Statistical analysis
Descriptive and statistical analyses were carried out with IBM SPSS
Statistics version 27 (IBM Corp., Armonk, NY, USA). The
Kolmogorov–Smirnov test was used to test the normality of the
continuous variables. Histograms were evaluated to assess normality.
Categorical variables were expressed as percentages and continuous
variables as medians with interquartile ranges (IQRs). Differences in
the continuous variables among the four DOACs were evaluated using the
Kruskal-Wallis test. The Chi-square test was used to compare categorical
variables. A two-sided significance level of 0.05 was used. Binary
logistic regression analysis was conducted to determine factors
associated with the under- and overdosing of the DOACs. Factors that
were significantly associated in the univariable analysis
(p<0.1) were included in the multivariable logistic regression
analysis. For the logistic regression models a corrected p-value
<0.05 (Benjamini-Hochberg correction for multiple comparisons)
was used, goodness of fit was assessed (R2, receiver
operator characteristics curve) and residuals were reviewed. The odds
ratios (OR) were reported with their 95% confidence intervals (CI).
Results
A total of 1688 consecutive and unique AF patients were included for
which the characteristics per DOAC are shown in table 1. Apixaban was
the most prescribed DOAC (34.7%) followed by edoxaban (32.7%),
rivaroxaban (23.8%) and dabigatran (8.8%). Apixaban users were
significantly older (median 81.0 years), weighed significantly less
(median 70.1 kg) and had a statistically lower renal function (median
52.0 mL/min) compared to users of another DOAC. Moreover, apixaban users
were diagnosed more often with arterial hypertension (73.0%) and heart
failure (HF) (35.5%). Combination with at least one antiplatelet drug
was observed in 23.6% and 21.8% of rivaroxaban and apixaban users,
respectively. Dual antiplatelet therapy was the highest in the apixaban
group (3.2%).
The overall inappropriate prescribing rate in this study was 16.9%
(n=286) with the highest underdosing and overdosing rates seen in the
apixaban (14.2%) and rivaroxaban (9.7%) group, respectively (Figure
1). Overall, underdosing, overdosing and contraindications were seen in
9.7%, 6.9% and 0.4% of patients, respectively.
Considering the four DOACs together (see Table 2), a body weight
<60 kg (adj. OR 0.46, 95% CI 0.27-0.77), the use of edoxaban
compared to rivaroxaban (adj. OR 0.42, 95% CI 0.24-0.74), undergoing
surgery (adj. OR 0.57, 95% CI 0.37-0.87), and being DOAC naive (adj. OR
0.45, 95% CI 0.29-0.71) were associated with a significantly lower odds
of underdosing. On the other hand, having a bleeding history (adj. OR
1.86, 95% CI 1.24-2.80) and the use of narcotic analgesics (adj. OR
1.67, 95% CI 1.13-2.46) were associated with a significantly higher
odds of underdosing. Determinants associated with a higher odds of
overdosing were renal impairment (adj. OR 11.29, 95% CI 6.23-20.45) and
a body weight <60 kg (adj. OR 2.34, 95% CI 1.42-3.85),
whereas the use of dabigatran (adj. OR 0.24, 95% CI 0.08-0.71) and
apixaban (adj. OR 0.18, 95% CI 0.10-0.32) were associated with a lower
odds of overdosing compared to rivaroxaban.
For rivaroxaban (adj. OR 100.95, 95% CI 23.23-438.70) and edoxaban
(adj. OR 3.25, 95% CI 1.49-7.12) users, a decreased renal function was
associated with a higher odds of overdosing compared to patients with a
normal renal function. For rivaroxaban, we observed a lower odds of
underdosing in patients with a CrCl <50 mL/min (adj. 0.17,
95% CI 0.06-0.48).
A lower body weight was a risk factor for underdosing in apixaban users
(adj. OR 0.26, 95% CI 0.12-0.55), whereas this factor was associated
with a higher odds of overdosing in the edoxaban group (adj. OR 4.16,
95% CI 1.97-8.77). Having a history of bleeding (adj. OR 2.14, 95% CI
1.22-3.75) in apixaban users was associated with a higher odds of
underdosing.
Of the 286 identified AF patients with an inappropriate DOAC dose, the
physician was contacted by telephone in 226 (79.0%) cases of which 131
and 90 calls concerned underdosed and overdosed prescriptions,
respectively. Five cases of dabigatran use and a CrCl <30
mL/min were classified as a contraindication. In addition, telephone
calls were conducted for eight cases concerning drug interactions (not
shown in figure 2) with rifampicin (n=5), carbamazepine (n=2) and
cyclosporine (n=1). Physicians accepted the pharmacists’ advice in 179
cases (79.2%) which consisted of 92 (51.4%) advices for underdosing,
82 (45.8%) for overdosing and 5 (2.8%) for contraindicated dosages.
Regarding the non-accepted interventions (n=47), it concerned 39
(83.0%) underdosed and 8 (17.0%) overdosed cases. The advices were
effectively implemented, as evidenced by a correction of the
prescription in the patient’s electronic medical record, for 75 out of
92 (81.5%) underdosed, 69 out of 82 (84.1%) overdosed and 4 out of 5
(80.0%) contraindicated cases, a total of 148 cases (65.5%).
Non-implemented advices, for which the reasons are listed in figure 2,
were observed for 15 underdosed, 11 overdosed and 1 contraindicated
case. For 2 underdosed as well as 2 overdosed cases we were unable to
track whether the intervention was implemented or not
Discussion
Despite their increased use and substantial research focusing on their
effectiveness and safety in clinical practice, appropriate DOAC
prescribing remains a problem as also evidenced by our study24, 25. Inappropriate first DOAC prescriptions were
found in 16.9% of the patients, with underdosing being more prevalent
than overdosing. This is in line with a previous study conducted at our
institution 3 as well as other studies1, 2, 7-10. The dosing recommendations differ
depending on the DOAC, with some of them requiring dose reductions based
solely on renal function and others taking additional criteria into
consideration. The high underdosing rate found in apixaban users seems
clinically relevant as underdosing with this DOAC was reported to be
associated with a nearly 5-fold increased stroke risk in AF patients26. On the other hand, it has been reported in a
prospective study that hydrophilic drugs like DOACs in frail older
patients with low muscle mass can lead to supratherapeutic DOAC plasma
levels, placing them at higher risk for major bleeding complications27.
Among patients prescribed DOACs, those receiving apixaban had a lower
renal function, were older and weighed significantly less compared to
users of other DOACs. According to recent literature, including a
systematic review in frail AF patients, apixaban was associated with a
lower risk of major bleedings compared to rivaroxaban and dabigatran,
although their effectiveness was comparable 28-31. As
shown in a registry of rivaroxaban users, renal impairment was a risk
factor for experiencing major bleeding events 32. The
risk of major bleedings was comparable between apixaban and edoxaban29. Intra DOAC comparisons still need to be confirmed
by findings from randomized controlled trials that are expected to be
released in the upcoming years e.g., the DARING-AF trial and DANNOAC-AF
trial 28, 29.
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, 33, 34. Results of
previous studies suggest an increased risk of falls and fractures among
older adults using opioids 35, 36. Walenga and
colleagues describe that the relative rate of clinically relevant
bleedings with the use of opioids was nearly twofold greater with low
dose rivaroxaban compared with enoxaparin 37.
The higher OR for underdosing apixaban in patients with a lower weight
may be related to the fact that weight is often used as a single
criterion for dose reduction in apixaban, while this is only to be
adapted in combination with an age ≥80 years and/or serum creatinine
≥1.5 mg/dL.
The association of weight with overdosing in edoxaban users is mainly
due to younger patients with a weight <60 kg who were
hospitalized to undergo an ablation.
The association between a reduced CrCl and the higher odds to receive a
supratherapeutic dose as found for rivaroxaban and edoxaban users could
be due to a fluctuating renal function or physicians being unaware of
the CrCl threshold for dose adjustment 2.
A high percentage of the advices by the clinical pharmacists was
immediately accepted (79.2%) and effectively implemented (65.5%) by
the physicians. The accepted advices consisted for 79.9% of
prescriptions for DOACs that were initiated prior to the hospital
admission. Physicians acknowledged that they did not consistently check
the DOAC dose upon admission due to a lack of time. A history of
bleeding and a fluctuating renal function were the most important
factors why advices to adjust the dose were not accepted. Some
physicians, less familiar with anticoagulation, preferred to discuss the
proposed dosage adjustment with the GP/cardiologist. In some cases, as
depicted in figure 2, renal function altered during hospitalization so
no adjustment was needed anymore, even if the advice was already
accepted. Other important reasons retrieved from the medical record for
non-implementation of accepted advices were the patients’ bleeding risk
(n=2) and concomitant use of antiplatelet drugs (n=2). Despite the
initial acceptance, physicians chose to keep the reduced DOAC dose in
these cases after consultation with the head of department. After
implementation of the recommended dose adjustments, the total
inappropriate prescribing rate according to the SmPC was 8.2% vs. the
initial 16.9%, keeping in mind most of these off-label doses were
intentional due to the abovementioned reasons.
Some institutions have an integrated pharmacist-led DOAC service or
antithrombotic stewardship programs with the aim of improving the safety
and efficacy of DOAC use through identification and resolution of dosing
errors, patient education, improved patient follow-up and laboratory
monitoring 16, 20, 22, 38, 39. Studies showed that
such services increase appropriate DOAC dosing at baseline and
follow-up, which is in line with the recommendations of organizations
like EHRA and the American College of Cardiology (ACC)38, 40, 41. Clinical pharmacists are well positioned
to provide recommendations regarding the DOAC choice and dose, presence
of a contraindication as well as potential drug-drug and drug-disease
interactions 20. They are also able to inform
physicians of patients who may not be the best candidates for DOACs
(e.g., extremes of body weight, severe renal impairment)16. In addition, they also provide motivational
interviewing to promote patient understanding of DOAC therapy and
emphasize the importance of DOAC adherence 38.
Involvement of clinical pharmacists should be more mainstream in the
hospitals, especially for HRM such as DOACs. Quintens et al. highlighted
the greater impact of advices given by telephone since half of the
advices were not accepted/read if only an electronic note was left20. In addition, a study of Dreijer et al. conducted
in patients using anticoagulants showed that implementation of a
multidisciplinary antithrombotic team over time significantly reduces
adverse drug reactions (ADRs) like bleedings or thrombotic events from
hospitalization until three months after hospitalization and resulted in
a lower all-cause mortality 42.
A useful recommendation for physicians could be to clearly document the
rationale for deviating from the approved dose in the patient’s medical
record to avoid unnecessary phone calls. Physicians should be aware of
the most common mistakes concerning DOAC prescriptions14.
To our knowledge, this is the first study to assess determinants for
DOAC under- and overdosing in AF patients, nevertheless there are
limitations to our study. First, this was a single center study,
therefore the results may not be generalizable to other populations. Due
to the cross-sectional nature of our study, only the initial DOAC
prescription of a patient was taken into account. However, the
conditions necessitating a DOAC change or dose adaptation during
hospitalization were only present in a minority of patients. We also did
not examine the effect of inappropriate dosing and the dose adaptations
on the thromboembolic/bleeding event rate. In addition, our results may
be biased by inaccurate or incomplete information in the electronic
medical records. Further, this study was neither directed to identify
high risk AF patients who did not receive oral anticoagulants, nor to
assess DOAC adherence.
Additional research regarding the long term effects of the clinical
pharmacists’ interventions is needed. Lastly, it would be of interest
for future research to focus on the interventions with the highest
impact on patient outcomes and to investigate which patients would
benefit most from the implementation of a multidisciplinary clinical
DOAC service.
In conclusion, in this study where for the first time determinants for
under- and overdosing of DOACs were assessed, inappropriate DOAC
prescribing was found to be still common. Interventions by clinical
pharmacists can reduce this burden. We recommend that clinical services
led by pharmacists play a greater role in assisting physicians during
the prescription process of high risk medications such as DOACs, in
order to reduce the number of inadequate prescriptions.