Predictors of adherence to direct oral anticoagulants after cardiovascular or bleeding events in Medicare Advantage Plan enrollees with atrial fibrillation.

BACKGROUND: Direct oral anticoagulants (DOACs) are recommended for patients with atrial fibrillation (AF) given their improved safety profile. Suboptimal adherence to DOACs remains a significant concern among individuals with AF. However, the extent of adherence to DOACs following a cardiovascular or bleeding event has not been fully evaluated. OBJECTIVE: To evaluate the pattern of adherence trajectories of DOACs after a cardiovascular or bleeding event and to investigate the sociodemographic and clinical predictors associated with each adherence trajectory by using claims-based data. METHODS: This retrospective study was conducted among patients with AF prescribed with DOACs (dabigatran/apixaban/rivaroxaban) between July 2016 and December 2017 and who were continuously enrolled in the Texas-based Medicare Advantage Plan. Patients who experienced a cardiovascular or bleeding event while using the DOACs were further included in the analysis. The sample was limited to patients who experienced a clinical event such as a cardiovascular or bleeding event while using the DOACs. The clinical events considered in this study were cardiovascular (stroke, congestive heart failure, myocardial infarction, systemic embolism) and bleeding events. To assess adherence patterns, each patient with a DOAC prescription was followed up for a year after experiencing a clinical event. The monthly adherence to DOACs after these events was evaluated using the proportion of days covered (PDC). A group-based trajectory model incorporated the monthly PDC to classify groups of patients based on their distinct patterns of adherence. Predictors associated with each trajectory were assessed using a multinomial logistic regression model, with the adherent trajectory serving as the reference group in the outcome variable. RESULTS: Among the 694 patients with AF who experienced clinical events after the initiation of DOACs, 3 distinct adherence trajectories were identified: intermediate nonadherent (30.50%), adherent (37.7%), and low adherent (31.8%); the mean PDC was 0.47 for the intermediate nonadherent trajectory, 0.93 for the adherent trajectory, and 0.01 for low adherent trajectory. The low-income subsidy was significantly associated with lower adherence trajectories (odds ratio [OR] = 4.81; 95% CI = 3.07-7.51) and with intermediate nonadherent trajectories (OR = 1.57; 95% CI = 1.06-2.34). Also, nonsteroidal anti-inflammatory drug use was significantly associated with lower adherence trajectories (OR = 5.10; 95% CI = 1.95-13.36) and intermediate nonadherent trajectories (OR = 3.17; 95% CI = 1.26-7.93). Other predictors significantly associated with both nonadherent trajectories are type of DOACs (OR = 0.53; 95% CI = 0.35-0.79), presence of coronary artery disease (OR = 1.89; 95% CI = 1.01-3.55), and having 2 or more clinical events (OR = 1.65; 95% CI = 1.09-2.50). CONCLUSIONS: Predictors identified provide valuable insights into the suboptimal adherence of DOACs among Medicare Advantage Plan enrollees with AF, which can guide the development of targeted interventions to enhance adherence in this high-risk patient population.

Serious Bleeding in Patients With Atrial Fibrillation Using Diltiazem With Apixaban or Rivaroxaban.

Importance: Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation. Objective: To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol. Design, Setting, and Participants: This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024. Exposures: Diltiazem and metoprolol. Main Outcomes and Measures: The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting. Results: The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26). Conclusions and Relevance: In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.

A real-world study of different doses of rivaroxaban in patients with nonvalvular atrial fibrillation.

To explore the anticoagulant effect and safety of utilizing different doses of rivaroxaban for the treatment of patients with atrial fibrillation (AF) in the real world. A retrospective case-control analysis was performed by applying the hospital database, and 3595 patients with non-valvular atrial fibrillation (NVAF) who were hospitalized and taking rivaroxaban at Wuhan Asia Heart Hospital and Wuhan Asia General Hospital from March 2018 to December 2021 were included in the study, and were divided into the rivaroxaban 10 mg and 15 mg groups according to the daily prescribed dose, of which 443 cases were in the 10 mg group and 3152 cases were in the 15 mg group. The patients were followed up regularly, and the incidence of thrombotic events, bleeding events and all-cause deaths were recorded and compared between the 2 groups, and logistic regression was applied to analyze the influencing factors for the occurrence of adverse events. Comparison of the incidence of thrombosis, bleeding and all-cause death between the 2 groups of patients showed that the 10 mg group was higher than the 15 mg group, but the difference was not statistically significant (χ2 = 0.36, 3.26, 1.99, all P > .05); the incidence of total adverse events between the 2 groups of patients was higher in the 10 mg group than in the 15 mg group, with a statistically significant difference (χ2 = 4.53, P = .033); multifactorial logistic regression results showed that age [OR (95% CI) = 1.02 (1.00-1.04)], diabetes mellitus [OR (95% CI) = 1.69 (1.09-2.62)], D-dimer level [OR (95% CI) = 1.06 (1.00-1.11)] and persistent AF [OR (95% CI) = 1.54 (1.03-2.31)] were risk factors for adverse events (P < .05). In the real world, Asian clinicians recommend rivaroxaban 10 mg once daily for NVAF patients for a variety of reasons; however, this dose is not superior or even inferior to the 15 mg group in terms of effectiveness and safety. Advanced age, elevated D-dimer levels, history of diabetes mellitus, and persistent AF are risk factors for adverse events, and the optimal dosage of rivaroxaban or optimal anticoagulation strategy for Asian patients with nonvalvular AF requires further study.

Quantitative Benefit-Risk Evaluation of Rivaroxaban in Patients After Peripheral Arterial Revascularization: The VOYAGER PAD Trial.

BACKGROUND: 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) trial compared rivaroxaban (2.5 mg twice a day) plus aspirin with aspirin alone in patients with symptomatic peripheral artery disease requiring endovascular or surgical limb revascularization, with 50% receiving clopidogrel background therapy. The New Drug Indication application includes benefit-risk assessments using clinical judgment to balance benefits against risks. During its review, the US Food and Drug Administration requested additional quantitative benefit-risk analyses with formal weighting approaches. METHODS AND RESULTS: Benefits and risks were assessed using rate differences between treatment groups (unweighted analysis). To account for clinical importance of the end points, a multi-criteria decision analysis was conducted using health state utility values as weights. Monte Carlo simulations incorporated statistical uncertainties of the event rates and utility weights. Intent-to-treat and on-treatment analyses were conducted. For unweighted intent-to-treat analyses, rivaroxaban plus aspirin would result in 120 (95% CI, -208 to -32) fewer events of the primary composite end point (per 10 000 patient-years) compared with aspirin alone. Rivaroxaban caused an excess of 40 (95% CI, 8-72) Thrombolysis in Myocardial Infarction major bleeding events, which was largely driven by nonfatal, nonintracranial hemorrhage Thrombolysis in Myocardial Infarction major bleeding events. For weighted analyses, rivaroxaban resulted in the utility equivalent of 13.7 (95% CI, -85.3 to 52.6) and 68.1 (95% CI, 7.9-135.7) fewer deaths per 10 000 patient-years (intent-to-treat and on-treatment, respectively), corresponding to probabilities of 64.4% and 98.7%, respectively, that benefits outweigh risks favoring rivaroxaban per Monte Carlo simulation. CONCLUSIONS: These analyses show a favorable benefit-risk profile of rivaroxaban therapy in the VOYAGER PAD trial, with findings generally consistent between the unweighted and weighted approaches.

Effectiveness and safety of rivaroxaban for anticoagulation therapy in COVID-19: A meta-analysis of randomized controlled trials.

OBJECTIVES: To evaluate the effectiveness and safety of rivaroxaban anticoagulation in COVID-19 patients. METHODS: PubMed, Embase, Cochrane Library electronic databases, and ClinicalTrials.gov were searched to identify all relevant randomized controlled trial studies from December 2019 to July 2023. RESULTS: A total of 6 randomized controlled trials, which included a total of 3323 patients, were considered for evaluation. Overall, short-term all-cause mortality and hospitalization rates were not significantly different between the rivaroxaban and control groups. Thrombotic events were significantly reduced in the rivaroxaban prophylaxis group compared to the placebo control group. However, the reduction in thrombotic events was not significantly different between rivaroxaban therapy and heparin or low-molecular-weight heparin (LMWH). Rivaroxaban prophylaxis and the therapeutic dose may be associated with a higher rate of overall bleeding rate, but major bleeding rates did not differ substantially. CONCLUSION: Rivaroxaban may reduce thrombotic events in COVID-19 patients, but it does not appear to have an advantage over heparin or LMWH, and it may increase the risk of bleeding.INPLASY Reg. No.: INPLASY 202370097.

Common P-glycoprotein (ABCB1) polymorphisms do not seem to be associated with the risk of rivaroxaban-related bleeding events: Preliminary data.

Introduction: Considering conflicting previous reports, we aimed to evaluate whether the common ABCB1 polymorphisms (rs1128503, rs2032582, rs1045642, rs4148738) affected the risk of bleeding in rivaroxaban-treated patients. Materials and methods: We report preliminary data from a larger nested case-control study. Consecutive adults started on rivaroxaban for any indication requiring > 6 months of treatment were followed-up to one year. Patients who experienced major or non-major clinically relevant bleeding during the initial 6 months were considered cases, whereas subjects free of bleeding over > 6 months were controls. The polymorphisms of interest (rs1128503, rs2032582, rs1045642, rs4148738) were in a strong linkage disequilibrium, hence patients were classified regarding the "load" of variant alleles: 0-2, 3-5 or 6-8. The three subsets were balanced regarding a range of demographic, comorbidity, comedication and genetic characteristics. A logistic model was fitted to probability of bleeding. Results: There were 60 cases and 220 controls. Raw proportions of cases were similar across the subsets with increasing number of ABCB1 variant alleles (0-2, N = 85; 3-6, N = 133; 6-8, N = 62): 22.4%, 21.8%, and 19.4%, respectively. Fully adjusted probabilities of bleeding were also similar across the subsets: 22.9%, 27.5% and 17.7%, respectively. No trend was observed (linear, t = -0.63, df = 273, P = 0.529; quadratic, t = -1.10, df = 273, P = 0.272). Of the 15 identified haplotypes, the completely variant (c.1236T_c.2677T(A)_c.3435T_c.2482-2236A) (40.7%) and completely wild-type (C_G_C_G) (39.5%) haplotypes prevailed, and had a closely similar prevalence of cases: 21.1% vs. 23.1%, respectively. Conclusions: The evaluated common ABCB1 polymorphisms do not seem to affect the risk of early bleeding in patients started on rivaroxaban.

Effectiveness and safety of direct oral anticoagulants among patients with non-valvular atrial fibrillation and liver disease: A multinational cohort study.

BACKGROUND AND AIMS: The effects of direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF) and liver disease remain poorly understood. Our multinational cohort study assessed the effectiveness and safety of DOACs in this high-risk population. METHODS: We assembled two population-based cohorts in United Kingdom and in Québec of NVAF patients with liver disease initiating DOACs or vitamin K antagonists (VKAs) between 2011 and 2020. Using an as-treated exposure definition, we compared DOACs to VKAs and apixaban to rivaroxaban. After inverse probability of treatment weighting, Cox proportional hazards models estimated site-specific hazard ratios (HRs) and 95 % confidence intervals (CIs) of ischemic stroke and major bleeding. Site-specific estimates were pooled using random-effects models. Analyses were repeated among NVAF patients with cirrhosis. RESULTS: There were 11,881 NVAF patients with liver disease (2683 with cirrhosis). Among those, 8815 initiated DOACs (4414 apixaban, 2497 rivaroxaban) and 3696 VKAs. The HRs (95 % CIs) for DOACs compared to VKAs were 1.01 (0.76-1.34) for ischemic stroke and 0.87 (0.77-0.99) for major bleeding. Results were consistent among patients with cirrhosis. The HRs (95 % CIs) for apixaban compared to rivaroxaban were 0.85 (0.60-1.20) for ischemic stroke and 0.80 (0.68-0.95) for major bleeding. This decreased bleeding risk was not observed among patients with cirrhosis (HR, 1.01; 95 % CI 0.72-1.43). CONCLUSIONS: Among NVAF patients with liver disease, DOACs were as effective and slightly safer than VKAs, and apixaban was as effective but safer than rivaroxaban. The safety benefit with apixaban was not present among patients with cirrhosis.

Real-world experience of direct oral anticoagulant use in a single pediatric center.

BACKGROUND: Pediatric venous thromboembolism has increased by 130%-200%, specifically in hospitalized children, and direct oral anticoagulants (DOACs) offer several therapeutic advantages. METHODS: This study aims to evaluate the real-world epidemiological and outcome data from a retrospective review of pediatric patients treated with DOACs from January 1, 2013 to December 31, 2022. In this single-center, IRB-approved study, 65 patients were identified and analyzed using SPSS statistical software, and a descriptive statistical analysis was conducted. RESULTS: Of the 65 patients, 37% were on apixaban, 61.5% were on rivaroxaban, and 1.5% were on dabigatran. Per the 2023 ISTH outcome definitions, one (2%) patient had a major bleeding episode, six (9%) had clinically relevant non-major bleeding, three (5%) patients had patient-important heavy menstrual bleeding (HMB), and one (1.5%) patient had minor bleeding. Seven (19%) of 37 postmenarchal patients had evidence of HMB. Six (9.2%) patients had recurrent venous thromboembolism while on a DOAC (one was on apixaban, and five were on rivaroxaban) and were transitioned to other forms of anticoagulation. CONCLUSION: Thus, bleeding rates after DOAC therapy are comparable to previous DOAC trials, as well as other anticoagulants in pediatrics. HMB is an important outcome measure and should continue to be investigated. This study reports a higher rate of recurrent thrombosis (9.2%) compared to other trials. However, this observation may be attributed to patients who had ongoing risk factors, as well as a longer duration of study follow-up. Additional multicentered outcome studies evaluating DOAC use in children are needed to determine long-term recurrence and HMB risks.

The Effect of Levetiracetam Compared with Enzyme-Inducing Antiseizure Medications on Apixaban and Rivaroxaban Peak Plasma Concentrations.

BACKGROUND AND OBJECTIVE: Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM. METHODS: In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (Cmax) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC Cmax of patients taking LEV were compared with the other two groups. RESULTS: In 203 patients, 55% were female and the mean age was 78 ± 0.8 years. One hundred and eighty-six patients received apixaban and 17 patients received rivaroxaban. The proportion of patients with DOAC Cmax below their therapeutic range was 7.1% in the LEV group, 10.6% in the non-ASM group, and 36.4% in the EI-ASM group (p < 0.001). The odds of having DOAC Cmax below the therapeutic range (compared with control groups) was not significantly different in patients taking LEV (adjusted odds ratio 0.70, 95% confidence interval 0.19-2.67, p = 0.61), but it was 12.7-fold higher in patients taking EI-ASM (p < 0.001). In an analysis in patients treated with apixaban, there was no difference in apixaban Cmax between patients treated with LEV and non-ASM controls, and LEV clinical use was not associated with variability in apixaban Cmax in a multivariate linear regression. CONCLUSIONS: In this study, we show that unlike EI-ASMs, LEV clinical use was not significantly associated with lower apixaban Cmax and was similar to that in patients not treated with any ASM. Our findings suggest that the combination of LEV with apixaban and rivaroxaban may not be associated with decreased apixaban and rivaroxaban Cmax. Therefore, prospective controlled studies are required to examine the possible non-pharmacokinetic mechanism of the effect of the LEV-apixaban or LEV-rivaroxaban combination on patients' outcomes.

Perioperative Treatment with Rivaroxaban and Dabigatran on Changes of Coagulation and Platelet Activation Biomarkers following Left Atrial Appendage Closure.

Insufficient data exist regarding the investigation of the impact of novel oral anticoagulants (NOACs) on coagulation activation biomarkers in the context of left atrial appendage closure (LAAC) and device-related thrombosis (DRT). The study was designed to investigate the changes and presence of coagulation activation biomarkers between different antithrombotic strategies following LAAC. A total of 120 nonvalvular atrial fibrillation patients intolerant of long-term anticoagulants, who underwent successful WATCHMAN closure implantation, were enrolled (rivaroxaban, n = 82; dabigatran, n = 38). Blood samples were obtained from left atrium (LA) and left atrial appendage (LAA) during the operation and fasting blood samples on the same day of LAAC and 45 days after discharge. The biochemical indicators, thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), von Willebrand factor (vWF), and CD40 ligand (CD40L), were measured by enzyme-linked immunosorbent assay. The primary endpoints of this study were the efficacy and safety characteristics of different antithrombotic strategies, including DRT incidence, stroke or transient ischemic attack, systemic embolism, and clinical major and nonmajor bleeding complications during the follow-up of 180 days. The results revealed that TAT, vWF, sP-selectin, and CD40L levels in vein were significantly reduced by 2.4% (p = 0.043), 5.0% (p < 0.001), 8.7% (p < 0.001), and 2.5% (p = 0.043) from their baseline levels after rivaroxaban treatment. Conversely, no significant changes were detected in the dabigatran group. Furthermore, the plasma levels of platelet activation biomarkers (CD40L and sP-selectin) in both LA and LAA groups were significantly lower after anticoagulation with rivaroxaban, as compared to dabigatran treatment (CD40L: 554.62 ± 155.54 vs. 445.02 ± 130.04 for LA p = 0.0013, 578.51 ± 156.28 vs. 480.13 ± 164.37 for LAA p = 0.0052; sP-selectin: 2849.07 ± 846.69 vs. 2225.54 ± 799.96 for LA p = 0.0105, 2915.52 ± 1402.40 vs. 2203.41 ± 1061.67 for LAA p = 0.0022). Notably, the present study suggests that rivaroxaban may be more effective in the prevention of DRT for patients undergoing LAAC.

Toward Genetic Testing of Rivaroxaban? Insights from a Systematic Review on the Role of Genetic Polymorphism in Rivaroxaban Therapy.

BACKGROUND: Investigations into the rivaroxaban response from the perspective of genetic variation have been relatively recent and wide in scope, whereas there is no consensus on the necessity of genetic testing of rivaroxaban. Thus, this systematic review aims to thoroughly evaluate the relationship between genetic polymorphisms and rivaroxaban outcomes. METHODS: The PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Chinese databases were searched to 23 October 2022. We included cohort studies reporting the pharmacogenetic correlation of rivaroxaban. Outcomes measured included efficacy (all-cause mortality, thromboembolic events and coagulation-related tests), safety (major bleeding, clinically relevant non-major bleeding [CRNMB] and any hemorrhage), and pharmacokinetic outcomes. A narrative synthesis was performed to summarize findings from individual studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the reporting guideline for Synthesis Without Meta-Analysis. RESULTS: A total of 12 studies published between 2019 and 2022 involving 1364 patients were included. Ten, one, and six studies focused on the ABCB1, ABCG2, and CYP gene polymorphisms, respectively. Pharmacokinetic outcomes accounted for the majority of the outcomes reported (n = 11), followed by efficacy (n = 5) [including prothrombin time (PT) or international normalized ratio (n = 3), platelet inhibition rate (PIR) or platelet reactivity units (PRUs; n = 1), thromboembolic events (n = 1)], and safety (n = 5) [including major bleeding (n = 2), CRNMB (n = 2), any hemorrhage (n = 1)]. For ABCB1 gene polymorphism, the relationship between PT and ABCB1 rs1045642 was inconsistent across studies, however there was no pharmacogenetic relationship with other efficacy outcomes. Safety associations were found in ABCB1 rs4148738 and major bleeding, ABCB1 rs4148738 and CRNMB, ABCB1 rs1045642 and CRNMB, and ABCB1 rs2032582 and hemorrhage. Pharmacokinetic results were inconsistent among studies. For ABCG2 gene polymorphism, no correlation was observed between ABCG2 rs2231142 and dose-adjusted trough concentration (Cmin/D). For CYP gene polymorphisms, PIR or PRUs have a relationship with CYP2C19 rs12248560, however bleeding or pharmacokinetic effects did not show similar results. CONCLUSIONS: Currently available data are insufficient to confirm the relationship between clinical or pharmacokinetic outcomes of rivaroxaban and gene polymorphisms. Proactive strategies are advised as a priority in clinical practice rather than detection of SNP genotyping. CLINICAL TRIALS REGISTRATION: PROSPERO registration number CRD42022347907.

Comparison of High- and Low-Dose Rivaroxaban Regimens in Elderly East Asian Patients With Atrial Fibrillation.

BACKGROUND: In the Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban 20 mg was the on-label dose, and the dose-reduction criterion for rivaroxaban was a creatinine clearance of < 50 mL/min. Some Asian countries are using reduced doses label according to the J-ROCKET AF trial. The aim of this study was to assess the safety and efficacy of a high-dose rivaroxaban regimen (HDRR, 20/15 mg) and low-dose rivaroxaban regimen (LDRR, 15/10 mg) among elderly East Asian patients with atrial fibrillation (AF) in real-world practice. METHODS: This study was a multicenter, prospective, non-interventional observational study designed to evaluate the efficacy and safety of rivaroxaban in AF patients > 65 years of age with or without renal impairment. RESULTS: A total of 1,093 patients (mean age, 72.8 ± 5.8 years; 686 [62.9%] men) were included in the analysis, with 493 patients allocated to the HDRR group and 598 patients allocated to the LDRR group. A total of 765 patients received 15 mg of rivaroxaban (203 in the HDRR group and 562 in the LDRR group). There were no significant differences in the incidence rates of major bleeding (adjusted hazard ratio [HR], 0.64; 95% confidential interval [CI], 0.21-1.93), stroke (adjusted HR, 3.21; 95% CI, 0.54-19.03), and composite outcomes (adjusted HR, 1.13; 95% CI, 0.47-2.69) between the HDRR and LDRR groups. CONCLUSION: This study revealed the safety and effectiveness of either dose regimen of rivaroxaban in an Asian population for stroke prevention of AF. Considerable numbers of patients are receiving LDRR therapy in real-world practice in Asia. Both regimens were safe and effective for these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04096547.

Safety profile of rivaroxaban in first-time users treated for venous thromboembolism in four European countries.

BACKGROUND: The European rivaroxaban post-authorization safety study evaluated bleeding risk among patients initiated on rivaroxaban or vitamin K antagonists for the treatment and secondary prevention of venous thromboembolism in routine clinical practice. METHODS: Cohorts were created using electronic healthcare databases from the UK, the Netherlands, Germany and Sweden. Patients with a first prescription of rivaroxaban or vitamin K antagonist during the period from December 2011 (in the UK, January 2012) to December 2017 (in Germany, December 2016) for venous thromboembolism indication, with no record of atrial fibrillation or recent cancer history, were observed until the occurrence of each safety outcome (hospitalization for intracranial, gastrointestinal, urogenital or other bleeding), death or study end (December 2018; in Germany, December 2017). Crude incidence rates of each outcome per 100 person-years were computed. RESULTS: Overall, 44 737 rivaroxaban and 45 842 vitamin K antagonist patients were enrolled, mean age, 59.9-63.8 years. Incidence rates were similar between rivaroxaban and vitamin K antagonist users with some exceptions, including higher incidence rates for gastrointestinal bleeding in rivaroxaban users than in vitamin K antagonist users. Among rivaroxaban users, mortality and bleeding risk generally increased with age, renal impairment and diabetes. CONCLUSIONS: This study provides further data from routine clinical practice that broadly support safety profile of rivaroxaban for VTE indication and complement findings from previous randomized clinical trials.

The impact of factor Xa inhibitors on bleeding risk in patients with respiratory diseases.

It is unclear which factor Xa (FXa) inhibitors are associated with higher bleeding risk in patients with respiratory diseases, and there are no studies on the association between prothrombin time-international normalized ratio (PT-INR) and bleeding risk. We conducted a retrospective cohort study comparing 1-year-outcomes and PT-INR between patients with respiratory diseases treated with rivaroxaban (R group, n = 82) or edoxaban (E group, n = 138) for atrial fibrillation or venous thromboembolism from 2013 to 2021. The most frequent event of all bleeding discontinuations was respiratory bleeding in both groups (7.3 and 4.3%, respectively). The cumulative incidence of bleeding discontinuation was significantly higher in the R group (25.6%) than in the E group (14.4%) (hazard ratio [HR], 2.29; 95% confidence interval [CI] 1.13-4.64; P = 0.023). PT-INR after initiation of therapy significantly increased and was higher in the R group than in the E group (median value, 1.4 and 1.2, respectively; P < 0.001). Multivariate analysis using Cox proportional hazards and Fine-Gray models revealed that PT-INR after initiation of therapy was an independent risk factor of bleeding discontinuation events (HR = 4.37, 95% CI 2.57-7.41: P < 0.001). Respiratory bleeding occasionally occurs in patients receiving FXa inhibitors, and monitoring the PT-INR may need to ensure safety.

Age-related variation in coagulation factors in non-valvular atrial fibrillation patients receiving direct oral anticoagulants.

Age is a significant risk factor for ischemic stroke. However, the influence of aging on coagulation parameters in non-valvular atrial fibrillation (NVAF) patients treated with direct oral anticoagulants (DOACs) remains unclear. A total of 775 samples were collected from 224 NVAF patients receiving apixaban, edoxaban or rivaroxaban. The samples were categorized into three age groups: (i) ≤ 64 years, (ii) 65-74 years, and (iii) ≥ 75 years (apixaban: N = 48, 108, 119; edoxaban: N = 63, 68, 126; rivaroxaban: N = 115, 90, 38, respectively). Coagulation parameters including fibrinogen (Fbg), factor II, factor V, factor VII, factor X, and D-dimer, were compared between the three age groups for each drug. The slopes in the correlation between drug concentrations and modified diluted prothrombin time (mdPT) were also assessed. Fbg and factor V increased with age, while factor II and factor X decreased. Factor VII and D-dimer showed no significant differences across age categories. The slope in response to drug concentrations was similar between the age groups. In NVAF patients treated with apixaban, edoxaban and rivaroxaban, some coagulation parameters exhibited age-related variation. However, the response of mdPT to drug concentration was consistent across age categories.

Andexanet Alfa: What We Have Learned from Clinical Trials and Real-World Data.

Andexanet alfa is a specific reversal agent for factor Xa inhibitors with immediate reversal of their anticoagulant effect. Andexanet alfa is currently approved for use in patients treated with rivaroxaban and apixaban who have life-threatening or uncontrolled bleeding. New data from both controlled clinical trials and real-world experience are continuously being published, providing greater insight into the clinical characteristics of the drug, such as efficacy and safety. It is worth considering that andexanet alfa could be of benefit in a variety of different clinical scenarios where patients receiving treatment with apixaban and rivaroxaban (and endoxaban) have life-threatening conditions. These different clinical scenarios, which range from pre-treatment of urgent surgery, especially neurosurgical interventions, and concomitant use of andexanet alfa and prothrombin complex concentrate to onset of bleeding more than 6 h prior to admission, should be clarified as well as the issue of "low/high" dose of andexanet alfa and the need for baseline anti-Xa inhibitor levels measured by point-of-care testing. Finally, management of patients at high risk of thrombosis or recent arterial/venous thrombotic events needs to be further explored. In this current opinion, we address these urgent questions in the light of recent literature and clinical trial data.

Direct oral anticoagulants in trauma patients.

PURPOSE OF REVIEW: Direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic events. Thus, trauma care providers are facing a steadily raising number of injured patients on DOACs. RECENT FINDINGS: Despite a predictable pharmacokinetic profile, the resulting plasma levels of trauma patients upon admission and bleeding risks remain uncertain. Therefore, recent guidelines recommend the measurement of DOAC plasma concentrations in injured patients. Alternatively, DOAC specific visco-elastic tests assays can be applied to identify DOAC patients at bleeding risk.Bleeding complications in trauma patients on DOACs are generally higher compared to nonanticoagulated subjects, but comparable to vitamin K antagonists (VKAs). In particular, a traumatic brain injury does not carry an increased risk of intracranial bleeding due to a DOAK intake compared to VKAs. Current studies demonstrated that up to 14% of patients with a hip fracture are on DOACs prior to surgery. However, the majority can be operated safely within a 24h time window without an increased bleeding rate.Specific antagonists facilitate rapid reversal of patients on DOACs. Idarucizumab for dabigatran, and andexanet alfa for apixaban and rivaroxaban have been approved for life threatening bleeding. Alternatively, prothrombin complex concentrate can be used. Dialysis is a potential treatment option for dabigatran and haemoabsorption with special filters can be applied in patients on FXa-inhibitors. SUMMARY: Current guidelines recommend the measurement of DOAC plasma levels in trauma patients. Compared to VKAs, DOACs do not carry a higher bleeding risk. DOAC specific antagonists facilitate the individual bleeding management.

Dispensing pharmacy chains and direct anticoagulants: Potential associations with patient outcomes.

PURPOSE: Pharmacy chains can differ with respect to the characteristics of their patient populations as well as their nonprescription products, services, and practices, and thus may serve as a surrogate for potential unmeasured confounding in observational studies of prescription drugs. This study evaluates whether a single-source drug can have different patient outcomes based on the dispensing pharmacy chain. METHODS: Separate analyses for two anticoagulant drugs, rivaroxaban and apixaban, were conducted using Medicare Fee-for-Service claims evaluating the association between dispensing pharmacy chain and outcomes of acute myocardial infarction, ischemic stroke, intracranial hemorrhage, gastrointestinal (GI) bleeding, all-cause mortality, and major GI bleeding. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates across pharmacy chain cohorts, and outcome association was assessed with a Cox Proportional Hazards model. RESULTS: We observed no differences in outcomes across pharmacy chains for apixaban recipients. Rivaroxaban recipients from pharmacy chain C, however, had lower rates of GI bleeding (adjusted HR 0.83; 95% CI 0.69-1.00) and ischemic stroke (adjusted HR 0.57; 95% CI 0.38-0.87) as compared to chain A in primary analyses with a 3-day grace period. The results moved closer to the null when 14- and 30-day grace periods were implemented. CONCLUSIONS: These results suggest that dispensing pharmacy chains may have the potential to act as a confounder of associations between drug exposure and outcome in some observational studies. Additional studies of potential confounding by pharmacy chain are needed. Further evaluation of potential pharmacy chain effects on safe use would be of value.

Incorporating Prior Data in Quantitative Benefit-Risk Assessments: Case Study of a Bayesian Method.

BACKGROUND: Multiple criteria decision analysis (MCDA) and stochastic multi-criteria acceptability analysis (SMAA) in their current implementation cannot incorporate prior or external information on benefits and risks. We demonstrate how to incorporate prior data using a Bayesian mixture model approach while conducting quantitative benefit-risk assessments (qBRA) for medical products. METHODS: We implemented MCDA and SMAA in a Bayesian framework. To incorporate information from a prior study, we use mixture priors on each benefit and risk attribute that mixes information from a previous study with a vague prior distribution. The degree of borrowing is varied using a mixing proportion parameter. RESULTS: A demonstration case study for qBRA using the supplementary New Drug Application (sNDA) filing for Rivaroxaban for the indication of reduction in the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD) was used to illustrate the method. Net utility scores, obtained from the randomized controlled trial data to support the sNDA, from the MCDA for Rivaraxoban and comparator were 0.48 and 0.56, respectively, with Rivaroxaban being the preferred alternative only 33% of the time. We show that with only 30% borrowing from a previous RCT, the MCDA and SMAA results are favorable for Rivaroxaban, accounting for the seemingly aberrant results on all-cause death in the trial data used to support the sNDA. CONCLUSION: Our method to formally incorporate prior data in MCDA and SMAA is easy to use and interpret. Software in the form of an RShiny App is available here: https://sai-dharmarajan.shinyapps.io/BayesianMCDA_SMAA/ .