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Vol. 72. Issue 5.
Pages 398-406 (May 2019)
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Vol. 72. Issue 5.
Pages 398-406 (May 2019)
Original article
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Would the Use of Edoxaban Be Cost-effective for the Prevention of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation in Spain?
¿El uso de edoxabán sería coste-efectivo para la prevención del ictus y la embolia sistémica en pacientes con fibrilación auricular no valvular en España?
Iñaki Lekuonaa, Manuel Anguitab, José Luis Zamoranoc, José Manuel Rodríguezd, Paloma Barja de Soroae, Ferran Pérez-Alcántaraf,
Corresponding author

Corresponding author: Oblikue Consulting S.L., Avda. Diagonal 514, 3.°-3.a, 08006 Barcelona, Spain.
a Servicio de Cardiología, Hospital de Galdakao, Usansolo, Vizcaya, Spain
b Servicio de Cardiología, Hospital Reina Sofía, Córdoba, Spain
c Servicio de Cardiología, Hospital Universitario Ramón y Cajal, Madrid, Spain
d Market Access Department, Daiichi Sankyo Europe GmbH, Munich, Germany
e Departamento de Acceso, Daiichi Sankyo España S.A., Madrid, Spain
f Oblikue Consulting S.L., Barcelona, Spain
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Figures (3)
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Tables (8)
Table 1. Monthly Transition Probabilities and Age Adjustment Factors
Table 2. Treatment Switches Due to Interruption
Table 3. Probability of Mortality Due to an Acute Event and After Surviving an Acute Event
Table 4. Utilities Used in Model
Table 5. Costs Associated With Health States in the Model
Table 6. Base-Case Results
Table 7. Analysis of Scenarios
Table 8. Minimum Treatment Time Needed for Edoxaban to Be a Cost-Effective Alternative to Vitamin K Antagonists
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Introduction and objectives

To assess the cost-effectiveness of edoxaban vs acenocoumarol in the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) in Spain.


Markov model, adapted to the Spanish setting from the perspective of the National Health System, stimulating the progression of a hypothetical cohort of patients with NVAF throughout their lifetime, with different health states: stroke, haemorrhage, and other cardiovascular complications. Efficacy and safety data were obtained from the available clinical evidence (mainly from the phase III ENGAGE AF-TIMI 48 study). The costs of managing NVAF and its complications were obtained from Spanish sources.


Edoxaban use led to 0.34 additional quality-adjusted life years (QALY) compared with acenocoumarol. The incremental cost with edoxaban was 3916€, mainly because of higher pharmacological costs, which were partially offset by lower costs of treatment monitoring and managing NVAF events and complications. The cost per QALY was 11 518€, within the thresholds commonly considered cost-effective in Spain (25 000-30 000 €/QALY). The robustness of the results was confirmed by various sensitivity analyses.


Edoxaban is a cost-effective alternative to acenocoumarol in the prevention of stroke and systemic embolism in patients with NVAF in Spain.

Cost-effectiveness analysis
Nonvalvular atrial fibrillation
Stroke prevention
Systemic embolism prevention
Introducción y objetivos

Analizar el coste-efectividad del edoxabán frente al acenocumarol en la prevención del ictus y la embolia sistémica en pacientes con fibrilación auricular no valvular (FANV) en España.


Modelo de Markov, adaptado a España desde la perspectiva del Sistema Nacional de Salud, que simula la evolución de una cohorte hipotética de pacientes con FANV a lo largo de toda su vida a partir de diferentes estados de salud: ictus, hemorragias y otras complicaciones cardiovasculares. Los datos de eficacia y seguridad se obtuvieron a partir de la evidencia clínica disponible (principalmente del estudio en fase III ENGAGE AF-TIMI 48). Los costes del tratamiento de la FANV y sus complicaciones se obtuvieron de fuentes españolas.


El edoxabán resultó en 0,34 años de vida ajustados por calidad (AVAC) adicionales en comparación con el acenocumarol. El coste incremental con el edoxabán fue de 3.916 euros, derivado principalmente de un mayor coste farmacológico, que se compensa parcialmente por los menores costes de la monitorización del tratamiento y del tratamiento de eventos y complicaciones de la FANV. Se obtuvo un coste por AVAC de 11.518 euros, dentro de los umbrales comúnmente considerados coste-efectivos en España (25.000-30.000 euros/AVAC). Los diferentes análisis de sensibilidad realizados confirmaron la robustez de los resultados.


El edoxabán es una alternativa coste-efectiva frente al acenocumarol en la prevención del ictus y la embolia sistémica en pacientes con FANV en España.

Palabras clave:
Análisis de coste-efectividad
Fibrilación auricular no valvular
Prevención de ictus
Prevención de embolia sistémica
Full Text

Atrial fibrillation (AF), with an estimated prevalence of 3%, is the most common arrythmia in the western world.1 It affects men and women equally and becomes more common with age; in Spain, 4.4% of patients with AF are older than 40 years. In addition, its prevalence increases in a stepwise fashion after the age of 60 years (17.7% of patients are older than 80 years).2 Over 1 million people are estimated to have AF in Spain and approximately 90 000 of these are undiagnosed.2

AF is the main cause of embolic events, of which the most common and most serious is stroke. Patients with AF are about 5 times as likely as those without AF to have a stroke,3 and they also have a higher risk of disability, recurrence, and mortality.4 The incidence of stroke in patients with AF not receiving anticoagulants is 3.1 cases per 100 patient-years vs 0.3 cases in those receiving anticoagulants.4

Stroke is the first cause of adult disability worldwide, the second cause of dementia, and the third cause of death. In patients older than 75 years, it is the main cause of death. It is also one of the most costly diseases from a socioeconomic perspective5,6 due to hospitalization and informal care costs.7 Nevertheless, many of the events associated with a diagnosis of AF can be prevented with anticoagulant therapy.8

Nonvalvular AF (NVAF) occurs in patients without a mechanical heart valve and without moderate to severe mitral stenosis (generally of rheumatic origin).9 The standard prophylactic treatment for stroke is oral anticoagulant therapy with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs).10 Although warfarin is the mainstay of VKA therapy, acenocumarol is more widely used in Spain.4 The procedures needed to check international normalized ratio (INR) values and monitor hemorrhagic and/or thromboembolic risk are similar for warfarin and acenocoumarol.11 Although VKAs are an effective treatment, they have several disadvantages that complicate their use. They have high dose-response variability, which requires regular INR testing and dose adjustments to ensure that the treatment has the desired effect but does not cause serious adverse outcomes, such as stroke or hemorrhage.12 Inadequate INR control determined using the direct method is associated with a time in therapeutic range of less than 60%10 (40%-54% of patients in Spain).13 In addition, the need for frequent testing and the risk of potentially harmful interactions with other drugs have traditionally been associated with underuse of VKA therapy in AF.14 Moreover, reports of adverse reactions to VKAs have increased.15 Adherence to VKA therapy in Spain is just 50%4 and there is thus an increased risk of stroke and hemorrhage.12

DOACs have the necessary efficacy and safety profile to meet most needs not covered by VKAs16,17: they have a wide therapeutic window, a predictable anticoagulant response unaffected by food intake, and few interactions with other drugs. In addition, they offer a constant anticoagulant effect and do not require regular monitoring or repeated dose adjustments.12

High-dose edoxaban is the most recent DOAC to be authorized for the treatment of NVAF in Spain. It is administered as a single daily dose of 60mg or, in the following cases, 30mg: moderate to severe kidney failure (creatinine clearance, 15-50mL/min), low body weight (≤60kg), and concomitant use of certain glycoprotein inhibitors (ciclosporin, dronedarone, erythromycin, and ketoconazole). Edoxaban is a direct oral selective factor Xa inhibitor. Based on the results of the ENGAGE AF-TIMI 48 clinical trial, high-dose edoxaban is at least as efficacious as warfarin in preventing stroke and systemic embolism and it is significantly safer than well-controlled warfarin therapy in terms of major bleeding events.18,19

The aim of this study, conducted in Spain, was to evaluate the cost-effectiveness of edoxaban in preventing stroke and systemic embolism in adults with NVAF and 1 or more risk factors.

METHODSStudy Population and Comparators

The characteristics of the population used for the base-case analysis were the same as in the ENGAGE AF-TIMI 48 trial,19 namely, a diagnosis of NVAF, a moderate to high risk of stroke (CHADS2 stroke risk score ≥ 2), a higher proportion of men than women (62.29%), and a mean age of 71 years.

We also compared high-dose edoxaban with VKA therapy,19 but instead of warfarin we analyzed acenocoumarol, the most widely used VKA in Spain,4 and assumed that the 2 drugs had identical safety and efficacy.

Type of Analysis

We estimated the mean per-patient cost-effectiveness of each treatment, calculated the incremental cost-effectiveness ratio of edoxaban vs VKA therapy, and determined the additional cost required to gain 1 quality-adjusted life year (QALY) with edoxaban.

The costs were analyzed from the perspective of the Spanish national health system and included direct medical costs (calculated in 2017 euros). The time horizon contemplated in the analyses was the patient's full lifetime. An annual discount of 3% was applied for costs and future effects.20

A group of experts selected for their experience and familiarity with clinical practice was formed to help adapt the necessary aspects of the study to Spain. The members of this group filled in individual questionnaires and were then presented with a base case for evaluation.

Pharmcoeconomic Model

A Markov model was used to simulate the course of events in patients with NVAF and a moderate to high risk of stroke through the analysis of different clinical situations (health states) associated with the use of different resources and specific clinical outcomes. A simplified version of this model is shown in Figure 1. The transition between health states and the resulting clinical/economic outcomes were evaluated in monthly cycles. The probability of a patient progressing from a milder to a more serious state, depending on the case, was derived from the clinical outcomes of the treatments.

Figure 1.

Markov model showing clinical events in patients with NVAF. AMI, acute myocardial infarction; NVAF, nonvalvular atrial fibrillation; TIA, transient ischemic attack.


At the start of the analysis, the patients had a stable NVAF status, and during each cycle they transitioned between the following health states: hemorrhagic or ischemic stroke (mild, moderate, or severe), systemic embolism, and acute myocardial infarction. These events were associated with an initial impact (acute event) and a long-term impact (postevent)

Other events (complications) considered were bleeding (intracranial, major extracranial, and clinically relevant nonmajor bleeding) and transient ischemic attacks. These were possible in any of the health states.

A stroke could be followed by new events (recurrence), complications, and temporary or permanent interruption of treatment (with a treatment switch).

Risk of death varied according to the demographic characteristics of each patient (age and sex) and their health status.

Clinical Data

The clinical data for the model were mainly obtained from the phase III ENGAGE AF-TIMI 48 trial19 and available scientific evidence.

The monthly transition probabilities are shown in Table 1. It was assumed that the risk of an event increased with age.

Table 1.

Monthly Transition Probabilities and Age Adjustment Factors

Health States/Complications  Edoxaban,19 HR  VKA vs Edoxaban,19 HR  Age Adjustment Factor 
Ischemic  0.07  1.061  1.4021,b 
Hemorrhagic  0.02  1.888  1.9722,b 
Systemic embolism  0.01  1.543  1.2923,b 
Acute myocardial infarction  0.06  1.066  1.3024,b 
Intracranial  0.03  1.929  1.9722,b 
Major extracranial  0.20  1.103  1.9722,b 
Nonmajor (clinically relevant)  0.72  1.170  1.9722,b 
Transient ischemic attack  0.05  0.843  1.923,c 

VKA, vitamin K antagonist; HR, hazard ratio.


Based on the ENGAGE AF-TIMI 48 trial, it was assumed that 43% of strokes would be mild, 16% would be moderate, and 41% would be severe.


In 10 years.


In 5 years.

The monthly risk of stroke recurrence is 0.25% for ischemic stroke and 0.26% for hemorrhagic stroke.25 This risk increases to 0.44% following an acute myocardial infarction.25

Data on treatment interruption and switching following a stroke were based on the opinions of the expert group (Table 2).

Table 2.

Treatment Switches Due to Interruption

  Aspirin  DOAC  VKA  Interruption 
If treated with VKA, %
Ischemic stroke  90  10 
Hemorrhagic stroke  90 
If treated with DOAC, %
Ischemic stroke  50  50 
Hemorrhagic stroke  75  10  15 

DOAC, direct oral anticoagulant; VKA, vitamin K antagonist.

Three types of mortality were considered for the analysis: overall mortality26 (adjusted for the risk associated with AF, hazard ratio [HR] = 1.3427), mortality due to an acute event, and mortality after surviving an acute event (Table 3).19,28–32

Table 3.

Probability of Mortality Due to an Acute Event and After Surviving an Acute Event

Probability of mortality due to an acute event
Event  Probability (%)  Source 
Ischemic stroke
Mild  0.0  Assumption 
Moderate  16.8  Janes et al.28 
Severe  16.8  Janes et al.28 
Hemorrhagic stroke
Mild  0.0  Assumption 
Moderate  31.6  Janes et al.28 
Severe  31.6  Janes et al.28 
Systemic embolism  0.0  Giugliano et al.19 
Acute myocardial infarction  13.2  Scarborough et al.29 
Intracranial bleeding  31.6  Janes et al.28 
Major nonintracranial bleeding  0.0  Assumption 
Nonmajor bleeding (clinically relevant)  0.0  Assumption 
Transient ischemic attack  0.0  Assumption 
Probability of mortality after surviving an acute event
Previous event  HR*   
Ischemic/hemorrhagic stroke
Mild  3.18  Bronnum-Hansen et al.30 
Moderate  5.84  Henriksson et al.31 
Severe  15.75  Huybrechts et al.32 
Systemic embolism  5.45  Giugliano et al.19 
Acute myocardial infarction  3.36  Bronnum-Hansen et al.30 

HR, hazard ratio.


Vs total mortality.

Quality of Life

Quality-of-life utility scores in relation to health states fell on a scale of 0 (death) to 1 (perfect health). The utilities for each state and the loss of utility due to complications were taken from the literature (Table 4).33–38

Table 4.

Utilities Used in Model

  Utility  Source 
Health state
Stable nonvalvular atrial fibrillation  0.780  Khan et al.33 
Ischemic/hemorrhagic stroke
Mild  0.720  Gage et al.34 
Moderate  0.350  Gage et al.34 
Severe  0.070  Gage et al.34 
Systemic embolia  0.680  Sullivan et al.35 
Acute myocardial infarction  0.683  Lacey et al.36 
Intracranial bleeding  -0.107  Thomson et al.37 
Major nonintracranial bleeding  -0.107  Thomson et al.37 
Nonmajor bleeding (clinically relevant)  -0.058  Sullivan et al.35 
Transient ischemic attack  -0.103  Sullivan et al.38 

Despite having a stable INR, patients being treated with a VKA may experience a slight deterioration in quality of life due to anxiety about remaining within the therapeutic range and potential interactions between the drug and other medication or food.39 For the base case, we considered a loss of utility of 0.012 in these patients.40

Use of Resources and Costs

The direct medical costs considered were pharmacologic costs, VKA monitoring costs, and the treatment costs for each event.

Daily pharmacologic costs were calculated according to the established treatment regimens and retail prices,41 with application of the corresponding deduction.42 The resulting estimates were a daily cost of €2.58 for edoxaban (60mg/d) and €0.07 for acenocoumarol (2.75mg/d).

VKA therapy requires regular INR monitoring (14 tests a year43) and possible dose adjustments. According to the expert group, 50% of these tests would be performed in an in-hospital setting and 50% in an outpatient setting. The estimated costs were €20.15 and €30.89, respectively.44 The annual cost of INR monitoring was therefore set at €357.28.

The costs per event type were calculated using data from the relevant literature and opinions expressed by the expert group (Table 5).

Table 5.

Costs Associated With Health States in the Model

Concept  Cost, €  Source 
Acute event
Ischemic stroke
Mild  4721.04  APR-DRG 4545,46 
Moderate  4891.04  APR-DRG 4545,46 
Severe  6695.19  APR-DRG 4545,46 
Hemorrhagic stroke
Mild  5526.54  APR-DRG 4445,46 
Moderate  5654.92  APR-DRG 4445,46 
Severe  6415.15  APR-DRG 4445,46 
Systemic embolism  3481.91  APR-DRG 4645 
Acute myocardial infarction  4041.82  APR-DRG 19045 
Intracranial bleeding  5817.26  APR-DRG 4445 
Major nonintracranial bleeding  3761.93  APR-DRG 25345 
Nonmajor bleeding (clinically relevant)  177.82  Based on assumption of 1 emergency visit45 
Transient ischemic attack  2933.21  APR-DRG 4745 
After event (monthly cost)
Ischemic stroke
Mild  121.09  Barón-Esquivias et al.47 
Moderate  749.27  Barón-Esquivias et al.47 
Severe  2100.59  Barón-Esquivias et al.47 
Hemorrhagic stroke
Mild  121.09  Assumed to be the equivalent of ischemic stroke, Barón-Esquivias et al.47 
Moderate  749.27  Assumed to be the equivalent of ischemic stroke, Barón-Esquivias et al.47 
Severe  2100.59  Assumed to be the equivalent of ischemic stroke, Barón-Esquivias et al.47 
Systemic embolism  117.88  Barón-Esquivias et al.47 
Acute myocardial infarction  166.27  Barón-Esquivias et al.47 
Death  4044.37  APR-DRG 46 (death)45,46 

APR-DRG, All Patient Refined–Diagnosis Related Group.

Sensitivity Analysis

To characterize the uncertainty surrounding the study input parameters and their potential influence on outcomes, we performed a probabilistic sensitivity analysis using second-order Monte Carlo simulation with a hypothetical cohort of 1000 patients.20 The main parameters from the base-case analysis were varied simultaneously and assigned the following distributions: normal distribution for age of onset; Dirichlet distribution for stroke severity; beta distribution for mortality due to an acute event, utilities, and probabilities (of events and recurrences); log-normal distribution for HRs, mortality following an event, adjustment factors for overall mortality, and risk for each decade of life; and gamma distribution for costs.

The results of the analysis were plotted on a cost-effectiveness plane, where each point corresponded to 1 simulation run according to the stipulated parameters and distributions. The results were also plotted on an acceptability curve.

Additional sensitivity analyses were conducted for the following scenarios:

  • To account for regional variability at INR testing sites, a scenario where 20% of tests are performed in a hospital and 80% in an outpatient setting and vice versa.

  • To account for possible overestimation of annual INR testing costs due to the use of potentially outdated data, a scenario contemplating a third of the annual base cost (€119.09).

  • A scenario with patients with CHADS2 ≥ 3.48.

  • A scenario with patients with a time in therapeutic range ≥ 60%.48

  • A scenario in which patients on VKA therapy had no loss of utility.

Time horizons and hence treatment durations are important considerations when evaluating treatment effectiveness. We therefore evaluated different time horizons for both the base case and the scenarios involving the subgroups of patients with a CHADS2 score of at least 3 and time in the therapeutic range of 60% or more.


Edoxaban was more effective than the VKA (0.34 QALYs and 0.30 life years gained) due to lower rates of stroke, intracranial and extracranial bleeding, systemic embolism, and acute myocardial infarction (Table 6).

Table 6.

Base-Case Results

  Edoxaban  VKA  Difference 
Total cost, €  19 163  15 247  3916 
Pharmacologic cost, €  9005  642  8363 
Monitoring cost, €  3192  -3189 
Cost of treating events and complications, €  10 155  11 413  -1258 
QALY  6.99  6.65  0.34 
LYG, y  9.70  9.40  0.30 
ICER (€/QALY)      11 518 
ICER (€/LYG)      13 053 

ICER, incremental cost-effectiveness ratio; LYG, life years gained; QALY, quality-adjusted life years; VKA, vitamin K antagonist.

Edoxaban was associated with an additional cost of €3916 compared with the VKA. This extra cost was mainly due to the higher price of the drug, but was partially offset by the lower costs of INR monitoring and treatment of events and complications (which are less common with edoxaban) (Table 6). Compared with the VKA, edoxaban was associated with an incremental cost-effectiveness ratio of €11 518 for each QALY gained, which is under the generally accepted threshold for cost-effectiveness (€25 000-€30 000 per QALY).49,50

Sensitivity Analysis

The results of the probabilistic sensitivity analysis, plotted on the cost-effectiveness plane (Figure 2) and the acceptability curve (Figure 3), show that edoxaban was cost-effective in 73% to 81% of the simulations run.

Figure 2.

Probabilistic sensitivity analysis. QALYs, quality-adjusted life years.

Figure 3.

Acceptability curve *Percentage of simulations under the cost-effectiveness threshold analyzed.


It was also cost-effective in the different subgroup analyses (see scenario results in Table 7).

Table 7.

Analysis of Scenarios

Scenario  Cost per QALY (€) 
INR testing site (80% hospital, 20% outpatient setting)  12 700 
INR testing site (20% hospital, 80% outpatient setting)  10 332 
Lower annual cost of INR monitoring for patients receiving VKA therapy  17 892 
Subgroup of patients with CHADS2 stroke risk score ≥ 3  8127 
Subgroup of patients with TRT ≥ 60%  16 170 
No loss of utility for patients treated with VKA  17 026 

TRT, time in therapeutic range; QALY, quality-adjusted life years; VKA, vitamin K antagonist.

Finally, as indicated in Table 8, edoxaban becomes cost-effective after 3 to 5 years of treatment (2-3 years for patients with CHADS2 ≥ 3 and 6-9 years for those with a time in the therapeutic rage ≥ 60%) (Table 8).

Table 8.

Minimum Treatment Time Needed for Edoxaban to Be a Cost-Effective Alternative to Vitamin K Antagonists

  Treatment time (cost/QALY)
  Threshold €25 000/QALY  Threshold €30 000/QALY 
Baseline case  5 y (€24 560)  3 y (€29 931) 
CHADS2 stroke risk score ≥ 3  3 y (€23 771)  2 y (€27 910) 
TRT s≥ 60%  9 y (€23 818)  6 y (€28 216) 

QALY, quality-adjusted life years; TRT, time in therapeutic range.


Although VKAs are an effective treatment for preventing thromboembolic events in patients with NVAF, the need for frequent INR testing and dose adjustments carries a substantial risk of poor anticoagulation control and may also lead to underuse and poor adherence.17,51

This cost-effectiveness study, conducted in Spain, shows that compared with VKAs, edoxaban is a cost-effective option for preventing stroke in patients with NVAF and similar characteristics to the patients in the ENGAGE AF-TIMI 48 trial.19

This is the first cost-effectiveness study of edoxaban vs a VKA to be undertaken in Spain and the findings are similar to those reported for other countries.52–58


The results presented in this study are based on mathematical modeling, and to run the necessary simulations, we had to extrapolate short-term data (collected over a period of 2.8 years in the ENGAGE AF-TIMI 48 trial19) to the lifetime horizon of the current study and assume that the safety and efficacy of edoxaban remained constant over time. This is an inherent limitation that applies to any studies that need to calculate long-term treatment effects based on short-term clinical evidence mainly from phase III trials. Data from phase IV studies would confer greater external validity to these studies. Risk of stroke assessed using the CHADS2 scale, for example, was higher in the ENGAGE AF-TIMI 48 trial than in clinical practice59 (mean score of 2.8 vs 2.3).

The external validity of the current study may also be limited, as CHAD2S2-VASc scores are now used to assess AF stroke risk1 (and not CHADS2 scores like in the ENGAGE AF-TIMI 48 trial).

Other limitations are related to the variability of the data used and assumptions made about missing data. The need to model parameters from different sources is an inherent aspect of studies of chronic disease,60 and data on utilities, for example, often need to be drawn from international studies because of a shortage of national data. That said, in our case these data were applied to the 2 drugs and the relevant result in the analyses is the incremental ratio. We also accounted for potential variations and influences by conducting a probabilistic sensitivity analysis.

We were unable to investigate the potential influence of age as there was insufficient evidence for subgroup analyses. Nonetheless, efficacy and safety outcomes for edoxaban vs warfarin appear to be independent of age.61

One of the main assumptions in our model was the therapeutic equivalence of warfarin and acenocoumarol. Other cost-effectiveness studies performed in Spain have made similar assumptions about efficacy, safety, and resource utilization.47,62,63

Although different criteria were used to account for the loss of utility (or not) associated with VKA therapy in the cost-effectiveness analyses in the above studies,47,62,63 omission of this loss did not affect the results of the analyses.

The efficacy of edoxaban in our study may be underestimated, as in clinical practice, many patients with NVAF are given aspirin to prevent stroke or are not treated.64 Consideration of other types of costs associated with the long-term disability costs of stroke (eg, indirect health costs or productivity loss) would strengthen the cost-effectiveness of edoxaban.

The cost-effectiveness of edoxaban vs VKA therapy decreases with improved anticoagulation control,57 and therefore, in line with current recommendations, edoxaban can be considered to be particularly cost-effective in patients on VKA therapy with poor control (time in therapeutic range <60%).10

Considering the absence of randomized controlled trials directly comparing DOACs in patients with NVAF, differences observed indirectly through network meta-analyses should be confirmed in clinical practice.51 In brief, there are no reliable data for guiding the optimal use of one DOAC or another,65 although all DOACs appear to be a safe and effective alternative to VKAs.17 Phase IV studies will help to evaluate the sustainability of the widespread use of DOACs in the industrialized world.


Over the past decade, DOACs have emerged as an alternative for preventing stroke and systemic embolism in patients with NVAF, remedying some of the limitations associated with VKAs. Edoxaban is as efficacious as VKAs in the treatment of NVAF and in addition it has a better safety profile. Despite its higher pharmacologic cost, it is a cost-effective option for the Spanish national health system.


Study funded by Daiichi Sankyo.


J.M. Rodríguez and P. Barja de Soroa work at Daiichi Sankyo. F. Pérez-Alcántara is a member of Oblikue, an independent consultancy firm that received funds to conduct the analysis. I. Lekuona, M. Anguita, and J.L. Zamorano received consultancy fees from Daiichi Sankyo.


  • DOACs are an alternative to VKAs for the prevention of stroke in patients with NVAF.

  • DOACs are at least as efficacious and safe as VKAs, but they are more convenient as they do not require regular INR testing and have fewer interactions with drugs and food.

  • Despite their advantages, DOACs are used less than VKAs and the reason sometimes given for this is the difference in price.


  • Edoxaban is the most recent DOAC authorized for use in NVAF in Spain.

  • This is the first cost-effectiveness analysis of edoxaban vs a VKA for the treatment of NVAF in Spain.

  • Edoxaban versus VKA therapy is a cost-effective option for NVAF.


P. Kirchhof, S. Benussi, D. Kotecha, et al.
Guía ESC 2016 sobre el diagnóstico y tratamiento de la fibrilación auricular, desarrollada en colaboración con la EACTS.
Rev Esp Cardiol., 70 (2017), pp. 50
J.J. Gómez-Doblas, J. Muñiz, J.J. Alonso, et al.
Prevalencia de fibrilación auricular en España. Resultados del estudio OFRECE.
Rev Esp Cardiol., 67 (2014), pp. 259-269
A.J. Camm, G.Y.H. Lip, R. De Caterina, et al.
Actualización detallada de las guías de la ESC para el manejo de la fibrilación auricular de 2012.
Rev Esp Cardiol., 66 (2013), pp. 54
F. Andrés-Nogales, I. Oyagüez, L. Betegón-Nicolás, C. Canal-Fontcuberta, J. Soto-Álvarez.
Situación del tratamiento anticoagulante oral en pacientes con fibrilación auricular no valvular en España. Estudio REACT-AF.
Rev Clin Esp., 215 (2015), pp. 73-82
J. Mar, J. Álvarez-Sabín, J. Oliva, et al.
The costs of stroke in Spain by aetiology: The CONOCES study protocol.
Neurología., 28 (2013), pp. 332-339
J. Martí-Fábregas, R. Delgado-Mederos, J. Mateo.
Limitaciones del tratamiento anticoagulante.
Neurología., 27 Supl 1 (2012), pp. 27-32
J. López-Bastida, J. Oliva, M. Worbes, L. Perestelo, P. Serrano-Aguilar, F. Montón-Álvarez.
Social and economic costs and health-related quality of life in stroke survivors in the Canary Islands, Spain.
BMC Health Services Research., 12 (2012), pp. 315
N. Hannon, L. Daly, S. Murphy, et al.
Acute hospital, community, and indirect costs of stroke associated with atrial fibrillation.
Stroke., 45 (2014), pp. 3670-3674
H. Heidbuchel, P. Verhamme, M. Alings, et al.
Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation.
Europace., 17 (2015), pp. 1467-1507
Agencia Española de Medicamentos y Productos Sanitarios. Informe de posicionamiento terapéutico. Criterios y recomendaciones generales para el uso de los anticoagulantes orales directos en la prevención del ictus y la embolia sistémica en pacientes con fibrilación auricular no valvular. 2016. Available at: Accessed 9 Dec 2016.
V. Barrios, C. Escobar, L. Prieto, J.M. Lobos, J. Polo, D. Vargas.
Control de la anticoagulación con warfarina o acenocumarol en España. ¿Hay diferencias?.
Rev Esp Cardiol., 68 (2015), pp. 1181-1182
A. Martínez-Rubio, R. Martínez-Torrecilla.
Evidencias actuales de los nuevos anticoagulantes orales en el tratamiento de la fibrilación auricular no valvular: comparación de subestudios.
Rev Esp Cardiol., 68 (2015), pp. 185-189
M. Anguita, V. Bertomeu, A. Cequier.
Insuficiencia cardiaca, fibrilación auricular no valvular y control de la anticoagulación con antagonistas de la vitamina K.
Rev Esp Cardiol., 69 (2016), pp. 75-85
I.M. Ogilvie, N. Newton, S.A. Welner, W. Cowell, G.Y. Lip.
Underuse of oral anticoagulation in atrial fibrillation: a systematic review.
Am J Med., 123 (2010), pp. 638-645
P. Carrasco-Garrido, V. Hernández-Barrera, J. Esteban-Hernández, et al.
Adverse drug reactions to anticoagulants in Spain: analysis of the Spanish National Hospital Discharge Data (2010-2013).
BMJ Open., 7 (2017), pp. e013224
P. Gallego, V. Roldán, G.Y. Lip.
Novel Oral Anticoagulants in Cardiovasulcar Disease.
J Cardiovasc Pharmacol Ther., 19 (2014), pp. 34-44
C.T. Ruff, R.P. Giugliano, E. Braunwald, et al.
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
Lancet., 383 (2014), pp. 955-962
European Medicines Agency. Lixiana European Public Assessment Report product information. Available at: Accessed 18 Jul 2016.
R.P. Giugliano, C.T. Ruff, E. Braunwald, et al.
Edoxaban versus warfarin in patients with atrial fibrillation.
N Engl J Med., 369 (2013), pp. 2093-2104
J. López-Bastida, J. Oliva, F. Antoñanzas, et al.
Propuesta de guía para la evaluación económica aplicada a las tecnologías sanitarias.
Gac Sanit., 24 (2010), pp. 154-170
Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154:1449-1457.
M.J. Ariesen, S.P. Claus, G.J. Rinkel, A. Algra.
Risk factors for intracerebral hemorrhage in the general population: a systematic review.
K.M. Flegel, J. Hanley.
Risk factors for stroke and other embolic events in patients with nonrheumatic atrial fibrillation.
Stroke., 20 (1989), pp. 1000-1004
J.V. Freeman, R.P. Zhu, D.K. Owens, et al.
Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation.
K.M. Mohan, S.L. Crichton, A.P. Grieve, A.G. Rudd, C.D. Wolfe, P.U. Heuschmann.
Frequency and predictors for the risk of stroke recurrence up to 10 years after stroke: the South London Stroke Register.
J Neurol Neurosurg Psychiatry., 80 (2009), pp. 1012-1018
Instituto Nacional de Estadística, 2017. Tablas de mortalidad 2015. Available at: Accessed 20 Apr 2018.
L. Friberg, H.N. Hammar, H. Pettersson, M. Rosenqvist.
Increased mortality in paroxysmal atrial fibrillation: report from the Stockholm Cohort-Study of Atrial Fibrillation (SCAF).
Eur Heart J., 28 (2007), pp. 2346-2353
F. Janes, G.L. Gigli, L. D’Anna, et al.
Stroke incidence and 30-day and six-month case fatality rates in Udine, Italy: a population-based prospective study.
Int J Stroke., 8 Suppl A (2013), pp. 100-105
P. Scarborough, P. Bhatnagar, K. Wickramasinghe, K. Smolina, C. Mitchell, M. Rayner.
Coronary Heart Disease Statistics 2010.
British Heart Foundation, (2010),
H. Bronnum-Hansen, M. Davidsen, P. Thorvaldsen.
Long-term survival and causes of death after stroke.
Stroke., 32 (2001), pp. 2131-2136
K.M. Henriksson, B. Farahmand, S. Johansson, S. Asberg, A. Terent, N. Edvardsson.
Survival after stroke--the impact of CHADS2 score and atrial fibrillation.
Int J Cardiol., 141 (2010), pp. 18-23
K.F. Huybrechts, J.J. Caro, J.J. Xenakis, K.N. Vemmos.
The prognostic value of the modified Rankin Scale score for long-term survival after first-ever stroke. Results from the Athens Stroke Registry.
Cerebrovasc Dis., 26 (2008), pp. 381-387
T.I. Khan, F. Kamali, P. Kesteven, P. Avery, H. Wynne.
The value of education and self-monitoring in the management of warfarin therapy in older patients with unstable control of anticoagulation.
Br J Haematol., 126 (2004), pp. 557-564
B.F. Gage, A.B. Cardinalli, D.K. Owens.
The effect of stroke and stroke prophylaxis with aspirin or warfarin on quality of life.
Arch Intern Med., 156 (1996), pp. 1829-1836
P.W. Sullivan, J.F. Slejko, M.J. Sculpher, V. Ghushchyan.
Catalogue of EQ-5D scores for the United Kingdom.
Med Decis Making., 31 (2011), pp. 800-804
E.A. Lacey, S.J. Walters.
Continuing inequality: gender and social class influences on selfperceived health after a heart attack.
J Epidemiol Community Health., 57 (2003), pp. 622-627
R. Thomson, D. Parkin, M. Eccles, M. Sudlow, A. Robinson.
Decision analysis and guidelines for anticoagulant therapy to prevent stroke in patients with atrial fibrillation.
Lancet., 355 (2000), pp. 956-962
P.W. Sullivan, T.W. Arant, S.L. Ellis, H. Ulrich.
The cost effectiveness of anticoagulation management services for patients with atrial fibrillation and at high risk of stroke in the US.
Pharmacoeconomics., 24 (2006), pp. 1021-1033
NICE technology appraisals. TA275. Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation. Available at: Accessed 18 Jul 2016.
M. Marchetti, A. Pistorio, M. Barone, S. Serafini, G. Barosi.
Low-molecular-weight heparin versus warfarin for secondary prophylaxis of venous thromboembolism: a cost-effectiveness analysis.
Am J Med., 111 (2001), pp. 130-139
Consejo General de Colegios Oficiales de Farmacéuticos 2017. Available at: Accessed 7 Feb 2017.
Real Decreto-ley 8/2010 de 20 de mayo, por el que se adoptan medidas extraordinarias para la reducción del déficit público. Boletín Oficial del Estado de 24 de mayo de 2010. Núm. 126. Sec. I, p. 45070-45075. Available at: Accessed 18 Jul 2016.
Á. Hidalgo-Vega, E. Askari, R. Vidal, et al.
Direct vitamin K antagonist anticoagulant treatment health care costs in patients with non-valvular atrial fibrillation.
BMC Health Serv Res., 14 (2014), pp. 46
Informe GENESIS de la SEFH, 2012. Anticoagulantes orales (apixaban, dabigatran, rivaroxaban). Prevención de eventos tromboembólicos en pacientes con fibrilación auricular no valvular. Available at: Accessed 18 Jul 2016.
Base de datos de costes sanitarios españoles: eSalud [Internet]. Barcelona: Oblikue Consulting, S.L. 2007. Available at: Accessed 7 Feb 2017.
Ministerio de Sanidad, Servicios Sociales e Igualdad. Conjunto Mínimo Básico de Datos. Available at: Accessed 15 Jan 2018.
G. Barón-Esquivias, G. Escolar-Albaladejo, J.L. Zamorano, et al.
Análisis coste-efectividad de apixabán frente a acenocumarol en la prevención del ictus en pacientes con fibrilación auricular no valvular en España.
Rev Esp Cardiol., 68 (2015), pp. 680-690
NICE technology appraisals. TA355. Edoxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation. Available at: Accessed 18 Jul 2016.
L. Vallejo-Torres, B. García-Lorenzo, P. Serrano-Aguilar.
Estimating a cost-effectiveness threshold for the Spanish NHS.
Health Economics., 27 (2018), pp. 746-761
J.A. Sacristán, J. Oliva, J. Del Llano, L. Prieto, J.L. Pinto.
¿Qué es una tecnología sanitaria eficiente en España?.
Gac Sanit., 16 (2002), pp. 334-343
N.L. Liberato, M. Marchetti.
Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for stroke prevention in non-valvular atrial fibrillation: a systematic and qualitative review.
Expert Rev Pharmacoecon Outcomes Res., 16 (2016), pp. 221-235
E. Nguyen, F. Egri, E.S. Mearns, C.M. White, C.I. Coleman.
Cost-effectiveness of high-dose edoxaban compared to adjusted-dose warfarin for stroke prevention in non-valvular atrial fibrillation patients.
Pharmacotherapy., 36 (2016), pp. 488-495
M. Krejczy, J. Harenberg, M. Wehling, K. Obermann, G.Y.H. Lip.
Cost-effectiveness of anticoagulation in patients with nonvalvular atrial fibrillation with edoxaban compared to warfarin in Germany.
BioMed Res Int., 2015 (2015), pp. 876923
E. Magnuson, K. Vilain, K. Wang, et al.
Cost-effectiveness of edoxaban vs warfarin in patients with atrial fibrillation based on results of the ENGAGE AF-TIMI 48 trial.
Am Heart J., 170 (2015), pp. 1140-1150
E. Mearns, Y. Doleh, C.I. Coleman.
Cost effectiveness of high-dose edoxaban compared to adjusted dose warfarin for prevention of stroke and systemic embolism in nonvalvular atrial fibrillation.
Eur Heart J., 35 (2014), pp. 896
C. Rognoni, M. Marchetti, S. Quaglini, N.L. Liberato.
Edoxaban versus warfarin for stroke prevention in non-valvular atrial fibrillation: a cost-effectiveness analysis.
J Thromb Thrombolysis., 39 (2015), pp. 149-154
A. Janzic, M. Kos.
Cost effectiveness of novel oral anticoagulants for stroke prevention in atrial fibrillation depending on the quality of warfarin anticoagulation control.
Pharmacoeconomics., 33 (2015), pp. 395-408
K.A. Vilain, M.C. Yang, E.C. Hui Tan, et al.
Cost-effectiveness of edoxaban vs. warfarin in patients with atrial fibrillation based on results of the ENGAGE AF-TIMI 48 trial: Taiwanese perspective.
Value Health Reg Issues., 12 (2017), pp. 74-83
J.J. Gómez-Doblas, J. Muñiz, J.J. Alonso-Martín, E. Roig.
Nuevos datos sobre fibrilación auricular, observaciones al estudio OFRECE. Respuesta.
Rev Esp Cardiol., 67 (2014), pp. 499-500
J.M. Rodríguez-Barrios.
Papel de los modelos en las evaluaciones económicas en el campo sanitario.
Farm Hosp., 28 (2004), pp. 231-242
E.T. Kato, R.P. Giugliano, C.T. Ruff, et al.
Efficacy and safety of edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial.
J Am Heart Assoc., 5 (2016), pp. e003432
J.R. González-Juanatey, J. Álvarez-Sabin, J.M. Lobos, et al.
Análisis coste-efectividad de dabigatrán para la prevención de ictus y embolia sistémica en fibrilación auricular no valvular en España.
Rev Esp Cardiol., 65 (2012), pp. 901-910
C. Rubio-Terrés, R. Graefenhain, D. Rubio-Rodríguez, T. Evers, S. Grau.
Cost-effectiveness analysis of rivaroxaban versus acenocoumarol in the prevention of stroke in patients with non-valvular atrial fibrillation in Spain.
JHEOR., 4 (2016), pp. 19-34
M. Giner-Soriano, C. Vedia, A. Roso-Llorach, et al.
Effectiveness, safety and costs of thromboembolic prevention in patients with non-valvular atrial fibrillation: phase I ESC-FA protocol study and baseline characteristics of a cohort from a primary care electronic database.
BMJ Open., 6 (2016), pp. e010144
A. Tawfik, J.M. Bielecki, M. Krahn, et al.
Systematic review and network meta-analysis of stroke prevention treatments in patients with atrial fibrillation.
Clin Pharmacol., 8 (2016), pp. 93-107
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