A comparative study of the clinical benefits of rivaroxaban and dabigatran in patients with nonvalvular atrial fibrillation with high bleeding risk.

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.

Construction of cytochrome P450 3A and P-glycoprotein knockout rats with application in rivaroxaban-verapamil interactions.

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.

Effect of Danhong injection on pharmacokinetics and pharmacodynamics of rivaroxaban in rats.

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-1ß, TNF-α and histopathological sections. Effect of DHI on CYP3A2 in rats was investigated by probe drug method. RESULTS: Cmax 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-1ß 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. Cmax 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.

Application of a Novel UPLC-MS/MS Method for Analysis of Rivaroxaban Concentrations in Dried Blood Spot and Plasma Samples Collected from Patients with Venous Thrombosis.

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).

In vitro assessment of the risk of ABCB1-mediated drug-drug interaction between rivaroxaban and tacrolimus in human embryonic kidney 293 recombinant cell lines.

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.

Impact of adherence on the cost-effectiveness of apixaban and rivaroxaban in stroke prevention among patients with atrial fibrillation in the United States.

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.

Due to the improved safety and efficacy profile, DOACs are preferred over warfarin for stroke prevention in AF patients. Suboptimal adherence to DOACs is commonly reported in real-world settings, leading to poorer patient outcomes. Prior pharmacoeconomic analyses have not incorporated real-world adherence data. The findings suggest that apixaban 5 mg is a cost-effective alternative to rivaroxaban 20 mg for stroke prevention. Apixaban was identified as the cost-effective option compared with rivaroxaban for stroke prevention among elderly AF patients after incorporating adherence data in the cost-effectiveness analysis. Healthcare decision-makers can utilize the findings of this study to inform formulary decisions and treatment guidelines.

Letter to the editor regarding the paper by A. Boileve et al.: Safety of direct oral anticoagulants in patients with advanced solid tumors receiving anti­VEGF agents: a retrospective study.

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.

An accurate haplotyping method using multiplex pyrosequencing with AS-PCR to detect ABCB1 haplotypes associated with rivaroxaban-derived hemorrhagic events.

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.

Assays for Monitoring Apixaban and Rivaroxaban in Emergency Settings, State-of-the-Art Routine Analysis, and Volumetric Absorptive Microsamples Deliver Discordant Results.

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.

Suspected adverse drug reactions of rivaroxaban reported in the United States food and drug administration adverse event reporting system database: a pharmacovigilance study.

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.

Effectiveness and safety of rivaroxaban or low-molecular-weight heparin in non-major orthopedic surgery: a meta-analysis of randomized controlled trials.

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.

Anti-Xa Activity Monitoring for Optimizing Rivaroxaban Dosage in Chinese Patients with Cerebral Venous Thrombosis.

BACKGROUND: Rivaroxaban, a direct Factor Xa inhibitor, is commonly used for cerebral venous thrombosis (CVT) correction. However, pharmacokinetic differences in Chinese may vary in sensitivity and tolerance, resulting in either insufficient or excessive anticoagulation. Herein, the optimizing dosages of rivaroxaban in Chinese patients with CVT were analyzed based on monitoring anti-Xa activity dynamically, to maintain therapeutic efficacy and reduce rivaroxaban-related bleeding. METHODS: A real-world cohort study was conducted involving 112 CVT patients in Xuanwu Hospital, from August 2021 through January 2024. Patients were grouped according to their doses of rivaroxaban use (5, 10, 15, and 20 mg daily) based on dynamic plasma anti-Xa activity monitored using the chromogenic anti-Xa assay. Plasma levels of anti-Xa activity reached the therapeutic range, bleeding events and the dosage of rivaroxaban among these groups were analyzed. RESULTS: The ratios of the patients whose plasma anti-Xa levels reached the standard therapeutic level (0.3-0.7 IU/mL) between the cohorts less than 20 mg/d and 20 mg/d showed no statistical difference, and no significant disparities were observed among 5, 10, 15, and 20 mg/d dose groups. There was a discernible increase in the proportion of patients with bleeding events in the 20 mg/d group, even though the results did not reach a statistical difference. Meanwhile, in patients with bleeding events, their plasma anti-Xa levels could exceed 0.7 IU/mL. CONCLUSION: Sensitivity and tolerance to rivaroxaban in Chinese may vary. Individualized therapy dosage under the guidance of anti-Xa activity monitoring may not only guarantee anticoagulation effect, but also reduce rivaroxaban-related bleeding events.

Antiplatelets for Cardiovascular Disease in Non-valvular AF with Rivaroxaban: A Subanalysis of the EXPAND Study.

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.

Rivaroxaban for stroke patients with antiphospholipid syndrome (RISAPS): protocol for a randomized controlled, phase IIb proof-of-principle trial.

Background: Optimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio (INR) target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-dose direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation. Objectives: The Rivaroxaban for Stroke patients with APS trial (RISAPS) seeks to determine whether high-dose rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations. Methods: This phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, target INR range 3.0-4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-dose rivaroxaban pharmacokinetic modeling. Conclusion: Should RISAPS demonstrate noninferior efficacy and safety of high-dose rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials.

Co-Administration of Amiodarone Increases Bleeding by Affecting Rivaroxaban Pharmacokinetics in Patients with Atrial Fibrillation.

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 (Ctrough) 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 Ctrough than those in the Control group (p = 0.009). Furthermore, in patients with moderate to severe renal impairment, rivaroxaban Ctrough 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.

Comparison of perioperative bleeding risk between direct oral anticoagulants in transurethral resection of prostate.

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.

Risk of ocular neovascular conversion and systemic bleeding complications in patients with AMD on DOACs or Warfarin.

PURPOSE: Conversion to neovascular disease in patients with non-neovascular age-related macular degeneration (AMD) initiated on direct oral anticoagulants (DOAC) compared to matched patients treated with warfarin. DESIGN: Retrospective cohort study. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: 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, INTERVENTION, OR TESTING: TriNetX (Cambridge, MA, USA), was used to identify patients diagnosed with non-neovascular AMD stratified by treatment with DOACs or warfarin with at least six 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-vascular endothelial growth factor (VEGF) therapy or pars plana vitrectomy (PPV)) within six months and one 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 higher risk of developing neovascular AMD at six months (RR,1.24, 95% CI, 1.12 - 1.39; P<.001) and one year (RR, 1.26, 95% CI, 1.14 - 1.40; P<.001) when compared to 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<.001; 1 year: RR, 1.31, 95% CI, 0.72 - 2.05; P<.001) and PPV (6 months: RR, 1.16; 95% CI, 1.16-3.94; P = .01; 1 year: RR, 2.29, 95% CI, 1.30 - 4.05; P=.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<.001; MH: RR, 1.86; 95% CI, 1.47-2.35; P<.001; VH: RR, 2.22; 95% CI, 1.51-3.26; P<.001) and need for intravitreal anti-VEGF therapy (RR, 1.34; 95% CI, 1.18-1.52; P<.001) over an extended 5-year period. There was no significant difference in the development of major systemic hemorrhagic events between the two cohorts over five 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 to matched patients initiated on DOACs.

Assessing Direct Oral Anticoagulants in the Clinical Laboratory.

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.

Early anti-coagulation therapy in new-onset atrial fibrillation after coronary artery bypass grafting: a randomized trial pilot study.

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/ .