Rivaroxaban-treated Patients Research Articles

Comparison of warfarin, rivaroxaban, and dabigatran for effectiveness and safety in atrial fibrillation patients with different CHA2DS2-VASc scores: a retrospective cohort study

BackgroundThis retrospective cohort study aims to compare the effectiveness and safety of warfarin, rivaroxaban, and dabigatran in atrial fibrillation (AF) patients with different CHA2DS2-VASc scores in northern China.MethodsA retrospective cohort study was performed to evaluate anticoagulation in AF patients at the second affiliated hospital of Harbin Medical University from September 2018 to August 2019. Patients included in this study (n = 806) received warfarin (n = 300), or rivaroxaban (n = 203), or dabigatran (n = 303). Baseline characteristics and follow-up data including adherence, bleeding events and ischemic stroke (IS) events were collected.ResultsPatients receiving rivaroxaban (73.9%) or dabigatran (73.6%) showed better adherence than those receiving warfarin (56.7%). Compared with warfarin-treated patients, dabigatran-treated patients had lower incidence of bleeding events (10.9% vs 19.3%, χ2 = 8.385, P = 0.004) and rivaroxaban-treated patients had lower incidence of major adverse cardiovascular events (7.4% vs 13.7%, χ2 = 4.822, P = 0.028). We classified patients into three groups based on CHA2DS2-VASc score (0–1, 2–3, ≥ 4). In dabigatran intervention, incidence of bleeding events was higher in patients with score 0–1 (20.0%) than those with score 2–3 (7.9%, χ2 = 5.772, P = 0.016) or score ≥ 4 (8.6%, χ2 = 4.682, P = 0.030). Patients with score 0–1 in warfarin or rivaroxaban therapy had a similar but not significant increase of bleeding compared with patients with score 2–3 or score ≥ 4, respectively. During the follow-up, 33 of 806 patients experienced IS and more than half (19, 57.6%) were patients with score ≥ 4. Comparing patients with score 0–1 and 2–3, the latter had an significant reduction of IS in patients prescribed warfarin and non-significant reduction in rivaroxaban and dabigatran therapy.ConclusionCompared with warfarin therapy, patients with different CHA2DS2-VASc scores receiving either rivaroxaban or dabigatran were associated with higher persistence. AF patients with score ≥ 4 were more likely to experience IS events while hemorrhagic tendency preferred patients with low score 0–1.

Common P-glycoprotein (ABCB1) polymorphisms do not seem to be associated with the risk of rivaroxaban-related bleeding events: Preliminary data.

Considering conflicting previous reports, we aimed to evaluate whether the common ABCB1 polymorphisms (rs1128503, rs2032582, rs1045642, rs4148738) affected the risk of bleeding in rivaroxaban-treated patients. We report preliminary data from a larger nested case-control study. Consecutive adults started on rivaroxaban for any indication requiring > 6 months of treatment were followed-up to one year. Patients who experienced major or non-major clinically relevant bleeding during the initial 6 months were considered cases, whereas subjects free of bleeding over > 6 months were controls. The polymorphisms of interest (rs1128503, rs2032582, rs1045642, rs4148738) were in a strong linkage disequilibrium, hence patients were classified regarding the "load" of variant alleles: 0-2, 3-5 or 6-8. The three subsets were balanced regarding a range of demographic, comorbidity, comedication and genetic characteristics. A logistic model was fitted to probability of bleeding. There were 60 cases and 220 controls. Raw proportions of cases were similar across the subsets with increasing number of ABCB1 variant alleles (0-2, N = 85; 3-6, N = 133; 6-8, N = 62): 22.4%, 21.8%, and 19.4%, respectively. Fully adjusted probabilities of bleeding were also similar across the subsets: 22.9%, 27.5% and 17.7%, respectively. No trend was observed (linear, t = -0.63, df = 273, P = 0.529; quadratic, t = -1.10, df = 273, P = 0.272). Of the 15 identified haplotypes, the completely variant (c.1236T_c.2677T(A)_c.3435T_c.2482-2236A) (40.7%) and completely wild-type (C_G_C_G) (39.5%) haplotypes prevailed, and had a closely similar prevalence of cases: 21.1% vs. 23.1%, respectively. The evaluated common ABCB1 polymorphisms do not seem to affect the risk of early bleeding in patients started on rivaroxaban.

Proteomic analysis of extracellular vesicle cargoes mirror the cardioprotective effects of rivaroxaban in patients with venous thromboembolism.

Venous thromboembolism (VTE) remains a significant cause of morbidity and mortality worldwide. Rivaroxaban, a direct oral factor Xa inhibitor, mediates anti-inflammatory and cardiovascular-protective effects besides its well-established anticoagulant properties; yet, these remain poorly characterized. Extracellular vesicles (EVs) are considered proinflammatory messengers regulating a myriad of (patho)physiological processes and may be highly relevant to the pathophysiology of VTE. The effects of Rivaroxaban on circulating EVs in VTE patients remain unknown. We have established that differential EV biosignatures are found in patients with non-valvular atrial fibrillation anticoagulated with Rivaroxaban versus warfarin. Here, we investigated whether differential proteomic profiles of circulating EVs could also be found in patients with VTE. We performed comparative label-free quantitative proteomic profiling of enriched plasma EVs from VTE patients anticoagulated with either Rivaroxaban or warfarin using a tandem mass spectrometry approach. Of the 182 quantified proteins, six were found to be either exclusive to, or enriched in, Rivaroxaban-treated patients. Intriguingly, these proteins are involved in negative feedback regulation of inflammatory and coagulation pathways, suggesting that EV proteomic signatures may reflect both Rivaroxaban's anti-coagulatory and anti-inflammatory potential. These differences suggest Rivaroxaban may have pleiotropic effects, supporting the reports of its emerging anti-inflammatory and cardiovascular-protective characteristics relative to warfarin.

Mutant CYP3A4/5 Correlated with Clinical Outcomes by Affecting Rivaroxaban Pharmacokinetics and Pharmacodynamics in Patients with Atrial Fibrillation.

This study was designed to investigate the impact of single-nucleotide polymorphism-encoded cytochrome P450 enzymes (CYP3A4/5) on clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) based on pharmacokinetics and pharmacodynamics (PK/PD) aspects. A prospective study enrolling 165 rivaroxaban-treated patients with NVAF was conducted. Genotyping of CYP3A4 (rs2242480, rs2246709, rs3735451, and rs4646440) and CYP3A5 (rs776746) was performed to explore their impact on the trough plasma concentrations (Ctrough) of rivaroxaban, coagulation indicators at the Ctrough including activated partial thromboplastin time (APTT) and prothrombin time (PT), and clinical outcomes. Patients with mutant genotype CYP3A4 (rs2242480, rs2246709, and rs3735451) and CYP3A5 (rs776746) had higher levels of rivaroxaban Ctrough, PT values than that of wild-type. Furthermore, a positive relationship was revealed between Ctrough and PT (r = 0.212, p = 0.007), while no significant correlation was found between Ctrough and APTT. Regarding the clinical outcomes, the minor allele carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were associated with higher incidence of minor bleeding (p = 0.028 and p = 0.038, respectively) and were identified as the independent risk factors of minor bleeding treated with rivaroxaban (p = 0.024 and p = 0.036, respectively), with the receiver operating characteristic (ROC) curve validated (AUC = 0.8956, 95% CI: 0.829-0.962). The CYP3A4 polymorphisms (rs2242480, rs2246709, and rs3735451) and CYP3A5 rs776746 were associated with variations in rivaroxaban PK/PD. The minor allele (C) carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were correlated with clinical outcomes.

Adverse Clinical Outcomes and Associated Predictors in Rivaroxaban-Treated Atrial Fibrillation Patients With Renal Impairment

Renal impairment confers worse prognosis in patients with atrial fibrillation (AF) but there is scarce evidence about the influence of direct-acting oral anticoagulants in routine clinical practice. Herein, we compared clinical outcomes between patients with AF with and without renal impairment on rivaroxaban and investigated predictors for clinical outcomes in patients with AF with renal impairment. This was a multicenter study including patients with AF on rivaroxaban for at least 6months. During 2.5years follow-up, ischemic strokes (IS)/transient ischemic attacks (TIA)/systemic embolisms (SE)/myocardial infarctions (MI), major bleeding, and major adverse cardiovascular events (MACE) were recorded. Creatinine clearance (CrCl) was estimated using the Cockroft-Gault equation, renal impairment was defined as a CrCl <60ml/min, and 1,433 patients (34.8% with CrCl <60ml/min) were included. Patients with CrCl <60ml/min showed higher event rates for major bleeding (1.87%/year vs 0.62%/year; p=0.003) and MACE (1.97%/year vs 0.62%/year; p=0.002) but similar event rates for IS/TIA/SE/MI (0.66%/year vs 0.67%/year; p=0.955). In patients with renal impairment, CHA2DS2-VASc was associated with higher risk of IS/TIA/SE/MI; HAS-BLED and any dependency level were associated with higher risk of major bleeding; and male gender and heart failure were associated with higher risk of MACE. Antiplatelets were independently associated with increased risk of IS/TIA/SE/MI and MACE. In conclusion, in patients with AF on rivaroxaban, the incidence of IS/TIA/SE/MI did not increase in those with renal impairment, suggesting that rivaroxaban may be an effective option in this subgroup. In patients with AF, male gender, heart failure, dependency, antiplatelets, CHA2DS2-VASc, and HAS-BLED were associated with increased risk of adverse outcomes.

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).

Rivaroxaban Treatment for Patients With Unprovoked or Provoked Venous Thromboembolism - Subanalysis of the J'xactly Study.

Background: The efficacy and safety of direct oral anticoagulants (DOACs) in patients with unprovoked venous thromboembolism (VTE) remain unclear.Methods and Results: In this subanalysis of the J’xactly study, a multicenter prospective observational study, we evaluated the safety and effectiveness of rivaroxaban in patients with acute VTE according to unprovoked (n=388) or provoked (n=557) VTE status. Median follow-up was 21.2 months. Compared with patients in the provoked group, patients in the unprovoked group were younger, less likely to be female, and had higher body weight. The incidence of symptomatic VTE recurrence was significantly higher in the unprovoked than provoked VTE group (3.54% vs. 1.77% per patient-year; P=0.032). There was no significant difference in the incidence of major bleeding events between rivaroxaban-treated patients with unprovoked and provoked VTE (2.31% vs. 3.75% per patient-year; P=0.289). Although the proportion of patients with a body mass index (BMI) ≥25 kg/m2 who were non-users of antiplatelet agents was higher in the unprovoked VTE group, there was no interaction effect (BMI: 4.58% vs. 1.55% per patient-year [P=0.040; P for interaction=0.361]; concomitant antiplatelet agent non-users: 3.65% vs. 1.72% per patient-year [P=0.028; P for interaction=0.627]).Conclusions: This subanalysis suggests the safety and effectiveness of rivaroxaban in patients with unprovoked VTE. In such patients, DOAC discontinuation should be considered carefully, particularly in those not using antiplatelet agents and those with a high BMI.

Modern anticoagulation with factor Xa inhibitors in oncology: is the gastrointestinal bleeding rate (also) decisive?

The increased risk of thrombosis and bleeding with an active tumor disease is known as the so-called "thrombo-hemorrhagic syndrome", which places high demands on anticoagulation. There are currently 4 randomized, prospective studies on the use of new, non-vitamin K dependent oral anticoagulants (NOAC) for the treatment of venous thromboembolism (VTE) that have occurred in oncology. The FXa inhibitors rivaroxaban, edoxaban and twice apixaban were each used in individual studies versus the standard therapeutic agent dalteparin. Since there is no direct head-to-head comparison of the FXa inhibitors mentioned within a study, the largest study - always compared to dalteparin - was evaluated for each NOAC. The studies were analyzed with regard to their effectiveness, safety, fatal bleeding rates, the risk of gastrointestinal bleeding (GIB) and other differences using descriptive statistics. With dalteparin, the mean VTE recurrence rate was approximately 9% over a 6-month treatment period. All three FXa inhibitors were not inferior to dalteparin in terms of potency. The VTE recurrence rate was - 2.3% lower in edoxaban and apixaban-treated patients and - 5.0% in rivaroxaban-treated patients. In terms of safety, there was an increased rate of severe bleeding (both + 2.4%) for rivaroxaban and edoxaban compared to dalteparin; in particular, the number of GIBs was significantly increased. In contrast, the number of severe bleeding was not increased for apixaban, as was the case for various bleeding types including GIB. In the Apixaban study, the overall rate of severe GIB, which accounted for about 50% of all severe bleeding, and that of clinically relevant non-severe bleeding, were the lowest. The FXa inhibitors are not inferior to the standard therapy with dalteparin in the VTE recurrence rate in oncological patients. The GIB rate appears to be an important predictive factor for the safety of this group of substances, so that tumor location, gastrointestinal risk factors and other individual criteria should be given greater consideration in future therapy decisions for or against an FXa inhibitor.

Rationale and design of a prospective study evaluating population pharmacokinetics and pharmacodynamics of rivaroxaban in Chinese patients with non-valvular atrial fibrillation

IntroductionRivaroxaban is one of the most commonly used non-vitamin K antagonists for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Different individual exposures exist for Asian and non-Asian populations,...

Influence of DOACS and DOAC-REMOVE® on coagulation assays during thrombophilia testing in DOAC-treated patients

Background/Aim. Direct oral anticoagulants (DOACs) administration significantly interferes with coagulation as-says. The aim of the study was to evaluate the effect of DOACs and DOAC-Remove? on coagulation assays during thrombophilia testing. Methods. The study was carried out from January 2019 to the end of June 2020. It included 30 DOAC-treated patients, 14 females and 16 males aged 23 to 63 (median age 47.6 years), tested for thrombophilia due to venous thromboembolism (VTE). Thrombophilia testing was performed using DOAC-Remove? tablets (activated charcoal). The results before and after DOAC-Remove? were compared. Results. Positive lupus anticoagulant (LA) results were observed in 20% apixaban, 100% dabigatran, and 70% rivaroxaban-treated patients, while in samples after DOAC-Remove?, the LA positivity was observed only in one from the apix-aban group. Before DOAC-Remove?, the activated protein C (APC) resistance (APC-R) was measurable in 40% dabigatran and 80% rivaroxaban-treated patients, while, after using DOAC-Remove?, the APC-R was measurable in all cases. Comparing the results obtained from the samples before and after DOAC-Remove?, a difference was noted in relation to all dilute Russell?s viper venom time (dRVVT) coagulation tests, except for the dRVVT ratio in the apixaban group. Clot-based methods for detecting the APC resistance were significantly affected by dabigatran and less by rivaroxaban. Conclusion. DOACs were practically inactivated after the addition of the DOAC-Remove?, which made it possible to perform analyses for the LA and APC-R testing freely and obtain relevant results.

Comprehensive Multi-Parameter Characterisation of Circulating Extracellular Vesicles from Rivaroxaban-Treated VTE Patients Reveals Reduced Inflammation and Ameliorated Endothelial Dysfunction

Venous Thromboembolism (VTE) remains a significant cause of morbidity and mortality worldwide. Rivaroxaban, a direct oral factor Xa inhibitor, mediates anti-inflammatory and cardiovascular-protective effects besides its well-established anticoagulant properties, however, these remain poorly characterized. Extracellular vesicles (EVs) are important circulating messengers regulating a myriad of biological and pathological processes and may be highly relevant to the pathophysiology of VTE as they reflect alterations in platelet and endothelial biology. However, the effects of Rivaroxaban on circulating pro-inflammatory EVs in VTE patients remain unknown. We hypothesized that rivaroxaban's anti-inflammatory properties are reflected upon differential molecular profiles of circulating EVs.Single-episode VTE patients anticoagulated with 20 mg Rivaroxaban or warfarin at a target INR of 2.0-3.0, respectively, who had commenced therapy no sooner than 3 months previously were recruited following informed written consent at the Mater Misericordiae University Hospital, Dublin, Ireland. Patient data including age, sex, BMI, prevalent risk factors and comorbidities were collected. Patients on warfarin therapy had a time in therapeutic range of at least 55% and an INR in target range at time of blood sampling. Exclusion criteria included known pro-inflammatory conditions, active malignancy, recurrent VTE, antiphospholipid syndrome, bleeding or platelet function disorders, use of anti-platelet drugs, and thrombocytopenia.To address the hypothesis, we firstly used a combination of Nanoparticle Tracking Analysis (NTA) and flow cytometry to comprehensively characterise differences in the concentration and size of small (0-200 nm) and large (200-1000 nm) circulating EVs, respectively. Statistical analysis revealed a trend towards reduced levels of circulating small and large EVs in Rivaroxaban-treated VTE patients compared with matched warfarin controls. Moreover, small and large EVs measured in the patients plasma correlated strongly and highly significantly (r=0.804, p<0.0001), indicating a concomitant decrease in both populations. As circulating EVs are considered pro-coagulant and pro-inflammatory, these results may point towards an ameliorated baseline pro-inflammatory state of VTE patients anticoagulated with Rivaroxaban. To further uncover Rivaroxaban-mediated alterations, we next compared proteomic profiles of circulating EVs. We robustly quantified over 300 vesicular proteins. Statistical analysis of the protein expression level using a student's t-test with a false discovery rate of 5% and a minimal fold change of 0.1 identified differential protein expression of a tightly regulated cluster of proteins involved in negative feedback regulation of inflammatory and coagulation pathways in Rivaroxaban-treated patients, which may in part contribute to the superior outcomes of Rivaroxaban-treated patients seen in recent clinical trials. Furthermore, we recently established that Rivaroxaban potentially ameliorates endothelial dysfunction in a cohort of non-valvular atrial fibrillation patients. Therefore, we aimed to also assess circulating markers of endothelial activation (Intercellular Adhesion Molecule 1 [ICAM-1] and Tissue Factor Pathway Inhibitor [TFPI]). Intriguingly, Rivaroxaban-treated patients exhibited an increase in plasma TFPI levels with a simultaneous decrease in soluble ICAM-1, potentially pointing towards ameliorated endothelial dysfunction in Rivaroxaban-treated VTE patients relative to warfarin.Collectively, we established that EV proteomic signatures are powerful biological sensors of Rivaroxaban's anti-inflammatory potential. Moreover, Rivaroxaban therapy may ameliorate endothelial dysfunction relative to warfarin. These findings are of translational relevance towards characterizing the anti-inflammatory and cardiovascular-protective mechanisms associated with Rivaroxaban therapy. DisclosuresKevane: Leo Pharma: Research Funding. Murphy: Bayer Pharma: Research Funding. Ni Ainle: Daiichi-Sankyo: Research Funding; Actelion: Research Funding; Leo Pharma: Research Funding; Bayer Pharma: Research Funding. Maguire: Bayer Pharma: Research Funding; Actelion: Research Funding.

Discordance between Treatment Guideline Recommendations and Real-World Practice in a Group of Large Integrated Delivery Networks for Venous Thromboembolism (VTE) Patients: A Closer Look at VTE Patients with Cancer

Background: For patients with VTE, current American Society of Hematology (ASH) guideline panel suggests using direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs) where VKAs are required to be bridged with a parenteral anticoagulant (PAC). For patients with VTE and cancer, current guidelines recommend DOACs over low molecular weight heparin (LMWH) and LMWH over unfractionated heparin (heparin) for the initial treatment of VTE. Limited evidence is available about the patterns of anticoagulant treatment for VTE in routine clinical practice of large healthcare delivery networks in the United States (US) and whether the VTE treatments are aligned with current guidelines. This study aimed to assess real-world anticoagulant treatment patterns among VTE patients using harmonized electronic health record (EHR) data from four Integrated Delivery Networks (IDNs) in the US.Methods: This was a retrospective, longitudinal, multicenter, cohort study using harmonized EHR data from both inpatient and outpatient settings. The study population included adult patients prescribed DOACs, warfarin, and/or PAC therapy as inpatient or outpatient treatment within ≤30 days of VTE diagnosis, between June 2015 through May 2018. Data from the four IDNs was pooled to describe demographic characteristics and treatment patterns among VTE patients overall and by subgroups.Results: A total of 10,527 patients who were treated with OACs after VTE diagnosis were included for analysis. The mean (SD) age was 61.9 (5.98) years, with 46.1% aged 65 or older. More than half (53.2%) were female, and White patients comprised the majority (74.4%), followed by African American patients (22.8%). Obese and morbidly obese patients comprised 39.1% and 16.1% of patients, respectively. Among all VTE patients, warfarin-only (n=3545; 33.7%) was the most commonly used OAC treatment, followed by warfarin + PAC (n=3128; 29.7%), rivaroxaban-only (n=1357; 12.9%), rivaroxaban + PAC (n=853; 8.1%), apixaban + PAC (n=839; 8.0%), apixaban-only (n=762; 7.2%), and Other OAC (n=357; 3.4%) (Table 1). When stratifying VTE patients by age, gender, race and BMI, some variations in OAC treatment were observed. Among both older (≥65 years) and younger (<65 years) patients, warfarin-only was most commonly used, then warfarin + PAC. Warfarin-only was more commonly used among obese (36.3%) and morbidly obese (40.4%) patients than non-obese (29.8%) patients. OAC treatment patterns were generally comparable among men and women. Among White patients, approximately equal proportions of patients received warfarin + PAC (31.9%) and warfarin-only (31.0%). However, among African-American patients, a higher proportion of patients used warfarin-only (40.9%) vs. warfarin + PAC (24.5%).Patterns of anticoagulant treatments including OACs and/or parental anticoagulants among VTE patients with cancer were further analyzed (Figure 1). Among VTE patients with cancer (n=3657), heparin had the highest use (26.7%), then enoxaparin (22.7%); approximately the same proportion of cancer patients received warfarin-only (16.0%) and warfarin + PAC (16.9%). Of DOACs, rivaroxaban-only was the most commonly used treatment (4.9%), then apixaban + PAC (3.5%), and lastly, rivaroxaban + PAC (3.4%) among cancer patients.Conclusion: Current VTE treatment guidelines recommend warfarin to be bridged with PAC, however, warfarin-only therapy remained the most used treatment option followed by warfarin + PAC. While rivaroxaban and apixaban are not required to be bridged with PAC, such practices were observed for a large proportion of apixaban- and rivaroxaban-treated VTE patients. VTE treatment among patients with cancer was not completely aligned with current guidelines, as heparin was more commonly used than LMWH (enoxaparin). Our findings suggest greater efforts are needed to improve anticoagulant treatment practices among VTE patients. [Display omitted] DisclosuresDhamane: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rosenblatt: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Jiang: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Guo: Bristol Myers Squibb: Ended employment in the past 24 months. Dorsch: Agency for Health Research and Quality: Research Funding; National Institutes of Health/National Institute of Aging: Research Funding; American Health Association Health IT Research Network: Research Funding; Janssen Pharmaceuticals: Honoraria; Bristol Myers Squibb/Pfizer: Research Funding; Amgen: Research Funding. Luo: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company.

Pharmacokinetics of Direct Oral Anticoagulants in Emergency Situations: Results of the Prospective Observational RADOA-Registry.

Background Direct oral anticoagulants (DOACs) are increasingly used worldwide. Little is known so far about their pharmacokinetics in emergency situations. Methods A prospective, observational registry was performed to determine the clinical course in consecutive patients with major bleeding or urgent surgery treated with DOACs. In samples collected as part of routine care DOAC drug concentrations were measured using ultraperformance liquid chromatography-tandem mass spectrometry. Anticoagulant intensity at first presentation and drug half-life ( t 1/2 ), tested in repeat samples, were evaluated. Results A total of 140 patients were prospectively included. Pharmacokinetic data were available in 94% (132/140) of patients. Note that 67% (89/132) experienced life-threatening bleeding and 33% (43/132) needed an urgent surgery. For pharmacokinetic analysis a total of 605 blood samples was available. Median concentration on admission was 205 ng/mL for rivaroxaban and 108 ng/mL for apixaban. All treatment groups showed a high variation of drug concentrations at baseline. In rivaroxaban-treated patients t ½ was 17.3 hours (95% confidence interval [CI]: 15.4–19.7) without significant difference in both groups (major bleeding: t ½ 16.7 hours, 95% CI: 14.7–19.3; urgent surgery: t ½ 19.7 hours, 95% CI: 15.2–27.9; p = 0.292). In apixaban-treated patients t ½ was 25.0 hours (95% CI: 22.9–27.6) with a longer t ½ after urgent surgery ( t 1/2 : 30.8 hours; 95% CI: 26.9–36.4) compared with severe bleeding ( t 1/2 : 20.8 hours; 95% CI: 18.8–23.2; p < 0.001). Conclusion Emergency patients under DOAC treatment show a high variation of anticoagulant concentrations at baseline. Compared with rivaroxaban, apixaban showed a lower median concentration on admission and a longer t ½ .

Bleeding risk with rivaroxaban compared with vitamin K antagonists in patients aged 80 years or older with atrial fibrillation

ObjectiveDirect oral anticoagulants have been evaluated in the general population, but proper evidence for their safe use in the geriatric population is still missing. We compared the bleeding risk of...

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

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

A Pooled Analysis of the Xalia and Xalia-Lea Non-Interventional Studies of Rivaroxaban Versus Standard Anticoagulation in Venous Thromboembolism

IntroductionXALIA was a prospective, non-interventional study of rivaroxaban versus standard anticoagulation for the treatment of deep vein thrombosis (DVT) with or without pulmonary embolism (PE). The companion XALIA-LEA study included regions not involved in XALIA (Latin America, Eastern Europe, the Middle East, Africa, and Asia-Pacific). Unlike XALIA, however, patients with isolated PE were also eligible for inclusion. This report is a pre-specified pooled analysis of the XALIA and XALIA-LEA study populations.MethodsXALIA and XALIA-LEA are international, prospective, non-interventional studies of rivaroxaban for the treatment of acute venous thromboembolism (VTE) with the same basic design. Patients aged ≥18 years scheduled to receive ≥3 months of anticoagulation with rivaroxaban or standard anticoagulation (heparin/fondaparinux alone or overlapping with/followed by a vitamin K antagonist [VKA]) were eligible; follow up ended 12 months after final patient enrollment. Patients who received >2-14 days heparin/fondaparinux or 1-14 days VKA before rivaroxaban were called ‘early switchers’ and analyzed in a separate sensitivity analysis. The primary outcomes were major bleeding, VTE recurrence, and all-cause mortality.Baseline characteristics, hospitalization, and primary outcome rates for the XALIA and XALIA-LEA pooled analysis set are described. Propensity score stratification (with 10 subclasses) was used to adjust for imbalances in baseline characteristics between treatment groups. Hazard ratios (HRs) for major bleeding and recurrent VTE were adjusted for active cancer at baseline and stratified by study, subclass, and type of VTE. The HR for all-cause mortality was stratified by active cancer at baseline, study, subclass, and type of VTE.Results7129 patients were enrolled; 3904 received rivaroxaban and 2551 received standard anticoagulation, comprising the safety analysis set. Twenty-one patients did not receive study medication; 653 patients were early switchers and not included in the main analysis. For the propensity score-stratified analysis, 2 patients from the rivaroxaban group and 8 standard anticoagulation-treated patients were excluded from the safety analysis set.Patients given rivaroxaban were younger, and had lower rates of renal impairment, cancer, and provoked VTE than those given standard anticoagulation (Table 1).In the propensity score-stratified analysis set, the least-squares mean duration of initial hospital stay was 6.5 days with rivaroxaban versus 9.7 days with standard anticoagulation (geometric means ratio 0.67; 95% confidence interval [CI] 0.63-0.73).Annualized major bleeding rates were 1.7 % (n=39) and 3.9% (n=63) (propensity-score stratified HR 0.65; 95% CI 0.39-1.08), recurrent VTE rates were 2.5% (n=55) and 4.5% (n=71) (propensity score-stratified HR=0.85; 95% CI 0.54-1.32) and all-cause mortality was 1.8% (n=41) and 7.3% (n=117) (propensity score-stratified HR=0.55; 95% CI 0.33-0.91) with rivaroxaban and standard anticoagulation, respectively.Summary and conclusionsThis pooled analysis of the XALIA and XALIA-LEA studies provides a prospective global dataset for rivaroxaban treatment in routine clinical practice. Rivaroxaban-treated patients had lower rates of risk factors than patients given standard anticoagulation. In the propensity score-stratified analysis, adjusting for baseline characteristic imbalances, hospital stay duration was lower in the rivaroxaban group than the standard anticoagulation group. The propensity score-stratified analysis showed lower risks of major bleeding, recurrent VTE and all-cause mortality in patients treated with rivaroxaban versus those treated with standard anticoagulation. These results show that the single-drug approach with rivaroxaban is a safe and effective treatment for VTE in routine clinical practice. Rivaroxaban may also reduce healthcare resource utilization in VTE. However, although propensity score stratification can balance baseline covariates between the treatment groups, potential effects of unmeasured characteristics and confounders cannot be excluded. [Display omitted] DisclosuresTurpie:Bayer HealthCare Pharmaceuticals: Consultancy; Janssen Research and Development: Consultancy, Honoraria. Mantovani:Shire: Research Funding; Boehringer Ingelheim: Research Funding; Bayer AG: Consultancy; Daiichi Sankyo: Consultancy; Janssen-Cilag: Research Funding. Haas:Aspen Pharmacare: Consultancy; Bayer AG: Consultancy; Bristol-Myers Squibb: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Sanofi SA: Consultancy. Kreutz:Daiichi Sankyo: Consultancy, Honoraria; Lundbeck: Consultancy; Bayer AG: Consultancy, Honoraria; Berlin-Chemie Menarini: Consultancy; Bristol-Myers Squibb: Honoraria; Servier Laboratories: Consultancy. Monje:Bayer AG: Employment. Schneider:Bayer AG: Employment. van Eickels:Bayer AG: Employment. Tamm:Bayer AG: Employment. Gebel:Bayer AG: Employment. Ageno:Daiichi Sankyo: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria, Research Funding; BMS-Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria.

Direct Oral Anticoagulants Plasma Levels in Patients with Atrial Fibrillation at the Time of Bleeding: A Pilot Prospective Study.

Patients with atrial fibrillation (AF) on long-term direct oral anticoagulants (DOACs) may be at higher risk of bleeding because of higher anti-Xa or anti-IIa levels. However, there is no postmarketing study investigating these DOAC plasma levels at the time of bleeding. The aim of this study was to evaluate DOAC levels at the time of a bleeding emergency. We analyzed 5440 patients examined at our Emergency Department in from April 1, 2019, to September 30, 2019. During this period, we prospective identified 105 consecutive patients with bleeding while on long-term antithrombotic therapy; 49 patients had AF on DOACs. We compared DOAC levels in patients who bled against a control sample of 55 patients who tolerated long-term high dose DOAC therapy without any emergency. Samples of these patients were tested with drug-specific anti-Xa chromogenic analysis (rivaroxaban and apixaban) and with Hemoclot Thrombin Inhibitor assay (dabigatran). Dabigatran-treated patients who bled had significantly higher anti-IIa levels when compared with trough (261.4 ± 163.7 vs. 85.4 ± 57.2 ng/mL, P < 0.001) and peak samples of controls (261.4 ± 163.7 vs. 138.8 ± 78.7 ng/mL, P < 0.05). Similarly, there were significantly higher anti-Xa levels in rivaroxaban-treated and apixaban-treated patients with bleeding compared with trough control samples (rivaroxaban: 245.9 ± 150.2 vs. 52.5 ± 36.4 ng/mL, P <0.001 and apixaban: 311.8 ± 142.5 vs. 119.9 ± 81.7 ng/mL, P < 0.001), as well as in apixaban-treated patients when compared with peak control samples (311.8 ± 142.5 vs. 210.9 ± 88.7 ng/mL, P < 0.05). Finally, rivaroxaban anti-Xa levels in patients who bled tended to be higher compared with peak control samples (245.9 ± 150.2 vs. 177.6 ± 38.6 ng/mL, P = 0.13). This observational study showed a significant difference in anti-IIa and anti-Xa plasma levels in patients with AF with bleeding complications compared with those who tolerated long-term high-dose DOAC therapy without bleeding complications.

Blood Loss in Rivaroxaban Anticoagulated Pigs with Severe Polytrauma Is Significantly Reduced By Early Therapy with Prothrombin Complex Concentrate

Introduction: The reversal of the anticoagulant effects of rivaroxaban in severely bleeding patients remains uncertain with conflicting evidence. In this ongoing study we assessed the ability of a four-factor prothrombin complex concentrate (PCC) to reverse rivaroxaban anticoagulation in a porcine polytrauma model.Methods: After ethical approval, rivaroxaban was infused over 30 min (1 mg/kg/h) prior to injury in anaesthetized male pigs (n=24); the sham group (n=8) received placebo. A standardized blunt liver injury and bilateral femur fractures were induced. After trauma and hemorrhagic shock, animals were resuscitated 5 min post injury with Ringer's solution and blood loss (BL) was recorded 12 min post trauma. Randomized animals (n=8/group) received a single injection of PCC (25 or 50 IU/kg), or vehicle (control). Animals were observed up to 180 min after trauma, and total BL was assessed after the observation period or animal's death. Coagulation variables included rivaroxaban plasma concentration, global coagulation assays (PT, aPTT) and thromboelastometry. For a differentiated risk assessment, thrombin generation and thrombin-antithrombin (TAT) levels, indicating the extent of coagulation activation were obtained. BL and hemodynamic variables were monitored over 3 h or until time of death. For statistical analysis, ANOVA (mean ± SD) and the log-rank test for survival were used.Results: After infusion and prior to injury rivaroxaban levels were 666 ± 88 ng/mL. In contrast to sham animals (BL: 467 ± 56 mL), BL in in all anticoagulated animals was significantly elevated 12 min post injury (BL: 810 ± 83 mL). Anticoagulation with rivaroxaban without PCC therapy resulted in a total BL of 3111 ± 479 mL with 88 % mortality (survival time: 50-180 min; p<0.05 vs PCC treated animals and sham). The application of 25 IU/kg PCC (1497 ± 292 mL) or 50 IU/kg PCC (1468 ± 107 mL) showed a significant reduction in total BL with 100% survival and no significant difference between groups. The application of PCC was associated with a dose-depended increase in peak thrombin generation (Peak height; figure 1). D-Dimer increased after trauma in sham and PCC treated animals. However, no difference in D-Dimer concentration in the PCC 25 or 50 IU/kg group was measured post injury. Clinically and macroscopically no adverse events were observed.Conclusions: This porcine model demonstrates a four-factor PCC may be a reasonable and safe intervention for rivaroxaban-treated patients with life-threatening haemorrhage, though these data need clinical confirmation. [Display omitted] DisclosuresGrottke:Boehringer Ingelheim: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Portola: Research Funding; Boehringer Ingelheim: Consultancy; Octapharma: Research Funding.

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

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

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.