• Non-recommended DOAC Dosing Associated with Higher Mortality Risk, Study Shows

    A new study from the GARFIELD-AF registry shows that patients who received non-recommended dosing of direct oral anticoagulants (underdosage and overdosage combined) were noted to have higher mortality than patients who received standard dosing.

    This study was published in the Sept. 22 issue of the Journal of the American College of Cardiology.  Dr. Alan John Camm, MD, of St. George's University of London is the first author of the study.

    Direct oral anticoagulants (DOACs) have been effective in stroke prevention in atrial fibrillation. The recommended doses for DOACs are described in specific regulatory authority approvals. However, the country-specific guidelines vary according to the different DOACs with anti-IIa or -Xa actions.  In this study, authors evaluated the patterns of DOAC prescription with regard to dosing and its impact on clinical events at 2 years’ follow-up.

    The authors used the GARFIELD-AF registry to identify patients who were discharged on DOACs. A total of 10,426 patients received DOACs from 2013 through 2016. The majority of patients (73%) received the recommended dosing, while 23% were underdosed and 4% were overdosed. Compared with patients who received recommended doses, patients with non-recommended doses were more likely to be women, older, and have higher CHA2DS2-VASc sores. Recommended dosing was in the range of 70% to 82% for rivaroxaban, dabigatran and apixaban but was lower for edoxaban. Non-recommended dosing was very high in the Middle East, India and China.

    At 2 years’ follow-up, more events occurred in patients who received non-recommended doses of DOACs. All-cause death, stroke and systemic embolism were higher in non-recommended doses for both overdosed and underdosed patients and the risks of bleeding were lower in underdosed patient. After adjustment, non-recommended dosing was associated with a higher risk of all-cause mortality (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.04-1.50) for underdosing and (HR, 1.19; 95% CI, 0.83-1.71) for overdosing when compared to recommended doses. A trend toward higher risk of stroke and systemic embolism with higher major bleeding events was observed in patients with overdosing.

    The authors noted a few limitations to this study. Some countries may have their own rules for prescription that differ from standard rules. Treatment discontinuation or changes in the dosage over time were not considered. Because of limited sample size, no firm conclusions can be drawn about overdosage and about edoxaban.

    In an accompanying editorial, Gerald V. Naccarelli, MD, of the Penn State University College of Medicine, stated that the results remind clinicians to dose DOACs properly and that there are consequences of dosing errors. He added that there are areas not covered in any of the studies, including missing a dose, taking extra doses, not taking rivaroxaban with meals, and switching of anticoagulants, placing patients at increased risk for clinical events. He reinforced that proper dosing must be made standard in electronic medical prescription software and prescription reconciliation during clinics. Primum non-nocere (first, do no harm) is part of the original Hippocratic Oath, and underdosing of a DOAC may break that oath, Naccarelli wrote.

    Camm and colleagues concluded that most patients receive the recommended DOAC doses according to the country-specific guidelines and that prescription of non-recommended doses is associated with increased risk of death. 


    Camm AJ, Cools F, Virdone S, et al. Mortality in Patients With Atrial Fibrillation Receiving Nonrecommended Doses of Direct Oral Anticoagulants. J Am Coll Cardiol 2020;76:1425-36.

    Naccarelli GV. Direct Oral Anticoagulant Dosing: Truth or Consequences. J Am Coll Cardiol 2020;76:1437-9.

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