Effectiveness and Safety of Direct Oral Anticoagulants Among Octogenarians with Venous Thromboembolism: An International Multidatabase Cohort Study

Published:September 20, 2022DOI:



      The effects of direct oral anticoagulants (DOACs) among octogenarian patients with venous thromboembolism remains poorly understood. To address this knowledge gap, our study aimed to assess the effectiveness and safety of DOACs compared to vitamin K antagonists (VKAs) among octogenarians with venous thromboembolism.


      We conducted an international cohort study using administrative health care databases from Québec, Canada, and Germany. We assembled 2 population-based cohorts of octogenarians with incident venous thromboembolism initiating treatment with DOACs or VKAs. The study period spanned from January 2012 to the most recent date of data availability (Québec: December 2016; Germany: December 2019). Using an as-treated exposure definition, we compared use of DOACs to use of VKAs, applying inverse probability of treatment weighting based on high-dimensional propensity scores to balance exposure groups. Cox proportional hazards models estimated site-specific hazard ratios (HRs) and 95% confidence intervals (CIs) of recurrent venous thromboembolism, major bleeding, and all-cause mortality. The results were meta-analyzed using random-effects models.


      Overall, our study included 6737 octogenarians with venous thromboembolism (Québec: n = 2556; Germany: n = 4181) who initiated use of DOACs (n = 3778) or VKAs (n = 2959). When compared to VKAs, DOACs were associated with similar risks of recurrent venous thromboembolism (weighted HR, 0.80; 95% CI, 0.43-1.46; I2 = 0.00), major bleeding (weighted HR, 0.96; 95% CI, 0.57-1.63; I2 = 0.59), and all-cause mortality (weighted HR, 1.04; 95% CI, 0.81-1.34; I2 = 0.00).


      Among octogenarians with venous thromboembolism, DOACs showed a comparable effectiveness and safety compared to VKAs. Our results support the use of DOACs in this high-risk group.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      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 to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Silverstein MD
        • Heit JA
        • Mohr DN
        • Petterson TM
        • O'Fallon WM
        • Melton III, LJ
        Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.
        Arch Intern Med. 1998; 158: 585-593
        • Heit JA
        • Mohr DN
        • Silverstein MD
        • Petterson TM
        • O'Fallon WM
        • Melton 3rd, LJ
        Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.
        Arch Intern Med. 2000; 160: 761-768
        • Anderson Jr., FA
        • Wheeler HB
        • Goldberg RJ
        • et al.
        A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study.
        Arch Intern Med. 1991; 151: 933-938
        • Pisters R
        • Lane DA
        • Nieuwlaat R
        • de Vos CB
        • Crijns HJ
        • Lip GY.
        A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
        Chest. 2010; 138: 1093-1100
        • Kearon C
        • Akl EA
        • Ornelas J
        • et al.
        Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report.
        Chest. 2016; 149: 315-352
        • Ortel TL
        • Neumann I
        • Ageno W
        • et al.
        American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
        Blood Adv. 2020; 4: 4693-4738
        • Schulman S
        • Kakkar AK
        • Goldhaber SZ
        • et al.
        Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis.
        Circulation. 2014; 129: 764-772
        • Bauersachs R
        • Berkowitz SD
        • et al.
        • EINSTEIN Investigators
        Oral rivaroxaban for symptomatic venous thromboembolism.
        N Engl J Med. 2010; 363: 2499-2510
        • Büller HR
        • Prins MH
        • et al.
        • EINSTEIN–PE Investigators
        Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
        N Engl J Med. 2012; 366: 1287-1297
        • Büller HR
        • Décousus H
        • et al.
        • Hokusai-VTE Investigators
        Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
        N Engl J Med. 2013; 369: 1406-1415
        • Agnelli G
        • Buller HR
        • Cohen A
        • et al.
        Oral apixaban for the treatment of acute venous thromboembolism.
        N Engl J Med. 2013; 369: 799-808
        • Schulman S
        • Kearon C
        • Kakkar AK
        • et al.
        Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
        N Engl J Med. 2009; 361: 2342-2352
        • Jun M
        • Lix LM
        • Durand M
        • et al.
        Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study.
        BMJ. 2017; 359: j4323
        • Lund JL
        • Richardson DB
        • Stürmer T.
        The active comparator, new user study design in pharmacoepidemiology: historical foundations and contemporary application.
        Curr Epidemiol Rep. 2015; 2: 221-228
      1. RAMQ. Public prescription drug insurance plan. Available at:

        • Tamblyn R
        • Lavoie G
        • Petrella L
        • Monette J.
        The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Quebec.
        J Clin Epidemiol. 1995; 48: 999-1009
        • Wilchesky M
        • Tamblyn RM
        • Huang A.
        Validation of diagnostic codes within medical services claims.
        J Clin Epidemiol. 2004; 57: 131-141
        • Andersohn F
        • Walker J.
        Characteristics and external validity of the German Health Risk Institute (HRI) Database.
        Pharmacoepidemiol Drug Saf. 2016; 25: 106-109
        • Douros A
        • Filliter C
        • Azoulay L
        • Tagalakis V.
        Effectiveness and safety of direct oral anticoagulants in patients with cancer associated venous thromboembolism.
        Thromb Res. 2021; 202: 128-133
        • Douros A
        • Basedow F
        • Cui Y
        • Walker J
        • Enders D
        • Tagalakis V.
        Effectiveness and safety of direct oral anticoagulants with antiplatelet agents in patients with venous thromboembolism: a multi-database cohort study.
        Res Pract Thromb Haemost. 2022; 6: e12643
        • Schneeweiss S
        • Rassen JA
        • Glynn RJ
        • Avorn J
        • Mogun H
        • Brookhart MA.
        High-dimensional propensity score adjustment in studies of treatment effects using health care claims data.
        Epidemiology. 2009; 20: 512-522
        • Durrleman S
        • Simon R.
        Flexible regression models with cubic splines.
        Stat Med. 1989; 8: 551-561
        • Kim DH
        • Schneeweiss S
        • Glynn RJ
        • Lipsitz LA
        • Rockwood K
        • Avorn J.
        Measuring frailty in medicare data: development and validation of a claims-based frailty index.
        J Gerontol A Biol Sci Med Sci. 2018; 73: 980-987
        • Austin PC.
        The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments.
        Stat Med. 2014; 33: 1242-1258
        • Crump RK
        • Hotz VJ
        • Imbens GW
        • Mitnik OA.
        Dealing with limited overlap in estimation of average treatment effects.
        Biometrika. 2009; 96: 187-199
        • DerSimonian R
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • van Es N
        • Coppens M
        • Schulman S
        • Middeldorp S
        • Büller HR.
        Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials.
        Blood. 2014; 124: 1968-1975
        • Chaudhary R
        • Pagali S
        • Garg J
        • Murad MH
        • Wysokinski WE
        • McBane 2nd, RD
        DOACs versus VKAs in older adults treated for acute venous thromboembolism: systematic review and meta-analysis.
        J Am Geriatr Soc. 2020; 68: 2021-2026
        • Douros A
        • Durand M
        • Doyle CM
        • Yoon S
        • Reynier P
        • Filion KB.
        Comparative effectiveness and safety of direct oral anticoagulants in patients with atrial fibrillation: a systematic review and meta-analysis of observational studies.
        Drug Saf. 2019; 42: 1135-1148
        • Poli D
        • Antonucci E
        • Bertù L
        • et al.
        Very elderly patients with venous thromboembolism on oral anticoagulation with VKAs or DOACs: results from the prospective multicenter START2-Register Study.
        Thromb Res. 2019; 183: 28-32
        • Metelli S
        • Chaimani A.
        Challenges in meta-analyses with observational studies.
        Evid Based Ment Health. 2020; 23: 83-87
        • Baumgartner C
        • Go AS
        • Fan D
        • et al.
        Administrative codes inaccurately identify recurrent venous thromboembolism: the CVRN VTE study.
        Thromb Res. 2020; 189: 112-118