Discontinuation Of Rivaroxaban Research Articles

Comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban in dogs.

Comparative pharmacokinetics and pharmacodynamics (PK/PD) of apixaban and rivaroxaban have not been studied in dogs and the propensity of these drugs to cause hypercoagulability after discontinuation is unknown. Compare the PK/PD of clinical dosing regimens of PO apixaban and rivaroxaban administered repeatedly to healthy dogs and assess the effect of abrupt drug discontinuation on coagulation. Six University-owned, purpose-bred, middle-aged, mixed-breed dogs (4 male, 2 female). Dogs were given apixaban or rivaroxaban PO at 0.5 mg/kg q12h for 7 days with a 14-day washout period between drugs. Plasma drug concentrations were quantitated, and anticoagulant effects were measured using clotting times, calibrated anti-Xa bioactivity assays, and measurements of thrombin generation. The potential for rebound hypercoagulability was assessed by measuring D-dimers, thrombin-antithrombin (TAT) complexes, and antithrombin activity after drug discontinuation. Plasma drug concentrations and anti-Xa bioactivities were closely correlated for both drugs, but drug concentrations varied considerably among dogs, despite consistent dose regimens. Thrombin generation variables were significantly correlated with the anti-Xa bioactivity of both drugs and no significant differences in the effects of apixaban and rivaroxaban on thrombin generation were observed. Drug discontinuation had no effect on D-dimer concentrations. The concentration of TAT complexes decreased after apixaban discontinuation and did not change after rivaroxaban discontinuation. Repeated PO administration of apixaban or rivaroxaban to healthy dogs produced comparable anticoagulant effects measured by inhibition of thrombin formation. Rebound hypercoagulability after drug discontinuation was not observed and weaning of these drugs in clinical patients might not be necessary.

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.

Clinical Outcome After Discontinuation of Anticoagulation Therapy in Japanese Patients With Venous Thromboembolism - Insights From the J'xactly Study.

Background: Rivaroxaban, a direct oral anticoagulant, is used as first-line treatment to prevent venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). However, the frequency of rivaroxaban discontinuation and the subsequent clinical outcomes remain unclear.Methods and Results: The study was a subanalysis of the prospective, multicenter, observational J’xactly study, conducted in Japan, and included patients who underwent anticoagulant discontinuation without major bleeding and recurrent VTE. The modified intention-to-treat population (n=1,016) included 579 patients (57%) who underwent anticoagulant discontinuation during a mean follow-up period of 20.2 months (mean [±SD] anticoagulation period 6.9±6.2 months). Patients were divided into 3 groups: those with active cancer, those without active cancer and a transient risk factor for VTE, and those without active cancer or a transient risk factor and/or with previous VTE (unprovoked group). After discontinuation, VTE recurrence occurred in 4.1% of patients, with an annual incidence of 4.6%/year and an increased tendency in the unprovoked group; major bleeding occurred in 8 patients (1.4%; annual incidence 1.1%/year), of whom half were in the cancer group.Conclusions: This analysis of a real-world observational study provides data on VTE recurrence after rivaroxaban discontinuation, which will facilitate anticoagulant discontinuation according to individual risk-benefit considerations.

Implant Placement in Patients under Treatment with Rivaroxaban: A Retrospective Clinical Study.

The management of patients under treatment with Direct Oral Anticoagulants (DOACs) has led clinicians to deal with two clinical issues, such as the hemorrhagic risk in case of non-interruption or the risk of thromboembolism in case of suspension of the treatment. The primary aim of this retrospective study was to evaluate the incidence of perioperative bleeding events and healing complications in patients who were under treatment with Rivaroxaban and who received dental implants and immediate prosthetic restoration. Patients treated with Rivaroxaban (Xarelto 20 mg daily) and who needed implant rehabilitation were selected. Four to six implants were placed in mandibular healed sites or fresh extraction sockets. All patients, in agreement with their physicians, interrupted the medication for 24 h and received implants and immediate restorations. Twelve patients and 57 implants were analyzed in the study. No major postoperative bleeding events were reported. Three patients (25%) presented slight immediate postoperative bleeding controlled with compression only. The implant and prosthetic survival rate were both 100% after 1 year. Within the limitations of this study, multiple implant placement with an immediate loading can be performed without any significant complication with a 24 h discontinuation of Rivaroxaban, in conjunction with the patient’s physician.

Rivaroxaban treatment of cancer‐associated venous thromboembolism: Memorial Sloan Kettering Cancer Center institutional experience

BackgroundLow‐molecular‐weight heparin has been the preferred treatment of cancer‐associated thrombosis (CAT); however, emerging data support the use of direct oral anticoagulants (DOACs). ObjectivesThe Memorial Sloan Kettering Cancer Center Clinical Pathway has served as the institutional guideline for the use of rivaroxaban to treat CAT since 2014. Key elements are to recommend against use of a DOAC in patients with active gastrointestinal (GI) or genitourinary tract lesions, and a prespecified dose reduction in the elderly (75+ years old). We present our institutional experience for treatment of CAT. MethodsFrom January 2014 through September 2016, 1072 patients began rivaroxaban treatment for CAT; 91.9% had a solid tumor, 8.1% had hematologic malignancies, and 75% of patients with solid tumors had metastatic disease. All patients with CAT treated with rivaroxaban were included in this analysis, regardless of adherence to the Clinical Pathway. ResultsThe 6‐month cumulative incidence of recurrent venous thromboembolism and major bleeding were 4.2% (95% confidence interval [CI], 2.7%‐5.7%) and 2.2% (95% CI, 1.1%‐3.2%), respectively. The incidence of clinically relevant non–major bleeding leading to discontinuation of rivaroxaban for at least 7 days was 5.5% (95% CI, 3.7%‐7.1%), and 73.3% of major bleeds occurred in the GI tract. The 6‐month cumulative mortality rate was 22.2% (95% CI, 19.4%‐24.9%). The elderly had similar rates of recurrent thrombosis and bleeding as those aged under 75 years. ConclusionOur institutional experience suggests that in appropriately selected patients, rivaroxaban may be used for treatment of CAT with promising safety and efficacy.

XANTUS-EL: A real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation in Eastern Europe, Middle East, Africa and Latin America.

BackgroundThe prospective, observational XANTUS study demonstrated low rates of stroke and major bleeding in real-world rivaroxaban-treated patients with non-valvular atrial fibrillation (NVAF) from Western Europe, Canada and Israel. XANTUS-EL is a component of the overall XANTUS programme and enrolled patients with NVAF treated with rivaroxaban from Eastern Europe, the Middle East and Africa (EEMEA) and Latin America.MethodsPatients with NVAF starting rivaroxaban for stroke prevention were consecutively recruited and followed for 1 year, at approximately 3-month intervals, or for ≥30 days after permanent rivaroxaban discontinuation. Primary outcomes were major bleeding, adverse events (AEs), serious AEs and all-cause mortality. Secondary outcomes included stroke, non-central nervous system systemic embolism (non-CNS SE), transient ischaemic attack (TIA), myocardial infarction (MI) and non-major bleeding. All major outcomes were centrally adjudicated.ResultsOverall, 2064 patients were enrolled; mean age ± standard deviation was 67.1 ± 11.32 years; 49.3% were male. Co-morbidities included heart failure (30.9%), hypertension (84.2%), diabetes mellitus (26.5%), prior stroke/non-CNS SE/TIA (16.2%) and prior MI (10.7%). Mean CHADS2, CHA2DS2-VASc and HAS-BLED scores were 2.0, 3.6 and 1.6, respectively. Treatment-emergent event rates were (events/100 patient-years, [95% confidence interval]): major bleeding 0.9 (0.5–1.4); all-cause mortality 1.7 (1.2–2.4); stroke/non-CNS SE 0.7 (0.4–1.2); any AE 18.1 (16.2–20.1) and any serious AE 8.3 (7.0–9.7). One-year treatment persistence was 81.9%.ConclusionsXANTUS-EL confirmed low stroke and major bleeding rates in patients with NVAF from EEMEA and Latin America. The population was younger but with more heart failure and hypertension than XANTUS; stroke/SE rate was similar but major bleeding lower.

Clinical Safety Outcomes in Patients With Nonvalvular Atrial Fibrillation on Rivaroxaban and Diltiazem.

It is unknown whether diltiazem, a moderate cytochrome P450 enzyme (CYP3A4) and P-glycoprotein (P-gp) inhibitor, increases the incidence of bleeding events in combination with rivaroxaban, a CYP3A4 and P-gp substrate. To assess major and clinically relevant nonmajor (CRNM) bleeding outcomes in patients with nonvalvular atrial fibrillation (NVAF) on rivaroxaban with concomitant diltiazem in a real-world setting. This retrospective case-cohort study included adult patients with NVAF prescribed both rivaroxaban and diltiazem for at least 30 days. Patients were matched 1:1 by age and baseline creatinine clearance (CrCl) to control patients taking rivaroxaban alone. The primary outcome was the composite of major and CRNM bleeding. Additional outcomes included bleeding events resulting in discontinuation of rivaroxaban, time to first bleeding event, and type of first bleed. A total of 143 cases and 143 controls were included. The mean age was 69 years and median baseline CrCl was 87 mL/min. Median follow-up time was 12.4 months for cases and 16.5 months for controls. There was no significant difference in proportion of patients experiencing a major and/or CRNM bleeding event between cases and controls: 23.1% versus 28.0%, respectively; 9 cases and 8 controls permanently discontinued rivaroxaban because of bleeding. Gastrointestinal/rectal bleeding and hematuria were the most frequently reported bleeding events in both groups. Conclusion and Relevance: This is the first study to assess major and CRNM bleeding outcomes in patients with NVAF on rivaroxaban and diltiazem. Diltiazem use was not associated with an increased rate of bleeding events.

Venous thromboembolism therapy with rivaroxaban in daily-care patients: Results from the Dresden NOAC registry

The effectiveness and safety of acute venous thromboembolism (VTE) treatment with rivaroxaban, demonstrated in phase-III trials, needs to be confirmed in daily care.To confirm the positive results of phase-III VTE treatment trials with rivaroxaban in daily care, we used data from the ongoing, prospective, non-interventional Dresden NOAC Registry.For this analysis, only patients with acute VTE who started rivaroxaban within 14days after diagnosis of VTE and who were enrolled within these 14days were evaluated with regard to patient characteristics, treatment persistence and clinical outcomes.Between December 1st 2011 and 30th September 2016, 418 patients with acute VTE and rivaroxaban treatment were enrolled. During rivaroxaban treatment (median rivaroxaban exposure 206d; median follow-up 862d) rates of recurrent VTE and ISTH major bleeding were 1.9% and 3.8%, respectively. At 6months. 58.3% of patients were still taking rivaroxaban, 28.2% had a scheduled end of treatment, 7.2% were switched to other anticoagulants, 1.7% had withdrawn their consent and the remaining 3.6% of patients had unplanned complete discontinuation of anticoagulation. After permanent discontinuation of rivaroxaban, 20 patients experienced a recurrent VTE (7 pulmonary embolism±deep vein thrombosis, 13 deep vein thrombosis) with a mean time between last intake of rivaroxaban and VTE recurrence of 374.3±247.6days (range 28–927d).In daily care patients with acute VTE, rivaroxaban demonstrated high effectiveness with acceptable major bleeding rates. Initial dosing was according to label in over 90% of patients and persistence to rivaroxaban therapy was adequate with low rates of unplanned complete discontinuation.

Residual rivaroxaban exposure after discontinuation of anticoagulant therapy in patients undergoing cardiac catheterization.

Patients treated with direct oral anticoagulants (DOACs) frequently undergo interventional procedures requiring temporary discontinuation of anticoagulant therapy. Little is known about remaining peri-procedural exposure to rivaroxaban in real-world patients. Fifty-six patients with rivaroxaban treatment and scheduled cardiac catheterization were included in this prospective, observational, and single-center study. Rivaroxaban concentrations were determined by LC-MS/MS and a chromogenic anti-Xa assay. Population pharmacokinetic modeling was carried out on LC-MS/MS concentration data using NONMEM software, and results were applied to Monte Carlo simulations to predict appropriate rivaroxaban discontinuation intervals. Rivaroxaban concentrations ranged from <LLOQ to 300.6ng/ml at the time of admission to hospital and from <LLOQ to 55.5ng/ml at the beginning of the procedure. Times since last rivaroxaban intake were (mean ± SD) 51.0 ± 31.7h (admission) and 85.5 ± 36.8h (start catheterization). LC-MS/MS and anti-Xa assay results were in good agreement (r = 0.958); however, the anti-Xa assay may underestimate low rivaroxaban concentrations and overestimate rivaroxaban exposure when performed on plasma samples contaminated with heparins. Pharmacokinetics of rivaroxaban were adequately described, and simulations predicted that 95% of patients will have rivaroxaban concentrations ≤ 28.4ng/ml (15mg dose group) and ≤ 31.9ng/ml (20mg dose group) after 48h of discontinuation. In the majority of patients, rivaroxaban plasma concentrations dropped below 30ng/ml after 48h of treatment discontinuation which is considered hemostatically safe before surgery with high bleeding risk. For accurate determination of low rivaroxaban concentrations, LC-MS/MS is the preferred choice.

Rivaroxaban for Stroke Prevention in Patients with Non-Valvular Atrial Fibrillation and Active Cancer

BACKGROUNDThe link between aging, cancer and atrial fibrillation is well known and the appropriate anticoagulation management of non-valvular atrial fibrillation (NVAF) in patients with active cancer is of growing clinical concern. Rivaroxaban has been broadly used for the primary prevention of stroke and systemic embolism in the general population of patients with NVAF. However, individuals with a serious concomitant illness associated with a life expectancy of less than 2 years were excluded from pivotal trials including the ROCKET-AF study, limiting the generalizability of results to patients with active cancer. There is little published evidence on the safety and efficacy of rivaroxaban for NVAF in this specific subgroup. OBJECTIVESThe aim of this study was to assess the safety and efficacy of rivaroxaban in patients with active cancer and NVAF. METHODSThe use of rivaroxaban in cancer patients at Memorial Sloan Kettering Cancer Center (MSKCC) was monitored in the setting of a Quality Assessment Initiative. Patients with active cancer and NVAF treated with rivaroxaban from 1/1/2014 through 3/31/2016 are included in this analysis. Endpoints of interest were defined a priori and include stroke, systemic embolism, major bleeding and clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days (CRNMB). Clinical events were assessed through text searches of medical records. The analysis was performed respecting different times on previous anticoagulation, considering the first 90 days as the acute phase of treatment and contrasting it with the subsequent chronic phase. RESULTSA total of 163 evaluable patients were included in the analysis, with a median age of 72.0 years (interquartile range=67.0-77.5 years) and 56% of these individuals being men. The majority had a solid tumor (85%), with stage IV disease reported in 50% of cases. The mean CHA2DS2-Vasc score was 3.2 (standard deviation=1.5) and 64% of patients were already in the chronic phase of anticoagulation. Results for the acute, chronic and combined phases of anticoagulation are presented in the Table and plotted in the Figure. The estimated cumulative incidence of ischemic stroke, major bleeding, and CRNMB at 1 year were 1.4% (95% CI=0-3.4%), 1.2% (95% CI=0-2.9%) and 14.0% (95% CI=4.2-22.7%) respectively, after adjusting for competing risks. Interestingly, the cumulative incidence of major bleeding in our cohort is lower than the value reported for the ORBIT-AF registry of cancer patients on dabigatran or a vitamin K antagonist for NVAF, in which the estimated rate of this complication was 5.1/100 patient-years. Lastly, the 1-year cumulative incidence of mortality was 22.6% (95% CI=12.2-31.7%). This high risk of death was present throughout the observation period and reflects the cancer population. One patient died after developing an acute ischemic cerebrovascular insult and a myocardial infarction. There were no deaths related to bleeding and no recorded systemic embolism episodes. CONCLUSIONSThe safety and efficacy profile of rivaroxaban treatment for NVAF in patients with active cancer seems comparable to what was observed for the general population in the ROCKET-AF study, but ideally a prospective study would be required to confirm these findings. [Display omitted] [Display omitted] DisclosuresYu:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Soff:Janssen Scientific Affairs, LLC: Consultancy, Research Funding. Mantha:Janssen Scientific Affairs, LLC: Research Funding.

Practice patterns and outcomes of rivaroxaban usage in patients with cancer.

194 Background: Patients with cancer have an increased risk of venous thromboembolism (VTE) and frequently require anticoagulation. In addition, many patients with cancer also have comorbidities such as atrial fibrillation (AF) and are on stroke prevention. Rivaroxaban (RV) is an oral (factor Xa inhibitor) used in these scenarios; however, there is little experience utilizing this agent in patients with cancer. Our aim is to describe practice patterns and outcomes of RV usage in patients with cancer. Methods: We conducted a retrospective study of 62 patients with cancer receiving RV for at least 5 days for VTE or non-valvular AF from 1/1/2012 through 10/31/2015. Practice patterns included RV perioperative use and blood and platelet transfusions. Outcomes of interest were recurrent VTE and bleeding. Descriptive statistics were utilized to summarize demographic and clinical variables. Results: Of 62 patients with cancer, the mean age was 62 years (range 31-83), 50% were male, and 77% white. The most common cancer types were gastrointestinal 9 (15%), sarcoma 9 (15%), and breast and hematologic each with 8 (13%). Of those, 49 (79%) had VTE, 9 AF (15%), and 4 (7%) had both. 42 (68%) patients were switched to RV from a prior anticoagulant, the majority from low molecular weight heparin. 22 (36%) had RV withheld temporarily; 15 due to surgical procedure and 5 due to bleeding. 5 (33%) received bridging anticoagulation prior to surgery. RV was held a mean of 2 days prior to surgery and resumed 9 days post-op. 14 (21%) received blood and 2 (3%) received platelet transfusions while on RV. 2 (3%) patients had VTE recurrence while on RV. 18 (29%) discontinued RV due to bleeding, 5 (28%) due to hematuria and only 1 patient due to thrombocytopenia (6%). There were no major bleeds or deaths related to RV. Conclusions: RV was used in solid and hematologic cancers. The majority were transitioned from another anticoagulant. Although VTE recurrence was low, discontinuation of RV due to bleeding was higher. Further study of the use of RV in patients with cancer is needed for continued guidance of appropriate and safe usage.

Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study

Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. Rivaroxaban was approved in 2012 for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but no prior studies have been reported specifically evaluating the efficacy and safety of rivaroxaban for cancer-associated thrombosis (CAT). Under a Quality Assessment Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT and now report a validation analysis of our first 200 patients. A 200 patient cohort with CAT (PE or symptomatic, proximal DVT), whose full course of anticoagulation was with rivaroxaban, were accrued. In competing risk analysis, primary endpoints at 6 months included new or recurrent PE or symptomatic proximal lower extremity DVT, major bleeding, clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. In competing risk analysis, the 6 months cumulative incidence of new or recurrent VTE was 4.4 % (95 % CI = 1.4–7.4 %), major bleeding was 2.2 % (95 % CI = 0−4.2 %) and all-cause mortality 17.6 % (95 % CI = 11.7–23.0 %). In this cohort of 200 patients with active cancer and CAT the rates of new or recurrent VTE and major bleeding were comparable to the cancer subgroup analysis from the EINSTEIN studies. The results of our Clinical Pathway provide guidance on Rivaroxaban use for treatment of CAT, and suggest that safety and efficacy is preserved, compared with past-published experience with LMWH.

Risk of Thromboembolic Events in Patients with Non-Valvular Atrial Fibrillation After Dabigatran or Rivaroxaban Discontinuation – Data from the Ljubljana Registry

Background and AimInterruption of anticoagulant treatment with warfarin or non-vitamin K antagonist oral anticoagulants (NOAC) represents a vulnerable period with an increased risk of thromboembolic events. What is the incidence of thromboembolic events in real-life patients with non-valvular atrial fibrillation treated with NOAC who had a discontinuation or cessation of treatment in comparison to patients on continuous treatment?Patients and MethodsRegistry data from 866 patients with non-valvular atrial fibrillation, aged 74.3 (SD 9.8) years, with an average CHADS2 score of 2.1 (SD 1.2), who were started on dabigatran or rivaroxaban, were analysed for thromboembolic events and survival. Patients who had temporary or permanent discontinuation of NOAC were compared to patients on continuous NOAC treatment.ResultsAmong 866 patients started on NOAC, 705 were treated without interruption, 84 patients had temporary interruption (69 because of planned invasive procedures, 10 due to bleeding, 5 for other causes) and 77 had permanent cessation of NOAC treatment. In patients without interruptions, the incidence of thromboembolic events was 1.0 (95% CI 0.4–2.1) per 100 patient-years, while in patients with interruption/cessation the rate of thromboembolic events was 21.6 (95% CI 10.3–45.2) per 100 patient-years, p < 0.001. There was a distinct clustering of thromboembolic events in the first weeks of NOAC discontinuation with the median occurring on day 14 (range 1–37 days) after discontinuation.ConclusionDabigatran and rivaroxaban offered good protection against thromboembolic events during treatment, but interruption of NOAC treatment increased the short-term thromboembolic risk more than 20-fold.

Effectiveness and safety of rivaroxaban therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry.

The effectiveness and safety of rivaroxaban for stroke prevention in atrial fibrillation (SPAF) demonstrated in ROCKET AF needs to be confirmed in daily care. To evaluate effectiveness and safety of rivaroxaban therapy in SPAF patients in daily care, we used data from an ongoing, prospective, non-interventional registry of more than 2700 patients on novel oral anticoagulants in daily care. Between October 1, 2011 and February 28, 2013, a total of 1204 SPAF patients receiving rivaroxaban were enrolled. During a mean follow-up of 796.2 ± 207.3 days, the combined endpoint of stroke/transient ischaemic attack/systemic embolism occurred at a rate of 2.03/100 patient-years in the intention-to-treat analysis (95 % confidence interval [CI] 1.5-2.7) and at 1.7/100 patient-years in the on-treatment analysis (events within 3 days after last intake). On-treatment rates were higher in patients selected for 15 mg rivaroxaban (n=384) once daily [OD] compared with the 820 patients selected for 20 mg OD (2.7 [95 % CI 1.6-4.2] vs 1.25/100 patient-years [95 % CI 0.8-1.9]). On treatment, major bleeding occurred at a rate of 3.0/100 patient-years and significantly more often in patients receiving the 15 mg OD dose compared with the 20 mg OD dose (4.5 vs 2.4/100 patient-years). Rivaroxaban treatment discontinuation occurred in a total of 277 patients during follow-up (12.0/100 patient-years in Kaplan-Meier analysis). Our data contribute to the confirmation of effectiveness and relative safety of rivaroxaban in daily-care patients. Furthermore, rivaroxaban discontinuation rates were considerably lower than those reported for vitamin K antagonists.

Safe and Effective Use of Rivaroxaban for Treatment of Cancer-Associated Venous Thromboembolic Disease: A Quality Improvement Initiative

▪Background: Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. LMWH injections are painful and costly. Rivaroxaban, an oral direct factor Xa inhibitor, was FDA approved in 2012 for treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but there has been a knowledge gap for its use in patients with cancer-associated thrombosis (CAT). Under a Quality Assurance Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT, and began to offer rivaroxaban as an alternative to enoxaparin, in January 2014, for patients who met appropriate clinical criteria. We are tracking all cancer patients with PE or symptomatic proximal DVT, whose full course of anticoagulation is with rivaroxaban (allowing up to 3 days of initial parenteral anticoagulation). We now report the characteristics of the first 200 patients, and an outcome analysis of our first 100 patients, who have been treated for at least 6 months or otherwise reached an endpoint.Materials and Methods: The Clinical Pathway guidelines will be available on request, pending publication. Patients were not treated with rivaroxaban if they had active gastrointestinal or genitourinary lesions, or had undergone gastric resection due to anticipated excess bleeding risk or reduced absorption. This excluded under 5% of patients. The Pathway provided dosing guidelines in the setting of thrombocytopenia, advanced age, transient renal, or hepatic dysfunction. Primary endpoints include new or recurrent PE, symptomatic proximal lower extremity DVT, major bleeding (ISTH definition), clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. Considering those outcomes as competing risks, the cumulative incidence of each event type was calculated using R 3.2.0 for Windows and package "Survival".Results: The characteristics of our first 200 patients are in Table 1. 70% of the patients had PE. Of the solid tumor patients, 65.6% had metastatic disease. The first 100 patients have completed at least 6 months of rivaroxaban anticoagulation or otherwise reached a primary endpoint. At 6 months, the cumulative incidence of death was 14.4% (95% CI=6.8-21.4%), new or recurrent VTE was 4.3% (95% CI=0.1-8.4%), major bleeding was 1.1% (95% CI=0-3.1%), and clinically relevant non-major bleeding leading to rivaroxaban discontinuation was 7.9% (95% CI=2.1-13.3%).Conclusions: In the analysis of the first 100 patients entered into our QAI program, the rates of major bleeding, and new or recurrent VTE compare favorably to two published studies of LMWH for treatment of cancer associated thrombosis. In the CLOT study (Lee et al, NEJM, 2003) and the Daltecan study (Francis et al, JTH, 2015), the 6-month rates of new or recurrent VTE were approximately 9%, and the rates of major bleeding were 6% and 9.5% respectively. Our final analysis awaits the completion of 6 months follow-up on 200 patients, to be completed in December 2015. But the rates of major bleeding and recurrent VTE at this point suggest safety and efficacy to be at least non-inferior to LMWH, with the advantage of reduced patient burden, and support the ongoing use of our Clinical Pathway.Our low rate of major bleeding likely is influenced by the exclusion of patients with active GI or GU lesions, who would be expected to have a high bleeding risk with an oral direct anticoagulant. However, we estimate this excluded less than 5% of cancer patients with VTE. Further, we anticipated reduced drug clearance in the elderly, and used a reduced dose for patients greater than 75 years of age. This appeared to be associated with no loss in efficacy, and helped maintain a low rate of major bleeding.A randomized trial is the optimal approach to establish non-inferiority or superiority of rivaroxaban to LMWH for cancer associated thrombosis. However, our QAI Clinical Pathway provides guidance and reassurance for rivaroxaban use until a randomized trial is conducted.TableBaseline Characteristics of PatientsCharacteristicNumber of IndividualsGenderMale82Female118Event TypePE, with or without DVT140Proximal, Symptomatic Lower extremity DVT60Cancer TypeSolid Tumor186Hematologic Malignancy14Cancer Stage (Of Solid Tumors)No Evidence of Disease (Post-Cancer Surgery)11 (5.9%)11 (0.5%)24 (2.2%)316 (8.6%)4122 (65.6%)Unknown32 (17.2%) [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Medication persistence and discontinuation of rivaroxaban and dabigatran etexilate among patients with non-valvular atrial fibrillation

Objective:To compare real-world persistence and discontinuation among non-valvular atrial fibrillation (NVAF) patients on rivaroxaban and dabigatran in the US.Methods:A large nationally representative US claims database was used to conduct a retrospective cohort analysis of patients with NVAF on rivaroxaban or dabigatran between October 2010 and March 2013. The index date was the date of the first prescription of rivaroxaban or dabigatran. All patients had ≥6 months of data prior to the index date and were followed until the earliest of inpatient death, end of continuous enrollment, or end of the study period. Rivaroxaban patients were matched 1:1 with dabigatran patients using the propensity score matching technique. Cox proportional hazards models were employed to estimate the adjusted hazard ratios (aHRs) of non-persistence and discontinuation. Persistence was defined as absence of a refill gap of ≥60 days. Discontinuation was defined as no additional refill for at least 90 days and until the end of follow-up.Results:A total of 30,337 NVAF patients on rivaroxaban or dabigatran met the study criteria. All 7259 rivaroxaban patients were matched 1:1 to dabigatran patients. Compared with dabigatran users, rivaroxaban patients were 11% less likely to become non-persistent with therapy (aHR: 0.89, 95% CI 0.84–0.95) and 29% less likely to discontinue therapy (aHR: 0.71, 95% CI 0.66–0.77).Limitations:Claims data are subject to miscoding and inaccuracies. Refill data may not fully reflect actual medication taken. Confounding may remain even after propensity score matching and additional adjustments in model. Longer follow-up may produce more precise estimates of persistence and discontinuation.Conclusions:This matched cohort analysis indicated that, compared to dabigatran, rivaroxaban was associated with better persistence and lower rates of discontinuation.

False-positive lupus anticoagulant in patients receiving rivaroxaban: 24 h since the last dose are needed to exclude antiphospholipid syndrome.

Rivaroxaban, a direct factor Xa inhibitor, affects laboratory clotting tests. We report here 10 venous thromboembolism patients with false-positive lupus anticoagulant during rivaroxaban therapy. Two dilute Russell Viper Venom time (dRVVT)-based integrated assays, HemosIL dRVVT Screen/HemosIL dRVVT Confirm (Instrumentation Laboratory, LA1/LA2 (Siemens, Germany) and LA1/LA2 (Siemens, Marburg, Germany), showed that the patients were lupus anticoagulant-positive. Antiphospholipid antibodies were negative except for one patient. Screening activated partial thromboplastin time-based assay PTT lupus anticoagulant was lupus anticoagulant-positive, whereas the confirmatory Staclot lupus anticoagulant (both Diagnostica Stago, France) was lupus anticoagulant-negative. Re-examination after discontinuation of rivaroxaban (>24 h) ruled out the presence of lupus anticoagulant. Our data indicate that to reliably evaluate lupus anticoagulant in patients on rivaroxaban, blood should be drawn 24 h after the last dose.

Drug persistence with rivaroxaban therapy in atrial fibrillation patients-results from the Dresden non-interventional oral anticoagulation registry.

AimsWorldwide, rivaroxaban is increasingly used for stroke prevention in atrial fibrillation (SPAF) but little is known about the rates of or reasons for rivaroxaban discontinuations in daily care. Using data from a prospective, non-interventional oral anticoagulation (NOAC) registry, we analysed rivaroxaban treatment persistence.Methods and resultsPersistence with rivaroxaban in SPAF was assessed in an ongoing, prospective, non-interventional registry of >2600 NOAC patients from daily care using the Kaplan–Meier time-to-first-event analysis. Reasons for and management of rivaroxaban discontinuation were assessed. Potential baseline risk factors for treatment discontinuation were evaluated using Cox regression analysis. Between October 2011 and April 2014, 1204 rivaroxaban SPAF patients were enrolled [39.3% switched from vitamin K antagonists (VKAs) and 60.7% newly treated patients]. Of these, 223 patients (18.5%) stopped rivaroxaban during follow-up (median 544 days), which translates into a discontinuation rate of 13.6 (95% CI 11.8–15.4) per 100 patient-years. Most common reasons for treatment discontinuations were bleeding complications (30% of all discontinuations), followed by other side-effects (24.2%) and diagnosis of stable sinus rhythm (9.9%). A history of chronic heart failure (HR 1.43; 95% CI 1.09–1.87; P = 0.009) or diabetes (HR 1.39; 95% CI 1.06–1.82; P = 0.018) were the only statistically significant baseline risk factors for rivaroxaban discontinuation. After discontinuation of rivaroxaban, patients received antiplatelet therapy (31.8%), VKA (24.2%), another NOAC (18.4%), heparin (9.9%), or nothing (15.7%).ConclusionOur data indicate that overall persistence with rivaroxaban therapy is high, with a discontinuation rate of ∼15% in the first year of treatment and few additional discontinuations thereafter.

Drug Persistence with Rivaroxaban Therapy in Atrial Fibrillation Patients Results from the Dresden NOAC registry

▪Aims: Worldwide, rivaroxaban is increasingly used for stroke prevention in atrial fibrillation (SPAF) but little is known about the rates of or reasons for rivaroxaban discontinuation in daily care. Using data from a prospective, non-interventional oral anticoagulation (NOAC) registry, we analysed rivaroxaban treatment persistence.Methods and results: Persistence with rivaroxaban in SPAF was assessed in an ongoing, prospective, non-interventional registry of >2600 NOAC patients from daily care using Kaplan-Meier time-to-first-event analysis. Reasons for and management of rivaroxaban discontinuation were assessed. Potential baseline risk factors for treatment discontinuation were evaluated using Cox regression analysis.Between October 2011 and April 2014, 2603 patients were enrolled in the registry. Of these, 1204 (46.3%) received rivaroxaban for SPAF, with 473 (39.3%) switched from VKA pretreatment to rivaroxaban and 731 (60.7%) newly anticoagulated rivaroxaban patients.As of 30 April 2014, follow-up information was available for all 1204 patients (100%). By that date, the median treatment duration with rivaroxaban was 544 days (25th and 75th percentile 444/639d) for all patients. During follow-up, the overall persistence with rivaroxaban therapy was 81.5% (223/1204 patients discontinued rivaroxaban) and similar for patients switched from VKA to rivaroxaban or newly treated rivaroxaban patients (82.0% vs 81.1%).In the intention-to-treat analysis, rates of treatment discontinuation per 100 patient-years were assessed as a Kaplan–Meier time-to-first-event analysis and found to be 13.6 [95% CI 11.8–15.4] for all patients and similar for newly treated rivaroxaban patients (14.1 [95% CI 11.9–16.7]) and patients switched from VKA to rivaroxaban (12.7 [95% CI 10.1–15.7]; p = 0.35; Figure 1a). This finding did not change if only patients with a completed 12-month follow-up were assessed (Figure 1b).Discontinuation rates were highest in the first 6 months of treatment (9.9% [95% CI 7.7–12.1%] for patients newly treated with rivaroxaban and 10% [95% CI 7.3–12.7%] for patients switched from VKA pretreatment to rivaroxaban) and declined similarly in both subgroups over time (for 6–12 months: 6% [95% CI 5.5–6.4%] and 3.9% [95% CI 3.5–4.4%], respectively; after 12 months: 4.4% [95% CI 3.9–5%) and 7.7% [95% CI 6.0–9.2%], respectively).Most common reasons for treatment discontinuations were bleeding complications (30% of all discontinuations), followed by other side-effects (24.2%) and diagnosis of stable sinus rhythm (9.9%). Within the group of 67 bleeding complications, according to the International Society on Thrombosis and Haemostasis bleeding definition, 14 were major and 53 were non-major clinically relevant bleeding events that led to treatment discontinuation. A history of chronic heart failure (HR 1.43; 95% CI 1.09-1.87; p=0.009) or diabetes (HR 1.39; 95% CI 1.06-1.82; p=0.018) were the only statistically significant baseline risk factors for rivaroxaban discontinuation. After discontinuation of rivaroxaban, patients received antiplatelet therapy (31.8%), VKA (24.2%), another NOAC (18.4%), heparin (9.9%) or nothing (15.7%).Conclusion: Our data indicate that overall persistence with rivaroxaban therapy is high, with a discontinuation rate of approximately 15% in the first year of treatment and few additional discontinuations thereafter. Non-major bleeding is the most common reason for riaroxaban discontinuation and nearly 50% of all discontinuing patients receive only antiplatelet or no antithrombotic treatment. [Display omitted] [Display omitted] DisclosuresBeyer-Westendorf:Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding. Weiss:Boehringer Ingelheim: Honoraria; Bayer: Honoraria.

Medication persistence and discontinuation of rivaroxaban versus warfarin among patients with non-valvular atrial fibrillation

Objectives:To compare real-world persistence and discontinuation among non-valvular atrial fibrillation (NVAF) patients on rivaroxaban and warfarin in the US.Research design and methods:A large nationally representative US claims database was used to conduct a retrospective cohort analysis of patients with NVAF treated with rivaroxaban or warfarin from 1 July 2010 through 31 March 2013. Index date was the date of the first prescription of rivaroxaban or warfarin. All patients were followed until the earliest of inpatient death, end of continuous enrollment, or end of study period. Rivaroxaban patients were matched 1:1 by propensity scores. Medication persistence was defined as absence of refill gap of ≥60 days. Discontinuation was defined as no additional refill for at least 90 days and until the end of follow-up. Cox proportional hazards models were estimated to examine the adjusted hazard ratios (aHRs) of rivaroxaban vs. warfarin on non-persistence and discontinuation.Results:A total of 32,886 NVAF patients on rivaroxaban or warfarin met the study inclusion criteria. Each of the 7259 rivaroxaban patients identified were matched 1:1 to warfarin patients. Patients on rivaroxaban had a significantly better rate of persistence (aHR: 0.63, 95% CI 0.59–0.68) and lower rate of discontinuation (aHR: 0.54, 95% CI 0.49–0.58) compared to warfarin recipients.Limitations:Claims data may have contained inaccuracies and miscoding. Confounding may remain even after propensity score matching and additional adjustments in model. Refill data may not fully reflect actual medication use. Longer follow-up may produce more precise estimates of persistence and discontinuation.Conclusion:This matched cohort analysis indicated that rivaroxaban was associated with significantly higher medication persistence and lower discontinuation rates compared to warfarin.