Dose Of Rivaroxaban Research Articles

Antithrombozytäre Therapie und Antikoagulation bei Patienten mit koronarer Herzerkrankung

Coronary heart disease (CHD) is a dynamic process with acute instable events and chronic periods leading to an increased mortality. Patients with CHD benefit from a differentiated antithrombotic therapy consisting of dual antiplatelet therapy in the acute phase and antiplatelet monotherapy or in combination with low dose anticoagulation (Xa-Inhibition) in the chronic phase. Current ESC-guidelines differentiate the acute coronary syndrome (ACS) and the chronic coronary syndrome (CCS). Depending on thrombotic burden, bleeding risk, comorbidities, such as atrial fibrillation, antiplatelet agents and oral anticoagulants in various combinations and dosages are used. In most scenarios in patients with ACS, the initial therapy will consist out of acetylsalicylic acid and a P2Y12-Inhibitor for 12 months followed by either a continuous monotherapy with acetylsalicylic acid (ASS), a prolonged dual antiplatelet therapy or a continuous dual antithrombotic therapy consisting of ASS and low dose rivaroxaban 2x daily. With atrial fibrillation as an underlying condition, an anticoagulant should be part of the therapy followed by anticoagulant monotherapy in the chronic phase of the disease (CCS). This article provides information about the different drugs and therapeutic algorithms based on the newest ESC-Guidelines and up to date studies.

How to handle the delayed or missed dose of rivaroxaban in patients with non-valvular atrial fibrillation: model-informed remedial dosing

ABSTRACT Background Rivaroxaban is an oral anticoagulant widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). During long-term anticoagulant therapy, delayed or missed doses are common. This study aimed to explore appropriate remedial dosing regimens for non-adherent rivaroxaban-treated patients. Methods Monte Carlo simulation based on a previously established rivaroxaban population pharmacokinetic/pharmacodynamic (PK/PD) model for patients with NVAF was employed to design remedial dosing regimens. The proposed regimens were compared with remedial strategies in the European Heart Rhythm Association (EHRA) guide by assessing deviation time in terms of drug concentration, factor Xa activity, and prothrombin time. Results The proposed remedial dosing regimens were dependent on delay duration. The missed dose should be taken immediately when the delay does not exceed 6 h; a half dose is advisable when the delay is between 6 and 20 h. A missed dose should be skipped if less than 4 h remains before the next dose. The proposed regimens resulted in shorter deviation time than that of the EHRA guide. Conclusion PK/PD modeling and simulation provide valid evidence on the remedial dosing regimen of rivaroxaban, which could help to minimize the risk of bleeding and thromboembolism.

Editor's Choice – External Applicability of the COMPASS and VOYAGER-PAD Trials on Patients with Symptomatic Lower Extremity Artery Disease in France: The COPART Registry

The aim of this study was to examine the external applicability of the COMPASS and the VOYAGER-PAD trials in patients with lower extremity artery disease (LEAD) in the real world. This was a multicentre retrospective analysis of prospectively collected COPART data, a French multicentre registry of patients hospitalised for symptomatic LEAD. The proportion of patients eligible for the combination of rivaroxaban 2.5 mg twice daily plus aspirin based on either COMPASS or VOYAGER-PAD criteria is reported. The one year cumulative incidence of outcomes between eligible and non-eligible patients, as well as eligible patients vs. control arms of the COMPASS (LEAD patient subgroup) and the VOYAGER-PAD trials were compared. Analyses were performed using Cox models. Of 2 259 evaluable patients, only 679 (30.1%) were eligible for a low dose rivaroxaban plus aspirin regimen. Others were not eligible because of the need for anticoagulant (48.5% and 38.9% of patients meeting COMPASS and VOYAGER-PAD exclusion criteria, respectively) or dual antiplatelet therapy use (15.7% and 16.5%, respectively), high bleeding risk (14.4% and 11.6%, respectively), malignancy (26.1% and 21.0%, respectively), history of ischaemic/haemorrhagic stroke (21.1% and 19.8%, respectively), and severe renal failure (13.2% and 10.5%, respectively). COMPASS and VOYAGER-PAD eligible and ineligible patients were at higher risk of ischaemic events than participants in these trials. The one year cumulative incidences were 6.0% (95% CI 4.3 - 8.1) in the COMPASS eligible subset vs. 3.5% (95% CI 2.9 - 4.3) in the COMPASS control arm for major adverse cardiovascular events, and 27.9% (95% CI 19.9 - 38.3) in the VOYAGER-PAD eligible subset vs. 6.0% (95% CI 5.3 - 6.9) in the VOYAGER-PAD control arm for major adverse limb events. Many patients hospitalised for symptomatic LEAD in France are not eligible for the low dose rivaroxaban plus aspirin combination. In turn, those eligible may potentially have greater absolute benefit because of higher risk than those enrolled in the trials.

Prediction of Rivaroxaban-Rifampin Interaction After Major Orthopedic Surgery: Physiologically Based Pharmacokinetic Modeling and Simulation.

Rivaroxaban is commonly used for the prophylaxis of venous thromboembolism (VTE) for patients undergoing major orthopedic surgery. Rivaroxaban is primarily eliminated by hepatic CYP450 metabolism and renal excretion. Rifampin is a commonly used antibiotic for prosthetic joint infections (PJI) and a potent inducer of CYP450 enzymes. Clinical data about drug-drug interactions of rivaroxaban and rifampin are limited. The present study is to describe DDI of rivaroxaban and rifampin in several prosthetic joint infections patients undergoing major orthopedic surgery. We retrospectively identified six patients concomitantly administered with rivaroxaban and rifampin between 2019 and 2020. Plasma samples of these patients with accurate sampling time were chosen from the biobank and plasma levels of rivaroxaban were measured at each time point. A physiologically based pharmacokinetic model for the rivaroxaban-rifampin interaction was developed to predict the optimal dosing regimen of rivaroxaban in the case of co-medication with rifampin. The model was validated by the observed plasma concentration of rivaroxaban from the above patients. From this model, it could be simulated that when rifampin starts or stops, gradually changing rivaroxaban dose during the first few days would elevate the efficacy and safety of rivaroxaban.

Characteristics of patients receiving extended treatment after incident venous thromboembolism

Given high recurrence risk after venous thromboembolism (VTE), guidelines recommend extended dose rivaroxaban (10mg OD) or apixaban (2.5mg BID) to be considered after 6months of initial treatment. This study aimed to provide insight into clinical practice regarding the use of extended preventive treatment and to describe duration of the initial treatment. Linkage of nationwide health registers identified all in- and outpatients with VTE from April 2017 through 2018. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated adjusting for other VTE-related factors. The study included 6030 patients with VTE. Among rivaroxaban users, 2.2% (n= 113) received the extended 10-mg dose after mean 9.4 (SD 3.1) months of standard treatment. For apixaban, 4.7% (n= 40) received extended 2.5-mg dose after mean 8.0months (SD 3.9). After adjustments, incident pulmonary embolism (HR 1.81 95% CI 1.12;2.91) and trauma/fracture (HR 1.42 95% CI 0.46;4.43) were associated with switching to extended dose, whereas patients with unprovoked VTE were less likely to receive the extended dose (HR 0.68 95% CI 0.30;1.55). Less than 3% of patients with incident VTE received extended treatment after initial standard treatment. Even though international guidelines suggest that the risk-benefit balance is in favour of extended VTE treatment, this was yet to be translated into clinical practice as of 2018. Studies using contemporary data are warranted to investigate routine clinical practice of extended treatment for VTE recurrence.

Rivaroxaban in patients with atrial fibrillation: from research to real practice (based on REGistry of Long-term AnTithrombotic TherApy-2 (REGATA))

Introduction. Despite the large evidence base for the use of rivaroxaban, cohort studies are interesting because shows the possibility of anticoagulant therapy in patients with high thromboembolic and bleeding risk and a burden of comorbidity in practice.Aim: to evaluate the efficacy and safety of rivaroxaban therapy in patients with atrial fibrillation in prospective REGATTA registry.Materials and methods. This study is a fragment of a single-center prospective REGATA registry (Registry of Long-term Antithrombotic Therapy (NCT043447187), conducted on the basis of the National Research Center of Cardiology of the Ministry of Health of the Russian Federation. 152 patients with high thromboembolic risk (median CHA2DS2-VASc = 4) received rivaroxaban therapy (median follow-up 1.5 years). The efficacy endpoint was the sum of cardiovascular complications (including cardiovascular death, ischemic stroke, and acute coronary syndrome). The safety endpoint bleedinds BARC types 2-5.Results. The frequency of cardiovascular events (combining cardiovascular death, ischemic stroke and acute coronary syndrome) was 5.8/100 patient-years. The use of a “reduced” dose of rivaroxaban was an independent predictor of the development of fatal cardiovascular complications. The rate of major bleeding was 3.7/100 patient-years, and the rate of clinical relevant bleedings was 19.4 /100 patientyears. The predictors of major/ clinical relevant bleedings were chronic kidney disease with a decrease in creatinine clearance of less than 50 ml/min and the anamneses of major/ clinical relevant bleedings.Conclusion. The main requirement for improving the safety of anticoagulants is follow up, focused in all changes in the cardiovascular and somatic status of the patient during treatment.

Modern concepts of the place of acetylsalicylic acid in the treatment of patients with various manifestations of atherothrombosis

The review is devoted to the analysis of the significance of acetylsalicylic acid (ASA) in the primary and secondary prevention of various manifestations of atherothrombosis. The results of the ARRIVE, ASPREE and ASCEND studies are considered, based on which the evidence base for the use of reduced low-dose ASA (75-100 mg) for primary prevention of cardiovascular diseases (CVD), including patients with diabetes mellitus is formed. Nevertheless, the question of the significance of ASA in primary prevention of CVDs has not been finally resolved, because the results of the latest TIPS-3 study, published in 2020, showed that the combination of enteric-coated ASA with a polypill consisting of a statin and three hypotensive drugs, compared with placebo, reduces the frequency of cardiovascular episodes (CVEs) in individuals without CVDs but with average cardiovascular risk. ASA is an immutable component of dual antiplatelet therapy (DAPT) in patients with acute coronary syndromes (ACS), in patients with coronary heart disease, subjected to planned stenting. Recently, evidence has been obtained about the impact of bleeding on prognostic outcomes, so there is a clear trend to reduce the duration of aspirin therapy in patients with atrial fibrillation and ACS or undergoing planned stenting. A new trend is enhancement of ASA therapy with a second antithrombotic drug in patients with stable manifestations of atherothrombosis with high risk of thrombotic complications. Thus, modern recommendations suggest to enhance ASA therapy with a vascular dose of rivaroxaban (2.5 mg 2 p/day) or a P2Y12-receptor platelet inhibitor. ASA appears to be a classic antiaggregant and an essential partner for new antithrombotic drugs.

Possibilities of the efficiency and safety control of rivaroxaban application in patients with atrial fibrillation

The results of a study of the concentration of rivaroxaban in the peripheral blood in patients with atrial fibrillation, receiving different doses of rivaroxaban, as well as in the case of developing hemorrhagic complications, are presented. 65 patients admitted for treatment for atrial fibrillation were examined. As an anticoagulant drug, rivaroxaban was prescribed at a dose of 15 or 20 mg once a day, depending on the state of renal function. The patients were divided into 3 groups depending on the prescribed dose of rivaroxaban and the presence or absence of hemorrhagic complications. At the same time, each patient underwent therapeutic drug monitoring of the drug. It was found that in patients, who received rivaroxaban at a dose of 15 mg, in 35% of cases its concentration in the blood was below the average minimum values. In patients, who received the drug at a dose of 20 mg, in 16% of cases its concentration in the blood serum exceeded the average maximum values. Patients treated with 15 mg of rivaroxaban lacked any hemorrhagic complications. In the group of patients with advanced hemorrhagic complications who received rivaroxaban at a dose of 20 mg, its serum concentration at all stages of therapeutic drug monitoring was significantly higher than the average maximum values and more than 4 times higher than in the control group (without hemorrhagic complications). The results of the study indicate the advisability of conducting therapeutic drug monitoring with the determination of rivaroxaban concentrations in the blood serum of patients receiving the drug, especially when they develop hemorrhagic complications.

Atrial fibrillation in old age: risk management and features of the use of direct oral anticoagulants

Senile patients with atrial fibrillation (AF) are at a higher risk of thromboembolism and hemorrhage than younger patients. Three direct oral anticoagulants (DOAC), apixaban, dabigatran, and rivaroxaban, are registered in the Russian Federation and are extensively used for prevention of stroke in patients with AF. The DOAC treatment of older patients requires considering peculiarities of these patients, clinical situation and properties of individual drugs to achieve the balance of efficiency and safety and a comprehensive protection. According to studies of real clinical practice DOAC may have advantages over warfarin (reduced risk of fractures, diabetes mellitus, and dementia). Compliance with and constancy of the DOAC treatment are important for its efficiency, particularly in senile age. Results of clinical trials and real clinical practice studies have confirmed that rivaroxaban may provide a comprehensive protection for a senile patient with AF due to favorable indexes of efficiency and safety, beneficial effect on the risk of coronary events and impairment оf renal function, whereas once a day dosing of rivaroxaban improves the compliance with this treatment and its constancy.

Effects of Routine Antithrombotic-Adjusted Dose of Rivaroxaban and Nadroparin Calcium on Tendon Healing of Rats: An Experimental Study

Introduction Achilles tendon injury necessitates thromboembolism prophylaxis after repair. This study aimed to investigate the effects of antithrombotic-adjusted prophylactic doses of nadroparin calcium and rivaroxaban on Achilles tendon healing.Materials and Methods Twenty-four young adult male Wistar Albino type rats were randomly divided into three groups. All rats underwent a full-thickness surgical incision of the Achilles tendon, followed by primary repair. After the procedure, group 1 was determined as the control group and received no medication. Group 2 received 2.03 mg/kg rivaroxaban daily via gastric lavage once daily, and group 3 was given subcutaneous 114 IU AXa nadroparin calcium once daily for 28 days. After euthanization, the degrees of inflammation, neovascularization, fibroblastic activity, and collagen fiber sequencing were examined and scored for histopathological evaluation. The Statistical Package for Social Science (SPSS) version 21.0 for Windows software (SPSS, Inc., Chicago, Illinois, United States) was used for all statistical analyses. The number of inflammatory cells, capillary vessels, and fibroblasts, which met the parametric tests' assumptions, were compared between three independent groups by one-way analysis of variance. The significance level was set at p-value < 0.05.Results Histological examination of the group 1 sample showed the presence of inflammatory cells, an increase in the number of fibroblasts, and sequencing of collagen fibers scattered. The presence of inflammatory cells, remarkable increases in the number of fibroblasts, the presence of mature collagen fibers, and regular sequencing of collagen fibers regular were shown in groups 2 and 3. There were statistically significant differences between the groups regarding the number of inflammatory cells and fibroblasts. In group 2, the number of inflammatory cells was lower than in groups 1 and 3. Elsewhere, the number of fibroblasts was higher in group 1 compared than in groups 2 and 3.Conclusion Both rivaroxaban and nadroparin calcium in their daily dosage have a beneficial effect on Achilles tendon healing.

Effectiveness and Safety of the 15 Mg Dose of Rivaroxaban Compared with Vitamin k Antagonists in Patients with Atrial Fibrillation: Results from a Cohort Study in the Nationwide French Claims and Hospitalization Database (SNIIRAM)

Background: Large randomized trials have established that non-vitamin K antagonist oral anticoagulants (NOACs) have a similar efficacy to warfarin but generally have a superior safety profile for stroke prevention in atrial fibrillation (SPAF). However, evidence on reduced dose regimens of NOACs from “real world” clinical practice is scarce. A recent Danish analysis found mixed results with higher mortality in patients treated with reduced doses of some NOACs. In response to this lack of firm evidence about reduced dose regimens for SPAF, a nationwide cohort study was conducted to examine effectiveness and safety for new users of reduced doses of rivaroxaban (R) vs vitamin K antagonists (VKA) for SPAF, rivaroxaban 15 mg being indicated for SPAF in patients with moderately impaired renal function.Methods: Cohorts of new users of R 15 mg once a day or VKA for SPAF in 2013 or 2014 were identified in the 66 million persons nationwide French claims and hospitalization database (SNIIRAM) and followed-up for at least one year and up to 2 years. AF was defined from full coverage, hospitalization or procedure for atrial fibrillation without valvular disease using 3-year database history. For each comparison, patients were matched 1:1 on gender, age, date of the first anticoagulant dispensing, and high-dimensional propensity score, including major arterial thrombosis and bleeding risk factors; Hazard ratios (HR) [95% confidence interval] were determined over follow-up during first prescribed anticoagulant exposure, using the Cox proportional hazard risk model or the Fine and Gray model.Results: Of 734,599 incident anticoagulant users in 2013 or 2014, 133,181 were NVAF patients treated with VKA or 15 mg R (108,641 VKA and 24,540 R). Mean age was 78.7 years, 51.0% were male, 81.6% had CHA2DS2VASc score ≥ 2 and 15.2% HAS-BLED score > 3 with significant differences between anticoagulants. For R vs. VKA, 23,314 patients were matched per arm; overall incidence during exposure was 2.5 % person-years (%PY) for stroke and systemic embolism (SSE), 3.0%PY for major bleeding (MB), 5.4%PY for clinically relevant bleeding (CRB), 1.9% for acute coronary syndromes (ACS), 11.1% for death and 15.3% for composite of stroke and SE, major bleeding and death. HR were 1.05 [0.92-1.21] for SSE, 0.84 [0.74-0.96] for MB, 0.89 [0.81-0.98] for CRB, 0.85 [0.73-1.00] for ACS, 0.85 [0.79-0.90] for death and 0.89 [0.84-0.94] for composite.Conclusions:In this large propensity score matched nationwide comparative cohort study, rivaroxaban 15 mg was associated with similar rates of stroke/systemic embolism but lower rates of bleeding and death compared with vitamin K antagonists. A recently reported higher mortality with reduced doses of some NOACs was not confirmed with rivaroxaban in this larger study. DisclosuresFauchier:bayer: Consultancy. Sacher:Bayer: Consultancy; boehringer-Ingelheim: Consultancy; Bristol-Myers-Squibb: Consultancy. Dallongeville:Bayer: Consultancy. Moore:bayer Pharma: Other: grant for the present study of Rivaroxaban on SPAF; Boehringer-Ingelheim: Other: grant for a similar study of dabigatran.

The Effects of Rivaroxaban Exposure and Clinical Risk Factors on Efficacy and Safety Outcomes in the Prevention of Venous Thromboembolism after Elective Hip or Knee Replacement Surgery

Introduction: The oral factor Xa inhibitor rivaroxaban has previously demonstrated a predictable pharmacokinetic (PK) and pharmacodynamic profile, and has been developed for fixed dose administration without routine coagulation or therapeutic drug monitoring (TDM). The objectives of this study were to investigate the relationship between rivaroxaban exposure and efficacy/safety outcomes, and to evaluate the relative influence of relevant clinical risk factors in patients receiving rivaroxaban for venous thromboembolism prevention (VTE-P) after elective total hip replacement (THR) or total knee replacement (TKR) surgery to assess whether TDM might further improve the benefit-risk profile of rivaroxaban in this population.Methods: An exposure-response analysis was conducted using data from patients receiving rivaroxaban (10 mg once daily [OD] for ≤35 days after THR or ≤14 days after TKR) in the phase 3 REgulation of Coagulation in ORthopedic Surgery to prevent DVT and PE (RECORD) trials (efficacy population, n = 4246; safety population, n = 6097). Due to a lack of measured PK data in the phase 3 trials, individual rivaroxaban exposure metrics (area under the plasma concentration-time curve, maximum concentration and trough concentration [Ctrough]) were estimated using an integrated population PK model based on clinical risk factors, regimen and (where available) PT measurements. Exposure estimates were improved by applying an adjustment function based on the linear relationship between PK and prothrombin time measurements (measured centrally using a rivaroxaban-sensitive thromboplastin reagent) obtained in the phase 2/3 rivaroxaban studies. The composite efficacy outcome was total VTE (any objectively-documented asymptomatic or symptomatic deep vein thrombosis [proximal and/or distal], non-fatal pulmonary embolism and death). Safety endpoints were major bleeding, and a composite of major and non-major clinically relevant (NMCR) bleeding occurring (1) ≤3 days after surgery (days 1-4) and (2) >3 days after surgery (after day 4). The relationships between exposure/clinical risk factors and outcomes in terms of event rates were evaluated using logistic regression models.Results: The model-estimated rivaroxaban exposures are summarized in the Table. In the final model, age and creatinine clearance were included as forced variables for all endpoints. Exposure was not found to be a significant predictor of total VTE, major bleeding (days 1-4 and after day 4), or of the composite safety endpoint of major and NMCR bleeding during days 1-4. For major and NMCR bleeding after day 4, a statistically significant exposure-response relationship was observed, with Ctrough displaying the strongest association. The odds ratios (ORs) associated with Ctrough in the 5th and 95th percentiles versus the median were 0.82 (95% confidence interval [CI]: 0.77-0.87) and 1.68 (95% CI: 1.21-2.33), respectively. The relationship was shallow, with a predicted absolute increase in major and NMCR bleeding of ~1% at the 5th percentile of Ctrough to 2% at the 95th percentile (Figure). No clinical risk factors were predictors of total VTE or of major bleeding (days 1-4 and after day 4), or of major and NMCR bleeding after day 4. Male versus female sex (OR: 3.05; 95% CI: 1.92-4.93) and geographical region (OR: 1.63; 95% CI: 0.98-2.70, for the USA/Canada vs Western Europe) were significant predictors (p < 0.00001 and p <0.001, respectively) of major and NMCR bleeding during days 1-4.Conclusions: An exposure-response relationship for total VTE and major bleeding events was not observed in patients enrolled in the RECORD trials despite significant reductions in VTE with rivaroxaban versus the comparator enoxaparin, indicating a favorable benefit-risk ratio over the range of rivaroxaban concentrations observed with the 10 mg OD fixed dose. Exposure, and particularly Ctrough, was the predominant predictor of major and NMCR bleeding after day 4. These data are consistent with rivaroxaban phase 2 VTE-P studies, in which no significant dose-response relationship was observed for total VTE, but post-operative bleeding events increased dose dependently over the ranges of rivaroxaban doses of 5-40 mg OD and 2.5-30 mg twice daily. Based on these findings it is unlikely that TDM would further improve the benefit-risk profile of rivaroxaban for VTE prevention after THR and TKR. [Display omitted] DisclosuresBerkowitz:Bayer US: Employment. Fox:Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; AstraZeneca: Research Funding; Janssen Biotech, Inc.: Consultancy, Honoraria. Schmidt:Bayer HealthCare Pharmaceuticals: Consultancy. Weitz:Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Pfizer, Inc.: Consultancy, Honoraria; Janssen Biotech, Inc.: Consultancy, Honoraria; Ionis Pharmaceuticals: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Merck & Co., Inc.: Consultancy, Honoraria. Garmann:Bayer AG: Employment. Kubitza:Bayer AG: Employment. Mueck:Bayer AG: Employment. Peters:Janssen Research & Development: Employment. Reinecke:Bayer AB: Employment; Bayer AG: Employment. Solms:Bayer AG: Employment. Spiro:Bayer US: Employment. Yan:Janssen Research & Development: Employment. Zhang:Janssen Research & Development: Employment. Willmann:Bayer AG: Employment.

Oral Anticoagulant Dosing, Administration, and Storage: A Cross-Sectional Survey of Canadian Health Care Providers

Background: Direct oral anticoagulant (DOAC) use is increasing worldwide. However, if not taken or prescribed correctly, DOACs have serious side effects. It is crucial that healthcare providers (HCPs) provide patients with accurate information and counselling around DOACs, to optimize safe and effective use.Aims: To assess HCPs' knowledge about oral anticoagulant indication, dosing, storage, and administration.Methods: An electronic survey was distributed to HCPs across Canada from June to July 2017, with 18 questions on oral anticoagulant practical use.Results: A total of 73 responses were received: 27 (37%) from Hematologists, 4 (5.4%) from Thrombosis Medicine specialists, 17 (23.3%) from nurse practitioners, 17 (23.3%) from pharmacists, and 8 (11%) from residents and fellows in Hematology training programs across Canada. The median duration of practice was 7 years (range 0.5 to 41). The majority of respondents (64 of 73; 88%) worked in the outpatient setting. Only 18 (25%) of the respondents correctly identified all the approved indications for warfarin and 4 DOACs including dabigatran, rivaroxaban, apixaban, and edoxaban. Most of the respondents (54 of 73; 74%) correctly identified that DOACs are not approved for treatment of heparin induced thrombocytopenia, cerebral sinus venous thrombosis, or mechanical prosthetic valves. However, 11 (15%) cited one or more of the above indications incorrectly; 7 of 11 (9.5%) alarmingly chose mechanical prosthetic valves as an indication for DOACs. Most of the respondents (51 of 73; 70%) felt comfortable or very comfortable prescribing oral anticoagulants. When counselling patients, 69 (95%) discussed the indication and bleeding side effects, 62 (85%) discussed when/how to take the drug, and only 37 (51%) discussed adherence and administration strategies. About two thirds of the respondents (63%) knew that dabigatran should not be crushed, however only 38 (52%) knew that it should not be exposed to moisture. Forty-five of the respondents (62%) knew that higher dose rivaroxaban should be taken with food. While 45 (62%) correctly adjusted the dose of apixaban based on age, only 35 (48%) did the same for dabigatran. 80%, 77%, 70%, and 45% correctly adjusted rivaroxaban, apixaban, dabigatran, and edoxaban, respectively for renal function.Conclusions: Although the majority of respondents expressed comfort with oral anticoagulants, there are important knowledge gaps around HCPs' practical understanding of oral anticoagulants, particularly in correctly identifying approved indications and counselling patients on adherence and administration. These knowledge gaps (e.g., inappropriate DOAC use in patients with mechanical valves) may lead to significant patient harm in the form of thrombosis or bleeding. Future research should focus on educational interventions to improve HCPs' knowledge around oral anticoagulants, with the goal of enhancing patient safety.Figure 1. What do health care providers counsel patients about when prescribing oral anticoagulants? [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Peak Plasma Rivaroxaban Levels in Individuals Weighing over 120 Kilograms

BackgroundRivaroxaban, a direct oral anticoagulant (DOAC), has been shown to be an efficacious and safe agent for treatment and secondary prevention of thromboembolism (TE). Currently, there is limited evidence available regarding its use in individuals weighing > 120 kg. Given the increasing prevalence of obesity in the general population, and that elevated weight itself is a risk factor for TE, this lack of data is a substantial issue. Theoretically, the greater volume of distribution in obesity may decrease DOAC peak drug concentration and half-life, potentially resulting in sub therapeutic anticoagulation. In fact, current ISTH guidelines recommend against empiric use of DOACs in patients over 120 kg, with the caveat that their use may be considered if drug specific peak and trough levels fall within the expected range (Martin et al. J Thromb Haemost. 2016). Additional data is required to guide the clinician regarding DOAC use for the management of TE in this growing demographic.ObjectivesOur primary objective was to assess peak rivaroxaban plasma levels (PRPL) in patients weighing > 120 kg on the standard 20 mg daily dose for treatment or secondary prevention of VTE and to compare these values to the expected range derived from pharmacokinetic studies in non-obese patients. The secondary objective was to assess for TE complications in this cohort.MethodsElectronic patient records were retrospectively reviewed at a thrombosis clinic at a single center from January 1, 2014 to May 31, 2017. Patients of age > 18, on rivaroxaban for treatment or secondary prevention of VTE, of weight > 120kg, and with at least one PRPL, measured 2-4 hours post drug ingestion at steady state, were included in the study. Patients with decreased renal function (creatinine clearance < 30mL/min), liver dysfunction (Child-Pugh score B or C), on concomitant strong P-glycoprotein or CYP 3A4 inducers or inhibitors, or with an additional indication for anticoagulation were excluded. Reference ranges for PRPL were extracted from pharmacokinetic studies (Buller et al. Blood. 2008). PRPL were measured using an anti-Xa assay calibrated to rivaroxaban (BIOPHENTM DiXal, HYPHEN BioMed).ResultsThere were 17 unique patients, each with a PRPL, weighing > 120kg, on rivaroxaban for treatment or secondary prevention of TE, over our study period. Six were female. The mean weight was 146.75 (SD +/- 20.19) kg. The mean calculated creatinine clearance (Cockcroft-Gault) was 208.53 (SD +/- 57.36) mL/min. The mean length of follow up from measurement of PRPL was 312.29 (SD +/- 265.47) days.The mean PRPL was 248.51 (5th to 95th percentile 174.6-380.4) ng/mL compared to the reference of 5th to 95th PRPL percentile of 175-360 ng/mL in non obese patients. Only 1 PRPL was found to be below the expected range at 161ng/mL (see figure 1). There were no recurrent TE events in any of the patients during the study.ConclusionsWe found that the majority of individuals weighing > 120 kg on standard dose rivaroxaban for treatment and secondary prevention of TE had a PRPL within the expected range, with only one value out of the seventeen falling below that range. There were no recurrent TE events in any of the patients. It is possible that the increased volume of distribution in obesity played a lesser role in decreasing PRPL given the lower lipophilicity of rivaroxaban compared to apixaban and dabigatran, although similar to edoxaban (Remko. Journal of Molecular Structure: THEOCHEM. 2009, Remko et al. Molecules. 2016). Despite the small sample size and lack of other pharmacokinetic values, this preliminary data is clinically reassuring that the use of rivaroxaban in patients weighing > 120kg seems to be safe. Further studies are required to fully elucidate the efficacy and safety of DOACs in the treatment of TE in morbidly obese patients. [Display omitted] DisclosuresSholzberg:Shire: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; NovoNordisk: Honoraria. Yeo:Bayer: Membership on an entity's Board of Directors or advisory committees.

Effectiveness and Safety of Rivaroxaban Vs. Warfarin in Patients with Nonvalvular Atrial Fibrillation and Moderate-to-Severe Chronic Kidney Disease

Background: Chronic kidney disease (CKD) is a potent risk factor for both ischemic stroke and major bleeding in patients with nonvalular atrial fibrillation (NVAF).Objective: To assess the effectiveness and safety of rivaroxaban vs. warfarin in NVAF patients with moderate-to-severe CKD treated in routine practice.Methods: Using US MarketScan claims data from 11/2011-3/2016, we identified oral anticoagulation (OAC) naïve NVAF patients with moderate-to-severe CKD and ≥12 months of continuous insurance coverage prior to the qualifying OAC dispensing. Rivaroxaban users (20 mg or 15 mg once daily) were 1:1 matched to warfarin users by applying propensity-scores that were calculated based on demographics, comorbidities, stroke and bleeding risk factors and concomitant medications. Balance between cohorts was evaluated by inspecting standardized differences for baseline covariates (differences >0.1 indicating imbalance). Patients were followed until an event, OAC discontinuation/switch (30 day permissible gap), insurance disenrollment or end of follow up. Rates of stroke/systemic embolism (SSE) and major bleeding (per the Cunningham algorithm) between cohorts were compared using Cox regression. A separate propensity-score matched analysis of reduced dose rivaroxaban vs. warfarin users was performed.Results: We assessed 777 rivaroxaban and 777 warfarin users with NVAF and moderate-to-severe CKD with a median (interquartile range) available follow up of 1.3 (0.6-2.2) years. All baseline covariates evaluated had a standardized difference <0.1. Median age was 76 (68-82) years and median CHA2DS2-VASc and HAS-BLED scores were 4 (3-5) and 3 (3-4). Rivaroxaban use was associated with nonsignificant relative hazard reductions in SSE and ischemic stroke vs. warfarin (Figure). No differences in major bleeding or hemorrhagic stroke were observed between cohorts. The reduced dose 15 mg rivaroxaban vs. warfarin user analysis yielded similar conclusions to the full cohort analysis.Conclusions: Results of this claims database analysis are generally consistent with those seen in the randomized ROCKET AF trial. Rivaroxaban's relative effectiveness and safety vs. warfarin appears to be maintained in NVAF patients with moderate-to-severe CKD treated in routine clinical practice. [Display omitted] DisclosuresColeman:Boehringer Ingelheim: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria, Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria, Research Funding. Turpie:Bayer HealthCare Pharmaceuticals: Consultancy; Janssen Research and Development: Consultancy, Honoraria. Kreutz:Bristol-Myers Squibb: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Berlin-Chemie Menarini: Consultancy; Bayer AG: Consultancy, Honoraria; Lundbeck: Consultancy; Servier Laboratories: Consultancy.

Relevance of genetic polymorphisms of the human cytochrome P450 3A4 in rivaroxaban-treated patients

Rivaroxaban is an anticoagulant drug that prevents forming of blood clots. In addition, it can be administered to prevent and treat thrombotic diseases such as atrial fibrillation, cardiac arrhythmia, heart valve disease, orthopedic surgery, and thrombophilia to reduce the risk of thrombosis. Various factors such as age, gender, diet, medications, and genetic factors effectively determine the dose of rivaroxaban. Genetic variability in drug-metabolizing enzymes, including the cytochrome P450 (CYP450) enzymes and especially CYP3A4, has been associated with rivaroxaban response. The current study aimed to identify the frequency of CYP3A4 common polymorphisms, as well as their association with rivaroxaban response in 100 patients of Arab descent (48.6% female). CYP3A4 gene polymorphisms were examined by the PCR-RFLP method, and the findings were analyzed by SPSS 16 software and t-test. The frequency of CYP3A4*1B/*1B, CYP3A4*1B/*1A, CYP3A4*1B/*1C, and CYP3A4*1A/*1C was 67.35%, 10.64%, 19.12% and 2.89%, respectively. According to our results, CYP3A4 *1B/*1B genotype was the most common, and patients with CYP3A4*1B/*1B alleles needed a higher daily dose of rivaroxaban than *1B/*1A, *1B/*1C, and *1A/*1C carriers (9.57 ± 1.54 mg/day, P=0.015). Therefore, according to the results, CYP3A4 gene polymorphism has an important effect on the dose of rivaroxaban required to maintain the International Normalized Ratio (INR) in the range of 2-3.

Reclassification, Thromboembolic, and Major Bleeding Outcomes Using Different Estimates of Renal Function in Anticoagulated Patients With Atrial Fibrillation: Insights From the PREFER-in-AF and PREFER-in-AF Prolongation Registries.

The Cockcroft-Gault formula is recommended to determine a renal indication for dose reduction of dabigatran, edoxaban, and rivaroxaban. Nephrology guidelines now recommend the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulae as more accurate estimates of glomerular filtration rate. We analyzed anticoagulated patients with atrial fibrillation who were enrolled in the Prevention of Thromboembolic Events - European Registry in Atrial Fibrillation (PREFER in AF). The proportion of patients with dissimilar renal dosing indications was assessed when applying Cockcroft-Gault, MDRD, or CKD-EPI. Thromboembolic and major bleeding events at 1 year were compared in patients in whom Cockcroft-Gault and CKD-EPI provided concordant or discordant results around a threshold of 50 mL/minute. Out of 1288 patients with atrial fibrillation with chronic kidney disease in whom Cockcroft-Gault suggested a dose reduction of dabigatran, edoxaban, or rivaroxaban (creatinine clearance ≤50 mL/minutes), 19% and 16% were reclassified to the respective higher doses, and 24% and 23% to the respective lower doses by applying the MDRD and CKD-EPI formulae, respectively. In patients potentially receiving a different dose of dabigatran, edoxaban, or rivaroxaban when using CKD-EPI, we observed an excess of thromboembolic events (4.1% versus 0.8%; odds ratio, 5.5 [95% CI, 1.5-20.8]; P=0.01). Major bleeding rates were nonsignificantly different in the discordance versus concordance group (5.7% versus 2.7%; odds ratio, 2.2 [95% CI, 0.9-5.6]; P=0.09). The MDRD and CKD-EPI formulae suggest a different dosing in up to a quarter of anticoagulated patients with atrial fibrillation. This seems to impact hard outcomes.

Treatment with the direct oral anticoagulants (DOACs) Apixaban and Rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD)

ObjectiveTo demonstrate the increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders.To raise awareness of the importance of frontline staff partaking in post marketing surveillance of medications.Case reportWe report the cases of two patients who developed worsening BPSD, coinciding with starting the factor Xa inhibitor DOAC medications Apixaban and Rivaroxaban respectively. Both patients required detaining under the Mental Health Act (MHA). Their symptoms improved significantly, within two weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward.DiscussionFrontline healthcare staff in acute settings and the community manage a heavy workload. It is all too easy to overlook potential neuropsychiatric drug side effects, especially if they are not clearly listed. They may be easily missed amongst older patients and wrongly attributed to dementia.Rivaroxaban is structurally related to the antibiotic Linezolid which has been reported to cause mitochondrial toxicity. Pre marketing In vitro studies concluded the risk of mitochondrial toxicity associated with this anticoagulant to be low. However a more recent in vitro study, using rat kidney mitochondria, reported evidence of mitochondrial swelling and a collapse of the membrane potential following exposure to low doses of Rivaroxaban. The effect of Apixaban, which is structurally related to Rivaroxaban, has yet to be investigated on mitochondrial function.Recent research supports not only an association between reduced cerebral mitochondrial function and neuropsychiatric symptoms and disorders, but also the aetiological role it may play.There is a need for a far greater awareness and understanding of the potential cerebral mitochondrial toxicity of drugs commonly prescribed to our older populations.ConclusionCerebral mitochondrial toxicity can have a significant impact on the health and well-being of patients.Older patients are particularly prone to experiencing neuropsychiatric side effects that may not have been apparent during preclinical trials.Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likelihood of them experiencing apparent behavioural and psychological symptoms of dementia.

Arterial Thrombosis and Acute Limb Ischemia as a Complication of COVID-19 Infection.

COVID-19 refers to viral respiratory infections and is the predisposing factor for the development of venous and arterial thrombotic events due to a pronounced inflammatory response, platelet activation, endothelial dysfunction, and stasis. Recent studies have confirmed a high incidence of thromboembolic events, especially in the group of patients with severe coronavirus pneumonia. There have been an increasing number of reports of peripheral arterial thrombosis as well. Most cases of arterial thrombosis are noted in critical ill patients in intensive care setting. However, an increase of adverse arterial events was also noted in cases of asymptomatic or mild forms of COVID-19. Herein, we report a case of patient with asymptomatic SARS-CoV-2 infection, who developed a threatening lower limb ischemia. Our own clinical observation suggests that COVID-19-associated arterial thrombosis can be successfully treated by embolectomy, administration of in-hospital parenteral anticoagulation, and continuation of antithrombotic therapy with a "vascular" dose of rivaroxaban after discharge.

Benefits and Harms of Low-Dose Rivaroxaban in Asian Patients With Atrial Fibrillation: A Systematic Review and Meta-analysis of Real-World Studies

Background: Low-dose prescription of rivaroxaban was common among patients with atrial fibrillation (AF) in Asia. However, the benefits and harms of rivaroxaban at a low dosage in Asian patients with AF remains unclear. Accordingly, we aimed to collect and summarize all available evidence to fill this important knowledge gap. Methods: In this systematic review and meta-analysis, we systematically searched databases of MEDLINE, EMBASE, and Cochrane Library for relevant studies from inception until February 23, 2021. Eligible retrospective nationwide or health insurance database studies or prospective registration studies that reported efficacy (stroke/systemic embolism), safety (major bleeding, intracranial hemorrhage, gastrointestinal bleeding), or other outcomes (myocardial infarction, death) of low-dose rivaroxaban in comparison with warfarin in AF patients were enrolled. Data extraction and study quality assessment were conducted by two authors independently. Low dosing of rivaroxaban (15/10 mg) was defined as the received dose lower than the recommended dose (20 mg) approved in most districts. Hazard ratio (HR) with 95% confidence intervals (95% CIs) was pooled using a random-effect model. Subgroup analyses were conducted according to different dose regimens. Sensitivity analyses were conducted by sequential elimination of each study from the pool. Since potential effect modifiers (patient demographics, differences of each study, and others) may lead to bias in primacy outcomes, we performed a meta-regression analysis to explore the influence of these factors on the primary efficacy and safety outcomes. Results: Totally, 12 studies involving 292,815 Asian patients with AF were included. All studies were detected as low to moderate risk bias. Low-dose rivaroxaban treatment in Asian AF patients was associated with a reduced risk of stroke/systemic embolism (HR: 0.76, 95% CI: 0.70–0.84, I 2: 57.8%), major bleeding (HR: 0.72, 95% CI: 0.62–0.84, I 2: 81.5%), and all-cause death (HR: 0.65, 95% CI: 0.58–0.73, I 2: 81.7%) when compared with warfarin. Furthermore, consistent results were observed among different dose regimens (10/15/20 mg) in all the clinical outcomes (P interaction > 0.05 for each outcome). Meta-regression analysis failed to detect any potential confounding to impact the primacy outcomes. Conclusion: Insights from the present meta-analysis, we found that low-dose rivaroxaban, even at a dosage of 10 mg daily, was associated with a reduced risk of stroke/SE and bleeding than warfarin in Asian AF patients. However, owing to considerable heterogeneity among included studies, further prospective studies are required to confirm these findings.