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\begin{document}

\title{Ten-year trends in the use of oral anticoagulants in Australian general
practice patients with atrial fibrillation}



\author[1]{Woldesellassie Bezabhe}%
\author[1]{Luke Bereznicki}%
\author[1]{Jan Radford}%
\author[1]{Barbabra Wimmer}%
\author[1]{Colin Curtain}%
\author[2]{Mohammed Salahudeen}%
\author[1]{Gregory Peterson}%
\affil[1]{University of Tasmania Faculty of Health}%
\affil[2]{University of Tasmania}%


\vspace{-1em}



  
  \date{June 17, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
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\selectlanguage{english}
\begin{abstract}
Objective: Appropriate use of oral anticoagulants (OACs) reduces the
risk of stroke in patients with atrial fibrillation (AF). The study
characterised the prescribing of OACs in people with AF in the
Australian primary care setting over 10 years. Methods: We performed 10
sequential cross-sectional analyses of patients with a recorded
diagnosis of AF between 2009 and 2018 using nationally representative
general practice data from the NPS MedicineWise's dataset,
MedicineInsight. The proportion of patients with AF who were prescribed
an OAC based on their stroke risk was examined. Results: The sample size
of patients with AF ranged from 9,874 in 2009 to 41,751 in 2018. The
proportion who were prescribed an OAC increased from 39.5\% (95\% CI
38.6\%-40.5\%) in 2009 to 52.0\% (95\% CI 51.5\%-52.4\%) in 2018 (p for
trend \textless{}0.001). During this time, the proportion of patients
with AF and high stroke risk who were prescribed an OAC rose from 41.7\%
(95\% CI 40.7\%-42.8\%) to 55.2\% (95\% CI 54.7\%-55.8\%; p for trend
\textless{}0.001) with the direct-acting oral anticoagulants accounting
for over three-quarters of usage by 2018. There was substantial
variation in OAC prescribing according to stroke risk between general
practices. In 2018, the proportion of moderate to high stroke risk
patients who were prescribed an OAC was 38.6\% (95\% CI 37.2\%-40.1\%)
in the lowest practice site quintile and 65.6\% (95\% CI 64.5\%-66.7\%)
in the highest practice site quintile. Conclusions: Over the ten years,
OAC prescribing in high stroke risk patients with AF increased by
one-third.%
\end{abstract}%



\sloppy


\textbf{Background{}}

Appropriate utilisation of oral anticoagulants (OACs) reduces stroke
risk in patients with atrial fibrillation (AF) (Aguilar \& Hart, 2005).
{}The vitamin K antagonist, warfarin, has been the mainstay of
anticoagulation in AF for over two decades. It decreases the risk of
stroke by almost two-thirds (Aguilar \& Hart, 2005). However, it has a
narrow therapeutic index and is associated with problematic drug and
food interactions that require monitoring and dose adjustments. The
direct-acting oral anticoagulants (DOACs) are at least non-inferior to
warfarin in efficacy and safety (Connolly et al., 2009; Granger et al.,
2011; Patel et al., 2011). In Australia, three DOACs (rivaroxaban,
dabigatran, and apixaban) were listed for Commonwealth subsidy under the
Pharmaceutical Benefits Scheme (PBS) for non-valvular AF in 2013; since
then their use has markedly increased (Admassie, Chalmers \& Bereznicki,
2017; Alamneh, Chalmers \& Bereznicki, 2017; Drug Utilisation
Sub-Committee (DUSC), June 2016; Pol, Curtis, Ramukumar \& Bittinger,
2018). In contrast, the prescribing of warfarin has declined
{}(Admassie, Chalmers \& Bereznicki, 2017; Alamneh, Chalmers \&
Bereznicki, 2017; Drug Utilisation Sub-Committee (DUSC), June 2016; Pol,
Curtis, Ramukumar \& Bittinger, 2018){}. \textbf{{}}

Recent studies on the utilisation of OAC have highlighted both underuse
and overuse in patients with AF in Australia (Admassie, Chalmers \&
Bereznicki, 2017; Alamneh, Chalmers \& Bereznicki, 2017). The Tasmanian
AF Study observed prescribing practice from 2011-2015, and reported that
55\% and 63\% of eligible AF patients with a high stroke risk were
prescribed an OAC before and after DOACs were listed on the PBS,
respectively (Admassie, Chalmers \& Bereznicki, 2017). This study,
however, involved only hospitalised patients, who might have been more
co-morbid than those managed in primary care; the results therefore may
not have reflected OAC prescribing rates in general practices
nationally. The current AF prescribing patterns, in relation to stroke
risk, in the Australian primary care setting remain unknown.

The primary objective of this study was to investigate the proportion of
Australian primary care patients with AF prescribed an OAC according to
their stroke risk, and temporal trends in prescribing patterns. The
secondary objective was to examine variation in OAC prescribing between
general practices.\textbf{}

\textbf{Methods}

Data for this study was obtained from NPS MedicineWise's dataset,
MedicineInsight. This is the largest and the most representative general
practice dataset available to researchers in Australia. In 2018, 671
(8.3\%) of the 8,065 general practices in Australia had been recruited
by NPS MedicineWise (Busingye et al., 2019; MedicineInsight, 2018).

MedicineInsight uses a third-party tool that extracts, de-identifies and
securely transmits patient data each week to its secure data repository.
The extraction tool allows developing a longitudinal database of
patients in general practices. The data that MedicineInsight collects
from general practices include patient demographics, diagnoses,
pathology test results, prescribed medications and reasons for
encounter. However, specific patient identifiers, such as patient name,
address, and date of birth, are not included in this dataset
(MedicineInsight, 2018).

We performed ten sequential cross-sectional analyses of data on 1
September every year (census date) from 01 September 2009 to 01
September 2018. Patients with a recorded diagnosis of non-valvular AF
were included in each analysis if (i) they were aged 18 years or older
and not deceased on or before the census date, (ii) their recorded AF
diagnosis date was at least 4 months before the census date, (iii) they
had had three or more recorded general practice visits in the previous
two years and at least one of these visits was in the last six months,
and (iv) they had been registered in the general practice's electronic
records at least one year before the census date.

We defined patients with AF as being prescribed an OAC (warfarin,
dabigatran, rivaroxaban or apixaban) or antiplatelet agent (clopidogrel,
ticagrelor, aspirin, ticlopidine, prasugrel, dipyridamole, abciximab,
eptifibatide or tirofiban) when they had at least one recorded
prescription, dated within 365 days before the census date. Aspirin is
available without a prescription, but we could only capture prescribed
data.

For most of our study period, guidelines recommended using the
CHA\textsubscript{2}DS\textsubscript{2}-VASc score (congestive heart
failure (1 point), hypertension (1 point), age [?] 75 years (2 points),
diabetes mellitus (1 point), stroke/transient ischaemic attack (TIA) (2
points), vascular disease (1 point), age 65-74 (1 point) and sex female
(1 point)) for assessing stroke risk and treatment eligibility in
patients with AF (Steffel et al., 2018). Patients with AF were
stratified as low risk when CHA\textsubscript{2}DS\textsubscript{2}-VASc
was 0 and male or 1 and female, moderate risk with
CHA\textsubscript{2}DS\textsubscript{2}-VASc =1 and male, and high risk
with CHA\textsubscript{2}DS\textsubscript{2}-VASc [?]2 (Steffel et al.,
2018). The proportion of patients who were prescribed an OAC,
antiplatelets alone, or neither were calculated with 95\% confidence
interval (CI) each year on 1 September from 01 September 2009 through 01
September 2018. Temporal trends were shown using graphs and a
Cochran-Armitage test for trend was used to determine if any observed
trends were statistically significant. Similarly, the proportion of
patients with moderate to high stroke risk
(CHA\textsubscript{2}DS\textsubscript{2}-VASc [?]1 and male or
CHA\textsubscript{2}DS\textsubscript{2}-VASc [?]2) or low stroke risk
(CHA\textsubscript{2}DS\textsubscript{2}-VASc =0 for male or
CHA\textsubscript{2}DS\textsubscript{2}-VASc =1 for female) who were
prescribed an OAC was calculated each year for each practice site. All
practice sites that contributed data at least for a year were included.
Prescribing rates were ranked into quintiles and used as an indicator of
general practice sites' prescribing performance. The variation between
the highest- and lowest-prescribing practice quintiles each year was
calculated as a prescribing gap.

Socio-economic indexes for areas (SEIFA) quintile is an index developed
by the Australian Bureau of Statistics (ABS) and ranks areas in
Australia from 1 (most disadvantaged area) to 5 (most advantaged area)
(Australian Bureau of Statistics, 2018). The ABS categorise rurality
into five categories using the Accessibility/Remoteness Index of
Australia (ARIA) score. These categories are major cities (ARIA 0-0.20),
inner regional (0.21-2.40), outer regional (2.41-5.92), remote
(5.93-10.53), and very remote (10.54-15) (Australian Statistical
Geography Standard (ASGS), 2017); we collapsed remote and very remote
areas into one group. SAS software (SAS version 9.4, SAS Institute Inc.,
Cary, NC, USA) was used for all data analyses, and a two-sided p-value
\textless{}0.05 was considered statistically significant.

Ethics approval was obtained from the Tasmanian Health and Medical Human
Research Ethics Committee (H0017648). We also obtained approval to
conduct this study from the MedicineInsight independent Data Governance
Committee (2018-033). Patients were not identifiable, and individual
patient consent was waived for our ethics application.

\textbf{RESULTS}

\textbf{Baseline characteristics}

The total number of patients with AF included in our consecutive
cross-sectional analyses ranged from 9,874 from 169 practice sites in
2009 to 41,751 from 429 practice sites in 2018. The mean age (standard
deviation) of patients with AF increased slightly from 75.1 (11.6) years
in 2009 to 76.0 (11.6) years in 2018. The proportion of male patients
increased from 51.4\% (95\% CI 50.4\%-52.4\%) in 2009 to 54.5\% (95\% CI
54.0\%-55.0\%) in 2018 (p for trend \textless{}0.001; Table 1).

\textbf{Oral anticoagulant prescribing}

The proportion of patients with AF and an OAC prescription recorded
decreased from 39.5\% (95\% CI 38.6\%-40.5\%) in 2009 to 35.1\% (95\% CI
34.5-35.8\%) in 2011 and then increased to 52.0\% (95\% CI
51.5\%-52.4\%) by 2018 (p \textless{}0.001; Figure 1). In all patients
with AF, lone antiplatelet prescribing dropped steadily from 17.6\%
(95\% CI 16.8\%-18.3\%) in 2009 to 2.9\% (95\% CI 2.7\%-3.0\%) in 2018
(p for decrease over time \textless{}0.001; Supplementary Table 1).
However, these latter data are unreliable as patients can obtain aspirin
without a prescription. The proportion of people who had no record of a
prescription for either treatment to prevent stroke increased from
42.9\% (95\% CI 41.9\%-43.9\%) to 51.1\% (95\% CI 50.5\%-51.7\%) in 2013
and plateaued around 47.0\% between 2014 and 2016, and then declined to
45.2\% (95\% CI 44.7\%-45.7\%) in 2018 (p for increase over time
\textless{}0.001; Supplementary Table 1).

In high-risk patients (CHA\textsubscript{2}DS\textsubscript{2}-VASc[?]2),
the proportion with an OAC prescription recorded increased from 41.7\%
(95\% CI 40.7\%-42.8\%) in 2009 to 55.2\% (95\% CI 54.7\%-55.8\%) in
2018 (p \textless{}0.001). In moderate stroke risk patients
(CHA\textsubscript{2}DS\textsubscript{2}-VASc=1 and male), the
proportion who were receiving an OAC increased from 30.9\% (95\% CI
27.2\%-34.7\%) in 2009 to 42.0\% (95\% CI 40.2\%-43.8\%) in 2018
(p\textless{}0.001). In low stroke risk patients with AF
(CHA\textsubscript{2}DS\textsubscript{2}-VASc=1 and female, 0 and male),
the proportion who were prescribed an OAC decreased from 14.6\% (95\% CI
11.8\%-17.8\%) in 2009-11.0\% (95\% CI 9.6\%-12.6\%) in 2013 and then
increased to 16.7\% (95\% CI 15.3\%-18.2\%) in 2018 (p \textless{}0.001;
Figure 1).

\textbf{General practices' prescribing performance gap over time}

In 2009, the proportion of moderate to high stroke risk patients
(CHA\textsubscript{2}DS\textsubscript{2}-VASc[?]1 and male or
CHA\textsubscript{2}DS\textsubscript{2}-VASc[?]2 and female) with AF and
an OAC prescription recorded among the lowest prescribing practice
quintile was 24.7\% (95\% CI 22.3\%-27.4\%), compared with 54.7\% (95\%
CI 52.6\%-56.9\%) in the highest quintile. By 2018, prescribing had
increased to 38.6\% (95\% CI 37.2\%-40.1\%) and 65.6\% (95\% CI
64.5\%-66.7\%) in the lowest and highest practice quintiles,
respectively. The gap between the highest- and lowest-prescribing
practice quintiles in OAC prescribing for patients with moderate to high
stroke risk remained wide, falling slightly from 30.0\% in 2009 to
25.9\% in 2018 (Figure 2).

A total of 429 practice sites contributed data in 2018. Of these, 169
(39.4\%) had provided data since 2009, of which 64 (37.9\%) of practice
sites' OAC prescribing quintile did not change, and 120 (71.0\%)
practice sites continued in the same or closest prescribing quintile.
There was a fair agreement in practices sites' prescribing quintile
between 2009 and 2018, weighted kappa=0.34 (95\% CI 0.24-0.45) (McHugh,
2012).

In 2009, the proportion of patients with AF who were prescribed an OAC
while potentially not recommended
(CHA\textsubscript{2}DS\textsubscript{2}-VASc=0 and male or
CHA\textsubscript{2}DS\textsubscript{2}-VASc=1 and female) in the
lowest- and highest-prescribing quintiles were 5.7\% (95\% CI
3.7\%-8.4\%) and 39.3\% (95\% CI 31.3\%-47.8\%), respectively. At the
end of the study period, the proportion of potentially inappropriate
prescribing in the lowest- and highest-prescribing quintiles increased
to 6.7\% (95\% CI 5.5\%-8.0\%) and 47.1\% (95\% CI 41.9\%-52.4\%),
respectively (Figure 2).

\textbf{Trends in the use of warfarin and DOACs}

Among all patients with an OAC prescription recorded, the proportion who
were prescribed a DOAC increased rapidly from 2.7\% (95\% CI
2.4\%-3.3\%) in 2011 to 76.3\% (95\% CI 75.7\%-76.8\%) in 2018, while
the proportion of those prescribed warfarin correspondingly decreased
from 97.3\% (95\% CI 96.8\%97.7\%) to 23.8\% (95\% CI 23.2\%-24.3\%)
(Figure 3).

\textbf{Discussion}

The analyses of this large and nationally representative data suggest
changing practice trends in the rate and type of OAC prescribing over
the last ten years. The proportion of patients with moderate to high
stroke risk who were prescribed an OAC increased steadily by one-third
from 2009-2018. This increase in the proportion patients with moderate
to high stroke risk who were prescribed an OAC was significantly higher
from 2013 onwards, corresponding with the PBS listing of DOACs for
Australian government subsidisation (rivaroxaban in August 2013, and
apixaban and dabigatran in September 2013) (Drug Utilisation
Sub-Committee (DUSC), June 2016). In 2010, the European Society of
Cardiology (ESC) guidelines recommended prescribing of an OAC for all AF
patients at moderate-high risk of stroke (i.e.,
CHA\textsubscript{2}DS\textsubscript{2}-VASc score [?]1) instead of
antiplatelet therapy (Camm et al., 2010). This was followed by the 2012
ESC's updated recommendation to avoid prescribing of aspirin in
low-stroke risk patients (Camm et al., 2012). These changes may also
explain the surge in OAC prescribing during the study period (Camm et
al., 2012). Similar trends of an increase in OAC use, with a slow
initial uptake after the introduction of DOACs, have been reported by
studies from the United Kingdom and Denmark (Gadsboll et al., 2017; Loo,
Dell'Aniello, Huiart \& Renoux, 2017).

In 2018, just over half of the high-risk patients were prescribed an
OAC. This rate is low compared with the rates reported from previous
studies. The Tasmanian AF study found 63\% of high-risk patients were
prescribed an OAC. However, that study involved hospitalised patients
who might have been more comorbid than general practice patients and it
excluded patients with known OAC contraindications. A study in the UK
using general practice data found that over three-quarters of high-risk
patients with AF were prescribed an OAC (Adderley, Ryan, Nirantharakumar
\& Marshall, 2018). Another study from Denmark found that two-thirds of
patients were prescribed an OAC (Gadsboll et al., 2017).

Despite an overall increase in OAC prescribing over the study period,
there remained wide gaps between the highest- and lowest-performing
practices in both appropriate (for moderate to high stroke risk) and
potentially inappropriate (for low stroke risk) prescribing, which
increased over time. One possible reason for the observed gaps in the
appropriate use of an OAC might be the absence of regular reassessment
of CHA\textsubscript{2}DS\textsubscript{2}-VASc scores. A study by Yoon
et al. (Yoon et al., 2018) found that 46.6\% of low-risk and 72\% of
moderate-risk patients at baseline were reclassified as being at high
stroke risk within 10 years of follow-up. Increasing general
practitioners' awareness of the need for annual stroke risk assessment
may improve OAC prescribing.

\textbf{Strengths and limitations}

This was the first AF study conducted using MedicineInsight dataset,
which provided a large and national study population and thus enabled an
more complete description of the GP prescribing of OACs in Australia
(Gonzalez-Chica, Vanlint, Hoon \& Stocks, 2018; MedicineInsight, 2018;
Radford et al., 2018). Furthermore, ten-year sequential cross-sectional
analyses enabled characterising the longitudinal trends in OAC
prescribing.

The study has several limitations. The MedicineInsight dataset contains
only records of medications prescribed by general practitioners.
However, general practitioners in Australia typically continue those
medications prescribed by cardiologists and so the trends described in
this study may still be considered accurate and useful with regard to
overall OAC prescribing. We did not account for medication
contraindications and adverse drug reactions that may have prevented
general practitioners from prescribing an OAC.

In this study, we used the guidelines retrospectively. For instance,
before 2012, OAC treatment was recommended for patients at moderate to
high stroke risk, and aspirin was widely used for patients at low stroke
risk (Camm et al., 2010). However, the guidelines used for this analysis
were in use for most of the study period and are appropriate to evaluate
the trends.

\textbf{Conclusion}

Over the past ten years, overall OAC prescribing increased by one-third.
By 2018, 55.2\% of the patients with a high stroke risk had an OAC
prescription recorded, with the proportion varying substantially between
practices. There remains scope to improve OAC prescribing for AF in the
primary care setting, and the reasons for withholding OAC therapy in
eligible patients need to be investigated.

\textbf{Data availability statement:}

The data for this study is not publicly as the data owner, NPS
MedicineWise MedicineInsight, restrict data sharing.

\textbf{Authors Contributions}

WB participated in the study design, data preparation and manipulation,
analysis and interpretation of the data and drafting and revising of the
manuscript. GM, LB, JR, and BW participated in the study concept and
design. GM, LB, JR, BW, MS, and CC participated in the critical revision
of the manuscript.

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