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Limited data exists on the safety and efficacy with the concomitant use of 4 factor prothrombic complex concentrate (4F-PCC) and andexanet alfa (AA). This case series describes 7 patients at our institution who received both 4F-PCC and AA for the management of life-threatening bleeding associated with apixaban or rivaroxaban. Four patients received AA due to worsening bleeding after 4F-PCC. Of the 7 patients in this case series, 1 had a documented thrombotic event which was an acute ischemic stroke. The thrombotic event rate in our case series was similar to the incidence of thrombotic events reported with the use of AA alone. In-hospital mortality occurred in 2 of 7 patients with 1 additional patient discharged to hospice care. [ABSTRACT FROM AUTHOR]

The antithrombotic management of chronic coronary syndrome (CCS) involves a 6-month course of dual antiplatelet therapy (DAPT), followed by chronic aspirin therapy. In patients with a baseline indication for anticoagulation, a variable duration of triple antithrombotic therapy is administered, followed by dual antithrombotic therapy until the sixth month post-percutaneous coronary intervention (PCI), and ultimately a transition to chronic anticoagulation. However, advancements in stent technology reducing the risk of stent thrombosis and a growing focus on the impact of bleeding on prognosis have prompted the development of new therapeutic strategies. These strategies aim to enhance protection against ischemic events in the initial stages after PCI while mitigating the risk of bleeding in the long term. This article delineates the therapeutic strategies outlined in European and American guidelines for CCS management, with special attention to investigational strategies. [ABSTRACT FROM AUTHOR]

Introduction: Pharmacovigilance is vital for drug safety. The process typically involves two key steps: initial signal generation from spontaneous reporting systems (SRSs) and subsequent expert review to assess the signals' (potential) causality and decide on the appropriate action. Methods: We propose a novel discovery and verification approach to pharmacovigilance based on electronic healthcare data. We enhance the signal detection phase by introducing an ensemble of methods which generated signals are combined using Borda count ranking; a method designed to emphasize consensus. Ensemble methods tend to perform better when data is noisy and leverage the strengths of individual classifiers, while trying to mitigate some of their limitations. Additionally, we offer the committee of medical experts with the option to perform an in-depth investigation of selected signals through tailored pharmacoepidemiological studies to evaluate their plausibility or spuriousness. To illustrate our approach, we utilize data from the German Pharmacoepidemiological Research Database, focusing on drug reactions to the direct oral anticoagulant rivaroxaban. Results: In this example, the ensemble method is built upon the Bayesian confidence propagation neural network, longitudinal Gamma Poisson shrinker, penalized regression and random forests. We also conduct a pharmacoepidemiological verification study in the form of a nested active comparator case-control study, involving patients diagnosed with atrial fibrillation who initiated anticoagulant treatment between 2011 and 2017. Discussion: The case study reveals our ability to detect known adverse drug reactions and discover new signals. Importantly, the ensemble method is computationally efficient. Hasty false conclusions can be avoided by a verification study, which is, however, time-consuming to carry out. We provide an online tool for easy application: https://borda.bips.eu. [ABSTRACT FROM AUTHOR]

Current guidelines exclusively recommend vitamin-K-antagonists (VKA) as anticoagulation for patients after mechanical aortic valve replacement due to the increased postoperative risk of valve thrombosis and thrombo-embolism. Strict and regular assessments are mandatory during VKA therapy to ensure a potent anticoagulatory effect within the desired range. From the patients' perspective, VKA are associated with relevant interactions and side effects reducing the quality of life and contributing to a high number of patients not achieving the optimal therapeutic target. Direct oral anticoagulants (DOAC) have replaced VKA therapy in the past for several indications, e.g., atrial fibrillation. However, it is still unclear if DOACs could replace VKA therapy in patients after mechanical aortic valve replacement. While the PROACT-Xa study did not show a sufficient anticoagulatory effect of apixaban plus aspirin compared to VKA therapy in patients after mechanical aortic valve replacement, the direct thrombin inhibitor dabigatran and the oral factor Xa inhibitors apixaban and rivaroxaban showed promising results in comparable patient cohorts in smaller studies and case reports. Factor Xa inhibitors were able to prevent thrombosis and thrombo-embolic events in patients after mechanical aortic valve replacement. Therefore, factor Xa inhibitors or factor XI inhibitors could provide a potent alternative to VKA for patients after a mechanical aortic valve replacement. [ABSTRACT FROM AUTHOR]

Background: The first purpose of this study was to determine whether a measurement of the level of direct oral anticoagulants (DOACs) was possible with heparin-calibrated chromogenic anti-factor Xa activity (AXA). The second purpose of this study was to evaluate whether the antidote treatment decision level (30 or 50 ng/mL of DOAC) can be determined by unfractionated heparin (UHF)/low molecular weight heparin (LMWH)-calibrated AXA. Methods: AXA was measured by using two reagents and dedicated analyzers (Sysmex CS-5100 analyzer and STA R Max3). Four types of calibrators were used: 1) Stago DOAC (rivaroxaban, edoxaban, and apixaban)-specific calibrator, 2) Stago LMWH calibrator, 3) Sysmex UHF calibrator, and 4) Sysmex LMWH calibrator. Regression analysis was used between assays. Receiver operating characteristic (ROC) curves were performed, and the concordance rate was calculated. Results: The correlation coefficients were in the range of 0.75 - 0.91 for rivaroxaban and 0.81 - 0.94 for apixaban. The correlation coefficient between edoxaban-calibrated AXA and Sysmex LMWH/Sysmex UHF calibrator-calibrated AXA was low (r = 0.47). Overall correlation between DOAC-calibrated AXA and Stago LMWH-calibrated AXA was linear, at only low concentration in all three DOACs. The concordance rate (89.3 - 100%) is good for determining the antidote management level by UFH/LMWH-calibrated AXA, compared with those of DOAC-calibrated AXA in rivaroxaban and apixaban. The concordance rate ranged from 63% to 67% between Sysmex UFH/LMWH-calibrated AXA and edoxaban-calibrated AXA. Conclusions: The findings of our study suggest limitations in calculating accurate concentrations, when using UFH/LMWH-calibrated AXA to measure DOAC. This study demonstrates that UFH/LMWH-calibrated AXA may be useful in determining the presence of DOACs at the cutoff level for the antidote treatment in rivarovaban and apixaban. However, in edoxaban, UFH/LMWH-calibrated AXA could not accurately measure the presence of DOACs at the cutoff for antidote treatment. [ABSTRACT FROM AUTHOR]

BackgroundMethodsResultsConclusionWith the increasing cases of TBI cases in the elderly population taking anticoagulants for comorbidities, there is a need to better understand the safety of new anticoagulants and how to manage anticoagulated TBI patients.A meta-analysis using a random-effect model was conducted to compare the effect of preinjury use of DOACs and VKAs on the outcomes following TBI.From 1951 studies, 49 studies with a total sample size of 15,180 met our inclusion criteria. Our meta-analysis showed no difference between preinjury use of DOACs or VKAs on ICH progression, in-hospital delayed ICH, delayed ICH at follow-up, and in-hospital mortality, but using DOACs was associated with a lower risk of immediate ICH (OR = 0.58; 95% CI = [0.42; 0.79]; p < 0.01) and neurosurgical interventions (OR = 0.59; 95% CI = [0.42; 0.82]; p < 0.01) compared to VKAs. Moreover, patients on DOACs experienced shorter length of stay in the hospital than those on VKAs (OR = -0.42; 95% CI = [−0.78; −0.07]; p = 0.02).We found a lower risk of immediate ICH and surgical interventions as well as a shorter hospital stay in patients receiving DOACs compared to VKA users before the head injury. [ABSTRACT FROM AUTHOR]

Introduction: Direct oral anticoagulants (DOACs) reflect anticoagulation agents given to treat or prevent thrombosis, having largely replaced vitamin K antagonists (VKAs) such as warfarin. DOACs are given in fixed daily doses and generally do not need monitoring. However, there may be a variety of reasons that justify measurement of plasma DOAC levels in individual patients. Methods: We report updated findings for DOAC testing in our geographic region, using recent data from the RCPAQAP, an international external quality assessment (EQA) program, currently with some 40–60 participants in each of the different DOAC (rivaroxaban, apixaban, dabigatran) modules, to assess laboratory performance in this area. Data has been assessed for the past 5 years (2019–2023 inclusive), with 20 samples each per DOAC. Results: Data shows a limited repertoire of assays in use, and mostly consistency in reported numerical values when assessing proficiency samples. Available assays mostly comprised reagents from four manufacturing suppliers. There was good consistency across what participants identified as 'DOAC detected', but some variability when participants attempted to grade DOAC levels as low vs moderate vs high. Inter‐laboratory/method coefficient of variation (CVs) were generally <15% for each DOAC, when present at >100 ng/mL. Conclusion: We hope our findings, reflecting on mostly consistent reporting of DOAC levels and interpretation provides reassurance for clinicians requesting these measurements, and helps support their implementation in regions where there is a paucity of test availability. [ABSTRACT FROM AUTHOR]

Intraoperative antithrombotic drug removal by haemoadsorption is a novel strategy to reduce perioperative bleeding in patients on antithrombotic drugs undergoing cardiac surgery. The international STAR registry reports real-world clinical outcomes associated with this application. All patients underwent cardiac surgery before completing the recommended washout period. The haemoadsorption device was incorporated into the cardiopulmonary bypass (CPB) circuit. Patients on P2Y12 inhibitors comprised group 1, and patients on direct-acting oral anticoagulants (DOAC) group 2. Outcome measurements included bleeding events according to standardised definitions and 24-hour chest-tube-drainage (CTD). 165 patients were included from 8 institutions in Austria, Germany, Sweden, and the UK. Group 1 included 114 patients (62.9 ± 11.6years, 81% male) operated at a mean time of 33.2 h from the last P2Y12 inhibitor dose with a mean CPB duration of 117.1 ± 62.0 min. Group 2 included 51 patients (68.4 ± 9.4years, 53% male), operated at a mean time of 44.6 h after the last DOAC dose, with a CPB duration of 128.6 ± 48.4 min. In Group 1, 15 patients experienced a BARC-4 bleeding event (13%), including 3 reoperations (2.6%). The mean 24-hour CTD was 651 ± 407mL. In Group 2, 8 patients experienced a BARC-4 bleeding event (16%) including 4 reoperations (7.8%). The mean CTD was 675 ± 363mL. This initial report of the ongoing STAR registry shows that the intraoperative use of a haemoadsorption device is simple and safe, and may potentially mitigate the expected high bleeding risk of patients on antithrombotic drugs undergoing cardiac surgery before completion of the recommended washout period. Clinical registration number: ClinicalTrials.gov identifier: NCT05077124. [ABSTRACT FROM AUTHOR]

Nearly one fifth of patients with venous thromboembolism (VTE) have cancer. When both of these conditions occur, especially in cases of cerebral vein thrombosis (CVT), patient management is often challenging. The aim of this study was to compare the characteristics and event courses in patients affected by CVT with and without cancer. Consecutive patients with CVT from the ACTION-CVT cohort study were included if cancer status was reported. Risk factors as well as the clinical and radiological characteristics of patients were compared. Univariable and multivariable analyses were performed to assess variables associated with cancer. Kaplan-Meier method and log-rank test, logistic regression analysis, and propensity score matching were used to investigate any association between cancer-related CVT and study outcomes (primary outcome at 3-months: recurrent VTE or major hemorrhage; recurrent VTE; major hemorrhage; recanalization status; all-cause-death). Overall, 1,023 patients with CVT were included, of which 6.5% had cancer. Older age (adjusted odds ratio [aOR] 1.28 per decade increase; 95% confidence interval [CI] 1.08–1.52) and absence of headache (aOR 0.47; 95% CI 0.27–0.84) were independently associated with cancer. Patients with cancer had a higher risk of recurrent VTE or major hemorrhage (aOR 3.87; 95% CI 2.09–7.16), all-cause-death (aOR 7.56 95% CI 3.24–17.64), and major hemorrhage (aOR 3.70 95% CI 1.76–7.80). Recanalization rates, partial or complete, was not significantly different. CVT patients with cancer were more likely to be older, have no referred headache, and have worse outcomes compared to CVT patients without cancer. Highlights: Among 1,023 patients with cerebral vein thrombosis from the ACTION-CVT study, 6.5% had cancer. Older age and absence of headache were independently associated with cancer. Cancer patients had worse outcomes. [ABSTRACT FROM AUTHOR]

Aims: Use of novel anticoagulation in mechanical circulatory support is controversial. We report the rationale and design of the ApixiVad pilot trial, a pilot study testing the safety of apixaban as an anticoagulant in patients bridged to transplant (BTT) or for destination (DT) with Heartmate 3 (HM3) left ventricular assist device (LVAD). Methods and results: Apixaban has been used in small non‐randomized cohorts in LVAD patients and shown to be effective in ex vivo studies. The ApixiVAD study examines apixaban use in a multicentre, international, open‐label, randomized, controlled trial aiming to include 50 BTT or DT HM3 patients with a 1:1 randomization ratio. This event‐driven study has a maximum follow‐up period of 24 months with interim analysis at 6 months. The primary outcome is death, thromboembolic events and major bleeding, including operative bleeding and immediate transplant outcomes. The secondary outcome focuses on patients' quality of life related to anticoagulation. This investigator‐driven pilot study is not powered to determine the non‐inferiority of apixaban. An increase in primary outcome in the apixaban group of 20% will be considered a signal of harm. Conclusions: A positive outcome in the ApixiVAD study would provide the basis for future, larger, pivotal anticoagulation trials in LVAD patients. [ABSTRACT FROM AUTHOR]

Background: Direct-acting oral anticoagulants (DOACs) have become the preferred drugs for managing venous thromboembolism (VTE). Despite their advantages over vitamin K antagonists such as warfarin, their use in obese patients remains controversial with many providers reluctant to switch patients managed on warfarin. Outcome research that opts to increase provider confidence when prescribing DOACs for patients with obesity will be invaluable. Objective: This investigation evaluated whether patients with a body mass index (BMI) 35 kg/m2 or greater who were prescribed a DOAC had a higher risk for a recurrent VTE or bleed event relative to warfarin. Methods: The study was conducted in West Virginia which has the highest rate of obesity in the United States. Results: Of the total study population (1633), 2.3% (37) had a recurrent thrombotic event, 5.5% (89) had a major bleed event, and 10.7% (174) had some type of bleeding event. No individual patient characteristic was associated with recurrent thrombosis—including BMI. Older age, antiplatelet use, and taking a medication with a theoretical risk of increasing the effect of DOACs were associated with any and major bleeding events. The use of warfarin was associated with major bleeding events more frequently versus a DOAC. Body mass index was not a predictor for recurrent VTE or any bleed or major bleed events. Conclusions: These findings support the conclusion that DOACs are an appropriate and effective drug class for the management of VTE in patients with obesity. [ABSTRACT FROM AUTHOR]

The administration of intravenous thrombolysis (IVT) for patients with acute ischemic stroke who have recently ingested direct oral anticoagulants (DOACs) presents a clinical challenge due to the perceived increased risk of intracranial hemorrhage (ICH). Traditional guidelines from the US and European authorities advise against IVT within 48 h of last DOAC ingestion, unless specific coagulation tests indicate safety. However, emerging observational studies suggest that IVT might be safe in selected patients. A US stroke registry study and a global multicenter cohort study both reported no significant increase in symptomatic ICH among patients on DOACs compared to those not on anticoagulants. A systematic review of all published observational studies further supported these findings, showing comparable bleeding rates and functional outcomes in DOAC-treated patients. Reversal agents like idarucizumab for dabigatran have demonstrated potential in facilitating safer IVT administration, though logistical and cost-related barriers limit their widespread use. The variability in global guidelines reflects differing approaches to risk assessment and resource availability, highlighting the need for individualized treatment decisions. In India, the increasing prevalence of atrial fibrillation and stroke as well as prescription of DOACs necessitate adapted guidelines that consider local health-care infrastructure. Despite the promising observational data, the lack of randomized controlled trials underscores the need for further research to establish robust evidence for IVT use in this context. Collaborative international efforts and inclusion of diverse patient populations in future studies will be crucial to refine treatment protocols and improve outcomes for stroke patients on DOACs.

Abstract Aims Use of novel anticoagulation in mechanical circulatory support is controversial. We report the rationale and design of the ApixiVad pilot trial, a pilot study testing the safety of apixaban as an anticoagulant in patients bridged to transplant (BTT) or for destination (DT) with Heartmate 3 (HM3) left ventricular assist device (LVAD). Methods and results Apixaban has been used in small non‐randomized cohorts in LVAD patients and shown to be effective in ex vivo studies. The ApixiVAD study examines apixaban use in a multicentre, international, open‐label, randomized, controlled trial aiming to include 50 BTT or DT HM3 patients with a 1:1 randomization ratio. This event‐driven study has a maximum follow‐up period of 24 months with interim analysis at 6 months. The primary outcome is death, thromboembolic events and major bleeding, including operative bleeding and immediate transplant outcomes. The secondary outcome focuses on patients' quality of life related to anticoagulation. This investigator‐driven pilot study is not powered to determine the non‐inferiority of apixaban. An increase in primary outcome in the apixaban group of 20% will be considered a signal of harm. Conclusions A positive outcome in the ApixiVAD study would provide the basis for future, larger, pivotal anticoagulation trials in LVAD patients.

Abstract Vitamin K antagonists (VKA) remain the only option of anticoagulation for people with mechanical valve replacement and due to their wider availability and lower acquisition costs, VKA’s remain widely used in low- and middle-income countries. It has been suggested that prolonged use of VKAs can increase the development of vascular and valvular calcification, though this effect has not been examined in larger randomized prospective trials. This investigator-initiated multicenter, prospective, randomized, open-label interventional trial randomized patients with baseline coronary or valvular calcification and an indication for prolonged oral anticoagulation therapy to Marcumar or Rivaroxaban. Patients were followed-up through repeat coronary computed tomographies to measure the progression of coronary and valvular calcification for up to 24 months. 192 patients were randomized between 2013 and 2018 to receive either Rivaroxaban or Marcumar and followed for up to 24 months. Coronary calcification significantly increased over time although there was no significant difference in progression between the groups after 12 and 24 months as measured by the Agatston score [360.7 (90.2; 1075.3) vs 380.4 (136.4; 1546.9) p = 0.69], the volume score [295.8 (93.0; 995.3) vs 335.5 (128.7; 1316.9) p = 0.95] and the mass score [58.5 (15.9; 172.0) vs 71.1 (24.8; 257.3) p = 0.5]. Dephosphorylated, uncarboxylated matrix Gla Protein (Dp-ucMGP) significantly decreased in the VKA group [Δ dp-uc MGP – 95.2 (− 554.1; 156.0) vs 231.3 (− 59.7; 388.1) p

Abstract Subclinical leaflet thrombosis (SLT) can be one of the causes of transcatheter heart valve (THV) failure after transcatheter aortic valve implantation (TAVI). We sought to clarify the formation process of SLT and thrombogenicity during the perioperative period of TAVI. This multicenter, prospective, single-arm interventional study enrolled 26 patients treated with edoxaban for atrial fibrillation and who underwent TAVI for severe aortic stenosis between September 2018 and September 2022. We investigated changes in maximal leaflet thickness detected by contrast-enhanced computed tomography between 1 week and 3 months after TAVI in 18 patients and measured the thrombogenicity by Total Thrombus-formation Analysis System (T-TAS) and flow stagnation volume by computational fluid dynamics (CFD) (n = 11). SLT was observed in 16.7% (3/18) at 1 week, but decreased to 5.9% (1/17) at 3 months after TAVI. Patients with SLT at 1 week had a significantly decreased maximal leaflet thickness compared to those without SLT. Thrombogenicity assessed by T-TAS decreased markedly at 1 week and tended to increase at 3 months. The stagnation volume assessed by CFD was positively associated with a higher maximum leaflet thickness. This study showed the course of leaflet thrombus formation and visualization of stagnation in neo-sinus of THV in the acute phase after TAVI.

Abstract Current guidelines exclusively recommend vitamin-K-antagonists (VKA) as anticoagulation for patients after mechanical aortic valve replacement due to the increased postoperative risk of valve thrombosis and thrombo-embolism. Strict and regular assessments are mandatory during VKA therapy to ensure a potent anticoagulatory effect within the desired range. From the patients’ perspective, VKA are associated with relevant interactions and side effects reducing the quality of life and contributing to a high number of patients not achieving the optimal therapeutic target. Direct oral anticoagulants (DOAC) have replaced VKA therapy in the past for several indications, e.g., atrial fibrillation. However, it is still unclear if DOACs could replace VKA therapy in patients after mechanical aortic valve replacement. While the PROACT-Xa study did not show a sufficient anticoagulatory effect of apixaban plus aspirin compared to VKA therapy in patients after mechanical aortic valve replacement, the direct thrombin inhibitor dabigatran and the oral factor Xa inhibitors apixaban and rivaroxaban showed promising results in comparable patient cohorts in smaller studies and case reports. Factor Xa inhibitors were able to prevent thrombosis and thrombo-embolic events in patients after mechanical aortic valve replacement. Therefore, factor Xa inhibitors or factor XI inhibitors could provide a potent alternative to VKA for patients after a mechanical aortic valve replacement.

The administration of intravenous thrombolysis (IVT) for patients with acute ischemic stroke who have recently ingested direct oral anticoagulants (DOACs) presents a clinical challenge due to the perceived increased risk of intracranial hemorrhage (ICH). Traditional guidelines from the US and European authorities advise against IVT within 48 h of last DOAC ingestion, unless specific coagulation tests indicate safety. However, emerging observational studies suggest that IVT might be safe in selected patients. A US stroke registry study and a global multicenter cohort study both reported no significant increase in symptomatic ICH among patients on DOACs compared to those not on anticoagulants. A systematic review of all published observational studies further supported these findings, showing comparable bleeding rates and functional outcomes in DOAC-treated patients. Reversal agents like idarucizumab for dabigatran have demonstrated potential in facilitating safer IVT administration, though logistical and cost-related barriers limit their widespread use. The variability in global guidelines reflects differing approaches to risk assessment and resource availability, highlighting the need for individualized treatment decisions. In India, the increasing prevalence of atrial fibrillation and stroke as well as prescription of DOACs necessitate adapted guidelines that consider local health-care infrastructure. Despite the promising observational data, the lack of randomized controlled trials underscores the need for further research to establish robust evidence for IVT use in this context. Collaborative international efforts and inclusion of diverse patient populations in future studies will be crucial to refine treatment protocols and improve outcomes for stroke patients on DOACs. [ABSTRACT FROM AUTHOR]

Background: During the COVID-19 pandemic many patients were switched from warfarin to direct)acting oral anticoagulants (DOACs), which require the creatinine clearance (CrCl) calculated to ensure the correct dose is prescribed to avoid bleeding or reduced efficacy. Aim: To identify the study population proportion prescribed a DOAC. Of these, the proportion with recorded: weight, estimated glomerular filtration rate (eGFR), creatinine, CrCl and atrial fibrillation (AF). To analyse the proportion of patients with recorded AF and CrCl prescribed a recommended DOAC dose. Design & setting: A retrospective cohort study of 20.5 million adult NHS patients’ electronic health records (EHRs) in England in the OpenSAFELY-TPP platform (January 2018–February 2023). Method: Patients on DOACs were analysed for age, sex, recorded weight, eGFR, creatinine, CrCl and AF. Prescribed DOAC doses in patients with recorded AF were compared with recommended doses for recorded CrCl and determined as either recommended, higher than recommended (overdose), or lower than recommended (underdose). Results: In February 2023, weight, eGFR, creatinine, CrCl, and AF were recorded in 72.8%, 92.4%, 94.3%, 73.5%, and 73.9% of study population, respectively. Both AF and CrCl were recorded for 56.7% of patients. Of these, 86.2% received the recommended, and 13.8% non-recommended, DOAC doses. Conclusion: CrCl is not recorded for a substantial number of patients on DOACs. We recommend that national organisations tasked with safety, collectively update guidance on the appropriate weight to use in the Cockcroft–Gault equation, clarify that CrCl is not equivalent to eGFR, and work with GP clinical system suppliers to standardise the calculation of CrCl in the EHR. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) carries a stroke risk, often necessitating anticoagulation, especially in patients with risk factors. With the advent of implantable and wearable heart monitors, episodes of short bouts of atrial arrhythmias called atrial high-rate episodes (AHREs) or subclinical AF (SCAF) are commonly identified. The necessity of anticoagulation in patients with SCAF is unclear. However, recent randomized controlled trials, the NOAH-AFNET 6 and ARTESIA, have offered insights into this matter. Furthermore, a study-level meta-analysis combining data from both these trials has provided more detailed information. Reviewing the information thus far, we can conclude that DOACs can result in a notable reduction in the risk of ischemic stroke and can potentially decrease the risk of debilitating stroke, albeit with an increased risk of major bleeding. Thus, informed, shared decision-making is essential, weighing the potential benefits of stroke prevention against the risk of major bleeding when considering anticoagulation in this patient population. [ABSTRACT FROM AUTHOR]

Summary: Hip fracture is a common serious injury among older adults, yet the management of hip fractures for patients taking direct oral anticoagulants remains inconsistent worldwide. Drawing from a synthesis of available evidence and expert opinion, best practice approaches for managing patients with a hip fracture and who are taking direct oral anticoagulants pre‐operatively were considered by a working group of the Fragility Fracture Network Hip Fracture Audit Special Interest Group. The literature and related clinical guidelines were reviewed and a two‐round modified Delphi study was conducted with a panel of experts from 16 countries and involved seven clinical specialities. Four consensus statements were achieved: peripheral nerve blocks can reasonably be performed on presentation for patients with hip fracture who are receiving direct oral anticoagulants; hip fracture surgery can reasonably be performed for patients taking direct oral anticoagulants < 36 h from last dose; general anaesthesia could reasonably be administered for patients with hip fracture and who are taking direct oral anticoagulants < 36 h from last dose (assuming eGFR > 60 ml.min‐1.1.73 m‐2); and it is generally reasonable to consider recommencing direct oral anticoagulants (considering blood loss and haemoglobin) < 48 h after hip fracture surgery. No consensus was achieved regarding timing of spinal anaesthesia. The consensus statements were developed to aid clinicians in their decision‐making and to reduce practice variations in the management of patients with hip fracture and who are taking direct oral anticoagulants. Each statement will need to be considered specific to each individual patient's treatment. [ABSTRACT FROM AUTHOR]

This case report concerns a 68-year-old man with atrial fibrillation who was being treated with edoxaban, a direct oral anticoagulant, to prevent stroke. In the patient's medical history, two episodes of post-surgical hemorrhagic diathesis were not investigated. He sought First Aid for intense asthenia and dark stool discharge. He presented with severe anemia (hemoglobin 40 g/L) and extended coagulation tests (prothrombin ratio 8.56; activated partial thromboplastin ratio 3.83), antral gastritis, and a gastric ulcer. The prolongation of both coagulation tests suggested a decrease in the activity of one of the common pathway factors. The subsequent performance of a mixing test, which helps to distinguish clotting time prolongation due to a coagulation factor deficiency rather than to an inhibitor, allowed us to understand that the patient might be suffering from a factor congenital deficiency. Measurements of coagulation factors showed a severe reduction in factor V activity (1.1%). The search for specific inhibitors directed against factor V was negative, confirming the suspicion that it was a congenital deficiency of factor V, a rare autosomal recessive disorder. Anticoagulant therapy and gastric ulcer made it possible to diagnose a rare congenital disease in an elderly man. The anticoagulant therapy was interrupted and a surgical closure of the left atrial appendage was established. Before starting anticoagulant therapy, according to consolidated guidelines, a blood count, full coagulation panel, renal, and liver function must be evaluated. Very likely, the patient, affected by congenital factor V deficiency, started the anticoagulant therapy without an adequate evaluation of the hemostasis status. [ABSTRACT FROM AUTHOR]

Introduction Materials and Methods Results Conclusions The monitoring of unfractionated heparin (UFH) by anti‐factor Xa activity (AXA) is commonly used to ensure effective anticoagulation and prevent bleeding risk. However, in patients previously treated with an anti‐Xa direct oral anticoagulant (DOAC) switching to UFH therapy, there is a risk of interference that may lead to inappropriate anticoagulation. The first objective of this study was to validate DOAC‐Remove to remove DOAC for measuring UFH specific AXA. The second objective was to assess the length of DOAC interference on UFH monitoring and to identify potential predictive factors.This monocentric retrospective study included all patients admitted from April 2019 to April 2021 previously treated with anti‐Xa DOAC, and for whom an interference on UFH monitoring was suspected. Interference was defined as a difference in the AXA measured before and after using DOAC‐Remove >2.8‐fold standard deviation of the method.Removal with DOAC‐Remove was specific of DOAC (apixaban n = 42, rivaroxaban n = 41, UFH n = 20) and sufficient to avoid interference on UFH AXA measurement. The exact interference length was 6.0 days [IQR 3.0–11.0] for apixaban (n = 26) and 4.5 days [IQR 2.0–5.8] for rivaroxaban (n = 20). Among the 89 patients sorted based on an interference length ≤ or >3 days, 74 (83.1%) presented an interference greater than 3 days. Correlations were observed with age for apixaban and creatinine for rivaroxaban.Our results suggest that DOAC‐Remove could be of high interest in patients receiving UFH previously treated with an anti‐Xa DOAC even if DOAC was stopped for more than 3 days. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusions The activity of direct oral anticoagulants (DOAC) is important in acute clinical situations. Recent studies have suggested a strong influence of DOAC on the diluted Russel's Viper Venom Time (dRVVT). Therefore, it may be a suitable screening parameter for antithrombotic plasma activity of different DOAC. This prospective study aims to evaluate the sensitivity and specificity of dRVVT to detect residual DOAC activity at recommended plasma level thresholds.A total of 80 patients were recruited, with 20 each treated with one of the four approved DOAC (apixaban, edoxaban, rivaroxaban or dabigatran), respectively. Blood plasma was collected before (baseline), at plasma peak time, and 6 and 12 h after DOAC. DRVVT was measured using the screen (LA1) and confirm (LA2) assay for lupus anticoagulant and compared with DOAC plasma levels. A reference range was calculated based on the dRVVT values of 61 healthy blood donors.All DOAC significantly prolonged the dRVVT especially at higher DOAC plasma levels. The LA1 time ≥41 s had a sensitivity ≥98% to detect edoxaban, dabigatran and rivaroxaban plasma levels ≥30 ng/mL but it was only 87% for apixaban. Sensitivity was ≥98% for all DOAC with the LA2 assay ≥36 s. The negative predictive value of a DOAC plasma level <30 ng/mL and dRVVT LA2 <36 s was 99%.The dRVVT confirm assay (LA2) reliably detects residual DOAC plasma levels ≥30 ng/mL and could be useful to rapidly rule out relevant DOAC activity in emergency situations and to guide treatment decisions. [ABSTRACT FROM AUTHOR]

IntroductionPharmacovigilance is vital for drug safety. The process typically involves two key steps: initial signal generation from spontaneous reporting systems (SRSs) and subsequent expert review to assess the signals’ (potential) causality and decide on the appropriate action.MethodsWe propose a novel discovery and verification approach to pharmacovigilance based on electronic healthcare data. We enhance the signal detection phase by introducing an ensemble of methods which generated signals are combined using Borda count ranking; a method designed to emphasize consensus. Ensemble methods tend to perform better when data is noisy and leverage the strengths of individual classifiers, while trying to mitigate some of their limitations. Additionally, we offer the committee of medical experts with the option to perform an in-depth investigation of selected signals through tailored pharmacoepidemiological studies to evaluate their plausibility or spuriousness. To illustrate our approach, we utilize data from the German Pharmacoepidemiological Research Database, focusing on drug reactions to the direct oral anticoagulant rivaroxaban.ResultsIn this example, the ensemble method is built upon the Bayesian confidence propagation neural network, longitudinal Gamma Poisson shrinker, penalized regression and random forests. We also conduct a pharmacoepidemiological verification study in the form of a nested active comparator case-control study, involving patients diagnosed with atrial fibrillation who initiated anticoagulant treatment between 2011 and 2017.DiscussionThe case study reveals our ability to detect known adverse drug reactions and discover new signals. Importantly, the ensemble method is computationally efficient. Hasty false conclusions can be avoided by a verification study, which is, however, time-consuming to carry out. We provide an online tool for easy application: https://borda.bips.eu.

Summary: Cirrhosis is a major health concern worldwide with a complex pathophysiology affecting various biological systems, including all aspects of haemostasis. Bleeding risk is mainly driven by portal hypertension, but in end-stage liver disease it is further increased by alterations in haemostatic components, including platelet function, coagulation, and fibrinolysis. Concurrently, patients with cirrhosis are prone to venous thromboembolic events (VTE) because of the altered haemostatic balance, in particular an increase in thrombin generation. In patients with cirrhosis, vitamin K antagonists (VKA) and low molecular weight heparins (LMWH) are currently the standard of care for VTE prevention, with VKA also being standard of care for stroke prevention in those with atrial fibrillation. However, direct oral anticoagulants (DOAC) could have specific advantages in this patient population. Clinical experience suggests that DOAC are a safe and possibly more effective alternative to traditional anticoagulants for the treatment of VTE in patients with compensated cirrhosis. In addition, emerging data suggest that primary prophylactic treatment with anticoagulants may improve clinical outcomes in patients with cirrhosis by reducing the risk of hepatic decompensation. The selection of the most appropriate DOAC remains to be clarified. This review focuses on the rationale for the use of DOAC in patients with cirrhosis, the specific effects of the different DOAC (as assessed by in vitro and in vivo pharmacokinetic and pharmacodynamic studies), as well as clinical outcomes in patients with cirrhosis on DOAC.

This article is an editorial that discusses the use of pharmacological therapy in patients with arrhythmias. It provides information on the prevalence and incidence of different types of arrhythmias, such as supraventricular tachycardia and atrial fibrillation, and their associated risk factors. The article emphasizes the importance of early detection and maintenance of sinus rhythm in patients with atrial fibrillation. It also discusses the use of catheter ablation and additional pharmacological therapy in managing arrhythmias. The article concludes by mentioning the importance of anticoagulation therapy and the potential benefits of direct-acting oral anticoagulants in certain patient populations. The given document is a list of references for various research articles related to heart disease, stroke, and atrial fibrillation. These articles cover topics such as the epidemiology of atrial fibrillation, predictors of specific types of atrial fibrillation, the impact of ablation on mortality, remote monitoring systems for implantable cardiac defibrillators, and the use of artificial intelligence in the treatment of atrial fibrillation. These articles provide valuable information for library patrons conducting research on these specific topics. [Extracted from the article]

Inhibitors of the factor FXI represent a new class of anticoagulant agents that are facing clinical approval for the treatment of acute coronary syndrome (ACS), venous thromboembolism (VTE), and stroke prevention of atrial fibrillation (AF). These new inhibitors include chemical small molecules (asundexian and milvexian), monoclonal antibodies (abelacimab, osocimab, and xisomab), and antisense oligonucleotides (IONIS-FXIRX and fesomersen), and thus, they have very peculiar and different pharmacokinetic and pharmacodynamic properties. Besides their clinical efficacy and safety, based on their pharmacological heterogeneity, the use of these drugs in patients with comorbidities may undergo drug–drug interactions (DDIs) with other concomitant therapies. Although only little clinical evidence is available, it is possible to predict clinically relevant DDI by taking into consideration their pharmacokinetic properties, such as the CYP450-dependent metabolism, the interaction with drug transporters, and/or the route of elimination. These characteristics may be useful to differentiate their use with the direct oral anticoagulant (DOAC) anti -FXa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran), whose pharmacokinetics are strongly dependent from P-gp inhibitors/inducers. In the present review, we summarize the current clinical evidence on DDIs of new anti FXI with CYP450/P-gp inhibitors and inducers and indicate potential differences with DOAC anti FXa.

Background: Direct oral anticoagulants (DOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. We aimed to describe the prevalence of inappropriate DOACs dose prescription in the START2-AF Registry, the outcomes according to the appropriateness of the dosage, and the factors associated with inappropriate dose prescription. Methods: Patients' demographics and clinical data were prospectively collected as electronic files in an anonymous form on the website of the START2-Registry; DOACs dosage was determined to be appropriate when prescribed according to the European Heart Rhythm Association Guidelines. Results: We included 5943 NVAF patients on DOACs; 2572 (46.3%) were female patients. The standard dose (SD) was prescribed to 56.9% of patients and the low dose (LD) was prescribed to 43.1% of patients; 38.9% of all NVAF patients received an inappropriate LD DOAC and 0.3% received inappropriate SD. Patients treated with LD DOAC had a significantly higher rate of all bleedings (RR 1.5; 95% CI 1.2–2.0), major bleedings (RR 1.8; 95% CI 1.3–1.7), and mortality (RR 2.8; 95% CI 1.9–4.1) with respect to patients treated with SD DOAC. No difference was found among patients treated with appropriate and inappropriate LD regarding bleeding, thrombotic, and mortality rates. Age, body weight <60 kg, and renal failure were significantly associated with inappropriate LD DOAC prescription. Conclusions: Inappropriate LD DOACs in NVAF patients is not associated with a reduction in bleeding risk, nor with an increased thrombotic risk. Instead, it is associated with higher mortality rate, suggesting that, in clinical practice, underdosing is preferred for patients at particularly high risk for adverse events. [ABSTRACT FROM AUTHOR]

Introduction: Ground level falls in the elderly often lead to complications due to use of anticoagulants (ACs). Intracranial hemorrhage (ICH), immediate or delayed, is a feared consequence of such falls. The rate of delayed ICH (dICH) in patients taking anticoagulants or antiplatelet (AP) agents ranges from.6% to 6%. Patients on warfarin have a persistent rate of dICH, leading to implementation of routine repeat head CTs at our institution. This policy was extended to direct oral anticoagulants (DOACs). This study aims to determine institutional incidence of DOAC-associated dICH. Methods: With IRB waiver approval, we conducted a retrospective review of trauma evaluations for falls on DOACs from 2016 to 2018. We reviewed records for neurologic status, DOAC use, and results of initial and delayed head CTs. Exclusion criteria included initial GCS ≤14, new neurologic deficits, traumatic findings on initial CT, concurrent use of additional AC/AP, or absence of repeat head CT. Results: Among 632 patients evaluated for falls on AC/AP therapy, 159 (25%) of patients were included in the review. The age range was 19-98 years old, with 99 females and 60 males. Half of the patients were on apixaban, with the rest on dabigatran or rivaroxaban. Ten patients presented with GCS of 14. No delayed hemorrhages were detected in this population. Conclusion: The necessity of a repeat head CT in patients taking DOACs is debated in the literature. Our analysis failed to demonstrate any delayed hemorrhage in neurologically intact patients after head strike on DOAC, suggesting no indication for follow-up imaging in this group. [ABSTRACT FROM AUTHOR]

Moderate-strong CYP3A4 or Pgp inhibitors and inducers alter direct oral anticoagulant (DOAC) pharmacokinetics. Whether the presence of a DOAC drug-drug interaction (DDI) prompts in- hospital changes in management remains unknown. We identified all hospitalized patients at our institution who were admitted with a clinically relevant DOAC DDI from 01/2021 to 06/2021. Clinically relevant DOAC DDIs were defined as those listed in the prescribing information or FDA CYP3A4/Pgp inhibitors clinical indexes. We assessed the prevalence of DOAC DDIs and categorized their management as: drug stopped, drug held, or drug continued. For drugs that were continued we assessed whether the dose of the DOAC or interacting drug was increased, decreased or unchanged during the admission. We ascertained the number of DOAC DDIs that prompted an automated prescribing alert in our electronic health record (EHR). Finally, we conducted a logistic regression model to compare users of DOACs with DDI who had their regimen adjusted versus those without adjustments, focusing on outcomes of rehospitalization and death, adjusting for age and gender. Among 3,725 hospitalizations with a DOAC admission order, 197 (5%) had a clinically relevant DOAC DDI. The DOAC and the interacting drug were continued at discharge for 124 (63%) hospitalizations. The most frequent adjustments were stopping the interacting drug (73%) and stopping the DOAC (15%). Only 7 (4%) of DOAC DDIs prompted an EHR alert. The adjusted odds ratios for rehospitalizations and death, respectively, among patients whose regimens were adjusted compared to those whose were not, were 1.29 (95% CI, 0.67 to 2.48; P = 0.44) and 1.88 (95% CI, 0.91 to 3.89; P = 0.09). Clinically relevant DDIs with DOACs occur infrequently among hospitalized patients and usually are managed without stopping the DOAC. The clinical impact of such DDIs and subsequent adjustments on thrombotic and hemorrhagic outcomes requires further investigation. [ABSTRACT FROM AUTHOR]

Inhibitors of the factor FXI represent a new class of anticoagulant agents that are facing clinical approval for the treatment of acute coronary syndrome (ACS), venous thromboembolism (VTE), and stroke prevention of atrial fibrillation (AF). These new inhibitors include chemical small molecules (asundexian and milvexian), monoclonal antibodies (abelacimab, osocimab, and xisomab), and antisense oligonucleotides (IONIS-FXIRX and fesomersen), and thus, they have very peculiar and different pharmacokinetic and pharmacodynamic properties. Besides their clinical efficacy and safety, based on their pharmacological heterogeneity, the use of these drugs in patients with comorbidities may undergo drug–drug interactions (DDIs) with other concomitant therapies. Although only little clinical evidence is available, it is possible to predict clinically relevant DDI by taking into consideration their pharmacokinetic properties, such as the CYP450-dependent metabolism, the interaction with drug transporters, and/or the route of elimination. These characteristics may be useful to differentiate their use with the direct oral anticoagulant (DOAC) anti -FXa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran), whose pharmacokinetics are strongly dependent from P-gp inhibitors/inducers. In the present review, we summarize the current clinical evidence on DDIs of new anti FXI with CYP450/P-gp inhibitors and inducers and indicate potential differences with DOAC anti FXa. [ABSTRACT FROM AUTHOR]

To evaluate the safety of direct oral anticoagulants (DOACs) versus low-molecular weight heparin (LMWH) in patients with central nervous system (CNS) malignancies and secondary metastases. All adult patients with CNS malignancies and secondary metastases who were treated with a DOAC or LMWH for any indication from 2018 to 2022 were included. The primary outcome was the incidence of any intracranial hemorrhage (ICH) after anticoagulation initiation. Secondary outcomes included non-ICH bleeding events and thromboembolic events. Tolerability was assessed by any changes in anticoagulant therapy during study period. 153 patients were included; 48 patients received enoxaparin and 105 received DOACs, of which apixaban was used most commonly. The population was predominantly White (74%) and male (59%) with a median age of 65. Data was censored for immortal time bias for outcomes evaluated beyond 3 months. ICH occurred in 7.7% of the population, more frequently in the enoxaparin group (DOACs 4, 4% vs. enoxaparin 7, 16%, p = 0.037). Non-ICH bleeds were predominantly minor and more common in the DOAC group (DOACs 13, 13% vs. enoxaparin 1, 2%, p = 0.037). Thromboembolic events were not different between groups (DOACs 9. 9% vs, enoxaparin 2, 4%, p = 0.503). Anticoagulant switches occurred more in the enoxaparin group (DOACs 12, 12.4% vs. enoxaparin, 37.8%, p < 0.001), primarily due to patient or provider preference. Our data supports DOACs to be preferred over LMWH for the treatment of VTE or for stroke prevention with AF to prevent ICH in patients with brain tumors or metastases. [ABSTRACT FROM AUTHOR]

Background: All available recommendations about the management of antithrombotic therapies (ATs) in patients who experienced traumatic brain injury (TBI) are mainly based on expert opinion because of the lack of strength in the available evidence-based medicine. Currently, the withdrawal and the resumption of AT in these patients is empirical, widely variable, and based on the individual assessment of the attending physician. The main difficulty is to balance the thrombotic and hemorrhagic risks to improve patient outcome. Methods: Under the endorsement of the Neurotraumatology Section of Italian Society of Neurosurgery, the Italian Society for the Study about Haemostasis and Thrombosis, the Italian Society of Anaesthesia, Analgesia, Resuscitation, and Intensive Care, and the European Association of Neurosurgical Societies, a working group (WG) of clinicians completed two rounds of questionnaires, using the Delphi method, in a multidisciplinary setting. A table for thrombotic and bleeding risk, with a dichotomization in high risk and low risk, was established before questionnaire administration. In this table, the risk is calculated by matching different isolated TBI (iTBI) scenarios such as acute and chronic subdural hematomas, extradural hematoma, brain contusion (intracerebral hemorrhage), and traumatic subarachnoid hemorrhage with patients under active AT treatment. The registered indication could include AT primary prevention, cardiac valve prosthesis, vascular stents, venous thromboembolism, and atrial fibrillation. Results: The WG proposed a total of 28 statements encompassing the most common clinical scenarios about the withdrawal of antiplatelets, vitamin K antagonists, and direct oral anticoagulants in patients who experienced blunt iTBI. The WG voted on the grade of appropriateness of seven recommended interventions. Overall, the panel reached an agreement for 20 of 28 (71%) questions, deeming 11 of 28 (39%) as appropriate and 9 of 28 (32%) as inappropriate interventions. The appropriateness of intervention was rated as uncertain for 8 of 28 (28%) questions. Conclusions: The initial establishment of a thrombotic and/or bleeding risk scoring system can provide a vital theoretical basis for the evaluation of effective management in individuals under AT who sustained an iTBI. The listed recommendations can be implemented into local protocols for a more homogeneous strategy. Validation using large cohorts of patients needs to be developed. This is the first part of a project to update the management of AT in patients with iTBI. [ABSTRACT FROM AUTHOR]

Background: The use of apixaban in the pediatric cardiac population is expanding. We describe our apixaban dosing and monitoring strategy in children and young adults awaiting heart transplantation, along with outcomes related to bleeding and thrombosis during wait‐list and early post‐transplant periods. Methods: This study is a retrospective, single‐center analysis of all patients receiving apixaban while awaiting cardiac transplantation. Weight‐based dosing was monitored with peak drug‐specific anti‐Xa chromogenic analysis. Significant post‐operative bleeding defined by chest tube output or need for surgical intervention. Results: From September 2020 to December 2022, 19 patients, median age 13.5 years (6.1, 15.8 years), weighing 48.9 kg (15.4, 67.6) received apixaban while awaiting transplant. Indication for apixaban was prophylaxis (n = 18, 3 with ventricular assist devices) and treatment of thrombus (n = 1). There were no clinically relevant non‐major or major bleeding, nor thrombotic events while awaiting transplant. The median time from last apixaban dose to arrival in the operating room was 23.2 h (15.6–33.8), with median random apixaban level of 37 ng/mL (28.3, 59), 6.3 h (4.8, 8.4) prior to arrival in the operating room. In this study, 32% of patients had significant post‐operative bleeding based on chest tube output post‐transplant or need for intervention. No patients meeting criteria for significant post‐operative bleeding were thought to be attributable to apixaban. Conclusions: Careful use of apixaban can be safe and effective while awaiting heart transplant. There was no appreciable increase in peri‐operative bleeding. The use of apixaban is promising in providing safe, predictable and efficacious anticoagulation while avoiding additional patient stressors. [ABSTRACT FROM AUTHOR]

Background: Patients with acute venous thromboembolism associated with cancer have an increased risk of recurrences and bleeding in the long term. Research question: To describe the clinical features and short-term course of patients with acute pulmonary embolism (PE) and active cancer, previous cancer or no cancer. Study design and methods: Patients with acute PE included in COPE—prospective, multicentre study of adult patients with acute, symptomatic, objectively diagnosed PE—were classified as having active cancer, previous cancer, or no cancer. Results: Overall, 832 patients had active cancer, 464 with previous cancer and 3660 patients had no cancer at the time of acute PE. The most prevalent primary sites of active cancer were urogenital (23.0%), gastrointestinal (21.0%), and lung (19.8%), with a high prevalence of metastatic disease (57.6%) and ongoing anticancer treatment (16.2%). At discharge, a direct oral anticoagulant was used in 43.1%, 78.8%, and 82.0% of patients with active cancer, previous cancer, and no cancer, respectively. Rates of death in-hospital and at 30 days were higher in patients with active cancer compared to patients with previous cancer and no cancer (7.9% vs. 4.3% vs. 2.2% and 13.8% vs. 5.2% vs. 2.6%, respectively). Rates of major bleeding were 4.8%, 2.6%, and 2.4%, respectively. Among patients with active cancer, lung or metastatic cancer were independent predictors of death; brain, hematological or gastrointestinal cancer had the highest risk of major bleeding. Interpretation: Among patients with acute PE, those with active cancer have high risks for death or major bleeding within 30 days. These risks vary based on primary site of cancer. Clinical trial registration: clinicaltrial.gov identifier: NCT03631810. [ABSTRACT FROM AUTHOR]

Background: During the COVID-19 pandemic many patients were switched from warfarin to direct-acting oral anticoagulants (DOACs), which require the creatinine clearance (CrCl) calculated to ensure the correct dose is prescribed to avoid bleeding or reduced efficacy. Aim: To identify the study population proportion prescribed a DOAC. Of these, the proportion with recorded: weight, estimated glomerular filtration rate (eGFR), creatinine, CrCl and atrial fibrillation (AF). To analyse the proportion of patients with recorded AF and CrCl prescribed a recommended DOAC dose. Design & setting: A retrospective cohort study of 20.5 million adult NHS patients’ electronic health records (EHRs) in England in the OpenSAFELY-TPP platform (January 2018–February 2023). Method: Patients on DOACs were analysed for age, sex, recorded weight, eGFR, creatinine, CrCl and AF. Prescribed DOAC doses in patients with recorded AF were compared with recommended doses for recorded CrCl and determined as either recommended, higher than recommended (overdose), or lower than recommended (underdose). Results: In February 2023, weight, eGFR, creatinine, CrCl, and AF were recorded in 72.8%, 92.4%, 94.3%, 73.5%, and 73.9% of study population, respectively. Both AF and CrCl were recorded for 56.7% of patients. Of these, 86.2% received the recommended, and 13.8% non-recommended, DOAC doses. Conclusion: CrCl is not recorded for a substantial number of patients on DOACs. We recommend that national organisations tasked with safety, collectively update guidance on the appropriate weight to use in the Cockcroft–Gault equation, clarify that CrCl is not equivalent to eGFR, and work with GP clinical system suppliers to standardise the calculation of CrCl in the EHR.

Aim. To evaluate the clinical course and inhospital outcomes of myocardial infarction (MI) in patients receiving continuous direct oral anticoagulant (DOAC) therapy.Material and methods. Data from 390 patients treated for MI were included in the analysis. The mean age was 64.1±12.8 years. The majority were men (61,5%; n=240). All patients underwent standard diagnostic and therapeutic procedures according to clinical guidelines, including coronary angiography and percutaneous coronary intervention when indicated. Clinical, anamnestic and laboratory data (including C-reactive protein level, troponin I, coagulation test) were analysed. The inhospital course of MI, mortality and incidence of complications were evaluated.Results. Patients were divided into two groups according to DOAC therapy received. The main group included 41 patients with constant DOAC intake, while the control group consisted of 349 patients not receiving DOAC. Patients aged 65 years and older accounted for 68,3% (n=28) of the main group (p=0,0033), with a high proportion of cerebral circulation disorders and venous thrombosis (p0,05). Prior DOAC administration had no significant effect on the incidence of gastrointestinal bleeding (odds ratio (OR), 3,96 (95% Confidence Interval (CI) 0,76–20,66)) and mortality (OR 1,47 (95% CI 0,37-5,85)) during hospitalization.Conclusion. Patients with MI who received continuous DOAC therapy had significantly more frequent ST-segment resolution at hospital admission compared with patients who did not receive DOAC. DOAC administration had no significant effect on mortality and incidence of inhospital complications of MI.

Objectives Quantification of direct oral anticoagulant (DOAC) plasma levels can guide clinical management, but insight into clinical scenarios surrounding DOAC-calibrated anti-FXa assays is limited. Methods Apixaban- and rivaroxaban-calibrated chromogenic anti-Xa assays performed over a 1-year period were retrospectively analyzed. Patient demographics, DOAC history, concomitant medications, and renal/liver comorbidities were obtained. Indications for testing and associated clinical actions were reviewed. Machine learning (ML) models predicting clinical actions were evaluated. Results In total, 371 anti-FXa apixaban and 89 anti-FXa rivaroxaban tests were performed for 259 and 67 patients in recurring urgent (acute bleeding, unplanned procedures) and nonurgent situations, including several scenarios not captured by existing testing recommendations (eg, drug monitoring, recurrent thromboembolic events, bleeding tendency). In urgent settings, andexanet reversal was guided by radiologic and clinical findings over DOAC levels in 14 of 32 instances, while 51% of apixaban patients qualified for nonreversal strategies through the availability of levels. Levels also informed procedure/intervention timing and supported management decisions when DOAC clearance or DOAC target levels were in question. The importance of clinical context was emphasized by exploratory ML models predicting particular clinical actions. Conclusions Although clinical situations are complex, DOAC testing facilitates clinical decision-making, including reversal, justifying more widespread implementation of these assays. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) in pregnancy remains a leading cause of maternal morbidity and mortality. As rates of pregnancy in women with additional risk factors and underlying diagnoses continue to rise, it is crucial that all obstetricians understand how to approach thromboprophylaxis at all stages of pregnancy. In this review we seek to provide a roadmap to understanding the physiology, pathology and pharmacology of VTE in pregnancy for the obstetrician in order to facilitate a greater understanding of how to best support all women at risk of VTE throughout their pregnancy journey from pre-conception to post-natally. Recent developments and emerging evidence to support changes in practice are explored as well as consideration of some more complex scenarios and discussion of ethical considerations in the hope of providing a comprehensive overview of the subject. [ABSTRACT FROM AUTHOR]

Purpose: Due to a better safety profile, direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic events. However, little is known about DOAC plasma concentrations in trauma patients upon hospital admission. Thus, we investigated the frequency and extent of DOAC possible over- and underdosing in trauma patients upon hospital admission. Methods: In this single-center retrospective study, DOAC plasma concentrations of adult trauma patients were analyzed with specific calibrated anti-IIa (dabigatran) and anti-Xa (apixaban, edoxaban and rivaroxaban) tests within 4 h after hospital admission. Results: A total of 210 trauma patients, admitted between 2019 and 2022, were included in the analyses. Low DOAC levels < 30 ng/mL were detected in 13.3% of the patients. In 7.1% of the patients, DOAC plasma levels ranged between 300–399 ng/mL and further 7.1% exhibited plasma concentrations > 400 ng/mL. The highest incidence of high to very high DOAC plasma concentration was observed for patients on rivaroxaban and dabigatran. A moderate correlation was observed between dabigatran plasma concentration and estimated glomerular filtration rate (rho = − 0.5338, p = 0.0003). For rivaroxaban no clear association between plasma concentration and liver or renal function could be detected. Patients on statins had significantly higher DOAC concentration in comparison with those not taking statins (153 (76–274) vs 108 (51–217) ng/mL, p = 0.046). Conclusion: The current study revealed that patients on dabigatran and rivaroxaban were prone to higher DOAC plasma levels upon hospital admission in comparison with apixaban and edoxaban. DOAC plasma level measurement in trauma patients might be warranted due to unpredictively low or high plasma concentrations. However, the clinical impact of altered plasma levels on both, bleeding and thromboembolic events, remains to be determined by future studies. [ABSTRACT FROM AUTHOR]

The 2021 International Society on Thrombosis and Haemostasis' (ISTH) recommends standard doses of apixaban and rivaroxaban regardless of high body mass index (BMI) and weight, but had not compare DOACs head-to-head in obesity or address underweight patients. Our aim is to evaluate the safety and efficacy of DOACs in underweight and obese patients compared to warfarin. The primary endpoints include incidence of thromboembolic and bleeding events. Descriptive statistics was used for continuous variables. The Kruskal-Wallis test was used to compare the four-groups for continuous measures and the chi-square test or Fisher's exact test was used to analyze categorical data. The chi-square test or Fisher's exact test, was used for categorical variables, and the Mann-Whitney test (the non-parametric counterpart to the two-sample t -test) for continuous data. Of 2940 patients receiving anticoagulation for venous thromboembolism (VTE) treatment or atrial fibrillation (AF), 492 met eligibility criteria. Within each group, 248 patients received warfarin, 101 received apixaban, 100 received rivaroxaban and 43 received dabigatran. Patients were characterized in 4 body mass index (BMI) categories, in which 80 were underweight and 412 were obese. When each DOAC was compared to warfarin in rates of VTE, apixaban showed statistically significant lower rate of VTE (p = 0.0149). However, no statistical significance was identified in the rate of VTE between DOACs combined vs. warfarin (p = 0.1529). When each DOAC was compared to warfarin, apixaban showed the lowest rate of overall bleeding (p = 0.0194). However, no statistical difference in the rate of bleeding was observed between DOACs combined vs. warfarin (p = 0.3284). Patients with extreme body weights requiring anticoagulation for VTE and AF may safety benefit from DOAC therapy. This evaluation showed apixaban with the lowest rate of VTE and bleeding compared to warfarin, rivaroxaban, and dabigatran. These results provide experience for the clinician to use DOACs, particularly apixaban, in underweight and obese populations. • What is the new aspect of your work? The new aspect of our work is to evaluate the safety and efficacy of oral anticoagulants in patients who are underweight or obese, since direct oral anticoagulants (DOACs) are fixed-dose and may have increased bleeding in underweight populations, but reduced efficacy in obese populations. • What is the central finding of your work? In underweight patients with BMI <18.5, DOACs have similar efficacy and safety to vitamin k antagonist (warfarin), p =0.1179 in the 4-group analysis and p =0.5658 in the 2-group analysis. When reviewed individually, apixaban has statistically significant less risk of bleeding in patients with BMI < 18.5, apixaban 1 (10%), rivaroxaban 5 (38.46%), dabigatran 5 (50%), and warfarin 7 (14.89%), p =0.0322. In obese patients with BMI > 40, there rate of VTE was lowest in the apixaban 0 (0%) and warfarin groups 0 (0%), followed by dabigatran 1 (12.5%), then rivaroxaban 3 (13.64%), p =0.0104 in the 4-group analysis and p =0.0346 in the 2-group analysis. In BMI > 40, the risk of bleeding was not statistically significant among the 4-group analysis, p=0.3417. • What is (or could be) the specific relevance of your work? The relevance of our work is DOACs may be safe and efficacious, compared to vitamin k agonist (warfarin), in patient with extreme weights. Monitoring DOAC plasma levels in extreme weights may be of utility. [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants (DOACs) have become the cornerstone for prevention of thromboembolic events in patients with atrial fibrillation and patients with a history of venous thromboembolism. However, studies show that DOAC prescriptions are commonly inconsistent with guideline recommendations. DOAC dosing in the acutely ill patient could impose an even greater challenge. In this review, we describe the prevalence of inappropriate inpatient prescribing of DOACs and the associated rationales, predictors and clinical consequences. With the aim of promoting appropriate prescriptions of DOACs to hospitalized patients, we further outline DOAC dose reduction criteria justified by various guidelines, illustrating the complexities of appropriate dosing, especially in acutely ill patients. Moreover, we will discuss the impact of anticoagulant stewardship programs and the vital role that pharmacists may play in optimizing inpatient DOAC treatment. [Display omitted] • Inhospital DOAC prescriptions are commonly inconsistent with recommendations. • DOAC dose reduction criteria are relatively complex. • Pharmacists may play a vital role in optimizing inhospital DOAC prescriptions. • Clinical consequences of inappropriate inhospital DOAC dosing are unknown. [ABSTRACT FROM AUTHOR]

Background Andexanet is U.S. Food and Drug Administration (FDA) approved for the reversal of critical bleeding from factor Xa inhibitors and off-label for surgical reversal. Data are lacking on andexanet administration processes.

Gediminas Gumbis,1 Inga &Ccaron;esnavi&ccaron;i&umacr;t&edot;,1 Gabija Did&zcaron;iokait&edot;,1,2 Daiva Gegeckien&edot;,3 Violeta Kvedarien&edot;4,5 1Faculty of Medicine, Vilnius University, Vilnius, Lithuania; 2Institute of Clinical Medicine, Faculty of Medicine, Vilnius University Clinic of Obstetrics and Gynaecology, Vilnius University, Vilnius, Lithuania; 3Centre of Cardiology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania; 4Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania; 5Centre of Innovative Allergology, Vilnius, LithuaniaCorrespondence: Gediminas Gumbis, Faculty of Medicine, Vilnius University, M. K. &Ccaron;iurlionio g. 21, Vilnius, LT-03101, Lithuania, Tel +37060680714, Email gediminas.gumbis@mf.stud.vu.ltAbstract: Here, we describe a case of anaphylaxis secondary to rivaroxaban in a 61-year-old woman 24 hours after orthopedic surgery. 10– 15 minutes after ingestion of rivaroxaban and nimesulide, the patient’s palms started itching, her face and lips swelled, her face flushed, she developed shortness of breath and subsequently lost consciousness. Serum tryptase levels at the time of the anaphylactic reaction were elevated, with subsequent measurement one month later returning a value within the normal range. Dabigatran and meloxicam were identified as suitable alternative drugs by oral provocation at an allergy clinic. Even though rivaroxaban rarely causes serious allergic reactions, when prescribing it, it is important to analyze patients’ medical history for possible previously experienced drug-induced allergic reactions and to be aware of the risks of possible undesired drug interactions.Keywords: Xarelto, anticoagulant, DOAC, adverse drug reaction, allergy

Abstract Introduction Despite clear, relatively easy-to-use guidance, many clinicians find the preoperative management of direct oral anticoagulants (DOACs) challenging. Inappropriate management can delay procedures and lead to haemorrhagic or thromboembolic complications. We aimed to describe preoperative management practices regarding DOACs in a tertiary hospital and clinicians’ adherence to in-house recommendations. Method We included all patients being treated with DOACs who underwent elective surgery in 2019 and 2020 (n = 337). In-house recommendations for perioperative management were largely comparable to the 2022 American College of Chest Physicians guidelines. Results Typical patients were older adults with multiple comorbidities and high thrombotic risk stratification scores, and 65.6% (n = 221) had not undergone recommended preoperative anticoagulation management protocols. Patients operated on using local anaesthesia (adjusted OR = 0.30, 95%CI 0.14–0.66; p