The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial.

End-stage renal disease (ESRD) patients on chronic hemodialysis have repeated blood exposure to artificial surfaces that can trigger clot formation within the hemodialysis circuit. Dialyzer clotting can lead to anemia despite erythropoietin and iron supplementation. Unfractionated heparin prevents clotting during hemodialysis, but it is not tolerated by all patients. Although heparin-free dialysis is performed, intradialytic blood entrapment can be problematic. To address this issue, we performed a randomized, double-blind, phase 2 study comparing AB023, a unique antibody that binds factor XI (FXI) and blocks its activation by activated FXII, but not by thrombin, to placebo in 24 patients with ESRD undergoing heparin-free hemodialysis. Patients were randomized to receive a single predialysis dose of AB023 (0.25 or 0.5 mg/kg) or placebo in a 2:1 ratio, and safety and preliminary efficacy were compared with placebo and observations made prior to dosing within each treatment arm. AB023 administration was not associated with impaired hemostasis or other drug-related adverse events. Occlusive events requiring hemodialysis circuit exchange were less frequent and levels of thrombin-antithrombin complexes and C-reactive protein were lower after AB023 administration compared with data collected prior to dosing. AB023 also reduced potassium and iron entrapment in the dialyzers, consistent with less blood accumulation within the dialyzers. We conclude that despite the small sample size, inhibition of contact activation-induced coagulation with AB023 was well tolerated and reduced clotting within the dialyzer. This trial was registered at www.clinicaltrials.gov as #NCT03612856.

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the treatment of venous thromboembolism.

Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN-DVT and EINSTEIN-PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure-response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure-efficacy relationships were shallow. Exposure-safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.

Thromboprophylaxis with Rivaroxaban in Acutely Ill Medical Patients with Renal Impairment: Insights from the MAGELLAN and MARINER Trials.

Patients with renal impairment are at higher risk of thrombosis and bleeding than those with normal renal function. The optimal rivaroxaban dose for thromboprophylaxis in acutely ill medical patients with renal impairment is unknown. MARINER and MAGELLAN were multicenter, randomized clinical trials of rivaroxaban in acutely ill medical patients. Efficacy and safety outcomes in patients with renal impairment in MARINER (7.5 mg once daily) were compared with those in patients with normal renal function in MARINER (10 mg once daily) and in a subpopulation of MAGELLAN that excluded patients at high risk for bleeding at baseline (10 mg once daily). Compared with enoxaparin/placebo in the MAGELLAN subpopulation, the relative risk (RR) of symptomatic venous thromboembolism (VTE) and VTE-related death with rivaroxaban 10 mg in patients with renal impairment (RR = 0.62; 95% confidence interval [CI] 0.27-1.44) was similar to that in those with normal renal function (RR = 0.78; 95% CI 0.44-1.40), while in MARINER, the 7.5 mg dose did not reduce the risk in patients with renal impairment (hazard ratio = 1.00; 95% CI 0.52-1.92). Major bleeding with rivaroxaban 10 mg once daily was higher in patients with renal impairment than in those with normal renal function in MAGELLAN (1.54% vs. 0.98%) and in the MAGELLAN subpopulation (0.94% vs. 0.61%). At a dose of 10 mg once daily, rivaroxaban is effective for thromboprophylaxis in acutely ill medical patients with impaired or normal renal function. The safety of this regimen is enhanced without loss of efficacy by excluding patients at high risk for bleeding, but not by using a reduced-dose strategy. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00571649 for the MAGELLAN trial, NCT02111564 for the MARINER trial.

Rivaroxaban and Dabigatran for Suppression of Mechanical Heart Valve-Induced Thrombin Generation.

BACKGROUND: Patients with mechanical heart valves (MHVs) require warfarin to prevent thromboembolism. Dabigatran was less effective than warfarin in patients with MHVs, which prompted a black box warning against the use of direct oral anticoagulants for this indication. However, rivaroxaban and apixaban, which inhibit factor Xa, have not been evaluated in patients with MHVs. To determine whether rivaroxaban and apixaban would be effective, we used MHV-induced thrombin generation assays to compare them with warfarin either alone or in combination with dabigatran. METHODS: Thrombin generation in the absence or presence of MHV leaflets or sewing ring segments (SRSs) was quantified. Studies were done in control plasma; plasma from patients on warfarin; plasma containing varying concentrations of rivaroxaban, apixaban, or dabigatran alone; or plasma containing rivaroxaban plus dabigatran. RESULTS: Mean endogenous thrombin potential (ETP) increased 1.2-fold, 1.5-fold, and 1.8-fold in the presence of leaflets, Teflon (Terumo Aortic (Sunrise, FL)) SRSs, or Dacron (Terumo Aortic (Sunrise, FL)) SRSs, respectively. Rivaroxaban and apixaban reduced ETP at concentrations above 50 ng/mL but were less effective than warfarin. When rivaroxaban and dabigatran were combined, they suppressed ETP in a more than additive manner. CONCLUSIONS: Whereas warfarin suppresses MHV-induced thrombin generation, MHVs induce the generation of factor Xa in concentrations that overwhelm clinically relevant concentrations of rivaroxaban or apixaban. When used in combination, rivaroxaban and dabigatran are more effective than either agent is alone, suggesting that concomitant inhibition of factor Xa and thrombin is better than inhibition of either clotting enzyme alone.

Rivaroxaban plus aspirin for cardiovascular protection: Rationale for the vascular dose and dual pathway inhibition.

This review provides the rationale for dual pathway inhibition with the combination of low-dose rivaroxaban (2.5 mg twice daily) to attenuate thrombin generation and aspirin (100 mg once daily) to reduce platelet activation. Such therapy has been licensed for secondary prevention in patients with coronary or peripheral artery disease.

Antithrombotic Agents.

Recent advances in our understanding of the contribution of thrombin generation to arterial thrombosis and the role of platelets in venous thrombosis have prompted new treatment paradigms. Nonetheless, bleeding remains the major side effect of such treatments spurring the quest for new antithrombotic regimens with better benefit-risk profiles and for safer anticoagulants for existing and new indications. The aims of this article are to review the results of recent trials aimed at enhancing the benefit-risk profile of antithrombotic therapy and explain how these findings are changing our approach to the management of arterial and venous thrombosis. Focusing on these 2 aspects of thrombosis management, this article discusses 4 advances: (1) the observation that in some indications, lowering the dose of some direct oral anticoagulants reduces the risk of bleeding without compromising efficacy, (2) the recognition that aspirin is not only effective for secondary prevention of atherothrombosis but also for prevention of venous thromboembolism, (3) the finding that dual pathway inhibition with the combination of low-dose rivaroxaban to attenuate thrombin generation plus aspirin to reduce thromboxane A2-mediated platelet activation is superior to aspirin or rivaroxaban alone for prevention of atherothrombosis in patients with coronary or peripheral artery disease, and (4) the development of inhibitors of factor XI or XII as potentially safer anticoagulants.

Synergy of Dual Pathway Inhibition in Chronic Cardiovascular Disease.

Although acetylsalicylic acid is of proven benefit for secondary prevention in patients with cardiovascular disease, the risk of recurrent ischemic events remains high. Intensification of antithrombotic therapy with more potent antiplatelet drugs, dual antiplatelet therapy, or vitamin K antagonists further reduces the risk of major adverse cardiovascular events compared with acetylsalicylic acid alone but increases the risk of bleeding without reducing mortality. In patients with prior coronary artery disease or peripheral arterial disease the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial revealed that compared with acetylsalicylic acid alone, dual pathway inhibition with low-dose rivaroxaban (2.5 mg twice-daily), an oral factor Xa inhibitor, plus acetylsalicylic acid reduced major adverse cardiovascular event by 24%, major adverse limb events by 47%, and mortality by 18%. Major bleeding was increased by 70%, but there was no increase in fatal or intracranial bleeding. This article (1) reviews the results of the COMPASS trial, (2) explains why dual pathway inhibition is superior to antiplatelet or anticoagulant therapy alone, (3) compares the results with rivaroxaban plus aspirin with those with other antithrombotic regimens, and (4) provides insight into how best to apply the COMPASS results into practice.

Rivaroxaban for prevention and treatment of venous thromboembolism.

Until recently, heparins and vitamin K antagonists (VKAs) were the cornerstones for prevention and treatment of venous thromboembolism (VTE). This situation changed with the introduction of the direct oral anticoagulants, which are now replacing low-molecular-weight heparin for thromboprophylaxis after elective hip or knee arthroplasty and VKAs for VTE treatment. Rivaroxaban, an oral factor Xa inhibitor, was the first direct oral anticoagulant licensed for VTE prevention and treatment. This paper provides the rationale for factor Xa as a target for anticoagulants, describes the development of rivaroxaban, reviews its pharmacological profile, discusses the clinical trials with rivaroxaban for VTE prevention and treatment and highlights areas of uncertainty.

Long-Term Management of Venous Thromboembolism: Lessons from EINSTEIN CHOICE and Other Extension Trials.

Many patients with venous thromboembolism (VTE) are at risk of recurrence if anticoagulant therapy is stopped. Whereas 3 months of anticoagulation treatment is sufficient for patients with VTE provoked by major surgery or trauma, in many cases a longer course is needed. Extended therapy with vitamin K antagonists (VKAs) requires frequent coagulation monitoring and dose adjustments to ensure that the international normalized ratio (INR) remains within the therapeutic range; furthermore, there is a risk of major bleeding even if a therapeutic INR is maintained. Therefore, more convenient and safer anticoagulants are needed.The non-VKA oral anticoagulants (NOACs)-apixaban, dabigatran, edoxaban and rivaroxaban-simplify extended therapy because they can be given in fixed doses without routine coagulation monitoring. Randomized clinical trials have demonstrated the efficacy and safety of NOACs for extended VTE treatment, but bleeding remains a concern. Patients and physicians may, therefore, be reluctant to continue anticoagulation beyond 3 to 6 months except in patients at high risk of recurrence. Acetylsalicylic acid (ASA) is often prescribed instead of an anticoagulant because of its perceived lower risk of bleeding; however, the recent EINSTEIN CHOICE trial demonstrated that once-daily rivaroxaban at a dose of either 20 or 10 mg reduced the risk of recurrent VTE by 70% compared with ASA without significantly increasing the risk of bleeding. In this review, we discuss the EINSTEIN CHOICE trial in the context of previous trials for extended VTE treatment and examine some of the lessons that can be applied to clinical practice.

The Non-Vitamin K Antagonist Oral Anticoagulants in Heart Disease: Section V-Special Situations.

Non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban and rivaroxaban, which inhibit factor Xa. In large clinical trials comparing the NOACs with the vitamin K antagonist (VKA) warfarin, dabigatran, apixaban, rivaroxaban and edoxaban were at least as effective for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, but were associated with less intracranial bleeding. In addition, the NOACs are more convenient to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. Consequently, the NOACs are now replacing VKAs for these indications, and their use is increasing. Although, as a class, the NOACs have a favourable benefit-risk profile compared with VKAs, choosing among them is complicated because they have not been compared in head-to-head trials. Therefore, selection depends on the results of the individual trials, renal function, the potential for drug-drug interactions and preference for once- or twice-daily dosing. In addition, several 'special situations' were not adequately studied in the dedicated clinical trials. For these situations, knowledge of the unique pharmacological features of the various NOACs and judicious cross-trial comparison can help inform prescription choices. The purpose of this position article is therefore to help clinicians choose the right anticoagulant for the right patient at the right dose by reviewing a variety of special situations not widely studied in clinical trials.

Advances in Antithrombotic Therapy.

Thrombosis remains a major cause of morbidity and mortality. Consequently, advances in antithrombotic therapy are needed to reduce the disease burden. This article focuses on 2 such advances. First, the prevention of atherothrombosis in patients with coronary or peripheral artery disease, which has been enhanced by the finding that the combination of low-dose rivaroxaban plus aspirin is superior to aspirin alone for prevention of recurrent ischemic events. However, this benefit comes at the cost of increased bleeding albeit not fatal bleeding. To overcome this problem, the second advance is the identification of factor XI as a target for new anticoagulants that are potentially safer than those currently available.

Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness.

BACKGROUND: Patients who are hospitalized for medical illness remain at risk for venous thromboembolism after discharge, but the role of extended thromboprophylaxis in the treatment of such patients is a subject of controversy. METHODS: In this randomized, double-blind trial, medically ill patients who were at increased risk for venous thromboembolism on the basis of a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (scores range from 0 to 10, with higher scores indicating a higher risk of venous thromboembolism) or a score of 2 or 3 plus a plasma d-dimer level of more than twice the upper limit of the normal range (defined according to local laboratory criteria) were assigned at hospital discharge to either once-daily rivaroxaban at a dose of 10 mg (with the dose adjusted for renal insufficiency) or placebo for 45 days. The primary efficacy outcome was a composite of symptomatic venous thromboembolism or death due to venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: Of the 12,024 patients who underwent randomization, 12,019 were included in the intention-to-treat analysis. The primary efficacy outcome occurred in 50 of 6007 patients (0.83%) who were given rivaroxaban and in 66 of 6012 patients (1.10%) who were given placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.52 to 1.09; P=0.14). The prespecified secondary outcome of symptomatic nonfatal venous thromboembolism occurred in 0.18% of patients in the rivaroxaban group and 0.42% of patients in the placebo group (hazard ratio, 0.44; 95% CI, 0.22 to 0.89). Major bleeding occurred in 17 of 5982 patients (0.28%) in the rivaroxaban group and in 9 of 5980 patients (0.15%) in the placebo group (hazard ratio, 1.88; 95% CI, 0.84 to 4.23). CONCLUSIONS: Rivaroxaban, given to medical patients for 45 days after hospital discharge, was not associated with a significantly lower risk of symptomatic venous thromboembolism and death due to venous thromboembolism than placebo. The incidence of major bleeding was low. (Funded by Janssen Research and Development; MARINER ClinicalTrials.gov number, NCT02111564 .).

The prothrombin time does not predict the risk of recurrent venous thromboembolism or major bleeding in rivaroxaban-treated patients.

INTRODUCTION: For treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), rivaroxaban is given in fixed doses without routine coagulation monitoring. PATIENTS AND METHODS: To determine whether monitoring would enhance its benefit-risk profile, we examined whether peak and trough prothrombin time (PT) values measured in 3797 rivaroxaban-treated patients included in the EINSTEIN DVT and PE studies correlated with subsequent recurrent VTE and major bleeding. In addition, we examined the stability of PT values over time and the impact of clinical variables on PT values. RESULTS: The mean peak PT values at months 3 and 6 or 12 were 21.9 ±â€¯5 and 21.7 ±â€¯6.0 s, respectively, while the mean trough PT values at months 2 and 6 were 15.1 ±â€¯5.1 and 15.3 ±â€¯2.9 s, respectively. Although peak and through PT values were higher in females, and with older age, frailty, active cancer, low body weight, impaired renal function and use of moderate to strong inhibitors of CYP3A4 and/or P-glycoprotein, and were lower in patients taking strong CYP 3A4 inducers, the differences were small and results were overlapping. Neither peak nor trough PT values correlated with recurrent VTE or major bleeding. CONCLUSIONS: PT monitoring is unlikely to improve the benefit-risk profile of rivaroxaban in patients with DVT or PE. The study was registered at www.clinicaltrials.gov as #NCT00440193 (EINSTEIN-DVT) and #NCT00439777 (EINSTEIN-PE).

Benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin.

BACKGROUND: Full- or lower-dose anticoagulant therapy or aspirin can be used for extended therapy in patients with venous thromboembolism (VTE), but information on their relative benefit-risk profiles is limited. METHODS: Data from the EINSTEIN-CHOICE trial were used to compare the benefit-risk profiles of extended treatment with rivaroxaban (20 or 10 mg once daily) and aspirin (100 mg once daily) in VTE patients who had completed 6 to 12 months of anticoagulation therapy. One-year cumulative incidences of recurrent VTE and major bleeding were estimated and benefits and risks were calculated by determining the between group differences in a hypothetical population of 10,000 VTE patients treated for 1 year. FINDINGS: A total of 1107 patients were treated with 20 mg of rivaroxaban, 1127 with 10 mg of rivaroxaban, and 1131 with aspirin. The cumulative incidences of recurrent VTE in the rivaroxaban 20-mg, rivaroxaban 10-mg and aspirin groups were 1.9%, 1.6%, and 5.0%, respectively, whereas the cumulative incidences of major bleeding were 0.7%, 0.4% and 0.5%, respectively. The incidences of the combined outcome of recurrent VTE and major bleeding were 2.8% and 3.4% lower in the rivaroxaban 20-mg and 10-mg groups than in the aspirin group. For 10,000 patients treated for 1 year, there would be 284 (95% confidence interval [CI] 106 to 462) and 339 (95% CI 165 to 512) fewer events with rivaroxaban 20 mg or 10 mg than with aspirin. INTERPRETATION: Compared with aspirin, extended anticoagulation with once daily rivaroxaban reduces recurrent VTE with a favourable benefit-risk profile. FUNDING: Bayer AG.

Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source.

BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001). CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

Risk of recurrent venous thromboembolism according to baseline risk factor profiles.

The optimal duration of anticoagulation for venous thromboembolism (VTE) is uncertain. In this prespecified analysis, we used data from 2 randomized trials, which compared once-daily rivaroxaban (20 mg or 10 mg) with aspirin (100 mg) or placebo for extended VTE treatment to estimate the risk of recurrence according to baseline risk factor profiles. Index VTE events were centrally classified as unprovoked, or provoked by major transient or persistent, or minor transient or persistent risk factors, and rates of recurrence at 1 year were calculated. A total of 2832 patients received rivaroxaban; 1131 received aspirin, and 590 received placebo. With unprovoked VTE, rates of recurrence in the 1173 patients given rivaroxaban, the 468 given aspirin, and the 243 given placebo were 2.0%, 5.9%, and 10.0%, respectively. There were no recurrences in patients with VTE provoked by major transient risk factors. With VTE provoked by minor persistent risk factors, recurrence rates in the 1184 patients given rivaroxaban, the 466 given aspirin, and the 248 given placebo were 2.4%, 4.5%, and 10.7%, respectively. For patients with minor transient risk factors, recurrence rates were 0.4% in the 268 patients given rivaroxaban, 4.2% in the 121 given aspirin, and 7.1% in the 56 given placebo. Recurrence rates in patients with VTE provoked by minor persistent or minor transient risk factors were not significantly lower than that with unprovoked VTE (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.56-1.16; and HR, 0.68; 95% CI, 0.32-1.30, respectively). Therefore, such patients may also benefit from extended anticoagulation therapy.

Treatment Challenges in Venous Thromboembolism: An Appraisal of Rivaroxaban Studies.

Venous thromboembolism (VTE) presents a continuing clinical burden to healthcare systems and there are patient groups for whom VTE management is challenging. Depending on the patient profile, the optimal duration of anticoagulation for VTE treatment can be unclear. EINSTEIN CHOICE was a Phase III, randomized, double-blind trial that compared the safety and efficacy of two once-daily (od) doses of the direct, oral factor Xa inhibitor rivaroxaban (20 and 10 mg) with acetylsalicylic acid (ASA; 100 mg daily) for prevention of recurrent VTE. Extended therapy with rivaroxaban at either dose was more effective than ASA at preventing recurrent VTE without increasing bleeding risk. Another group that is challenging to treat in the context of VTE is patients with cancer-associated thrombosis. Cancer is associated with a hypercoagulable state, while cancer treatment itself may increase VTE risk. Evidence supporting the use of non-vitamin K antagonist oral anticoagulants in patients with cancer is growing through specifically designed studies. Cancer Associated thrombosis-expLoring soLutions for patIentS through Treatment and prevention with rivarOxaban (CALLISTO) is an international research program exploring the role of rivaroxaban for the prevention and treatment of cancer-associated thrombosis. Here, we present overviews of three CALLISTO studies: PRO-LAPS II, CASTA-DIVA and COSIMO. Currently available and anticipated results from studies in a variety of patients at risk of or with VTE will provide valuable insights and seek to optimize future VTE management.

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism.

BACKGROUND: Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin. METHODS: In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. RESULTS: A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups. CONCLUSIONS: Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439 .).