Effectiveness and safety of rivaroxaban versus warfarin in patients with unprovoked venous thromboembolism: A propensity-score weighted administrative claims cohort study

      Highlights

      • VTE treatment effectiveness of rivaroxaban vs. VKA needs confirmation in real-world.
      • In 36,853 unprovoked VTE cases rivaroxaban demonstrated reduced complication rates.
      • This finding was robust across several sensitivity analyses.

      Abstract

      Background

      In phase III trials, rivaroxaban demonstrated non-inferiority over enoxaparin/warfarin to prevent recurrent venous thromboembolism (VTE), with a reduction of major bleeding. However, compared to provoked VTE, the risk-benefit ratio of rivaroxaban may be different for patients with unprovoked VTE.

      Methods

      In a retrospective claims data analysis using US MarketScan claims from 1/2012 to 12/2016, we included adults with a primary diagnosis of VTE newly-initiated on rivaroxaban or warfarin within 30-days of the incident VTE and with ≥12-months of continuous insurance benefits prior to the VTE (baseline). Patients with provoked VTE, a claim for anticoagulation during baseline or who redeemed prescriptions for ≥1 oral anticoagulant were excluded. Our primary outcomes were recurrent VTE and major bleeding at 6-months using an intention-to-treat (ITT) analysis. Three-month ITT and 12-month on-treatment (30-day permissible gap) analyses were also performed. Inverse probability-of-treatment weights based on propensity-scores and Cox regression were used to compare outcomes.

      Findings

      We identified 10,489 rivaroxaban users and 26,364 warfarin users with incident unprovoked VTE. At 6-months, rivaroxaban was associated with a hazard ratio (HR) of 0.60 (95% confidence interval [CI] = 0.54–0.67) for recurrent VTE (number-needed-to-treat: 59; 95%CI 49–76) and a HR = 0.80 (95% CI = 0.66–0.98) for major bleeding versus warfarin. Our findings remained consistent in the 3- and 12-month analyses.

      Interpretation

      Consistent with the results from the EINSTEIN phase-III trials, findings of our routine practice study suggest that, in patients with unprovoked VTE, rivaroxaban has the potential to reduce both the risk of major bleeding and recurrent VTE compared to warfarin.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Thrombosis Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Goldhaber S.Z.
        Preventing pulmonary embolism and deep vein thrombosis: a ‘call to action’ for vascular medicine specialists.
        J. Thromb. Haemost. 2007; 5: 1607-1609
        • Kearon C.
        • Akl E.A.
        • Ornelas J.
        • Blaivas A.
        • Jimenez D.
        • Bounameaux H.
        • et al.
        Antithrombotic therapy for vte disease: chest guideline and expert panel report.
        Chest. 2016; 149: 315-352
        • Limone B.L.
        • Hernandez A.V.
        • Michalak D.
        • Bookhart B.K.
        • Coleman C.I.
        Timing of recurrent venous thromboembolism early after the index event: a meta-analysis of randomized controlled trials.
        Thromb. Res. 2013; 132: 420-426
        • Coleman C.I.
        • Baugh C.
        • Crivera C.
        • Milentijevic D.
        • Wang S.W.
        • Lu L.
        • et al.
        Healthcare costs associated with rivaroxaban or warfarin use for the treatment of venous thromboembolism.
        J. Med. Econ. 2017; 20: 200-203
        • Prandoni P.
        • Lensing A.W.A.
        • Cogo A.
        • Cuppini S.
        • Villalta S.
        • Carta M.
        • et al.
        The long-term clinical course of acute deep venous thrombosis.
        Ann. Intern. Med. 1996; 125: 1-7
        • Douketis J.
        • Tosetto A.
        • Marcucci M.
        • Baglin T.
        • Cosmi B.
        • Cushman M.
        • et al.
        Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis.
        BMJ. 2011; 342: d813
        • Prins M.H.
        • Lensing A.W.
        • Bauersachs R.
        • van Bellen B.
        • Bounameaux H.
        • Brighton T.A.
        • et al.
        Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies.
        Thromb. J. 2013; 11: 21
        • Larsen T.B.
        • Skjoth F.
        • Kjaeldgaard J.N.
        • Lip G.Y.H.
        • Nielsen P.B.
        • Sogaard M.
        Effectiveness and safety of rivaroxaban and warfarin in patients with unprovoked venous thromboembolism: a propensity-matched nationwide cohort study.
        Lancet Haematol. 2017; 4: e237-e244
        • Beyer-Westendorf J.
        • Lensing A.W.
        • Arya R.
        • Bounameaux H.
        • Cohen A.T.
        • Wells P.S.
        • et al.
        Choosing wisely: the impact of patient selection on efficacy and safety outcomes in the EINSTEIN-DVT/PE and AMPLIFY trials.
        Thromb. Res. 2017; 149: 29-37
        • Benchimol E.I.
        • Smeeth L.
        • Guttmann A.
        • Harron K.
        • Moher D.
        • Petersen I.
        • et al.
        The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement.
        PLoS Med. 2015; 12e1001885
      1. Truven Health Analytics. MarketScan research databases.

        • Fang M.C.
        • Fan D.
        • Sung S.H.
        • Witt D.M.
        • Schmelzer J.R.
        • Steinhubl S.R.
        • et al.
        Validity of using inpatient and outpatient administrative codes to identify acute venous thromboembolism: the CVRN VTE study.
        Med. Care. 2017; 55: e137-e143
        • Ray W.A.
        Evaluating medication effects outside of clinical trials: new-user designs.
        Am. J. Epidemiol. 2003; 158: 915-920
        • Cunningham A.
        • Stein C.M.
        • Chung C.P.
        • Daugherty J.R.
        • Smalley W.E.
        • Ray W.A.
        An automated database case definition for serious bleeding related to oral anticoagulant use.
        Pharmacoepidemiol. Drug Saf. 2011; 20: 560-566
        • Austin P.C.
        An introduction to propensity score methods for reducing the effects of confounding in observational studies.
        Multivar. Behav. Res. 2011; 46: 399-424
        • Moore B.J.
        • White S.
        • Washington R.
        • Coenen N.
        • Elixhauser A.
        Identifying increased risk of readmission and in-hospital mortality using hospital administrative data: the AHRQ Elixhauser Comorbidity Index.
        Med. Care. 2017; 55: 698-705
        • Buller H.R.
        • Decousus H.
        • Grosso M.A.
        • Mercuri M.
        • Middeldorp S.
        • Prins M.H.
        • et al.
        Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
        N. Engl. J. Med. 2013; 369: 1406-1415
        • Schulman S.
        • Kakkar A.K.
        • Goldhaber S.Z.
        • Schellong S.
        • Eriksson H.
        • Mismetti P.
        • et al.
        Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis.
        Circulation. 2014; 129: 764-772
        • Coleman C.V.T.
        • Nguyen E.
        • Weeda E.R.
        • Sood N.A.
        • Bunz T.J.
        • et al.
        Do coding schemas used to identify bleeding-related hospitalizations in claims analyses of nonvalvular atrial fibrillation patients agree?.
        Circulation. 2017; 136: A16541
        • Ageno W.
        • Mantovani L.G.
        • Haas S.
        • Kreutz R.
        • Monje D.
        • Schneider J.
        • et al.
        Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study.
        Lancet Haematol. 2016; 3: e12-e21
        • Kucher N.
        • Aujesky D.
        • Beer J.H.
        • Mazzolai L.
        • Baldi T.
        • Banyai M.
        • et al.
        Rivaroxaban for the treatment of venous thromboembolism. The SWIss Venous ThromboEmbolism Registry (SWIVTER).
        Thromb. Haemost. 2016; 116: 472-479
        • Trujillo-Santos J.
        • Di Micco P.
        • Dentali F.
        • Douketis J.
        • Diaz-Peromingo J.A.
        • Nunez M.J.
        • et al.
        Real-life treatment of venous thromboembolism with direct oral anticoagulants: the influence of recommended dosing and regimens.
        Thromb. Haemost. 2017; 117: 382-389
        • Gaertner S.
        • Cordeanu E.M.
        • Nouri S.
        • Faller A.M.
        • Frantz A.S.
        • Mirea C.
        • et al.
        Rivaroxaban versus standard anticoagulation for symptomatic venous thromboembolism (REMOTEV observational study): analysis of 6-month outcomes.
        Int. J. Cardiol. 2017; 226: 103-109
        • Coleman C.I.
        • Fermann G.J.
        • Weeda E.R.
        • Wells P.S.
        • Ashton V.
        • Crivera C.
        • et al.
        Is rivaroxaban associated with shorter hospital stays and reduced costs versus parenteral bridging to warfarin among patients with pulmonary embolism?.
        Clin. Appl. Thromb. Hemost. 2017; 23: 830-837
        • Sindet-Pedersen C.
        • Langtved Pallisgaard J.
        • Staerk L.
        • Gerds T.A.
        • Fosbol E.L.
        • Torp-Pedersen C.
        • et al.
        Comparative safety and effectiveness of rivaroxaban versus VKAs in patients with venous thromboembolism. A Danish nationwide registry-based study.
        Thromb. Haemost. 2017; 117: 1182-1191
        • Gandhi S.
        • Salmon J.W.
        • Kong S.X.
        • Zhao S.Z.
        Administrative databases and outcomes assessment: an overview of issues and potential utility.
        J. Manag. Care Pharm. 1999; 5: 215-222
        • Baglin T.
        • Luddington R.
        • Brown K.
        • Baglin C.
        Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study.
        Lancet. 2003; 362: 523-526