Cost Effectiveness of Apixaban vs. Other (1)

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Cost-Effectiveness of Apixaban vs. Other New Oral Anticoagulants for the
Prevention of Stroke: An Analysis on Patients with Non-Valvular Atrial
Fibrillation in the Greek Healthcare...
Article  in  Clinical Drug Investigation · September 2015
DOI: 10.1007/s40261-015-0321-7

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Clin Drug Investig
DOI 10.1007/s40261-015-0321-7

ORIGINAL RESEARCH ARTICLE

Cost-Effectiveness of Apixaban vs. Other New Oral
Anticoagulants for the Prevention of Stroke: An Analysis
on Patients with Non-Valvular Atrial Fibrillation in the Greek
Healthcare Setting
Kostas Athanasakis1 • Eleftheria Karampli1 • Dimitrios Tsounis2
Aikaterini Bilitou2 • John Kyriopoulos1

•

Ó Springer International Publishing Switzerland 2015

Abstract
Background and Objectives Three new oral anticoagulants (NOACs) are currently approved for stroke prevention and systemic embolism in patients with non-valvular
atrial fibrillation (NVAF). The objective of this analysis
was to assess the cost effectiveness of apixaban against
other NOACs for the prevention of stroke in patients with
NVAF in Greece.
Methods A Markov model that evaluated clinical events,
quality-adjusted life expectancy, and costs for patients
treated with apixaban or other NOACs formed the basis of
the analysis. Clinical events were modeled for a lifetime
horizon, based on clinical efficacy data from an indirect
comparison, using the ARISTOTLE, ROCKET-AF, and
RE-LY clinical trials. Resource use associated with patient
monitoring was elicited via a panel of experts (cardiologists and internists). Cost calculations reflect the local
clinical setting and followed a third-party payer perspective

(Euros, discounted at 3 %).
Results Apixaban was projected to reduce the occurrence
of clinical events and increase quality-adjusted life
expectancy and incremental costs of treatment compared
with other NOACs. Taking into account costs of medications, patient monitoring, and management of events, the
incremental cost-effectiveness ratios for apixaban 5 mg

twice daily vs. dabigatran 110 mg twice daily, dabigatran
150 mg twice daily, and rivaroxaban 20 mg once daily
were estimated at €9907/quality-adjusted life-year
(QALY), €13,727/QALY, and €6936/QALY gained,
respectively. Extensive sensitivity analyses indicated that
results were robust over a wide range of inputs.
Conclusions Based on the results of this analysis, apixaban can be a cost-effective alternative to other NOACs for
the prevention of stroke in patients with NVAF in Greece.

Key Points
New oral anticoagulants (NOACs) are the preferred
option to vitamin K antagonists in the majority of
patients with non-valvular atrial fibrillation (NVAF).

Apixaban is approved for the prevention of stroke
and systemic embolism in adult patients with NVAF,
with one or more risk factors.
Patients treated with apixaban were predicted to
experience fewer major cardiovascular events and a
lower number of cardiovascular-related deaths and
hospitalizations compared with those taking the
comparator NOACs.
The projected treatment cost of apixaban over a
lifetime was higher than for other NOACs; however,
it was mostly offset by the reduction in the
occurrence of clinical events

& Eleftheria Karampli
ekarabli@esdy.edu.gr
1

Department of Health Economics, National School of Public
Health, Athens, Greece

2

Pfizer Hellas, Athens, Greece

The incremental cost-effectiveness ratio of apixaban
relative to other NOACs ranged between €5300 and
€12,900 per quality-adjusted life-year gained,
constituting apixaban as a cost-effective therapeutic
option for the target population

K. Athanasakis et al.

1 Introduction
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a significant cause of cardiovascular
morbidity and mortality [1]. The overall prevalence of AF is
estimated at 0.9–1.2 %, rising to 3–5 % in people aged
65–80 years and to 10 % in those aged older than 80 years
[1–4]. Population aging, improved survival rates for patients
with cardiovascular diseases, and prolonged exposure to
predisposing cardiovascular risk factors will contribute to a

considerable increase in AF prevalence in the future [5]. AF
is an independent risk factor for stroke [6]; furthermore,
strokes related to AF are typically more severe and result in
higher disability and mortality [7]. Apart from its clinical
consequences, AF poses a significant financial burden on the
healthcare system, driven mostly by hospitalizations [8–10].
Evidence from the Berlin Acute Stroke Study also suggests
that acute hospitalization costs are higher for patients
experiencing an AF-related stroke [11].
Prevention of thromboembolism is one of the key goals in
AF management [12]. Until a few years back, vitamin K
antagonists (VKAs) (e.g., warfarin, acenocoumarol) were
recommended for patients with non-valvular AF (NVAF) and
moderate-to-high risk of stroke, whereas antiplatelet therapy
(aspirin plus clopidogrel or aspirin monotherapy) was considered an option in patients at low risk when oral anticoagulation was contraindicated or refused [13, 14]. Although
VKAs have been proven effective, in both randomized trials
and large ‘‘real-world’’ studies [15], their use presents
important limitations associated with their narrow therapeutic
range, interactions with drugs and foods, high risk of adverse
events including hemorrhages, and frequent monitoring

requirements [14, 16]. These limitations, together with
patient, physician, and healthcare system factors have been
connected to the underuse of anticoagulation therapy and
poor adherence to guidelines in clinical practice [17].
The need for novel anticoagulants that address these
limitations has led to the development of two classes of new
oral anticoagulants (NOACs): the oral direct thrombin inhibitors (e.g., dabigatran) and oral direct factor Xa inhibitors
(e.g., rivaroxaban, apixaban, edoxaban) [18]. In clinical trials, NOACs have demonstrated non-inferiority compared
with VKAs and an improved safety profile regarding bleeding complications [18]. Furthermore, NOACs are used in
fixed doses with no need for regular laboratory monitoring
[12]. On this basis, the updated 2012 guidelines from the
European Society of Cardiology recommend NOACs as
preferable to VKAs in the majority of patients with NVAF,
and suggest that antiplatelet therapy be limited to patients
who refuse any form of oral anticoagulant [18].

Apixaban, has been approved by the European
Medicines Agency for the prevention of stroke and
systemic embolism in adult patients with NVAF, with
one or more risk factors, such as having had a previous

stroke, high blood pressure, diabetes mellitus, heart
failure, or being C75 years old [19]. In two randomized
clinical trials for stroke prevention in AF [20, 21],
apixaban was superior to warfarin and aspirin among
those patients who were unsuitable or refused to receive
warfarin [12].
In Greece, the prevalence of cardioembolic strokes is
higher than in other European countries; in addition, a
significant proportion of patients with a first-ever cardioembolic stroke have experienced AF [22–24]. Future
trends such as population aging and increasing prevalence
of obesity and diabetes are expected to increase AF
prevalence and the risk for cardiovascular disease [23],
thus leading to higher demand for anticoagulation therapy. Currently, all three NOACs are included in the
positive list of medicines reimbursed by social insurance.
From the decision-makers’ perspective, it is important to
evaluate both costs and outcomes related to the introduction of each of the NOACs in clinical practice. Costeffectiveness analysis (CEA) assesses the (incremental)
cost and (incremental) benefit (in terms of relevant health
outcomes) of a health technology. CEA is increasingly
used internationally to inform drug reimbursement decisions and development of guidelines on cost-effective
prescribing [25]. A plethora of published CEAs have

compared dabigatran, rivaroxaban, and apixaban to VKAs
(mainly warfarin). All three NOACs have consistently
presented favorable cost-effectiveness ratios as alternatives to VKAs for stroke prevention in AF [26, 27], thus
gaining ground as treatment options. Apart from the costeffectiveness evidence, NOACs are expected to be widely
used in the near future, following their rapid current
uptake, as documented by recent studies [28, 29]. In this
light, cost-effectiveness analyses among the newer alternatives are of value, to inform current and future decisions on the costs and outcomes for each of the available
NOACs for the treatment of NVAF patients that follow
anticoagulation. This evaluation of the impact of NOACs
from a clinical, organizational, and cost perspective on the
Greek healthcare system is necessary to inform decision
making, especially under the current pressure of financial
constraints.
Given the above, the purpose of the present study was to
perform the first CEA of apixaban compared with other
NOACs (rivaroxaban or dabigatran) for patients with AF in
Greece.

CE of Apixaban vs. Other NOACs for the Prevention of Stroke in Greece

2 Methods
2.1 Health Economics Model
A previously developed Markov model that simulated
clinical events, quality-adjusted life years (QALYs), and
costs for a cohort of patients with NVAF subsequent to
treatment with apixaban or other NOACs formed the basis
of the analysis [30] (Fig. 1). The model was adapted to
reflect resource use and cost data from a Greek healthcare
perspective.
Patients in the Markov model are assumed to start in the
NVAF health state (Fig. 1). As the simulation progresses,
patients either remain at the NVAF state or move to other
health states based on specific transition probabilities, i.e.,
patients may experience disease episodes, such as ischemic
stroke, systemic embolism, myocardial infarction (MI), or
bleeding (intracranial hemorrhage (ICH), other major

bleeds, clinically relevant nonmajor (CRNM) bleeds). Nonfatal strokes (ischemic as well as hemorrhagic) are classified according to severity, based on the modified Rankin
Scale (mRS) score into three categories, i.e., mild (mRS:
0–2), moderate (mRS: 3–4), and severe (mRS: 5). Patients
in the model are subject to the risk of one recurrent stroke
event, in which case they are transitioned to the most
severe health state between primary and recurrent stroke
and remain there until death. An additional health state in
the model (‘‘NVAF with subsequent aspirin treatment’’) is
incorporated to simulate the clinical pathway of patients
that discontinue their first-line treatment and switch to
aspirin. In this case, transition probabilities for subsequent
events are those that correspond to the second-line therapy
with aspirin.
Finally, death is an absorbing state in the model with
patients simulated to die either due to a clinical event or
general (‘‘background’’) mortality.

Fig. 1 Outline of the Markov model. Modified after Lip et al. [30]. AC anticoagulant, ASA aspirin, CRNM clinically relevant nonmajor, HS
hemorrhagic stroke, ICH intracranial hemorrhage, IS ischemic stroke, NVAF non-valvular atrial fibrillation

K. Athanasakis et al.
Table 1 Clinical event rates for apixaban and comparators
Clinical event

Apixaban (rate/100 PY)

Hazard ratio vs. apixaban
Dabigatran (110 mg)

Dabigatran (150 mg)

Rivaroxaban
0.980

Stroke

0.981

1.198

0.823

Intracranial hemorrhage

0.330

0.733

1.020

1.731

Other major bleed

1.790

1.205

1.371

1.436

Clinically relevant nonmajor bleed

2.083

1.155

1.303

1.488

Myocardial infarction

0.530

1.474

1.456

0.935

Systemic embolism

0.090

1.000

1.000

1.000

Other CV hospitalization
Other death rate

10.460
3.0825

1.000
1.000

1.000
1.000

1.000
1.000

Other treatment discontinuation

13.177

1.452

1.505

1.184

Source: modified after Lip et al. [30]
CV cardiovascular, PY patient-years

The model follows a lifetime horizon (running until all
patients in the initial cohort are transferred to the ‘‘death’’
state) in 6-week cycle iterations.
2.2 Patient Characteristics
The baseline patient cohort of the model follows the
characteristics of patients enrolled in the ARISTOTLE
(Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) clinical trial [20],
i.e., patients in the analysis are VKA suitable, 64.7 % were
male, with a mean age of 70 years and an average CHADS2
score of 2.1.
2.3 Efficacy Considerations for Comparators
The key efficacy measure for each comparator is the rate of
occurrence of the clinical events included in the model. In
the case of apixaban, clinical event rates were obtained
from the ARISTOTLE clinical trial (apixaban 5 mg twice
daily vs. warfarin, dose adjusted to maintain an international normalized ratio of 2.0–3.0) [20]. In the absence of
head-to-head clinical trials between NOACs, comparative
efficacy data for other NOACs are based on an indirect
comparison as per the strategy and methodology proposed
by Lip et al. [30]. Specifically, comparative efficacy data
are produced by an indirect treatment comparison based on
the data from the phase III clinical trials of each of the
medication under evaluation, using warfarin as the common comparator. Studies included in the indirect comparison were the ARISTOTLE [20] trial, the ROCKET–AF
(Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition
Compared With Vitamin K Antagonism for Prevention of
Stroke and Embolism Trial in Atrial Fibrillation) [31] trial
(rivaroxaban, 20 mg once daily vs warfarin, INR 2.0–3.0),
and the RE-LY (Randomized Evaluation of Long-Term

Table 2 Clinical event rates for patients who receive aspirin after
first-line treatment discontinuation
Clinical event

Rate/100 PY

Stroke

3.453

Intracranial hemorrhage

0.322

Other major bleed

0.887

Clinically relevant nonmajor bleed

2.936

Myocardial infarction

1.110

Systemic embolism

0.400

Source: modified after Lip et al. [30]
PY patient-years

Anticoagulation Therapy) trial (dabigatran, 110 mg twice
daily vs dabigatran 150 mg twice daily vs. warfarin, INR
2.0–3.0) [32]. For each comparator, hazard ratios (HRs)
were calculated that were subsequently applied to the
clinical event rates observed in patients treated with apixaban. Table 1 depicts clinical event rates for apixaban and
the HRs calculated for comparator treatments. The indirect
comparison strategy is described in detail in the publication
by Lip et al. [30].
The rates of clinical events for patients in the
‘‘NVAF with subsequent aspirin treatment’’ health state
(Table 2) were based on a subgroup analysis of patients
in the AVERROES (Apixaban Versus Acetylsalicylic
Acid to Prevent Strokes) trial [21], who had discontinued VKA treatment and were subsequently treated
with aspirin.
Because aging is an important risk factor for the
occurrence of cardiovascular events, an adjustment should
be made to avoid miscalculations during the projections in
the model. Based on literature data, ischemic stroke,
bleeding, and MI risks were adjusted by a factor of 1.46
[33], 1.97 [34], and 1.30 [35] per decade, respectively, to

CE of Apixaban vs. Other NOACs for the Prevention of Stroke in Greece
Table 3 Distribution (%) of
stroke severity and case fatality
rate (mRS 6) by treatment

Stroke severity

Apixaban

Aspirin

Dabigatran
(110 mg)

Dabigatran
(150 mg)

Rivaroxaban

Mild (mRS 0–2)

53

36

35

35

49

Moderate (mRS 3–4)

21

38

28

22

18

8

15

10

8

6

18

11

27

35

27

Stroke

Severe (mRS 5)
Fatal (mRS 6)
Hemorrhagic stroke
Mild (mRS 0–2)

23

7

35

35

49

Moderate (mRS 3–4)

32

20

28

22

18

Severe (mRS 5)

10

27

10

8

6

Fatal (mRS 6)

35

46

27

35

27

Source: Modified after Lip et al. [30]
mRS modified Rankin scale

incorporate the factor of aging. Risk of stroke recurrence
was derived from a subgroup analysis of patients with AF
from the South London Stroke Registry [36]. Severity
distributions for stroke and hemorrhagic stroke, respectively, by treatment were used as previously published [30]
(Table 3).
Data regarding fatal events due to other ICH and other
major bleeds were derived from pooling the events
observed in the AVERROES and the ARISTOTLE trials,
calculating a case fatality rate of 13 % for other ICH and
2 % for other major bleeds in the case of apixaban and
aspirin. Results were applied across all treatment
comparators.
2.4 Cost Calculations
Cost calculations in the analysis follow a third-party payer
perspective, include direct medical costs (only), and are
reported in year 2013 values. Given the time horizon of the
analysis, discounting was deemed necessary; therefore
costs and outcomes were discounted at a 3 % rate per
annum. Prices for medications were sourced from the most
recent official price list available at the time of model
adaptation [37]. Patients who experience an event in the
model are assigned a cost per acute care episode as well as
a per month long-term maintenance cost. Acute care episode costs were sourced from the Greek Diagnosis-related
group (DRG) price list and the study by Gioldasis et al.
[38] (costs updated to year 2013 values). Maintenance
costs were calculated based on the proportion of the acute
to total per year costs, as reported previously [39], and the
allocation of (the remaining) maintenance costs on a
monthly basis. Resource use associated with patient monitoring was elicited via a panel of experts (cardiologists and
internists). Unit costs for medications and events are
reported in Table 4.

2.5 Utilities
Utility inputs were derived from a UK-based utility catalog
[40] and presented in Table 5. The calculation method for
utility estimations subsequent to events is based on
assigning a baseline utility to all patients with AF and
subtracting a disutility decrement, specific to the event that
is modeled for a particular duration of time; utility decrement durations were used as previously published [30].
2.6 Sensitivity Analyses
To test the robustness of findings, probabilistic sensitivity
analysis (PSA) was conducted by simultaneously drawing
random values from a series of variables, based on a set of
pre-specified types of distributions for each variable and
calculating incremental cost- effectiveness ratios (ICERs).
Beta distributions were used for utilities and for the probabilities of clinical events. Dirichlet distributions were fitted for the distributions of patients among a number of
different occurrences, such as by stroke severity. The
characteristics of the gamma distribution (non-negative
results, skewness) rendered it suitable for the simulation of
cost inputs [41].
In addition to the PSA, a series of one-way deterministic
sensitivity analyses were performed by varying a number
of variables by ?10/-10 % of their original (baseline)
values to estimate their effect to the baseline ICER
calculations.

3 Results
Based on simulation of a cohort of 1000 patients with AF
in a lifetime horizon, apixaban was predicted to reduce the
occurrence of major CV events (mainly ischemic and

K. Athanasakis et al.
Table 4 Medication and
clinical event costs

Medications

Cost/tablet (€)a

Apixaban 5 mg/tablet

1.25

10

Dabigatran 110 mg/tablet

1.12

220

Dabigatran 150 mg/tablet

1.28

300

Rivaroxaban 20 mg/tablet

2.52

20

Clinical event costs

c

Acute (cost/episode, €)

Daily dosage (mg)b

Maintenance (cost/month, €)

Ischemic/hemorrhagic stroke
Mild

2900.50

295.42

Moderate

3204.20

326.35

Severe

6061.80

617.41

Fatal

4168.80

Systemic embolism

3069.00

Other intracranial hemorrhage (ICH)

2161.00

312.58

Other major bleeds (excluding ICH)
Gastrointestinal bleed
Non gastrointestinal-related bleed
Clinically relevant nonmajor bleed

654.50
2209.50
345.00

Myocardial infarction

1443.50

Other cardiovascular hospitalization

1218.30

4.61

ICH intracranial hemorrage
a

Cost of drugs was based on latest available price bulletin (February 2014) at the time of model adaptation

b

The daily dosage was based on each approved summary of product characteristic for apixaban, dabigatran, and rivaroxaban, respectively

c

Clinical event costs were based on last published DRG list available

Table 5 Utility scores and decrements
Health state

Utility score

Non-valvular atrial fibrillation (baseline)

0.7270

Stroke
Mild

0.6151

Moderate

0.5646

Severe

0.5142

Systemic embolism

0.6265

Myocardial infarction

0.6098

Clinical events

Utility decrement

Other intracranial hemorrhage
(excluding hemorrhagic stroke)

0.1511

Other major bleed

0.1511

Clinically relevant nonmajor bleed

0.0582

Other cardiovascular hospitalization

0.1276

Source: modified after Lip et al. [30]

hemorrhagic strokes and cases of systemic embolism) as
well as CV deaths, compared with rivaroxaban or dabigatran (regardless of dosage) (Table 6).
Apixaban was accompanied by higher incremental costs
of treatment as well as higher gains in quality-adjusted life

expectancy, compared with alternatives, thus leading to
favorable ICERs across all comparisons. Compared with
the least effective alternative (dabigatran 110 mg), dabigatran 150 mg (next best alternative) presented an ICER of
€3464.1 per QALY gained whereas the ICERs for
rivaroxaban vs. dabigatran 150 mg and apixaban vs.
dabigatran 150 mg were €24,576.3 and €13,781.6 per
QALY gained, respectively. In this light, apixaban and
dabigatran 150 mg presented extended dominance [42]
over rivaroxaban (Fig. 2).
3.1 Probabilistic Sensitivity Analysis
Figure 3 depicts the results of the PSA. Cost-effectiveness
planes for apixaban vs. all other NOACs show a concentration of points (i.e., results from PSA iterations) in
the North-East quadrant and below the €30,000/QALY
implicit threshold, suggesting a more effective and more
costly outcome for apixaban compared with all treatments. Using a threshold of €30,000 cost per QALY
gained, apixaban was a cost-effective treatment choice
compared with dabigatran 110 mg, dabigatran 150 mg,
and rivaroxaban in 92, 79 and 80 % of the iterations,
respectively (Fig. 4).

CE of Apixaban vs. Other NOACs for the Prevention of Stroke in Greece
Table 6 Occurrence of cardiovascular events, life-years gained (quality adjusted and un-adjusted), and costs by treatment (lifetime horizon)
Apixaban

Dabigatran (110 mg)

Dabigatran (150 mg)

Rivaroxaban

Number of events (per cohort)
Ischemic stroke (including recurrent)

258

278

265

261

Hemorrhagic stroke (including recurrent)

29

19

18

30

Systemic embolism

24

27

27

26

Other ICH

13

13

18

22

Other major bleeds

147

156

170

196

Clinically relevant nonmajor bleeds

268

287

304

338

Myocardial infarction (non-fatal)

73

84

85

73

Myocardial infarction (fatal)

11

12

12

11

Other CV hospitalization

1182

1179

1196

1187

Other treatment discontinuation
Deaths (event-related)

636
372

710
397

722
388

665
381

Deaths (total)

1000

1000

1000

1000

Life-years gained

9.069

8.953

8.996

9.021

QALYs gained

6.450

6.351

6.388

6.412

Health outcomes (per patient)

Costs (€ discounted per patient)
Anticoagulants

4170.00

2962.26

3268.15

3731.77

Routine care

183.70

175.39

175.21

179.51

Monitoring

25.12

30.81

31.60

28.28

CV event costs

5210.51

5430.67

5252.98

5385.28

Management costs

11.78

19.35

18.71

11.64

9601.11

8618.48

8746.65

9336.48

9907.37

13,727.17

6935.92

Total cost
ICER (cost/QALY gained, apixaban vs comparator)

CV cardiovascular, ICER incremental cost-effectiveness ratio, ICH intracranial hemorrage, QALY quality-adjusted life-year

ICERs in all three cases were the daily cost of apixaban as
well as the daily cost of the comparator. Nevertheless,
the results remained favorable for apixaban, on an
implicit threshold of €30,000/QALY. Variables with
significant impact, although at a quite lesser extent than
daily costs, were the baseline utility for atrial fibrilation
and MI, mean age, as well as the risks for major events
(mainly stroke, myocardial infarction, and intracranial
haemorrhage).

4 Discussion
Fig. 2 Cost-effectiveness plane: costs and QALYs per person for
each comparator. The bold line represents the efficiency frontier.
Rivaroxaban is extendedly dominated by dabigatran 150 mg and
apixaban. QALYs quality-adjusted life-years

3.2 One-Way Sensitivity Analysis
The results of the one-way sensitivity analyses of the
ICERs for apixaban vs. comparators are presented in
Fig. 5. Variables with the highest impact on the baseline

The present analysis assessed the incremental costs and
benefits of apixaban compared with other NOACs as a firstline treatment in the prevention of stroke for patients with
AF suitable for treatment with VKAs in Greece. The
analysis was performed from a third-party payer perspective (social insurance fund).
According to CEA results, in a cohort of 1000 patients
simulated over a lifetime, apixaban was found to be a costeffective therapeutic option compared with other NOACs
at an implicit threshold of €30,000/QALY with an ICER

K. Athanasakis et al.
Fig. 3 Probabilistic sensitivity
analysis scatterplots for
a apixaban vs. dabigatran
110 mg, b apixaban vs.
dabigatran 150 mg, and
c apixaban vs. rivaroxaban.
Input lines represent the
€30,000 (bold line) and €20,000
(thinner line) thresholds

relative to dabigatran 110 mg, dabigatran 150 mg, and
rivaroxaban over-projected lifetime of €9907, €13,727, and
€6936 per QALY gained respectively. Overall, patients
treated with apixaban were predicted to experience fewer
major CV events as well as a lower number of CV-related

deaths and hospitalizations compared with those taking
dabigatran and rivaroxaban. Although the treatment cost of
apixaban compared with dabigatran 110 mg, dabigatran
150 mg, and rivaroxaban over projected lifetime was
higher, it was off-set to a great extent by the reduction in

CE of Apixaban vs. Other NOACs for the Prevention of Stroke in Greece
Fig. 4 Cost-effectiveness
acceptability curve for
a apixaban vs. dabigatran
110 mg, b apixaban vs.
dabigatran 150 mg, and
c apixaban vs. rivaroxaban.
Percentages of acceptability at
the threshold of €20,000 and
€30,000/QALY are shown.
QALY quality-adjusted life-year,
ICER incremental costeffectiveness ratio

the occurrence of clinical events, leading to modest
incremental costs (€983, €854, and €265 respectively).
Apixaban as well as other NOACs have demonstrated
acceptable ICERs when independently compared with
warfarin and/or aspirin in various settings [43–45]. However, cost-effectiveness comparisons between the three

NOACs are rather scarce in the literature, probably owing
to the absence of head-to-head clinical trials and, thus, the
need to use indirect comparisons for the production of
relative efficacy data.
The strengths of the present analysis include the use of
data from completed phase III randomized trials, the

K. Athanasakis et al.
Fig. 5 Tornado diagrams of the
one-way sensitivity analyses of
the ICERs for a apixaban vs.
dabigatran 110 mg, b apixaban
vs. dabigatran 150 mg, and
c apixaban vs. rivaroxaban.
QALY quality-adjusted life-year,
ICER incremental costeffectiveness ratio, AF atrial
fibrillation, MI myocardial
infarction, ICH intracranial
hemorrage

CE of Apixaban vs. Other NOACs for the Prevention of Stroke in Greece

combination of data on efficacy, major bleeding and tolerability profile for the assessment of drugs in the analysis,
detailed modeling of mortality for patients with AF, and
the lifetime horizon of the analysis. However, this study
has some limitations, as well, that should be acknowledged.
First, the use of indirect treatment comparison of available
NOACs in the absence of head-to-head trials, which constitutes a source of uncertainty; the analysis was based on a
comparison of the pivotal trials ARISTOTLE, ROCKETAF, and RE-LY using warfarin as the common comparator
as per the strategy and methodology described in Lip et al.
[30]. The reason for the use of this comparison vs. a more
broad meta-analysis that could potentially include a larger
sample of studies is based on the observation by Mitchell
et al. [46] that there exist significant between-study differences (in the total population of studies available) that
could introduce additional statistical heterogeneity into the
network meta analysis (NMA) for a particular outcome in
the case of a broad meta-analysis. Nevertheless, the results
generated from this analysis are highly consistent with
earlier indirect comparisons [47–49]; however, as more
data become available, an analysis in a systematic manner
could be the scope of a future manuscript. Another limitation is the third-party payer perspective from which the
analysis is undertaken and does not include costs to society,
mainly the productivity losses as a result of the disease and
the costs of informal care. The latter constitute an important cost variable, especially for patients whose daily
activities are severely impaired by the CV events associated with AF. Indicatively, informal care costs can account
for up to 21 or 25 % of the total cost for patients that have
experienced a cerebrovascular or coronary heart disease
episode, respectively [50, 51]. Inclusion of such costs
typically favors the treatment that averts the most clinical
events, compared with alternatives.

5 Conclusions
A significant advantage attributed to NOACs is that they do
not require routine INR monitoring. This is especially
important in the Greek healthcare setting, where
antithrombotic therapy in eligible patients remains suboptimal [23, 52, 53]. Although all NOACs have successfully
reduced the risk of thromboembolism, treatment with
apixaban is predicted to lead to reduced morbidity and
mortality, compared with other NOACs. Furthermore, the
ICER of apixaban relative to other NOACs ranged between
€5300 and €12,900 per QALY gained, a ratio well under
commonly accepted thresholds. Apixaban therefore could
be considered a cost-effective therapeutic option for the
prevention of stroke in AF patients with one or more risk

factors and suitable for treatment with VKAs, from a thirdparty payer perspective.
Acknowledgments The authors would like to thank Elena
Armelidou and Periklis Giovas from Pfizer Hellas for their in-depth
review of the draft manuscript, and Ms. Daphne Arzoumanidou for
her assistance in the early stages of the study.
Author contributions KA and AB participated in the design and
coordination of the study and KA conducted the analyses and interpreted the results. KA and EK wrote the manuscript. AB and DT
revised the manuscript for important intellectual content. JK supervised the study and made critical comments to the final draft of the
paper. All authors read and approved the final manuscript.

Compliance with Ethical Standards
The study was sponsored by Pfizer and Bristol Myers Squibb. KA,
EK, and JK are employees of the National School of Public Health
who were paid consultants to Pfizer in connection with conducting
this analysis and the development of this manuscript. AB is full-time
employee at Pfizer Hellas. At the time of manuscript submission, DT
was a full-time employee at Pfizer Hellas. Nothing contained in this
paper is intended to guarantee the appropriateness of any medical
treatment or to be used for therapeutic purposes or as a substitute for a
health professional’s advice.

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