Advertisement

Long-Term Clinical Outcomes of Underdosed Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Atrial Flutter

Published:January 11, 2021DOI:https://doi.org/10.1016/j.amjmed.2020.12.022

      Abstract

      Background

      Although direct oral anticoagulants (DOACs) have been shown to be effective at reducing the risk of stroke in patients with atrial fibrillation/flutter (AF), they are sometimes underdosed off-label to mitigate their associated higher bleeding risk. We sought to evaluate frequency and clinical outcomes of inappropriate underdosing of DOACS in patients with AF.

      Methods

      We conducted a study of subjects with AF who had a clinical indication for stroke prophylaxis (with a congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 47 years, sex category [CHA2DS2-VASc] of 2 or greater) and were prescribed 1 of the 4 clinically approved DOACs (apixaban, rivaroxaban, dabigatran, or edoxaban). We compared all-cause mortality, composite of stroke and systemic embolism, composite of myocardial infarction (MI), acute coronary syndromes (ACS), and coronary revascularization, and major bleeding between patients appropriately dosed and inappropriately underdosed.

      Results

      A total of 8125 patients met inclusion criteria, with a mean follow up of 2.2 ± 2 years. Of those, 1724 patients (21.2%) were inappropriately dosed. After adjusting for baseline variables, there was no difference in all-cause mortality, risk of stroke or systemic embolism, International Society on Thrombosis and Haemostasis (ISTH) major bleeding, or composite of myocardial infarction, acute coronary syndromes, or coronary revascularization between patients appropriately dosed and inappropriately underdosed. In subgroup analysis, only apixaban demonstrated an increased incidence all-cause mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.03-1.49) with inappropriate underdosing. There was no difference in the remaining clinical outcomes noted on subgroup analysis.

      Conclusion

      Underdosing of DOACs did not minimize risk of bleeding, systemic embolization or all-cause mortality in patients with AF. Inappropriate underdosing with apixaban in particular was associated with increased all-cause mortality.

      Keywords

      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:

      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

      References

        • Wolf PA
        • Abbott RD
        • Kannel WB
        Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.
        Stroke. 1991; 22: 983-988
        • Wolf PA
        • Abbott RD
        • Kannel WB
        Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study.
        Arch Intern Med. 1987; 147: 1561-1564
        • Brand FN
        • Abbott RD
        • Kannel WB
        • Wolf PA
        Characteristics and prognosis of lone atrial fibrillation. 30-year follow-up in the Framingham Study.
        JAMA. 1985; 254: 3449-3453
        • Wolf PA
        • Kerzner LJ
        • Hiltbrunner AV
        • Kannel WB
        Stroke resulting from nonvalvular atrial fibrillation.
        J Am Geriatr Soc. 1984; 32: 751-757
        • Wolf PA
        • Dawber TR
        • Thomas Jr., HE
        • Kannel WB
        Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study.
        Neurology. 1978; 28: 973-977
        • Corrado G
        • Sgalambro A
        • Mantero A
        • et al.
        Thromboembolic risk in atrial flutter. The FLASIEC (FLutter Atriale Societa Italiana di Ecografia Cardiovascolare) multicentre study.
        Eur Heart J. 2001; 22: 1042-1051
        • Irani WN
        • Grayburn PA
        • Afridi I
        Prevalence of thrombus, spontaneous echo contrast, and atrial stunning in patients undergoing cardioversion of atrial flutter. A prospective study using transesophageal echocardiography.
        Circulation. 1997; 95: 962-966
        • Chugh SS
        • Havmoeller R
        • Narayanan K
        • et al.
        Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.
        Circulation. 2014; 129: 837-847
        • Connolly SJ
        • Ezekowitz MD
        • Yusuf S
        • et al.
        Dabigatran versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2009; 361: 1139-1151
        • Patel MR
        • Mahaffey KW
        • Garg J
        • et al.
        Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
        N Engl J Med. 2011; 365: 883-891
        • Granger CB
        • Alexander JH
        • McMurray JJ
        • et al.
        Apixaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2011; 365: 981-992
        • Giugliano RP
        • Ruff CT
        • Braunwald E
        • et al.
        Edoxaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2013; 369: 2093-2104
        • Heidbuchel H
        • Verhamme P
        • Alings M
        • et al.
        Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation.
        Europace. 2015; 17: 1467-1507
        • Beasley BN
        • Unger EF
        • Temple R
        Anticoagulant options–why the FDA approved a higher but not a lower dose of dabigatran.
        N Engl J Med. 2011; 364: 1788-1790
        • Steinberg BA
        • Holmes DN
        • Piccini JP
        • et al.
        Early adoption of dabigatran and its dosing in US patients with atrial fibrillation: results from the outcomes registry for better informed treatment of atrial fibrillation.
        J Am Heart Assoc. 2013; 2e000535
        • Camm AJ
        • Amarenco P
        • Haas S
        • et al.
        XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation.
        Eur Heart J. 2016; 37: 1145-1153
        • Weitz JI
        • Eikelboom JW
        Appropriate apixaban dosing: prescribers take note.
        JAMA Cardiol. 2016; 1: 635-636
        • Tanigawa T
        • Kaneko M
        • Hashizume K
        • et al.
        Model-based dose selection for phase III rivaroxaban study in Japanese patients with non-valvular atrial fibrillation.
        Drug Metab Pharmacokinet. 2013; 28: 59-70
        • Hori M
        • Matsumoto M
        • Tanahashi N
        • et al.
        Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation in relation to the CHADS2 score: a subgroup analysis of the J-ROCKET AF trial.
        J Stroke Cerebrovasc Dis. 2014; 23: 379-383
        • Cho MS
        • Yun JE
        • Park JJ
        • et al.
        Outcomes after use of standard- and low-dose non-vitamin k oral anticoagulants in asian patients with atrial fibrillation.
        Stroke. 2019; 50: 110-118
        • January CT
        • Wann LS
        • Calkins H
        • et al.
        2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons.
        Circulation. 2019; 140: e125-e151
        • Kannel WB
        • Wolf PA
        • Benjamin EJ
        • Levy D
        Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates.
        Am J Cardiol. 1998; 82: 2n-9n
        • Hart RG
        • Pearce LA
        • Aguilar MI
        Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
        Ann Intern Med. 2007; 146: 857-867
        • Ruff CT
        • Giugliano RP
        • 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
        • Hylek EM
        • Go AS
        • Chang Y
        • et al.
        Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.
        N Engl J Med. 2003; 349: 1019-1026
        • Xian Y
        • O'Brien EC
        • Liang L
        • et al.
        Association of preceding antithrombotic treatment with acute ischemic stroke severity and in-hospital outcomes among patients with atrial fibrillation.
        JAMA. 2017; 317: 1057-1067
        • Yao X
        • Shah ND
        • Sangaralingham LR
        • Gersh BJ
        • Noseworthy PA
        Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction.
        J Am Coll Cardiol. 2017; 69: 2779-2790
        • Nielsen PB
        • Skjoth F
        • Sogaard M
        • Kjaeldgaard JN
        • Lip GY
        • Larsen TB
        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
        • Chan YH
        • Chao TF
        • Chen SW
        • et al.
        Off-label dosing of non-vitamin K antagonist oral anticoagulants and clinical outcomes in asian patients with atrial fibrillation.
        Heart Rhythm. 2020; 17: 2102-2110
        • Steinberg BA
        • Shrader P
        • Pieper K
        • et al.
        Frequency and outcomes of reduced dose non-vitamin K Antagonist anticoagulants: results from ORBIT-AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II).
        J Am Heart Assoc. 2018; 7e007633
        • Jacobs MS
        • van Hulst M
        • Campmans Z
        • Tieleman RG
        Inappropriate non-vitamin K antagonist oral anticoagulants prescriptions: be cautious with dose reductions.
        Neth Heart J. 2019; 27: 371-377
        • Steinberg BA
        • Shrader P
        • Thomas L
        • et al.
        Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: The ORBIT-AF II Registry.
        J Am Coll Cardiol. 2016; 68: 2597-2604
        • Conen D
        • Rodondi N
        • Muller A
        • et al.
        Relationships of overt and silent brain lesions with cognitive function in patients with atrial fibrillation.
        J Am Coll Cardiol. 2019; 73: 989-999
        • Cha MJ
        • Park HE
        • Lee MH
        • Cho Y
        • Choi EK
        • Oh S
        Prevalence of and risk factors for silent ischemic stroke in patients with atrial fibrillation as determined by brain magnetic resonance imaging.
        Am J Cardiol. 2014; 113: 655-661
        • Holmes Jr, DR
        • Reddy VY
        • Gordon NT
        • et al.
        Long-term safety and efficacy in continued access left atrial appendage closure registries.
        J Am Coll Cardiol. 2019; 74: 2878-2889
        • Schupke S
        • Neumann FJ
        • Menichelli M
        • et al.
        Ticagrelor or prasugrel in patients with acute coronary syndromes.
        N Engl J Med. 2019; 381: 1524-1534