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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.)

Objective: Given recent concerns regarding the updated Beers Criteria, we sought to compare the effectiveness and safety of rivaroxaban with oral anticoagulants in older adults with nonvalvular atrial fibrillation (AF)., Methods: We used an administrative healthcare database and included AF patients ≥ 65 years who were new users of rivaroxaban or the comparators. We created three pairwise comparisons: rivaroxaban vs. warfarin; rivaroxaban vs. dabigatran; and rivaroxaban vs. apixaban. Study outcomes included stroke or systemic embolism (effectiveness), and gastrointestinal or intracranial bleeding (safety). In the propensity score matched sample, we used Cox proportional hazards regression to estimate hazard ratios [HRs] and 95% confidence intervals [CIs]., Results: In the matched cohorts, use of rivaroxaban (vs. warfarin) increased risk of bleeding (HR 1.13; CI 1.03 to 1.23) with no difference in ischemic stroke or systemic embolism (HR 0.90; CI 0.79 to 1.02); use of rivaroxaban (vs. dabigatran) increased risk of bleeding (HR 1.18; CI 1.03 to 1.35) with no difference in ischemic stroke and systemic embolism (HR 1.00; CI 0.83 to 1.22); and use of rivaroxaban (vs. apixaban) increased risk of stroke and systemic embolism (HR 1.23; CI 1.08 to 1.40) and bleeding (HR 1.60; CI 1.45 to 1.76)., Conclusion: In this comparative effectiveness and safety study of older patients with nonvalvular AF, use of rivaroxaban was associated with a significantly increased risk of ischemic stroke and systemic embolism compared with apixaban, and bleeding compared with warfarin, dabigatran, and apixaban. Our findings may inform anticoagulant selection in older adults with nonvalvular AF., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objectives : Rivaroxaban is a direct-acting anticoagulant used to prevent stroke in patients with atrial fibrillation. Rivaroxaban is a substrate for P-glycoprotein, which is encoded by the ABCB1 gene. Rivaroxaban is also metabolized by the CYP3A5 gene. Therefore, the current study is carried out to study the effects of polymorphisms in the ABCB1 and CYP3A5 genes, which may affect the plasma levels of rivaroxaban, with subsequent clinical outcomes (bleeding events) associated with the therapy. Materials and Methods : The study was conducted on 66 naive patients with atrial fibrillation treated with rivaroxaban. Blood samples of rivaroxaban were taken at 3 h and after 1 month following the administration of the drug to measure plasma levels. The blood level of rivaroxaban was measured with an HPLC-UV detector. Sanger sequencing was used to find polymorphisms in the targeted genes. Coagulation parameters were measured at 3 h and after 1 month of administration of rivaroxaban. Frequencies of bleeding events were recorded throughout the one-month course of drug therapy. Results : The heterozygous and homozygous mutant genotypes of ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) showed lower plasma concentrations as compared to the wild-type genotype. ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a statistically significant impact on the plasma concentration of rivaroxaban among the heterozygous and homozygous mutant genotypes compared to the wild-type genotype. The heterozygous variant of ABCB1 and homozygous variant of CYP3A5 suffered more events of bleeding. Conclusions : It was concluded that ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a significant impact on the plasma levels of rivaroxaban in patients treated for atrial fibrillation on day three as well as after one month of the therapy. The lowest plasma levels were observed in patients with a homozygous variant of ABCB1 (rs2032582, rs1045642, or rs4148738) along with the CYP3A5*1/*3 allele. The heterozygous variant of ABCB1 SNPs and homozygous variant of CYP3A5 SNPs suffered more events of bleeding.

Background: Hypothermia and acidosis individually inhibit haemostasis. We designed this study with the aim to investigate whether rivaroxaban combined with hypothermia or acidosis exhibit synergistic inhibitory effects on haemostasis using ROTEM ® ., Methods: Patients with a clinical indication to start rivaroxaban treatment were prospectively included. Blood samples were collected before initiation of treatment and the day after. All blood samples were in vitro modified with respect to temperature (incubated and analysed at 28, 33, 37 and 40 degrees Celsius (°C)) and pH (6.8, 7.0, 7.2 and 7.4). The temperature and acidosis effects on the ROTEM EXTEM variables clotting time (CT), clot formation time (CFT) and alpha-angle (AA) were measured along with the individual effect of rivaroxaban on the same variables. The additive effect was calculated. The observed (potential synergistic) effects for the temperature and pH modified rivaroxaban samples on the same ROTEM variables, were registered. Differences between the additive and observed (potential synergistic) effects were analysed using matched non-parametric hypothesis testing., Results: In total, 13 patients were included. Hypothermia and rivaroxaban exhibited a synergistic effect on CT at 28 °C (p = 0.0002) and at 33 °C (p = 0.0007). The same applied for acidosis at pH 6.8 (p = 0.003) and pH 7.0 (p = 0.003). There were no signs of synergistic effects of rivaroxaban and temperature or acidosis on CFT. In AA there were signs of synergism at 28 °C (p = 0,001), but not at other tested temperatures or pH levels., Conclusions: The combination rivaroxaban together with hypothermia or acidosis demonstrated inhibitory synergistic effects on haemostasis., Trial Registration: The study was retrospectively registered 2023-03-01 at ClinTrials.gov with NCT05669313., (© 2024. The Author(s).)

Background: Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD., Objectives: We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime., Methods: A cohort of stable CVD patients (N = 40) who participated in the COMPASS trial and were previously randomized to receive aspirin were prospectively recruited and assigned a revised regimen of open-label aspirin plus rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis., Results: The COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up., Conclusion: The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen., Competing Interests: Declaration of competing interests P.B.M., F.N.A., and S.M. received an investigator-initiated research grant from Bayer AG, Germany. All other authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/Objectives : Rivaroxaban and dabigatran are commonly used for thromboembolic disease management in active cancer patients. However, limited research explores the impact of concurrent chemotherapy on the pharmacodynamics of direct oral anticoagulants (DOAC). The aim of our study was to evaluate the impact of combined chemotherapy with rivaroxaban and dabigatran on the pharmacodynamics in patients with diffuse large B-cell lymphoma (DLBCL).; Methods : This was a prospective, pharmacodynamic study. Eligible subjects were ≥18 years old, diagnosed with DLBCL and initiating R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. The enrolled adults received either rivaroxaban (10 mg once daily) or dabigatran etixalate (110 mg twice daily). Plasma anti-factor Xa (FXa) in participants on rivaroxaban and diluted thrombin time (dTT) in participants on dabigatran were assessed over the dosing interval before and after R-CHOP administration. Pharmacodynamic parameters of rivaroxaban and dabigatran were determined using a non-compartmental analysis.; Results : Twenty-six adults participated, with twelve in the rivaroxaban group and fourteen in the dabigatran group. The mean age was 59 ± 14.4 years. In the rivaroxaban group, the AUEC of FXa inhibition showed no significant change after R-CHOP (mean difference 3.8 ng·h/mL, 95% confidence interval (CI) -155.4 to 163.0, p = 0.96). Similarly, in the dabigatran group, the AUEC of dTT remained unchanged post R-CHOP (mean difference 54.41 ng·h/mL, 95% CI -99.09 to 207.9 ng/mL, p = 0.46). However, the median time-to-peak dTT was significantly faster with R-CHOP (3 h, [min-max, 1.5-8] compared to without it (4 h, [min-max, 3-8], p = 0.04); Conclusions : Concurrent R-CHOP chemotherapy did not significantly impact FXa inhibition by rivaroxaban or dTT by dabigatran. The time-to-peak dTT was faster when dabigatran was administered with R-CHOP.

Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), as important metabolic enzymes and transporters, participate in the biological transformation and transport of many substances in the body. CYP3A and P-gp are closely related, with very high substrate overlap and regulation similarity, making it particularly difficult to investigate the function of one or the other individually in vivo. Rivaroxaban and verapamil are commonly used together to treat nonvalvular atrial fibrillation in clinical practice. However, this combination therapy can increase systemic exposure to rivaroxaban and the risk of major bleeding and intracranial hemorrhage. In this study, Cyp3a1/2 and Mdr1a/b quadruple gene knockout (qKO) rat model was generated and characterized for the first time. CYP3A1/2 and P-gp are completely absent in this novel rat model. Then, the qKO rat model was applied for the evaluation of the drug-drug interactions (DDI) between rivaroxaban and verapamil. The results demonstrated that CYP3A and P-gp were jointly and selectively involved in the pharmacokinetic interactions between rivaroxaban and verapamil. This study may provide useful information for understanding the role of CYP3A and P-gp in rivaroxaban-verapamil therapy and predicting the potential interaction between CYP3A and P-gp., 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. Published by Elsevier Inc.)

Background and Objectives: Rivaroxaban is often used in combination with DHI to treat thromboembolic disease. Whether the combination causing HDIs is still unknown. The purpose of this study was to evaluate effects of DHI on pharmacokinetics and pharmacodynamics of rivaroxaban in rats and effects on CYP3A2., Methods: Plasma concentration of rivaroxaban with or without DHI was determined by HPLC. Pharmacokinetics parameters were calculated. Effect of DHI on pharmacodynamics of rivaroxaban was investigated by APTT, PT, TT, FIB, INR, length of tail thrombosis, vWF, t-PA, PAI-1, IL-1β, TNF-α and histopathological sections. Effect of DHI on CYP3A2 in rats was investigated by probe drug method., Results: C max and AUC of rivaroxaban increased significantly in combination group (P < 0.05). APTT, PT, INR and TT increased (P < 0.05), length of tail thrombosis, FIB, vWF, PAI-1, IL-1β and TNF-α of combination group decreased significantly (P < 0.05) compared with rivaroxaban or DHI alone. Histopathologic section of tail thrombus had significant improvement. C max and AUC of dapsone increased (P < 0.05) in DHI group., Conclusion: In summary, DHI is an inhibitor of CYP3A2 and could significantly affect pharmacokinetics and pharmacodynamic of rivaroxaban, enhance anticoagulant and antithrombotic efficacy in rats. However, the combination of rivaroxaban and DHI might lead to potential HDIs. The dosage of rivaroxaban should be adjusted in clinical., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: It is uncertain whether prothrombin complex concentrate (PCC) improves hemostasis in patients on treatment with oral factor Xa-inhibitors (XaI) who require emergency surgery., Objectives: To evaluate whether, in patients with therapeutic levels of oral XaI, preoperative PCC prevents excessive bleeding during and after emergency surgery and is not associated with thrombotic complications., Methods: We conducted a prospective cohort study wherein a fixed 2000 IU dose of 4-factor PCC was given to patients taking oral XaI with plasma XaI levels of at least 75 ng/mL before the emergency surgery with an expected blood loss of at least 50 mL. Patients were followed for 30 days. The primary efficacy outcome was the incidence of normal or mildly abnormal surgical hemostasis, as assessed by the surgeon; primary safety outcome was the incidence of thromboembolic events within 7 days., Results: We included 20 patients, of which 50% were female, on apixaban (75%) or rivaroxaban (25%) with median XaI level of 128 ng/mL (range, 77-497 ng/mL). The median duration of surgery was 2 hours 42 minutes (range, 15 minutes to 8 hours 17 minutes). Normal or mildly abnormal hemostasis was observed in 16 patients (80%); 2 patients had moderately abnormal and 2 had severely abnormal hemostasis, 1 each of those was considered due to local or technical factors. There were 4 deaths (20%) secondary to underlying disease and 1 incidental pulmonary embolism in a patient with cancer., Conclusion: A fixed dose of PCC appears to control hemostasis in patients with therapeutic plasma levels of apixaban or rivaroxaban requiring emergency surgery., Competing Interests: Declaration of competing interests S.S. served on data safety monitoring boards for Alexion, Bayer, Boehringer-Ingelheim, Regeneron, and Sanofi; served on a steering committee for Octapharma; served on event adjudication for Daiichi Sankyo and Takeda. V.B. received honorarium from Bayer. F.G.’s institution received research funding from Novo Nordisk, Roche, Takeda, Bayer, Pfizer, BioMarin, and CSL. R.I. received honoraria for advisory boards for Aspen, LeoPharma, Sanofi, and Inari. P.L.G. is named on a patent, “Novel methods to measure protease inhibitors.” N.C., A.I., S.M., and J.I.W. have no relevant conflicts., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The efficacy of factor Xa inhibitors in patients with atrial fibrillation (AF) and rheumatic heart disease (RHD) is unknown., Methods/results: The objective of this article was to conduct a comprehensive evaluation of the INVICTUS trial, an open-label randomized controlled study that compared vitamin K antagonists (VKA) to rivaroxaban in patients with AF and RHD while also considering the existing evidence from literature in this particular area of research., Conclusion: The findings of the INVICTUS trial indicated that rivaroxaban was found to be inferior in efficacy to VKA. However, it is important to note that the primary outcome of the trial was driven by sudden death and death caused by mechanical pump failure. As a result, it is necessary to approach the data from this study with caution, and it would be inappropriate to draw parallel conclusions for other causes of valvular AF. Particularly, the perplexing issue of how rivaroxaban could have contributed to both pump failure and sudden cardiac death requires further explanation. Additional data regarding changes in heart failure medication and ventricular function would be essential for proper interpretation., (© 2023. The Author(s).)

Background: Bariatric surgery (BS) induces significant changes in gastrointestinal anatomy, potentially influencing the pharmacokinetics of orally administered drugs such as rivaroxaban., Objectives: This phase 1 study aimed to assess the pharmacokinetics and safety of full-dose rivaroxaban in post-BS patients., Methods: The ABSORB (Rivaroxaban Pharmacokinetics and Pharmacodynamics After Bariatric Surgery and in Morbid Obesity) study was a single-center, nonrandomized, multiple-dose, parallel-design bioequivalence trial. Adult patients with stable weight after Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) were compared with subjects with class III obesity and healthy controls. Participants received 20 mg of rivaroxaban daily for 8 days., Results: Post-BS patients exhibited altered rivaroxaban pharmacokinetics, suggesting reduced absorption. Mean area under the concentration-time curve from time 0 to 24 hours after the first dose (RYGB, 1806.8 ng.h/mL; SG, 1648.9 ng.h/mL) was lower compared with that in controls (1893.5 ng.h/mL). At steady state, the area under the concentration-time curve values remained lower in BS groups (RYGB, 2129.9 ng.h/mL; SG, 1946.4 ng.h/mL) than in controls (2224.8 ng.h/mL). The maximum concentration after the first dose was lower in post-RYGB subjects (214.9 ng/mL) than in controls (264.1 ng/mL). This difference was less pronounced at steady state (RYGB, 256.9 ng/mL vs controls, 288.8 ng/mL). Neither BS group met bioequivalence criteria compared with controls, whereas the group with class III obesity met bioequivalence criteria compared with controls at steady state., Conclusion: Rivaroxaban displayed minor pharmacokinetic variations in post-BS patients. Given reported interindividual variability in the general population, these variations are unlikely to be of clinical significance. Our findings support rivaroxaban use in BS patients, emphasizing the need for further research in this area., Competing Interests: Declaration of competing interests J.T. reports personal fees from Sanofi and Viatris outside the submitted work. F.C. reports having received research grant support from Bristol Myers Squibb/Pfizer and Bayer and fees for board memberships or symposia from Bayer, Bristol Myers Squibb/Pfizer, Merck Sharp and Dohme, Sanofi, Leo Pharma, Janssen, and Astra Zeneca and has received travel support from Bayer, Bristol Myers Squibb/Pfizer, Merck Sharp and Dohme, Leo Pharma, Astra Zeneca, Sanofi, and Chiesi. The remaining authors have no known competing interests related to this work., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Objective: There is significant practice variation in the use of antithrombotic therapy after endovascular intervention for lower limb peripheral arterial disease, with differences in medication choice and duration. Prescriber decision making is complex, and patient factors have been shown to substantially contribute to prescribing variation. To determine the influence of patient factors on antithrombotic prescribing, a discrete choice experiment was distributed to vascular surgeons and trainees across Australia and Aotearoa New Zealand., Methods: After pilot testing, the discrete choice experiment questionnaire was distributed to 300 vascular surgeons and trainee members of the Australian and New Zealand Society for Vascular Surgery. Multinomial logistic regression models were used to analyse patient factors that had the most influence on decisions to prescribe a second antithrombotic agent, and the preferred choice of antithrombotic (clopidogrel 75 mg daily or rivaroxaban 2.5 mg twice daily) in addition to aspirin 100 mg daily. The odds ratio (OR) with 95% confidence interval (CI) reported preference strength., Results: A total of 44 questionnaires were completed between September and October 2023, reaching the 15% targeted response rate. Prescribing a second antithrombotic was more likely after femoropopliteal stenting compared with angioplasty (OR 1.89, 95% CI 1.20 - 2.13), and in chronic limb threatening ischaemia compared with intermittent claudication (OR 1.58, 95% CI 1.20 - 2.13). Most respondents preferred clopidogrel over rivaroxaban (62%), with over a third of respondents exclusively prescribing clopidogrel. Patients with stents (OR 1.77, 95% CI 1.32 - 2.37) or moderate bleeding risk (OR 1.38, 95% CI 0.97 - 1.84) were more likely to receive clopidogrel than rivaroxaban., Conclusion: This study demonstrates that vascular surgeons primarily prioritise antithrombotic prescribing decisions by procedure type. Clopidogrel is more likely to be prescribed than rivaroxaban as a second agent in combination with aspirin, especially after stenting. Knowing these clinician preferences can target implementation strategies towards supporting decision making in subgroups of patients according to individual risk profiles., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: In this subanalysis of the EXPAND study, we evaluated the risks and benefits of rivaroxaban plus antiplatelet therapy (APT) for patients with non-valvular atrial fibrillation (NVAF) complicated by stable coronary artery disease (CAD), ischemic stroke, or peripheral artery disease (PAD)., Methods: From the EXPAND study population (n=7,141), patients with NVAF complicated by stable CAD (n=886), ischemic stroke (n=1,231), or PAD (n=160) were included. Patients complicated by any of them were set as ALL (n=2,030). Patients were all treated with rivaroxaban (10 or 15 mg/day) with (+) or without (-) APT. Efficacy outcomes were symptomatic stroke＋systemic embolism (SE), symptomatic stroke＋SE＋myocardial infarction＋cardiovascular death, and all-cause death. Safety outcomes included major and any bleeding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for differences between the APT(+) and APT(-) groups., Results: There were no significant differences in the efficacy outcomes between the APT(+) and APT(-) groups in the ALL cohort or in the CAD and STROKE sub-cohorts. In the PAD subcohort, the HR [95% CI] for all-cause death in the APT(+) group increased (4.43 [1.05-18.71]; p=0.043). In the APT(+) group, the HR [95% CI] for any bleeding increased in the ALL cohort (1.28 [1.01-1.62]; p=0.044) and STROKE subcohort (1.42 [1.01-2.01]; p=0.047), and for major bleeding in the CAD subcohort (2.00 [1.01-3.93]; p=0.046)., Conclusions: Rivaroxaban with APT did not reduce ischemic outcomes in patients with stable CAD or ischemic stroke; however, it did increase the risk of bleeding in patients with stable CAD or ischemic stroke.

Background: Patients undergoing non-major orthopedic surgery often face an increased risk of venous thromboembolism due to the necessity of immobilization postoperatively. Current guidelines commonly recommend the use of low-molecular-weight heparin (LMWH) for prophylaxis, but it is associated with low patient compliance and certain side effects. We conducted a meta-analysis of randomized controlled trials (RCTs) to assess the effectiveness and safety of rivaroxaban or LMWH for thromboprophylaxis following non-major orthopedic surgery., Method: Relevant literature was systematically searched in PubMed, Web of Science, Cochrane Library, and Embase from their inception to October 1, 2023, to evaluate the effectiveness and safety of rivaroxaban or LMWH in RCTs for thromboprophylaxis following non-major orthopedic surgery., Results: A total of 5 randomized controlled trials involving 5,101 patients were included. There was no statistically significant difference in the preventive effect against venous thromboembolism (VTE) when using rivaroxaban or LMWH following non-major orthopedic surgery (RR 0.80; 95%CI 0.31 to 2.07). In terms of safety, there was also no statistically significant difference in the incidence of bleeding events in patients undergoing non-major orthopedic surgery when using rivaroxaban or LMWH (RR 1.15; 95% CI 0.75 to 1.76)., Conclusion: In non-major orthopedic surgery, the risk of venous thromboembolism and bleeding complications is similar when using rivaroxaban or LMWH., (© 2024. The Author(s).)

Objective: Rivaroxaban and dabigatran are approved to reduce the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF). However, the clinical benefits of rivaroxaban and dabigatran in people with high bleeding risk are unclear., Methods: A retrospective study was conducted on NVAF patients admitted to the First Affiliated Hospital of Zhengzhou University from May 31, 2016 to May 31, 2019. These patients had a high risk of bleeding and were taking at least one study medication. The aim of the study was to evaluate clinical benefits by comparing the efficacy and safety risks of these two medications., Results: A total of 1,301 patients with high bleeding risk were enrolled, including 787 patients in the rivaroxaban group and 514 patients in the dabigatran group. Results of the primary efficacy benefit endpoint were obtained from 104 patients (13.21%) in the rivaroxaban group and 81 (15.76%) patients in the dabigatran group [hazard ratio (HR): 0.860; 95% confidence interval (CI): 0.637-1.162; P  = 0.327], this indicates that there was no significant difference between dabigatran and rivaroxaban in preventing stroke and systemic embolism in patients with high bleeding risk NVAF. The principal safety end points were observed in 49 (6.23%) patients in the rivaroxaban group and in 36 (7.00%) patients in the dabigatran group (HR: 0.801 in the rivaroxaban group; 95% CI: 0.512-1.255; P  = 0.333), this indicates that there was no a significant difference in reducing fatal bleeding and critical organ bleeding. With respect to secondary efficacy and benefit endpoints, 28 (3.56%) patients in the rivaroxaban group and 26 (5.06%) patients in the dabigatran group died, with an HR of 0.725 (95% CI: 0.425-1.238; P  = 0.239); 32 (4.07%) patients in the rivaroxaban group; and 31 (6.03%) patients in the dabigatran group had myocardial infarction (MI), with an HR of 0.668 (95% CI: 0.405-1.102, P  = 0.114) in the rivaroxaban group, this indicates that there was no significant difference between dabigatran and rivaroxaban in preventing all-cause death and MI., Conclusions: In NVAF patients with high bleeding risk, there was no significant difference between dabigatran and rivaroxaban in preventing stroke and systemic embolism. There was also no significant difference between dabigatran and rivaroxaban in reducing fatal and critical organ bleeding., Clinical Trial Registration: Chinese Clinical Trials Registry, identifier ChiCTR2100052454., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Liu.)

Concomitant direct oral anticoagulants (DOACs) and tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (anti-VEGF TKI) have been associated with a higher risk of bleeding. Nevertheless, concomitant administration seems frequent in clinical practice in patients with cancer-associated thrombosis and appears to be safe according to the retrospective study by Boileve A. et al. But the risk of an additional pharmacokinetic interaction between anti-VEGF TKI and DOACs must be considered, in case of P-glycoprotein (P-gp) inhibition by the TKI. We describe a case report with a major bleeding event in a renal metastatic cancer patient treated with cabozantinib and rivaroxaban. This case highlights the difficult therapeutic decision in a complex patient with cancer-associated thrombosis, who refused the anticoagulant subcutaneous route. Accumulation of bleeding risk factors (genito-urinary tumor localization) was additive to several pharmacodynamic interactions (acetylsalicylic acid, venlafaxine) and a potential pharmacokinetic interaction between cabozantinib and rivaroxaban. Indeed, cabozantinib-related P-glycoprotein inhibition could have led to a supratherapeutic level of rivaroxaban, contributing partly to the bleeding event. Before combining an anti-VEGF TKI and DOACs, a multidisciplinary pretherapeutic assessment seems crucial to evaluate the patient's bleeding risk factors, pharmacodynamic interactions, and the risk of pharmacokinetic interactions mediated by P-gp., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study aimed to characterize the safety profiles of rivaroxaban-associated suspected adverse events by mining the Food and Drug Administration Adverse Event Reporting System (FAERS)., Methods: A disproportionality analysis of spontaneously reported suspected adverse drug reactions (ADRs) was conducted. The reports in FAERS from 2014 to 2024 were compiled. Frequentist and Bayesian statistics were both applied to calculate drug-AE combinations in system organ classes and preferred-term levels. Reporting odds ratio (ROR), proportional reporting ratio (PRR), the Medicines and Healthcare products Regulatory Agency (MHRA), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) methods were analyzed and used to compare the suspected AEs., Results: Of 77,384 ADR reports, 66,705 (86.20%) were serious rivaroxaban AE reports. The most common age group was above 65 years. The suspected adverse effects of rivaroxaban emerging for system organ classes (SOCs) primarily included "Gastrointestinal disorders"; "Injury, poisoning, and procedural complications", "Nervous system disorders" and "Vascular disorders". Ranked by EBGM, the top signal strength of suspected AE signals of rivaroxaban under ROR algorithm at the preferred-term (PT) level were "Haemorrhagic arteriovenous malformation" ( N = 571, ROR = 756.520, PRR = 754.029, Information Component (IC) = 7.197, Empirical Bayesian Geometric Mean (EBGM) = 146.725), "Gastrointestinal vascular malformation haemorrhagic" ( N = 197, ROR = 211.138, PRR = 210.950, IC = 6.614, EBGM = 97.923), and "Diverticulum intestinal haemorrhagic" ( N = 722, ROR = 169.898, PRR = 169.210, IC = 6.458, EBGM = 97.920). Moreover, uncommon but significantly suspected AE signals, such as "Coagulation factor X level increased", "Basal ganglia haematoma", and "Proctitis haemorrhagic" were observed. Notably, "Gastrointestinal haemorrhage" ( N = 13,436, ROR = 80.477, PRR = 74.460, IC = 5.729, EBGM = 53.042), "Upper gastrointestinal haemorrhage"( N = 2,872, ROR = 73.978, PRR = 72.797, IC = 5.706, EBGM = 52.198) and "Internal haemorrhage" ( N = 2,368, ROR = 91.979, PRR = 80.899, IC = 5.813, EBGM = 56.212) exhibited relatively high occurrence rates and signal strengths. From 2014 to 2024, the IC values of rivaroxaban-associated suspected AEs for "Surgical and medical procedures" and "Cardiac disorders" showed an annual increasing trend in the time-span analysis. Based on the various visulization plots, a key discovery is that "Gastrointestinal hemorrhage" emerged as the most significant suspected AE across five algorithms. The exciting finding was that the MGPS algorithm revealed a higher risk of suspected AEs under the "Investigations" category. However, the results of the analyses of the other algorithms at the SOC level were not akin to this. Moreover, the results of signal mining for the three main types of indication populations with adverse drug reactions (ADRs), including Atrial fibrillation, Cerebrovascular accident prophylaxis, and Deep vein thrombosis were shown that "Gastrointestinal haemorrhage", "Epistaxis", "Haematuria", "Rectal haemorrhage", and "Upper gastrointestinal haemorrhage" were detected as the most common and significant signals of suspected adverse events., Conclusion: Rivaroxaban has risks of various suspected adverse reactions while providing therapeutic effects and being used widely. Our pharmacovigilance study may provide valuable hints that practitioners should closely monitor occurrences of "Gastrointestinal disorders", "Injury, poisoning, and procedural complications" and "Nervous system disorders", and other events in clinical applications. Consequently, it remains to persist in monitoring rivaroxaban, assessing the associated risks in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Wu, Tang, Wang, Wei, Zhang, Li, Li, Wang, Wu and Hong.)

Objective: Despite the beneficial effects of DOACs, suboptimal adherence is widely documented, and real-world adherence is lower than in clinical trials. The objective of this study is to compare the cost-effectiveness of apixaban versus rivaroxaban for stroke prevention by incorporating real-world adherence from the US payer's perspective., Methods: We developed a Markov model with three health states to evaluate the total costs and quality-adjusted life years (QALY) at a willingness to pay threshold of $100,000. The population was a hypothetical cohort of 65-year-old patients with moderate to high stroke risk. The transition probabilities of healthy adherent, nonadherent, and stroke were obtained from a Medicare Advantage Plan. The utilities and costs were obtained from prior clinical studies. Deterministic and probabilistic sensitivity analyses were conducted., Results: Apixaban was cost-effective than rivaroxaban at a willingness to pay threshold of $100,000. Apixaban yielded an additional 0.12 QALYs at a cost of $1904.39, resulting in an incremental cost-effectiveness ratio (ICER) of $16,279.25 per QALY gained. The Monte Carlo simulations indicated that apixaban was cost-effective at 89.67% of simulations. The ICER results were impacted by the medical costs among nonadherent patients., Conclusion: After incorporating adherence, apixaban 5 mg was a cost-effective alternative to rivaroxaban 20 mg for stroke prevention among elderly atrial fibrillation (AF) patients.

Our aim was to compare the performance of complementary clinical laboratory approaches to monitoring exposure to apixaban and rivaroxaban, the most prescribed direct-acting oral anticoagulants (DOAC's): an automated commercial anti-Xa chromogenic assay suitable for emergency and pre-surgery testing and a laboratory-developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method employed for non-emergency analysis in plasma and in dried blood volumetric absorptive microsamples (VAMS) collectible by the patients in their homes. The full validation of the LC-MS/MS method was performed. Cross-validation of the methodologies was accomplished by processing 60 specimens collected for whole blood count and DOAC monitoring in a central clinical laboratory. For VAMS samples, dried plasma and whole blood calibrators were found to be suitable, and a cycle run for seven days could be implemented for rational and economic sample processing. The anti-Xa chromogrenic assay and the LC-MS/MS method delivered discordant plasma analyte concentrations. Moreover, the lack of agreement between plasma and VAMS concentrations was observed. Clinical laboratories must be aware of the differences between the performance of apixaban and rivaroxaban LC-MS/MS and anti-Xa assays. Hematocrit must always be measured along with VAMS samples to obtain accurate results.

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., (© 2024. The Author(s).)

Objective: Assess the safety and efficacy of anticoagulants in treating isolated superficial vein thrombosis (iSVT)., Materials and Methods: A systematic review was conducted according to PRISMA 2020 guidelines, for randomized controlled trials (RCTs) investigating anticoagulants in the treatment of iSVT. The primary endpoint of thrombotic complications encompassed any incident of iSVT progression/recurrence and the development of new-onset (deep vein thrombosis) DVT or (pulmonary embolism) PE., Results: Eight RCT's and 4721 patients treated once daily with either fondaparinux 2.5 mg, rivaroxaban 10 mg, therapeutic, intermediate, and prophylactic low molecular weight heparin (LMW) were included. While all anticoagulants displayed a statistically significant risk reduction compared to placebo in terms of thrombotic complications and iSVT progression/recurrence, only fondaparinux reduced the risk for DVT/PE. Additionally, fondaparinux exhibited enhanced efficacy in decreasing DVT/PE events relative to prophylactic and therapeutic LMWH. Furthermore, rivaroxaban and fondaparinux demonstrated superior outcomes in terms of preventing thrombotic complications compared to all three dosing regimens of LMWH without significant differences between the two, risk ratio RR 1.00(95%CI:0.51-1.92). SUCRA identified fondaparinux as the most effective treatment regarding thrombotic complications, (SUCRA,91.6) and DVT/PE, (SUCRA,96) and rivaroxaban in terms of iSVT progression/recurrence (SUCRA,94.68). Ultimately and despite certain model limitations, meta-regression analysis suggested a possible trend towards improved outcomes with longer treatment durations for thrombotic complications β = -0.34(95%CI:-16.39to12.23)., Conclusions: Despite inherent limitations such as variations in treatment durations and follow-up periods, this review displayed the efficacy of fondaparinux, rivaroxaban and LMWH in treating iSVT. The improved efficacy of fondaparinux over therapeutic LMWH in terms of DVT/PE outcomes necessitates cautious interpretation underscoring the need for further investigation through adequately powered RCTs., 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. Additionally, no funding or grants were received to support this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Direct oral anticoagulants (DOACs) have significant advantages over vitamin K antagonists including lack of need for routine laboratory monitoring. However, assessment of DOAC effect and concentration may be important to guide clinical management including need for DOAC reversal, particularly in acute or emergent situations. In this manuscript, the authors describe tests to screen for DOAC presence and tests that have demonstrated equivalence to gold standard testing for quantifying DOAC exposure. They also discuss the effect of DOACs on other coagulation assays and strategies for monitoring unfractionated heparin in patients with concomitant DOAC exposure., Competing Interests: Disclosure R. C. Gosselin received consulting fees from Sysmex America, Inc. A. Cuker served as a consultant for MingSight, Sanofi, and Synergy and has received authorship royalties from UpToDate. There was no funders or funding sources for this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Direct oral anticoagulants (DOACs) are increasingly prescribed for life-long anticoagulation in chronic thromboembolic pulmonary hypertension (CTEPH) patients, despite not being recommended in the guidelines. This study aims to evaluate the efficacy and safety of DOACs in CTEPH patients., Methods: From May 2013 to December 2022, patients who were first diagnosed with CTEPH in Fuwai Hospital and started long-term anticoagulation treatment with warfarin or DOACs were retrospectively included and followed up until (1) death, (2) transition to other kinds of anticoagulants, or (3) discontinuation of anticoagulation. Propensity score matching was used to balance confounding bias of baseline characteristics. All-cause death, major bleeding, clinically relevant nonmajor bleeding and venous thromboembolism (VTE) recurrence were obtained and analysed., Results: After propensity score matching, 115 patients taking warfarin and 206 patients taking DOACs were included in our study and followed up for 5.5 [3.4, 7.1] years. There was no significant difference of survival between the warfarin and the DOAC group (p = 0.77). The exposure adjusted event rate of major bleeding (0.3 %/person-year vs 0.4 %/person-year, p = 0.705) and clinically relevant nonmajor bleeding (3.1 %/person-year vs 3.2 %/person-year, p > 0.999) was similar between two groups. The exposure adjusted rate of VTE recurrence was significantly higher in the DOAC group (1.5 %/person-year vs 0.3 %/person-year, p = 0.030)., Conclusion: In anticoagulation of CTEPH patients, DOACs have similar survival rate, similar risk of bleeding but higher risk of VTE recurrence than warfarin., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In clinical practice, owing to the comprehensive genetic insights they offer, haplotypes have attracted greater attention than individual single nucleotide polymorphisms (SNPs). Due to the long distances across SNP locations, detecting the haplotype using genomic DNA is challenging. Current haplotyping methods are either expensive and labor-intensive (high-throughput DNA sequencing), or haplotyping a single clinical sample (computational approach) is impossible. Herein, we propose using mRNA as a haplotyping target to minimize the distance among SNPs and employing allele-specific PCR (AS-PCR) to pick up a desired haplotype, followed by multiplex pyrosequencing to type the alleles at the SNP location of interest. AS-PCR was improved by combining an additional 3'-phosphorylated modified probe to achieve the specific separation of two closely similar templates. Only the sample with more than two heterozygotes needs to be haplotyped; therefore, we propose a stratification strategy to screen the samples for further haplotyping. This method was evaluated by associating ABCB1 haplotypes with the rivaroxaban-derived side effect in a cohort of 505 patients with nephrotic syndrome, focusing on the SNPs of ABCB1: rs1236C > T, rs2677G > T/A, and rs3435C > T. We successfully identified five bleeding-related haplotypes: rs1236T-rs2677T-rs3435T, rs1236C-rs2677G-rs3435T, rs1236T-rs2677G-rs3435C, rs1236C-rs2677G-rs3435C, and rs1236T-rs2677T-rs3435C. We compared the results with those from the conventional computational algorithm PHASE and observed that PHASE results dismissed the impact of rs1236C-rs2677G-rs3435C and rs1236C-rs2677G-rs3435T on bleeding risk and erroneously suggested a false positive association of rs1236C-rs2677A-rs3435T with increased bleeding risk., 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 B.V. All rights reserved.)

Despite a higher safety profile compared to vitamin K antagonists, rivaroxaban therapy is still connected with multiple adverse effects, such as a high risk of bleeding. Thus, therapeutic drug monitoring (TDM) of rivaroxaban concentrations is suggested. An alternative to plasma samples can be dried blood spots (DBS), which minimize the cost of sample storage and transport. In this study, we developed a UPLC-MS/MS method for the analysis of rivaroxaban in DBS and plasma samples. Chromatographic separation was achieved on a Zorbax Eclipse Plus C18 column (2.1 × 100 mm; 3.5 µm, Agilent Technologies Inc., Santa Clara, CA, USA) with a mobile phase consisting of water and acetonitrile, both containing 0.1% formic acid. The analytes were detected using a positive ionization mode by multiple reaction monitoring. We validated the method according to ICH guidelines. The precision and accuracy were satisfactory. Extraction recovery was approximately 57% and 66% for DBS and plasma samples, respectively. A high correlation between rivaroxaban concentrations in plasma and DBS samples collected from patients was confirmed with Deming regression. The suitability of both sampling techniques for the rivaroxaban TDM was also verified by Bland-Altman plots based on DBS-predicted and observed plasma concentrations. In addition, we found a significant relationship between rivaroxaban concentrations and coagulation parameters, including prothrombin time (PT) and international normalized ratio (INR).

Objectives: To evaluate the perioperative morbidity and mortality associated with direct oral anticoagulants (DOACs) and warfarin for patients receiving transurethral resection of prostate (TURP)., Patients and Methods: This was a single-centre, retrospective cohort analysis of patients who underwent TURP for benign prostate hyperplasia from April 2019 to December 2023. The primary objective was to evaluate the perioperative bleeding and thromboembolic risk between anticoagulated (AC) vs no-AC patients. The secondary objective was to evaluate perioperative bleeding and thromboembolic risk between different formulations of DOACs. Patient demographics, prior treatment, prostate size, baseline bleeding risk, and operative details were collected. Bleeding and thromboembolic-related morbidity were captured within a 3-month postoperative period. Perioperative management of AC therapy was recorded, and all patients had their AC therapy withheld. Cohort characteristic between the AC vs no-AC, and DOAC groups were analysed with two-sided t-test, and chi-square test. Further logistic regression analyses were carried out to identified significant variables between the groups. These significant variables were used for adjustment in inverse probability-weighted treatment effect analysis to evaluate bleeding risk., Results: There were 629 patients in the cohort, and 113 (18%) patients were receiving AC therapy. The AC patients were at 1.6 times statistically significant increased risk of acute bleeding, and 11 times increased risk of prolonged haematuria for >14 days. When compared to apixaban, patients on rivaroxaban conferred a statistically significant increased risk of acute bleeding by 2.21 times. Patients receiving AC therapy had a statistically significant increased risk of stroke in the perioperative setting (no-AC vs AC: 0.4% vs 2.7%, P = 0.01)., Conclusion: This is the first study to evaluate risk of bleeding for TURP patients receiving DOACs. The AC patients are more likely to experience haematuria and stroke in the perioperative period despite withholding therapy. Apixaban appears to cause less bleeding-related complications than rivaroxaban., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Rivaroxaban 2.5 mg plus aspirin reduced limb and cardiovascular events and increased bleeding in patients with symptomatic peripheral artery disease (PAD) after lower extremity revascularization in the VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) study. Fragile patients are at heightened risk for ischemic and bleeding events., Objectives: The purpose of this study was to investigate the safety and efficacy of rivaroxaban 2.5 mg in fragile patients from VOYAGER PAD., Methods: Patients were categorized as fragile based on prespecified criteria (age >75 years, weight ≤50 kg, or baseline estimated glomerular filtration rate <50 mL/min/1.73 m 2 ). The primary efficacy outcome was the composite of acute limb ischemia, major amputation of a vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was TIMI major bleeding., Results: Of 6,564 randomized patients, a total of 1,674 subjects were categorized as fragile at baseline. In the placebo arm, fragile patients were at higher risk of the primary outcome (HR: 1.34; 95% CI: 1.12-1.61) and TIMI major bleeding (HR: 1.57; 95% CI: 0.83-2.96), compared with nonfragile patients. The effect of rivaroxaban on the primary endpoint was not modified by frailty status (fragile HR: 0.93; 95% CI: 0.75-1.15; nonfragile HR: 0.83; 95% CI: 0.72-0.97; P interaction = 0.37). Rivaroxaban increased TIMI major bleeding in fragile (HR: 1.54; 95% CI: 0.82-2.91) and nonfragile patients (HR: 1.37; 95% CI: 0.84-2.23; P interaction = 0.65)., Conclusions: Patients with PAD after lower extremity revascularization meeting fragile criteria are at higher risk of ischemic complications and bleeding. Rivaroxaban reduces ischemic risk and increases bleeding regardless of frailty status. These data may assist in personalization of antithrombotic therapy in fragile population., Competing Interests: Funding Support and Author Disclosures VOYAGER PAD was funded by Bayer and Janssen Pharmaceuticals. The Colorado Prevention Center Clinical Research held the database and performed all analyses, and the decision to submit this manuscript for publication was made by the VOYAGER PAD Publications Committee. Drs Canonico, Low Wang, Hsia, Nehler, Capell, Berkowitz, and Bonaca receive salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding between July 2021 and July 2023 from the following organizations: Abbott Laboratories, Agios Pharmaceuticals, Inc, Alexion Pharma Godo Kaisha, Amgen Inc, Anthos Therapeutics, Inc, ARCA biopharma, Inc, AstraZeneca Pharma India, AstraZeneca Pharmaceuticals LP, AstraZeneca UK Ltd, AstraZeneca Produtos Farmaceuticos, Lda, Atentiv, LLC, Bayer, Bayer (Proprietary) Limited, Bayer Aktiengesellschaft, Bayer Pharma AG, Beth Israel Deaconess Medical Center, Better Therapeutics, Boston Clinical Research Institute, LLC, Bristol Myers Squibb, CellResearch Corporation Pte Ltd, Cleerly, Inc, Colorado Department of Public Health and Environment, Cook Regentec LLC, CSL Behring LLC, Eidos Therapeutics, Inc, EPG Communication Holdings Ltd, Esperion Therapeutics, Inc, Faraday Pharmaceuticals, Inc, HeartFlow Inc, Insmed, Ionis Pharmaceuticals, IQVIA Inc, Janssen Pharmaceuticals, Inc, Janssen Research and Development, LLC, Janssen Scientific Affairs LLC, Lexicon Pharmaceuticals, Inc, LSG Corporation, MedImmune Limited, Medpace, Inc, Medscape, Merck Sharp and Dohme Corp, Nectero Medical Inc, Novartis Pharmaceuticals Corporation, Novo Nordisk, Osiris Therapeutics, Inc, Pfizer, PPD Development, LP, Prothena Biosciences Limited, Regeneron, Regents of the University of Colorado (aka UCD), Sanifit Therapeutics SA, Sanofi, Silence Therapeutics PLC, Stanford University, Stealth BioTherapeutics Inc, The Brigham and Women's Hospital, Inc, Thrombosis Research Institute, University of Colorado Denver, University of Pittsburgh, VarmX, and WraSer, LLC. Dr Hsia owns stock in AstraZeneca. Dr Debus has received grant support from Cook and Terumo Aortic. Dr Patel has received grant support, advisory board fees, and consulting fees from AstraZeneca, Bayer, and Janssen; has received grant support from Medtronic and Philips Healthcare; and has received grant support and advisory board fees from Heartflow. Dr Anand has received lecture fees from Bayer and Janssen. Dr Muehlhofer was employed by Bayer. Dr Haskell was employed by Janssen Pharmaceuticals; and has owned stock in Johnson and Johnson. Dr Berkowitz was employed by Bayer during the operationalization of the VOYAGER PAD study. Dr Bauersachs has received consulting fees and lecture fees from Bayer, Bristol Myers Squibb, and Pfizer. Dr Bonaca has received support from the AHA SFRN under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project); and has stock in Medtronic and Pfizer. Dr Ycas has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Intracranial pial arteriovenous fistulas (PAVFs) are uncommon neurovascular anomalies that primarily affect the pediatric population. PAVFs are often linked to hereditary hemorrhagic telangiectasia, yet the specific genetic mutations remain unidentified. While endovascular embolization is the preferred treatment for PAVFs, complications like hydrocephalus and sinus thrombosis pose challenges in management., Observations: The authors present a rare case of PAVF in a 6-month-old male neonate with a hereditary GDF2 mutation, where the fistula was supplied by the posterior inferior cerebellar artery and drained directly into the sigmoid sinus. The PAVF was effectively treated with endovascular embolization using coils and Onyx. Furthermore, the authors describe the successful use of rivaroxaban in managing subsequent sinus thrombosis after the embolization of PAVFs. Additionally, the authors review treatment strategies and complications following fistula disconnection., Lessons: Endovascular embolization is the primary treatment choice for the majority of pediatric PAVFs, while a hereditary GDF2 mutation is considered a potential contributing factor to the formation of these malformations in children. Rivaroxaban has shown promise as an effective therapeutic option for pediatric sinus thrombosis, supported by its established safety profile. https://thejns.org/doi/10.3171/CASE24182.

Background: Despite many atrial fibrillation (AF) patients being at risk of bleeding, very limited data are available on bleeding rates of different direct oral anticoagulants based on the spectrum of bleeding risk., Objective: We aimed to compare the risk of major bleeding and thromboembolic events with apixaban vs rivaroxaban for AF patients stratified by bleeding risk., Methods: We conducted a population-based, retrospective cohort study of all adult patients (66 years or older) with AF in Ontario, Canada, who were treated with apixaban or rivaroxaban between April 1, 2011, and March 31, 2020. Bleeding risk was estimated by the HAS-BLED score, with high bleeding risk defined as a score of ≥3. The primary safety outcome was major bleeding, and the primary efficacy outcome was thromboembolic events. Comparisons were adjusted for baseline comorbidities by inverse probability of treatment weighting., Results: This study included 18,156 AF patients with high bleeding risk and 55,186 AF patients with low bleeding risk. Apixaban use was more common in patients with high bleeding risk; 63% of high-risk patients used apixaban compared with 56% of low-risk patients. Apixaban users had lower rates of major bleeding in high-risk patients (2.9% vs 4.2% per year; hazard ratio [HR], 0.69; 95% CI, 0.58-0.81) and in low-risk patients (1.8% vs 2.9% per year; HR, 0.63; 95% CI, 0.56-0.70) compared with rivaroxaban. There were no differences in rates of thromboembolic events, 3.1% vs 3.0% per year (HR, 1.02; 95% CI, 0.86-1.22) in high-risk patients and 1.9% vs 1.9% per year (HR, 1.00; 95% CI, 0.89-1.14) in low-risk patients., Conclusion: In older AF patients with high or low bleeding risk, treatment with apixaban was associated with lower rates of major bleeding with no difference in risk for thromboembolic events compared with rivaroxaban., Competing Interests: Disclosures 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 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Thromboembolism is a recognized complication of nephrotic syndrome (NS). Evidence supporting the use of rivaroxaban to prevent NS-related thrombosis is limited and controversial. This study aimed to explore the impact of NS on rivaroxaban pharmacokinetics and to collect observational data on the efficacy and safety of rivaroxaban as primary thromboprophylaxis in patients with NS., Methods: This prospective study analyzed 141 patients with NS who received rivaroxaban (10 mg/day) for thromboprophylaxis. High-performance liquid chromatography-tandem mass spectrometry was used to measure the trough and peak plasma concentrations (C trough and C max ) of rivaroxaban. The influence of clinical and genetic factors on these concentrations was examined using multivariate logistic regression., Results: The median C max and C trough were 68.5 ng/mL (interquartile range [IQR], 31.7-105.5 ng/mL) and 4.4 ng/mL (IQR, 1.2-11.9 ng/mL), respectively. The incidence of thromboembolic events (TEs) was 12.8%, while that of bleeding events was 14.2%, although all were classified as minor. Albumin level was the most significant factor affecting C max (ρ = 0.55; p < 0.001) and was also significantly associated with TEs (0.81; 0.71-0.91 per 1.0 g/dL increase; p = 0.001) and bleeding risks (1.11; 1.03-1.19 per 1.0 g/dL increase; p = 0.008). Single nucleotide polymorphisms in the ABCB1 gene significantly influenced C trough but were not associated with clinical outcomes., Conclusion: Hypoalbuminemia significantly affects the pharmacokinetics of rivaroxaban in NS patients. A dose-adjustment strategy based on rivaroxaban concentrations, accounting for variable albumin levels, may improve the safety and efficacy of thromboprophylaxis in this population., Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Conversion to neovascular disease in patients with non-neovascular age-related macular degeneration (AMD) initiated on direct oral anticoagulants (DOACs) compared with matched patients treated with warfarin., Design: Retrospective cohort study., Participants: The study included 20 300 patients and 13 387 patients with non-neovascular AMD initiated on DOACs or warfarin, respectively, before propensity score matching (PSM)., Methods: TriNetX was used to identify patients diagnosed with non-neovascular AMD stratified by treatment with DOACs or warfarin with at least 6 months of follow-up. Propensity score matching was performed to control for baseline demographics and medical comorbidities., Main Outcome Measures: Relative risk (RR) of developing neovascular AMD, macular hemorrhage (MH), vitreous hemorrhage (VH), and requiring an ocular intervention (intravitreal anti-VEGF therapy or pars plana vitrectomy [PPV]) within 6 months and 1 year. Patients with chronic atrial fibrillation (AF) on anticoagulation were separately evaluated for the same measures within 5 years after initiating therapy., Results: Treatment with warfarin was associated with a higher risk of developing neovascular AMD at 6 months (RR, 1.24, 95% confidence interval [CI], 1.12-1.39; P < 0.001) and 1 year (RR, 1.26, 95% CI, 1.14-1.40; P < 0.001) when compared with matched patients treated with DOACs. There was an increased risk of requiring intravitreal anti-VEGF therapy (6 months: RR, 1.30; 95% CI, 1.13-1.49; P < 0.001; 1 year: RR, 1.31, 95% CI, 0.72-2.05; P < 0.001) and PPV (6 months: RR, 2.13; 95% CI, 1.16-3.94; P = 0.01; 1 year: RR, 2.29, 95% CI, 1.30-4.05; P = 0.003). Among patients with AMD and AF treated with warfarin, there was an increased risk of ocular complications (neovascular AMD: RR, 1.25; 95% CI, 1.14-1.38; P < 0.001; MH: RR, 1.86; 95% CI, 1.47-2.35; P < 0.001; VH: RR, 2.22; 95% CI, 1.51-3.26; P < 0.001) and need for intravitreal anti-VEGF therapy (RR, 1.34; 95% CI, 1.18-1.52; P < 0.001) over an extended 5-year period. There was no significant difference in the development of major systemic hemorrhagic events between the 2 cohorts over 5 years., Conclusions: Patients with non-neovascular AMD treated with warfarin were more likely to develop neovascular disease and require ocular intervention for hemorrhagic complications when compared with matched patients initiated on DOACs., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: New-onset postoperative atrial fibrillation (POAF) is a common complication after coronary artery bypass grafting (CABG) surgery, increasing the risk of embolism and stroke. There is a lack of information on the use of anticoagulants in this context. The choice between Warfarin and Direct oral anticoagulants (DOACs) also is not well-established. This randomized study aimed to compare the feasibility and safety of Warfarin and Rivaroxaban in preventing thrombotic events in POAF patients after isolated CABG., Methods: A total of 66 patients were randomized parallelly with 1:1 allocation to receive either Rivaroxaban (n = 34) or Warfarin (n = 32). Major bleeding events within 30 days after discharge were the primary outcome. Secondary outcomes included minor bleeding events and thrombotic episodes. Clinical characteristics, medication regimens, and left atrial diameter were assessed. Statistical analyses were performed using appropriate tests., Results: No thrombotic episodes were observed in either treatment arm. No major bleeding events occurred in either group. Four minor bleeding events were reported, with no significant difference between the treatment groups (P = 0.6). Patients with atrial fibrillation had significantly larger left atrial diameters compared to those with normal sinus rhythm (40.5 vs. 37.8 mm, P = 0.01)., Conclusions: This pilot study suggests that Warfarin and Rivaroxaban are both safe and effective for preventing thrombotic episodes in POAF patients after isolated CABG. No significant differences in major bleeding events were observed between the two anticoagulants. These findings may support the preference for DOACs like Rivaroxaban due to their convenience and easier maintenance., Trial Registration: Number IRCT20200304046696N1, Date 18/03/2020 https//irct.behdasht.gov.ir/ ., (© 2024. The Author(s).)

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., (© 2024 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Background: No study has investigated the perioperative management and clinical outcomes in patients who are receiving rivaroxaban 2.5 mg twice a day and acetylsalicylic acid (ASA) 81 to 100 mg daily., Objective: To assess perioperative management and outcomes in patients who are receiving low-dose rivaroxaban, 2.5 mg twice-daily, and low-dose ASA, 81 to 100 mg daily. To assess perioperative management and outcomes in patients who are receiving low-dose rivaroxaban, 2.5 mg twice-daily, and low-dose ASA, 81 to 100 mg daily., Methods: Subanalysis of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial was performed to assess perioperative management and clinical outcomes in patients with stable coronary or peripheral artery disease who were randomized to receive rivaroxaban 2.5 mg twice a day plus ASA 100 mg daily, rivaroxaban 5 mg twice a day, or ASA 100 mg daily. Patients studied required a surgery/procedure during the trial. The study outcomes, which included myocardial infarction, angina, stroke, acute limb ischemia, bleeding, and death, were assessed according to treatment allocation., Results: There were 2632 patients studied (mean age, 68 years; 80% male) who had a surgery/procedure, comprising percutaneous coronary interventions (∼43%), carotid or other arterial angioplasty (∼15%), pacemaker or internal cardiac defibrillator implantation (∼9%), and coronary artery bypass graft surgery (∼7%). Perioperative study drug management varied, with about one-third of patients not interrupting study drug and the remainder interrupting it between 1 and ≥10 days preprocedure. The incidences of adverse outcomes across treatment groups were 12.7% to 15.3% for myocardial ischemia, 0.8% to 1.2% for stroke, 0.1% to 0.2% for venous thromboembolism, and 3.1% to 4.2% for any bleeding. There was no statistically significant difference in outcome rates across treatment groups., Conclusion: In patients in the COMPASS trial who required a surgery/procedure, there was no significant difference in perioperative adverse outcomes whether patients were receiving rivaroxaban 2.5 mg twice a day and ASA 100 mg daily, rivaroxaban 5 mg twice a day, or ASA alone., Competing Interests: Declaration of competing interests There was no funding provided for the development and for any other aspect of the work in this manuscript. J.D.D. reports consulting and lecture honoraria from Servier Canada, Leo Pharma, Pfizer, and Fresinius Kabi. Q.L. reports no disclosures. D.L.B. reports advisory for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys and research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio. E.M. reports being employed as a global clinical lead by Bayer AG, Germany. M.K.W. reports no disclosures. S.C. reports grants from Bayer AG and personal fees from BMS, Pfizer, Portola, Boehringer Ingelheim, Servier, Daiichi Sankyo, and Medtronic. S.Y. reports grants and personal fees from Bayer, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, and Cadila. A.P.M. reports receiving personal fees from Bayer, AstraZeneca, and Novartis. J.W.E. reports grants and/or personal fees from Anthos, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Idorsia, Janssen, Astra Zeneca, Eli Lilly, GlaxoSmithKlein, and Sanofi Aventis., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Rivaroxaban is a direct oral anticoagulant approved for therapeutic and prophylactic anticoagulation in both adults and children. Studies on rivaroxaban use in pediatric patients with congenital heart disease (CHD) are limited. Currently, warfarin (oral) and enoxaparin (injection) are the primary options for pediatric outpatient anticoagulation. Rivaroxaban may be a less burdensome alternative, but its use has not been well described in the pediatric CHD population. We describe our single-center experience. From May 2020-July 2022, we identified all pediatric CHD patients started on rivaroxaban. Dosing was based on recommendations reported in the EINSTEIN-Jr (Male et al. in Lancet Haematol 7:e18-e27, 2020) and UNIVERSE study (McCrindle et al. in J Am Heart Assoc 10:e021765, 2021) protocols. Qualitative outcomes on safety and efficacy are reported. There were 27 patients studied with an age range of 4 months-15 years at time of medication initiation. Single ventricle heart disease was present in 70% (19/27) of patients. Of the 27 patients initiated on rivaroxaban, 15 (56%) were started for VTE prophylaxis and 12 (44%) were started for VTE treatment. No patients started on rivaroxaban for prophylaxis developed a VTE. There was resolution or lack of propagation in 10 of the 12 patients started for treatment. There were two clinically relevant bleeding episodes. Our single-center case series describes the experience with rivaroxaban for VTE prophylaxis and treatment in pediatric congenital heart disease. Larger studies are required to further investigate safety, efficacy, and use indications., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Post-thrombotic syndrome (PTS) is common in patients with deep vein thrombosis (DVT). It is unclear if different types of anticoagulant therapies (e.g. vitamin K antagonists (VKA), direct oral anticoagulants (DOACs) or low molecular weight heparin (LMWH)) are associated with different risks of PTS. We sought to assess the incidence rates of PTS development following a proximal DVT of the lower extremity managed with different types of anticoagulation regimens., Methods: A systematic search of MEDLINE, EMBASE and PubMed, from inception to June 2023 was performed. The primary outcome was development of PTS. The secondary outcomes included severe PTS, venous ulcers, and major bleeding. Incidence rates were pooled using the random effects model and expressed as event per 100 patient-years with its associated 95 % confidence intervals (CI) using R software., Results: A total of 21 (4342 patients) articles were included in the analysis. The adjusted pooled incidence of PTS was 15.1 (95 % CI: 8.7 to 26.1), 18.2 (95 % CI: 9.4 to 35.1) and 24.6 (95 % CI: 9.2 to 65.5) per 100 patient-years patients managed with VKA, DOAC and LMWH, respectively. The adjusted pooled incidence of severe PTS was 5.1 (95 % CI: 2.6 to 10.0) and 0.2 (95 % CI: 0.01 to 2.7) per 100 patient-years for VKAs and DOACs, respectively., Conclusions: The development of PTS is common in patients with proximal lower extremity DVT. The incidence rates of PTS seem to be similar across the different anticoagulation regimens, but severe PTS may be lower among patients receiving a DOAC., Competing Interests: Declaration of competing interest M. Carrier has received research funding from BMS, Pfizer, and Leo Pharma, and honoraria from Bayer, Pfizer, BMS, Servier, and Leo Pharma. A. Delluc reports grants from Leo Pharma and Pfizer, personal fees from BMS, Leo Pharma, Pfizer, Servier. C Brown and L Tokessy have no relevant conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Treating cancer-associated venous thromboembolism (CAT) with anticoagulation prevents recurrent venous thromboembolism (rVTE), but increases bleeding risk., Objectives: To compare incidence of rVTE, major bleeding, and all-cause mortality for rivaroxaban versus low molecular weight heparin (LMWH) in patients with CAT., Methods: We developed a cohort study using Swedish national registers 2013-2019. Patients with CAT (venous thromboembolism within 6 months of cancer diagnosis) were included. Those with other indications or with high bleeding risk cancers were excluded (according to guidelines). Follow-up was from index-CAT until outcome, death, emigration, or end of study. Incidence rates (IR) per 1000 person-years with 95% confidence interval (CI) and propensity score overlap-weighted hazard ratios (HRs) for rivaroxaban versus LMWH were estimated., Results: We included 283 patients on rivaroxaban and 5181 on LMWH. The IR for rVTE was 68.7 (95% CI 40.0-109.9) for rivaroxaban, compared with 91.6 (95% CI 81.9-102.0) for LMWH, with adjusted HR 0.77 (95% CI 0.43-1.35). The IR for major bleeding was 23.5 (95% CI 8.6-51.1) for rivaroxaban versus 49.2 (95% CI 42.3-56.9) for LMWH, with adjusted HR 0.62 (95% CI 0.26-1.49). The IR for all-cause mortality was 146.8 (95% CI 103.9-201.5) for rivaroxaban and 565.6 (95% CI 541.8-590.2) for LMWH with adjusted HR 0.48 (95% CI 0.34-0.67)., Conclusions: Rivaroxaban performed similarly to LMWH for patients with CAT for rVTE and major bleeding. An all-cause mortality benefit was observed for rivaroxaban which potentially may be attributed to residual confounding., Trial Registration Number: NCT05150938 (Registered 9 December 2021)., (© 2024. The Author(s).)

Background: Rivaroxaban and amiodarone are commonly used for treating patients with atrial fibrillation. Drug-drug interactions between rivaroxaban and amiodarone may increase exposure to rivaroxaban. However, the clinical relevance of this drug-drug interaction is still not clear., Objective: The aim was to investigate the risk of bleeding in patients receiving a combination of rivaroxaban and amiodarone., Methods: This was a prospective observational study in which we included atrial fibrillation patients treated with rivaroxaban. The patients were divided into the rivaroxaban group and the combination of rivaroxaban and amiodarone group (the combination group). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to adjust between-group differences. The primary endpoint was defined as the time to the first occurrence of a composite of major, clinically relevant nonmajor, and minor bleeding., Results: In total, 481 atrial fibrillation patients were included in the analysis. After PSM, 154 patients in the rivaroxaban group were matched with 154 patients in the combination group. The bleeding events mainly consisted of clinically relevant nonmajor and minor bleeding. Only one patient experienced major bleeding. The primary outcome was recorded in 26.0% of patients in the combination group and 10.4% of patients in the rivaroxaban group (hazard ratio = 2.76, 95% CI = 1.55-4.93, P < 0.001). The bleeding risk was significantly higher in the combination group compared with that in the rivaroxaban group in the IPTW and stabilized IPTW analyses (hazard ratio = 2.17, 95% CI = 1.32-3.56, P = 0.002)., Conclusion and Relevance: The combination of rivaroxaban and amiodarone increased the risk of bleeding in patients with atrial fibrillation, especially clinically relevant nonmajor and minor bleeding. Physicians prescribing rivaroxaban and amiodarone together should be concerned about an increase in the risk of nonmajor 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.

Background: Direct oral factor (F)Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity., Objectives: The ability of FXa variants to bypass the direct oral FXa inhibitors was assessed., Methods: Human FXa variants were generated through substitution of phenylalanine 174 (F174) for either alanine, isoleucine, or serine. FXa variants were stably expressed in HEK293 cells and purified to homogeneity using ion-exchange chromatography., Results: F174-substituted human FX variants demonstrated efficacy in restoring thrombin generation in plasma containing direct FXa inhibitors (apixaban, rivaroxaban, edoxaban). Their ability to bypass the anticoagulant effects stems from a significantly reduced sensitivity for the direct FXa inhibitors due to a decrease in binding affinity determined using molecular dynamics simulations and free energy computation. Furthermore, F174 modification resulted in a partial loss of inhibition by tissue factor pathway inhibitor, enhancing the procoagulant effect of F174-substituted FX. Consequently, the F174A- and F174S-substituted FX variants effectively counteracted the effects of 2 widely used anticoagulants, apixaban and rivaroxaban, in plasma of atrial fibrillation and venous thromboembolism patients., Conclusion: These human FX variants have the potential to serve as a rescue reversal strategy to overcome the effect of direct FXa inhibitors in case of life-threatening bleeding events or emergency surgical interventions., Competing Interests: Declaration of competing interests P.H.R. and D. Verhoef own equity in VarmX B.V. T.M.H. and S.T. own equity in Coagulation Profile B.V. M.H.A.B. has received consultancy fees from VarmX B.V. (all fees to the institution) and is inventor on intellectual property related to this work. The remaining authors declare no competing financial interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Once considered relatively benign, superficial vein thrombosis (SVT) of the lower limbs is linked to deep vein thrombosis (DVT) or pulmonary embolism (PE) in up to one fourth of cases. Treatment goals include alleviating local symptoms and preventing SVT from recurring or extending into DVT or PE. Fondaparinux 2.5 mg once daily for 45 days is the treatment of choice for most patients with SVT. Potential alternatives include intermediate-dose low-molecular-weight heparin or the direct oral factor Xa inhibitor rivaroxaban, however, these require further evidence. Despite these treatment options, significant gaps remain, including the role of systemic or topical anti-inflammatory agents alone or combined with anticoagulants, and the optimal duration of anticoagulation for patients at varying risk levels. Additionally, the efficacy and safety of factor Xa inhibitors other than rivaroxaban, management of upper extremity SVT, and optimal treatment for SVT near the sapheno-femoral or sapheno-popliteal junctions are not well understood. This narrative review aims to summarize current evidence on anticoagulant treatment for SVT, highlight key unmet needs in current approaches, and discuss how ongoing studies may address these gaps.

This study aimed to investigate the impact of the drug-drug interaction between rivaroxaban and amiodarone on the clinical outcomes in patients with non-valvular atrial fibrillation (NVAF), focusing on pharmacokinetic and pharmacodynamic (PK/PD) aspects. A prospective study enrolling 174 patients with NVAF who were treated with rivaroxaban was conducted. The patients were divided into two groups based on postoperative antiarrhythmic and anticoagulation strategies: the rivaroxaban group (Control group) and the rivaroxaban plus amiodarone group (Riv/Amio group). The trough plasma concentrations (C trough ) of rivaroxaban, activated partial thromboplastin time (APTT), prothrombin time (PT), and the clinical outcomes between the two groups were compared. Patients receiving 20 mg of rivaroxaban in the Riv/Amio group had a higher concentration of rivaroxaban C trough than those in the Control group ( p = 0.009). Furthermore, in patients with moderate to severe renal impairment, rivaroxaban C trough was significantly increased in the Riv/Amio group. There was no significant difference in PT and APTT between the two groups. Regarding the clinical outcomes, the combination of rivaroxaban and amiodarone medication was associated with a higher incidence of bleeding events ( p = 0.041; HR = 2.83, 95% CI 1.05-7.66) and clinically relevant non-major bleeding ( p = 0.021; HR = 3.65, 95% CI 1.21-10.94). Finally, independent risk factors for bleeding in NAVF patients treated with rivaroxaban were identified as its combination with amiodarone ( p = 0.044; OR = 2.871, 95% CI 1.028-8.023). The combination of rivaroxaban and amiodarone led to changes in rivaroxaban pharmacokinetics and an elevated risk of bleeding events. Therefore, physicians prescribing rivaroxaban medications should assess the potential bleeding risk associated with the concurrent use of amiodarone, particularly in patients with renal impairment.

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 < 0.001]. There does not appear to be a relevant effect of vitamin K inhibition by the vitamin K antagonist marcumar upon coronary calcification., (© 2024. The Author(s).)

Key Clinical Message: The precise management of hypersensitivity reactions to direct oral anticoagulants (DOACs) and the potential for cross-reactivity among different DOACs remain unclear. In such cases, switching between DOACs may be feasible and could be considered, but close monitoring for adverse effects is essential, tailored to individual patient responses and tolerability., Abstract: Hypersensitivity reactions to DOACs, though considered rare, have been documented. This report describes the case of a 28-year-old male with a history of testicular cancer who was recently diagnosed with deep vein thrombosis. He was referred to an outpatient pharmacotherapy clinic due to suspected rivaroxaban-induced cutaneous reactions. Following a thorough evaluation, his anticoagulant therapy was switched from rivaroxaban to apixaban. This change was successfully implemented, and no hypersensitivity symptoms recurred during subsequent follow-up. This case demonstrates the importance of recognizing potential adverse reactions to DOACs and illustrates the feasibility of switching anticoagulants under close medical supervision to ensure patient safety and effective treatment., Competing Interests: All listed authors were enabled access to relevant data and had a role in writing the manuscript. This project received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: In lung transplant patients, direct oral anticoagulants are often taken in combination with immunosuppressive drugs such as tacrolimus. Since tacrolimus is a substrate and inhibitor of the efflux protein ABCB1, also transporting direct oral anticoagulants, a possible drug-drug interaction mediated by competition for this transporter needs to be investigated., Objectives: To determine the in vitro effect of tacrolimus on ABCB1-mediated rivaroxaban transport in order to support clinician practice., Methods: Recombinant cell line models, based on human embryonic kidney 293 cells, were generated by a stable transfection process to overexpress ABCB1 or not (control cells). The impact of tacrolimus on ABCB1-mediated rivaroxaban transport was assessed by accumulation experiments., Results: ABCB1 expression decreased the cellular accumulation of rivaroxaban and tacrolimus at their respective clinically relevant concentrations when compared with control cells. This confirms the involvement of ABCB1 in the active transport of tacrolimus and rivaroxaban. However, tacrolimus had no significant influence on rivaroxaban disposition at those clinically relevant concentrations., Conclusion: Our study does not provide evidence for a possible interaction between tacrolimus and rivaroxaban when used together in practice., (© 2024 The Authors.)

Direct oral anticoagulants (DOACs) are widely used in cardiovascular medicine. Although rivaroxaban has potential benefits for anticoagulation in certain contexts, DOACs remain contraindicated in patients with mechanical heart valves. This case report highlights the life-threatening risks of rivaroxaban use in patients with mechanical aortic valves, underscoring the lack of proven efficacy and the necessity of adhering to established anticoagulation protocols with warfarin for this patient population. Here, we report a case of a 65-year-old man who had previously undergone aortic valve replacement and developed a thrombus in the mechanical aortic valve six months after switching from warfarin to rivaroxaban. The patient experienced a sudden loss of consciousness and chest discomfort. Echocardiography revealed a thrombus in the valve requiring urgent reoperation and replacement with a bioprosthetic valve. The postoperative recovery was uneventful., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kinoshita et al.)

Introduction: This research is one of the pioneering randomized clinical trials (RCTs) aimed at assessing the effectiveness and safety of rivaroxaban in treating left ventricular thrombus (LVT) in patients who have experienced acute coronary syndrome (ACS)., Materials and Methods: This is a randomized, controlled, interventional, open-label study. The patients were randomly divided into warfarin and rivaroxaban groups. We performed transthoracic echocardiography at the start of the study and again after three months to measure the thrombus area in square millimeters. The morphology of the thrombus was categorized into mural and round, and the mobility was classified into immobile, semi-mobile and hypermobile. We also monitored for adverse events including bleeding, systemic embolic occurrences, rehospitalization, and major adverse cardiac events (MACE)., Results: The study included fifty-two patients in the intention-to-treat analysis, with an equal split between the rivaroxaban and warfarin groups (26 patients each). The average follow-up duration was three months. The thrombus resolution rates in the rivaroxaban (76.9%) and warfarin (69.2%) groups, as well as the thrombus size reduction, did not show statistical significance between groups. All semi-mobile or hypermobile thrombi transformed into immobile and all of the round LVTs changed into a mural in both rivaroxaban and warfarin groups. No significant difference was observed in bleeding complications and rehospitalization between the two groups., Conclusion: The trial demonstrated that rivaroxaban is as effective as warfarin in terms of thrombus resolution rate, reduction in thrombus size, bleeding risk, and rehospitalization rate. Our findings suggest that rivaroxaban is a viable alternative to warfarin for managing left ventricular thrombus., (© 2024. The Author(s).)

Background: This retrospective cohort study aims to compare the effectiveness and safety of warfarin, rivaroxaban, and dabigatran in atrial fibrillation (AF) patients with different CHA2DS2-VASc scores in northern China., Methods: A retrospective cohort study was performed to evaluate anticoagulation in AF patients at the second affiliated hospital of Harbin Medical University from September 2018 to August 2019. Patients included in this study (n = 806) received warfarin (n = 300), or rivaroxaban (n = 203), or dabigatran (n = 303). Baseline characteristics and follow-up data including adherence, bleeding events and ischemic stroke (IS) events were collected., Results: Patients receiving rivaroxaban (73.9%) or dabigatran (73.6%) showed better adherence than those receiving warfarin (56.7%). Compared with warfarin-treated patients, dabigatran-treated patients had lower incidence of bleeding events (10.9% vs 19.3%, χ 2  = 8.385, P = 0.004) and rivaroxaban-treated patients had lower incidence of major adverse cardiovascular events (7.4% vs 13.7%, χ 2  = 4.822, P = 0.028). We classified patients into three groups based on CHA2DS2-VASc score (0-1, 2-3, ≥ 4). In dabigatran intervention, incidence of bleeding events was higher in patients with score 0-1 (20.0%) than those with score 2-3 (7.9%, χ 2  = 5.772, P = 0.016) or score ≥ 4 (8.6%, χ 2  = 4.682, P = 0.030). Patients with score 0-1 in warfarin or rivaroxaban therapy had a similar but not significant increase of bleeding compared with patients with score 2-3 or score ≥ 4, respectively. During the follow-up, 33 of 806 patients experienced IS and more than half (19, 57.6%) were patients with score ≥ 4. Comparing patients with score 0-1 and 2-3, the latter had an significant reduction of IS in patients prescribed warfarin and non-significant reduction in rivaroxaban and dabigatran therapy., Conclusion: Compared with warfarin therapy, patients with different CHA2DS2-VASc scores receiving either rivaroxaban or dabigatran were associated with higher persistence. AF patients with score ≥ 4 were more likely to experience IS events while hemorrhagic tendency preferred patients with low score 0-1., (© 2024. The Author(s).)

Background: Intracerebral hemorrhage (ICH) affects up to 1% of chronic oral anticoagulation (OAC) users per year. This study explored the knowledge, attitude and practice (KAP) towards ICH prevention among patients taking OACs., Methods: This multicenter cross-sectional survey was conducted at 4 hospitals from February to May 2023, and a self-administered questionnaire was developed to assess KAP toward ICH prevention among patients taking OACs. Structural equation modeling was used to assess the relationship between KAP., Results: A total of 536 valid questionnaires (67.25%) were analyzed, from 43.8% participants on Warfarin, 40.5% on Rivaroxaban and 15.7% on Dabigatran. The average knowledge, attitudes and practice scores were 9.22, 24.11, and 28.01 out of 16, 35 and 40, respectively. Participants who received Rivaroxaban had lower knowledge scores but higher attitude and practice store compared to those who received Warfarin or Dabigatran (all p < 0.001). According to Structure Equation Modeling, attitude had direct positive effect on practice (β = 0.694 [0.603-0.804], p = 0.012), while knowledge had direct negative effect on attitude (β = -2.077 [-2.507-1.651], p = 0.013), as well as negative effect on practice, both direct (β = -0.450[-0.689-2.03], p=0.012), and indirect (β = -1.441 [-1.928-1.192], p = 0.004)., Conclusion: Patients taking OACs showed insufficient knowledge, negative attitude and proactive practice regarding ICH; practice scores were affected by age, type of anticoagulation medication, and attitude rather than knowledge., Competing Interests: The authors declare that they have no competing interests in this work., (© 2024 Xiao et al.)

Objective: To assess the characteristics and clinical outcomes of patients with lower extremity peripheral artery disease (PAD) in XATOA receiving dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin according to lower extremity revascularisation (LER) history., Methods: XATOA is an international, multicentre, prospective, single arm registry study. This subanalysis investigated patients with lower extremity PAD according to LER history. Patients with coronary artery disease, PAD, or both, receiving DPI were followed for 12 or more months. Baseline characteristics and clinical outcomes were assessed according to LER history. A time dependency analysis assessed outcomes by time between the most recent LER procedure and the start of DPI. A multivariable analysis assessed the influence of patient characteristics on clinical outcomes., Results: In XATOA (n = 5 532), 2 820 (51.0%) patients had lower extremity PAD, of whom 1 736 (61.6%) had prior LER and 1 084 (38.4%) had no prior LER. Baseline characteristics were generally similar between patients with or without prior LER. A higher proportion of patients with prior LER experienced any treatment emergency clinical events compared with those without prior LER (15.0% vs. 9.4%, respectively), with greater differences observed between incidence rates of limb events, including major adverse limb events (9.06 vs. 4.09 events per 100 patient years, respectively). Similar rates of myocardial infarction, stroke, and major bleeding were observed in both subgroups. Clinical event rates were generally higher in patients who had previous LER for six months or less compared with patients who had previous LET for more than six months before starting DPI, regardless of LER type. Multivariable analyses showed that prior LER was predictive of limb events., Conclusion: This subanalysis of XATOA found that prior LER was associated with increased rates of limb events, consistent with results of COMPASS and VOYAGER PAD. Rates of bleeding were also low regardless of LER history and consistent with the findings from these trials., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)