Administration Of Rivaroxaban Research Articles

Rivaroxaban, a specific FXa inhibitor, improved endothelium-dependent relaxation of aortic segments in diabetic mice

Activated factor X (FXa) plays a central role in the coagulation cascade, while it also mediates vascular function through activation of protease-activated receptors (PARs). Here, we examined whether inhibition of FXa by rivaroxaban, a direct FXa inhibitor, attenuates endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice. Induction of diabetes increased the expression of a major FXa receptor, PAR2, in the aorta (P < 0.05). Administration of rivaroxaban (10 mg/kg/day) to diabetic wild-type (WT) mice for 3 weeks attenuated endothelial dysfunction as determined by acetylcholine-dependent vasodilation compared with the control (P < 0.001), without alteration of blood glucose level. Rivaroxaban promoted eNOSSer1177 phosphorylation in the aorta (P < 0.001). Induction of diabetes to PAR2-deficient (PAR2−/−) mice did not affect endothelial function and eNOSSer1177 phosphorylation in the aorta compared with non-diabetic PAR2−/− mice. FXa or a PAR2 agonist significantly impaired endothelial function in aortic rings obtained from WT mice, but not in those from PAR2−/− mice. FXa promoted JNK phosphorylation (P < 0.01) and reduced eNOSSer1177 phosphorylation (P < 0.05) in human coronary artery endothelial cells (HCAEC). FXa-induced endothelial dysfunction in aortic rings (P < 0.001) and eNOSSer1177 phosphorylation (P < 0.05) in HCAEC were partially ameliorated by a JNK inhibitor. Rivaroxaban ameliorated diabetes-induced endothelial dysfunction. Our results suggest that FXa or PAR2 is a potential therapeutic target.

Early initiation of a factor Xa inhibitor can attenuate tissue repair and neurorestoration after middle cerebral artery occlusion

The timing of anti-coagulation therapy initiation after acute cardioembolic stroke remains controversial. We investigated the effects of post-stroke administration of a factor Xa inhibitor in mice, focusing on tissue repair and functional restoration outcomes. We initiated administration of rivaroxaban, a Xa inhibitor, immediately after permanent distal middle cerebral artery occlusion (pMCAO) in CB-17 mice harboring few leptomeningeal anastomoses at baseline. Rivaroxaban initiated immediately after pMCAO hindered the recovery of blood flow in ischemic areas by inhibiting leptomeningeal anastomosis development, and led to impaired restoration of neurologic functions with less extensive peri-infarct astrogliosis. Within infarct areas, angiogenesis and fibrotic responses were attenuated in rivaroxaban-fed mice. Furthermore, inflammatory responses, including the accumulation of neutrophils and monocytes/macrophages, local secretion of pro-inflammatory cytokines, and breakdown of the blood–brain barrier, were enhanced in infarct areas in mice treated immediately with rivaroxaban following pMCAO. The detrimental effects were not found when rivaroxaban was initiated after transient MCAO or on day 7 after pMCAO. Collectively, early post-stroke initiation of a factor Xa inhibitor may suppress leptomeningeal anastomosis development and blood flow recovery in ischemic areas, thereby resulting in attenuated tissue repair and functional restoration unless occluded large arteries are successfully recanalized.

Comparison of Once-Daily Administration of Edoxaban and Rivaroxaban in Asian Patients with Atrial Fibrillation

It is unclear whether the two once-daily dosing non-vitamin K antagonist oral anticoagulants (NOACs), edoxaban and rivaroxaban, have similar effectiveness and safety in Asian patients with non-valvular atrial fibrillation (AF). This study aimed to compare the effectiveness and safety of edoxaban and rivaroxaban in a Korean population with non-valvular AF. Using the Korean National Health Insurance Service database from January 2014 to December 2016, we compared the risk of ischemic stroke, intracranial hemorrhage (ICH), hospitalization for gastrointestinal (GI) bleeding, hospitalization for major bleeding, all-cause death, and composite outcome in a 3:1 propensity score matched cohort in patients with AF who were naïve to rivaroxaban (n = 12,369) and edoxaban (n = 4,123). Hazard ratios for the six clinical outcomes were analyzed using Cox regression analysis with rivaroxaban as the reference. Baseline characteristics were balanced between the two groups (median age, 71 years; median CHA2DS2-VASc score, 3; 56% of patients received a reduced dose). Edoxaban users showed comparable results in all six clinical outcomes (all p = nonsignificant) when compared to rivaroxaban users for total, standard, and reduced doses. We provide for the first time the comparison of effectiveness and safety between the two once-daily NOACs in a large-scale Asian AF population. In both standard and reduced dose regimens, edoxaban showed comparable effectiveness and safety compared to rivaroxaban.

Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE-/- mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE-/- deletion, and many were absent in Alox-/- mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.

Therapeutic monitoring of rivaroxaban in dogs using thromboelastography and prothrombin time.

BackgroundThe chromogenic anti‐Xa assay, the gold standard for monitoring the anti‐Xa effect of rivaroxaban, is not available as a cage‐side diagnostic test for use in a clinical setting.Hypothesis/ObjectivesTo evaluate clinical modalities for measuring the anticoagulant effects of rivaroxaban using a point‐of‐care prothrombin time (PT) and thromboelastography (TEG).AnimalsSix healthy Beagle dogs.MethodsProspective, experimental study. Four different doses of rivaroxaban (0.5, 1, 2, and 4 mg/kg) were administered PO to dogs. Single PO and 3 consecutive dosing regimens also were assessed. Plasma rivaroxaban concentration was determined using a chromogenic anti‐Xa assay, point‐of‐care PT, and TEG analysis with 4 activators (RapidTEG, 1 : 100 tissue factor [TF100], 1 : 3700 tissue factor [TF3700], and kaolin), and results were compared. Spearman correlation coefficients were calculated between ratios (peak to baseline PT; peak reaction time [R] of TEG to baseline [R] of TEG) and anti‐Xa concentration.ResultsAnti‐Xa concentration had a significant correlation with point‐of‐care PT (R = 0.82, P < .001) and RapidTEG‐TEG, TF100‐TEG, and TF3700‐TEG (R = 0.76, P < .001; R = 0.82, P < .001; and R = 0.83, P < .001, respectively).Conclusions and Clinical ImportanceOverall, a 1.5‐1.9 × delay in PT and R values of TEG 3 hours after rivaroxaban administration is required to achieve therapeutic anti‐Xa concentrations of rivaroxaban in canine plasma. The R values of TEG, specifically using tissue factors (RapidTEG, TF100, TF3700) and point‐of‐care PT for rivaroxaban can be used practically for therapeutic monitoring of rivaroxaban in dogs.

Targeting Coagulation Factor Xa Promotes Regression of Advanced Atherosclerosis in Apolipoprotein-E Deficient Mice

Atherosclerosis is a progressive inflammatory vascular disorder, complicated by plaque rupture and subsequently atherothrombosis. In vitro studies indicate that key clotting proteases, such as factor Xa (FXa), can promote atherosclerosis, presumably mediated through protease activated receptors (PARs). Although experimental studies showed reduced onset of atherosclerosis upon FXa inhibition, the effect on pre-existing plaques has never been studied. Therefore, we investigated effects of FXa inhibition by rivaroxaban on both newly-formed and pre-existing atherosclerotic plaques in apolipoprotein-e deficient (ApoE−/−) mice. Female ApoE−/− mice (age: 8–9 weeks, n = 10/group) received western type diet (WTD) or WTD supplemented with rivaroxaban (1.2 mg/g) for 14 weeks. In a second arm, mice received a WTD for 14 weeks, followed by continuation with either WTD or WTD supplemented with rivaroxaban (1.2 mg/g) for 6 weeks (total 20 weeks). Atherosclerotic burden in aortic arch was assessed by haematoxilin & eosin immunohistochemistry (IHC); plaque vulnerability was examined by IHC against macrophages, collagen, vascular smooth muscle cells (VSMC) and matrix metalloproteinases (MMPs). In addition, PAR1 and -2 expressions and their main activators thrombin and FXa in the plaque were determined in the plaque. Administration of rivaroxaban at human therapeutic concentrations reduced the onset of atherosclerosis (−46%, p < 0.05), and promoted a regression of pre-existing plaques in the carotids (−24%, p < 0.001). In addition, the vulnerability of pre-existing plaques was reduced by FXa inhibition as reflected by reduced macrophages (−39.03%, p < 0.05), enhanced collagen deposition (+38.47%, p < 0.05) and diminished necrotic core (−31.39%, p < 0.05). These findings were accompanied with elevated vascular smooth muscle cells and reduced MMPs. Furthermore, expression of PARs and their activators, thrombin and FXa was diminished after rivaroxaban treatment. Pharmacological inhibition of FXa promotes regression of advanced atherosclerotic plaques and enhances plaque stability. These data suggest that inhibition of FXa may be beneficial in prevention and regression of atherosclerosis, possibly mediated through reduced activation of PARs.

Rivaroxaban administration after acute ischemic stroke: The RELAXED study.

The efficacy of early anticoagulation in acute stroke with nonvalvular atrial fibrillation (NVAF) remains unclear. We performed a study to evaluate the risk of recurrent ischemic stroke (IS) and major bleeding in acute IS patients with NVAF who started rivaroxaban. This observational study evaluated patients with NVAF and acute IS/transient ischemic attack (TIA) in the middle cerebral arterial territory who started rivaroxaban within 30 days after the index IS/TIA. The primary endpoints were recurrent IS and major bleeding within 90 days after the index IS/TIA. The relationship between the endpoints and the time to start rivaroxaban was evaluated by correlation analysis using cerebral infarct volume, determined by diffusion-weighted magnetic resonance images within 48 hours of onset of the index IS/TIA. Of 1309 patients analyzed, recurrent IS occurred in 30 (2.3%) and major bleeding in 11 (0.8%) patients. Among patients with known infarct size (N = 1207), those with small (<4.0 cm3), medium (≥4.0 and <22.5 cm3), and large (≥22.5 cm3) infarcts started rivaroxaban a median of 2.9, 2.9, and 5.8 days, respectively, after the index IS/TIA. Recurrent IS was significantly less frequent when starting rivaroxaban ≤14 days versus ≥15 days after IS (2.0% versus 6.8%, P = 0.0034). Incidences of recurrent IS and major bleeding in whom rivaroxaban was started <3 days (N = 584) after IS were also low: 1.5% and 0.7%, respectively. Initiation of rivaroxaban administration in acute IS or TIA was associated with a low recurrence of IS (2.3%), and a low incidence of major bleeding events (0.8%) for 90 days after the index stroke. For the prevention of recurrent attacks in acute IS patients with NVAF, it is feasible to start the administration of rivaroxaban within 14 days of onset. Rivaroxaban started within 3 days of onset may be a feasible treatment option for patients with a small or medium-sized infarction.

Improved Dosing and Administration of Rivaroxaban when Prescribed by a Cardiologist.

This retrospective study assessed real-world prescribing and patient adherence to dietary requirements during use of rivaroxaban in 116 patients with AF. Associations between prescriber specialty and the correct dosing and administration were assessed using the Chi-Square test. Most rivaroxaban prescriptions were ordered by cardiologists (50.9%). Sixty-nine patients (59.5%) were taking the right dose at the correct time with an adequate meal. Of the 47 (40.5%) taking rivaroxaban incorrectly, 39 (33.6%) had not been administered an adequate meal and eight (6.9%) were not prescribed the correct dose. Compared with other prescribers, patients were most likely to be taking the correct dose and administration when prescribed by cardiologists (72.9% versus 45.6%; p=0.003). Patients were least likely to be taking the correct dose and administration when prescribed by primary care providers (44.4% versus 69.0%; p=0.009). This difference was driven by patients who did not take the treatment with an adequate meal. Inappropriate prescribing, administration and non-adherence to DOACs can have devastating consequences. This highlights the importance of formal systematic education of patients prescribed DOACs across the whole health system. Future studies are warranted to explore the impact of non-adherence to rivaroxaban dietary requirements on clinical outcomes.

Contemporary approaches to determine the duration of anticoagulant therapy for venous thromboembolism

The review is devoted to the issue of optimal duration of anticoagulant therapy for venous thromboembolic complications (VTEC) using oral anticoagulants (OAC). These drugs are characterized by higher safety in comparison with vitamin K antagonists and make it possible to increase the duration of treatment for not only spontaneous thrombosis (with high risk of recurrence), but also thrombosis provoked by minor persistent and transient risk factors of VTEC. Efficacy and safety of prolonged treatment of VTEC using OAC was analyzed. Different classifications of primary thrombotic episode depending on risk of subsequent recurrence are presented. Moreover, scales for individual assessment of risk of recurrent thrombosis after anticoagulant therapy cancellation and risk of bleeding in case of continued treatment are given. Outcomes of long-term administration of rivaroxaban for VTEC are analyzed. It was concluded that OAC are safe for prolonged management of primary thrombotic episode. However, overall duration of treatment should be determined considering individual balance of benefits and risks.

Single Dose Bioequivalence Study of Two Rivaroxaban Tablet Formulations, Administered Orally after Being Crushed and Suspended in Apple Puree

The bioavailability of an active substance might be altered when a solid oral dosage form (SODF) is crushed or disintegrated and mixed with fluids or food in order to assist swallowing. In consequence, the current European Medicines Agency (EMA) practice is to request comparative bioavailability testing for bridging safety and efficacy data from a formulation administered whole to the same product administered crushed. Specific criteria for waiving in vivo testing of crushed products are available only for BCS Class I and Class III drugs. Since rivaroxaban is a Class II drug which can be administered crushed and mixed with fluids, any generic formulation has to be tested against the originator in this setting. Therefore, an open label, randomized, single dose, two-period, two-sequence, crossover bioequivalence study with administration of rivaroxaban 10 mg crushed tablets suspended in apple puree was conducted in 24 fasting healthy volunteers. Both rivaroxaban treatments were well tolerated by the study subjects. A standardized, dose efficient and fully reproducible protocol for grinding, mixing and administering investigational medicinal products was developed and applied. Assessment of bioequivalence was based on plasma concentrations of parent rivaroxaban, quantified using a validated HPLC/ MS/MS method. The 90% confidence intervals for Cmax and AUC0-t least square mean T/R ratios were within the bioequivalence acceptance range of 80% to 125%. Results from the present study reinforced the bioequivalence conclusion reached for the same test and reference products following administration of whole tablets in fasting state. No notable changes in bioavailability occurred when rivaroxaban tablets were crushed, immediately dispensed in 70 mL apple puree and quantitatively (entire dose recovered) administered to fasting volunteers.

Rivaroxaban Promotes Reduction of Embolus Size within Cerebrocortical Microvessels in a Mouse Model of Embolic Stroke.

Previous reports have suggested that direct oral anticoagulants exert a prothrombolytic effect against intracardiac thrombi. We hypothesized that these anticoagulants may also help recanalize occluded intracranial arteries via prothrombolytic effects. In this study, we evaluated the effects of rivaroxaban, a direct oral anticoagulant, on fibrin emboli within the cerebrocortical microvessels in a mouse model of embolic stroke. Fibrin emboli prepared ex vivo were injected into the common carotid artery of male C57BL/6 mice, and embolization in the microvessels on the brain surface was observed through a cranial window. Oral administration of rivaroxaban was initiated a week before injection of the emboli. The number and sizes of the emboli were measured at two time points: immediately after and 3 h after the embolus injection in the rivaroxaban-treated mice (n =6) and untreated mice (n =7). The rates of recanalization and change in the embolus size were analyzed between the two groups. Complete recanalization was observed only in the rivaroxaban group (three mice in the rivaroxaban group compared with none in the control group). A significantly higher rate of reduction of the embolus size was observed in the rivaroxaban group than in the control group (P=0.0216). No significant differences between the two groups were observed in the serum levels of the following coagulation markers: thrombin-antithrombin III complexes, D-dimers, or plasmin-α2-plasmin inhibitor complex. Our findings indicate that rivaroxaban may promote reduction in the size of stagnated fibrin emboli in cerebrocortical microvessels in cases of embolic stroke.

Rivaroxaban improves hidden blood loss, blood transfusion rate and reduces swelling of the knee joint in knee osteoarthritis patients after total knee replacement.

Osteoarthritis (OA) is the third most common diagnosis made by general practitioners in older patients. The purpose of the current study is to investigate effects rivaroxaban had on both hidden blood loss and blood transfusion rate (BTR) in patients with knee OA (KOA) after going through a total knee replacement (TKR).Between the time periods of December 2011 up until January 2015, a total of 235 patients underwent TKR and were selected to be assigned to either the rivaroxaban or nonanticoagulant groups. Coagulation function indexes before surgery and following administration of rivaroxaban, total blood loss, hidden blood loss, dominant blood loss, blood transfusion volume, hemoglobin reduction, degree of postoperative pain (visual analogue scale), the degree of knee swelling, and range of motion following surgery were all recorded. Hospital for special surgery (HSS) scores offered an objective evaluation for the knee joint functions before surgery at the intervals of 2 weeks and after surgery at intervals of 3 months, 6 months, 12 months, and 24 months.Patients in the rivaroxaban group had shown a higher hidden blood loss, as well as a higher BTR, compared to those involved in the nonanticoagulant group. BTR was found to have been 49.59% in the rivaroxaban group, and 35.09% for the nonanticoagulant group. Patients in the rivaroxaban group had lower degrees of knee swelling than those involved in the nonanticoagulant group. There was no deep vein thrombosis (DVT) detected in the rivaroxaban group, whereas 5 DVT cases were detected in the nonanticoagulant group. In the rivaroxaban group, the HSS scores of the knee joint functions were remarkably higher at the 2-week mark in succession to the surgery than those involved with the nonanticoagulant group.This overall data demonstrated that KOA patients after TKR had presented with a higher hidden blood loss, BRT, and lower swelling degrees of the knee joint after being treated by the rivaroxaban.

A9612 The combination therapy of Xa inhibitor and antihypertensive therapy improved anticoagulant activity and hypertensive target organ damage in nonvalvular atrial fibrillation patients.

Objectives: The anticoagulant activity and blood pressure increase in morning. The aim of this study was to evaluate the change of anticoagulant activity, blood pressure and target organ damage in combination therapy of Xa inhibitor and antihypertensive therapy in nonvalvular atrial fibrillation patients. Methods: We enrolled 72 NVAF patients. Rivaroxaban (10–15 mg) was continuously administered once daily over 8 weeks (study period I). To subjects who have shown early-morning hypertension in the study period I (N = 50), nifedipine was additionally administered at bedtime, and the rivaroxaban administration was continued for additional 8 weeks. We assessed prothrombin fragment 1 + 2, optimal range of prothrombin fragment 1 + 2 was defined 69–229pmol/L, D-Dimer, positive D-dimer measurement (≥1.0 μg/mL), and evaluated urinary albumin creatinine ratio (UACR) as hypertensive target organ damage. Results: The percentage of optimal range of prothrombin fragment 1 + 2 was significantly increased from baseline at 4 weeks (70.8 vs. 86.1%, p = 0.033). Clinic systolic blood pressure was reduced at 12 weeks (134.7 ± 9.6 vs. 118.7 ± 9.6mmHg, p < 0.003) and 16weeks (134.7 ± 9.6 vs. 118.7 ± 9.6mmHg, p < 0.003)). UACR was significantly reduced from 8 weeks at 12 weeks (median UACR: 13.7 vs. 8.8 mg/gCR, p = 0.006). The percentage of positive D-dimer reduced from baseline to 8 weeks (8% vs. 0%, p = 0.044), and remained 0% at 16 weeks. Conclusion: The combination therapy of Xa inhibitor and antihypertensive therapy improved anticoagulant activity and hypertensive target organ damage in nonvalvular atrial fibrillation patients.

D-Dimer Levels and Effect of Rivaroxaban on Those Levels and Outcomes in Patients With Acute Coronary Syndrome (An ATLAS ACS-TIMI 46 Trial Substudy)

D-dimer has been used as both a diagnostic and prognostic biomarker in the assessment of patients with venous thromboembolism, but its prognostic value in the setting of arterial acute coronary syndromes (ACS) and the ability of pharmacotherapy to reduce D-dimer in ACS is less well characterized. It was hypothesized that elevated baseline D-dimer would be associated with poor clinical outcomes in ACS, and that Factor Xa inhibition with Rivaroxaban would reduce D-dimer acutely and chronically. The ATLAS ACS TIMI-46 trial assessed the safety and efficacy of rivaroxaban compared with placebo in ACS patients. A subset of subjects had a D-dimer measured at baseline (n = 1,834, 52.5%). A univariate and multivariable logistic regression assessed the relation between baseline D-dimer and a composite end point of cardiovascular death, myocardial infarction, or stroke through 6 months. The Wilcoxon rank sum test was used to compare change in D-dimer level between the treatment groups from baseline. Baseline D-dimer was associated with the composite efficacy outcome in a univariate logistic regression (odds ratio 1.15, 95% confidence interval 1.03 to 1.29, p = 0.015) and a multivariable logistic regression (odds ratio 1.13, 95% confidence interval 1.00 to 1.28, p = 0.048). Rivaroxaban administration lowered D-dimer levels compared wth placebo after administration of the first dose of study drug (p = 0.026), at day 30 (p < 0.001) and day 180 (p < 0.001). In conclusion, elevated baseline D-dimer was associated with an increased risk of the composite outcome within 6 months of the ACS event and administration of the Factor Xa inhibitor rivaroxaban was associated with lower D-dimer levels compared with placebo after the first dose, at day 30 and day 180.

Association between prothrombin time and bleeding in hospitalized patients receiving rivaroxaban.

Results of an investigation of the pharmacodynamic effect of rivaroxaban anticoagulation, as measured by prothrombin time (PT), on bleeding risk and other outcomes in hospitalized patients are reported. In a single-center retrospective cohort study, adult inpatients who had a PT measured within 24 hours after rivaroxaban administration during a designated 23-month period were identified. Patients who experienced in-hospital bleeding events were compared with those who did not. A multivariable logistic regression model was used to quantify the association between PT and bleeding events while adjusting for albumin levels and use of nonsteroidal antiinflammatory drugs and/or antiplatelet agents. Thromboembolic events were assessed as a secondary outcome. A total of 199 patients met the criteria for inclusion in the analysis; 41 experienced a bleeding event. Among patients with a PT of ≥30 seconds versus a PT of <30 seconds, the overall rate of bleeding events was significantly higher (38.7% versus 17.3%, p = 0.0067). Results of multivariable regression modeling showed that a PT of ≥30 seconds correlated with an approximately 3-fold higher bleeding risk (odds ratio, 3.25; 95% confidence interval, 1.09-9.66). Hypoalbuminemia was also a positive predictor of bleeding risk. There was no significant between-group difference in thromboembolic events. In hospitalized patients receiving rivaroxaban who had coagulation tests performed, a PT of ≥30 seconds was associated with a higher risk of bleeding. Hypoalbuminemia was also associated with bleeding in this population.

Thrombolysis with rt-PA under Rivaroxaban Anticoagulation in a Hypertensive Rat Model of Intraluminal Middle Cerebral Artery Occlusion

BackgroundThe aim of this study was to assess the risk and the threshold of hemorrhagic transformation (HT) after treatment with recombinant tissue plasminogen activator (rtPA) under the novel oral anticoagulant, rivaroxaban. MethodsFifty-three spontaneous hypertensive rats were used in this study. We performed transient middle cerebral artery occlusion for 270 minutes. Placebo, 10 mg/kg or 20 mg/kg rivaroxaban were administered via a stomach tube 180 minutes after induction of ischemia, and rtPA (10 mg/kg) was administered just before reperfusion. Ninety minutes after rivaroxaban administration we measured the rivaroxaban plasma concentration and prothrombin time (PT). HT volume was assessed by hemoglobin spectrophotometry. Additionally, infarct volume, IgG leakage volume, and neurological outcome were assessed. ResultsRivaroxaban plasma concentration and PT increased in a dose dependent manner but were lower than human peak levels after a once-daily dose of 20 mg rivaroxaban. HT volume increased after treatment with 20 mg/kg rivaroxaban compared with placebo treated controls or those treated with 10 mg/kg rivaroxaban (26.5 ± 5.4, 26.8 ± 8.7, and 41.4 ± 12.6 μL in placebo, 10 mg/kg, and 20 mg/kg treated groups, respectively; P < .05). ConclusionsOur results suggest that even at therapeutic plasma concentrations, rivaroxaban may increase the risk of HT after thrombolysis in some conditions, such as hypertension and/or a prolonged ischemic period.

Factor Xa inhibitors differently modulate electrical activities in pulmonary veins and the sinoatrial node

Factor Xa inhibitors reduce stroke in patients with atrial fibrillation. Pulmonary veins (PVs) and the sinoatrial node (SAN) are crucial for genesis of atrial fibrillation. However, the electrophysiological effects of factor Xa inhibitors (edoxaban and rivaroxaban) on PVs and the SAN remain unclear. Conventional microelectrodes were used to record the action potential in isolated rabbit PVs and SAN preparations before and after administration of edoxaban (0.1, 0.3, and 1 μM) or rivaroxaban (0.01, 0.03, 0.1, and 0.3 μM). A whole-cell patch-clamp was used to record the late sodium current (INa-late) in isolated single rabbit PV cardiomyocytes. Edoxaban significantly reduced PV spontaneous beating rates at 0.3 and 1 μM (N = 6 rabbits, P < 0.05), and reduced SAN beating rates at 1 μM (N = 6, P < 0.05). Similarly, rivaroxaban reduced PV spontaneous beating rates at 0.1 and 0.3 μM (N = 7, P < 0.05), and reduced SAN beating rates at 0.3 μM (N = 6, P < 0.05). However, neither edoxaban (1 μM) nor rivaroxaban (0.3 μM) reduced PV spontaneous beating rates in the presence of 1 μM BMS200261 (an inhibitor of protease-activated receptors type 1, PAR1 inhibitor) or 10 μM ranolazine (an inhibitor of late sodium current, INa-late inhibitor). Edoxaban (0.3 and 1 μM) and rivaroxaban (0.1 and 0.3 μM) respectively decreased the INa-late by 47%, 47%, 36%, and 49% (n = 9 PV cardiomyocytes from 5 rabbits, P < 0.05). In conclusion, Factor Xa inhibitors reduce PV spontaneous activities and may modulate occurrence of atrial fibrillation by inhibiting PAR1 and reducing the INa-late in PVs.

The factor Xa inhibitor rivaroxaban reduces cardiac dysfunction in a mouse model of myocardial infarction

IntroductionRivaroxaban selectively inhibits factor Xa (FXa), which plays a central role in blood coagulation. In addition, FXa activates protease-activated receptor-2 (PAR-2). We have shown that PAR-2−/− mice exhibit less cardiac dysfunction after cardiac injury. Material and methodsWild-type (WT) and PAR-2−/− mice were subjected to left anterior descending artery (LAD) ligation to induce cardiac injury and heart failure. Mice received either placebo or rivaroxaban chow either starting at the time of surgery or 3 days after surgery and continued up to 28 days. Cardiac function was measured by echocardiography pre-surgery and 3, 7 and 28 days after LAD ligation. We also measured anticoagulation, intravascular thrombi, infarct size, cardiac hypertrophy and inflammation at various times. ResultsRivaroxaban increased the prothrombin time and inhibited the formation of intravascular thrombi in mice subjected to LAD ligation. WT mice receiving rivaroxaban immediately after surgery had similar infarct sizes at day 1 as controls but exhibited significantly less impairment of cardiac function at day 3 and beyond compared to the placebo group. Rivaroxaban also inhibited the expansion of the infarct at day 28. Rivaroxaban did not significantly affect the expression of inflammatory mediators or a neutrophil marker at day 2 after LAD ligation. Delaying the start of rivaroxaban administration until 3 days after surgery failed to preserve cardiac function. In addition, rivaroxaban did not reduce cardiac dysfunction in PAR-2−/− mice. ConclusionsEarly administration of rivaroxaban preserves cardiac function in mice after LAD ligation.

Possible role of rivaroxaban in attenuating pressure-overload-induced atrial fibrosis and fibrillation

BackgroundCoagulation factor Xa (FXa) promotes thrombus formation and exacerbates inflammation via activation of protease-activated receptor (PAR)-2. We tested the hypothesis of whether administration of direct oral anticoagulant, rivaroxaban, would attenuate transverse aortic constriction (TAC)-induced atrial inflammatory fibrosis and vulnerability to atrial fibrillation (AF) in mice. MethodsTen-week-old male CL57/B6 mice were divided into a sham-operation (CNT) group and TAC-surgery group. These two groups were then subdivided into vehicle (VEH) and rivaroxaban (RVX) treatment (30μg/g/day) groups. We assessed PAR-2 expression in response to TAC-related stimulation using rat cultured cells. ResultsTAC-induced left atrial thrombus formation was not observed in the TAC-RVX group. Cardiac PAR-2 upregulation was observed in both TAC groups. In the quantitative analysis of mRNA levels, cardiac PAR-2 upregulation was attenuated in the TAC-RVX group compared to TAC-VEH group. In histological evaluation, the TAC-VEH group showed cardiac inhomogeneous interstitial fibrosis and abundant infiltration of macrophages, which were attenuated by RVX administration. Electrophysiological examination revealed that AF duration in the TAC group was shortened by RVX administration. TAC-induced protein overexpression of monocyte chemoattractant protein-1, and mRNA overexpression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 in the left atrium was suppressed by RVX treatment. In cardiac fibroblasts, persistent intermittent stretch upregulated PAR-2, which was suppressed by RVX pre-incubation. ConclusionsThese observations demonstrate that coagulation FXa inhibitor probably has a cardioprotective effect against pressure-overload-induced atrial remodeling.

Efficacy and safety of Rivaroxaban anticoagulant therapy in the treatment of atrial fibrillation cryoablation

Objective: To observe the efficacy and safety of the novel oral anticoagulant Rivaroxaban for anticoagulation therapy in patients with nonvalvular atrial fibrillation (AF) during cryoablation. Methods: A total of 137 AF patients from October 2013 to December 2016 underwent cryoablation were divided into two groups according to the application of anticoagulant drugs: Rivaroxaban group (65 cases) and Heparin group (72 cases). Rivaroxaban group: oral administration of Rivaroxaban 20 mg, once a day, was started 3 days before the cryoablation, no anticoagulant was additionally added during cryoablation, the activated clotting time (ACT) was measured, and oral administration of Rivaroxaban was continued for 3 months after cryoablation. Heparin group: oral administration of Rivaroxaban 20 mg, once a day, was stopped 24 hours before the cryoablation, heparin (100 U/kg) anticoagulation was given during cryoablation, ACT was controlled between 250 and 300 seconds, and oral administration of Rivaroxaban was continued for 3 months after cryoablation. The ACT results, the incidence of bleeding and thromboembolic events between the two groups were compared. Results: The ACT result between the two groups were with statistically significance[(110±16) vs (323±61) seconds, P=0.000)]. The bleeding events for Rivaroxaban group were two cases of local hematoma of the femoral vein puncture site, with the incidence rate of 3.1%(2/65); Heparin group were two cases of local hematoma of the femoral vein puncture site, and one case of epistaxis, with the incidence rate of 4.2%(3/72), with no statistical significance(P=0.549) between the two groups. No thromboembolic event occurred in the Rivaroxaban group, one cerebellar thromboembolic event occurred in the Heparin group during anticoagulant bridging phase after cryoablation. Conclusion: Rivaroxaban is safe and effective for anticoagulation therapy in patients with atrial fibrillation cryoablation.