Dose Of Rivaroxaban Research Articles

Reduced-Dose Rivaroxaban Is Associated with Lower All-Cause Mortality in Older Patients with Nonvalvular Atrial Fibrillation.

Reduced-dose rivaroxaban (10 mg) was used in the J-ROCKET AF trial, demonstrating safety in the Asian population. It remains unclear whether treatment with reduced-dose versus full-dose rivaroxaban (20 mg/15 mg) is associated with all-cause mortality in older patients with nonvalvular atrial fibrillation. Proposed: To evaluate the effects of reduced-dose rivaroxaban on all-cause mortality in patients over 85. We retrospectively enrolled medical records representing the period from October 2012 to November 2016. The 2 × 2 factorial design incorporated age (≥85 vs. <85) and rivaroxaban use (reduced vs. full dose). The primary study outcomes were all-cause and cardiac-related mortality. The study enrolled 2386 patients with a mean age of 76.6 ± 10.4 years; 51.8% were male. In the ≥85 group (n = 593), the reduced-dose subgroup had lower all-cause (5.3% vs. 10.6%, p = 0.02) and cardiac-related mortality (1.9% vs. 5.1%, p = 0.04), whereas the younger patients receiving reduced-dose rivaroxaban had higher all-cause mortality (3.7% vs. 1.8%, p = 0.01) but no difference in cardiac-related mortality (1.2% vs. 0.7%, p = 0.33). The rate of hospitalization for heart failure was significantly lower in the elderly group with reduced-dose rivaroxaban (7.2% vs. 15.7%, p < 0.01) but not in the younger group. After adjusting for confounders in the older group, treatment with reduced-dose rivaroxaban was associated with lower risk of all-cause mortality (adjusted HR (aHR): 0.40, 95% CI: 0.21-0.74, p < 0.01) and hospitalization for heart failure (aHR: 0.54, 95% CI: 0.29-0.99, p = 0.05). No associations were found between rivaroxaban dose and cardiac-related mortality in either group, nor between younger age and any outcome. Reduced-dose rivaroxaban was associated with lower risks of all-cause mortality and hospitalization for heart failure in older patients with nonvalvular atrial fibrillation. Future studies can investigate the effect of reduced-dose rivaroxaban on prognoses in elderly individuals ≥85 years in the west.

In vivo evaluation of the pharmacokinetic interactions between almonertinib and rivaroxaban, almonertinib and apixaban.

Background: Almonertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is commonly used as a first-line treatment for non-small cell lung cancer (NSCLC) patients with EGFR T790M mutations. Rivaroxaban and apixaban are a selective, direct factor Xa inhibitor used to treat venous thromboembolism (VTE), which is a frequent complication of NSCLC. Rivaroxaban and apixaban are substrates of CYP3A4, P-gp and BCRP, whereas almonertinib is an inhibitor of P-gp and BCRP. Rivaroxaban or apixaban are often prescribed together with almonertinib in NSCLC patients, but clear information on pharmacokinetic drug interaction is lacking. Therefore, this study aimed to unravel the extent of interactions between almonertinib-rivaroxaban and almonertinib apixaban in rats, and whether the pharmacokinetic interaction can be mitigated by rivaroxaban and apixaban dose adjustment. Methods: Rats were divided into ten groups (n = 6) that received rivaroxaban (2mg/kg) (group 1), apixaban (0.5mg/kg) (group 2), almonertinib (15mg/kg) (group 3, group 4), almonertinib with rivaroxaban (2mg/kg) (group 5), almonertinib with rivaroxaban (1mg/kg) (group 6), almonertinib with apixaban (0.5mg/kg) (group 7), almonertinib with apixaban (0.25mg/kg) (group 8), rivaroxaban (2mg/kg) with almonertinib (group 9), apixaban (0.5mg/kg) with almonertinib (group 10). The concentrations of drugs were determined by an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The levels of messenger RNA were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Results and Discussion: The results indicate that almonertinib increased the Cmax and AUC0-t of 2mg/kg rivaroxaban by 3.30 and 3.60-fold, 1mg/kg rivaroxaban by 1.28 and 1.90-fold. Almonertinib increased the Cmax and AUC0-t of 0.5mg/kg apixaban by 2.69 and 2.87-fold, 0.25mg/kg apixaban by 2.19 and 2.06-fold. In addition, rivaroxaban also increased systemic exposure to almonertinib. The results of qRT-PCR showed that almonertinib reduced the expression of Cyp3a1 in liver and intestine, and Abcb1a, Abcg2 in intestine and kidney. The pharmacokinetic results suggest that it is important to take special care of the interactions of these drugs in clinical applications.

Effect of a High-Fat Diet on the Pharmacokinetics and Safety of Rivaroxaban in Healthy Chinese Subjects.

The effects of food on the pharmacokinetics (PKs) and safety of 10-mg rivaroxaban tablets in healthy Chinese subjects were investigated from 1 bioequivalence trial. The bioequivalence trial was designed as randomized, open-label, 2-sequence, 4-period crossover under both fasted and fed conditions. A total of 56 healthy subjects were enrolled, 62.5% were male. These subjects received a single oral 10-mg dose of rivaroxaban with a 7-day washout between 4 periods. Serial PK samples were collected and plasma concentrations were analyzed using validated high-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental methods. The BE module of WinNonLin was used for statistical analysis of the maximum concentration (Cmax ), the area under the concentration-time curve from zero to the final measurable concentration (AUC0-t ), and the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) of rivaroxaban in plasma. Compared with the fasted state, the Cmax , AUC0-t , and AUC0-∞ of rivaroxaban significantly increased by 47%, 28%, and 26%, respectively, with oral administration of rivaroxaban 10mg in the fed state. The incidence of adverse events (AEs) was similar between the fasted and fed states, and no serious AEs were observed. Food significantly increased the exposure to rivaroxaban 10mg in Chinese subjects.

Who may benefit from low-dose Rivaroxaban plus Aspirin? Practical implications for outpatients with cardiovascular disease.

Despite the availability of effective preventive therapies based on guidelines, patients with vascular diseases continue to be at a high risk for recurrent ischemic events. Therefore, novel therapeutic strategies are required to further reduce the residual risk present in these patients at high risk. Platelet aggregation and fibrin organization are involved in arterial thrombosis, and rivaroxaban is capable of targeting both processes and has a synergistic effect when used in combination with acetylsalicylic acid (ASA), the so-called dual pathway inhibition (DPI). The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the DPI (a combination of rivaroxaban 2.5 mg/bid (vascular dose) and ASA 100 mg once daily), reduced cardiovascular death, stroke, or myocardial infarction by 24% in patients with chronic coronary artery disease (CAD) and peripheral artery disease (PAD). Subsequently, the VOYAGER PAD (Vascular Outcomes Study of ASA Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) trial confirmed the effectiveness of the vascular dose of rivaroxaban in patients with PAD after lower-extremity revascularization, compared to ASA alone. Therefore, DPI is recommended in patients with CAD (+/- PAD) or symptomatic PAD at high ischaemic risk. The purpose of this review is to examine the clinical benefits and practical implications of DPI in CAD and PAD patients.

Comparisons of Effectiveness and Safety between On-label Dosing, Off-label Underdosing and Off-label Overdosing in Asian and Non-Asian Atrial Fibrillation Patients Treated with Rivaroxaban: A Systematic Review and Meta-analysis of Observational Studies.

Limited real-world data show that rivaroxaban following dosage criteria from either ROCKET AF (20mg/day or 15mg/day if creatinine clearance [CrCl]<50ml/min) or J-ROCKET AF (15mg/day or 10mg/day if CrCl<50ml/min) are associated with comparable risks of thromboembolism and bleeding with each other in patients with non-valvular atrial fibrillation (NVAF). We are aimed to study whether these observations differ between Asian and non-Asian subjects. A systematic review and meta-analysis with random effects was conducted to estimate the aggregate hazard ratio (HR) and 95% confidence interval (CI) using PubMed and MEDLINE databases from September 8, 2011 to December 31, 2022 searched for adjusted observational studies that reported relevant clinical outcomes of NVAF patients receiving rivaroxaban 10mg/day if CrCl>50ml/min, on-label dose rivaroxaban eligible for ROCKET AF or J-ROCKET AF, and rivaroxaban 20mg/day if CrCl<50ml/min. Effectiveness and safety endpoints were compared between ROCKET AF and J-ROCKET AF dosing regimen in Asian and non-Asian subjects, separately. Also, risks of events of rivaroxaban 10mg/day despite of CrCl>50ml/min and rivaroxaban 20mg/day despite of CrCl<50ml/min were compared to that of "ROCKET AF/J-ROCKET AF dosing". Sensitivity analyses were performed by sequential elimination of each study from the pool. The meta-regression analysis was performed to explore the influence of potential factors on the effectiveness and safety outcomes. Eighteen studies involving 67,571 Asian and 54,882 non-Asian patients were included. Rivaroxaban following J-ROCKET AF criteria was associated with comparable risks of thromboembolism in the Asian subgroup, whereas rivaroxaban following J-ROCKET AF criteria was associated with higher risks of all-cause mortality (HR:1.30; 95%CI:1.05-1.60) compared with that of ROCKET AF criteria in the non-Asian population. There were no differences in risks of major bleeding between rivaroxaban following J-ROCKET AF versus ROCKET AF criteria either in the Asian or non-Asian population. Use of rivaroxaban 10mg despite of CrCl>50ml/min was associated with a higher risk of thromboembolism (HR:1.64; 95%CI:1.28-2.11) but lower risk of major bleeding (HR:0.72; 95%CI:0.57-0.90) compared with eligible dosage criteria. Use of rivaroxaban 20mg despite of CrCl<50ml/min was associated with worse clinical outcomes in the risks of thromboembolism (HR:1.32; 95%CI:1.09-1.59), mortality (HR:1.33; 95%CI:1.10-1.59) and major bleeding (HR:1.26; 95%CI:1.03-1.53) compared with eligible dosage criteria. The pooled results were generally in line with the primary effectiveness and safety outcomes by removing a single study at one time. Meta-regression analyses failed to detect the bias in most potential patient characteristics associated with the clinical outcomes. Rivaroxaban dosing regimen following J-ROCKET criteria may serve as an alternative to ROCKET-AF criteria for the Asian population with NVAF, whereas the dosing regimen following ROCKET AF criteria was more favorable for the non-Asian population. Use of rivaroxaban 10mg despite of CrCl>50ml/min was associated with a higher risk of thromboembolism but a lower risk of major bleeding, while use of rivaroxaban 20mg despite of CrCl<50ml/min was associated with worse outcome in most clinical events.

Predictors of Cerebral Embolic Debris During Transcatheter Aortic Valve Replacement: The SafePass 2 First-in-Human Study

Transcatheter aortic valve replacement (TAVR) generates significant debris, and strategies to mitigate cerebral embolization are needed. The novel Emboliner embolic protection catheter (Emboline, Inc., Santa Cruz, California) is designed to capture all particles generated during TAVR. This first-in-human study sought to assess the safety and feasibility of the device and to characterize the distribution and histopathology of the debris generated during TAVR. The SafePass 2 study was a prospective, nonrandomized, multicenter, single-arm investigation of the Emboliner device. Primary end points included 30-day major adverse cardiac and cerebrovascular events (MACCE) and technical performance. Computed tomography angiography was analyzed by an independent core laboratory, and filters were sent for histopathology of captured debris. Predictors of particle number were identified using >150 µm and >500 µm size thresholds. Of 31 subjects enrolled, technical success was 100%, and 30-day MACCE was 6.5% (2 cerebrovascular accidents, with 1 attributed to subtherapeutic dosing of rivaroxaban along with atrial fibrillation and the other to possible previous small ischemic strokes on magnetic resonance imaging; neither MACCE event had a causal relation to the Emboliner). All filters contained debris, with a median of 191.0 particles >150 µm and 14.0 particles >500 µm. Histopathology revealed mostly acute thrombus and valve or arterial tissue with lesser amounts of calcified tissue. A history of atrial fibrillation predicted a greater number of particles >500 µm (p=0.0259) and its presence on admission was associated with 4.1 times more particles >150 µm (p=0.0130) and 8.1 times more particles >500 µm (p=0.0086). Self-expanding valves were associated with twice the number of particles >150 µm (p=0.0281). TASK score was positively correlated with number of particles >500 µm (p=0.0337). The Emboliner device was safe and feasible. Emboli after TAVR appear more numerous than previously documented. Atrial fibrillation, higher TASK score, and self-expanding valve use conferred higher embolic burden. Notably, none of the tested computed tomography angiography features were able to identify with higher embolic risk. Larger-scale studies are needed to identify high-risk patients for selective embolic protection device use.

Safety and efficacy of oral anticoagulants in extreme weights

BackgroundThe 2021 International Society on Thrombosis and Haemostasis' (ISTH) recommends standard doses of apixaban and rivaroxaban regardless of high body mass index (BMI) and weight, but had not compare DOACs head-to-head in obesity or address underweight patients. MethodsOur aim is to evaluate the safety and efficacy of DOACs in underweight and obese patients compared to warfarin. The primary endpoints include incidence of thromboembolic and bleeding events. Descriptive statistics was used for continuous variables. The Kruskal-Wallis test was used to compare the four-groups for continuous measures and the chi-square test or Fisher's exact test was used to analyze categorical data. The chi-square test or Fisher's exact test, was used for categorical variables, and the Mann-Whitney test (the non-parametric counterpart to the two-sample t-test) for continuous data. ResultsOf 2940 patients receiving anticoagulation for venous thromboembolism (VTE) treatment or atrial fibrillation (AF), 492 met eligibility criteria. Within each group, 248 patients received warfarin, 101 received apixaban, 100 received rivaroxaban and 43 received dabigatran. Patients were characterized in 4 body mass index (BMI) categories, in which 80 were underweight and 412 were obese. ConclusionsWhen each DOAC was compared to warfarin in rates of VTE, apixaban showed statistically significant lower rate of VTE (p = 0.0149). However, no statistical significance was identified in the rate of VTE between DOACs combined vs. warfarin (p = 0.1529). When each DOAC was compared to warfarin, apixaban showed the lowest rate of overall bleeding (p = 0.0194). However, no statistical difference in the rate of bleeding was observed between DOACs combined vs. warfarin (p = 0.3284). Patients with extreme body weights requiring anticoagulation for VTE and AF may safety benefit from DOAC therapy. This evaluation showed apixaban with the lowest rate of VTE and bleeding compared to warfarin, rivaroxaban, and dabigatran. These results provide experience for the clinician to use DOACs, particularly apixaban, in underweight and obese populations.

Appropriateness of rivaroxaban and apixaban dosing in hospitalized patients with a newly diagnosed nonvalvular atrial fibrillation at a single tertiary hospital.

Possible challenges in dosing non-vitamin K antagonist oral anticoagulants in nonvalvular atrial fibrillation (NVAF) and limited evidence in Saudi Arabia make it difficult to assess their appropriateness. This study aimed to assess the appropriateness of prescribing rivaroxaban and apixaban in hospitalized patients with newly diagnosed NVAF. This single-center, descriptive, retrospective study was conducted at a tertiary hospital in Saudi Arabia between December 2018 and December 2019. The included patients were aged 18 years and older with newly diagnosed NVAF who received either rivaroxaban or apixaban during hospitalization. The primary outcome was the dosing appropriateness of rivaroxaban and apixaban in NVAF based on recent food and drug administration prescribing guidelines. Descriptive statistics including frequencies and percentages as well as mean ± standard deviation was used to summarize the data. Pearson Chi-square was used to test for significant difference in proportions of appropriate and inappropriate dosing. Pearson Correlation was used to test for associations between underdosing and overdosing with other patients characteristics. A priori P value < .05 was considered significant throughout. A total of 203 patients were included in our analysis. Majority of the patients {125 (61.6%), P = .001} received rivaroxaban. Overall, the dosing appropriateness observed in 143 (70.5%) of the patients who received the rivaroxaban and apixaban was significantly higher than the dosing inappropriateness observed in 60 (29.5%) of the patients who received the same drugs, P < .001. Apixaban had the highest proportion of patients, 45 (57.7%) with dosing inappropriateness. Overall, underdosing was the most common dosing inappropriateness observed in 53 (26.1%) of the patients. There was a significant negative correlation between the drugs underdosing and creatinine clearance, r = -0.223, P = .001. The findings in our present study showed that majority of the patients received appropriate dosing of rivaroxaban and apixaban in hospitalized patients with NVAF. Healthcare providers should update themselves with the recent dosing recommendations for the non-vitamin K-antagonist oral anticoagulants in NVAF to further improve the dosing appropriateness in hospitalized patients with NVAF.

Budget and health impact of switching eligible patients with atrial fibrillation to lower- dose dabigatran

ABSTRACT Objectives: To assess the comparative budget and health impact of lower-dose dabigatran versus reduced doses of apixaban and rivaroxaban in atrial fibrillation (AF) patients eligible for a lower-/reduced-dose due to individual patient characteristics in the Netherlands. Methods: A budget impact model was developed in accordance with ISPOR guidelines. A 3-year-time horizon was considered, and analyses were conducted from a Dutch healthcare payer’s perspective. The model applies published data to local AF-epidemiology, allowing calculations to estimate clinical events (strokes and haemorrhages) and costs. The analyses were based on real-world outcomes from patients with AF receiving a first direct oral anticoagulant (DOAC) prescription for low-dose dabigatran (110 mg) and a reduced dose of apixaban (2.5 mg) or rivaroxaban (15 mg). Two situations of switching treatments from one to another DOAC were modelled: switching from apixaban to dabigatran and from rivaroxaban to dabigatran. Base case results were given as savings per 100 patient-year, per total Dutch population, and events avoided. A univariate sensitivity analysis was conducted to explore the uncertainty around epidemiological and event costs input data. Scenario analyses were performed to estimate the effect of different market shares and potential price reductions due to future patent expiry for the total real-world population from the Netherlands. Results: The 3-years outcomes of switching patients eligible for a lower-/reduced-dose due to individual patient characteristics from apixaban or rivaroxaban to dabigatran resulted in cost savings estimated at €157 or €72 thousand per 100 patient-years, respectively, or €146 million per total Dutch population. Looking into the clinical events, dabigatran reflected the lowest number of mortalities, ischemic strokes, major bleeding, non-major bleeding, and haemorrhagic stroke compared to apixaban and rivaroxaban. The sensitivity analysis consistently reflected cost savings, with the ischeamic stroke events having the biggest impact. Accounting for the Dutch situation, both scenarios showed total savings ranging from €45 to €229 million over 3 years. Conclusions: Switching eligible AF-patients from reduced-dose apixaban or rivaroxaban to lower-dose dabigatran has the potential to reduce healthcare payer’s budget expenditures and provide health gains. Cost savings can potentially be further enhanced by market share adjustments and further price reductions.

Safety Profile and Effectiveness of Rivaroxaban for Patients With Venous Thromboembolism in Japan - Results From Post-Marketing Surveillance (XASSENT).

The incidence of venous thromboembolism (VTE; pulmonary embolism [PE] and/or deep vein thrombosis [DVT]) in Japan is increasing, but relatively small numbers of patients from Japan have been included in studies investigating rivaroxaban (a direct factor Xa inhibitor) for the treatment of VTE and preventing its recurrence.Methods and Results: An open-label, prospective, observational study (XASSENT [NCT02558465]) investigated the safety profile and effectiveness of rivaroxaban for ≤2 years in the treatment of VTE and prevention of its recurrence in Japanese clinical practice. Primary outcomes were major bleeding and symptomatic recurrent VTE. Statistical analyses were exploratory and descriptive. Overall, 2,540 patients were enrolled (safety analysis population [SAP], n=2,387; effectiveness analysis population [EAP], n=2,386). In the SAP, >80% of patients received the approved rivaroxaban dose, the mean (standard deviation) age was 66.6 (15.0) years, ≈74% were >50 kg, and 43% had a creatinine clearance ≥80 mL/min. PE+DVT, PE only, and DVT only were reported in 42%, 8%, and 50% of patients, respectively, and active cancer in 17% of patients. Major bleeding was reported in 69 patients (2.89%; 3.60%/patient-year; SAP) and symptomatic PE/DVT recurrence in 26 patients (1.09%; 1.36%/patient-year; EAP) during the treatment period. XASSENT provided information on the expected proportions of bleeding and VTE recurrence during rivaroxaban treatment in Japanese clinical practice; no new concerns of safety or effectiveness were found.

Effectiveness and safety of reduced-dose rivaroxaban for elderly patients with non-valvular atrial fibrillation: A subanalysis of the EXPAND study

BackgroundEstablishing the appropriate rivaroxaban dose in older patients with non-valvular atrial fibrillation (NVAF) is important because of the high risk of adverse events. In this EXPAND study subanalysis, we examined the safety and efficacy of standard-dose (15 mg/day) and non-recommended reduced-dose (10 mg/day) rivaroxaban in patients aged ≥65 years with NVAF and preserved renal function. MethodsThe entire analysis population (ALL cohort [n = 3982]; ≥65 years) was divided into early elderly (ELD) (65–74 years [n = 1444]) and late ELD (≥75 years [n = 2386]) sub-cohorts. Each sub-cohort was divided into reduced-dose and standard-dose groups. Kaplan–Meier survival curves with adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were used to assess efficacy (thromboembolic events) and safety (hemorrhagic events) outcomes. ResultsThe aHR for major bleeding did not differ between the dosages in any of the cohorts (aHRs: 0.86–0.93). There were no significant differences in the occurrence of stroke + systemic embolism (SE) or stroke + SE + myocardial infarction (MI) + cardiovascular (CV) death among the cohorts. The aHR for MI/unstable angina + interventional/CV surgery + CV death was higher with 10-mg/day rivaroxaban than 15-mg/day rivaroxaban in the ALL cohort (aHR: 1.56 [95% CI 1.02–2.37], p = 0.039) and the late ELD sub-cohort (aHR: 1.86 [95% CI 1.01–3.42], p = 0.045). ConclusionsReduced-dose rivaroxaban may increase the risk of coronary artery events. The use of rivaroxaban 15 mg/day in patients with NVAF aged ≥75 years with preserved renal function was supported.

The clinical outcomes of different doses of rivaroxaban in patients with isolated distal deep vein thrombosis

ObjectiveIsolated distal deep vein thrombosis (IDDVT) is defined as thrombosis involving the infrapopliteal veins. The optimal anticoagulant therapy of IDDVT remains controversial. This study aimed to assess whether reduced dose of rivaroxaban was suitable in patients with IDDVT. MethodsConsecutive patients with acute IDDVT were identified by reviewing the venous thromboembolism (VTE) registry databases. Outcomes including VTE recurrence, major bleeding, clinically relevant non-major (CRNM) bleeding, and death. Patients were followed until the first occurrence of any outcomes or the study end date (December 31, 2018). Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed. ResultsA total of 1246 patients were divided into low-dose (10 or 15 mg/day; n = 716) and standard-dose (20 mg/day; n = 530) groups. The incidences of VTE recurrence, major bleeding, CRNM bleeding, and death between the two groups were 9.64% vs 5.66%, 1.68% vs 3.02%, 4.61% vs 8.68%, and 13.83% vs 10.75%, respectively. After the inverse probability of treatment weighting, HRs for standard-dose vs low-dose of VTE recurrence, major bleeding, CRNM bleeding, and death were 0.54 (95% CI, 0.35-0.84), 1.71 (95% CI, 0.80-3.67), 2.28 (95% CI, 1.40-3.74), and 1.30 (95% CI, 0.91-1.86), respectively. For the subgroup analysis, the interaction with anticoagulation duration and treatment was evident for VTE recurrence (P for interaction = .002), but not for major bleeding. Patients with residual vein thrombosis were associated with an increased risk of VTE recurrence (HR, 1.95; 95% CI, 1.29-2.95). The interaction between risk factors and residual vein thrombosis was evident for VTE recurrence (P for interaction = .085). ConclusionsStandard-dose rivaroxaban reduced the risk of VTE recurrence without increasing the risk of major bleeding in patients with IDDVT. Anticoagulant therapy for >1.5 months should be preferred over shorter durations. Residual vein thrombosis should be assessed as a predictor of recurrence in patients with IDDVT, especially for patients with non-transient factors.

Real-world Experience in Managing Atrial Fibrillation in Patients with Renal Impairment; Rivaroxaban versus Warfarin.

The use of rivaroxaban in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) poses the risk of over- or underdosing. We aimed to compare rivaroxaban and warfarin in AF patients with moderate and severe renal impairment. This retrospective study was conducted between 2015 and 2016 to compare the use of warfarin (n = 164) and rivaroxaban (n = 149) in patients with AF and moderate or severe CKD. The study outcomes were survival, stroke, and major bleeding events. The median follow-up was 50 months (interquartile range: 23-60). Thirty-six patients had major bleeding: 24 with rivaroxaban and 12 with warfarin (P = 0.01). The rivaroxaban group had major bleeding in 3 patients with moderate CKD, 4 with severe CKD, and 17 on dialysis. Multivariable analysis of factors affecting major bleeding revealed that warfarin use lowered the risk of bleeding (hazard ratio: 0.34; P = 0.004). Stroke occurred in 14 patients: 6 in the rivaroxaban group and 8 in the warfarin group (P = 0.44). Survival at 1, 3, and 5 years was 89%, 77%, and 71% with warfarin and 99%, 94%, and 88% with rivaroxaban, respectively (P < 0.001). Multivariable analysis showed higher mortality in patients with lower creatinine clearance and those on warfarin. The safety of warfarin could be better than rivaroxaban in patients with CKD with fewer bleeding complications but similar stroke rates. Further studies on rivaroxaban dosing in patients on dialysis are required.

Rivaroxaban versus Apixaban for Treatment of Cancer-Associated Venous Thromboembolism in Patients at Lower Risk of Bleeding

This retrospective study, utilizing U.S. electronic health record (EHR) data from January 2013 to December 2020, sought to assess whether rivaroxaban and apixaban had similar effectiveness and safety in the treatment of cancer-associated venous thromboembolism (VTE) in patients with a cancer type not associated with a high risk of bleeding. We included adults diagnosed with active cancer, excluding esophageal, gastric, unresected colorectal, bladder, noncerebral central nervous system cancers and leukemia, who experienced VTE and received a therapeutic VTE dose of rivaroxaban or apixaban on day 7 post-VTE, and were active in the EHR ≥12 months prior to the VTE. Primary outcome was the composite of recurrent VTE or any bleed resulting in hospitalization at 3 months. Secondary outcomes included recurrent VTE, any bleed resulting in hospitalization, any critical organ bleed, and composites of these outcomes at 3 and 6 months. Inverse probability of treatment-weighted Cox regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). We included 1,344 apixaban and 1,093 rivaroxaban patients. At 3 months, rivaroxaban was found to have similar hazard to apixaban for developing recurrent VTE or any bleed resulting in hospitalization (HR: 0.87; 95% CI: 0.60–1.27). No differences were observed between cohorts for this outcome at 6 months (HR: 1.00; 95% CI: 0.71–1.40) or for any other outcome at 3 or 6 months. In conclusion, patients receiving rivaroxaban or apixaban showed similar risks of the composite of recurrent VTE or any bleed resulting in hospitalization in patients with cancer-associated VTE. This study was registered at www.clinicaltrials.gov as #NCT05461807. Key Points

Clinical characteristics and dosing of apixaban and rivaroxaban for the management of venous thromboembolism: A multi-center retrospective observational study

BackgroundSince the risk of recurrence of venous thromboembolism (VTE) increases with duration or inadequate anticoagulation dosage, a proper regimen of apixaban and rivaroxaban is essential in patients with VTE, especially during the acute phase. This study aims to describe the clinical characteristics and dosing of anticoagulants for patients who received apixaban or rivaroxaban for VTE treatment. MethodsThe multi-center retrospective observational study included patients diagnosed with VTE who had received apixaban or rivaroxaban between January 1, 2016, and December 31, 2021. The study’s description of real-world practices includes patients’ characteristics, along with anticoagulant dose and duration used for lead-in or maintenance therapy to manage VTE. ResultsThe study involved 695 patients with VTE; 342 of whom were treated with apixaban (49.2%), while 353 were treated with rivaroxaban (50.8%). During the acute phase, 30.1% and 19.3% of patients did not receive lead-in therapy with apixaban and rivaroxaban, respectively, and 1.2% received reduced doses of either medication. Among the patients who received apixaban alone for lead-in, the majority (79.5%) received the recommended duration, while 17.1% received a shorter lead-in duration (≤5 days), with an overall mean duration of 6.5 days. Most patients who received rivaroxaban alone for lead-in (93.0%) received the drug for the recommended duration, with an overall mean duration of 20.2 days. Most of the patients who did not receive apixaban or rivaroxaban for lead-in used parenteral anticoagulants for varying durations; however, around 25.0% of these patients did not receive any lead-in anticoagulant and started on maintenance therapy. Overall, patients who did not receive apixaban or rivaroxaban lead-in therapy were commonly associated with a higher risk of bleeding according to their clinical characteristics. ConclusionA notable proportion of patients with VTE who were mostly at low to intermediate risk of bleeding received non-recommended doses or durations of apixaban or rivaroxaban for lead-in therapy. Large studies are needed to establish evidence about the outcomes associated with these practices.

Persistence to rivaroxaban therapy for stroke prevention in clinical practice in Italy: Rationale and design of the RITMUS-AF prospective observational cohort study

BackgroundNon-valvular atrial fibrillation (NVAF) is a cardiac rhythm disturbance that increases the risk of stroke and is highly prevalent in Europe and Italy, increasingly with advancing age. Oral anticoagulation is a key component of stroke prevention in patients with NVAF, yet withdrawal or interruption of anticoagulation may transiently increase the risk of embolic events. Treatment persistence to anticoagulation is an important metric but one that is not well studied in patients with NVAF in Italy. The RITMUS-AF study aims to evaluate the persistence with rivaroxaban treatment for stroke prevention in patients with NVAF in Italy. MethodsRITMUS-AF is a prospective, observational cohort study of patients with NVAF in hospital cardiology departments with a non–vitamin K antagonist oral anticoagulant surveillance program across all 20 regions of Italy. The study population comprises consecutively screened, consenting patients with NVAF naïve to and newly treated with rivaroxaban for stroke prevention in routine clinical practice. The target enrollment is 800 patients; each patient will be followed for a maximum duration of 24 months. The primary endpoint is the proportion of patients who discontinue rivaroxaban treatment. Secondary endpoints are reasons for rivaroxaban discontinuation, dose changes and reasons for changes, switches to alternative therapies and the reasons for these decisions, and self-reported adherence. Data analyses will be exploratory and descriptive. ConclusionRITMUS-AF will help to address the limited data in Italian clinical practice on treatment persistence and reasons for drug interruptions in patients with NVAF on rivaroxaban.

In vitro evaluation of anticoagulant therapy management when urgent percutaneous coronary intervention is required in rivaroxaban-treated patients.

We investigated in vitro the management of intraprocedural anticoagulation in patients requiring immediate percutaneous coronary intervention (PCI) while using regular direct oral anticoagulants (DOACs). Twenty-five patients taking 20 mg of rivaroxaban once daily comprised the study group, while five healthy volunteers included the control group. In the study group, a beginning (24 h after the last rivaroxaban dose) examination was performed. Then, the effects of basal and four different anticoagulant doses (50 IU/kg unfractionated heparin (UFH), 100 IU/kg UFH, 0.5 mg/kg enoxaparin, and 1 mg/kg enoxaparin) on coagulation parameters were investigated at the 4th and 12th h following rivaroxaban intake. The effects of four different anticoagulant doses were evaluated in the control group. The anticoagulant activity was assessed mainly by anti-factor Xa (anti-Xa) levels. Beginning anti-Xa levels were significantly higher in the study group than in the control group (0.69 ± 0.77 IU/mL vs. 0.20 ± 0.14 IU/mL; p < 0.05). The study group's 4th and 12th-h anti-Xa levels were significantly higher than the beginning level (1.96 ± 1.35 IU/mL vs. 0.69 ± 0.77 IU/mL; p < 0.001 and 0.94 ± 1.21 IU/mL vs. 0.69 ± 0.77 IU/mL; p < 0.05, respectively). Anti-Xa levels increased significantly in the study group with the addition of UFH and enoxaparin doses at the 4th and 12th h than the beginning (p < 0.001 at all doses). The safest anti-Xa level (from 0.94 ± 1.21 to 2.00 ± 1.02 IU/mL) was achieved 12 h after rivaroxaban with 0.5 mg/kg enoxaparin. Anticoagulant activity was sufficient for urgent PCI at the 4th h after rivaroxaban treatment, and additional anticoagulant administration may not be required at this time. Twelve hours after taking rivaroxaban, administering 0.5 mg/kg of enoxaparin may provide adequate and safe anticoagulant activity for immediate PCI. This experimental study result should confirm with clinical trials (NCT05541757).

Why Does Rivaroxaban Not Work in Severe Mitral Stenosis?

Mitral stenosis is not a rare disease. Rheumatic fever is the principal cause of mitral stenosis. Anulus calcification and congenital heart disease are recognized as other causes of mitral stenosis.[1] In developed countries, the prevalence is approximately 0.6 in 1,000 in the United States, but it is much higher in developing nations: 21 cases per 1,000 in Asia, 15 cases per 1,000 in Africa, and 17 cases per 1,000 in South America.[2] Atrial fibrillation occurs in approximately 32% of symptomatic patients, thus decreasing cardiac output and exercise capacity, and greatly increasing the risk of thromboembolism.[3] Oral anticoagulation is therefore mandatory in these patients. Although direct oral anticoagulants (DOACs) have been found to be noninferior or superior versus vitamin K antagonists (VKAs; e.g., warfarin) in preventing cardioembolism in patients with atrial fibrillation,[4] patients with atrial fibrillation and rheumatic heart disease were not enrolled in earlier trials, thus excluding this pathological condition from approved indications.[5] Since ensuring adequate anticoagulation with laboratory monitoring while using VKAs may be difficult in developing countries, DOACs have the potential to improve the extension of oral anticoagulation without the need of any laboratory control. The commitment to plan a superiority trial (DOAC vs. VKA) came in 2016 from the cardiology community, which aimed to design a superiority trial involving a single-dose DOAC (no laboratory monitoring) versus VKA (with laboratory monitoring), and since the latter showed a poor time in the therapeutic range in countries of Asia, Africa, and Latin America.[6] Thus, a multicenter, randomized, noninferiority trial to evaluate the efficacy and safety of the factor Xa inhibitor, rivaroxaban, in comparison with VKA was planned and recently completed (INVICTUS trial). The trial involved patients with rheumatic heart disease from Africa, Asia, and Latin America,[7] enrolling patients with atrial fibrillation and echocardiographically documented rheumatic heart disease. Eighty-five percent of trial participants had mitral-valve stenosis, which was moderate-to-severe in 82%. These participants had a CHA2DS2VASc score of at least 2, a mitral-valve area of no more than 2 cm2, left atrial spontaneous echo contrast (SEC), or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban (20 mg/day) or dose-adjusted VKA (INR: 2.0–3.0). The mean ± standard deviation (SD) duration of follow-up was 3.1 ± 1.2 years. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. The primary safety outcome was major bleeding according to the International Society on Thrombosis and Hemostasis (ISTH).[8] A total of 4,531 participants were included in the final analysis. Mean age of the patients (72.3% women) was 50.5 years.

Low dose rivaroxaban for the management of atherosclerotic cardiovascular disease.

Atherosclerotic cardiovascular disease is characterized by some risk of major adverse events despite the availability of effective medical therapies for secondary prevention. There is emerging evidence suggesting that thrombin partly contributes to this residual risk. In fact, thrombin (i.e., activated coagulation factor II) triggers not only the conversion of fibrinogen to fibrin but also platelet activation and various pathways responsible for pro-atherogenic and/or pro-inflammatory effects through interaction with protease activated receptors. To reduce the risk associated with thrombin activation, oral anticoagulants antagonists of vitamin K showed promise, but were associated with unacceptable bleeding rates. Direct oral anticoagulants targeting the activated factors X and II carry a lower risk of bleeding than vitamin K antagonists. Rivaroxaban, a direct inhibitor of activated factor X approved at the dose of 20mg once daily for the prevention of thromboembolic events, has been also investigated at a reduced dose of 2.5mg twice daily in several alternative scenarios of atherosclerotic cardiovascular disease, in combination with standard of care. Current guidelines recommend that low-dose rivaroxaban is given in an adjunct to standard therapy to patients with stable atherosclerosis and acute coronary syndromes at low bleeding risk. Several studies are underway to evaluate its putative benefits in other clinical settings.

Application of the Population Pharmacokinetics Model-Based Approach to the Prediction of Drug-Drug Interaction between Rivaroxaban and Carbamazepine in Humans.

Rivaroxaban (RIV) is one of the direct oral anticoagulants used to prevent and treat venous and arterial thromboembolic events. Considering the therapeutic indications, RIV is likely to be concomitantly administered with various other drugs. Among these is carbamazepine (CBZ), one of the recommended first-line options to control seizures and epilepsy. RIV is a strong substrate of cytochrome P450 (CYP) enzymes and Pgp/BCRP efflux transporters. Meanwhile, CBZ is well known as a strong inducer of these enzymes and transporters. Therefore, drug-drug interaction (DDI) between CBZ and RIV is expected. This study aimed to predict the DDI profile of CBZ and RIV in humans by using a population pharmacokinetics (PK) model-based approach. We previously investigated the population PK parameters of RIV administered alone or with CBZ in rats. In this study, those parameters were extrapolated from rats to humans by using simple allometry and liver blood flow scaling, and then applied to back-simulate the PK profiles of RIV in humans (20 mg RIV per day) used alone or with CBZ (900 mg CBZ per day). Results showed that CBZ significantly reduced RIV exposure. The AUCinf and Cmax of RIV decreased by 52.3% and 41.0%, respectively, following the first RIV dose, and by 68.5% and 49.8% at the steady state. Therefore, the co-administration of CBZ and RIV warrants caution. Further studies investigating the extent of DDIs between these drugs should be conducted in humans to fully understand their safety and effects.