Inappropriate direct oral anticoagulant dosing in atrial fibrillation patients is associated with prescriptions for outpatients rather than inpatients: a single-center retrospective cohort study

Abstract

Background: Inappropriate dosing of direct oral anticoagulants (DOACs) has been associated with clinical safety and efficacy; however, little is known about clinical data associated with an inappropriate DOAC dosing in Japan. In addition, there is no report in which the appropriateness of DOAC dosing between prescription for inpatients and for outpatients was examined. In this study, we aimed to investigate the prevalence and factors associated in the inappropriate dosing of DOACs in patients with atrial fibrillation (AF).Methods: The retrospective cohort study was conducted at a single Japanese university hospital. Both inpatients and outpatients, who were diagnosed with AF and for whom treatment with either dabigatran, rivaroxaban, apixaban, or edoxaban was initiated between April 1, 2014 and March 31, 2018, were enrolled in the study. Appropriateness of DOAC dosing was assessed according to the manufacturer's labeling recommendations (dose reduction criteria) of each DOAC. Inappropriate reduced dose, namely, underdosing, was defined as prescription of a reduced dose of DOAC despite the patient not meeting the dose reduction criteria. Inappropriate standard dose, namely, overdosing, was defined as prescription of a standard dose of DOAC despite the patient meeting the dose reduction criteria. Inappropriate DOAC dosing was defined as a deviation of the recommended dose (both underdosing and overdosing). Results: A total of 316 patients (dabigatran, 28; rivaroxaban, 107; apixaban, 116; and edoxaban, 65) were included, with a median (interquartile range) age of 75 (66-81) years and 62.3% male. DOACs were prescribed at an appropriate standard dose in 39.2% of patients, an appropriate reduced dose in 36.7%, an inappropriate standard dose in 2.5%, and an inappropriate reduced dose in 19.3%. Multivariate analysis revealed that the inappropriate dosing of DOACs was significantly associated with prescriptions for outpatients (vs. inpatients; odds ratio [OR] 2.87, 95% confidence interval [CI] 1.53-5.62, p < 0.001) and those with higher HAS-BLED scores (OR 1.87, 95% CI 1.42-2.51, p < 0.001).

Off-label-dosing of non-vitamin K-dependent oral antagonists in AF patients before and after stroke: results of the prospective multicenter Berlin Atrial Fibrillation Registry

“…This finding is in line with a German single-center observation based on 254 acute stroke patients with known AF, reporting an off-label dose in one out of three patients on factor Xa inhibitors. [32] In the Berlin Atrial Fibrillation Registry, under-dosing of apixaban and rivaroxaban at stroke onset was associated with old age, which is in line with prospective AF registries like ORBIT AF II, including only a subset of patients with prior (but not acute) ischemic stroke [14][15][16][17]. Compared to on-label dosing, under-dosing of apixaban or rivaroxaban was not significantly associated with stroke severity on hospital admission or at hospital discharge.…”

“…Treating physicians are advised to prescribe the guideline-recommended in-label NOAC dosage in each patient, taking patients' age (for dabigatran, apixaban, and edoxaban), renal function (dabigatran, apixaban, rivaroxaban, and edoxaban) as well as body weight (apixaban and edoxaban) into account [13]. According to prior investigations, up to 50% of all patients prescribed NOACs were inappropriately dosed, the vast majority of patients being under-dosed [14][15][16][17]. This is of clinical relevance, as results from a meta-analysis of randomized controlled trials as well as several registries showed that off-label NOAC dosing is associated with worse clinical outcome [18][19][20].…”

Determinants for under‐ and overdosing of direct oral anticoagulants and physicians' implementation of clinical pharmacists' recommendations

“…According to the literature, physicians may place more value on the avoidance of bleeding in high‐risk AF patients, especially in those with a high fall and bleeding risk 3,34,35 . Results of previous studies suggest an increased risk of falls and fractures among older adults using opioids 36,37 .…”

Off-Label Underdosing or Overdosing of Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation: A Meta-Analysis

“…A total of 257 records from the PubMed database were identified, and 33 full-text studies were reviewed for more details. Among them, 18 studies were excluded because: (1) eight studies (8)(9)(10)(11)(12)(13)(14)(15) did not report the adjusted RRs; (2) five individual studies have overlapping data (16)(17)(18)(19)(20) (3) two studies presented the data of off-label dose (including overdosing and underdosing) vs. on-label dose of NOACs (21,22), and (4) three studies were not observational cohorts (23)(24)(25). No additional studies were found in the screenings of the reference lists of the relevant studies.…”