Search

AIM: The 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Patients With Atrial Fibrillation provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation and the 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Direct oral anticoagulants (DOACs) exert anticoagulation effect by directly inhibiting Factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran). Though DOACs are characterized by fixed-dose prescribing and generally do not require routine laboratory drug-level monitoring (DLM), circumstances may arise where the DLM may aid in clinical decision-making, including DOAC dose adjustment, anticoagulant class change, or decisions to withhold or administer reversal agents. We review the current literature that describes high-risk patient groups in which DLM may be beneficial for improved patient anticoagulation management and stewardship. The review also summarizes the limitations of conventional coagulation testing and discuss the emerging utility of quantitative methods for routine and rapid emergent evaluation of DOAC drug levels-in particular, the Anti-Xa activity to detect Factor Xa Inhibitors (rivaroxaban, apixaban, and edoxaban). Both technical and regulatory barriers to widespread DLM implementation are limiting factors to further clinical research that must be overcome, in order to propose universal DOAC DLM strategies and provide clinical-laboratory correlation to formally classify high-risk patient groups.

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%, χ2 = 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%, χ2 = 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. [ABSTRACT FROM AUTHOR]

Rivaroxaban is a direct oral anticoagulant medication that has been found to be beneficial for the management of thromboembolic events linked to the Corona virus disease 2019 (COVID-19) pandemic, which has resulted in more than 6 million deaths worldwide. Hence, a sensitive, selective, and green bioanalytically validated method was developed using RP-HPLC coupled with DAD for the simultaneous determination of rivaroxaban in human plasma, and two co-administered drugs, namely, paracetamol, an analgesic, and ceftriaxone, an antibiotic, that are used in the management of COVID-19. An Exsil 100 ODS C18 column (250 × 4.6 mm, 5 μm) was used as the stationary phase, and acetonitrile: water: methanol at a ratio of 60:30:10 (v/v/v) was used in isocratic mode as the mobile phase with a flow rate of 0.7 ml/min. The method was validated over a concentration range of 0.1–10.0 µg/mL for rivaroxaban, and 1.0–15.0 µg/mL for paracetamol and ceftriaxone. The lower limits of detection (LLODs) were found to be 0.03, 0.32, and 0.32 µg/ml for rivaroxaban, paracetamol, and ceftriaxone, respectively. Moreover, the lower limits of quantitation (LLOQs) were found to be 0.1, 0.96, and 0.98 µg/ml. The developed method showed excellent accuracy and precision for the determination of the aforementioned drugs. Four metrics were used to evaluate the greenness of the developed method. The results revealed that the suggested method is green, with values of 81 and 0.6 for the analytical eco-scale and analytical greenness assessment (AGREE), respectively. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Hypothesis Animals Methods Results Conclusions and Clinical Importance Comparative pharmacokinetics and pharmacodynamics (PK/PD) of apixaban and rivaroxaban have not been studied in dogs and the propensity of these drugs to cause hypercoagulability after discontinuation is unknown.Compare the PK/PD of clinical dosing regimens of PO apixaban and rivaroxaban administered repeatedly to healthy dogs and assess the effect of abrupt drug discontinuation on coagulation.Six University‐owned, purpose‐bred, middle‐aged, mixed‐breed dogs (4 male, 2 female).Dogs were given apixaban or rivaroxaban PO at 0.5 mg/kg q12h for 7 days with a 14‐day washout period between drugs. Plasma drug concentrations were quantitated, and anticoagulant effects were measured using clotting times, calibrated anti‐Xa bioactivity assays, and measurements of thrombin generation. The potential for rebound hypercoagulability was assessed by measuring D‐dimers, thrombin‐antithrombin (TAT) complexes, and antithrombin activity after drug discontinuation.Plasma drug concentrations and anti‐Xa bioactivities were closely correlated for both drugs, but drug concentrations varied considerably among dogs, despite consistent dose regimens. Thrombin generation variables were significantly correlated with the anti‐Xa bioactivity of both drugs and no significant differences in the effects of apixaban and rivaroxaban on thrombin generation were observed. Drug discontinuation had no effect on D‐dimer concentrations. The concentration of TAT complexes decreased after apixaban discontinuation and did not change after rivaroxaban discontinuation.Repeated PO administration of apixaban or rivaroxaban to healthy dogs produced comparable anticoagulant effects measured by inhibition of thrombin formation. Rebound hypercoagulability after drug discontinuation was not observed and weaning of these drugs in clinical patients might not be necessary. [ABSTRACT FROM AUTHOR]

Background: Convexity subarachnoid hemorrhage (cSAH) is an uncommon presentation of subarachnoid bleeding, referring to bleeding more localized to the convexities of the brain. The diagnosis of cerebral venous sinus thrombosis (CVST) can be difficult especially when patients initially present with cSAH. The authors present a case and then discuss the pathophysiology and management. Case presentation: A 56-year-old woman with a previous history of hypertension and ischemic heart disease presented to the emergency department after experiencing it. Two seizures following a severe headache. The patient's history was negative for recent illnesses, head trauma, history of migraines, smoking, alcohol consumption, or intravenous drug use. The patient was diagnosed with CVST based on magnetic resonance venography (MRV). Genetic studies further identified homozygous mutations in the Prothrombin and MTHFR genes. Anticoagulant therapy was initiated with 60 mg of Enoxaparin twice daily and subsequently transitioned to Warfarin after 48 h continued for 3 months, and then replaced by rivaroxaban. Conclusions: This study highlights the importance of considering CVST as a cause of SAH, emphasizes the role of advanced imaging in diagnosis, and demonstrates a successful treatment approach using both traditional and direct oral anticoagulants. The insights provided in this article can contribute to improving the management of patients with CVST-related SAH. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: To evaluate the safety and efficacy of percutaneous biopsy and microwave ablation (B + MWA) in patients with pulmonary nodules (PNs) who are receiving antithrombotic therapy by rivaroxaban as bridging therapy. Methods: The study comprised 187 patients with PNs who underwent 187 B + MWA sessions from January 1, 2020, to December 31, 2021. The enrolled patients were divided into two groups: Group A, who received antithrombotic therapy five days before the procedure and received rivaroxaban as a bridging drug during hospitalization, and group B, who had no antithrombotic treatment. Information about the technical success rate, positive biopsy rate, complete ablative rate, and major complications were collected and analyzed. Results: Group A comprised 53 patients and group B comprised 134 patients. The technical success rate was 100% in both groups. The positive biopsy rates were 88.68% and 91.04%, respectively (p = 0.6211, X2 = 0.2443). In groups A and B, the complete ablative rates at 6, 12, and 24 months were 100.0% versus 99.25%, 96.23% versus 96.27%, and 88.68% versus 89.55%, respectively. There were no significant differences in bleeding and thrombotic complications between the two groups. No grade 5 complications occurred. Conclusions: It is generally considered safe and effective that patients who are on antithrombotic therapy by rivaroxaban as bridging to undergo B + MWA for treating PNs. [ABSTRACT FROM AUTHOR]

Purpose To investigate the safety and efficacy of direct oral anticoagulants (DOACs) in the treatment of the acute phase of heparin-induced thrombocytopenia (HIT). Summary A systematic review of the literature was conducted on PubMed, MEDLINE, Embase, and Web of Science Core Collection through July 2023. Search terms included "heparin-induced thrombocytopenia AND direct-oral-anticoagulants" in addition to a list of oral anticoagulants. Adult patients who used direct oral anticoagulants as the initial treatment for the acute phase of HIT were included. A total of 1,188 articles were initially identified, with 770 articles reviewed following removal of duplicates. Following the application of inclusion and exclusion criteria, 12 articles were ultimately included. Rivaroxaban was the most-utilized DOAC (28 patients), followed by apixaban (7 patients) and dabigatran (1 patient). All patients with thrombocytopenia demonstrated successful platelet recovery, with two patients presenting with normal platelet counts. One patient developed a deep venous thrombosis with no other new or recurrent thromboses. There were no reported clinically significant adverse events in any patient. Obstacles and deterrents to the use of the standards of care in the acute phase of HIT exist. Argatroban and bivalirudin require intravenous infusion and require close aPTT monitoring and dose adjustment. Fondaparinux requires injection and is contraindicated with body weight <50kg. DOACs would offer the novel ability for an oral treatment in the treatment of the acute phase HIT and allow for minimal monitoring and consistent dosing strategies. Therefore, DOACs are an intriguing choice for the treatment of the acute phase of HIT. Conclusion Data from 12 publications and across 36 patients suggests that the use of DOACs in the acute phase of HIT may be a safe and efficacious treatment option with favorable ease of monitoring and management. [ABSTRACT FROM AUTHOR]

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

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Background/Aim: There is a dearth of studies addressing the effects of next-generation anticoagulants on epistaxis. The aim of this investigation was to determine whether there are any differences between traditional and next-generation anticoagulants in the etiology of epistaxis. Methods: This retrospective cohort study focused on a total of 7,110 individuals (3,278 females (46.1%) and 3,832 males (53.9%)) diagnosed with epistaxis between 2018 and 2022; the mean age of the patients was 37.7 years. Patient data (age, gender, outpatient and inpatient treatments, relevant laboratory parameters, and treatment evidence) were retrospectively reviewed from a hospital database. The severity of epistaxis was assessed based on treatment notes. Patients with hypertension and those undergoing antiaggregant therapy were excluded from the study. International Classification of Diseases (ICD) codes from the automated system were examined retrospectively. The data were used to establish three patient groups: the first group consisted of individuals taking next-generation oral anticoagulants, the second group consisted of individuals taking traditional oral anticoagulants, and the third group consisted of healthy controls. Results: We found statistically significant differences among the groups in terms of age, the severity of epistaxis, the treatment modality, and laboratory findings (P<0.001); no statistically significant difference was found in terms of gender (P=0.954). Group 2 contained the largest number of hospitalized patients and patients with severe active nosebleeds. Conclusion: Next-generation anticoagulants are more reliable than traditional anticoagulants in terms of the severity of epistaxis, the need for hospitalization, and laboratory results. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to characterize the safety profiles of rivaroxabanassociated 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. [ABSTRACT FROM AUTHOR]

Background/aim: The comparative risk of gastrointestinal bleeding (GIB) among users of direct-acting oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) is a topic of ongoing debate. This study leverages a comprehensive national health database to evaluate the incidence of GIB, associated risk factors, and postbleeding management strategies among anticoagulated patients. Materials and methods: Utilizing the Turkish Ministry of Health's e-Nabız system, we conducted a retrospective analysis of patients treated with DOACs and warfarin from January 2017 to July 2023. GIB events were identified using ICD codes, and comorbidities, prior medication use, interventions, and mortality rates were analyzed. Drug survival and patterns of changes following GIB were also evaluated. Results: Among 102,545 patients with a GIB event during anticoagulant treatment, DOAC users were older with a higher prevalence of comorbidities, except for chronic obstructive lung disease, compared to VKA users. GIB-related mortality was 0.6% in the DOAC group and 0.4% in the VKA group at admission after the GIB (p < 0.01). In all drug groups, approximately half of the patients discontinued anticoagulation due to GIB after 3 months, the rate being highest with apixaban (61.9%). In patients who continued anticoagulation, the anticoagulant prior to GIB remained the most common agent in all groups, with rivaroxaban having the highest retention rate (40.7%). Conclusion: This nationwide study indicates a higher frequency of GIB in DOAC users versus VKA users, with age and comorbidities potentially contributing to this trend. Mortality rates were comparable to the previous literature but warrant further investigation. The significant rate of discontinuation following GIB raises concerns about ongoing anticoagulation management. These findings underscore the need for cautious case management. [ABSTRACT FROM AUTHOR]

Background and Objective: Prospective sequential analyses after a new drug approval allow proactive surveillance of new drugs. In the current study, we demonstrate feasibility of frailty-specific sequential analyses for dabigatran, rivaroxaban, and apixaban versus warfarin. Methods: We partitioned Medicare data from 2011 to 2020 into datasets based on calendar year following the date of drug approval. Each calendar year of data was added sequentially for analysis. We used a new-user, active comparative design by comparing the initiators of dabigatran versus warfarin, rivaroxaban versus warfarin, and apixaban versus warfarin. Patients aged ≥ 65 years with atrial fibrillation without contraindication to the anticoagulants were included. Claims-based frailty index ≥ 0.25 was used to define frailty. The initiators of each direct oral anticoagulant were propensity-score matched to the initiators of warfarin within each frailty status. The effectiveness outcome was ischemic stroke or systemic thromboembolism, and the safety outcome was major bleeding. For each calendar year, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazards models using all data available up to that year. Results: As an example of the results, in the 2020 dataset, compared with warfarin, apixaban was associated with a reduced risk of ischemic stroke or systemic thromboembolism (frail: HR 0.73, 95% CI 0.63–0.85; non-frail: HR 0.65, 95% CI 0.59–0.72) and major bleeding (frail: HR 0.63, 95% CI 0.57–0.69; non-frail: HR 0.59, 95% CI 0.56–0.63) in both frail and non-frail patients. We found evidence for apixaban's effectiveness and safety within 1–2 years after the drug approval in frail older patients. Conclusion: Our frailty-specific sequential analyses can be applied to future near-real-time monitoring of newly approved drugs. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

The incidence of venous thromboembolism (VTE) in the pediatric population has increased more than 10-fold in the last 20 years, as a consequence of the advancement of resuscitation and surgical techniques and the global increase in life expectancy of children suffering from chronic pathologies. Monitoring anticoagulant therapy to achieve outcomes within the target range in childhood VTE, parenteral administration of medications, and frequent blood tests in children are often cumbersome. Availability of safe and effective oral agents with pediatric data to support use would be of clear benefit. A physiologically based pharmacokinetic model was developed to estimate the appropriate dosing schedule for rivaroxaban in children. This incorporated growth/maturation and variability in anthropometrics (e.g., body height, weight, and body mass index), anatomy (e.g., organ weight), physiology (e.g., blood flow rates), metabolism and excretion. Rivaroxaban use in pediatric population underwent a complete investigational program, consisting mainly of one phase I pharmacokinetics/pharmacodynamics trial, three phase II trials, one phase III trial. The phase III trial enrolled 500 patients from birth to <18 years and documented the efficacy and safety of rivaroxaban regimens at dose equivalent to the adult 20 mg dose for the prevention of fatal or symptomatic nonfatal recurrent VTE and major bleeding versus heparin or vitamin K antagonists. Results were similar to those in rivaroxaban studies in adults. The efficacy and safety of rivaroxaban in children reported in the EINSTEIN JUNIOR trial provide further support to previous trials in adults (EINSTEIN Program), which demonstrate a favorable profile for the use of rivaroxaban for the management of VTE in challenging patient populations. Other clinical evidence contributing to the use of rivaroxaban among different risk groups in pediatric VTE population confirms the consistency with principal trial. Our review aims to describe the rationale for using rivaroxaban oral suspension in clinical practice and to summarize its multiple indications in each vascular bed (e.g., cerebral venous thrombosis, symptomatic or asymptomatic central venous catheter-associated thrombosis), etiology, and patients setting. [ABSTRACT FROM AUTHOR]

Background: The combination of rivaroxaban plus aspirin compared with aspirin alone reduces the risk of major adverse cardiovascular and limb events for high-risk patients with peripheral artery disease. It is unknown whether rivaroxaban plus aspirin improves intermittent claudication for adults with lower-risk peripheral arterial disease. Methods: In this randomized, open-label, multicenter, 24-week clinical trial, we randomly assigned patients with peripheral artery disease and intermittent claudication to receive either 2.5 mg of rivaroxaban twice daily plus 100 mg of aspirin once daily or 100 mg of aspirin once daily. The primary outcome was a 24-week change in total walking distance, measured by the 6-minute walking test. The primary safety outcome was the incidence of major bleeding or clinically relevant nonmajor bleeding. Results: Eighty-eight patients were randomly assigned to either rivaroxaban plus aspirin (n=46) or aspirin alone (n=42). The mean age was 67 years, and 54% were female. The total walking distance measured by 6-minute walk test improved by 89 ± 18 m (mean±standard error) in the rivaroxaban-plus-aspirin group versus 21 ± 16 m in the aspirin-alone group. This corresponded to an absolute difference of 68 ± 24 m (95% confidence interval [CI], 19 to 116 m; P=0.007) and a relative improvement over the aspirin-alone group of 327% (95% CI, 94 to 560%). No major bleeding events were observed in either group. Conclusions: In patients with peripheral artery disease and intermittent claudication, 2.5 mg of rivaroxaban twice daily plus 100 mg of aspirin daily improved the total walking distance by a 6-minute walking test compared with 100 mg of aspirin daily alone. (Funded by Bayer S.A.; Clinicaltrials.gov number, NCT04853719.) [ABSTRACT FROM AUTHOR]

Rivaroxaban, a direct oral anticoagulant, is widely used in the management and prevention of thrombotic conditions. Dose adjustments are necessary to optimize efficacy based on individual physiological differences. However, current analytical methods are impractical for clinical use due to complex sample preparation and lengthy detection times. This paper presents a terahertz (THz) metamaterial biosensor for the rapid determination of rivaroxaban within 10–15 min. The THz absorption peaks of rivaroxaban were first identified based on THz spectroscopy. Subsequently, a metamaterial structure with rotational symmetry was designed to resonate at the absorption peaks of rivaroxaban. Theoretical simulations and experimental measurements analyzed changes of the resonance peak at different rivaroxaban concentrations, including frequency shifts and amplitude variations. Based on these changes, rivaroxaban concentration can be quantified with the limits of detection (LODs) of 5.01 μmol/mL for peak shift and 1.067 μmol/mL for peak absorbance, respectively. This study presents a novel approach for the rapid determination of rivaroxaban, providing potential improvements in therapeutic drug monitoring and personalized medical treatment. [ABSTRACT FROM AUTHOR]

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

The Beers Criteria are a tool for optimizing pharmacotherapy in elderly patients, containing information on potentially inappropriate drugs, which is only advisory in nature and is not mandatory for use in Russian Federation. In the updated version of the Beers Criteria from 2023, the expert opinion on rivaroxaban has changed — instead of "use with caution", as stated in the previous document from 2019, the experts now believe that "long-term treatment with rivaroxaban in non-valvular atrial fibrillation (AF) and venous thromboembolic complications (VTE) should be avoided in favor of safer alternative anticoagulants". This statement is based on moderate-quality evidence obtained from observational studies and network meta-analyses, which are significantly inferior to randomized controlled trials and have numerous limitations. The available evidence base for the use of rivaroxaban in elderly patients with AF and VTE and critical comments on the Beers criteria methodology, indicate the recommendations of the American Geriatrics Society experts regarding direct oral anticoagulants (DOAC) should be treated thoughtfully and carefully. When choosing a DOAC in elderly patients with AF or VTE, one should primarily focus on current clinical guidelines mandatory for use in Russian Federation, and on the data of studies that studied the efficacy and safety of specific DOACs in this category of patients. Rivaroxaban is a well-studied anticoagulant in elderly patients with AF and VTE, since its efficacy and safety have been established in RCTs and specially designed multicenter prospective observational studies with a fairly high quality of evidence. Based on this, rivaroxaban is a justified treatment option for elderly and senile patients with AF or VTE.

Abstract 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.

Introduction. The most important stage of pharmaceutical development of a generic drug is a clinical trial involving humans – a bioequivalence study. Considering the importance of finding rivaroxaban drugs in the list of vital and essential drugs, as part of ensuring technological sovereignty, the use of scientific robust and effective methods for determining the quality of the dosage form is required.Aim. Conduct a study of rivaroxaban tablets on a physiologically relevant tester to predict pharmacokinetic profiles.Materials and methods. The objects of the study are "Xarelto®, film-coated tablets, 10 mg" (series BXJS871, with an expiration date of October 31, 2024, Bayer AG, Germany), "Xarelto®, film-coated tablets, 20 mg" (series BXKDF32, with an expiration date of May 17, 2026, Bayer AG, Germany) and "Rivaroxaban, film-coated tablets, 10 mg" and "Rivaroxaban, film-coated tablets, 20 mg", domestically produced, with valid expiration dates. During the study, reagents were used to prepare dissolution media and perform quantitative determination. The physiologically relevant test was performed on the SC PRT-6 device (LLC "Scientific Compliance", Russia). The quantitative content of released rivaroxaban within the comparative dissolution kinetics test in a medium of 0.1 in a medium of 0.1 % sodium lauryl sulfate solution in a phosphate buffer solution pH 6.5 was carried out on a SF-2000 spectrophotometer (LLC "OKB Spektr", Russia). The quantitative content of released rivaroxaban within the comparative dissolution kinetics test in biorelevant dissolution media and physiological relevance test was assessed on a high-performance liquid chromatograph "Chromatec-Crystal HPLC 2014" (CJSC "Chromatec", Russia). Pharmacokinetic profiles were modeled in the PK-Sim® (Systems Biology Software Suite 11.2, Bayer Technology Services GmbH, Germany) program based on the data obtained within the physiologically relevant test. The clinical study of rivaroxaban tablets was a prospective, open-label, randomized, crossover, two-stage comparative study in two groups of volunteers with a single dose of drugs on the fast condition. The study randomized 30 healthy male volunteers aged 18–45 years.Results and discussion. A complex of in vitro tests was conducted, profiles were obtained that allow us to evaluate the dynamics and degree of release of the studied drugs in various parts of the human gastrointestinal tract. A comparison of the sequential and hybrid schemes for conducting the physiological relevance test was carried out. Within the framework of the set of tests, qualitative and quantitative correlation with the clinical trials data was observed only for the hybrid physiological relevance test scheme. Based on the results of physiological relevance test using different schemes, pharmacokinetic profiles for a pair of drugs were predicted and the prediction error was assessed.Conclusion. A set of scientific in vitro tests was conducted for the drugs "Xarelto®, film-coated tablets, 10 mg and 20 mg", "Rivaroxaban, film-coated tablets, 10 mg and 20 mg". Based on the physiological relevance test results, pharmacokinetic profiles for a pair of drugs were predicted with low error and high reliability. As part of the comparison of data obtained during clinical trial and modeling, the smallest prediction error was noted when performing physiological relevance test using a hybrid scheme.