Determinants for under- and overdosing of direct oral
anticoagulants and physicians’ implementation of clinical pharmacists’
recommendations
Souad Moudallel1*, Pieter Cornu1,
Alain Dupont1**, Stephane
Steurbaut1**
1Research Group Clinical Pharmacology and Clinical
Pharmacy; Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette,
Belgium
*Corresponding author. Laarbeeklaan 103, 1090 Jette, Belgium. Tel:
+3224763385. E-mail address:
Souad.Moudallel@vub.be
**Stephane Steurbaut and Alain Dupont should be considered joint senior
authors
Running title: DOAC dosing/implementation of advices
Word count abstract: 246
Word count article: 2850
Number of References: 42
Number of Tables: 2
Number of Figures: 2
Key words: DOACs, clinical pharmacist, inappropriate prescribing,
interprofessional collaboration
What is already known about this subject:
• DOACs are increasingly used high risk medications for stroke
prevention in atrial fibrillation and other indications.
• DOAC prescribing is error prone given different dosage regimes
depending on drug, indication and other factors.
• Only determinants associated with inappropriate prescribing in
general have been identified so far.
What this study adds:
• Distinct determinants associated with under- and overdosing were
identified and studied per DOAC.
• Acceptance and implementation rates of interventions by clinical
pharmacists were studied in detail and high.
• Clinical services led by pharmacists help physicians to
reduce the number of inadequate DOAC prescriptions.
Aim : To analyze the appropriateness of DOAC dosing and
determinants for under-and overdosing as well as acceptance and
implementation rates of interventions by clinical pharmacists.
Methods : Cross-sectional study from January
2019-December 2019 in a tertiary hospital in hospitalized patients with
atrial fibrillation on DOACs (n=1688). Primary outcome was the
proportion of patients with inappropriate DOAC prescribing with
identification of determinants for under-and overdosing. Secondary
outcomes included acceptance and implementation rates of pharmacists’
advices and determination of reasons for
non-acceptance/non-implementation.
Results : In 16.9% of patients, inappropriate
prescribing was observed. For all DOACs considered together, body
weight<60 kg(OR 0.46 [0.27-0.77]), edoxaban use(OR 0.42
[0.24-0.74]), undergoing surgery(OR 0.57 [0.37-0.87]) and being
DOAC naïve(OR 0.45 [0.29-0.71]) were associated with a significantly
lower odds of underdosing. Bleeding history(OR 1.86 [1.24-2.80]) and
narcotic use(OR 1.67 [1.13-2.46]) were associated with a
significantly higher odds for underdosing. Determinants with a
significantly higher odds of overdosing were renal impairment(OR 11.29
[6.23-20.45]) and body weight<60 kg(OR 2.34
[1.42-3.85]), whereas the use of dabigatran(OR 0.24 [0.08-0.71])
and apixaban(OR 0.18 [0.10-0.32]) were associated with a
significantly lower odds of overdosing compared to rivaroxaban.
Physicians accepted the pharmacists’ advice in 179 cases (79.2%)
consisting of 92 (51.4%) advices for underdosing, 82 (45.8%) for
overdosing and 5 (2.8%) for contraindications. The advices were
effectively implemented for 75 (81.5%) underdosed, 69 (84.1%)
overdosed and 4 (80.0%) contraindicated cases.
Conclusion: Inappropriate DOAC prescribing remains
common. Clinical services led by pharmacists helps physicians to reduce
the number of inadequate prescriptions for high risk medications such as
DOACs.
Introduction
The direct oral anticoagulants (DOACs) are increasingly used as the
treatment of choice for stroke prevention in atrial fibrillation (AF)
and as treatment and prophylaxis of venous thromboembolisms (VTE)1, 2. DOACs are at least as effective as vitamin K
antagonists (VKAs) and do not need routine monitoring, but also come
with specific requirements and risks. DOACs require dosage adjustments
for renal function, weight, age, and concomitant medications2-4. Several studies have shown that DOACs are
frequently prescribed incorrectly with inappropriate dosing varying from
12.8% to 42.8% of AF patients as well as other patients3, 5-19. Inappropriate prescribing has been shown to
be an independent risk factor for adverse drug events (ADE) leading to
potential clinical consequences including thromboembolism, bleeding,
hospitalization and death 1, 20. Older patients are
especially susceptible to ADEs associated with inappropriate prescribing
due to decreased drug metabolism, increased prevalence of hepatic/renal
dysfunction, and the higher likelihood of drug-drug interactions as a
result of polypharmacy 1. Although prescribers may
have valid reasons for using dosages that deviate from the Summary of
Product Characteristics (SmPC), no studies have demonstrated improved
anticoagulation therapy outcomes associated with this practice. It is
therefore important to consistently monitor DOAC prescriptions and
identify any related patient safety issues 2.
According to the literature, pharmacists can help patients and providers
in preventing and managing DOAC related problems21-23. The purpose of this study was to assess the
rate of inappropriate DOAC dosing and identify determinants associated
with under- and overdosing. To the best of our knowledge, this hasn’t
been investigated before since previous literature commonly has focused
only on determinants for inappropriate prescribing in general1, 3, 11. Given the increasing prescription rates of
DOACs (including edoxaban) over the last years, this study intended to
yield additional information about possible determinants for under- and
overdosing compared to the study of 2018 3. Moreover
and also innovative in aim, we assessed the physicians’ acceptance and
implementation rate of the pharmacists’ DOAC dosing advice with listing
of the reasons for non-acceptance and non-implementation for the cases
where the pharmacists’ advice was not followed.
Methods