Original Study| Volume 19, ISSUE 11, P936-941, November 2018

Safety of Direct Oral Anticoagulants and Vitamin K Antagonists in Oldest Old Patients: A Prospective Study



      The safety of direct oral anticoagulants (DOACs) in oldest old patients with nonvalvular atrial fibrillation (NVAF) in daily clinical practice has not been systematically assessed. This study examined the safety of DOACs and dicumarol (a vitamin K antagonist) in NVAF geriatric patients.


      Prospective study from January 2010 through June 2015, with follow-up through January 2016.


      Geriatric medicine department at a tertiary hospital.


      A total of 554 outpatients, 75 years or older, diagnosed of NVAF and starting oral anticoagulation.


      The main outcome was bleeding, which was classified into major (including those life-threatening) and nonmajor episodes. Statistical analyses were performed with Cox regression.


      A total of 351 patients received DOACs and 193 dicumarol. Patients on DOACs were older, with more frequent comorbidities, mobility limitation and disability in activities of daily living, as well as higher mortality, than those treated with dicumarol. The incidence of any bleeding was 19.2/100 person-years among patients on DOACs and 13.7/100 person-years on dicumarol; corresponding figures for major bleeding were 5.2 for those on DOACs, and 3.3 for those on dicumarol. In crude analyses, hazard ratios (95% confidence intervals) for any bleeding, and for mayor bleeding in patients on DOACs vs dicumarol were 1.60 (1.04-2.44) and 2.22 (0.88-5.59), respectively. Excess risk of bleeding associated with DOACs vs dicumarol disappeared after adjustment for clinical characteristics, so that corresponding figures were 1.19 (0.68-2.08) and 1.01 (0.35-2.93). Results did not vary across subgroups of high-risk patients.


      In very old patients with NVAF, the higher risk of bleeding associated with DOACs vs dicumarol could be mostly explained by the worse clinical profile of patients receiving DOACs. Risk of bleeding was rather high, and warrants close clinical monitoring.


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        • Go A.S.
        • Hylek E.M.
        • Phillips K.A.
        • et al.
        Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.
        JAMA. 2001; 285: 2370-2375
        • Lloyd-Jones D.M.
        • Wang T.J.
        • Leip E.P.
        • et al.
        Lifetime risk for development of atrial fibrillation: The Framingham Heart Study.
        Circulation. 2004; 110: 1042-1046
        • Miyasaka Y.
        • Barnes M.E.
        • Gersh B.J.
        • et al.
        Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence.
        Circulation. 2006; 114: 119-125
        • Zoni-Berisso M.
        • Lercari F.
        • Carazza T.
        • Domenicucci S.
        Epidemiology of atrial fibrillation: European perspective.
        Clin Epidemiol. 2014; 6: 213-220
        • Wolf P.A.
        • Abbott R.D.
        • Kannel W.B.
        Atrial fibrillation as an independent risk factor for stroke: The Framingham study.
        Stroke. 1991; 22: 983-988
        • Go A.S.
        • Mozaffarian D.
        • Roger V.L.
        • et al.
        American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2014 update: A report from the American Heart Association.
        Circulation. 2014; 129: e28-e292
        • Coppens M.
        • Eikelboom J.W.
        • Hart R.G.
        • et al.
        The CHA2DS2-VASc score identifies those patients with atrial fibrillation and a CHADS2 score of 1 who are unlikely to benefit from oral anticoagulant therapy.
        Eur Heart J. 2013; 34: 170-176
        • Lip G.Y.
        • Clementy N.
        • Pericart L.
        • et al.
        Stroke and major bleeding risk in elderly patients aged >75 years with atrial fibrillation: The Loire Valley atrial fibrillation project.
        Stroke. 2015; 46: 143-150
        • Singer D.E.
        • Chang Y.
        • Fang M.C.
        • et al.
        The net clinical benefit of warfarin anticoagulation in atrial fibrillation.
        Ann Intern Med. 2009; 151: 297-305
        • Friberg L.
        • Rosenqvist M.
        • Lip G.Y.
        Net clinical benefit of warfarin in patients with atrial fibrillation: A report from the Swedish Atrial Fibrillation Cohort Study.
        Circulation. 2012; 125: 2298-2307
        • Hart R.G.
        • Pearce L.A.
        • Aguilar M.I.
        Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
        Ann Intern Med. 2007; 146: 857-867
        • Van der Meer F.J.
        • Rosendaal F.R.
        • Vandenbroucke J.P.
        • Briët E.
        Bleeding complications in oral anticoagulant therapy. An analysis of risk factors.
        Arch Intern Med. 1993; 153: 1557-1562
        • Hutten B.A.
        • Lensing A.W.
        • Kraaijenhagen R.A.
        • Prins M.H.
        Safety of treatment with oral anticoagulants in the elderly. A systematic review.
        Drugs Aging. 1999; 14: 303-312
        • Dodson J.A.
        • Petrone A.
        • Gagnon D.R.
        • et al.
        Incidence and determinants of traumatic intracranial bleeding among older veterans receiving warfarin for atrial fibrillation.
        JAMA Cardiol. 2016; 1: 65-72
        • Go A.S.
        • Hylek E.M.
        • Borowsky L.H.
        • et al.
        Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: The AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study.
        Ann Intern Med. 1999; 131: 927-934
        • Hylek E.M.
        • D’Antonio J.
        • Evans-Molina C.
        • et al.
        Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation.
        Stroke. 2006; 37: 1075-1080
        • Nieuwlaat R.
        • Capucci A.
        • Lip G.Y.
        • et al.
        Euro Heart Survey Investigators. Antithrombotic treatment in real-life atrial fibrillation patients: a report from the Euro Heart Survey on Atrial Fibrillation.
        Eur Heart J. 2006; 27: 3018-3026
        • Eikelboom J.W.
        • Wallentin L.
        • Connolly S.J.
        • et al.
        Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial.
        Circulation. 2011; 123: 2363-2372
        • Halperin J.L.
        • Hankey G.J.
        • Wojdyla D.M.
        • et al.
        • ROCKET AF Steering Committee and Investigators
        Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).
        Circulation. 2014; 130: 138-146
        • Halvorsen S.
        • Atar D.
        • Yang H.
        • et al.
        Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial.
        Eur Heart J. 2014; 35: 1864-1872
        • Lauw M.N.
        • Eikelboom J.W.
        • Coppens M.
        • et al.
        Effects of dabigatran according to age in atrial fibrillation.
        Heart. 2017; 103: 1015-1023
        • Lip G.Y.
        • Lane D.A.
        Stroke prevention with oral anticoagulation therapy in patients with atrial fibrillation—focus on the elderly.
        Circ J. 2013; 77: 1380-1388
        • Barco S.
        • Cheung Y.W.
        • Eikelboom J.W.
        • Coppens M.
        New oral anticoagulants in elderly patients.
        Best Pract Res Clin Haematol. 2013; 26: 215-224
        • Sharma M.
        • Cornelius V.R.
        • Patel J.P.
        • et al.
        Efficacy and harms of direct oral anticoagulants in the elderly for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism: Systematic review and meta-analysis.
        Circulation. 2015; 132: 194-204
        • Romanelli R.J.
        • Nolting L.
        • Dolginsky M.
        • et al.
        Dabigatran versus warfarin for atrial fibrillation in real-world clinical practice: A systematic review and meta-analysis.
        Circ Cardiovasc Qual Outcomes. 2016; 9: 126-134
        • Ho P.
        • Brooy B.L.
        • Hayes L.
        • et al.
        Direct oral anticoagulants in frail older adults: A geriatric perspective.
        Semin Thromb Hemost. 2015; 41: 389-394
        • Charlson M.E.
        • Pompei P.
        • Ales K.L.
        • MacKenzie C.R.
        A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation.
        J Chronic Dis. 1987; 40: 373-383
        • Katz S.
        • Down T.D.
        • Cash H.R.
        • Grotz R.C.
        Progress in the development of the index of ADL.
        Gerontologist. 1970; 10: 20-30
        • Lawton M.P.
        • Brody E.M.
        Assessment of older people: Self-maintaining and instrumental activities of daily living.
        Gerontologist. 1969; 9: 179-186
        • Reisberg B.
        • Ferris S.H.
        • De Leon M.J.
        • Crook T.
        The global deterioration scale for assessment of primary degenerative dementia.
        Am J Psychiatry. 1982; 139: 1136-1139
        • Levey A.S.
        • Coresh J.
        • Greene T.
        • et al.
        Chronic kidney disease epidemiology collaboration. Using standardized serum creatinine values in the Modification of Diet in Renal Disease study equation for estimating glomerular filtration rate.
        Ann Intern Med. 2006; 145: 247-254
        • Gage B.F.
        • Waterman A.D.
        • Shannon W.
        • et al.
        Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation.
        JAMA. 2001; 285: 2864-2870
        • Lip G.Y.H.
        • Nieuwlaat R.
        • Pisters R.
        • et al.
        Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey on Atrial Fibrillation.
        Chest. 2010; 137: 263-272
        • Pisters R.
        • Lane D.A.
        • Nieuwlaat R.
        • et al.
        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
        • Perera V.
        • Bajorek B.V.
        • Matthews S.
        • Hilmer S.N.
        The impact of frailty on the utilization of antithrombotic therapy in older patients with atrial fibrillation.
        Age Ageing. 2009; 38: 156-162
        • Ruff C.T.
        • Giugliano R.P.
        • Braunwald E.
        • et al.
        Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials.
        Lancet. 2014; 383: 955-962
        • Sardar P.
        • Chatterjee S.
        • Chaudhari S.
        • Lip G.Y.
        New oral anticoagulants in elderly adults: Evidence from a meta-analysis of randomized trials.
        J Am Geriatr Soc. 2014; 62: 857-864
        • Lin L.
        • Lim W.S.
        • Zhou H.J.
        • et al.
        Clinical and safety outcomes of oral antithrombotics for stroke prevention in atrial fibrillation: A systematic review and network meta-analysis.
        J Am Med Dir Assoc. 2015; 16: 1103.e1-1103.e19
        • Bai Y.
        • Guo S.D.
        • Deng H.
        • et al.
        Effectiveness and safety of oral anticoagulants in older patients with atrial fibrillation: A systematic review and meta-regression analysis.
        Age Ageing. 2017; 5: 767-773
        • Avgil-Tsadok M.
        • Jackevicius C.A.
        • Essebag V.
        • et al.
        Dabigatran use in elderly patients with atrial fibrillation.
        Thromb Haemost. 2016; 115: 152-160
        • Abraham N.S.
        • Singh S.
        • Alexander G.C.
        • et al.
        Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: Population based cohort study.
        BMJ. 2015; 350: h1857
        • Abraham N.S.
        • Noseworthy P.A.
        • Yao X.
        • et al.
        Gastrointestinal safety of direct oral anticoagulants: A large population-based study.
        Gastroenterology. 2017; 152: 1014-1022.e1
        • Nielsen P.B.
        • Skjøth F.
        • Søgaard M.
        • et al.
        Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study.
        BMJ. 2017; 356: j510
        • Voukalis C.
        • Lip G.Y.H.
        Oral anticoagulation for elderly patients with non-valvular atrial fibrillation: Recent insights from randomised trials and the “real world”.
        Heart. 2017; 103: 977-978