One-Year Adherence to Warfarin Treatment for Venous Thromboembolism in High-Risk Patients and Its Association with Long-term Risk of Recurrent Events

    AUTHORS: Shih-Yin Chen, Ning Wu, Michael Gulseth, Joyce LaMori, Brahim K. Bookhart, Luke Boulanger, Larry Fields, Jeff Schein



    BACKGROUND: Warfarin is the predominant oral anticoagulant used for the prevention of recurrent venous thromboembolism (VTE) events. However, its long-term use is complicated by the need to manage the drug within a narrow therapeutic range and by possible food and drug interactions.
    Objective: To examine the association between 1-year adherence, measured through compliance with and persistence on warfarin treatment for VTE, and long-term risk of recurrent events among patients at high risk.
    METHODS: Medical and pharmacy claims for patients with commercial or Medicare supplemental insurance in the Thomson Reuters MarketScan database were analyzed. Adult patients with medical claims with an associated VTE diagnosis between January 1, 2006, and March 31, 2008, were identified. The index date was defined as the date of the first observed VTE claim or the date of discharge if the index event was a hospital stay. High-risk patients (patients with cancer, or noncancer patients who did not have reversible risk factors during the 3-month period prior to the index date) who filled a warfarin prescription within 2 weeks of the index date were included. Persistence was evaluated in terms of discontinuation, defined as a 90-day gap in warfarin supply during a 1-year assessment period following the index date. Compliance was measured by the proportion of days covered (PDC) over the 1-year assessment period, with PDC < 0.8 defined as noncompliance. Recurrent VTE events were identified as hospitalizations where VTE was the primary diagnosis after the 1-year assessment period and until patients were lost to follow-up. The association between adherence to warfarin therapy and VTE recurrence was evaluated descriptively via Kaplan-Meier curves and a Cox proportional hazards model, adjusted for patient demographic and clinical characteristics. A similar analysis using the medication possession ratio (MPR) as a measure of compliance was also performed in a subset of patients who had filled at least 2 warfarin prescriptions. 
    RESULTS: The study included 8,040 VTE patients identified as being at high risk of recurrence (mean age 61 years, 59.4% male), of whom 76.9% were not compliant with warfarin therapy based on PDC, and 51.5% discontinued therapy. Among those with at least 2 warfarin prescriptions (n = 7612), 34.1% of high-risk patients were not compliant with warfarin therapy between the first and last refills based on MPR. Kaplan-Meier curves showed that patients who were compliant or continued warfarin therapy were less likely to experience a VTE event (all P < 0.05). Noncompliant patients had a 3 times greater risk of VTE recurrence than compliant patients, based on PDC (hazard ratio [HR] = 3.01, 95% confidence interval [CI]: 1.28-4.97). Among the subpopulation who filled at least 2 warfarin prescriptions, noncompliant patients (based on MPR) were also found to be more likely to have recurrent VTE events, compared with compliant patients (HR = 1.60, 95% CI: 1.18-2.16). Patients who discontinued warfarin were more likely to have recurrent VTE events compared with patients who did not discontinue on warfarin treatment (HR = 1.48, 95% CI: 1.09-2.01). 
    CONCLUSION: Adherence to a year of therapy was low in patients at high risk of recurrent VTE, even though long-term therapy should be considered in this population. Noncompliance and discontinuation of warfarin treatment over a 1-year period was associated with a higher risk of recurrent VTE. Future research should investigate and differentiate between patient and provider discontinuation to develop strategies to improve compliance and persistence with appropriate anticoagulation therapy that may potentially reduce recurrent VTE.

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