Dosing accuracy of direct oral anticoagulants in an academic medical center

Accuracy of search results was confirmed by review of the first 200 patients’ records. Records were manually reviewed for encounters lacking ICD-9/10 codes and approved DOAC indications (30%) and encounters having multiple coded diagnostic indications (to identify the indication). ICD-9 codes for venous thrombosis were reviewed to differentiate acute from chronic events.

Data Analysis

The main outcome was concordance or discordance between the first DOAC prescribing order and the FDA-approved prescribing information at the time. Initial classification, performed by 2 independent reviewers (a pharmacist and a physician, or 2 pharmacists), was followed by adjudication and individual record review (by 2 independent reviewers) of all initial prescribing orders classified as discordant. A third reviewer adjudicated any disagreement. Records and notes were reviewed to identify stated or potential reasons for dosing variation and pre-admission prescriptions. Data are presented as means and standard deviations (SDs) and as raw numbers and percentages. Differences in patient characteristics by DOAC or therapeutic indication were determined by analysis of variance (ANOVA) with Bonferroni correction for post hoc comparisons. Dosing information was categorized as the same as recommended, lower than recommended, higher than recommended, or avoid drug use (drug–drug or drug–disease interaction), per FDA-approved prescribing information, and χ² tests were used to determine whether variation in dosing occurred by individual DOAC, therapeutic indication, or prescriber specialty. Relationships between dosing variation and age or renal function were tested by ANOVA with Bonferroni correction for post hoc comparisons.

RESULTS

There were 635 admissions with apixaban, dabigatran, or rivaroxaban prescribed for 508 patients (Table 1). Edoxaban was not on the formulary and not prescribed during the period studied. The therapeutic indication was prevention of embolic stroke in patients with atrial fibrillation/flutter or AF (465 admissions, or 73%, with valvular disease and/or tissue valve in 35), chronic DVT (67 admissions, or 11%, with active malignancy in 14), acute DVT (32 admissions, with malignancy in 2), chronic PE (23 admissions, with malignancy in 3), acute PE (19 admissions, with malignancy in 4), and DVT prevention after hip or knee surgery (19 admissions). DOACs were prescribed for unapproved indications in 10 admissions, and these were excluded from further analysis (mural thrombus in 3 admissions, low ejection fraction in 2, bedrest immobilization in 2, aortic aneurysm in 1, thrombocytosis in 1, and extensive superficial venous thrombosis in 1) (Table 2).

Patients with AF were older with lower creatinine clearance compared to patients with other diagnoses. Mean (SD) patient age was 72.1 (12.7) years for AF, 53.1 (10.9) years for chronic PE, 55.5 (14) years for acute PE, 56.4 (15.9) years for chronic DVT, 57.9 (18.4) years for acute DVT, and 61.4 (11.6) years for DVT prevention after hip or knee surgery (P < 0.0001 for all comparisons). Mean (SD) estimated creatinine clearance was 76.8 (43.5) mL/min for AF, 92.4 (44.4) mL/min for DVT prevention after hip or knee surgery, 111 (53) mL/min for chronic DVT, 118 (55) mL/min for acute DVT, 126 (60) mL/min for chronic PE, and 127 (54) mL/min for acute PE (P < 0.0001 for all comparisons). Differences between patient groups by therapeutic indication were not detected for weight, body mass index, or serum creatinine level.

The most frequent deviation from prescribing recommendations was omission of directions to administer rivaroxaban with food—93% (248/268) of orders—but not for DVT prevention after hip or knee surgery, for which the 10-mg dose is appropriately administered without food. Doses were the same as recommended for 82% of apixaban orders, 84% of rivaroxaban orders, and 93% of initial dabigatran orders (P < 0.05 for differences; Table 3). Dosages not concordant with FDA recommendations were prescribed in 44 (18.1%) of 243 apixaban orders, 41 (14.3%) of 286 rivaroxaban orders, and 7 (7.2%) of 89 initial dabigatran orders. Lower than recommended doses were more common than higher than recommended doses (Table 3, Figure 1): 15.2% versus 2.1% of apixaban orders, 9.4% versus 3.5% of rivaroxaban orders, and 4.2% versus 1.0% of initial dabigatran orders (P < 0.05). Failure to avoid drug use (for potential drug–drug or drug–disease interactions) was uncommon (1%-2%). There were more deviations from recommended doses for patients with AF or DVT prevention after hip or knee surgery than for patients with acute or chronic PE or acute DVT (Table 3). No significant differences were detected between prescribed and recommended doses by prescriber specialty.

In most cases, a reason for deviating from FDA dosing recommendations was not stated in the EMR. The exception was fluctuating renal function, which was cited in 8 cases.

For apixaban, patients who were prescribed lower than recommended doses were older than those prescribed recommended doses: mean (SD), 78.1 (12.2) years versus 71 (13.6) years (P = 0.003). Seventy-six percent of those prescribed lower than recommended doses were older than 75. Prescriptions for apixaban at lower than recommended doses were continuations of prior outpatient prescriptions in 20 of 37 cases (almost half), and in 12 cases (one-fourth) antiplatelet drugs were coprescribed (aspirin in 10 cases, clopidogrel in 1, prasugrel in 1). For rivaroxaban, older age was associated with both lower than recommended dosing (P = 0.003) and higher than recommended dosing (P < 0.001). Variations from prescribing recommendations were continuations of outpatient rivaroxaban doses in about two-thirds (26 of 41; 63.4 %) with 13 receiving antiplatelet drugs. For dabigatran, 6 of 7 orders not in agreement with recommendations were continuations of outpatient dosing.

The specific equation used to estimate renal function also had the potential to lead to dosing errors. Among the 41 rivaroxaban patients categorized as receiving doses discordant with recommendations, 8 would have had an inappropriate DOAC dose if eGFR were used instead of eCrCL as recommended. No relationships were detected for other patient variables/measures and dosing deviations from recommendations.