Calibration-free electrochemical sensor to monitor factor-Xa inhibitors at the point-of-care anticoagulation therapy.

This article presents a novel proof of concept for the blood plasma quantification of clinically relevant concentrations of direct oral anticoagulants, DOACs, including rivaroxaban and edoxaban, as well as low-molecular-weight heparins, LMWHs, such as enoxaparin and dalteparin, utilising a calibration-free disposable electrochemical sensor with co-facing electrodes. A dose-response curve was generated for rivaroxaban and edoxaban to demonstrate the sensor's ability to detect ≥9.00 ng mL-1 rivaroxaban and quantify it in the 11.0-140 ng mL-1 range. Similarly, the lower detection limit for edoxaban was 12.9 ng mL-1, with a quantification range of 16.8-140 ng mL-1. The significance of this sensor lies in its ability to quantify rivaroxaban and edoxaban below 30 ng mL-1, which is crucial in emergency care centres when patients undergoing DOAC therapy require emergency surgery or reversal of DOACs due to bleeding or ischemic stroke. Furthermore, the sensor can detect ≥0.016 IU mL-1 enoxaparin and ≥0.013 IU mL-1 dalteparin and quantify them in the 0.025-0.75 and 0.019-0.75 IU mL-1 range, respectively. Additionally, a dose-response curve was presented to demonstrate the potential ability of this sensor to quantify factor-Xa inhibitors independently of which DOACs or LMWHs are used. With the assay completed in less than 30 s using a minimal volume of 7 µL sample, the possibility to work at physiological pH and under calibration-free format makes this assay an excellent candidate for point-of-care testing.

Clot-regression effects of rivaroxaban in venous thromboembolism treatment in cancer patients-a prospective interventional study.

Rivaroxaban, a direct oral anticoagulant, is effective against venous thromboembolism (VTE) recurrence without increasing the risk of major bleeding in patients with cancer-associated venous thromboembolism (CAT). However, its clot regression effects are poorly understood. This single-arm, prospective interventional study aimed to investigate the clot regression effects of rivaroxaban in 40 CAT patients, through a contrast-enhanced computed tomography at baseline, 3 weeks, and 3 months of rivaroxaban treatment. The primary endpoint was the clot-regression ratio calculated from the thrombus volumes at 3 weeks and 3 months. Compared with baseline, the total clot volume was significantly reduced at both 3 weeks and 3 months after initiation (p < 0.01). The clot-regression rates were statistically significant with 83.1% (95% confidence interval [CI], 73.8-92.3%) at 3 weeks and 98.7% (95% CI, 97.1-100.2%) at 3 months, with complete resolution in 36.1% and 80.8% of patients at 3 weeks and 3 months, respectively. One patient had recurrent VTE after dose reduction, and seven had non-fatal major bleeding. Therefore, rivaroxaban had a sufficient clot-regression effect against CAT with caution of bleeding complication.

The treatment effect of rivaroxaban on clot characteristics in patients who present acutely with first time deep vein thrombosis.

BACKGROUND: The acute vascular disease deep vein thrombosis (DVT) requires oral anticoagulants to prevent progression. Monitoring therapeutic efficacy of direct oral anticoagulants (DOAC), including rivaroxaban, is problematic as no reliable test is available. Advances in rheometry have led to the development of a functional coagulation biomarker using Gel Point (GP) analysis which assesses clot structure formation. The biomarker measures incipient clot formation time (TGP) and quantifies fibrin clot structure in terms of fractal dimension (df). OBJECTIVE: This study aimed to investigate clot structure formation in first time DVT and the effect of rivaroxaban treatment. METHODS: This prospective observational cohort study measured the GP and standard laboratory markers at three sample points: pre-treatment and at 20 and 60 days following 15 mg BD and 20 mg OD rivaroxaban respectively. RESULTS: Forty DVT patients (mean age 64 years [SD±14.8]; 23 males, 17 female) were recruited. The results show that DVT vs non-DVT patients did not have a significantly different GP profile (df: 1.72±0.06 vs 1.70±0.06 and TGP: 267±68 sec vs 262±73 sec) with both within the defined healthy index. In addition, rivaroxaban therapy increased TGP to 392 s (±135 s) after 20 days, and subsequently increased to 395 s (±194 s) at 60 days but did not significantly increase df (from 1.69±0.05 to 1.71±0.06). CONCLUSIONS: The results indicate in this cohort of DVT patients there was no underlying hypercoagulable effect as determined by gel point analysis. Furthermore, the anticoagulant effect of rivaroxaban prolonged clotting, suggesting a protective effect against clot formation, without significantly reducing clot microstructural properties.

Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: Patients hospitalised with COVID-19 are at risk for thrombotic events after discharge; the role of extended thromboprophylaxis in this population is unknown. METHODS: In this open-label, multicentre, randomised trial conducted at 14 centres in Brazil, patients hospitalised with COVID-19 at increased risk for venous thromboembolism (International Medical Prevention Registry on Venous Thromboembolism [IMPROVE] venous thromboembolism [VTE] score of ≥4 or 2-3 with a D-dimer >500 ng/mL) were randomly assigned (1:1) to receive, at hospital discharge, rivaroxaban 10 mg/day or no anticoagulation for 35 days. The primary efficacy outcome in an intention-to-treat analysis was a composite of symptomatic or fatal venous thromboembolism, asymptomatic venous thromboembolism on bilateral lower-limb venous ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism, and cardiovascular death at day 35. Adjudication was blinded. The primary safety outcome was major bleeding. The primary and safety analyses were carried out in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04662684. FINDINGS: From Oct 8, 2020, to June 29, 2021, 997 patients were screened. Of these patients, 677 did not meet eligibility criteria; the remaining 320 patients were enrolled and randomly assigned to receive rivaroxaban (n=160 [50%]) or no anticoagulation (n=160 [50%]). All patients received thromboprophylaxis with standard doses of heparin during hospitalisation. 165 (52%) patients were in the intensive care unit while hospitalised. 197 (62%) patients had an IMPROVE score of 2-3 and elevated D-dimer levels and 121 (38%) had a score of 4 or more. Two patients (one in each group) were lost to follow-up due to withdrawal of consent and not included in the intention-to-treat primary analysis. The primary efficacy outcome occurred in five (3%) of 159 patients assigned to rivaroxaban and 15 (9%) of 159 patients assigned to no anticoagulation (relative risk 0·33, 95% CI 0·12-0·90; p=0·0293). No major bleeding occurred in either study group. Allergic reactions occurred in two (1%) patients in the rivaroxaban group. INTERPRETATION: In patients at high risk discharged after hospitalisation due to COVID-19, thromboprophylaxis with rivaroxaban 10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis. FUNDING: Bayer.

Risk of Severe Bleeding With Extended Rivaroxaban to Prevent Venous Thromboembolism in Acute Medically Ill Patients With Bronchiectasis.

Background: Bronchiectasis is a chronic inflammation of the bronchi with recurrent infections and hemoptysis. The MAGELLAN study compared oral rivaroxaban, 10 mg once daily (QD), for 35 ± 4 days with subcutaneous enoxaparin 40 mg QD for 10 ± 4 days followed by placebo for 25 ± 4 days to prevent venous thromboembolism in patients hospitalized with an acute medical illness. MAGELLAN included a subset of patients with bronchiectasis. In a post hoc analysis, we evaluated the incidence and severity of pulmonary bleeding in patients with bronchiectasis who were hospitalized for an acute medical illness. This analysis included MAGELLAN patients diagnosed with bronchiectasis at baseline. Patients were evaluated by treatment group for International Society on Thrombosis and Haemostasis major bleeding, non-major clinically relevant (NMCR) bleeding, and the composite of the 2 (ie, clinically relevant bleeding). Results: Medically ill patients with bronchiectasis were randomized to rivaroxaban (n = 60) or enoxaparin/placebo (n = 61). There were 2 fatal pulmonary bleeds and 1 fatal gastrointestinal bleed in the rivaroxaban arm and no fatal or major bleeding in the enoxaparin/placebo arm. The incidence of major bleeding was 5% in the rivaroxaban arm. One NMCR bleed occurred in the rivaroxaban arm and 2 NMCR bleeds occurred in the enoxaparin/placebo arm. The incidence of clinically relevant bleeding was 6.7% versus 3.3% in the rivaroxaban and enoxaparin/placebo groups, respectively (relative risk = 2.06 [95% confidence interval: 0.351-12.046]). Conclusion: In-patients hospitalized with bronchiectasis and an acute medical illness, clinically relevant bleeding, including fatal pulmonary hemorrhage, occurs more frequently with extended rivaroxaban thromboprophylaxis than with enoxaparin followed by placebo.

What is Standard Dose of Rivaroxaban in Elderly Asian Patients with Atrial Fibrillation: 20ms versus. 15mg?

Although there is no age criterion for rivaroxaban dose reduction, elderly patients with atrial fibrillation (AF) are often prescribed an off-label reduced dose. We aimed to evaluate whether age is a necessary criterion for rivaroxaban dose reduction in Korean patients with AF. Among 2208 patients who prescribed warfarin or rivaroxaban, 552 patients over 75 years without renal dysfunction (creatinine clearance >50 mL/min) were compared based on propensity score matching. The rivaroxaban group was further divided into a 20 mg (R20; on-label) and a 15 mg (R15; off-label). Primary net clinical benefit (NCB) was defined as the composite of stroke, systemic embolism, major bleeding, and all-cause mortality. Secondary NCB was defined as the composite of stroke, systemic embolism, and major bleeding. Patients were followed for 1 year, or until the first outcome occurrence. Both rivaroxaban groups had comparable efficacy compared with warfarin. However, both R20 (0.9% vs 7.4%, p = .014) and R15 (2.3% vs 7.4%, p = .018) had a significant reduction in major bleeding. There were no differences in efficacy or safety outcomes between R20 and R15. R20 had significantly reduced primary (hazard ratio [HR] 0.33, 95% confidence interval [CI]: 0.12-0.93) and secondary (HR 0.31, 95% CI: 0.10-0.93) NCBs compared with warfarin. However, primary and secondary NCBs were not reduced in R15. In real-world practice with elderly patients with AF, off-label rivaroxaban dose reduction to 15 mg conferred no benefits. Therefore, guideline-adherent rivaroxaban 20 mg is favorable in elderly Korean patients with AF.

Effect of Rivaroxaban and Aspirin in Patients With Peripheral Artery Disease Undergoing Surgical Revascularization: Insights From the VOYAGER PAD Trial.

BACKGROUND: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER. METHODS: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee. RESULTS: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method (P-interaction, 0.43). After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81 [95% CI, 0.67-0.98]; P=0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding (P-interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding (P-interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39-1.95]; P=0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage (P=0.95) and postprocedural bleeding requiring intervention (P=0.93) was not significantly increased. CONCLUSIONS: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage, or postprocedural bleeds requiring intervention. Registration: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT02504216.

Does atorvastatin therapy change the anti-Xa activity in xabans-treated patients with atrial fibrillation?

Atorvastatin and direct oral factor Xa inhibitors (xabans) are frequently co-administrated in patients with atrial fibrillation (AF). However, no studies investigating the possibility of the pharmacologic interaction between these agents have been conducted. The aim of this prospective observational study was to determine the impact of atorvastatin therapy on anti-Xa activity in xabans-treated patients with AF. We enrolled 115 AF patients on long-term rivaroxaban (52 patients) and long-term apixaban (63 patients) therapy. Long-term atorvastatin (40 mg once daily) was administrated to 28 rivaroxaban-treated patients and to 28 apixaban-treated patients. Trough and peak samples were tested for anti-Xa activity with drug-specific anti-Xa chromogenic analysis. For rivaroxaban, there were no significant differences in trough activity (45.5 ± 39.5 ng/ml vs. 46.2 ± 30.1 ng/ml; p = .34) and peak anti-Xa activity (179.2 ± 108.8 ng/ml vs. 208.1 ± 104.1 ng/ml; p = .94) between atorvastatin-treated patients and those without atorvastatin. Similarly, atorvastatin did not impact the trough activity (127.7 ± 71.1 ng/ml vs. 100.8 ± 61.1 ng/ml; p = .12) or peak anti-Xa activity (213.8 ± 103.6 ng/ml vs. 179.3 ± 72.9 ng/ml; p = .14) among apixaban-treated patients with AF. This observational study did not show a significant impact of atorvastatin on trough and peak anti-Xa activity in xabans-treated patients with AF.

Increased Levels of Platelets and Endothelial-Derived Microparticles in Patients With Non-Valvular Atrial Fibrillation During Rivaroxaban Therapy.

It is known that atrial fibrillation (AF) is associated with the procoagulant state. Several studies have reported an increase of circulating microparticles in AF, which may be linked to a hypercoagulable state, atrial thrombosis and thromboembolism. We evaluated in our study alterations in both platelet (PMP, CD42b) and endothelial-derived (EMP, CD144) microparticle levels on anticoagulant therapy with rivaroxaban in nonvalvular AF. After administration of rivaroxaban, PMP levels were increased (median, [IQR] 35.7 [28.8-47.3] vs. 48.4 [30.9-82.8] cells/µL; P = 0.012), along with an increase in EMP levels (14.6 [10.0-18.6] vs. 18.3 [12.9-37.1] cells/µL, P < 0.001). In the multivariable regression analysis, the independent predictor of post-dose change in PMPs was statin therapy (HR -0.43; 95% CI -0.75,-0.10, P = 0.011). The post-dose change in EMPs was also predicted by statin therapy (HR -0.34; 95% CI -0.69, -0.01, P = 0.046). This study showed an increase in both EMPs and PMPs at the peak plasma concentration of rivaroxaban. Statins have promising potential in the prevention of rivaroxaban-related PMP and EMP release. The pro-thrombotic role of PMPs and EMPs during rivaroxaban therapy requires further study.

Activated Factor X Signaling Pathway via Protease-Activated Receptor 2 Is a Novel Therapeutic Target for Preventing Atrial Fibrillation.

BACKGROUND: Activated factor X (FXa), which contributes to chronic inflammation via protease-activated receptor 2 (PAR2), might play an important role in atrial fibrillation (AF) arrhythmogenesis. This study aimed to assess whether PAR2 signaling contributes to AF arrhythmogenesis and whether rivaroxaban ameliorates atrial inflammation and prevents AF.Methods and Results:In Study 1, PAR2 deficient (PAR2-/-) and wild-type mice were infused with angiotensin II (Ang II) or a vehicle via an osmotic minipump for 2 weeks. In Study 2, spontaneously hypertensive rats (SHRs) were treated with rivaroxaban, warfarin, or vehicle for 2 weeks after 8 h of right atrial rapid pacing. The AF inducibility and atrial remodeling in both studies were examined. Ang II-treated PAR2-/- mice had a lower incidence of AF and less mRNA expression of collagen1 and collagen3 in the atrium compared to wild-type mice treated with Ang II. Rivaroxaban significantly reduced AF inducibility compared with warfarin or vehicle. In SHRs treated with a vehicle, rapid atrial pacing promoted gene expression of inflammatory and fibrosis-related biomarkers in the atrium. Rivaroxaban, but not warfarin, significantly reduced expression levels of these genes. CONCLUSIONS: The FXa-PAR2 signaling pathway might contribute to AF arrhythmogenesis associated with atrial inflammation. A direct FXa inhibitor, rivaroxaban, could prevent atrial inflammation and reduce AF inducibility, probably by inhibiting the pro-inflammatory activation.

The Net Clinical Benefit of Rivaroxaban Compared to Low-Molecular-Weight Heparin in the Treatment of Cancer-Associated Thrombosis: Systematic Review and Meta-Analysis.

Cancer-associated thrombosis (CAT) carries significant morbidity and mortality. Low-molecular-weight heparin (LMWH) remains the standard of care, with recent systematic studies suggesting the efficacy and safety of rivaroxaban in the treatment of CAT. Uncertainty, however, remains regarding rivaroxaban efficacy and safety in real-world settings. We performed a systematic review and meta-analysis of studies comparing rivaroxaban to LMWH. We searched PubMed, MEDLINE, and EMBASE. The primary outcome was the net clinical benefit (NCB), while rates of major bleeding (MB), venous thromboembolism (VTE), clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality events were secondary outcomes. Seventeen studies were included in the final analysis. Rivaroxaban had a better NCB (relative risk [RR] = 0.82; 95% CI = 0.75-0.89, Q = 10.51, I 2 = 0%), less VTE events (RR = 0.73, 95% CI = 0.65-0.82, Q = 6.76, I 2 = 0%), and lower all-cause mortality (RR = 0.72, 95% CI = 0.57-0.91, Q = 32.8, I 2 = 79%) compared to LMWH. Additionally, comparable MB events (RR = 1.07, 95% CI = 0.85-1.33, Q = 16.9, I 2 = 11%). However, CRNMB events were higher in the rivaroxaban group (RR = 2.02, 95% CI = 1.46-2.80, Q = 9.9, I 2 = 19%). Additional analyses demonstrated consistency of results. Our review encompassing data from randomized and real-world data suggested rivaroxaban superiority compared to LMWH in terms of a better NCB, fewer VTE events, lower all-cause mortality, and comparable MB risk while carrying a higher risk of CRNMB. These findings support the use of rivaroxaban in the treatment of CAT. Additionally, it warrants a sizable randomized controlled study testing the superiority of rivaroxaban versus LMWH formulation and ascertaining bleeding outcomes according to cancer type and site.

Rivaroxaban Attenuates Right Ventricular Remodeling in Rats with Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive condition that frequently results in right ventricular (RV) remodeling. The objectives of this study are to investigate effects of rivaroxaban on RV remodeling in a rat model of PAH, created with Sugen5416 and chronic hypoxia, and the in vitro effects of rivaroxaban on human cardiac microvascular endothelial cells (HCMECs). To create the PAH model, male Sprague-Dawley rats were subcutaneously injected with Sugen5416 (20 mg/kg) and exposed to 2 weeks of hypoxia (10% O2), followed by 2 weeks of exposure to normoxia. The animals were then divided into 2 groups with or without administration of rivaroxaban (12 mg/kg/d) for a further 4 weeks. HCMECs were cultured under hypoxic conditions (37 °C, 1% O2, 5% CO2) with Sugen5416 and with or without rivaroxaban. In the model rats, RV systolic pressure and Fulton index increased by hypoxia with Sugen5416 were significantly decreased when treated with rivaroxaban. In HCMECs, hypoxia with Sugen5416 increased the expression of protease-activated receptor-2 (PAR-2) and the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB), while treatment with rivaroxaban significantly suppressed the expression of these proteins. Rivaroxaban attenuated RV remodeling in a rat model of PAH by reducing ERK, JNK and NF-κB activation. Rivaroxaban has the possibility of providing additive effects on RV remodeling in patients with PAH.

The Pharmacology, Efficacy, and Safety of Rivaroxaban in Renally Impaired Patient Populations.

Rivaroxaban is a factor Xa inhibitor oral anticoagulant first approved for use in the United States in 2011. Under the drug class commonly termed direct oral anticoagulants, rivaroxaban is approved for the most indications within its class, 7 indications, which are: (1) reduction of risk of stroke and systemic embolism (SE) in nonvalvular atrial fibrillation, (2) treatment of deep vein thrombosis (DVT), (3) treatment of pulmonary embolism (PE), (4) reduction in the risk of recurrence of DVT and/or PE, (5) prophylaxis of DVT following hip or knee replacement surgery, (6) prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, and (7) reduction of risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease. Considering the relationship between cardiovascular disease, renal impairment, and the use of oral anticoagulants, the following targeted review was created. This review reports the results of the primary pharmacology, pharmacokinetic modeling, clinical safety and efficacy, and real-world postmarketing effectiveness and safety of rivaroxaban in patients with various degrees of renal impairment. Based on these data, rivaroxaban is a viable option for when anticoagulation is needed in patients who have both cardiovascular disease and renal impairment. However, as with any therapy, the benefits and risks of intervention should be carefully assessed and balanced. Patients treated with rivaroxaban for several of its approved indications should have their kidney function assessed prior to and during continued therapy to ensure consistency with the drug label.

Monitoring DOACs with a Novel Dielectric Microsensor: A Clinical Study.

BACKGROUND: There are acute settings where assessing the anticoagulant effect of direct oral anticoagulants (DOACs) can be useful. Due to variability among routine coagulation tests, there is an unmet need for an assay that detects DOAC effects within minutes in the laboratory or at the point of care. METHODS: We developed a novel dielectric microsensor, termed ClotChip, and previously showed that the time to reach peak permittivity (T peak) is a sensitive parameter of coagulation function. We conducted a prospective, single-center, pilot study to determine its clinical utility at detecting DOAC anticoagulant effects in whole blood. RESULTS: We accrued 154 individuals: 50 healthy volunteers, 49 rivaroxaban patients, 47 apixaban, and 8 dabigatran patients. Blood samples underwent ClotChip measurements and plasma coagulation tests. Control mean T peak was 428 seconds (95% confidence interval [CI]: 401-455 seconds). For rivaroxaban, mean T peak was 592 seconds (95% CI: 550-634 seconds). A receiver operating characteristic curve showed that the area under the curve (AUC) predicting rivaroxaban using T peak was 0.83 (95% CI: 0.75-0.91, p < 0.01). For apixaban, mean T peak was 594 seconds (95% CI: 548-639 seconds); AUC was 0.82 (95% CI: 0.73-0.91, p < 0.01). For dabigatran, mean T peak was 894 seconds (95% CI: 701-1,086 seconds); AUC was 1 (p < 0.01). Specificity for all DOACs was 88%; sensitivity ranged from 72 to 100%. CONCLUSION: This diagnostic study using samples from "real-world" DOAC patients supports that ClotChip exhibits high sensitivity at detecting DOAC anticoagulant effects in a disposable portable platform, using a miniscule amount of whole blood (<10 µL).

Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans.

AIMS: To investigate the influence of a cytochrome P450 CYP3A4 and efflux transporter P-glycoprotein (P-gp) inducing Hypericum perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban. METHODS: Open-label, nonrandomized, sequential treatment interaction study. Following CYP3A4 and P-gp phenotyping using low-dose midazolam and fexofenadine, 12 healthy volunteers received a single oral dose of 20 mg rivaroxaban and rivaroxaban plasma concentrations and inhibition of the activated coagulation factor X (factor Xa) activity were measured prior to and up to 48 h postdosing. The procedures were repeated after 2 weeks' treatment with the H. perforatum extract. RESULTS: The geometric mean ratios for the area under the concentration-time curve and Cmax of rivaroxaban after/before induction with the H. perforatum extract were 0.76 (90% confidence interval [CI] 0.70, 0.82) and 0.86 (90% CI 0.76, 0.97), respectively. Inhibition of factor Xa activity was reduced with a geometric mean area under the effect-time curve ratio after/before induction of 0.80 (90% CI 0.71, 0.89). No clinically significant differences were found regarding Tmax (median 1.5 vs 1 h, P = .26) and terminal elimination half-life (mean 10.6 vs 10.8 h, P = .93) of rivaroxaban. The H. perforatum extract significantly induced CYP3A4 and P-gp activity, as evidenced by phenotyping. CONCLUSION: The CYP3A4/P-gp inducing H. perforatum extract caused a decrease of rivaroxaban exposure with a proportional decrease of the pharmacodynamic effect. Although the data do not justify a contraindication for the combination or a systematic adjustment of rivaroxaban dosage, avoidance of the combination or laboratory monitoring should be considered in patients taking hyperforin-containing H. perforatum extracts with rivaroxaban.

Factor Xa inhibitor rivaroxaban suppresses experimental abdominal aortic aneurysm progression via attenuating aortic inflammation.

OBJECTIVE: Rivaroxaban is a specific factor Xa (FXa) inhibitor for venous thromboembolism treatment. Recently, increasing evidence have reported the beneficial effects of rivaroxaban on treating cardiovascular disorders such as coronary and peripheral artery disease. However, its potential influence on abdominal aortic aneurysm (AAA) remains unclear. This study aims to investigate whether rivaroxaban treatment could attenuate experimental AAA progression and its related mechanisms. APPROACHES AND RESULTS: In human aneurysmal aorta, FXa protein expression was significantly upregulated. Further investigations identified a positive correlation among plasma FXa level, AAA severity (the maximal aortic diameter), and intra-aneurysmal thrombus percentage. In Ang II (angiotensin II)-infused ApoE-/- mice, the administration of high dose rivaroxaban (15 mg/kg/d) for 14 days significantly reduced the maximal aortic diameter, while low dose rivaroxaban (5 mg/kg/d) did not display such a protective role. Although rivaroxaban treatments reduced the incidence of AAA and thrombus formation, these differences did not reach statistical significance. Immunohistochemistry revealed a pronounced aortic remodeling including increased collagen content and enhanced elastin degradation in Ang II-induced AAAs, which was inhibited by high dose rivaroxaban treatment. Further analysis demonstrated that rivaroxaban exerted its protective effects by decreasing leukocyte infiltration, inflammatory cytokines expression, and matrix metalloproteinases (MMPs) expression in the aortic wall. The inhibitory effect of rivaroxaban on aneurysm development was also observed in calcium chloride-induced AAA model. Mechanistically, in human aortic endothelial cells, FXa stimulation increased the expression of inflammatory cytokines (interleukin (IL)-1ß, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesive molecules, which were all reversed by the cotreatment of rivaroxaban. Subsequent monocyte-endothelial cell interaction was enhanced after FXa stimulation and was alleviated by rivaroxaban cotreatment. In addition, FXa induced a significantly heightened expression of MMP2 in human aortic endothelial cells, which was ameliorated by rivaroxaban coadministration. CONCLUSIONS: Rivaroxaban attenuated both angiotensin II- and calcium chloride-induced abdominal aortic aneurysm (AAA) progressions, through inhibiting aortic remodeling and inflammation. Rivaroxaban could be a promising therapeutic agent in attenuating AAA development by counteracting FXa-induced aortic wall inflammation.

Rivaroxaban Compared to Placebo for the Treatment of Leg Superficial Vein Thrombosis: A Randomized Trial.

The role of rivaroxaban in the treatment of leg superficial venous thrombosis (SVT) is uncertain. This article aims to determine if rivaroxaban is an effective and safe treatment for leg SVT. Patients with symptomatic leg SVT of at least 5 cm length were randomized to 45 days of rivaroxaban 10 mg daily or to placebo, and followed for a total of 90 days. Treatment failure (required a nonstudy anticoagulant; had proximal deep vein thrombosis or pulmonary embolism; or had surgery for SVT) at 90 days was the primary efficacy outcome. Secondary efficacy outcomes included leg pain severity, and venous disease-specific and general health-related quality of life over 90 days. Major bleeding at 90 days was the primary safety outcome. Poor enrollment led to the trial being stopped after 85 of the planned 600 patients were randomized to rivaroxaban (n = 43) or placebo (n = 42). One rivaroxaban and five placebo patients had a treatment failure by 90 days (absolute risk reduction = 9.0%, 95% confidence interval: -22 to 5.9%). Leg pain improvement did not differ at 7 (p = 0.16) or 45 days (p = 0.89), but was greater with rivaroxaban at 90 days (p = 0.011). There was no difference in venous disease-specific (p = 0.99) or general health-related (p = 0.37) quality of life over 45 days. There were no major bleeds or deaths in either group. There were no identifiable differences in efficacy or safety between rivaroxaban and placebo in patients with symptomatic SVT but comparisons were undermined by a much smaller than planned sample size (NCT1499953).

Rivaroxaban Versus Warfarin for Management of Obese African Americans With Non-Valvular Atrial Fibrillation or Venous Thromboembolism: A Retrospective Cohort Analysis.

African Americans (AAs) and obese individuals have increased thrombotic risk. This study evaluated the effectiveness and safety of rivaroxaban versus warfarin in obese, AAs with nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). Optum® De-Identified Electronic Health Record (EHR) data was used to perform separate propensity-score matched analyses of adult, oral anticoagulant (OAC)-naïve AAs with NVAF or acute VTE, respectively; who had a body mass index≥30kg/m2 and ≥12-months EHR activity with ≥1-encounter before OAC initiation. Cox regression was performed and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). For the NVAF analysis, 1,969 rivaroxaban- and 1,969 warfarin-users were matched. Rivaroxaban was not associated with a difference in stroke/systemic embolism versus warfarin (HR = 0.88, 95%CI = 0.60-1.28), but less major bleeding (HR = 0.68, 95%CI = 0.50-0.94) was observed. Among 683 rivaroxaban-users with VTE, 1:1 matched to warfarin-users, rivaroxaban did not alter recurrent VTE (HR = 1.36, 95%CI = 0.79-2.34) or major bleeding (HR = 0.80, 95%CI = 0.37-1.71) risk versus warfarin at 6-months (similar findings observed at 3- and 12-months). Rivaroxaban appeared to be associated with similar thrombotic, and similar or lower major bleeding risk versus warfarin in these obese, AA cohorts.