Cost-Effectiveness of Apixaban versus Warfarin in Chinese Patients with Non-Valvular Atrial Fibrillation: A Real-Life and Modelling Analyses
Cost-Effectiveness of Apixaban versus Warfarin in Chinese Patients with Non- Valvular Atrial Fibrillation: A Real-Life and Modelling Analyses
Xue Li 0 1
Vicki C. Tse 0 1
Wallis C. Y. Lau 0 1
Bernard M. Y. Cheung 1
Gregory Y. H. Lip 1
Ian C. K. Wong 0 1
Esther W. Chan 0 1
0 Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong , Hong Kong SAR , China , 2 Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong SAR , China , 3 University of Birmingham Centre for Cardiovascular Sciences, City Hospital , Birmingham , United Kingdom , 4 Research Department of Practice and Policy, School of Pharmacy, University College London , London , United Kingdom
1 Editor: Nanette H Bishopric, University of Miami School of Medicine , UNITED STATES
We used a Markov model incorporating 12 health state transitions, and simulated the disease progression of NVAF in 1,000 hypothetical patients treated with apixaban/warfarin. Risks of clinical events were based on the ARISTOTLE trial and were adjusted with local International Normalized Ratio control, defined as the time in therapeutic range. Real-life input for the model, including patients' demographics and clinical profiles, post-event treatment patterns, and healthcare costs, were determined by a retrospective cohort of 40,569 incident patients retrieved from a Hong Kong-wide electronic medical database. Main outcome measurements included numbers of thromboembolic and bleeding events, life years, quality-adjusted life years (QALYs) and direct healthcare cost. When comparing apixaban and warfarin, treatment with incremental cost-effectiveness ratio (ICER) less than one local GDP per capita (USD 33,534 in 2014) was defined to be cost-effective.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: This study was supported by a grant from
Bristol Myers Squibb and Pfizer (reference number:
260007295). EWC received financial support from
Janssen, a division of Johnson and Johnson, Bristol
Myers Squibb, Pfizer and Eisai; The Pharmaceutical
Society of Hong Kong; The University of Hong Kong;
Early Career Scheme and the General Research
Fund, Research Grants Council, Hong Kong. The
funders had no role in study design, data collection
Many of the cost-effectiveness analyses of apixaban against warfarin focused on Western populations but Asian evidence remains less clear. The present study aims to evaluate the cost-effectiveness of apixaban against warfarin in Chinese patients with non-valvular atrial fibrillation (NVAF) from a public institutional perspective in Hong Kong.
In the lifetime simulation, fewer numbers of events were estimated for the apixaban group,
resulting in reduced event-related direct medical costs. The estimated ICER of apixaban
was USD 7,057 per QALY at base-case analysis and ranged from USD 1,061 to 14,867 per
QALY under the 116 tested scenarios in deterministic sensitivity analysis. While in
and analysis, decision to publish, or preparation of
Competing Interests: EWC received financial
support from Janssen, a division of Johnson and
Johnson, Bristol Myers Squibb, Pfizer and Eisai; The
Pharmaceutical Society of Hong Kong; The University
of Hong Kong; Early Career Scheme and the General
Research Fund, Research Grants Council, Hong
Kong. There are no patents, products in
development, or marketed products to declare. This
does not alter the authors’ adherence to PLOS ONE
policies on sharing data and materials.
probabilistic sensitivity analysis, the probability of apixaban being the cost-effective
alternative to warfarin was 96% and 98% at a willingness to pay threshold of USD 33,534 and
100,602 per QALY, respectively.
Apixaban is likely to be a cost-effective alternative to warfarin for stroke prophylaxis in Chinese patients with NVAF in Hong Kong.
Non-valvular atrial fibrillation (NVAF), the most common sustained cardiac arrhythmia,
affects 1–2% of the general population worldwide and its prevalence increases with age [
As one of the risk factors for stroke and systemic embolism, NVAF is associated with
longterm morbidity, impaired quality of life, mortality and considerable financial burden. The
healthcare cost for patients with NVAF is estimated to increase 1.6–3.1 fold after the
occurrence of thromboembolic events, particularly in the first three years . Therefore, stroke
prevention in patients with NVAF is important from both individual and societal perspectives.
Long-term anticoagulation management is required for stroke prophylaxis in patients with
NVAF. Traditionally, warfarin (a vitamin K antagonist) has been the most commonly used
]. However warfarin poses challenges with respect to clinical management due
to its narrow therapeutic range and drug metabolism affected by multiple factors such as
genetic variables, diet and drug interactions[
]. Apixaban (a novel direct factor Xa inhibitor)
was therefore developed as an alternate anticoagulant. A multinational trial of ARISTOTLE
(Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation)
demonstrated apixaban to be superior to warfarin in prevention of ischaemic stroke (21%
reduction), bleeding (31% reduction) and mortality (11% reduction) without the need for
]. Recent subgroup analysis of the landmark trial showed consistent protective effect
of apixaban on stroke, bleeding and mortality in East Asian and non-East Asian patients [
In addition to improved clinical efficacy and safety compared against standard treatment,
cost-effectiveness is also an important consideration for new treatments in the setting of
increased healthcare costs globally. Apixaban has been found to be cost-effective against
warfarin in Europe [
], Australia  and USA [
]. Notably, the current CE literature all
focused on Western populations. Although Asians and Westerns share similar risk factor
profiles, they might not be the same due to more history of stroke, increased tendency to bleed and
suboptimal international normalised ratio (INR) control when treated with warfarin [
These factors may have an impact on the cost-effective manner of anticoagulation therapies.
Hence, it is important to incorporate local data to evaluate CE in the Asian population. The
objective of the present study is to evaluate the cost-effectiveness of apixaban versus warfarin
for stroke prophylaxis in Chinese patients with NVAF, from the public institutional perspective
in Hong Kong.
The research protocol was approved by the Institutional Review Board of the University of
Hong Kong/Hospital Authority Hong Kong West Cluster, Hong Kong. No written informed
consent was obtained from patients for their clinical records to be used in this study, due to
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this is a retrospective study based on electronic medical database. All of the patient records/
information was anonymized and de-identified prior to analysis.
This study compares the cost-effectiveness of apixaban against warfarin in Chinese patients
with NVAF using a Markov model. Data sources and the retrieval procedure are illustrated in
Fig 1. Lifetime cost and health outcomes were estimated from Markov cohort simulations. A
retrospective cohort study was conducted to obtain real-life data for the model inputs. Clinical
event risks were based on the ARISTOTLE trial [
] and incorporated by local INR control.
Where local data were not available, data retrieved from comprehensive literature review and
expert opinion were used. Baseline inputs are listed in Tables A and B in S1 File. Model inputs
were entered, cross-checked and analysed independently by two researchers.
A previously developed Microsoft Excel Markov model incorporating 12 health states was
adapted to simulate lifetime disease progression in 1,000 patients treated by apixaban (5mg
BID) or warfarin (any strength)[
]. The health states modeled include NVAF, ischaemic
stroke, systemic embolism, myocardial infarction, bleeding and death. A simplified schematic
representation of the model structure and the health states transitions starting from NVAF are
shown in Figures A and B in S1 File. A detailed description of the model can be found in
previous publications [
8, 10, 15
]. For each treatment group, the number of events in each health
state, life years (LYs), quality-adjusted life years (QALYs) and direct healthcare cost were
calculated at the end of each model cycle and accumulated across lifetime.
The target population of the model are patients with NVAF who are suitable for warfarin
therapy. Patient profiles were determined by a retrospective cohort analysis of incident patients
with NVAF in the Clinical Data Analysis and Reporting System (CDARS). In brief, CDARS is
an electronic medical database in Hong Kong that covers a population of over 7 million
utilising public healthcare services and accounts for 80% of inpatient records in the territory [
De-identified electronic patients’ records, including demographics, diagnoses, procedures,
drug descriptions, laboratory tests and date of consultation, hospital admission and discharge,
were all imported to CDARS for audit and research purposes.
At the time of the study, CDARS was unable to identify patients with NVAF directly. Target
patients were identified by first retrieving patients with documented diagnosis of atrial
fibrillation from Jan 1st 2010 to Dec 31st 2013 using ICD-9 diagnosis codes (Table C in S1 File for
ICD-9 codes used). Among these patients, those with diagnoses of valvular heart disease,
hyperthyroidism or had undergone valvular replacement surgery within 1 year prior to the
index date were further excluded according to corresponding ICD-9 codes. The follow-up of
each patient was commenced from the index date until the occurrence of any clinical events,
death or July 31st 2014, whichever came first. This resulted in the identification of 40,569
eligible patients with 76,196 patient-years of follow-up. The key demographic and clinical profiles
of these patients are shown in Table 1.
Risk of clinical events
The clinical event rates of apixaban and warfarin were obtained from the ARISTOTLE trial [
As the risk of ischaemic stroke and bleeding associated with warfarin are highly dependent on
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Fig 1. Data sources for Markov cohort simulation. ARISTOTLE: Apixaban for Reduction in Stroke and Other Thromboembolic
Events in Atrial Fibrillation; CDARS: Clinical Data Analysis and Reporting System of Hong Kong; NVAF: non-valvular atrial
the quality of INR control [
], the model was developed to adjust the event risks by local
INR control. Time in therapeutic range (TTR) distribution was defined as the indicator of INR
control and collected from the CDARS retrospective cohort study.
Fatality and mortality
For thromboembolic and bleeding events, annual case-fatality rates were estimated from the
CDARS retrospective cohort study. All-cause mortality was modelled based on life tables in the
general population, adjusting by age, gender and the occurrence of NVAF and relevant co-morbidities.
Healthcare resource consumption regarding anticoagulation management was reflected by the
frequency of routine care and monitoring visits, proportion of patients experiencing dyspepsia
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and proportion of patients requiring annual renal monitoring whilst on treatment from the
CDARS retrospective cohort (Table A in S1 File).
Treatment pattern post-events
Treatment patterns post-event were determined from the CDARS retrospective cohort study,
published literature or expert opinion wherever appropriate (Table A in S1 File). Following all
bleeding events, a certain number of patients were assumed to switch to aspirin as second line
treatment. The rate of treatment switch (± 90 days of the event index date) was determined by
retrieving prescription records from CDARS and literature. The remaining patients were
modelled to have their original treatment interrupted for 6 weeks then restarted [
] (i.e. as shown
in Table A in S1 File, post intracranial haemorrhage, 44% of patients switched to aspirin and
the remaining 56% discontinued their original treatment temporarily and restarted the same
treatment 6 weeks later). [
]Following occurrence of ischaemic stroke and systemic embolism,
all patients were assumed to continue the original treatment as advised by experts.
Utility for NVAF was adopted from Ho et al [
], which was the only study to assess the health
utility of Hong Kong patients with NVAF on oral anticoagulants. Due to the absence of
population-specific utility estimations, a UK-based utility catalogue was adopted for other health
]. Marginal disutility was assumed to be associated with INR monitoring when treated
with warfarin due to the required blood test [
]. All utility inputs were discounted at 3.5% per
year and detailed in Table B in S1 File.
The analysis was conducted from a public institutional perspective in Hong Kong so only direct
medical costs were considered. Costs are presented to the value of US dollars in 2014 (1 USD
to 7.75 HKD) and discounted at 3.5% per year according to cost-effectiveness analyses (CEA)
The total cost components are outlined in Table B in S1 File. Daily drug costs for warfarin
and apixaban were based on local retail prices (internal communication with Bristol-Myers
Squibb, Hong Kong, November 2014). Annual monitoring and management costs were
determined by multiplying the cost for blood and renal tests per visit by number of clinical visits per
patient from the CDARS retrospective cohort. Similarly, acute care costs associated with
clinical events were calculated by multiplying daily inpatient charges in public hospital [
the average hospital length of stay estimated from the same cohort. Long-term care costs
include medication costs only.
We compared the cost-effectiveness of apixaban versus warfarin by assessing the differences in
lifetime cost and clinical benefits. Base-case analysis was performed based on model inputs described
earlier. Treatment with incremental cost-effective ratio (ICER) less than the willingness-to-pay
(WTP) threshold of one local GDP per capita (USD 33,534 in 2014 [
]) for each QALY gained
was considered a cost-effective alternative as recommended by the WHO-CHOICE guideline [
The effect of uncertainties in the base-case analysis was evaluated by deterministic and
probabilistic sensitivity analyses (SA). In deterministic SA, each of the 116 input parameters
varied from a predefined range (95% CI or SD, as listed in Tables A and B in S1 File) while all
the others were constant to project its effect on ICER. All tested parameters were ranked
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according to ICER variation and the top 15 most influential parameters were presented in
In probabilistic SA, probability distributions were assigned to each parameter (gamma
distribution to event rates, beta distribution to utilities and log-normal distribution to cost) and
varied simultaneously in 2,000 iterations for the pair-wise comparisons. The cost and health
outcomes were further assessed using cost-effectiveness acceptability curves (CEACs). Two
willingness-to-pay (WTP) thresholds, one-time and three-times of local GDP per capita (USD
33,534 and USD 100,602 in 2014 [
]) were applied to explore the proportion of acceptable
trials for each treatment.
From a cohort of 1,000 patients over a lifetime, the use of apixaban was predicted to result in 116
fewer NVAF-related events (12 fewer ischaemic strokes, 15 fewer haemorrhagic strokes, 12 fewer
other intracranial haemorrhages, 25 fewer other major bleeds, 2 fewer myocardial infarctions)
and 31 fewer event-related deaths than patients treated with warfarin in the base-case analysis
(Table 2). Compared with warfarin, 36 patients need to be treated with apixaban to avoid one
additional stroke, and apixaban is the dominant treatment in reducing bleeding events.
The cost of treating one patient with apixaban was USD 1,228 more than warfarin
(Table 2). This was predominantly attributed to the higher drug price of apixaban, in contrast
to lower costs related to management, monitoring and clinical events. Compared with
warfarin, the net cost, net health benefits and incremental cost-effective ratios of apixaban were
detailed in Table 3.
Deterministic sensitivity analyses
As illustrated in Fig 2, tested model inputs had limited impact on the ICER. The ICER ranged
from USD 1,061 to 14,867 per QALY gained under 116 tested scenarios, all of which were
within the threshold of USD 33,534 per QALY (one local GDP per capita). Uncertainties in
drug costs, the risk of cardiovascular hospitalisation for both treatments, risk of ischaemic
stroke for apixaban and risk of intracranial haemorrhage for warfarin had greatest impact on
Probabilistic sensitivity analyses
The probabilistic sensitivity analysis demonstrated that apixiban is more cost-effective against
warfarin over a life-time horizon (Fig 3). ICER was below the threshold of USD 33,534 per
QALY (one local GDP per capita) in 96% of the trials. When the upper range of the WHO
threshold of USD 100,602 per QALY gained (three-times of local GDP per capita) was applied,
98% of the trials supported the cost-effectiveness of apixaban.
The uncertainties in the cost-effective estimates are further summarised in the
cost-effectiveness acceptability curve in Fig 4. This demonstrates that apixaban was a superior treatment
choice representing the maximum net benefit over warfarin, when payers are willing to pay
USD 7,500 or above for one QALY gained.
Summary of findings
In this study, our principal findings were as follows: (i) fewer thromboembolic events were
estimated for the apixaban group in the lifetime cohort simulations, resulting in corresponding
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increased LYs, QALYs and reduced event-related healthcare costs; (ii) compared with warfarin,
apixaban presented an ICER of USD 1,061–14,867 per QALY gained which is within the
common acceptable WTP of one local GDP per capita as recommended by the WHO[
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Fig 2. Tornado diagram of apixaban versus warfarin.
both deterministic and probabilistic sensitivity analyses support the cost-effectiveness of
apixaban over a range of uncertainties. This study utilises the strength of CDARS, which collects
clinical data in the public healthcare setting across the whole territory. As far as we are aware,
this is the only study which utilises real-life, Hong Kong-specific cost, patient demographics
and clinical profiles, treatment patterns and case fatality rates to compare the cost-effectiveness
of apixaban versus warfarin.
The greater health benefits and cost-effectiveness of apixaban findings in this study are in
line with other modeling CE studies conducted in western developed countries [
]. Lee et al
demonstrated apxiaban as a dominant strategy (both cost and life year savings) from the US
Medicare perspective , while the remaining four studies all found apixaban more
costeffective against warfarin in Australia, Netherlands, Sweden and United Kingdom at ICERs of
], EUR 10,576[
], SEK 33,458[
], GBP 11,909[
] per QALY respectively,
applying locally relevant WTP thresholds.
In light of the widely reported cost-effectiveness of apixaban in Caucasians, evaluation of the
Asian population is still limited. However, from a clinical perspective, Asian and Western
patients with AF are not necessarily the same. Firstly, among the five components of the
CHADS2 (congestive heart failure, hypertension, age 75 years, diabetes mellitus and stroke)
score, similar risk factor profiles were shared, except previous stroke is more prevalent in
Asians (29% vs. 18%) [
]. Secondly, stroke risk is higher in Asians when treated with warfarin
as reflected in the subgroup analysis of ARISTOTLE trial (3.4% vs. 1.4%) [
]. Thirdly, despite
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Fig 3. Probabilistic sensitivity analysis of apxiaban versus warfarin.
a lower INR in general, warfarin users in Asia are more likely to bleed than non-Asians (3.8%
vs. 3.0%) [
]. Although the mechanism for these differences remains to be determined, they
may all challenge the proper use and cost-effectiveness of warfarin and its alternatives in Asia.
For the first time, our analysis showed that apixaban is cost-effective in a Chinese population.
This is an important ethnic group in Asia with a high prevalence of stroke [
] and rapidly
increasing ageing population [
], which highlights the prominence of this study.
Another important differentiator and strength of our study is the use of real-life, local INR
control data in our model. It is well documented in the published literature that good INR control,
although important for good clinical outcome [
], is unusual in both clinical trial [
real-life settings [
]. The ARISTOTLE trial reported that only 50% of warfarin patients have
TTR 66.0% [
]. Hong Kong practice is not an exception. Consistent with our findings from
the CDARS retrospective cohort study, which found a median TTR of 40.9%, Ho et al also
reported unsatisfactory INR control among patients in Hong Kong with similar TTR (median:
]. As TTR is negatively correlated with bleeding and thromboembolic events [
suboptimal INR control in real-life may worsen the performance of warfarin [
health benefits offered by apixaban may be greater than that in the clinical trial setting for
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Fig 4. Cost-effectiveness acceptability curves of apixaban and warfarin.
patients with poor TTR [
] when compared to warfarin. By incorporating real-life INR control
for event risks adjustment, our study provides a more realistic picture compared to previous
studies where the risks were based on clinical trials [
] or tested in scenario analyses [
Of note, variations in healthcare system and services have been well recognised worldwide
] and this is another key reason why country-specific CEA needs to be conducted. This
study summarised local relevant information and will contribute to anticoagulation policy
consideration in Hong Kong and other Asian countries with similar healthcare systems.
There are limitations in this modeling analysis. Firstly, clinical efficacy and safety parameters
were based on the landmark trial with 1.8 years of follow-up. They were assumed to be constant
over the lifetime in the model, but might not reflect the long-term performance of treatments
in real terms. Secondly, following a major bleeding event, treatment options were limited to
switching to aspirin or restarting the original anticoagulant in 6 weeks. In real-life clinical
practice, some patients may cease treatment or choose other anticoagulants. However, aspirin is
perceived as a safer alternative to oral anticoagulants in the Chinese population [
] given the
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particular concerns of increased bleeding risk among the Chinese [
]. As indicated in our
previous work , more than twice the number of NVAF patients was receiving antiplatelet
drugs including aspirin, compared to oral anticoagulants in Hong Kong, despite having a
higher risk of stroke (CHADS2 2). In addition, the cut-off point of assessing treatment switch
was restrict to 90 days, based on Witt et al’s study on the association of warfarin interruption
and gastrointestinal tract bleeding . This may be arbitrary as there are no published
guidelines on the optimal anticoagulation approach for those experiencing a thromboembolic event
at the time our study was conducted . Thirdly, in the baseline analysis, we optimistically
assumed no renal monitoring was required for patients on apixaban based on the subgroup
analysis of ARISTOTLE  which may not be the case in real clinical practice. The subgroup
analysis was pre-specified for patients with impaired renal function and showed that apixaban
was more effective than warfarin in preventing stroke or systemic embolism and reducing
mortality, irrespective of renal function. Considering the median age of 78.9 years in this cohort of
patients, we analysed two other scenarios—assuming 50% and 100% of patients will have their
renal function evaluated annually, respectively, whilst on apixaban. Both scenarios show that
the frequency of renal monitoring had very limited impact on the ICERs (USD 7,270 and USD
7,482 per QALY saved respectively) therefore baseline conclusions remains robust. Fourthly,
treatment attributes such as convenience of drug administration, food and drug interaction
were not included in this model, which may underestimate the benefits of apixaban. Lastly, the
estimate for acute event cost per episode was restricted to general ward charges only and the
costs of emergency and intensive care or rehabilitation have not been included. These would
have led to underestimates of event related costs for both groups.
In conclusion, the current comprehensive modeling assessment based on real-life, local clinical,
economic evidence and ARISTOTLE trial, demonstrate that apixaban is a cost-effective
alternative against warfarin for the prevention of stroke and bleeding events in Chinese patients
with NVAF. Our results suggest that apixaban is relatively more favourable in terms of health
benefits and incremental cost.
S1 File. Figure A. Schematic representation of Markov model. NVAF: non-valvular atrial
fibrillation. Figure B. Health states transitions from NVAF. CRNM Bleed: Clinically relevant
non-major bleed; ICH: Intracerebral haemorrhage; NVAF: Non-valvular atrial fibrillation;
NVAF without original anticoagulation: patients with NVAF who discontinue the initially
assigned anticoagulation treatment but have not yet experienced any of the events including
ischaemic stroke, haemorrhagic stroke, myocardial infarction, systematic embolism or death.
Table A. Base-case and sensitivity analyses inputs for clinical events, deaths, post-event
treatment and anticoagulation management. Table B. Base-case and sensitivity analyses
inputs for utility and cost. Table C. The ICD-9 codes (diagnosis codes unless other
specified) used in this study. Supplemental References.
We thank our colleague in the Department of Pharmacology and Pharmacy of the University
of Hong Kong–Dr. Shweta Anand for literature search and review; and Ms. Lisa Wong for the
proofreading our manuscript.
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Conceived and designed the experiments: EWC XL IW. Performed the experiments: XL WL.
Analyzed the data: XL WL. Contributed reagents/materials/analysis tools: EWC IW. Wrote the
paper: XL VT WL BC GL IW EWC.
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