Edoxaban for the Long‐Term Therapy of Venous Thromboembolism: Should the Criteria for Dose Reduction be Revised?

Abstract

Edoxaban is used for venous thromboembolism (VTE) treatment. Real-life data are lacking about its use in long-term therapy. We aimed to assess the efficacy and the safety of edoxaban for long-term VTE treatment in a real-life setting. Patients with VTE included in the Registro Informatizado Enfermedad TromboEmbólica (RIETE) registry, receiving edoxaban 60 or 30 mg daily were prospectively followed up to validate the benefit of using different dosages. The main outcome was the composite of VTE recurrences or major bleeding in patients with or without criteria for dose reduction. Multivariable analysis to identify predictors for the composite outcome was performed. From October 2015 to November 2019, 562 patients received edoxaban for long-term therapy. Most (94%) of the 416 patients not meeting criteria for dose reduction received 60 mg daily, and 92 patients meeting criteria (63%) received 30 mg daily. During treatment, two patients developed recurrent VTE, six had major bleeding and nine died (2 from fatal bleeding). Among patients not meeting criteria for dose reduction, those receiving 30 mg daily had a higher rate of the composite event (hazard ratio (HR) 8.37; 95% confidence interval (CI) 1.12-42.4) and a significant higher mortality rate (HR 31.1; 95% CI 4.63-262) than those receiving 60 mg. Among patients meeting criteria for dose reduction, those receiving 60 mg daily had no events, and a nonsignificantly higher mortality rate (HR 5.04; 95% CI 0.54-133) than those receiving 30 mg daily. In conclusion, edoxaban seems to be effective and safe for long-term VTE treatment in real life. Criteria for dose reduction should be reformulated. Current guidelines of antithrombotic therapy, 1,2 based on the evidence from randomized trials, 3-7 recommend the use of direct oral anticoagulants (DOACs) as initial and long-term therapy in patients with venous thromboembolism (VTE). However, the pivotal trials where their indication was based applied strict exclusion criteria, aimed to exclude patients with a presumed high risk of bleeding. The International Regulatory Authorities encourage the pharmaceutical companies to develop postauthorization safety studies that should start shortly after the approval of the

Efficacy and Safety Considerations With Dose-Reduced Direct Oral Anticoagulants

“…In the RIETE registry, as of July 2021, among 4716 patients treated with DOACs for acute VTE, 475 (10%) received a lower-than-recommended dose for short-term treatment. Use of DOACs was assessed in some prior studies from RIETE . In a study of 999 fragile patients with VTE (defined by history of recent major bleeding, severe kidney dysfunction, liver failure, or thrombocytopenia) 180 patients receiving rivaroxaban (25%) and 114 patients receiving apixaban (40%) were given nonrecommended doses .…”

“…In a study of 999 fragile patients with VTE (defined by history of recent major bleeding, severe kidney dysfunction, liver failure, or thrombocytopenia) 180 patients receiving rivaroxaban (25%) and 114 patients receiving apixaban (40%) were given nonrecommended doses . Among 562 patients treated with edoxaban, 23 (5.5%) received nonrecommended dose reduction (ie, 30 mg once daily) …”

“…Areas of knowledge gap include whether low-intensity DOACs should be used instead of full-intensity regimens among fragile patients who have high risk for both thrombotic and hemorrhagic complications and how to use DOACs for isolated distal deep vein thrombosis. In these scenarios, while awaiting high-quality evidence, large registries indicate variations in treatment regimens …”