Association of anti-factor Xa-guided anticoagulation with hemorrhage during ECMO support: A systematic review and meta-analysis.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) is associated with complex hemostatic changes. Systemic anticoagulation is initiated to prevent clotting in the ECMO system, but this comes with an increased risk of bleeding. Evidence on the use of anti-Xa-guided monitoring to prevent bleeding during ECMO support is limited. Therefore, we aimed to analyze the association between anti-factor Xa-guided anticoagulation and hemorrhage during ECMO. METHODS: A systematic review and meta-analysis was performed (up to August 2023). PROSPERO: CRD42023448888. RESULTS: Twenty-six studies comprising 2293 patients were included in the analysis, with six works being part of the meta-analysis. The mean anti-Xa values did not show a significant difference between patients with and without hemorrhage (standardized mean difference -0.05; 95% confidence interval [CI]: -0.19; 0.28, p = .69). We found a positive correlation between anti-Xa levels and unfractionated heparin dose (UFH; pooled estimate of correlation coefficients 0.44; 95% CI: 0.33; 0.55, p < .001). The most frequent complications were any type of hemorrhage (pooled 36%) and thrombosis (33%). Nearly half of the critically ill patients did not survive to hospital discharge (47%). CONCLUSIONS: The most appropriate tool for anticoagulation monitoring in ECMO patients is uncertain. Our analysis did not reveal a significant difference in anti-Xa levels in patients with and without hemorrhagic events. However, we found a moderate correlation between anti-Xa and the UFH dose, supporting its utilization in monitoring UFH anticoagulation. Given the limitations of time-guided monitoring methods, the role of anti-Xa is promising and further research is warranted.

Comparison of Fixed Versus Weight-Based Prothrombin Complex Concentrate Dosing Strategies for Factor Xa Inhibitor Reversal.

Background: Our institution introduced fixed-dose prothrombin complex concentrate (PCC) to streamline order verification and medication administration. Previous studies using fixed-dose PCC for vitamin K antagonist reversal showed comparable efficacy to weight-based dosing. Objective: To compare fixed versus weight-based PCC dosing for reversal of Factor Xa Inhibitor (FXaI) effects. Methods: Retrospective cohort study conducted at a tertiary care academic medical center. Patients who received PCC to reverse the effects of apixaban or rivaroxaban were eligible. Subjects in the fixed-dose group (5000 units or 2000 units) were compared to weight-based PCC (50 units/kg). The primary outcome was time between order entry and medication administration. Secondary outcomes included: average PCC dose, postadministration procedures, achieved hemostasis, 30-day mortality, hospital length of stay, and adverse drug events. Results: 72 patients received fixed-dose PCC and 101 received weight-based PCC. Median time between order entry and administration was 4.5 min shorter in the fixed-dose group compared to weight-based (34.5 vs 39 min, P = .10). In patients who received fixed-dose, 79.2% achieved hemostasis versus 71.3% in the weight-based group (RR = 1.11, 95% CI = 0.94-1.32). There was no difference in the number of subsequent hemorrhage-related surgeries (29.2% vs 36.7%, RR = 0.80, 95% CI = 0.51-1.24) or mortality rate (26.4% vs 35.6%, RR = 0.73, 95% CI = 0.46-1.17). There were zero adverse drug events reported. Rates of thrombosis were 2.8% and < 1% (P = .57) in the fixed and weight-based groups, respectively. Conclusion and Relevance: The fixed-dosing strategy did not reduce time to PCC administration nor impact hemostasis or mortality. These data support that the fixed-dosing method is a viable option.

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.

Direct Oral Anticoagulation in Lung Transplant Recipients.

OBJECTIVES: Presently, the management of direct oral anticoagulants lacks specific guidelines for patients before and after transplant, particularly for lung transplant recipients. We aimed to consolidate the existing literature on direct oral anticoagulants and explore their implications in lung transplant recipients. MATERIALS AND METHODS: We conducted a comprehensive search in PubMed and Google Scholar databases for studies published between January 2000 and December 2022, using specific search terms. We only included studies involving lung transplant recipients and focusing on direct oral anticoagulants. RESULTS: Five relevant publications were identified, providing varied insights. None of the studies specifically addressed bleeding complications associated with direct oral anticoagulants in lung transplant recipients. Limited details were available on the type of solid-organ transplant or the specific direct oral anticoagulant used in these studies. CONCLUSIONS: Varied bleeding complications associated with direct oral anticoagulants in lung transplant recipients were reported, but studies lacked specificity on transplant type and direct oral anticoagulant variations. Notably, the incidence of venous thrombotic embolism in lung transplant recipients was comparatively higher than in other solid-organ transplant recipients, potentially linked to factors such as corticosteroid therapy, calcineurin inhibitors, and cytomegalovirus infections. Our synthesis on findings of use of direct oral anticoagulant in lung transplant recipients emphasized challenges of managing these medications in urgent transplant situations. Recommendations from experts suggested caution in initiation of direct oral anticoagulants posttransplant until stability in renal and hepatic function is achieved. The limited evidence on safety of direct oral anticoagulants in lung transplant recipients underscores the need for further research and guidance in this specific patient population.

Use of apixaban in adults with congenital heart disease and atrial arrhythmias: The PROTECT-AR study.

BACKGROUND: Adults with congenital heart disease (ACHD) and atrial arrhythmias (AA) face an increased risk of thromboembolic events. Limited data exist on the use of non-vitamin K oral anticoagulants for thromboprophylaxis in ACHD. We aimed to assess the effectiveness and safety of apixaban in ACHD patients with AA. METHODS: PROTECT-AR (NCT03854149) was a prospective, multicenter, observational study conducted from 2019 to 2023. ACHD patients with atrial fibrillation, atrial flutter, or intra-atrial re-entrant tachycardia on routine apixaban treatment were included. The historical control group consisted of patients previously on vitamin K antagonist (VKA), who were analyzed prior to their transition to apixaban. The primary effectiveness endpoint was the composite of stroke or thromboembolism. The primary safety endpoint was major bleeding. RESULTS: The study enrolled 218 ACHD patients with AA on apixaban, of which 73 were previous VKA users. The analysis covered 527 patient-years of prospective exposure to apixaban and 169 patient-years of retrospective exposure to VKA. The annualized rate of stroke or thromboembolism was 0.6% in the apixaban group and 1.8% in the VKA group (absolute difference - 1.2%; upper limit of one-sided 95% confidence interval [CI] 0.9%, lower than the predefined non-inferiority margin of +1.8%, Pnon-inferiority < 0.001). The annualized rate of major bleeding was 1.5% in the apixaban group and 2.4% in the VKA group (hazard ratio 0.64; 95% CI 0.19-2.10, P = 0.48). CONCLUSION: In ACHD patients with AA, routine apixaban use exhibited a non-inferior rate of stroke or thromboembolism compared to historical VKA use, alongside a similar rate of major bleeding.

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.

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.

Half-dose direct oral anticoagulation versus warfarin for atrial fibrillation following cardiac surgery.

BACKGROUND: Optimal anticoagulation strategies have not been defined for patients with atrial fibrillation following cardiac surgery. METHODS: From a total cohort of 228 patients with pre-existing or new onset atrial fibrillation following coronary artery bypass grafting and/or valve surgery, we compared in-hospital and 30-day outcomes in 119 patients treated with low-dose aspirin and a half-dose direct oral anticoagulant (DOAC) versus 109 treated with low-dose aspirin and warfarin. RESULTS: DOAC patients were older (73.1±7.0 vs. 68.7±11.4 years, P<0.001) and had a lower incidence of preoperative atrial fibrillation (37 [31.1%] vs. 69 [63.3%], P<0.001). Otherwise, the two cohorts were well matched for baseline demographics, cardiovascular risk factors, comorbidities, prior cardiac history and STS Risk Score. In comparison to Warfarin patients, DOAC patients had a shorter length of post-surgical stay (6 [5-8] vs. 7 [5-10] days, P=0.037). The two cohorts, however, had a similar incidence of stroke, transient ischemic attack, reoperation for bleeding and postoperative blood bank product usage. Follow-up 30-day outcomes did not differ between the two groups with respect to mortality (0 [0.0%] vs. 0 [0.0%], P=1.000) and hospital readmission (16 [13.4%] vs. 14 [12.8%], P=0.893), although two DOAC patients required drainage of sanguineous pericardial effusions. CONCLUSIONS: In comparison to warfarin, half-dose DOAC anticoagulation in patients with atrial fibrillation following cardiac surgery is associated with a shorter postoperative length of stay, without a significant increase in stroke/transient ischemic attack, reoperation for bleeding or postoperative blood product transfusion. Follow-up echocardiography in anticoagulated patients is recommended to rule out significant sanguineous pericardial effusions in the early postoperative period following hospital discharge.

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.

Appropriateness of direct oral anticoagulant prescribing in older subjects with atrial fibrillation discharged from acute medical wards.

AIMS: Knowledge on the prescriptive practice of direct oral anticoagulants (DOACs) in older subjects with atrial fibrillation (AF) hospitalized in acute medical wards is limited. This study aimed to evaluate the prevalence and appropriateness of DOAC prescriptions in hospitalized older subjects with AF, discharged from acute medical wards. METHODS: We analysed a cohort of 609 subjects with AF, aged ≥65 years (mean age 85 years) enrolled from 39 geriatric and nephrology wards in Italy. DOAC prescriptive appropriateness was evaluated according to the summary of product characteristics (smPC), 2019 Beers and STOPP criteria, and drug-drug interactions (DDIs). RESULTS: At hospital discharge, 33% of patients with AF were prescribed with DOAC, 26% with vitamin-K antagonist, while 41% did not receive any anticoagulant. Among subjects on DOAC therapy, 31% presented a violation of the smPC criteria (mainly underdosage-17%), while 48% and 18% presented a Beers/STOPP inappropriate prescription, or a DDI, respectively. Older age, lower body mass index (BMI), cancer and higher estimated glomerular filtration rate (eGFR) were independently associated with DOAC underdosage or missed prescription (age: adjusted odds ratio [aOR] 1.06, 95% confidence interval [95% CI] 1.00-1.12 for underdosage; eGFR: aOR 1.04, 95% CI 1.02-1.07 for underdosage; BMI: aOR 0.95, 95% CI 0.91-0.99 for missed prescription; cancer: aOR 1.93, 95% CI 1.19-3.13 for missed prescription). CONCLUSIONS: This study showed a suboptimal DOAC prescriptive practice in older in-patients, with frequent missed prescription and DOAC underdosage. Contrary to current recommendations, physicians appear overly concerned by bleeding risk in real-life older and frailer subjects. Strategies should be developed to promote appropriate DOAC prescription in the hospital setting.

Management of patients with proximal femur fractures under DOACs.

PURPOSE: In the past, preinjury direct oral anticoagulant (DOAC) intake has led to delays in time to surgery (TTS) in patients with proximal femur fractures and delays in surgery have been associated with impaired outcomes. Although healthcare institutions/federal committees have set rules for treatment within 24 h of injury, comprehensive guidelines for the perioperative management of these patients, in particular when on preinjury DOACs, are still lacking. This contribution aims to summarize the current evidence on the safe time window for surgery in patients with proximal femur fractures on preinjury DOACs and to outline therapeutic options if emergency DOAC reversal becomes necessary. METHODS: Narrative review based upon selective review of the pertinent literature. RESULTS: For the majority of patients with proximal femur fractures and on preinjury DOACs, early surgery appears safe as soon as medical clearance has been obtained. There may be an increase in the need for blood products but with data not yet conclusive. Work-up including assessment of remaining anticoagulant activity and potential reversal should be restricted to patients at risk for bleeding complications, in particular in the presence of renal/hepatic impairment. Methodology for rapid assessment of DOACs including quantitative/qualitative concentration levels is work in progress. In the case of bleeding, rapidly acting reversal agents are available. CONCLUSION: Preinjury DOAC use should not routinely delay surgery in patients with proximal femur fractures.

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.

Mortality after major bleeding in Asian atrial fibrillation patients receiving different direct oral anticoagulants: a nationwide, propensity score study.

In this research, we assessed mortality after major bleeding events in atrial fibrillation (AF) patients taking four direct oral anticoagulants (DOACs). Drawing data from the Taiwan National Health Insurance Research Database between 2016 and 2019, we focused on AF patients on DOACs who had major bleeding episodes. Using propensity score stabilized weighting, we established four comparable pseudo-DOAC groups. Among 2770 patients (460 dabigatran, 1322 rivaroxaban, 548 apixaban, 440 edoxaban), 85.3% were prescribed low-dose regimens. The 7-day mortality rate was 9.0%, surging to 16.0% by the 30th day. Compared with dabigatran, there was a distinct divergence in 7-day mortality of factor Xa inhibitors (p = 0.012), with hazard ratios of 1.83 (95% CI 1.11-3.00, p = 0.017) for rivaroxaban, 2.13 (95% CI 1.23-3.66, p = 0.007) for apixaban, and 2.41 (95% CI 1.39-4.19, p = 0.002) for edoxaban. This pattern remained consistent when analyzing the subgroup that received lower dosages of DOACs. In conclusion, factor Xa inhibitors were associated with a significantly higher risk of 7-day mortality following major bleeding events than dabigatran among AF patients.

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/ .