Derivation of the non-inferiority margin for the evaluation of direct oral anticoagulants in the treatment of venous thromboembolism

BACKGROUND: Direct oral anticoagulants that target a single coagulation factor have been developed as an alternative to standard therapies with heparin and/or vitamin K antagonists. The purpose of this study was to derive non-inferiority margins suitable for randomised clinical studies designed to evaluate these agents for the treatment of venous thromboembolism (VTE). METHODS: We performed a systematic review to derive non-inferiority margins suitable for use in studies evaluating direct oral anticoagulants for the treatment of VTE. A PubMed search identified publications that evaluated current standard treatment versus placebo, ‘no treatment’ or ‘less intensive treatment’ in patients with symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Publications were eligible if they had a randomised study design, included patients with symptomatic DVT and/or PE, used objective diagnostic methods to document the index event and reported objectively confirmed symptomatic recurrent VTE. RESULTS: Fourteen publications were included in the analysis. Recurrent VTE occurred in 25 (1.5%) out of 1715 patients who received current standard of care and in 157 (9.2%) out of 1711 patients who received placebo, ‘no treatment’ or ‘less intensive treatment’, for an odds ratio of 0.18 (95% confidence interval, 0.14−0.25; test for heterogeneity, p=0.87). In order to preserve 50% or 75% of the established treatment effect using a linear scale, the corresponding thresholds for non-inferiority equalled 2.50 and 1.75, respectively. CONCLUSIONS: This systematic review and statistical approach determined non-inferiority margins suitable for use in studies of direct oral anticoagulants for the treatment of DVT and/or PE

Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism : a pooled analysis of the EINSTEIN-DVT and PE randomized studies

Background: Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects. Methods: A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15 mg twice-daily for 21 days, followed by 20 mg once-daily) with standard-therapy (enoxaparin 1.0 mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12 months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75. Results: 8282 patients were enrolled. 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 rivaroxaban-treated patients (2.1%) compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66-1.19; pnoninferiority<0.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37-0.79; p=0.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban was similar compared with standard-therapy. Conclusion: The single-drug approach with rivaroxaban resulted in similar efficacy to standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups

Choosing wisely: The impact of patient selection on efficacy and safety outcomes in the EINSTEIN-DVT/PE and AMPLIFY trials

The results of the EINSTEIN-DVT/PE and AMPLIFY trials, which compared rivaroxaban and apixaban with conventional anticoagulation therapy for acute venous thromboembolism (VTE), respectively, are often compared. However, the trials differed in duration of therapy (3-12 and 6months, respectively) and in patient selection (few exclusion criteria and more stringent exclusion criteria, respectively).publisher: Elsevier articletitle: Choosing wisely: The impact of patient selection on efficacy and safety outcomes in the EINSTEIN-DVT/PE and AMPLIFY trials journaltitle: Thrombosis Research articlelink: http://dx.doi.org/10.1016/j.thromres.2016.11.014 content_type: article copyright: © 2016 Elsevier Ltd. All rights reserved.status: publishe

Long-term anticoagulation with rivaroxaban for preventing recurrent VTE:A benefit–risk analysis of EINSTEIN EXTENSION

Background:Short-term anticoagulant treatment for acute deep-vein thrombosis (DVT) or pulmonary embolism (PE) effectively reduces the risk of recurrent disease during the first 6 to 12 months of therapy. Continued anticoagulation is often not instituted because of the perception among physicians that the risk of major bleeding will outweigh the risk of new venous thrombotic episodes. Methods:Benefit-risk analysis using the randomized EINSTEIN-EXTENSION trial, which compared continued rivaroxaban versus placebo in 1197 patients with symptomatic DVT or PE who had completed 6-12 months of anticoagulation and in whom physicians had equipoise with respect to the need for continued anticoagulation. One-year Kaplan-Meier rates and rate differences of recurrent venous thromboembolism (VTE) and major bleeding were calculated. Benefits and risks were assessed using rate differences scaled to a population size of 10000 patients treated for 1 year. Results:Recurrent VTE occurred in 8 (3.0%) rivaroxaban recipients and 42 (9.6%) placebo patients. In a population of 10000 patients treated for 1 year, rivaroxaban treatment would have resulted in 665 (95% CI 246-1084) fewer recurrent VTEs than placebo (number needed to treat=15). Major bleeding occurred in 4 (0.7%) and 0 patients, respectively. Rivaroxaban treatment would have resulted in 68 (95% CI 2-134) more major bleeding events than placebo (number needed to harm=147). Kaplan–Meier analysis showed early recurrent VTE reduction with rivaroxaban that continued to improve throughout treatment; major bleeding increased gradually, plateauing at ±100 days. Conclusions:A clinically important benefit and a favorable benefit–risk profile of continued rivaroxaban anticoagulation was observed

Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism

Patients with unprovoked venous thromboembolism (VTE) are at high risk for recurrence. Although rivaroxaban is effective for extended VTE treatment at a dose of 20 mg once daily, use of the 10 mg dose may further improve its benefit-to-risk ratio. Low-dose aspirin also reduces rates of recurrent VTE, but has not been compared with anticoagulant therapy. The EINSTEIN CHOICE study is a multicentre, randomised, double-blind, active-controlled, event-driven study comparing the efficacy and safety of two once daily doses of rivaroxaban (20 and 10 mg) with aspirin (100 mg daily) for the prevention of recurrent VTE in patients who completed 6-12 months of anticoagulant therapy for their index acute VTE event. All treatments will be given for 12 months. The primary efficacy objective is to determine whether both doses of rivaroxaban are superior to aspirin for the prevention of symptomatic recurrent VTE, while the principal safety outcome is the incidence of major bleeding. The trial is anticipated to enrol 2,850 patients from 230 sites in 31 countries over a period of 27 months. In conclusion, the EINSTEIN CHOICE study will provide new insights into the optimal antithrombotic strategy for extended VTE treatment by comparing two doses of rivaroxaban with aspirin (clinicaltrials.gov NCT02064439).status: publishe

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.status: publishe

Long-term risk of major bleeding after discontinuing anticoagulation for unprovoked venous thromboembolism: a systematic review and meta-analysis.

BACKGROUND The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. OBJECTIVES To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE. METHODS We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked VTE who had completed ≥3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies. RESULTS Of 1123 records identified by the search, 20 studies (17 RCTs) and 8740 patients were included in the analysis. During 13 011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding (n=41) and fatal bleeding (n=7) per 100 person-years was 0.35 (95% confidence interval [CI], 0.20-0.54) and 0.09 (95% CI, 0.05-0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI, 0.4%-2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI, 10.6%-31.1%). CONCLUSIONS Patients with a first unprovoked VTE have a non-trivial risk of major bleeding once anticoagulants are discontinued. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE