Rivaroxaban-treated Patients Research Articles

The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitor

BackgroundAn increasing number of patients are treated with direct-acting oral anticoagulants (DOACs), but the optimal way to reverse the anticoagulant effect is not known. Specific antidotes are not available and prothrombin complex concentrate (PCC), activated PCC (aPCC) and recombinant factor VIIa (rFVIIa) are variously used as reversal agents in case of a major bleeding. We aimed to determine the most effective haemostatic agent and dose to reverse the effect of rivaroxaban in blood samples from patients taking rivaroxaban for therapeutic reasons.MethodsBlood samples from rivaroxaban-treated patients (n = 50) were spiked with PCC, aPCC and rFVIIa at concentrations imitating 80%, 100% and 125% of suggested therapeutic doses. The reversal effect was assessed by thromboelastometry in whole blood and a thrombin generation assay (TGA) in platelet-poor plasma. Samples from healthy subjects (n = 40) were included as controls.ResultsIn thromboelastometry measurements, aPCC and rFVIIa had a superior effect to PCC in reversing the rivaroxaban-induced lenghtening of clotting time (CT). aPCC was the only haemostatic agent that shortened the CT down to below the control level. Compared to healthy controls, patients on rivaroxaban also had a prolonged lag time and decreased peak concentration, velocity index and endogenous thrombin potential (ETP) in platelet-poor plasma. aPCC reversed these parameters more effectively than rFVIIa and PCC. There were no differences in efficacy between 80%, 100% and 125% doses of aPCC.ConclusionsaPCC seems to reverse the anticoagulant effect of rivaroxaban more effectively than rFVIIa and PCC by evaluation with thromboelastometry and TGA in vitro.

Abstract 20: Specific Point-of-care Testing of Coagulation in Patients Treated with Non-vitamin K Antagonist Oral Anticoagulants Part I (SPOCT-NOAC I)

Introduction: Non-vitamin K antagonist oral anticoagulants (NOAC) are increasingly replacing vitamin K antagonists for prevention of thromboembolism in atrial fibrillation (AF). Despite treatment, stroke rate in NOAC-treated AF-patients remains 1-2% per year. Subsequently, stroke physicians face a growing number of NOAC-treated patients with acute stroke. Rapid assessment of coagulation in NOAC-treated patients is vital prior to thrombolysis or reversal therapy, but existing point-of-care testing (POCT) is suboptimal. For the first time we evaluate NOAC-specific POCT. Hypothesis: Ecarin clotting time (ECT)- and anti-Xa activity (ENOX)-POCT predict plasma concentrations of dabigatran and apixaban/edoxaban/rivaroxaban. Methods: 80 patients receiving first NOAC-dose and 80 already on NOAC-treatment are enrolled in the SPOCT-NOAC I trial (N=40 for each NOAC). Subjects receiving other anticoagulants are excluded. Six blood samples are collected from each patient: before drug intake, 30min, 1, 2, and 8h after intake, and before next dose. NOAC-concentrations are measured by mass spectrometry. Results: 240 blood samples of 40 dabigatran-treated patients were analyzed. Dabigatran-concentrations ranged from 0-274ng/mL. ECT-POCT ranged from 20-196s. Pearson’s correlation coefficient showed strong correlation between ECT-POCT and dabigatran-concentrations (r=0.87). Performance was improved through the use of citrated in place of non-citrated whole blood (r=0.93). Dabigatran-concentrations >50ng/mL (threshold for thrombolysis according to expert recommendation) were detected by ECT-POCT >50s with 98% sensitivity and 79% specificity. Baseline-samples not containing any dabigatran yielded normal ECT values. Conclusions: This is the first study evaluating NOAC-specific POCT. Final results in the dabigatran group of SPOCT-NOAC show excellent correlation between ECT-POCT and dabigatran plasma concentrations; performance of ECT-POCT is even increased through the use of citrated whole blood. Relevant dabigatran-concentrations are detected with excellent sensitivity and specificity. In addition to ECT-POCT, we will present data on ENOX-POCT from apixaban-, edoxaban- and rivaroxaban-treated patients.

Risk of Venous Thromboembolism Recurrence Among Rivaroxaban Treated Patients Who Continued Versus Discontinued Therapy: Analyses Among VTE Patients

Background: The American College of Chest Physicians (ACCP) guidelines for venous thromboembolism (VTE) disease recommend treatment with anticoagulation for at least 3 months in patients with VTE. Moreover, the EINSTEIN-extension study assessed the effect of rivaroxaban on the risk of VTE recurrences in patients who had completed 6 to 12 months of treatment for VTE. Results showed that rivaroxaban significantly reduced the risk of VTE recurrences with a small increased risk of major bleeding. The objective of this study was to assess the risk of VTE recurrences and major bleeding associated with extended rivaroxaban treatment in a real-world setting among all VTE patients (i.e., unprovoked, provoked, and cancer related). Methods: A retrospective study was conducted using Truven Health Analytics MarketScan Databases from 02/2011 to 04/2015. The study included adult patients who initiated rivaroxaban therapy within 7 days after their first VTE and continuously used rivaroxaban for at least 3 months. The end of the initial 3-month rivaroxaban treatment was defined as the index date and patients were categorized into discontinued (treatment ended) and continued cohorts. Patients were followed from index date until end of continuous treatment for the continued cohort or end of data or re-initiation of oral anticoagulant therapy for the discontinued cohort. The outcomes included VTE recurrences identified as a primary diagnosis documented during a hospitalization and major bleeding events identified by a validated algorithm (Cunningham et al., 2011). Kaplan-Meier rates for VTE recurrences and major bleeding events at 3, 6, 9, and 12 months after the index date were compared between cohorts with adjustment for baseline confounding using the inverse probability of treatment weights (IPTW) method based on propensity score. Patients with unprovoked VTEs, defined as not having recent surgery, cancer, pregnancy or estrogen therapy, were also evaluated. Sample sizes of patients with provoked VTEs and cancer were too small to analyze these populations. A sensitivity analysis was also conducted among VTE patients receiving rivaroxaban for at least 6 months. Results: Among the 3-month treatment population, a total of 5,933 (63.4% unprovoked VTE) and 1,536 (68.4% unprovoked VTE) rivaroxaban users formed the continued and discontinued cohorts, respectively. The mean (SD) observation period was 149.3 (124.4) days in the continued cohort and 211.1 (191.6) days in the discontinued cohort. The Kaplan-Meier analysis (Figure 1) showed that patients in the continued cohort had significantly lower rates of VTE recurrences after an additional 3 months (0.70% vs. 1.70%), 6 months (1.41% vs. 2.34%), 9 months (1.82% vs. 3.01%), and 12 months (1.97% vs. 3.01%; all p-values 0.05). Among the 6-month treatment population, a total of 2,676 (65.9% unprovoked VTE) and 1,127 (70.4% unprovoked VTE) rivaroxaban users formed the continued and discontinued cohorts, respectively. The mean (SD) observation period was 158.5 (130.6) days in the continued cohort and 206.5 (171.5) days in the discontinued cohort. Patients in the continued cohort had lower rates of VTE recurrences after an additional 3 months (0.82% vs. 1.41%), 6 months (1.22% vs. 2.69%), 9 months (1.35% vs. 3.02%), and 12 months (1.72% vs. 3.70%; except at 3 months all p-values Similar results were found among patients with unprovoked VTE for the 3- and 6-month analyses. The interaction term between the cohort variable (Continued vs. Discontinued) and the type of VTE (unprovoked vs. other types of VTE) was non-significant in both populations (p-value > 0.05), which suggests that the benefit of extended treatment do not depend on the type of VTE events. Conclusions: Our study results suggest that all patients with VTE who continued rivaroxaban therapy after the first 3-month and 6-month treatment periods had significantly lower risk of VTE recurrences without an increased risk of major bleeding. Disclosures Khorana:Halozyme: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Leo: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding. Berger:AZ: Research Funding; Merck: Membership on an entity9s Board of Directors or advisory committees. Wells:BMS/Pfizer: Research Funding; Itreas: Other: Served on a Writing Committee; Janssen Pharmaceuticals: Consultancy; Bayer Healthcare: Other: Speaker Fees and Advisory Board. Seheult:Janssen Scientific Affairs, LLC: Consultancy. Ashton:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment. Laliberte:Janssen Scientific Affairs: Research Funding. Crivera:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Lejeune:Janssen Scientific Affairs: Research Funding. Schein:Johnson & Johnson: Employment, Equity Ownership, Other: Own in excess of $10,000 of JJ Pfizer: Honoraria; CSL Behring: Honoraria; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Consultancy; Bristol-Myers Squibb: Consultancy; Boehringer Ingelheim: Honoraria; Janssen: Honoraria.

Pulmonary Embolism Inpatients Treated With Rivaroxaban Had Shorter Hospital Stays and Lower Costs Compared With Warfarin

PurposeUsing real-world data, this study compares inpatient length of stay (LOS) and costs for patients with a primary diagnosis of pulmonary embolism (PE) initiating treatment with oral anticoagulation with rivaroxaban versus warfarin. MethodsHospitalizations from MarketScan’s Hospital Drug Database were selected from November 1, 2012, through December 31, 2013, for adults with a primary diagnosis of PE initiating treatment with rivaroxaban or warfarin. Warfarin patients were matched 1:1 to rivaroxaban patients using exact and propensity score matching. Hospital LOS, treatment patterns, and hospitalization costs were evaluated. FindingsMatched cohorts included 751 rivaroxaban-treated patients and 751 warfarin-treated patients. Adjusted mean LOS was 3.77 days for rivaroxaban patients (95% CI, 3.66–3.87 days) and 5.48 days for warfarin patients (95% CI, 5.33–5.63 days; P < .001). Mean (SD) LOS was shorter for patients taking rivaroxaban whether admission was for provoked PE (rivaroxaban: 5.2 [5.1] days; warfarin: 7.0 [6.5] days; P < .001) or unprovoked PE (rivaroxaban: 3.4 [2.3] days; warfarin: 5.1 [2.7] days; P < .001). Mean (SD) days from first dose to discharge were 2.5 (1.7) (rivaroxaban) and 4.0 (2.9) (warfarin) when initiated with parenteral anticoagulants (P < .001) and 2.7 (1.7) (rivaroxaban) and 4.0 (2.2) (warfarin) without parenteral anticoagulants (P < .001). The rivaroxaban cohort incurred significantly lower unadjusted mean (SD) hospitalization costs (rivaroxaban: $8473 [$9105]; warfarin: $10,291 [$9185]; P < .001), confirmed by covariate adjustment with generalized linear modeling estimating predicted mean hospitalization costs of $8266 for rivaroxaban patients (95% CI, $7851–$8681) and $10,511 for warfarin patients (95% CI, $10,031–$10,992; P < .001). Implicationspatients with PE treated with rivaroxaban incurred significantly lower hospitalization costs by $2245 per admission compared with patients treated with warfarin, which was attributable to cost offsets from 1.71 fewer days of stay in the hospital.

Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation

Dabigatran and rivaroxaban are non-vitamin K oral anticoagulants approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). There are no randomized head-to-head comparisons of these drugs for stroke, bleeding, or mortality outcomes. To compare risks of thromboembolic stroke, intracranial hemorrhage (ICH), major extracranial bleeding including major gastrointestinal bleeding, and mortality in patients with nonvalvular AF who initiated dabigatran or rivaroxaban treatment for stroke prevention. Retrospective new-user cohort study of 118 891 patients with nonvalvular AF who were 65 years or older, enrolled in fee-for-service Medicare, and who initiated treatment with dabigatran or rivaroxaban from November 4, 2011, through June 30, 2014. Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores. The data analysis was performed from May 7, 2015, through June 30, 2016. Dabigatran, 150 mg, twice daily; rivaroxaban, 20 mg, once daily. Adjusted hazard ratios (HRs) for the primary outcomes of thromboembolic stroke, ICH, major extracranial bleeding including major gastrointestinal bleeding, and mortality, with dabigatran as reference. Adjusted incidence rate differences (AIRDs) were also estimated. A total of 52 240 dabigatran-treated and 66 651 rivaroxaban-treated patients (47% female) contributed 15 524 and 20 199 person-years of on-treatment follow-up, respectively, during which 2537 primary outcome events occurred. Rivaroxaban use was associated with a statistically nonsignificant reduction in thromboembolic stroke (HR, 0.81; 95% CI, 0.65-1.01; P = .07; AIRD = 1.8 fewer cases/1000 person-years), statistically significant increases in ICH (HR, 1.65; 95% CI, 1.20-2.26; P = .002; AIRD = 2.3 excess cases/1000 person-years) and major extracranial bleeding (HR, 1.48; 95% CI, 1.32-1.67; P < .001; AIRD = 13.0 excess cases/1000 person-years), including major gastrointestinal bleeding (HR, 1.40; 95% CI, 1.23-1.59; P < .001; AIRD = 9.4 excess cases/1000 person-years), and with a statistically nonsignificant increase in mortality (HR, 1.15; 95% CI, 1.00-1.32; P = .051; AIRD = 3.1 excess cases/1000 person-years). In patients 75 years or older or with CHADS2 score greater than 2, rivaroxaban use was associated with significantly increased mortality compared with dabigatran use. The excess rate of ICH with rivaroxaban use exceeded its reduced rate of thromboembolic stroke. Treatment with rivaroxaban 20 mg once daily was associated with statistically significant increases in ICH and major extracranial bleeding, including major gastrointestinal bleeding, compared with dabigatran 150 mg twice daily.

How to manage patients on rivaroxaban in the emergency department: a statement of the Italian society of emergency medicine advisory board.

Rivaroxaban, a new oral anticoagulant, has been approved in many countries and its everyday use in clinical practice is increasing. Thus, the chances for an emergency physician to encounter rivaroxaban-treated patients in emergency situations have increased. Here, the authors address the main issues in terms of the prescription of rivaroxaban and the management of these patients in cases of minor or major bleeding, urgent surgery, atrial fibrillation requiring cardioversion, acute ischemic stroke, ST-elevation myocardial infarction, and new onset of atrial fibrillation in recent ST-elevation myocardial infarction. The recommendations reached are based on a literature review and a panel discussion of the advisory board of SIMEU, the Italian Society of Emergency Medicine.

Hospitalizations and Other Health Care Resource Utilization Among Patients with Deep Vein Thrombosis Treated with Rivaroxaban Versus Low-molecular-weight Heparin and Warfarin in the Outpatient Setting

PurposeCompared with low-molecular-weight heparin (LMWH) and warfarin, the oral anticoagulant rivaroxaban has advantages, such as simplified care, that may lead to less health care resource utilization. MethodsA retrospective, matched-cohort analysis was conducted using claims dated between January 2011 and December 2013 from the Truven Health Analytics MarketScan databases. Adult patients who had a primary diagnosis of deep vein thrombosis (DVT) during an outpatient or emergency room (ER) visit after November 2, 2012, and who were treated with rivaroxaban or LMWH/warfarin on the same day, were identified. Patients were observed over 1, 2, 3, and 4 weeks after the DVT diagnosis. The mean numbers of hospitalizations for all causes and for venous thromboembolism (VTE) (which included those for DVT or pulmonary embolism), as well as other health care resource utilization (ER, outpatient, and other visits), and the associated health care costs and pharmacy costs, were evaluated and compared between cohorts using the Lin method. FindingsAll of the 512 rivaroxaban-treated patients were well matched with the LMWH/warfarin-treated patients. The mean numbers of all-cause hospitalizations were significantly lower in the rivaroxaban users compared with those in the LMWH/warfarin users over 1 week (0.012 vs 0.032; P = 0.044) and 2 weeks (0.022 vs 0.048; P = 0.040). The corresponding mean numbers of VTE-related hospitalizations were significantly lower with rivaroxaban over 1 week (0.008 vs 0.028; P = 0.020), 2 weeks (0.016 vs 0.042; P = 0.020), and 4 weeks (0.034 vs 0.068; P = 0.036). The mean numbers of all-cause and VTE-related outpatient visits were also significantly lower in rivaroxaban users compared with those in LMWH/warfarin users over 1, 2, 3, and 4 weeks (all, P < 0.001). In terms of all-cause and VTE-related ER and other visits, no statistically significant differences were found between cohorts over the first 4 weeks. The associated mean all-cause total health care costs were significantly lower in the rivaroxaban users compared with those in the LMWH/warfarin users over 1 week (US $2332 vs $3428; P < 0.001) and 2 weeks ($3108 vs $4524; P < 0.001); moreover, significantly lower mean costs related to all-cause hospitalizations (weeks 1 and 2) and pharmacy (weeks 1–4) were observed in patients treated with rivaroxaban, while no differences were found in costs related to ER visits (weeks 1–4), outpatient visits (weeks 1–4), or other visits (with the exception of week 1). ImplicationsPatients with DVT treated with rivaroxaban after an outpatient/ER visit had significantly lower mean numbers of hospitalizations and outpatient visits, as well as lower mean total, hospitalization, and pharmacy costs during the first 2 weeks of treatment compared with those in matched LMWH/warfarin users.

Evaluation of Dose-Reduced Direct Oral Anticoagulant Therapy

BackgroundCompared with vitamin K antagonists, direct-acting oral anticoagulants (DOACs) have fixed dosing, limited drug interactions, and do not require therapeutic drug level monitoring. Dose adjustments are recommended for moderate renal dysfunction, low body weight, and select drug interactions. ObjectivesThe aim of our study is to determine if DOAC dose reductions were appropriate based on the manufacturer labeling recommendations for each agent. We also followed patients' treatment outcomes. MethodsWe retrospectively reviewed patients administered a DOAC at a reduced dose between January 2011 and August 2014. The primary outcome was adherence to current manufacturer dose recommendations. The secondary outcome measures were the incidence of thromboembolic events or any bleeding episodes, regardless of severity, while on therapy. ResultsOf 224 patients included in the analysis, 43.3% of patients fit criteria for a dose adjustment according to manufacturer recommendations. Only 3 of 28 (10.7%) patients treated with apixaban met 2 out of 3 clinical criteria required for a dose reduction per manufacturer recommendations. Only 54.7% of rivaroxaban-treated patients and 32.2% of dabigatran-treated patients had renal insufficiency requiring a dose reduction. Half of our patient population received aspirin therapy, with 6.3% of patients on triple antithrombotic therapy (dual antiplatelet agents plus an anticoagulant). A past medical history significant for bleeding was prevalent in patients treated with a reduced-dose DOAC (32.1%, 20.4%, and 25.4% of patients in the apixaban-, rivaroxaban-, and dabigatran-treated groups, respectively). Thromboembolic events occurred in 10.7%, 3.6%, and 5.1% of patients in the apixaban, rivaroxaban, and dabigatran groups, respectively. Frequency of bleeding complications, regardless of severity, was 17.9%, 18.2%, and 23.7% of patients in the apixaban, rivaroxaban, and dabigatran groups, respectively. ConclusionWe found that dose-adjusted DOAC therapy was often prescribed in a dose that was lower than package insert recommendations.

Circadian variations in laboratory measurements of coagulation assays after administration of rivaroxaban or warfarin in patients with nonvalvular atrial fibrillation

BackgroundAlthough rivaroxaban has a relatively shorter half-life and peak and trough plasma concentrations throughout the day than warfarin, rivaroxaban has been found to be non-inferior to warfarin in preventing thromboembolic events in patients with nonvalvular atrial fibrillation (NVAF). We measured circadian variations in laboratory measurements of coagulation assays for chronic treatment with rivaroxaban or warfarin in patients with NVAF. MethodsWe included 28 consecutive patients with NVAF who were treated with rivaroxaban (n=13) or warfarin (n=15). Blood samples were collected at 6 AM, 11 AM, and 3 PM on the same day and on the next morning at 6 AM. Prothrombin time (PT), international normalized ratio of the PT (PT-INR), activated partial thromboplastin time (APTT), prothrombin fragment 1+2 (F1+2), and protein C level/activity were measured in each patient. ResultsPT and PT-INR were significantly and consistently lower, and the F1+2 and protein C level/activity were significantly and consistently higher throughout the day in rivaroxaban-treated patients than in warfarin-treated patients. Significant increases in PT and PT-INR were observed 3h after oral administration in the patients taking rivaroxaban in the morning, whereas, significant increases in the protein C level/activity were observed 3h after oral administration in the patients taking warfarin in the morning. ConclusionsThe protein C level/activity was significantly and consistently higher in the rivaroxaban-treated patients than in the warfarin-treated patients throughout the day, which was in contrast to the findings for other coagulation assays. These findings may partly explain the specific persistent anticoagulant effects of rivaroxaban even during the trough phase of the plasma concentration.

Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study

The efficacy and safety of the anticoagulant rivaroxaban for the treatment and secondary prevention of deep-vein thrombosis and pulmonary embolism has been shown in phase 3 trials. However, data about rivaroxaban use in routine clinical practice are needed. XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) was a multicentre, international, prospective, non-interventional study of patients with deep-vein thrombosis, done in hospitals and community care centres in 21 countries. The study investigated the safety and effectiveness of rivaroxaban compared with standard anticoagulation therapy (initial treatment with unfractionated heparin, low-molecular-weight heparin, or fondaparinux, usually overlapping with and followed by a vitamin K antagonist) for at least 3 months. Eligible patients were adults (aged ≥18 years) with an objectively confirmed diagnosis of deep-vein thrombosis, and an indication to receive anticoagulation treatment for at least 3 months. Following approval of rivaroxaban for the pulmonary embolism indication, patients with deep-vein thrombosis and concomitant pulmonary embolism were also eligible; however, those with isolated pulmonary embolism were not included. Type, dose, and duration of therapy for each patient were at the physician's discretion. The primary effectiveness and safety outcomes were major bleeding, recurrent venous thromboembolism, and all-cause mortality. Propensity score-adjusted analyses were done to account for potential imbalances between groups. This study is registered with ClinicalTrials.gov, number NCT01619007. Between June 26, 2012, and March 31, 2014, 5142 patients were enrolled. The safety population (all patients who received at least one dose of the anticoagulant of interest) comprised 2619 patients in the rivaroxaban group and 2149 in the standard anticoagulant therapy group. Patients in the rivaroxaban group were younger and fewer had active cancer or concomitant pulmonary embolism than those in the standard anticoagulation group. In the propensity score-adjusted population, the frequency of major bleeding was 0·8% (19/2505) in the rivaroxaban group and 2·1% (43/2010) in the standard anticoagulation group, with a propensity score-adjusted hazard ratio (HR) of 0·77 (95% CI 0·40-1·50); p=0·44. The frequency of recurrent venous thromboembolism was 1·4% (36/2505) in the rivaroxaban group and 2·3% (47/2010) in the standard anticoagulation group (propensity score-adjusted HR 0·91 [95% CI 0·54-1·54], p=0·72). The all-cause mortality frequency was 0·4% (11/2505) in the rivaroxaban group and 3·4% (69/2010) in the standard anticoagulation group (propensity score-adjusted HR 0·51 [95% CI 0·24-1·07], p=0·074). The incidence of treatment-emergent adverse events in the safety population was similar between the two groups (944 [36·0%] of 2619 in the rivaroxaban group vs 805 [37·5%] of 2149 in the standard anticoagulation group). In routine clinical practice, rivaroxaban-treated patients had a lower risk profile at baseline than those treated with standard anticoagulation. Propensity score-adjusted results confirm that rivaroxaban is a safe and effective alternative to standard anticoagulation therapy in a broad range of patients. Rates of major bleeding and recurrent venous thromboembolism were low in rivaroxaban-treated patients and consistent with phase 3 findings. Bayer HealthCare Pharmaceuticals and Janssen Research & Development, LLC.

Rivaroxaban Limits Complement Activation Compared to Warfarin in Antiphospholipid Syndrome Patients with Venous Thromboembolism

BackgroundComplement activation may play a role in the pathogenesis of thrombosis and other pathological processes in the antiphospholipid syndrome (APS). Since coagulation proteases, such as factor Xa, can cleave complement proteins, we investigated complement activation in thrombotic APS patients receiving rivaroxaban, a direct factor Xa inhibitor.AimsTo assess markers of complement activation (C3a, C5a, terminal complement complex (SC5b-9) and Bb fragment) in patients with thrombotic APS treated with rivaroxaban or warfarin in a prospective randomised controlled trial.Methods116 APS patients with previous venous thromboembolism, including 22 with systemic lupus erythematosus (SLE), on long-term warfarin (target INR 2.5) were studied. 59 patients remained on warfarin and 57 (11 with SLE in each group) switched to rivaroxaban (20mg daily). EDTA samples were collected at baseline (all patients on warfarin) and on day 42 (2-4 hours after the last dose of rivaroxaban in patients on rivaroxaban). 5/116 patients were excluded (samples from four patients were haemolysed and one patient withdrew from the trial after randomisation), leaving 111 (55 rivaroxaban and 56 warfarin) patients for analysis at both baseline and day 42. Samples were also collected from 55 normal controls (NC). C3a, C5a SC5b-9 and Bb fragment were assessed using ELISA assay kits (QUIDEL Corp).ResultsMedian (95% CI) C3a, C5a, SC5b-9 and Bb fragment were 48.9 (30.1-100.2) ng/mL, 6.8 (2.2-11.8 ng/mL, 113.9 (50.5-170) ng/mL and 1.1 (0.64-1.86) µg/mL in NC, respectively. APS patients had significantly higher complement activation markers compared to NC at both time points irrespective of the anticoagulant (p<0.0001 for C3a, C5a, SC5b-9 and Bb). There were no differences in the markers between the two patient groups at baseline, or in patients remaining on warfarin at day 42 [median (95% CI) for C3a, C5a, SC5b-9 and Bb fragment levels in patient on warfarin on day 0 vs day 42 were: C3a (ng/mL) 77.2 (33.4-180.1) vs 73.6 (34.7-156), C5a (ng/mL) 10.8 (3.2-19.4) vs 10.3 (3.7-19.8), SC5b-9 (ng/mL) 203.5 (70.5-440.3) vs 214.4 (78.3-470.4) and Bb fragment (µg/mL) 1.3 (0.6-2.8) vs 1.4 (0.7-2.4)].In 55 patients randomised to rivaroxaban, C3a, C5a and SC5b-9 decreased significantly compared with baseline values on warfarin [day 0 versus day 42: C3a (ng/mL): 82.8 (34.6-146.6) vs 64.0 (29.2-125.1), (p=0.004); C5a (ng/mL):12.0 (4.1-17.9) vs 9.0 (2.4-14.8), p=0.01; SC5b-9 (ng/mL): 201.0 (65.6-350.2) vs 171.5 (55.6-245.5), (p=0.001)]. However, Bb fragment levels were unchanged.ConclusionsComplement activation occurs in APS despite anticoagulation with warfarin. Rivaroxaban decreased complement activation compared to warfarin, although levels of the markers did not normalise in the majority of patients. This action of rivaroxaban appears to occur via the classical pathway, since Bb fragment (a marker of alternative pathway activation) was unchanged. The observations in rivaroxaban-treated patients may reflect inhibition of factor Xa cleavage of complement proteins, or inhibition of its pro-inflammatory effects (and consequent complement activation). These data suggest that rivaroxaban may have an additional therapeutic modality in thrombotic APS patients by limiting complement activation. DisclosuresMackie:Volution Immuno Pharmaceuticals (Uk) Ltd: Research Funding. Cohen:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria diverted to local charity, Research Funding, Speakers Bureau.

Abstract 17246: Risk Factors for Major Bleeding Events in Rivaroxaban Users With Atrial Fibrillation: A Nested Case-control Study

Introduction: Rivaroxaban is a novel oral anticoagulant indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). Anticoagulation therapies carry a risk of major bleeding (MB), for which patient characteristics may play a role. Methods: Using data obtained from the Department of Defense (DoD), we examined risk factors for MB within a cohort of rivaroxaban-treated patients with NVAF using a nested case-control design. Cases with MB were selected by a validated claims-based algorithm that approximates the definition of MB used in clinical trials. Incidence density sampling was used to identify 5 controls without MB for each case. Controls had the same year of entry into the cohort and were at risk for a MB event at the time of each matched case’s event (index date). Potential risk factors for MB included demographic characteristics and comorbidities from the 12 months prior to the index date. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from multivariable conditional logistic regression models to identify risk factors for bleeding. Results: Among 542 MB cases and 2,710 controls, MB cases were older and had more comorbidities (Table 1). Based on the multivariable modeling, increased age, anemia, prior gastrointestinal bleeding, heart failure, and vascular disease were identified as the strongest risk factors for MB (p&lt;0.0001 for all). Conclusions: Several risk factors for MB were identified, although some findings may be affected by unmeasured confounding effects. These risk factors may assist in the development of clinical management strategies.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Point-of-Care Testing of Coagulation in Patients Treated With Non-Vitamin K Antagonist Oral Anticoagulants.

Specific coagulation assays for non-vitamin K antagonist oral anticoagulants (NOAC) are relatively slow and often lack availability. Although specific point-of-care tests (POCT) are currently not available, NOAC are known to affect established coagulation POCT. This study aimed at determining the diagnostic accuracy of the CoaguChek POCT to rule out relevant concentrations of rivaroxaban, apixaban, and dabigatran in real-life patients. We consecutively enrolled 60 ischemic stroke patients newly started on NOAC treatment and obtained blood samples at 6 prespecified time points. Samples were tested using the CoaguChek POCT, laboratory-based coagulation assays (prothrombin time and activated partial thromboplastin time, anti-Xa test and Hemoclot), and liquid chromatography-tandem mass spectrometry for direct determination of NOAC concentrations. Three hundred fifty-six blood samples were collected. The CoaguChek POCT strongly correlated (r=0.82 P<0.001) with rivaroxaban concentrations but did not accurately detect dabigatran or apixaban. If used to estimate the presence of low rivaroxaban concentrations, POCT was superior to predictions based on normal prothrombin time and activated partial thromboplastin time values even if sensitive reagents were used. POCT-results≤1.0 predicted rivaroxaban concentrations<32 and <100 ng/mL with a specificity of 90% and 96%, respectively. If anti-Xa test is not available, we propose the use of the CoaguChek POCT to guide thrombolysis decisions after individual risk assessment in rivaroxaban-treated patients having acute ischemic stroke. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02371044.

Fatal intracerebral bleeding under rivaroxaban

Rivaroxaban is a factor-Xa-inhibitor which has been shown to be non-inferior to the vitamin-K-antagonist (VKA) warfarin in atrial fibrillation patients. In the manufacturer-sponsored trial, the rate of intracranial hemorrhage in rivaroxaban-treated patients was lower than in VKA-treated. It is unknown if this advantage of rivaroxaban is also present outside clinical trials. We report a patient with fatal cerebral bleeding 4months after initiation of rivaroxaban. Bleeding might be favored by hypertension, hypoalbuminemia, renal impairment, hepatopathy and drug–drug interactions of rivaroxaban with amiodarone and bisoprolol. Patients have to be monitored closely after initiation of rivaroxaban, especially if they are treated with possibly interacting drugs. Additionally, hepatic function, albumin level, and renal function have to be closely monitored. Therapy with VKA seems more convenient, safer and more favorable for the patient than rivaroxaban with its associated uncertainties concerning metabolization and drug–drug interactions and no possibility to reverse its activity in emergency situations.

Cost of Treating Venous Thromboembolism With Heparin and Warfarin Versus Home Treatment With Rivaroxaban.

Target-specific anticoagulants such as rivaroxaban facilitate immediate discharge of low-risk venous thromboembolism (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) allowing treatment at home instead of hospitalization. The objective was to compare costs accrued over 6 months by patients diagnosed with low-risk VTE and treated at home with rivaroxaban versus usual care with heparin-warfarin. This case-control study calculated costs using the established charge-to-cost ratio from UB-04 billing claims of patients diagnosed at two metropolitan hospitals. Patients were defined as low risk by the Hestia criteria. All patients were anticoagulated for 6 months. Control patients were treated with usual care using low-molecular-weight heparin (LMWH) and then warfarin. Case patients were treated with an initial dose of rivaroxaban in the ED followed by same-day discharge home with rivaroxaban. Medians were compared by Mann-Whitney U-test. Fifty cases and 47 controls were identified. Groups were well matched according to mean age, Charlson comorbidity score, and proportions by sex and location of thrombus. For all VTEs, median hospital charges for 6 months after diagnosis were $11,128 (interquartile range [IQR] = $8,110 to $23,390) for controls, compared with $4,787 (IQR = $3,042 to $7,596) for cases (Mann-Whitney U-test p < 0.001). Subgroup analyses of the first week of therapy, PE, DVT, and inpatient pharmacy costs retained significance, with costs for rivaroxaban-treated PE patients 57% lower than control PE patients (p < 0.001) and 56% lower for DVT patients (p = 0.003). Cost of medical care was lower for low-risk VTE patients discharged immediately from the ED with rivaroxaban therapy compared with patients treated with LMWH-warfarin.

Rates of hospitalization among patients with deep vein thrombosis before and after the introduction of rivaroxaban

Background. Compared to warfarin, the non-vitamin K antagonist oral anticoagulant rivaroxaban may have advantages in treating patients with venous thromboembolism, because injectable bridging therapy and routine laboratory monitoring are not required. The objective of this study was to compare the rate of hospitalization in patients treated with rivaroxaban after its introduction with what it would have been before the introduction of rivaroxaban. Methods. A retrospective claims analysis was conducted using the MarketScan Hospital Drug Database from January 2011 to December 2013. Adult patients with a primary diagnosis of deep vein thrombosis (DVT) treated with rivaroxaban or low-molecular-weight heparin (LMWH) bridged to warfarin during the first day of an evaluation at a hospital were identified. Based on propensity-score methods, historical LMWH/warfarin patients (i.e., patients who received LMWH/warfarin before the approval of rivaroxaban) were matched 4:1 to rivaroxaban patients, and the rates of hospitalization were compared. Results. All rivaroxaban-treated patients (n = 134) in the database were well matched with four historical LMWH/warfarin-treated patients (n = 536). Among the rivaroxaban cohort, 60% of the patients were admitted to the hospital, compared to 82% of the historical patients treated with LMWH/warfarin in the matched cohort. The difference was statistically significant and corresponded to a 27% reduction in hospital admissions (rate ratio [95% confidence interval]: 0.73 [0.62–0.84]). Hospital admission rates adjusted for time-trend analyses also led to similar results. Conclusion. The availability of rivaroxaban significantly reduced the hospitalization rate in patients with DVT treated with rivaroxaban compared to what it would have been if only LMWH/warfarin were available.

Rivaroxaban and warfarin achieve effective anticoagulation, as assessed by inhibition of TG and in-vivo markers of coagulation activation, in patients with venous thromboembolism

IntroductionRivaroxaban is non-inferior to warfarin for the treatment of venous thromboembolism, with regard to clinical efficacy and safety. The ex-vivo effects of warfarin versus therapeutic dose rivaroxaban on in-vivo markers of coagulation activation and thrombin generation remain undefined. The aim of this study was to compare the effects of warfarin and therapeutic dose rivaroxaban on ex-vivo thrombin generation (TG), and the in-vivo markers of coagulation activation, prothrombin fragment 1.2 (F1.2), thrombin-antithrombin complex (TAT), and D-dimer. MethodsEighty-five patients with venous thromboembolism were studied, 45 on warfarin, target INR 2.5 and 40 on rivaroxaban 20mg once daily. ResultsAnticoagulation was in therapeutic range in 71% (32/45) warfarin and 65% (26/40) rivaroxaban treated patients. 8 patients on warfarin and 9 patients on rivaroxaban had subtherapeutic INR and rivaroxaban levels respectively. Both rivaroxaban and warfarin reduced endogenous thrombin potential (ETP) and peak thrombin, and prolonged lag time and time to peak, compared to normal controls (p<0.0001). The lag time and time to peak TG were longer, and peak thrombin was lower in patients receiving rivaroxaban (p<0.0001) compared with warfarin, although warfarin-treated patients had lower ETP (p=0.0008). In-vivo coagulation activation markers were within the normal ranges in all rivaroxaban-treated patients (including those with levels considered to be subtherapeutic) and in 37/45 warfarin-treated patients who had an INR ≥2.0. The warfarin-treated patients with subtherapeutic INRs exhibited slightly raised F1.2 and/or TAT. ConclusionIn conclusion, both rivaroxaban and warfarin provided effective anticoagulation, as assessed by inhibition of TG and makers of in-vivo coagulation activation.

Hospital Length of Stay of Nonvalvular Atrial Fibrillation Patients who Were Administered Rivaroxaban versus Warfarin with and without Pretreatment Parenteral Anticoagulants Therapies

Background: Warfarin has been the only anticoagulant used for decades to prevent strokes and systemic embolisms in nonvalvular atrial fibrillation (NVAF) patients. Compared with rivaroxaban, warfarin has a narrow therapeutic range and many genetic and food–drug interactions that could potentially prolong hospital length of stay (LOS).Objective: To compare hospital LOS between NVAF patients who were administered rivaroxaban versus warfarin with and without pretreatment of parenteral anticoagulant agents in a population of rivaroxaban-treated patients.Methods: A retrospective matched-cohort analysis was conducted using the Premier Perspective Comparative Hospital Database from November 2010 to September 2012. Adult patients were included in the study if they had a hospitalization for NVAF. Rivaroxaban users were matched with up to 4 warfarin users based on propensity score analyses. Patients with and without pretreatment of parenteral anticoagulant agents were evaluated separately. Hospital LOS was compared between treatment groups using generalized estimating equations.Results: The matched cohorts' characteristics were well balanced. Among the matched rivaroxaban and warfarin users who were administered parenteral agents, the mean age of the cohorts was 70 years and 47% of patients were female, whereas in the sample of patients who were not administered parenteral agents, the mean age was 72 years and 50% of patients were female. In the sample of patients who were administered parenteral agents, rivaroxaban users had significantly shorter hospital LOS (LOS difference: 1.38 days, P < 0.001) compared with warfarin users among rivaroxaban-treated patients. No significant difference in LOS was found in the sample of patients who were not administered parenteral anticoagulant agents (P = 0.169).Conclusion: In the study sample of NVAF patients who were administered parenteral anticoagulant agents, rivaroxaban was associated with a significantly shorter hospital LOS compared with warfarin. The difference in LOS was not statistically significant in the sample of patients who were not administered parenteral anticoagulant agents.

Rivaroxaban for the treatment of venous thromboembolism. A “real-life” perspective in 103 patients

IntroductionRandomized clinical trials have demonstrated non-inferiority of rivaroxaban compared with vitamin K antagonists (VKAs) in the treatment of venous thromboembolism (VTE). Our objective was to analyze in real life, tolerance, recurrence, bleeding and adverse events of rivaroxaban in patients with acute symptomatic VTE. Material and MethodsOpen follow-up study of a cohort of patients aged 18 and over diagnosed with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) treated with rivaroxaban from December 2011 to January 2014. ResultsThe total number of patients treated with rivaroxaban was 103. The mean age was 58+/-17years. The most frequent co-morbidities were: hypertension (30.0%), dyslipidemia (23.3%) and respiratory disease (25.2%). The type of thromboembolic event treated was: DVT (64.1%), PE (18.4%), DVT+PE (17.5%). Of the rivaroxaban-treated patients, 30% did so from the initial anticoagulant therapy and the other 70% in long-term or extended anticoagulant therapy. The median time of treatment with rivaroxaban was 5months. There was one recurrence and no deaths occurred. Six patients had bleeding, one of which was severe. ConclusionsRivaroxaban provides a therapeutic alternative in a group of patients with VTE with advantages over VKAs, because of the convenience in dosing, lack of requirements for periodic monitoring and limited interaction with other drugs.