Recurrent Venous Thromboembolism during Anticoagulation: An Investigator-Initiated Post-Hoc Analysis of the Hokusai-VTE Trial
Authors: Eichinger Sabine , Lin Min , Kyrle Paul A. , Grosso Michael A. 
Published: October 2019

Abstract
Introduction
Patients with acute venous thromboembolism (VTE) receive intensive anticoagulant treatment to reduce the risk of thrombus progression, embolization and recurrence. Nonetheless, VTE recurs in about 1-3% of patients while they are on anticoagulation. In a post-hoc analysis of the Hokusai-VTE trial we aimed to evaluate the risk of recurrent VTE during anticoagulation with heparin, edoxaban or warfarin and to identify predictors of recurrence.
Methods
The Hokusai-VTE study was a randomized, double-blind, double-dummy trial comparing edoxaban with warfarin in patients with acute VTE. Minimal treatment duration was 3 months with a maximum of 12 months, depending on the discretion of the physician. The primary efficacy outcome was objectively adjudicated recurrent symptomatic deep vein thrombosis or pulmonary embolism. In the present analysis only venous thrombotic events that occurred from the first dose to the last dose plus 3 days of anticoagulation were considered. Rates of recurrent VTE during anticoagulation are reported. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) for edoxaban versus warfarin were calculated based on a Cox proportional hazard model with stratification factors as covariates.
Results
A total of 8240 patients received at least one dose of study drug, 4118 were assigned to edoxaban and 4122 to warfarin. 147 of 8240 patients (1.8%) had a recurrent VTE during anticoagulation. In 80 (54%) patients recurrence occurred within the first 30 days, 39 of those during heparin lead-in. There were 13 VTE-related deaths during the first 30 days; 4 of those during heparin lead-in. Patients with recurrence did not significantly differ from those without recurrence as regards age, sex, location of index VTE, renal function, right ventricular function, dose of edoxaban, or history of cancer or previous VTE. The risk of recurrence during anticoagulation was numerically lower in patients receiving edoxaban compared to those receiving warfarin [1.6% vs. 1.9%; HR 0.84 (95% CI 0.61, 1.16)] (Figure). The mean time in therapeutic range was lower in warfarin treated patients with recurrence compared to those without recurrence (56% vs 64%), but the proportion of patients with INR greater than 3.0 was higher in those who recurred compared to those who did not (26% vs 17%).
Conclusions
The risk of recurrent VTE during anticoagulation is considerable and particularly high during the first month and heparin lead-in. The risk is lower in patients treated with edoxaban compared to warfarin. Predictors of recurrence during VTE remain to be identified.

Disclosures
Lin: Daiichi-Sankyo: Employment. Kyrle:Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Grosso:Daiichi-Sankyo: Employment.