Impact of Prolonged Anticoagulation with Rivaroxaban on Provoked Venous Thromboembolism Recurrence: The Improve-VTE Study
Authors: Coleman Craig I. , Turpie Alexander G. , Bunz Thomas J. , Beyer-Westendorf Jan , Baker William L 
Published: October 2019

Abstract
Background: The optimal duration of anticoagulation following an incident provoked venous thromboembolism (VTE) remains unclear. Two randomized trials have shown extended duration rivaroxaban use in patients experiencing an unprovoked or provoked VTE can reduce patients' risk of recurrent thrombosis without a significant increased risk of major bleeding compared to placebo or aspirin.
Objectives: We sought to evaluate the real-world effectiveness and safety of prolonged anticoagulation with rivaroxaban following an incident provoked VTE.
Methods: Using claims data from the US Truven MarketScan databases from November 1, 2012 through March 31, 2017, we identified adult patients with a primary discharge diagnosis of VTE (deep vein thrombosis and/or pulmonary embolism) during a hospitalization or emergency department visit, who had a provoking (major or minor, persistent or transient) risk factor, at least 3-months of continuous rivaroxaban treatment and ≥12-months of continuous medical and prescription insurance benefits prior to their incident VTE. Patients were categorized as either continuing rivaroxaban or discontinuing anticoagulation (no anticoagulation or antiplatelet agents, with or without aspirin) after the initial 3-months of rivaroxaban treatment (index date). Differences in baseline covariates between cohorts were adjusted for using inverse probability-of-treatment weights (IPTW) based on propensity-scores (residual standardized differences <0.1 achieved for all covariates after adjustment). Study endpoints included recurrent VTE and major bleeding (per the Cunningham algorithm). Patients were followed until occurrence of an endpoint, insurance disenrollment or up to 12-months post-index date. The incidences of recurrent VTE or major bleeding were compared between cohorts using Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Subgroup analyses were performed for each endpoint according to whether patients had a major persisting (i.e. cancer), minor persisting (i.e. inflammatory bowel disease, lower extremity paralysis, heart failure, stage III or worse chronic kidney disease, hereditary or acquired thrombophilia), minor transient (i.e. admitted to hospital for ≥3-consecutive days in past 3-months, hormonal therapy, pregnancy or puerperium, leg injury with impaired mobility) or major transient risk factor (i.e. major surgery or trauma).
Results: Among patients experiencing an incident provoked VTE and treated with rivaroxaban for the first 3-months (N=4,990), continued rivaroxaban use beyond 3-months [median (25%, 75% range) duration of additional rivaroxaban use = 3 (2, 5) months] was associated with a 44% lower hazard of recurrent VTE without significantly altering major bleeding risk when compared to anticoagulation discontinuation with or without aspirin use (Table). The highest risk of recurrent thrombosis following provoked VTE (3.1% in the discontinued anticoagulation cohort) appeared to occur in patients with a minor persisting risk factor; with continued rivaroxaban use associated with a significant 73% reduction in recurrent VTE.
Conclusions: Although the absolute incidence of recurrence was low, our study suggests continuing rivaroxaban after the initial 3-month period was associated with a decreased risk of recurrent VTE, particularly in those with a minor persisting risk factor. The observed reduction in recurrent VTE with prolonged rivaroxaban use was not associated with a significantly increased risk of major bleeding.

Disclosures
Coleman: Bayer AG: Consultancy, Honoraria, Research Funding; Janssen Scientific Affairs LLC: Consultancy, Honoraria, Research Funding. Turpie:Bayer AG: Consultancy, Honoraria, Research Funding; Janssen Scientific Affairs LLC: Consultancy, Speakers Bureau. Beyer-Westendorf:Boehringer-Ingelheim: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding.