rivaroxaban and Body-Weight

Obesity is an epidemic with rising prevalence, and obese patients are predisposed to comorbid conditions that increase risk for thromboembolic events. It is critical to identify safe and effective anticoagulation therapy for use in this population. Direct oral anticoagulants (DOACs) are a preferred option for anticoagulation in patients of normal weight due to many benefits and equivalent safety and efficacy to their vitamin K antagonist counterparts. However, the safety and efficacy of DOACs in obese patients is not well understood. This review describes recent studies on the pharmacokinetics, safety and efficacy, and clinical outcomes of the DOACs apixaban, rivaroxaban, edoxaban and dabigatran in obese patient populations. DOACs may be a beneficial alternative to vitamin K antagonist therapy in obese patient populations.. The incidence of obesity within the USA is on the rise, as is that of the medical conditions that often accompany it. These include conditions that can predispose individuals to forming clots in the blood, such as atrial fibrillation, which is a form of an abnormal heartbeat, and nonalcoholic fatty liver disease, which is caused by fat buildup around the liver. Therefore, it is important that we have effective medicines that can prevent clotting in an obese patient population. Direct oral anticoagulants are a new, preferred medication option for this, but it is unclear how safe or effective they are in obese people; there is some concern that because of increased body weight, individuals may not get enough medicine to effectively prevent clots from forming, which would ultimately put them at risk for clotting and serious adverse health outcomes such as stroke. This review describes recent studies on the use of the direct oral anticoagulants apixaban, rivaroxaban, edoxaban and dabigatran in obese patients, and whether they are a safe and effective form of anticoagulation in this population.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Body Mass Index; Body Weight; Dabigatran; Hemorrhage; Humans; Obesity; Pyridones; Rivaroxaban; Stroke; Vitamin K

Cardiovascular disease (CVD) remains the leading cause of death in the USA. Several risk factors have been identified, and obesity has become one of prominent concern. Excessive weight is considered a risk factor for CVD based on evidence linking it to a hypercoagulable state. Considering the prevalence of CVD and obesity in the USA, along with the increased risk for thrombus-related events, anticoagulation plays a significant role in prevention and treatment. Direct oral anticoagulants have taken the place of many traditional anticoagulants. Considering the recently approved indications and continued postmarketing studies conducted with rivaroxaban, this updated review provides data on the overall impact of obesity on this compound. This includes data obtained from both healthy obese volunteers and obese patients with various CVD conditions enrolled in rivaroxaban clinical trials, along with data obtained from postmarketing real-world evidence studies. Assessment of the clinical pharmacology and population pharmacokinetics in obese individuals revealed no clinically relevant effects of increased weight. Additionally, subgroup analyses from each of the pivotal phase III trials supporting the current approved labeling also demonstrated consistent efficacy and safety results in obese patients. Lastly, these findings are further supported by several recent real-world evidence studies assessing the continued effectiveness and safety of rivaroxaban. In conclusion, rivaroxaban's overall pharmacological and clinical profile remained consistent in obese adults when assessed in both drug development and postmarketing studies, supporting the premise that higher weight does not necessitate adjustment in either dose strength or regimen.

Topics: Anticoagulants; Area Under Curve; Body Weight; Cardiovascular Diseases; Humans; Metabolic Clearance Rate; Obesity; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Venous Thrombosis

To review the literature on treatment of venous thromboembolism (VTE) and prevention of cardioembolic stroke with direct-acting oral anticoagulants (DOACs) in low- and high-body-weight patients and to make recommendations regarding agent selection and dosing in these patient populations.. The selection and optimal dosing of DOACs in low- and high-body-weight patients has not yet been fully elucidated by clinical trials; however, evidence suggests that issues of both safety and efficacy in patients at the extremes of body weight may warrant careful consideration when selecting a DOAC for such patients. This review provides a thorough discussion of the use of DOACs in the treatment of VTE and prevention of cardioembolic stroke in patients at the extremes of body weight and provides guidance regarding agent selection.. While the published evidence on use of DOACs in patients at extremes of body weight is sparse, apixaban and rivaroxaban appear to have the most favorable safety and efficacy profiles. Edoxaban and dabigatran should be avoided.

Topics: Anticoagulants; Body Weight; Dabigatran; Drug Dosage Calculations; Factor Xa Inhibitors; Humans; Obesity; Overweight; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism

Being overweight or obese is associated with a higher individual risk of venous thromboembolism and poorer postprocedural outcomes after hip or knee replacement surgery. In addition, there is evidence that obesity represents a significant driving factor for the current and projected prevalence of atrial fibrillation. Rivaroxaban and other direct oral anticoagulants offer fixed-dose regimens for these indications. They do not require therapeutic drug monitoring or dose adjustment according to the weight of the patient. However, primary care physicians seem to be hesitant to accept the concept of a fixed-dose regimen for patients at extremes of weight, perhaps because of familiarity with weight-based dosing of other drugs including low molecular weight heparins. The main concerns related to unadjusted dosing are increased exposure in underweight patients leading to a risk of excessive bleeding and conversely to underanticoagulation of overweight patients. Rivaroxaban has shown similar efficacy and a similar or better safety profile compared with standard treatment for several venous and arterial indications, including venous thromboembolism, nonvalvular atrial fibrillation, and acute coronary syndrome. Prespecified subgroup analyses of patients stratified by weight or body mass index demonstrated outcomes that were consistent with the overall analysis and within each weight and body mass index group. The results suggest that standard-dose rivaroxaban can be safely prescribed in adult patients of all weights.

Topics: Body Mass Index; Body Weight; Clinical Trials, Phase III as Topic; Factor Xa Inhibitors; Humans; Rivaroxaban

Rivaroxaban is the first agent available within a new class of anticoagulants called direct factor Xa inhibitors. Rivaroxaban is approved for use in the United States for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, for the prevention of deep vein thrombosis in patients undergoing total hip replacement and total knee replacement, for the treatment of deep vein thrombosis and pulmonary embolism, and for the reduction in risk of recurrence of deep vein thrombosis and pulmonary embolism (with additional indications under review). Rivaroxaban dose and frequency of administration vary depending on the indication. As of result of predictable pharmacokinetics and pharmacodynamics, a fixed dose of rivaroxaban is administered without routine coagulation testing. Rivaroxaban has a short half-life, undergoes a dual mode of elimination (hepatic and renal), and is a substrate for P-glycoprotein. Rivaroxaban has a lower potential for drug interactions compared with warfarin. Despite the advantages of a once/day fixed-dose oral agent, in many clinical situations limited evidence is available to guide optimal management of rivaroxaban therapy. In this article, we review the available evidence and provide recommendations where possible for such situations including the desire to monitor the anticoagulation intensity, use in special patient populations, managing drug interactions, and transitioning across anticoagulant agents. Potential strategies for reversing rivaroxaban's anticoagulant effect are reviewed. Health systems will need to perform a systematic safety evaluation and ensure that numerous hospital policies related to anticoagulation are updated to include rivaroxaban. A comprehensive approach to education is needed for clinicians, patients, and technical support personnel involved in patient interactions to ensure safe use.

Topics: Administration, Oral; Anticoagulants; Body Weight; Clinical Trials, Phase III as Topic; Hemorrhage; Humans; Morpholines; Rivaroxaban; Thiophenes; Treatment Outcome

Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents.. In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843.. Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events.. Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism.. Bayer AG, Janssen Research and Development.

Topics: Adolescent; Anemia; Anticoagulants; Body Weight; Child; Child, Preschool; Drug Administration Schedule; Drug Dosage Calculations; Factor Xa; Female; Half-Life; Hemorrhage; Humans; Infant; Male; Neutropenia; Prothrombin Time; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

Patients on rivaroxaban have variable international normalized ratios (INRs) but it is uncertain if INR impacts procedural heparin requirement during left atrial ablation. We sought to examine the determinants of heparin dosing in this patient population.. We reviewed consecutive patients who received rivaroxaban within 24 hours of left atrial ablation and compared them to patients on uninterrupted warfarin. The determinants of heparin requirement were evaluated using regression analysis. We then tested a weight-based heparin dose prospectively in rivaroxaban patients.. There were 258 patients on rivaroxaban and 213 on warfarin. The mean INR was 1.4 in the rivaroxaban group and 2.3 in the warfarin group (P < 0.01). To achieve an activated clotting time (ACT) >350 seconds, rivaroxaban patients required significantly more heparin (166.9 vs. 78.3 units/kg, P < 0.001). In the rivaroxaban group, body weight was the strongest predictor of heparin dose (r = 0.52), while INR was weakly correlated (r = -0.21). In the prospective group, 25 patients were given an initial heparin dose of 120 units/kg with 22/25 (88%) achieving an ACT > 300 seconds. There were seven and three cases of pericardial effusion in rivaroxaban and warfarin patients, respectively (P = 0.41). The average volume drained in the rivaroxaban group was elevated (988.6 vs. 275.0 mL, P = 0.21).. Body weight is the strongest predictor of procedural heparin requirement during left atrial ablation in patients on uninterrupted rivaroxaban, even in those with an elevated INR. A heparin dose of 120 units/kg achieves an ACT > 300 seconds in the majority of patients. In cases of pericardial effusion, bleeding may be prolonged.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Body Weight; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fibrinolytic Agents; Heart Atria; Heparin; Humans; Male; Middle Aged; Postoperative Complications; Premedication; Prevalence; Risk Factors; Rivaroxaban; Thromboembolism; Treatment Outcome; United States

The pharmacokinetics of oral rivaroxaban are highly predictable and only affected to a limited extent by bodyweight; therefore, dose adjustments for bodyweight are not required. However, this raises concerns among physicians for potential under- or overdosing. This substudy of the randomised EINSTEIN DVT and EINSTEIN PE trials, which compared rivaroxaban with enoxaparin/vitamin K antagonist (VKA) therapy, aimed to determine the incidence of major bleeding in patients with a low bodyweight and recurrent venous thromboembolism (VTE) in patients with a high bodyweight during rivaroxaban or enoxaparin/VKA therapy. More than 8,000 patients with objectively diagnosed deep-vein thrombosis or pulmonary embolism were included. Adjusted hazard ratios for recurrent VTE and bleeding were calculated using the Cox proportional hazards model. Analyses were performed for both the first 21 days of treatment and the whole treatment period. For rivaroxaban recipients, there was no association between bodyweight or body mass index (BMI) and risk of recurrent VTE (ptrend=0.87 and 0.62, respectively), major bleeding (ptrend=0.24 and 0.36, respectively) or clinically relevant bleeding (ptrend=0.17 and 0.63, respectively). Major bleeding events were numerically lower in rivaroxaban patients across all bodyweight and BMI categories. Hazard ratios for rivaroxaban vs enoxaparin/VKA were similar in all bodyweight and BMI categories, both during the first 21 days and the whole treatment period. The fixed-dose rivaroxaban regimen is not associated with an increased risk of major bleeding or recurrent VTE in patients with either a low or high bodyweight. A high BMI was not associated with an increased risk of recurrent VTE during anticoagulation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Body Weight; Enoxaparin; Female; Humans; Male; Middle Aged; Recurrence; Rivaroxaban; Venous Thromboembolism; Vitamin K; Young Adult

Rivaroxaban is an oral, direct Factor Xa inhibitor, which is at an advanced stage of clinical development for prevention and treatment of thromboembolic disorders. Two phase II studies, ODIXa-DVT and EINSTEIN DVT, assessed the efficacy and safety of oral rivaroxaban (once daily or twice daily) for treatment of acute deep-vein thrombosis (DVT). Population pharmacokinetic and pharmacodynamic analyses of rivaroxaban in patients in these two phase II studies were conducted to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban and the relationship between important patient covariates and model parameters. Exposure simulations in patients with atrial fibrillation (AF) were also performed in order to predict the exposure of rivaroxaban, using modified demographic data reflecting the characteristics of a typical AF population.. A population pharmacokinetic model was developed using plasma samples from these patients. Various simulations were conducted to explore the pharmacokinetics of rivaroxaban in patients with DVT and to predict exposure in those with AF. Correlations between plasma rivaroxaban concentrations and the prothrombin time, Factor Xa activity, HepTest® and activated partial thromboplastin time were also described.. The pharmacokinetics of rivaroxaban in patients with DVT were found to be consistent and predictable across all doses studied. The area under the plasma concentration-time curve (AUC) increased dose dependently. The same total daily doses given once daily achieved higher maximum plasma concentration (C(max)) values (∼20%) and lower trough (minimum) plasma concentration (C(trough)) values (∼60%) than when given twice daily; however, the 5th-95th percentile ranges for these parameters overlapped. Rivaroxaban clearance was moderately influenced by age and renal function, and the volume of distribution was influenced by age, body weight and sex; the effects were within the observed interindividual variability. Simulations in virtual patient populations with AF showed that a rivaroxaban dose of 15 mg once daily in patients with creatinine clearance of 30-49 mL/min would achieve AUC and C(max) values similar to those observed with 20 mg once daily in patients with normal renal function. The prothrombin time correlated almost linearly with plasma rivaroxaban concentrations (≤500 μg/L).. Population analyses of phase II clinical data indicated that the pharmacokinetics and pharmacodynamics of all rivaroxaban doses were predictable and were affected by expected demographic factors in patients with acute DVT.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Body Weight; Computer Simulation; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Models, Biological; Morpholines; Rivaroxaban; Stroke; Thiophenes; Venous Thrombosis; Young Adult

Anticoagulants are often dose adjusted, or their use restricted, in patients with extremes of body weight. Rivaroxaban (BAY 59-7939) is a novel, oral, direct factor Xa inhibitor in clinical development. This was a randomized, single-blind, placebo-controlled, parallel-group study in healthy male and female subjects to assess the effect of extreme body weight (< or = 50 kg and >120 kg), and gender, on the safety, tolerability, pharmacokinetics, and pharmacodynamics of rivaroxaban 10 mg, compared with subjects of normal weight (70-80 kg). Rivaroxaban was well tolerated. Cmax of rivaroxaban was unaffected in subjects >120 kg but was increased by 24% in subjects weighing < or = 50 kg, resulting in a small (15%) increase in prolongation of prothrombin time, which was not considered clinically relevant. The area under the curve was unaffected by body weight or gender. No other clinically relevant differences were observed, suggesting that rivaroxaban is unlikely to require dose adjustment for body weight or gender.

Topics: Adult; Anticoagulants; Antithrombin III; Body Weight; Female; Humans; Male; Middle Aged; Morpholines; Partial Thromboplastin Time; Prothrombin Time; Rivaroxaban; Thiophenes

The pharmacokinetics (PK) of rivaroxaban have been studied in different populations, and there were differences in the PK parameters. However, most of these studies were conducted on healthy subjects from different ethnic groups. Thus, this study aimed to investigate the PK of rivaroxaban in real-world patients to determine the covariates that may cause differences in the pharmacokinetics of rivaroxaban. This was a prospective observational study. Five blood samples were collected at different time points after starting the rivaroxaban dose. Plasma concentrations were analyzed, and population PK models were developed using Monolix version 4.4 software. In total, 100 blood samples from 20 patients (50% men/50% women) were analyzed. The patients' mean (±standard deviation) age was 53.1 (±15.5) years and their mean body weight was 81.7 (±27.2) kg. The PK of rivaroxaban were described by a 1-compartment model. The initial estimates for the absorption rate constant, apparent clearance (CL/F), and apparent volume of distribution were 1.8/h, 4.46 L/h, and 21.7 L, respectively. The interindividual variability for absorption rate constant, CL/F, and volume of distribution was 14%, 24%, and 29.3%, respectively. Covariates were tested for their influence on rivaroxaban pharmacokinetics. The aspartate aminotransferase, alanine aminotransferase, body mass index, and albumin concentrations had an effect on the CL/F of rivaroxaban. In this analysis, the population PK model of rivaroxaban found significant interindividual variability. Several covariates influenced the clearance of rivaroxaban and contributed to this variability. The results may provide a guide that can aid the clinician during the initiation and adjustment of therapeutic regimens.

Topics: Adult; Aged; Body Weight; Female; Humans; Male; Middle Aged; Models, Biological; Prospective Studies; Rivaroxaban

Rivaroxaban is approved in various regions for the treatment of acute venous thromboembolism (VTE) in children aged between 0 and 18 years and was recently investigated for thromboprophylaxis in children aged between 2 and 8 years (with body weights <30 kg) with congenital heart disease who had undergone the Fontan procedure. In the absence of clinical data, rivaroxaban doses for thromboprophylaxis in post-Fontan children aged 9 years and older or ≥30 kg were derived by a bridging approach that used physiologically-based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) models based on pharmacokinetic (PK) data from 588 pediatric patients and from adult patients who received 10 mg once daily for thromboprophylaxis after major orthopedic surgeries as a reference. Both models showed a tendency toward underestimating rivaroxaban exposure in post-Fontan patients aged between 2 and 5 years but accurately described rivaroxaban PK in post-Fontan patients aged between 5 and 8 years. Under the assumption that hepatic function is not impaired in post-Fontan patients, PBPK and popPK simulations indicated that half of the rivaroxaban doses for the same body weight given to pediatric patients treated for acute VTE would yield in pediatric post-Fontan patients exposures similar to the exposure observed in adult patients receiving 10 mg rivaroxaban once daily for thromboprophylaxis. Simulation-derived doses (7.5 mg rivaroxaban once daily for body weights 30-<50 kg and 10 mg once daily for body weights ≥50 kg) were therefore included in the recent US label of rivaroxaban for thromboprophylaxis in children aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

Topics: Adolescent; Adult; Anticoagulants; Body Weight; Child; Child, Preschool; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Rivaroxaban; Venous Thromboembolism

To analyse the appropriateness of direct oral anticoagulant (DOAC) dosing and determinants for under-and overdosing as well as acceptance and implementation rates of pharmacists' interventions.. Cross-sectional study in a tertiary hospital in hospitalized patients with atrial fibrillation on DOACs in 2019 (n = 1688). Primary outcome was the proportion of patients with inappropriate DOAC prescribing with identification of determinants for under-and overdosing. Secondary outcomes included acceptance and implementation rates of pharmacists' recommendations and determination of reasons for nonacceptance/nonimplementation.. Inappropriate prescribing was observed in 16.9% of patients (n = 286) with underdosing (9.7%) being more prevalent than overdosing (6.9%). For all DOACs considered together, body weight<60 kg (odds ratio [OR] 0.46 [0.27-0.77]), edoxaban use (OR 0.42 [0.24-0.74]), undergoing surgery (OR 0.57 [0.37-0.87]) and being DOAC naïve (OR 0.45 [0.29-0.71]) were associated with significantly lower odds of underdosing. Bleeding history (OR 1.86 [1.24-2.80]) and narcotic use (OR 1.67 [1.13-2.46]) were associated with significantly higher odds for underdosing. Determinants with a significantly higher odds of overdosing were renal impairment (OR 11.29 [6.23-20.45]) and body weight<60 kg (OR 2.34 [1.42-3.85]), whereas dabigatran use (OR 0.24 [0.08-0.71]) and apixaban (OR 0.18 [0.10-0.32]) were associated with a significantly lower odds of overdosing compared to rivaroxaban. Physicians accepted the pharmacists' advice in 179 cases (79.2%) consisting of 92 (51.4%) recommendations for underdosing, 82 (45.8%) for overdosing and 5 (2.8%) for contraindications.. Inappropriate DOAC prescribing remains common, although there is a slight improvement compared to our study of 2016. Clinical services led by pharmacists help physicians to reduce the number of inadequate prescriptions for high-risk medications such as DOACs.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Body Weight; Cross-Sectional Studies; Dabigatran; Humans; Pharmacists; Physicians; Retrospective Studies; Rivaroxaban; Stroke

Topics: Anticoagulants; Body Weight; Humans; Rivaroxaban; Thiophenes

To investigate the association of extremes in bodyweight (EBW) and outcomes in patients with acute venous thromboembolism (VTE). Recurrent VTE, major bleeding, and clinically relevant non-major bleeding were compared between patients with bodyweight <60 kg, 60-120 kg, and >120 kg.. Consecutive patients enrolled in the Mayo Clinic VTE Registry (03/28/2013-8/31/2019) with acute VTE were followed prospectively. Patient status was assessed in person, by mailing a written questionnaire, or by a scripted phone interview.. Among 2577 patients with weight ranging from 27.0 kg to 263.2 kg, 2123 (82%) had a bodyweight between 60 and 120 kg, 223 (8.7%) had bodyweight < 60 kg, and 230 (8.9%) had bodyweight >120 kg. Patients with bodyweight <60 kg treated with DOACs had higher 3- and 6-month incidence of major bleeding compared to the bodyweight 60-120kg group (4.4% vs 1.1%, P = .03, and 4.4% vs 1.4%, P = .05, respectively). Patients with bodyweight >120 kg and cancer on rivaroxaban had higher VTE recurrence compared to bodyweight 60-120kg group (P = .01).. Treatment of acute VTE is associated with a higher incidence of bleeding in patients with bodyweight <60 kg. A higher VTE recurrence rate occurred only in cancer patients with bodyweight >120 kg on rivaroxaban.

Topics: Acute Disease; Anticoagulants; Body Weight; Disease Management; Drug Therapy, Combination; Factor Xa Inhibitors; Health Care Surveys; Hemorrhage; Humans; Pyrazoles; Pyridones; Registries; Rivaroxaban; Venous Thromboembolism

The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population-specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI). Rivaroxaban PK were adequately described by a one-compartment disposition model with a first-order absorption rate constant. Significant effects of CrCL, use of comedications, and study population on CL/F, age, weight, and gender on V/F, and dose on F were identified. CrCL had a modest influence on exposure, whereas age and BMI had a minor influence. The model was suitable to predict rivaroxaban exposure in patient subgroups of special interest.

Topics: Adult; Body Weight; Clinical Trials, Phase II as Topic; Female; Humans; Kidney; Kidney Function Tests; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Rivaroxaban

Warfarin and rivaroxaban are highly effective in reducing stroke risk in patients with atrial fibrillation (AF). However, their effects on anticoagulation and neurovascular unit (NVU) change remain elusive. In this study, we assessed the risks and benefits of pre-treatment with warfarin or rivaroxaban after tissue-type plasminogen activator (tPA) thrombolysis in ischemic rat brain.. Pre-treatment with warfarin (.2 mg/kg/day), low dose rivaroxaban (60 mg/kg/day), high dose rivaroxaban (120 mg/kg/day) or vehicle was performed for 2 weeks, transient middle cerebral artery occlusion (tMCAO) was induced for 90 min, then followed by reperfusion with tPA. At 24 hours (h) after reperfusion, we observed the changes of matrix metalloproteinase-9 (MMP-9), tissue factor, caspase 3 and NVU dissociation.. Prothrombin time (PT) was significantly prolonged in the warfarin and rivaroxaban pretreated groups. MMP-9 expression greatly increased in the warfarin group, and this was reduced in the rivaroxaban groups compared with the vehicle group. Tissue factor expression remarkably decreased in the warfarin and rivaroxaban groups. The number of caspase 3-positive cells had no difference among all the groups. Marked dissociations between astrocyte foot processes and the basal lamina or pericytes were observed in the warfarin pretreated group, but such dissociations were improved in the rivaroxaban groups.. Our present study shows that pre-treatment with rivaroxaban was noninferior to warfarin in the anticoagulation, but a lower risk of NVU dysfunction and dissociation after tPA treatment in rivaroxaban. This finding could partly explain the mechanism of reducing hemorrhagic complications by rivaroxaban in clinical studies.

Topics: Animals; Anticoagulants; Body Weight; Brain; Caspase 3; Collagen; Disease Models, Animal; Drug Administration Schedule; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 9; Plant Lectins; Rats; Rats, Wistar; Receptors, Platelet-Derived Growth Factor; Rivaroxaban; Warfarin

Topics: Adult; Aged; Body Weight; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Life Change Events; Male; Middle Aged; Overweight; Recurrence; Rivaroxaban; Treatment Outcome; Venous Thromboembolism

Topics: Anticoagulants; Body Weight; Enoxaparin; Factor Xa Inhibitors; Humans; Morpholines; Rivaroxaban; Thiophenes; Venous Thromboembolism