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      Outcomes and drivers of inappropriate dosing of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a systematic review and meta-analysis

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          Abstract

          Objective

          There has been limited systematic evaluation of outcomes and drivers of inappropriate non-vitamin K antagonist oral anticoagulants (NOACs) dosing among patients with atrial fibrillation (AF). This review identified and systematically evaluated literature on clinical and economic outcomes of inappropriate NOAC dosing and associated patient characteristics.

          Methods

          MEDLINE, Embase, Cochrane Library, International Pharmaceutical Abstracts, Econlit, PubMed and NHS EEDs databases were searched for English language observational studies from all geographies published between 2008 and 2020, examining outcomes of, or factors associated with, inappropriate NOAC dosing in adult patients with AF.

          Results

          One hundred and six studies were included in the analysis. Meta-analysis showed that compared with recommended NOAC dosing, off-label underdosing was associated with a null effect on stroke outcomes (ischaemic stroke and stroke/transient ischaemic attack (TIA), stroke/systemic embolism (SE) and stroke/SE/TIA). Meta-analysis of 15 studies examining clinical outcomes of inappropriate NOAC dosing found a null effect of underdosing on bleeding outcomes (major bleeding HR=1.04, 95% CI 0.90 to 1.19; p=0.625) but an increased risk of all-cause mortality (HR=1.28, 95% CI 1.10 to 1.49; p=0.006). Overdosing was associated with an increased risk of major bleeding (HR=1.41, 95% CI 1.07 to 1.85; p=0.013). No studies were found examining economic outcomes of inappropriate NOAC dosing. Narrative synthesis of 12 studies examining drivers of inappropriate NOAC dosing found that increased age, history of minor bleeds, hypertension, congestive heart failure and low creatine clearance (CrCl) were associated with an increased risk of underdosing. There was insufficient evidence to assess drivers of overdosing.

          Conclusions

          Our analysis suggests that off-label underdosing of NOACs does not reduce bleeding outcomes. Patients prescribed off-label NOAC doses are at an increased risk of all-cause mortality. These data underscore the importance of prescriber adherence to NOAC dosing guidelines to achieve optimal clinical outcomes for patients with AF.

          PROSPERO registration number

          CRD42020219844.

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          Most cited references48

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          OUP accepted manuscript

          (2020)
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            Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.

            Manesh R Patel, Kenneth Mahaffey, Jyotsna Garg … (2012)
            The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).
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              Apixaban versus Warfarin in Patients with Atrial Fibrillation

              Christopher B Granger, John H Alexander, John J.V. McMurray … (2012)
              Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.).
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                Author and article information

                Journal
                Journal ID (nlm-ta): Heart
                Journal ID (iso-abbrev): Heart
                Journal ID (hwp): heartjnl
                Journal ID (publisher-id): heart
                Title: Heart
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Print): 1355-6037
                ISSN (Electronic): 1468-201X
                Publication date (Print): February 2023
                Publication date (Electronic): 31 October 2022
                Volume: 109
                Issue: 3
                Pages: 178-185
                Affiliations
                [1 ] departmentStroke Unit, Santa Maria della Misericordia Hospital , University of Perugia , Perugia, Italy
                [2 ] departmentHeart Center, Department of Cardiology , Amsterdam UMC Location AMC , Amsterdam, The Netherlands
                [3 ] departmentCardiology Department , Hospital Ramon y Cajal , Madrid, Spain
                [4 ] departmentDeparment of Neurology , Hospital General Universitario de Albacete , Albacete, Spain
                [5 ] departmentSchool of Medical Sciences , Örebro University , Orebro, Sweden
                [6 ] departmentStroke Medicine , East Kent Hospitals University NHS Foundation Trust , Canterbury, UK
                [7 ] departmentCardiovascular Medicine , Barts Health NHS Trust , London, UK
                [8 ] South East London Integrated Card Systemt, and UCLPartners , London, UK
                [9 ] Wickenstones , Carlow, Ireland
                [10 ] Bayer AG , Berlin, Germany
                [11 ] departmentCardiovascular Division, Deparmtent of Medicine , Brigham and Women's Hospital , Boston, Massachusetts, USA
                [12 ] Harvard Medical School , Boston, Massachusetts, USA
                Author notes
                [Correspondence to ] Dr Christian T Ruff, 60 Fenwood Rd, 7th Floor, Suite 702, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA; cruff@ 123456bwh.harvard.edu
                Author information
                http://orcid.org/0000-0001-5469-4579
                http://orcid.org/0000-0003-3625-0987
                http://orcid.org/0000-0003-4968-4952
                Article
                Publisher ID: heartjnl-2022-321114
                DOI: 10.1136/heartjnl-2022-321114
                PMC ID: 9872251
                PubMed ID: 36316100
                SO-VID: c85189df-b19c-4ac9-84d1-14ba5be8465d
                Copyright © © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
                License:

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Date received : 20 April 2022
                Date accepted : 29 September 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100004326, Bayer;
                Award ID: NA
                Categories
                Subject: Systematic Review
                Subject: 1506
                Custom metadata
                special-feature unlocked

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: atrial fibrillation,stroke
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: atrial fibrillation, stroke

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