who require antithrombotic drugs, according to current guidelines, for the treatment or prevention of cardiovascular diseases or venous thromboembolism. Managing antithrombotic therapy or thromboprophylaxis in these individuals is challenging, due to profound changes in body composition, metabolism and organ function, and altered drug pharmacokinetics and pharmacodynamics, as well as weak or no evidence from clinical trials. The document also includes artificial intelligence simulations derived from in silico pharmacokinetic/pharmacodynamic models, which can mimic the pharmacokinetic changes and help identify optimal regimens of antithrombotic drugs for severely underweight or severely obese individuals. Further, bariatric surgery in morbidly obese subjects is frequently performed worldwide. Bariatric surgery causes specific and additional changes in metabolism and gastrointestinal anatomy, depending on the type of the procedure, which can also impact the pharmacokinetics of antithrombotic drugs and their management. Based on existing literature, the document provides consensus statements on optimizing antithrombotic drug management for underweight and all classes of obese patients, while highlighting the current gaps in knowledge in these complex clinical settings, which require personalized medicine and precision pharmacology., (© 2024 the European Society of Cardiology.)

Background: P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy (DAPT) may balance ischaemic and bleeding risks in patients with acute coronary syndrome (ACS). However, it remains uncertain how different P2Y12 inhibitors used as monotherapy affect outcomes., Methods and Results: Randomized controlled trials comparing P2Y12 inhibitor monotherapy after a short course of DAPT (≤3 months) vs. 12-month DAPT in ACS were included. The primary endpoint was major adverse cardiovascular events (MACE). All analyses included an interaction term for the P2Y12 inhibitor used as monotherapy. Trial sequential analyses were run to explore whether the effect estimate of each outcome may be affected by further studies. Seven trials encompassing 27 284 ACS patients were included. Compared with 12-month DAPT, P2Y12 inhibitor monotherapy after a short course of DAPT was associated with no difference in MACE [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.76-1.12] and a significant reduction in net adverse clinical events (NACE) (OR 0.75; 95% CI 0.60-0.94), any bleeding (OR 0.54, 95% CI 0.43-0.66), and major bleeding (OR 0.47, 95% CI 0.37-0.60). Significant interactions for subgroup difference between ticagrelor and clopidogrel monotherapy were found for MACE (Pint = 0.016), all-cause death (Pint = 0.042), NACE (Pint = 0.018), and myocardial infarction (Pint = 0.028). Trial sequential analysis showed conclusive evidence of improved NACE with ticagrelor, but not with clopidogrel monotherapy, compared with standard DAPT., Conclusions: In patients with ACS, P2Y12 inhibitor monotherapy after short DAPT halves bleeding without increasing ischaemic events compared with standard DAPT. Ticagrelor, but not clopidogrel monotherapy, reduced MACE, NACE, and mortality compared with standard DAPT, supporting its use after aspirin discontinuation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: This study investigated drug-drug interactions in patients with atrial fibrillation taking both a direct oral anticoagulant (DOAC) and an antiarrhythmic drug., Methods and Results: Using data from the National Health Insurance database (2012-2018), we identified 78 805 patients with atrial fibrillation on DOACs, with 24 142 taking amiodarone, 8631 taking propafenone, 2784 taking dronedarone, 297 taking flecainide, 177 taking sotalol, and 42 772 on DOACs alone. Patients with bradycardia, heart block, heart failure, mitral stenosis, prosthetic valves, or incomplete data were excluded. Propensity score matching compared those taking both DOACs and antiarrhythmic drugs with those on DOACs alone. There was an increased risk of major bleeding in patients concomitantly taking DOACs with amiodarone when compared with matched patients taking DOACs alone (hazard ratio [HR],1.13 [95% CI, 1.04-1.23]; P =0.0044), particularly in patients taking dabigatran (HR, 1.19 [95% CI, 1.03-1.38]; P =0.0175). No significant difference in bleeding risk was found for propafenone, dronedarone, flecainide, or sotalol. The small sample sizes in the flecainide and sotalol groups limit interpretation. Notably, intracranial bleeding risk was higher in patients on DOACs and amiodarone, regardless of age. Additionally, patients <80 years old taking dabigatran with amiodarone or propafenone had a higher risk of gastrointestinal bleeding., Conclusions: Concomitant use of DOACs with amiodarone, but not dronedarone or propafenone, increases the risk of major bleeding, particularly intracranial bleeding. This study provides new evidence to guide clinicians to tailor concomitant anticoagulation and antiarrhythmic therapy for patients with atrial fibrillation.

Objectives: Evidence of the optimal antiplatelet therapy for elderly patients who had a stroke is limited, especially those elder than 80 years. This study aimed to explore the efficacy and safety of dual antiplatelet therapy (DAPT) in old-old patients compared with younger patients in the ticagrelor or Clopidogrel with aspirin in High-risk patients with Acute Non-disabling Cerebrovascular Events-II (CHANCE-2) trial., Methods: CHANCE-2 was a randomised, double-blind, placebo-controlled trial in China involving patients with high-risk transient ischaemic attack or minor stroke with CYP2C19 loss-of-function alleles. In our substudy, all enrolled patients were stratified by age: old-old (≥80 years), young-old (65-80 years) and younger (<65 years). The primary outcomes were stroke recurrence and moderate to severe bleeding within 90 days, respectively., Results: Of all the 6412 patients, 406 (6.3%) were old-old, 2755 (43.0%) were young-old and 3251 (50.7%) were younger. Old-old patients were associated with higher composite vascular events (HR 1.41, 95% CI 1.00 to 1.98, p=0.048), disabling stroke (OR 2.43, 95% CI 1.52 to 3.88, p=0.0002), severe or moderate bleeding (HR 8.40, 95% CI 1.95 to 36.21, p=0.004) and mortality (HR 7.56, 95% CI 2.23 to 25.70, p=0.001) within 90 days. Ticagrelor-aspirin group was associated with lower risks of stroke recurrence within 90 days in younger patients (HR 0.68, 95% CI 0.51 to 0.91, p=0.008), which was no differences in old-old patients., Conclusion: Elderly patients aged over 80 in CHANCE-2 trial had higher risks of composite vascular events, disabling stroke, severe or moderate bleeding and mortality within 90 days. Genotype-guided DAPT might not be as effective in old-old patients as in younger ones., Trial Registration Number: NCT04078737., Competing Interests: Competing interests: SCJ reports compensation from Everest CRO for data and safety monitoring services and compensation from AstraZeneca AB for consultant services. PMB reports grants from Alzheimer’s Society; compensation from DiaMedica for consultant services; compensation from Sanofi for consultant services; compensation from Phagenesis for consultant services; compensation from Moleac for consultant services; grants from British Heart Foundation; and grants from NIHR. YoW reports grants from Amgen; compensation from SANOFI-AVENTIS US for consultant services; grants from SANOFI-AVENTIS US; and grants from AstraZeneca. The other authors report no conflicts., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Intravenous thrombolysis is not recommended in anticoagulated patients receiving direct oral anticoagulants (DOACs) and a recent intake within the last 48 hours in US and European guidelines. However, three observational studies now suggest safety of thrombolysis in patients with recent intake of DOACs, and thus support previous experimental data. In this perspective, the current evidence and practical consequences are discussed., Competing Interests: Competing interests: JCP has received consultation fees and travel expenses from Akcea, Bayer, Boehringer Ingelheim, Daiichi Sankyo and BMS/Pfizer, outside the submitted work. TRM reports grants from Bangerter-Rhyner Foundation. YX has received a research grant from the National Institute on Aging, American Heart Association and Genentech, and honorarium from Boehringer Ingelheim. DJS is on the advisory board of Bayer Switzerland and Portola/Alexion. He reports research funding from the Swiss National Science Foundation, Swiss Heart Foundation, Bangerter-Rhyner Foundation, Bayer Foundation and Portola/Alexion. All other authors report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite the use of conventional dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI), the risk of adverse events remains high among patients with increased thrombotic risk. Until recently, the optimal antiplatelet strategy to balance the ischaemic and bleeding risks in patients who are undergoing complex high-risk PCI has been unclear. The TAILored Versus COnventional AntithRombotic StratEgy IntenDed for Complex HIgh-Risk PCI (TAILORED-CHIP) trial is an investigator-initiated, multicentre, prospective randomised trial to evaluate the efficacy and safety of a time-dependent tailored antiplatelet therapy with an early (<6 months post-PCI) escalation (low-dose ticagrelor at 60 mg twice daily plus aspirin) and a late (>6 months post-PCI) de-escalation (clopidogrel monotherapy) in patients undergoing complex high-risk PCI as compared with standard DAPT (clopidogrel plus aspirin for 12 months). Eligible patients had to have at least one high-risk anatomical or procedural feature or clinical characteristic associated with an increased risk of ischaemic or thrombotic events. The primary endpoint was the net clinical outcome, a composite of death from any cause, myocardial infarction, stroke, stent thrombosis, urgent revascularisation, or clinically relevant bleeding (Bleeding Academic Research Consortium type 2, 3, or 5) at 12 months after randomisation. (ClinicalTrials.gov: NCT03465644).

Balancing the risks of ischemic and bleeding events in patients who have undergone coronary angioplasty with drug-eluting stents (DES) is a delicate task. Individuals recovering from myocardial infarction are at increased risk of recurrent ischemic events, highlighting the potential benefits of rigorous secondary prevention measures. 1 Dual antiplatelet therapy (DAPT), combining aspirin with P2Y12 inhibitors such as clopidogrel or ticagrelor, forms the cornerstone of post-percutaneous coronary intervention (PCI) care aimed at preventing stent thrombosis and lowering the risk of ischemic events. Current medical guidelines recommend a 6-month duration of DAPT for stable coronary disease and 12 months for acute coronary syndrome (ACS)., (© Journal of the Association of Physicians of India 2024.)

Diffuse alveolar hemorrhage (DAH) is a form of hemoptysis caused by disruption of the alveolar-capillary basement membrane causing alveolar bleeding. Inhalation of cocaine and other sympathomimetic agents are described as one of many pathologic causes. We describe what is to the author's knowledge the first reported case of DAH caused by inhalation of bupropion, a norepinephrine-dopamine reuptake inhibitor, which was successfully treated with systemic steroids. This case adds a novel agent to the known pathologic causes of DAH and introduces a novel form of bupropion toxicity, which should be considered as a cause in cases of DAH in the appropriate clinical context. The case also highlights the potential for further research into the pathologic interactions of bupropion at the alveolar basement membrane., Competing Interests: Financial/Nonfinancial Disclosures None declared, (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: In the AUGUSTUS trial (An Open-Label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs Vitamin K Antagonist and Aspirin vs Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention), the combination of dual antiplatelet therapy plus oral anticoagulation increased the risk of bleeding without reducing ischemic events compared with a P2Y12 inhibitor plus oral anticoagulation among patients with atrial fibrillation and acute coronary syndrome or elective percutaneous coronary intervention. However, AUGUSTUS enrolled patients up to 14 days after acute coronary syndrome or percutaneous coronary intervention, and there may be a benefit to dual antiplatelet therapy plus oral anticoagulation early after an ischemic event., Methods: In this secondary analysis of AUGUSTUS, we divided patients into groups based on whether they were enrolled <6 days (early) or ≥6 days (later) after their index acute coronary syndrome or percutaneous coronary intervention, and tested the interaction between time from the index event to enrollment and randomized treatment (apixaban versus vitamin K antagonist and aspirin versus placebo) on 30-day and 6-month clinical outcomes using Cox proportional hazards models., Results: Among 4605 patients enrolled in AUGUSTUS with data available on time from the index event to enrollment, the median time from the index event to enrollment was 6 (range, 0-14) days. There were no significant interactions between time from the index event and aspirin versus placebo on clinical outcomes at 30 days or 6 months, though patients with time from the index event <6 days had a nominally significant reduction in death or ischemic events at 30 days with aspirin (hazard ratio, 0.55 [95% CI, 0.30-0.99]), whereas patients with time from the index event ≥6 days did not (hazard ratio, 0.88 [95% CI, 0.54-1.43]; interaction P =0.23). There were no significant interactions between time from the index event and apixaban versus vitamin K antagonist on clinical outcomes., Conclusions: Among patients with atrial fibrillation with acute coronary syndrome or undergoing percutaneous coronary intervention, there was no difference in the relative benefit of apixaban versus vitamin K antagonist or aspirin versus placebo when patients were enrolled early versus later after their index event., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02415400., Competing Interests: Dr Fanaroff: research grants from the American Heart Association, National Institutes of Health, and Cardiovascular Systems Inc; and consulting fees from Intercept Pharmaceuticals and Abbott Laboratories. Dr Granger: research grants from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, Armetheon, AstraZeneca, US Food and Drug Administration (FDA), GlaxoSmithKline, The Medicines Company, Medtronic Foundation, Medtronic, Inc, and Novartis; consulting fees from Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, Abbvie, Armetheon, AstraZeneca, Eli Lilly, Gilead, GlaxoSmithKline, Hoffmann-La Roche, The Medicines Company, National Institutes of Health (NIH), Novartis, Sirtex, Verseon, Apple, Medscape, LLC, Merck, Novo Nordisk, Roche Diagnostics, and Rho Pharmaceuticals. Dr Goodman: research grant support and speaker/consulting honoraria from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, CYTE, Ltd, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma; salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Failure Society, Canadian Heart Research Centre and MD Primer, Canadian Virtual Coordinating Centre for Global Collaborative Cardiovascular Research, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, Baim Institute for Clinical Research, and Thrombolysis in Myocardial Infarction Study Group (Brigham Health). Dr Aronson: employee of Bristol Myers Squibb. Dr Windecker: research, travel, or educational grants to the institution without personal remuneration from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Braun, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Cordis Medical, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Farapulse, Inc, Fumedica, Guerbet, Idorsia, Inari Medical, InfraRedx, Janssen-Cilag, Johnson & Johnson, MedAlliance, Medicure, Medtronic, Merck Sharp & Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pharming Tech, Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave; advisory board member and steering/executive group member of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, and V-Wave, with payments to the institution but no personal payments; steering/executive committee group member of several investigator-initiated trials funded by industry without impact on his personal remuneration. Dr Mehran: institutional research grants from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol Myers Squibb/Sanofi, CSL Behring, Eli Lilly/Daiichi Sankyo, Medtronic, Novartis, and OrbusNeich; consulting fees from Boston Scientific, Abbott Vascular, Medscape, Siemens Medical Solutions, Roivant Sciences, Inc, and Sanofi; consulting (no fees) to Regeneron Pharmaceuticals, Inc; institutional consulting fees from Abbott Vascular, Spectranetics/Phillips/Volcano Corporation, Bristol Myers Squibb, Novartis, and Watermark Research; executive committee member for Janssen Pharmaceuticals and Bristol Myers Squibb; <1% equity in Claret Medical and Elixir Medical. Dr Alexander: research grants from Bristol Myers Squibb, Boehringer Ingelheim, AstraZeneca, CryoLife, CSL Behring, US FDA, NIH, Sanofi, and VoluMetrix; consulting fees from Pfizer, Bristol Myers Squibb, AbbVie Pharmaceuticals, CSL Behring, Novo Nordisk, Portola Pharmaceuticals, Quantum Genomics, Teikoku Pharmaceuticals, VA Cooperative Studies, and Zafgen. Dr Lopes: research grants from Bristol Myers Squibb, Pfizer, Amgen, Inc, GlaxoSmithKline, Medtronic PLC, and Sanofi Aventis; consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, and Bayer AG. The other authors report no conflicts.

Objective: The incidence of splanchnic vein thrombosis (SVT) is reported to be <25 times lower than that of deep vein thrombosis and pulmonary emboli, which occur in 70 to 270/100,000 cases in the general population. Current guidelines recommend initial treatment with therapeutic low-molecular-weight heparin followed by a transition to a vitamin K antagonist (VKA) or a direct oral anticoagulant (DOAC) in patients with cirrhosis who develop SVT without severe liver dysfunction. This, however, is based on observational data. This study aimed to evaluate the efficacy and safety of anticoagulant therapy in patients with cirrhosis who present with SVT and receive either a DOAC or a VKA., Methods: This multicenter retrospective cohort study was conducted from December 2021 to November 2022. Patients between the ages of 18 and 75 years with cirrhosis and acute SVT who received either a VKA or a DOAC between July 2019 and July 2021 were eligible for inclusion. The primary outcome was the efficacy of treatment, defined as a new thrombotic event. The secondary outcome was the safety of treatment, defined as the development of major bleeding. Readmission data were followed up at 6 and 10 months. Bivariate analysis was conducted to assess the relationship between the medication groups and each outcome and summarized as odds ratios (ORs) with 95% confidence intervals (CIs). Statistical significance was set at 5% for all of the comparisons., Results: A total of 80 patients from 50 hospitals were included in this study. Sixty-one patients (59.02% male) received DOACs and 19 (57.89% male) received a VKA. Of the patients who received DOACs, 41 (67.21%) received apixaban, one (1.64%) received dabigatran, and 19 (31.15%) received rivaroxaban. The results from the bivariate analysis revealed no significant differences between DOACs and warfarin for both the efficacy (OR 1.46, 95% CI 0.44-4.84, P = 0.53) and safety outcomes (OR 1.03, 95% CI 0.04-26.43, P = 1) at 10 months., Conclusions: The use of DOACs in patients with cirrhosis who present with SVT may be efficacious and safe compared with warfarin. The findings from our study may inform power analyses for well-conducted randomized trials to confirm these findings.

Background: The prospective, single-arm, observational, phase 4 ETNA-AF Europe study collected real-world data about safety, effectiveness and therapeutic adherence in European patients with non-valvular atrial fibrillation newly prescribed with edoxaban and followed up for 4 years., Methods: Overall, 13 164 patients were included in the full-analysis set, which means that they had at least one documentation after baseline at 4 years. The current paper reports about the 3329 Italian patients out of the whole European population., Results: In the Italian cohort, median age was 76.0 (69.0-82.0) years, with 57.4% of the patients being ≥75 years old. The CHA2DS2-VASc score was >4 in 586 (18.1%) patients. At baseline, 670 (20.8%) patients were classified as frail by the investigators. Edoxaban 30 mg/day was prescribed to 1013 (31.8%) patients: these were older, with more comorbidities and a lower estimated creatinine clearance compared with those receiving 60 mg/day. All-cause mortality was 4.1%/year and there were very low yearly rates of bleeding and thromboembolic events: major bleeding, 0.9%; intracranial hemorrhage, 0.2%; ischemic stroke, 0.3%; systemic embolism, <0.1%. These events were more frequent in patients ≥75 years or in patients with renal impairment or treated with edoxaban 30 mg/day. Advancing age was not associated with an increased incidence of intracranial bleeding., Conclusions: These findings confirm the favorable long-term safety and effectiveness profile of edoxaban in non-valvular atrial fibrillation patients treated in routine clinical care in Italy.

Introduction: SARS-CoV-2 (COVID-19) infection and multisystem inflammatory syndrome in children (MIS-C) are risk factors for venous thromboembolism (VTE). Guidelines for VTE prophylaxis were established at our institution at the beginning of the pandemic. Patients who had any VTE risk factors in addition to COVID-19 met criteria for anticoagulation prophylaxis. Patients who were diagnosed with MIS-C met criteria regardless of additional risk factors., Materials and Methods: We conducted a retrospective review of patients admitted with COVID-19 or MIS-C to determine compliance with VTE prophylaxis guidelines and to evaluate the incidence of VTE and bleeding events in our population., Results and Conclusions: Among a total of 678 patients admitted with COVID-19 or MIS-C, 519 (76 %) patients met criteria for VTE prophylaxis and 348 (65.6 %) started prophylaxis. Logistic regression analysis identified a personal or family history of thrombosis or thrombophilia, diagnosis of MIS-C, admission to the intensive care unit, and presence of a central venous catheter as significantly associated with starting VTE prophylaxis. There were 18 patients who developed VTE. Minor bleeding events occurred in 19 patients (5 %), patient important bleeding, no intervention occurred in 8 patients (2 %), clinically relevant nonmajor bleeding in 8 patients (2 %), and major bleeding in 10 patients (3 %). The incidence of VTE in our patients with COVID-19 and MIS-C is similar to VTE rates at other institutions. We found that universally recognized VTE risk factors were appropriate to include as risk factors for thrombosis in hospitalized children with COVID-19 and MIS-C., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lauren Amos reports a relationship with Sanofi that includes: consulting or advisory and speaking and lecture fees. Lauren Amos reports a relationship with HemaBiologics that includes: consulting or advisory. Lauren Amos reports a relationship with Genentech that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Factor Xa inhibitor (FXaI)-associated bleeding events are common and associated with substantial morbidity. Systematic evaluation of widely available, effective, and affordable FXaI bleed management strategies is needed., Materials and Methods: We conducted a single-center retrospective cohort study of FXaI-treated patients presenting to a tertiary academic medical center from January 2018 to May 2019 who received 25-50 IU/kg 4F-PCC for either FXaI-associated major bleeding or urgent surgery. The primary outcome was hemostatic efficacy, and the safety outcome was the 30-day risk of thromboembolism., Results: PCC was used to treat FXaI-associated bleeding in 83 cases (79.1 %) and was given before urgent surgery in 22 cases (20.9 %). Sixty-six patients were on apixaban, 38 were on rivaroxaban and one patient was on edoxaban. Intracranial hemorrhage (ICH) and gastrointestinal bleeding accounted for most bleeds (74.7 %). Median interval between last DOAC intake and presentation to triage was 9 h [IQR 5.3-14.8] and median PCC dosing was 40.0 IU/kg [IQR 28.5-46.6]. Forty-two patients (40.0 %) had pre-PCC FXaI levels drawn with median FXaI levels of 114.5 ng/mL [IQR 70.0-175.0]. Effective hemostasis occurred in 66.7 % [95%CI 55.4-76.3] of patients receiving PCC for bleeding and surgical hemostasis was rated as normal in 95.5 % (95%CI 76.5-100.0) for patients having urgent surgery. The 30-day risk of thromboembolism was 7.6 % [95%CI 3.7-14.5] and 22.9 % [95%CI 15.8-31.8] of patients died., Conclusions: PCC for FXaI-associated bleeding was associated with hemostatic efficacy in two-thirds of patients and thromboembolic events were uncommon. PCC represents a promising treatment strategy for FXaI-associated bleeding., Competing Interests: Declaration of competing interest J.R. Shaw has received in-kind laboratory support from Diagnostica Stago. J.H. Levy serves on steering committees for Merck, Octapharma, Takeda, and Werfen. S. Schulman reports research grant funding from Octapharma and honoraria from Alexion, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Regeneron, Sanofi, and Takeda. D.M. Siegal has received honoraria paid indirectly to her institution from Astra Zeneca, BMS-Pfizer, Servier. D. Dowlatshahi has provided consultation to Astra Zeneca Canada. M. Carrier has received research funding from Leo Pharma and Pfizer, in addition to honoraria from BMS, Valeo Pharma, Leo Pharma, Sanofi and Servier. L. Castellucci's research institution has received honoraria from Bayer, BMS-Pfizer Alliance, The Academy for Continued Advancement in Healthcare Education, Amag Pharmaceutical, LEO Pharma, Sanofi, Valeo Pharma, and Servier., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: We conducted a prespecified subanalysis of the POEM trial to assess the association between sex and clinical outcomes following a short 1-month dual-antiplatelet-therapy (DAPT) period after percutaneous coronary intervention (PCI) with bioresorbable polymer everolimus-eluting stent (BP-EES) among patients at high bleeding risk (HBR)., Background: Shortening the DAPT period after PCI is an effective bleeding avoidance strategy with contemporary drug-eluting stents. Whether sex affects the risk of adverse events following PCI is still debated., Methods: Patients at HBR undergoing PCI with BP-EES were enrolled and treated with 1-month DAPT. If anticoagulation was needed, study participants received an oral anticoagulant (OAC) in addition to a P2Y 12 inhibitor for 1 month, followed by OAC only thereafter. The primary endpoint was a composite of cardiac death, myocardial infarction, or definite/probable stent thrombosis at 12 months. We report sex-based outcomes of patients included in the POEM study., Results: We enrolled 129 (29.1%) women and 314 (70.9%) men. Women were older, with lower hemoglobin levels, and worse renal function. Accordingly, they had a trend for a greater number of HBR criteria fulfilled and a higher PARIS bleeding score. However, they were not at a significantly higher risk for the primary endpoint (men vs. women: 5.17% vs. 3.94%; HR 1.30; 95% CI: 0.48-3.54, p = 0.61), or any of the hemorrhagic and ischemic secondary endpoints., Conclusions: This prespecified subanalysis of the POEM trial suggests that 1-month DAPT following PCI with BP-EES may be a safe and effective therapeutic strategy for women at HBR., (© 2024 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Introduction: Oral anticoagulant drugs reduce the risk of stroke associated with atrial fibrillation. Vitamin K antagonists, gold standard therapy for decades, have been deposed by the direct oral anticoagulants that exhibit superior safety profiles. However, hemorrhagic complications remain a major concern to anticoagulation., Areas Covered: We searched available data in the literature to review the current knowledge on the safety profiles of available anticoagulants., Expert Opinion: Despite a relevant leap forward with the introduction of DOACs, safety concerns persist in some fields of the current pharmacotherapy for stroke prevention in atrial fibrillation. In-depth knowledge of the safety profile of available anticoagulants and dealing with safety issues in patient subgroups is of utmost importance. Bleeding risk scores should not be dichotomously used to decide anticoagulation treatment but rather to promote shared decision, identify and correct modifiable risk factors, and set monitoring frequency. Additional issues that wait to be investigated in order to improve the safety of therapy include circulating levels of direct oral anticoagulants and anticoagulation in patient sub-groups: very elderly, frail, those with advanced kidney or liver disease, and so on. Safety may be improved from the in-depth knowledge of safety concerns and therapeutic options.

Anticoagulation management in the surgical patient requires clinical expertise and careful attention. For patients already receiving anticoagulation for a defined indication (ie, stroke prevention for atrial fibrillation, treatment of venous thromboembolism (VTE), or presence of a mechanical heart valve), understanding how to manage these agents by weighing the risks of thromboembolic events and bleeding is paramount. Additionally, prevention of VTE in the surgical patient involves the identification of patient-specific and procedure-specific risk factors for both VTE and bleeding. With this information, as well as familiarity with the several antithrombotic options available, an appropriate prophylaxis strategy can be employed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Despite advancements in coronary artery disease (CAD) management, major adverse cardiovascular events persist. Vitamin K antagonists and direct oral anticoagulants present bleeding risks. Low-dose rivaroxaban (2.5 mg) is approved by the European Society of Cardiology and the US Food and Drug Administration for CAD. The survival advantage and risk-benefit profile of combining low-dose rivaroxaban with aspirin for CAD patients remain uncertain. This meta-analysis aims to compare the efficacy of low-dose rivaroxaban plus aspirin versus aspirin monotherapy in CAD patients., Methods: We systematically searched databases for randomized controlled trials exploring low-dose rivaroxaban with aspirin in CAD patients. Of the 6220 studies screened, five met the inclusion criteria. Primary outcomes included myocardial infarction, stroke, major bleeding events, and all-cause mortality. The analysis employed a fixed-effects model, calculating hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Five randomized controlled trials involving 41,351 participants were included. Rivaroxaban (2.5 mg) significantly reduced all-cause mortality (HR, 0.88; 95% CI, 0.81-0.95; P = 0.002), myocardial infarction (HR, 0.81; 95% CI, 0.70-0.94; P = 0.006), and stroke (HR, 0.61; 95% CI, 0.49-0.76; P < 0.00001) compared to aspirin alone. However, it increased major bleeding risk (HR, 1.66; 95% CI, 1.40-1.97; P < 0.01). Meta-regression revealed no dose-dependent impact on all-cause mortality., Conclusion: Low-dose rivaroxaban demonstrates survival benefits and reduces myocardial infarction and stroke risks in CAD patients, albeit with an increased risk of major bleeding. Consideration of patient bleeding risk is crucial when adding rivaroxaban to antiplatelet therapy. Further research is warranted to compare its effectiveness and safety with dual antiplatelet therapy or P2Y12 inhibitors., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Vitamin-K antagonists (VKA) are considered the first-line anticoagulants for thrombotic antiphospholipid syndrome (TAPS), particularly with triple positivity or arterial events. However, thrombotic recurrence remains high despite anticoagulation and other clinical issues may arise. Long-term parenteral anticoagulants may therefore be considered, however little is known about the viability of fondaparinux in this setting., Materials and Methods: We describe the efficacy and safety of long-term fondaparinux for TAPS (>3-months duration) treated at a single centre in the UK. Clinical features and the outcomes of recurrence and bleeding were reviewed using electronic patient records., Results: 46 patients were identified with history of either venous or arterial TAPS and a total 175 patient-years using fondaparinux (median duration 2.7 years/patient (IQR 1.4-4.8)). 43 (93%) had VKA as first-line anticoagulation with a median duration of 6.5 years (IQR 4.0 - 9.8). All patients received fondaparinux as second-to fourth-line anticoagulation.Thrombosis recurrence occurred in 1 (1%) patient (0.6 events/100-patient years). Major, clinically relevant non-major (CRNM) or minor bleeding occurred in 2 (7%), 5 (10.9%) and 8 (17.4%) patients respectively. Major/CRNM bleeding rates were 1.1 and 2.9 events/100-patient-years. Age >65years was associated with bleeding ( p = .047) and concurrent antiplatelets were associated with major/CRNM bleeding ( p = .011). Logistic regression showed increasing age was associated with bleeding (OR = 1.097, p = .009)., Conclusions: We suggest that fondaparinux may be used for TAPS when VKA is not appropriate. Thrombotic recurrence was infrequent, and the number of major bleeding events appeared comparable to conventional therapies., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Bleeding and stroke are frequent complications after transcatheter aortic valve implantation (TAVI). The mortality risk associated with these events has been reported before, but data regarding their impact on health-related quality of life (QoL) is limited., Aim: To evaluate the impact of bleeding and stroke occurring within 30 days after TAVI, on mortality and QoL during the first year after TAVI., Methods: POPular TAVI was a randomized clinical trial that evaluated the addition of clopidogrel to aspirin or oral anticoagulation in patients undergoing TAVI. Besides clinical outcomes, QoL was assessed using the Short Form-12 and EuroQoL Five Dimensions questionnaires before, and at 3, 6, and 12 months after TAVI., Results: Major or life-threatening bleeding occurred in 81 patients (8.3%) and was associated with an increased risk of death (hazard ratio [HR] 1.95 [95% confidence interval (CI) 1.00-3.79]); minor bleeding occurred in 104 patients (10.6%) and was not associated with mortality (HR 0.75 [95% CI 0.30-1.89]). Stroke occurred in 35 patients (3.6%) and was associated with an increased risk of death (HR 2.90 [95% CI 1.23-6.83]). Mean mental component summary (MCS-12) scores over time were lower in patients with major or life-threatening bleeding (p = 0.01), and similar in patients with minor bleeding, compared to patients without bleeding; mean physical component summary (PCS-12) scores, EQ-5D index, and visual analog scale (VAS) were similar between those patients. Mean MCS-12 scores were lower in patients with stroke (p = 0.01), mean PCS-12, EQ-5D index, and VAS were similar compared to patients without stroke., Conclusion: Major or life-threatening bleeding and stroke were associated with an increased risk of death and decreased mental QoL in the first year after TAVI., (© 2024 Wiley Periodicals LLC.)

Background: Direct oral anticoagulants (DOACs) have shown comparable efficacy and a superior safety profile in clinical trials for patients with venous thromboembolism (VTE). However, further study is needed to assess DOACs' effectiveness and safety compared to warfarin in a real-world context. Thus, this meta-analysis compares the effectiveness and safety of warfarin and DOACs in patients with VTE., Method: A systematic review of the literature using PubMed and EMBASE was conducted from inception until June 2024. We examined observational studies that compared safety and effectiveness between DOACs and warfarin when used in treating VTE and reported adjusted hazard ratios (HRs) and/or odds ratios (ORs) for recurrent VTE, major bleeding, clinically relevant non-major bleeding, gastrointestinal bleeding, intracranial hemorrhage, and death from any cause. We then estimated the pooled effect using the random-effects model for meta-analysis., Results: A total of 25 studies were included in the current meta-analysis. DOAC therapy was associated with significantly lower risks of recurrent VTE (HR 0.76, 95% confidence interval [CI] 0.69-0.85), major bleeding (HR 0.77, 95% CI 0.72-0.83), clinically relevant non-major bleeding (HR 0.82, 95% CI 0.77-0.88), and gastrointestinal bleeding (HR 0.75, 95% CI 0.68-0.83) compared to warfarin. However, no statistically significant difference was observed in all-cause mortality between the two groups (HR 0.96, 95% CI 0.83-1.10)., Conclusion: This meta-analysis found that DOACs are associated with a significant reduction in VTE recurrence in addition to the known favorable safety profile when compared to warfarin., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose of Review: To summarize the recent evidence and guideline recommendations on aspirin or P2Y 12 inhibitor monotherapy in patients with stable ischemic heart disease and provide insights into future directions on this topic, which involves transition to a personalized assessment of bleeding and thrombotic risks., Recent Findings: It has been questioned whether the evidence for aspirin as the foundational component of secondary prevention in patients with coronary artery disease aligns with contemporary pharmaco-invasive strategies. The recent HOST-EXAM study randomized patients who had received dual antiplatelet therapy for 6 to 18 months without ischemic or major bleeding events to either clopidogrel or aspirin for a further 24 months, and demonstrated that the patients in the clopidogrel arm had significantly lower rates of both thrombotic and bleeding complications compared to those in the aspirin arm. The patient-level PANTHER meta-analysis showed that in patients with established coronary artery disease, P2Y 12 inhibitor monotherapy was associated with lower rates of myocardial infarction, stent thrombosis as well as gastrointestinal bleeding and hemorrhagic stroke compared to aspirin monotherapy, albeit with similar rates of all-cause mortality, cardiovascular mortality and major bleeding. Long-term low-dose aspirin is recommended for secondary prevention in patients with stable ischemic heart disease, with clopidogrel monotherapy being acknowledged as a feasible alternative. Dual antiplatelet therapy for six months after percutaneous coronary intervention remains the standard recommendation for patients with stable ischemic heart disease. However, the duration of dual antiplatelet therapy may be shortened and followed by P2Y 12 inhibitor monotherapy or prolonged based on individualized evaluation of the patient's risk profile., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In patients with atrial fibrillation (AF), the association between cancer and cardioembolic or bleeding risk during oral anticoagulant therapy still remains unclear., Purpose: We aimed to assess the impact of cancer present at baseline (CB) or diagnosed during follow-up (CFU) on bleeding events in patients treated with direct oral anticoagulants (DOACs) for non-valvular AF (NVAF) compared with patients without CB or CFU, respectively., Methods: All consecutive patients with NVAF treated with DOACs for stroke prevention were enrolled between January 2017 and March 2019. Primary outcomes were bleeding events or cardiovascular death, non-fatal stroke and non-fatal myocardial infarction, and the composite endpoint between patients with and without CB and between patients with and without CB., Results: The study population comprised 1170 patients who were followed for a mean time of 21.6 ± 9.5 months. Overall, 81 patients (6.9%) were affected by CB, while 81 (6.9%) were diagnosed with CFU. Patients with CFU were associated with a higher risk of bleeding events and major bleeding compared with patients without CFU. Such an association was not observed between the CB and no CB populations. In multivariate analysis adjusted for anemia, age, creatinine, CB and CFU, CFU but not CB remained an independent predictor of overall and major bleeding (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.8-3.89, p < 0.001; HR 3.02, 95% CI 1.6-3.81, p = 0.001, respectively)., Conclusion: During follow-up, newly diagnosed primitive or metastatic cancer in patients with NVAF taking DOACs is a strong predictor of major bleeding regardless of baseline hemorrhagic risk assessment. In contrast, such an association is not observed with malignancy at baseline. Appropriate diagnosis and treatment could therefore reduce the risk of cancer-related bleeding., (© 2024. The Author(s).)

Direct oral anticoagulants (DOACs) are the first-line anticoagulants for the secondary prevention of venous thromboembolism (VTE). However, patients with severe inherited thrombophilias represent a group in whom the efficiency and safety of DOACs is poorly studied. In this communication, we focus on the utility of DOACs in the secondary prevention of VTE in patients with severe thrombophilia. Current evidence is based only on cohort or single-center studies, and poor data are available on compliance of the patients in the studies. Analysis of the studies suggested that full-dose DOACs and vitamin K antagonists have a similar efficacy and bleeding risk in the secondary prevention of VTE in patients with thrombophilia, with a low hazard ratio for recurrent VTE calculated from cohort studies for DOAC vs warfarin, ranging from 0.3 to 0.75. We wish to highlight that treatment failure is greater in those with severe forms of protein S deficiency (below 20%) and possibly in antithrombin deficiency type II heparin-binding site homozygous Budapest 3. In summary, the current approach to using DOACs in patients with severe thrombophilia is dependent on clinical judgment and experience. Limited evidence suggests that for those with severe thrombophilias, full-dose DOACs have similar utility as vitamin K antagonists. We recommend caution in using low-dose DOACs due to lack of evidence. Ideally, large randomized multicenter studies are required to develop a reliable treatment algorithm., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. All rights reserved.)

Objective: Extracorporeal membrane oxygenation (ECMO) requires systemic anticoagulation to maintain the circuit patency. However, the use of anticoagulation carries a risk of severe hemorrhage, necessitating rigorous monitoring. Activated clotting time (ACT) is a widely used monitoring tool; however, the evidence of its correlation with unfractionated heparin (UFH) infusion dose is limited. Here we aimed to analyze the correlation between ACT and UFH infusion during ECMO., Design: Systematic literature review and meta-analysis of correlation coefficients (Scopus and PubMed, up to July 13, 2024)., Prospero: CRD42023448888 SETTING: All retrospective and prospective studies PARTICIPANTS: Patients receiving ECMO support INTERVENTION: Anticoagulation monitoring during ECMO support MEASUREMENTS AND MAIN RESULTS: Nineteen studies were included in the analysis, and the meta-analysis encompassed 16 studies. The vast majority of studies (n = 15) found a weak correlation, and no study reported a strong correlation between ACT and UFH infusion dose. The meta-analysis (n = 12,625 samples) identified a weak correlation, with a pooled estimate of correlation coefficients of 0.132 (95% confidence interval 0.03-0.23). The most common adverse events were hemorrhage (pooled incidence, 45%) and thrombosis (30%), and 47% of the patients died during their hospital stay., Conclusions: Even though ACT is a widely used UFH monitoring tool in ECMO patients, our meta-analysis found a weak correlation between ACT and UFH infusion dose. New trials are needed to investigate the role of emerging tools and to clarify the most appropriate monitoring strategy for patients receiving ECMO support., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk., Methods: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years., Conclusion: The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter., Trial Registration: ClinicalTrials.gov NCT05757869., Competing Interests: Disclosures SSJ reports consulting fees from Bristol Myers Squibb, ARTIS Ventures, and Broadview Ventures outside of the submitted work. KWM’s financial disclosures can be reviewed at http://med.stanford.edu/profiles/kenneth-mahaffey. KSP is a member of The Thrombosis Research Institute which has received institutional research grant support from Anthos Therapeutics and Bayer Pharmaceuticals. She has received honoraria from Element Science and Artivion, Inc. WS has received honoraria (>10K USD) from Daiichi Sankyo, Nippon Boehringer Ingelheim, and Pfizer Japan, and research grants (>50K USD) from Daiichi Sankyo and Nippon Boehringer Ingelheim. CTR reports Research Grants through Institution from: Athos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis. Honoraria for scientific ad boards and consulting from: Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen and Pfizer. He is a member of The TIMI Study Group which has received institutional research grant support through Brigham and Women's Hospital from: Abbott, Abiomed, Inc, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc, Janssen Research & Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, Roche, Saghmos Therapeutics, Inc, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc, Zora Biosciences. PRK reports consultancy from Anthos, J&J, BMS and Bayer. GS has received research grants from Amarin, AstraZeneca, and Sanofi; has participated in clinical trials, consulting, or speaking for Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Idorsia, Janssen, Novartis, Novo Nordisk, PhaseBio, Pfizer, and Sanofi; is a Senior Associate Editor at Circulation; and serves as the CMO for Bioquantis. RM reports institutional research payments from: Abbott, Affluent Medical, Alleviant Medical, Amgen, AstraZeneca, BAIM, Beth Israel Deaconess Medical Center, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CERC, Chiesi, Concept Medical, Daiichi Sankyo, Duke, Faraday, Idorsia, Janssen, MedAlliance, Medscape, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Pi-Cardia, Protembis, RM Global Bioaccess Fund Management, Sanofi; consultant to Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, Esperion Science/Innovative Biopharma, Gaffney Events, Educational Trust, Global Clinical Trial Partners, Ltd., IQVIA, Medscape/WebMD Global, NovoNordisk, PeerView Institute for Medical Education, TERUMO Europe N.V., Radcliffe and honoararia from AMA and ACC. SCJ has received research support from Jansen, BMS, and AstraZeneca. GJH reports personal honoraria outside the submitted work from the American Heart Association (Associate Editor, Circulation), Bristol Myers Squibb (Steering Committee, AXIOMATIC-SSP trial of milvexian [factor XIa inhibitor] for secondary stroke prevention) and Janssen (Co-chair, Executive Committee, Librexia Stroke trial of milvexian for secondary stroke prevention). RAH has received research grants/contracts from NHLBI (ISCHEMIA), Duke/PCORI (ADAPTABLE), Janssen (Factor Xia inhibitor), CSL (HDL), Baim Institute, UColorado, Harvard (BWH), and Merck; has served as a consultant/advisor for NHLBI (COVID/CONNECTS), Atropos Health, Bitterroot Bio, Bristol Myers Squibb, Bridge Bio, Chiesi, CSL Behring, Edwards Lifesciences Corp, Element Science, Foresight, Merck, and WebMD; and serves on the Board of Directors for AHA and Cytokinetics. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has Received research support from Novo Nordisk and Roche Diagnostics; has Served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Hanmi, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as Co-founder and nonexecutive director of Us2.ai. The remaining authors report no relevant disclosures or competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: Oral anticoagulants (OACs) reduce the risk of ischemic stroke but may increase the risk of major bleeding in patients with non-valvular atrial fibrillation (NVAF). Various risk scores, such as HAS-BLED, ATRIA, ORBIT, and DOAC, have been proposed to assess the risk of major bleeding in patients with NVAF receiving OACs. However, limited data are available regarding bleeding risk stratification in Japanese patients with NVAF., Methods: Of the 16,098 NVAF patients from the J-RISK AF study, the combined data of the five major AF registries in Japan (J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and Hokuriku-Plus AF Registry), we analyzed 11,539 patients receiving OACs (median age, 71 years old; women, 29.6%; median CHA 2 DS 2 -VASc score, 3)., Results: During the 2-year follow-up period, major bleeding occurred in 274 patients (1.3% per patient-year). In a multivariate Cox proportional hazards analysis, an advanced age, hypertension (systolic blood pressure ≥ 150 mmHg), bleeding history, anemia, thrombocytopenia, and concomitant antiplatelet agents were significantly associated with a higher incidence of major bleeding. We developed a novel risk stratification system, HED-[EPA] 2 -B 3 score, which had a better predictive performance for major bleeding (C-statistics 0.67, [95% confidence interval, 0.63-0.70]) than the HAS-BLED (0.64, [0.60-0.67], P for difference 0.02) and ATRIA (0.63, [0.60-0.66], P for difference ＜0.01) scores. Furthermore, it was non-significantly higher than the ORBIT (0.65, [0.62-0.68], P for difference 0.07) and DOAC (0.65, [0.62-0.68], P for difference 0.17) scores., Conclusion: Our novel risk stratification system, the HED-[EPA] 2 -B 3 score, may be useful for identifying Japanese patients receiving OACs at a risk of major bleeding.

Introduction: Recent randomized clinical trials have demonstrated that prehospital tranexamic acid (TXA) administration following injury is safe and improves survival. However, the effect of prehospital TXA on adverse events, transfusion requirements, and any dose-response relationships require further elucidation., Methods: A secondary analysis was performed using harmonized data from two large, double-blinded, randomized prehospital TXA trials. Outcomes, including 28-day mortality, pertinent adverse events, and 24-hour red cell transfusion requirements, were compared between TXA and placebo groups. Regression analyses were used to determine the independent associations of TXA after adjusting for study enrollment, injury characteristics, and shock severity across a broad spectrum of injured patients. Dose-response relationships were similarly characterized based upon grams of prehospital TXA administered., Results: A total of 1,744 patients had data available for secondary analysis and were included in the current harmonized secondary analysis. The study cohort had an overall mortality of 11.2% and a median Injury Severity Score of 16 (interquartile range, 5-26). Tranexamic acid was independently associated with a lower risk of 28-day mortality (hazard ratio, 0.72; 95% confidence interval [CI], 0.54-0.96; p = 0.03). Prehospital TXA also demonstrated an independent 22% lower risk of mortality for every gram of prehospital TXA administered (hazard ratio, 0.78; 95% CI, 0.63-0.96; p = 0.02). Multivariable linear regression verified that patients who received TXA were independently associated with lower 24-hour red cell transfusion requirements ( β= - 0.31; 95% CI, -0.61 to -0.01; p = 0.04) with a dose-response relationship ( β= - 0.24; 95% CI, -0.45 to -0.02; p = 0.03). There was no independent association of prehospital TXA administration on thromboembolism, seizure, or stroke., Conclusion: In this secondary analysis of harmonized data from two large randomized interventional trials, prehospital TXA administration across a broad spectrum of injured patients is safe. Prehospital TXA is associated with a significant 28-day survival benefit and lower red cell transfusion requirements at 24 hours and demonstrates a dose-response relationship., Level of Evidence: Therapeutic/Care Management; Level III., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Surgery of Trauma.)

Background: The optimum duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in patients with acute coronary syndromes (ACS) remains controversial. Ticagrelor monotherapy after short duration of DAPT (1-3 months) is a subject of research. We conducted an updated systematic review and meta-analysis comparing the ticagrelor monotherapy with continued DAPT after short duration of DAPT in patients with ACS undergoing PCI., Methods: PubMed, Embase, and Cochrane databases were searched for studies comparing ticagrelor monotherapy to DAPT after PCI and reported the outcomes of major adverse cardiovascular and cerebrovascular events (MACCE); net adverse clinical events (NACE); myocardial infarction (MI); major bleeding; death from any cause; definite or probable stent thrombosis; and target vessel revascularization (TVR). Data were extracted from published reports and quality assessment was performed per Cochrane recommendations. Statistical analysis was performed using Review Manager (Cochrane collaboration). Heterogeneity was examined with I2 test., Results: Of 3,208 results, five studies with 21,407 patients were included of which 50% received ticagrelor monotherapy. Studies had reported follow up of 12 months. Major bleeding [hazard ratio 0.47; 95% confidence interval (CI), 0.37-0.61; P  < 0.001], NACE (hazard ratio 0.71; 95% CI, 0.56-0.90; P  = 0.005), and all-cause death (hazard ratio 0.76; 95% CI, 0.59-0.98; P  = 0.04) were significantly less with ticagrelor monotherapy. Other outcomes were comparable in both groups., Conclusion: In patients with ACS undergoing PCI, ticagrelor monotherapy reduces major bleeding, NACE and all-cause death as compared to continued DAPT for 12 months. Major ischemic outcomes were similar. Ticagrelor monotherapy is the way forward after short duration of DAPT after PCI in ACS., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Rivaroxaban is a new direct oral anticoagulant, and the same dose is recommended for older and young patients. However, recent real-world studies show that older patients may need dose adjustment to prevent major bleeding. At present, the evidence for dose adjustment in older patients is extremely limited with only a few reports on older atrial fibrillation patients. The aim of this study was to review the morbidity data of adverse events and bleeding events across all indications for older and young patients treated with the same dose of rivaroxaban to provide some support for dosage adjustment in older patients. The PubMed, EMBASE, ClinicalTrials, Cochrane and Web of Science databases were searched for randomized controlled trials (RCTs) published between January 1, 2005, and October 10, 2023. The primary outcomes were the morbidity of bleeding events and efficacy-related adverse events. Summary estimates were calculated using a random effects model. Eighteen RCTs were included in the qualitative analysis. The overall morbidity of primary efficacy endpoints was higher in older patients compared to the young patients (3.37% vs. 2.60%, χ 2  = 5.24, p = 0.022). Similarly, a higher morbidity of bleeding was observed in older patients compared to the young patients (4.42% vs. 6.03%, χ 2  = 13.22, p < 0.001). Among all indications, deep vein thrombosis, pulmonary embolism and atrial fibrillation were associated with the highest incidence of bleeding in older patients, suggesting that these patients may be most need dose adjustment. Patients older than 75 years may require extra attention to prevent bleeding. The same dose of rivaroxaban resulted in higher bleeding morbidity and morbidity of efficacy-related adverse events in older patients compared to the young patients. An individualized dose adjustment may be preferred for older patients rather than a fixed dose that fits all., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Chronic systemic anticoagulation use is prevalent for various thromboembolic conditions. Anticoagulation (usually through heparin products) is also recommended for the initial management of non-ST-elevation myocardial infarction (NSTEMI)., Aims: To evaluate the in-hospital outcomes of patients with NSTEMI who have been on chronic anticoagulation., Methods: Using the National Inpatient Sample (NIS) years 2016-2020, NSTEMI patients and patients with chronic anticoagulation were identified using the appropriate International Classification of Diseases, 10th version (ICD-10) appropriate codes. The primary outcome was all-cause in-hospital mortality while the secondary outcomes included major bleeding, ischemic cerebrovascular accident (CVA), early percutaneous coronary intervention (PCI) (i.e., within 24 h of admission), coronary artery bypass graft (CABG) during hospitalization, length of stay (LOS), and total charges. Multivariate logistic or linear regression analyses were performed after adjusting for patient-level and hospital-level factors., Results: Among 2,251,914 adult patients with NSTEMI, 190,540 (8.5%) were on chronic anticoagulation. Chronic anticoagulation use was associated with a lower incidence of in-hospital mortality (adjusted odds ratio [aOR]: 0.69, 95% confidence interval [CI]: 0.65-0.73, p < 0.001). There was no significant difference in major bleeding (aOR: 0.95, 95% CI: 0.88-1.0, p = 0.15) or ischemic CVA (aOR: 0.23, 95% CI: 0.03-1.69, p = 0.15). Chronic anticoagulation use was associated with a lower incidence of early PCI (aOR: 0.78, 95% CI: 0.76-0.80, p < 0.001) and CABG (aOR: 0.43, 95% CI: 0.41-0.45, p < 0.001). Chronic anticoagulation was also associated with decreased LOS and total charges (adjusted mean difference [aMD]: -0.8 days, 95% CI: -0.86 to -0.75, p < 0.001) and (aMD: $-19,340, 95% CI: -20,692 to -17,988, p < 0.001)., Conclusions: Among patients admitted with NSTEMI, chronic anticoagulation use was associated with lower in-hospital mortality, LOS, and total charges, with no difference in the incidence of major bleeding., (© 2024 Wiley Periodicals LLC.)

Background:  Real-world data on clinical characteristics and outcomes related to the use of different direct oral anticoagulants (DOACs) for cancer-associated venous thromboembolism (VTE) is lacking., Methods:  The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive patients with acute symptomatic VTE from 31 centers in Japan from January 2015 to August 2020. Our study population comprised 1,197 patients with active cancer who were divided into the edoxaban ( N  = 643, 54%), rivaroxaban ( N  = 297, 25%), and apixaban ( N  = 257, 22%) groups., Results:  The cumulative 5-year incidence of recurrent VTE (9.3, 10.2, and 8.5%, respectively, p  = 0.82) and all-cause death (67.5, 66.8, and 63.8%, respectively, p  = 0.22) did not differ among the groups. Despite adjusting for confounders, the risks of recurrent VTE and all-cause death did not differ significantly among the groups. The cumulative 5-year incidence of major and clinically relevant bleeding was significantly lower in the rivaroxaban group than those in the other groups (22.6, 14.0, and 22.8%, p  = 0.04; and 37.6, 26.8, and 38.3%, p  = 0.01, respectively). After adjusting for confounders, in the rivaroxaban group, the risk for major bleeding was numerically lower (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.40-1.01) and that of clinically relevant all bleeding was significantly lower (HR: 0.67, 95% CI: 0.48-0.92) than those in the edoxaban group., Conclusion:  The risks of recurrent VTE and all-cause death did not differ significantly among the different DOACs ; however, the risk of bleeding events could differ, with a potentially lower risk of bleeding with rivaroxaban., Competing Interests: Y.Y. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo, and grant support from Bayer Healthcare and Daiichi-Sankyo. T.M. reports lecturer's fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; manuscript fees from Bristol-Myers Squibb and Kowa; advisory board for Sanofi. Y.N. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. K.K. received lecture fees from Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. N.I. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. S.I. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. Y.O. received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo, and research funds from Bayer Healthcare and Daiichi-Sankyo. K.T. received significant research grant from AMI Co., Ltd., Bayer Yakuhin, Ltd., Bristol-Myers K.K., EA Pharma Co., Ltd., MOCHIDA PHARMACEUTICAL CO., LTD., and scholarship fund from AMI Co., Ltd., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Edwards Lifesciences Corporation, Johnson & Johnson K.K., ONO PHARMACEUTICAL CO., LTD., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and honoraria from Amgen K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Kowa Pharmaceutical Co. Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., and belongs to the endowed departments donated by Abbott Japan Co., Ltd., Boston Scientific Japan K.K., Fides-one, Inc., GM Medical Co., Ltd., ITI Co., Ltd., Kaneka Medix Co., Ltd., NIPRO CORPORATION, TERUMO Co, Ltd., Abbott Medical Co., Ltd., Cardinal Health Japan, Fukuda Denshi Co., Ltd., Japan Lifeline Co., Ltd., Medical Appliance Co., Ltd., Medtronic Japan Co., Ltd. All other authors have reported that they have no relationships relevant to the contents of this article to disclose., (Thieme. All rights reserved.)

Background: Prophylactic dose of rivaroxaban is often used in treatment of isolated calf muscle vein thrombosis (ICMVT); nevertheless, its effect is less reported. This study aims to evaluate short-term outcomes in patients with ICMVT who received prophylactic dose of rivaroxaban or warfarin therapy., Methods: A retrospective analysis of 472 ICMVT patients who received 2 different treatment regimens was undertaken. Propensity score matching method was used to balance the confounding effect of baseline clinical data. Chi-squared test and logistic regression analysis were used to compare outcomes (venous thromboembolism events, bleeding events, complete clot resolution) according to the type of treatment regimens before and after propensity score matching. Univariate and multivariable analysis were used to investigate risk factors for incomplete clot resolution of ICMVT after propensity score matching., Results: 242 ICMVT patients received prophylactic dose of rivaroxaban (rivaroxaban group, RG), and 230 received warfarin (warfarin group, WG). After propensity score matching, 156 patients were included in each group; Venous thromboembolism (VTE) events occurred in 14 (9.0%) patients in the RG and 10 (6.4%) in the WG (P = 0.395); no major bleeding events occurred in each group, and clinically relevant nonmajor bleeding events occurred in 5 (3.2%) patients in the RG and 10 (6.4%) in the WG (P = 0.186); complete clot resolution at 3 months occurred in 80 (51.3%) patients in the RG and 100 (64.1%) in the WG (P = 0.022). Logistic regression analysis showed that there were no significant differences between RG and WG in VTE events (odds ratio 1.439, 95% confidence interval 0.619-3.347, P = 0.397) and clinically relevant nonmajor bleeding events (odds ratio 0.483, 95% confidence interval 0.161-1.449, P = 0.194); it revealed that complete clot resolution rate at 3 months was different in the 2 groups (odds ratio 0.589, 95% confidence interval 0.375-0.928, P = 0.022). Treatment regimens (prophylactic dose of rivaroxaban), thrombosis (maximum diameter >7 mm), and risk factors for VTE (nonsurgery risk factors, mainly referring to active malignancy) were risk factors for incomplete clot resolution of ICMVT (P < 0.05)., Conclusions: In this retrospective study with a short-term follow-up, ICMVT patients who received prophylactic dose of rivaroxaban had no significant differences in VTE and bleeding events compared to those who received warfarin therapy (the overall INR >2.0 for >50% of the time); but it was not conducive to complete clot resolution., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To assess the risk of venous thromboembolic events (VTEs) and bleeding with or without thromboprophylaxis during neoadjuvant chemotherapy in bladder cancer patients scheduled for radical cystectomy., Materials and Methods: We conducted a retrospective cohort study in 4886 patients with non-metastatic bladder cancer undergoing cystectomy across 28 centres in 13 countries between 1990 and 2021. Inverse probability weighting analyses were performed to estimate the effect of thromboprophylaxis on VTE and bleeding., Results: In 147 patients (3%) VTEs were recorded within the first year. These occurred a median (interquartile range [IQR]) of 127 (82-198) days after bladder cancer diagnosis. Bleeding events occurred in 131 patients (3%) within the first year. These occurred a median (IQR) of 101 (83-171) days after cancer diagnosis. In inverse probability weighting analyses, compared to patients without thromboprophylaxis during chemotherapy, patients with thromboprophylaxis had not only a lower risk of VTE (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.12-0.81; P = 0.016) but also a lower bleeding risk (HR 0.03, 95% CI 0.09-0.12; P <0.0001). The retrospective nature of the study was its main limitation., Conclusions: In this retrospective analysis, the benefit of thromboprophylaxis during neoadjuvant chemotherapy before cystectomy is in line with data from randomised trials in other malignancies. Our data suggest thromboprophylaxis is protective against VTEs and should be the standard of care during neoadjuvant chemotherapy., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Limited data exist on the safety and effectiveness of using direct oral anticoagulants (DOACs) in patients with atrial fibrillation aged 80 years or more with and without low bodyweight (LBW)., Objectives: We aimed to evaluate the safety and effectiveness of using DOACs in this population compared with warfarin., Methods: This retrospective active comparator new-user cohort study included veteran patients with atrial fibrillation who were newly initiated on either warfarin or DOACs between January 1, 2015, and January 1, 2021. The primary outcome was incidence of major bleeding and ischemic stroke. All outcomes were compared between treatment groups in 2 propensity score-matched cohorts of patients aged 80 years older with (AW) and without LBW (age-only cohort). Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs)., Results: Matched AW and age-only cohorts included 493 and 11 909 patients, respectively, in each of the DOAC and warfarin exposure groups. Greater than 90% were male, with a mean age of ∼87 years. The rate of major bleeding was lower in the DOAC group compared with warfarin in both the AW (aHR, 0.63; 95% CI, 0.46-0.87) and age-only cohorts (aHR, 0.58; 95% CI, 0.49-0.77). A significantly lower rate of ischemic stroke occurred in the DOAC group compared with warfarin in the AW cohort (aHR, 0.62; 95% CI, 0.45-0.84) and age-only cohort (aHR, 0.63; 95% CI, 0.58-0.68)., Conclusion: DOAC use was associated with lower risk of major bleeding and ischemic stroke compared with warfarin in patients aged 80 years or older with and without LBW., Competing Interests: Declaration of competing interests There are no competing interests to disclose. The results of this study do not represent the views of the federal government or the Veterans Health Administration., (Published by Elsevier Inc.)

Antidepressants, in particular selective serotonin reuptake inhibitors (SSRIs), are the most commonly prescribed psychopharmacological drug group. Thus, a precise knowledge of the expected adverse drug reactions is indispensable. The increased risk of bleeding events is well documented, especially in patients treated with SSRIs. However, many other antidepressant drug groups have also been implicated in increasing the risk of bleeding. In the following review, the thrombocytic serotonin system and the respective targets of the different antidepressants are explained. Subsequently, the available literature on bleeding under the respective antidepressant classes or individual substances is presented, using data from meta-analyses whenever possible. In addition to the risk of bleeding in general, individual bleeding entities are also considered, such as gastrointestinal and cerebral hemorrhages. Finally, the effects of other drugs that increase the risk of bleeding (i. e., nonsteroidal anti-inflammatory drugs, platelet aggregation inhibitors and anticoagulants) in combination with antidepressant drugs are discussed. The information presented here is meant to guide practitioner's decision making regarding an appropriate antidepressant pharmacotherapy based on the patient's individual risk constellation., Competing Interests: DB: Vortragshonorar von Aristo Pharma. ST: Vortragshonorare Janssen-Cilag GmbH, Otsuka/Lundbeck, Recordati Pharma GmbH und Servier, Advisory Board Otsuka und Janssen-Cilag GmbH. JS: Teilnahme an 2 von Otsuka/Lundbeck gesponsorten Fortbildungsveranstaltungen. JH, RG, GE, SB: keine Interessenskonflikte., (Thieme. All rights reserved.)

Objectives: To demonstrate how health technology assessment methods can be used to support Medicare's price negotiations for apixaban and rivaroxaban., Methods: Following the statutory outline of evidence that will be considered by Medicare, we conducted a systematic literature review, network meta-analyses, and decision analyses to evaluate the health outcomes and costs associated with apixaban and rivaroxaban compared with warfarin and dabigatran for patients with nonvalvular atrial fibrillation. Our methods inform discussions about the therapeutic impact of apixaban and rivaroxaban and suggest price premiums above their therapeutic alternatives over a range of cost-effectiveness thresholds., Results: Network meta-analyses found apixaban resulted in a lower risk of major bleeding compared with warfarin and dabigatran and a lower risk of stroke/systemic embolism compared with warfarin but not compared with dabigatran. Rivaroxaban resulted in a lower risk of stroke/systemic embolism versus warfarin but not dabigatran, and there was no difference in major bleeding. Decision-analytic modeling of apixaban suggested annual price premiums up to $4350 above the price of warfarin and up to $530 above the price for dabigatran at cost-effectiveness thresholds up to $200 000 per equal value of life-years gained. Analyses of rivaroxaban showed an annual price premium of up to $3920 above warfarin and no premium above that paid for dabigatran., Conclusions: Although health technology assessment is typically performed near the time of regulatory approval, with modifications, we produced comparative clinical and relative cost-effectiveness findings to help guide negotiations on a "fair" price for drugs on the market for over a decade., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

The role of aspirin in cardiovascular primary prevention remains controversial. There are physiological reasons to explore its potential benefits in patients with high levels of lipoprotein(a) [Lp(a)], mainly due to its antifibrinolytic properties and interactions with platelets. The primary objective of this systematic review was to evaluate the cardiovascular benefits and bleeding risks associated with aspirin use in patients who have elevated Lp(a) levels but no history of cardiovascular disease. This systematic review was conducted following PRISMA guidelines. We performed a literature search to identify studies assessing the cardiovascular benefits and bleeding risks of aspirin use in patients with elevated Lp(a) levels (or a related genetic variant) who have no history of cardiovascular disease. Five studies (49,871 individuals) were considered for this systematic review. Three studies assessed the impact of aspirin use in relation to genetic variants associated with elevated Lp(a) levels (SNP rs379822), while the remaining two studies directly measured plasma levels of Lp(a). The endpoints evaluated varied among the studies. Overall, the findings consistently show that carriers of the apolipoprotein(a) variant or patients with Lp(a) levels > 50 mg/dL experience a reduction in cardiovascular risk with aspirin use. No significant bleeding issues were observed, although such events were reported in only two studies. This systematic review suggests that aspirin use in patients with elevated Lp(a) levels and no prior cardiovascular history may reduce cardiovascular risk. The available data on bleeding risk is insufficient., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background:  Bleeding events are often reported among patients with atrial fibrillation (AF), irrespective of antithrombotic use. This study is to determine clinical outcomes of patients with AF who survived from bleeding event., Methods:  We analyzed data from COOL-AF (Cohort of Antithrombotic Use and Optimal International Normalized Ratio Levels in Patients with Atrial Fibrillation) Thailand registry. Outcomes of patients who experienced any bleeding were compared with patients who had never bleed. Time updated multivariate Cox-proportional hazard models were used to estimate the risk for clinical outcomes of patients with and without bleeding., Results:  Of total 3,405 patients (mean age: 67.8 ± 11.3 years; 41.9% female) in COOL-AF registry, 609 patients (17.9%) reported bleeding event occurs and 568 patients (93.3%) survived though hospital discharge. Patients who survived major bleeding ( n  = 126) were at increased risk for both death (adjusted hazard ratio [HR]: 4.44, 95% confidence interval [CI]: 2.91-6.75, p  < 0.001) and stroke/systemic embolism (adjusted HR: 4.49, 95% CI: 2.19-9.24, p  < 0.001). Minor bleeding also increased subsequent death (adjusted HR: 2.13, 95% CI: 1.56-2.90, p  < 0.001). Up to 30% of patients who survived major bleeding and 6.3% of minor bleedings discontinued oral anticoagulation. Discontinuation was associated with very high death rate (42.1%), whereas patients who resumed oral anticoagulation after bleeding had lower mortality (10%). The most common causes of death in patients who survived a bleeding event were not related to cardiovascular causes nor bleeding., Conclusion:  Patients with AF who have bleeding events have an increased risk for subsequent death and stroke and systemic embolism. These patients should be identified as vulnerable clinically complex patients and require a holistic approach to their AF management., Competing Interests: G.Y.H.L.: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Anthos, and Daiichi-Sankyo. No fees are directly received personally. He is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 899871. All other authors hereby declare no personal or professional conflicts of interest relating to any aspect of this particular study., (Thieme. All rights reserved.)

Objectives: Direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, commonly used direct oral anticoagulant (DOAC), are widely used to prevent and treat stroke and venous thromboembolic events in patients with atrial fibrillation (AF). This study aimed to assess and compare reports of adverse events associated with rivaroxaban, apixaban, and edoxaban, including hemorrhagic and non-hemorrhagic events., Methods: Reporting odds ratio (ROR), proportional reporting ratio (PRR), Medications and Health Care Products Regulatory Agency (MHRA), and the information component (IC) were used to perform a risk assessment of adverse event reports in the FDA Adverse Event Reporting System (FAERS) database for the years 2018-2022., Results: Combined with disproportionality analysis in different backgrounds, the salient risks of the three-factor Xa inhibitors varied. Rivaroxaban had the most significant risk of hemorrhage, apixaban had a higher incidence and risk of death, cardiac and cerebral adverse events, and edoxaban showed a more prominent risk in the kidneys and urinary system., Conclusion: Hemorrhage is a common risk with factor Xa inhibitors, with rivaroxaban being the most significant. Apixaban and edoxaban also showed significant association with non-hemorrhagic adverse events, and increased attention to non-hemorrhagic adverse events is needed in clinical use.

Aims: We aim to research the efficacy and safety of single(SAPT), dual(DAPT), and triple(TAPT) antiplatelets approaches across IHD patients undergoing PCI., Methods and Results: A network meta-analysis was conducted until April 1st, 2024, using the netmeta package in R studio 4.3.3. Primary outcomes were cardiac death, myocardial infarction(MI), stent thrombosis, stroke, and major bleeding(BARC 3-5). From 25 studies, a total of 65115 patients were included. For cardiac death, TAPT had no different risk than DAPT compared to SAPT [RR = 0.74; 95%CI (0.40 to 1.35); p-value = 0.33], [RR = 1.01, 95%CI (0.84 to 1.19); p-value = 0.87] respectively. For MI, TAPT had no different risk than DAPT compared to SAPT [RR = 0.77; 95%CI (0.51 to 1.16); p-value = 0.2047], [RR = 0.81, 95%CI (0.64 to 1.03); p-value = 0.0850] respectively. For stent thrombosis, DAPT had no different risk than TAPT compared to SAPT [RR = 0.74; 95%CI (0.45 to 1.21); p-value = 0.2284], [RR = 0.84, 95%CI (0.27 to 2.59); p-value = 0.7630] respectively. For stroke, DAPT had no different risk than TAPT in comparison to SAPT [RR = 0.91; 95%CI (0.75 to 1.10); p-value = 0.3209], and [RR = 0.87, 95%CI (0.43 to 1.76); p-value=0.6937], respectively. For Major bleeding(BARC 3-5), DAPT and TAPT increased major bleeding compared to SAPT, with only DAPT showing statistical significance. [RR = 1.43; 95%CI (1.09 to 1.88); p-value = 0.0107], and [RR = 2.78, 95%CI (0.90 to 4.78); p-value = 0.0852], respectively., Conclusion: DAPT and TAPT increased the risk of bleeding events compared to SAPT. However, we found no significant differences between these regimens for the other primary outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Deep vein thrombosis (DVT) is a medical condition characterized by forming a blood clot, or thrombus, in one of the deep veins, typically in the legs. It is a type of venous thromboembolism, which refers to the formation of blood clots in the veins. It is caused by Virchow's triad (stasis, hypercoagulation, and endothelial injury)., Objective: Our main objective is to explore the effectiveness and safety of rivaroxaban and edoxaban in treating lower extremity DVT., Methods: We conducted a retrospective study involving 406 patients subjected to DVT treatment using direct oral anticoagulants (edoxaban and rivaroxaban) at our hospital. We recruited adult patients (aged 18 years and more) diagnosed with lower extremity DVT and received treatment with either rivaroxaban or edoxaban as the primary anticoagulant therapy for DVT. We excluded patients who received treatment with other anticoagulant medications (warfarin and heparin) as the primary therapy for DVT., Results: The groups showed statistically significant differences in red blood cell count and hemoglobin levels, with the edoxaban group having high values. However, the 2 groups observed no statistically significant differences in creatinine clearance, white blood cell count, platelet count, C-reactive protein, and D-dimer levels. The difference in the incidence of pulmonary embolism between the 2 groups was statistically significant (P value < 0.001). The edoxaban group had fewer pulmonary embolism patients than the rivaroxaban group. The reduction in recurrent thrombosis was significantly higher in the rivaroxaban group compared to the edoxaban group. There were no significant differences in the major bleeding at various sites across the 2 treatment groups (P > 0.05)., Conclusions: Rivaroxaban's pharmacokinetic profile includes rapid absorption and a relatively short half-life. It means that once administered, rivaroxaban quickly reaches its peak concentration in the blood and is subsequently eliminated from the body within a relatively short period. Edoxaban's pharmacokinetic profile may include slower absorption and a longer half-life than rivaroxaban. It can result in a slower rate of achieving peak concentration and a more prolonged presence in the bloodstream. These results emphasize the need for careful consideration of anticoagulant therapy in patients with underlying cancer and underscore the importance of managing risks while providing adequate anticoagulation to prevent thrombotic events., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Limited understanding exists regarding the hemorrhagic risk resulting from potential interactions between P-glycoprotein (P-gp) inhibitors and direct oral anticoagulants (DOACs). Utilizing the Food and Drug Administration Adverse Event Reporting System (FAERS) data, we analyzed hemorrhagic adverse events (AEs) linked with the co-administration of P-gp inhibitors and DOACs, aiming to offer guidance for their safe and rational use., Methods: Hemorrhagic events associated with P-gp inhibitors in combination with DOACs were scrutinized from the FAERS database. Hemorrhagic signals mining was performed by estimating the reported odds ratios (RORs), corroborated by additive and multiplicative models and a combination risk ratio (PRR) model., Results: Our analysis covered 4,417,195 cases, revealing 11,967 bleeding events associated with P-gp inhibitors. We observed a significantly higher risk of bleeding with the combination of apixaban and felodipine (ROR 118.84, 95% CI 78.12-180.79, additive model 0.545, multiplicative model 1.253, PRR 22.896 (2450.141)). Moreover, consistent associations were found in the co-administration analyzes of rivaroxaban with dronedarone and diltiazem, and apixaban with losartan, telmisartan, and simvastatin., Conclusion: Our FAERS data analysis unveils varying degrees of bleeding risk associated with the co-administration of P-gp inhibitors and DOACs, underscoring the importance of vigilance about them in clinical practice.

Background: Bleeding is a potential complication following haemodialysis catheter-related procedures. Besides uraemia, bleeding risk is perceived to be even higher in patients receiving antiplatelets. This study aims to evaluate the risk factors for bleeding following dialysis catheter-related procedures., Methods: This is a secondary analysis of a single-centre, prospective cohort study between March 2019 and June 2020. Potential risk factors for bleeding were collected, including use of antiplatelets and anticoagulants, serum urea and haematological results. Patients were observed closely for external bleeding following haemodialysis catheter-related procedures., Results: From 413 patients screened, 250 were recruited. Of these, 177 underwent dialysis catheter insertion (157 tunnelled and 20 non-tunnelled) while 73 had dialysis catheter removed (35 tunnelled and 38 non-tunnelled). One hundred and four patients (41.6%) were on a single anti-platelet agent, of whom 75 (30.0%) were on aspirin and 29 (11.6%) had clopidogrel alone. Twenty-nine patients (11.6%) were on both aspirin and clopidogrel.There were 36 episodes (14.4%) of bleeding. The risk of bleeding was not significantly higher with the use of aspirin alone (odds ratio = 0.85, 95% CI: 0.36-2.02, p  = 0.709), clopidogrel alone (odds ratio = 1.04, 95% CI: 0.31-3.49, p  = 0.953) and both aspirin and clopidogrel (odds ratio = 0.95, 95% CI: 0.28-3.25, p  = 0.938). In a multivariate analysis, none of the known bleeding risk factors had a statistically significant association with bleeding., Conclusions: Overall, the use of antiplatelet agents was not associated with an increased risk of bleeding., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.