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Vol. 68. Issue 8.
Pages 680-690 (August 2015)
Original article
DOI: 10.1016/j.rec.2014.08.010
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Cost-effectiveness Analysis Comparing Apixaban and Acenocoumarol in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation in Spain
Análisis coste-efectividad de apixabán frente a acenocumarol en la prevención del ictus en pacientes con fibrilación auricular no valvular en España
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Gonzalo Barón Esquiviasa, Ginés Escolar Albaladejob, José Luis Zamoranoc, Lourdes Betegón Nicolásd, Cristina Canal Fontcubertad, Marina de Salas-Cansadoe, Darío Rubio-Rodríguezf, Carlos Rubio-Terrésf,
Corresponding author
crubioterres@healthvalue.org

Corresponding author: Health Value, Virgen de Aránzazu 21, 5.o–B, 28034 Madrid, Spain.
a Servicio de Cardiología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
b Servicio de Hemoterapia y Hemostasia, Hospital Clínic, Barcelona, Spain
c Servicio de Cardiología, Hospital Universitario Ramón y Cajal, Madrid, Spain
d Departamento de Economía de la Salud, Bristol-Myers Squibb España, Madrid, Spain
e Departamento de Farmacoeconomía y Resultados en Salud, Pfizer España, Madrid, Spain
f Health Value, Madrid, Spain
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Tables (5)
Table 1. Population and Risks Considered in the Markov Model
Table 2. Utilities Considered in the Markov Model
Table 3. Costs Considered in the Markov Model
Table 4. Number of Complications Predicted in the Life-long Follow-up of a Cohort of 1000 Patients With Nonvalvular Atrial Fibrillation
Table 5. Results of the Cost-effectiveness Analysis of Apixaban vs Acenocoumarol
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Abstract
Introduction and objectives

Cost-effectiveness analysis of apixaban (5mg twice daily) vs acenocoumarol (5mg/day) in the prevention of stroke in patients with nonvalvular atrial fibrillation in Spain.

Methods

Markov model covering the patient's entire lifespan with 10 health states. Data on the efficacy and safety of the drugs were provided by the ARISTOTLE trial. Warfarin and acenocoumarol were assumed to have therapeutic equivalence. Perspectives: The Spanish National Health System and society. Information on the cost of the drugs, complications, and the management of the disease was obtained from Spanish sources.

Results

In a cohort of 1000 patients with nonvalvular atrial fibrillation, administration of apixaban rather than acenocoumarol would avoid 18 strokes, 71 hemorrhages (28 intracranial or major), 2 myocardial infarctions, 1 systemic embolism, and 23 related deaths. Apixaban would prolong life (by 0.187 years) and result in more quality-adjusted life years (by 0.194 years) per patient. With apixaban, the incremental costs for the Spanish National Health System and for society would be € 2488 and € 1826 per patient, respectively. Consequently, the costs per life year gained would be € 13 305 and € 9765 and the costs per quality-adjusted life year gained would be € 12 825 and € 9412 for the Spanish National Health System and for society, respectively. The stability of the baseline case was confirmed by sensitivity analyses.

Conclusions

According to this analysis, apixaban may be cost-effective in the prevention of stroke in patients with nonvalvular atrial fibrillation compared with acenocoumarol.

Keywords:
Apixaban
Acenocoumarol
Cost-effectiveness
Nonvalvular atrial fibrillation
Abbreviations:
AF
NVAF
QALY
TTR
VKA
Resumen
Introducción y objetivos

Análisis de coste-efectividad de apixabán (5 mg dos veces al día) frente a acenocumarol (5 mg/día) en la prevención del ictus en pacientes con fibrilación auricular no valvular en España.

Métodos

Modelo de Markov durante toda la vida del paciente con 10 estados de salud. Los datos de eficacia y seguridad de los fármacos proceden del ensayo clínico ARISTOTLE. Se asumió la equivalencia terapéutica de warfarina y acenocumarol. Perspectivas: Sistema Nacional de Salud y la sociedad. El coste de los medicamentos, las complicaciones y el manejo de la enfermedad se obtuvieron de fuentes españolas.

Resultados

En una cohorte de 1.000 pacientes con fibrilación auricular no valvular, con apixabán se evitarían frente a acenocumarol: 18 ictus, 71 hemorragias (28 intracraneales o mayores), 2 infartos de miocardio, 1 embolia sistémica y 23 muertes relacionadas. Con apixabán se obtendrían más años de vida (0,187) y más años de vida ajustados por calidad (0,194) por paciente. Los costes incrementales con apixabán para el Sistema Nacional de Salud y la sociedad serían de 2.488 y 1.826 euros por paciente. En consecuencia, se obtendría unos costes por año de vida ganado de 13.305 y 9.765 euros, y unos costes por año de vida ajustado por calidad ganado de 12.825 y 9.412 euros para el Sistema Nacional de Salud y la sociedad respectivamente. Los análisis de sensibilidad confirmaron la estabilidad del caso base.

Conclusiones

Según este análisis, apixabán puede ser coste-efectivo en la prevención del ictus en pacientes con fibrilación auricular no valvular frente a acenocumarol.

Palabras clave:
Apixabán
Acenocumarol
Coste-efectividad
Fibrilación auricular no valvular
Full Text
INTRODUCTION

Atrial fibrillation (AF) is a cardiac arrhythmia associated with aging, hypertension, valve diseases, and other heart diseases.1 Nonvalvular AF (NVAF) refers to those cases with a change in rhythm in the absence of rheumatic mitral valve disease, artificial heart valve, or mitral valve repair. Atrial fibrillation is associated with a higher risk of death (twice that of patients without AF), cerebrovascular disease (5-fold higher), and systemic embolism.1

The prevalence of AF is estimated to be 2% in the general Spanish population,1 4.4% in the population aged ≥ 40 years,2 and up to 10.9% and 11.1% in individuals older than 60 years and 79 years, respectively.3,4

The average annual cost of a patient with AF in Spain is estimated to be € 2365; of this sum, € 1008 would correspond to hospital stays, € 723 to surgical interventions, and € 247 lost productivity at work.5 The cost of cardioembolic stroke during the first 38 days after onset has been estimated to be € 13 353.6 The direct nonhealth care costs of stroke, corresponding to informal care of patients with sequels, are calculated to range, depending on severity, from € 252 to € 1031 during the acute phase (2 weeks) and from € 1367 to € 1942 a month during subsequent patient follow-up.7

Vitamin K antagonists (VKA) (acenocoumarol and warfarin) are currently the standard treatment for stroke prevention in patients with AF.8 It is estimated that 84% of the AF patients9 in Spain are taking oral anticoagulation therapy, and that 66% are being treated with VKA as monotherapy.10 However, the use of VKA is limited by the risk of bleeding, its narrow therapeutic margin, and the inconvenience to the patient due to the need for monitoring and drug-drug and food-drug interactions. When VKA doses are adjusted, these agents reduce the risk of stroke by 64% vs placebo but they also double the risk of the development of additional and intracranial hemorrhages.11 In Spain, the most widely used agent for oral anticoagulant therapy is acenocoumarol, whereas warfarin is administered in Anglo-Saxon countries.12 According to the available data, the effectiveness of the 2 drugs is assumed to be similar in clinical practice.12,13

According to the recommendations of the European Society of Cardiology,14 direct oral anticoagulants, such as apixaban, are preferable to VKA for the treatment of most cases of NVAF, since they are not inferior in terms of efficacy and reduce the number of intracranial hemorrhages.

Apixaban is a new drug for oral administration that exerts a potent, direct and highly selective inhibition of factor Xa to reduce the conversion of prothrombin to thrombin.15 A randomized, double-blind trial16 compared apixaban and warfarin in 18 201 patients with NVAF. The results of that study indicate that apixaban (5mg twice daily) was significantly superior to warfarin in the prevention of stroke and systemic embolism, produced fewer episodes of major bleeding, and reduced death from any cause.16

The differences observed between apixaban and acenocoumarol/warfarin may have a health care-related and economic impact. Consequently, we carried out a cost-effectiveness analysis of stroke prevention with apixaban or acenocoumarol in patients with NVAF.

METHODSStudy Design

A cost-effectiveness analysis17 was carried out by adapting the economic model proposed by Dorian et al18 to the Spanish health care setting. This model covers the life-long course (with a life expectancy of 80.4 years for both sexes) of a cohort of 1000 patients with NVAF18,19 whose characteristics were those of the patients in the ARISTOTLE trial.16 It is a Markov model (Figures 1 and 2), with 6-week cycles and 10 major health states. The entire patient cohort was in a state of NVAF and, after each cycle, they remained in NVAF or passed to other states, in accordance with certain transition probabilities.

Figure 1.

Markov economic model of stroke prevention in patients with nonvalvular atrial fibrillation. Course of a patient with nonvalvular atrial fibrillation. Patients who progress to the state of nonvalvular atrial fibrillation without anticoagulant, return to nonvalvular atrial fibrillation. Patients who progress to states of myocardial infarction or systemic embolism can die a posteriori as a consequence of these complications. AC, anticoagulant; CRNM, clinically relevant nonmajor; ICH, intracranial hemorrhage; MI, myocardial infarction; NVAF, nonvalvular atrial fibrillation; SE, systemic embolism. *Change of treatment to acetylsalicylic acid.

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Figure 2.

Markov economic model of stroke prevention in patients with nonvalvular atrial fibrillation. Course of a patient who has had a stroke (ischemic or hemorrhagic).

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Effectiveness Data

These probabilities of transition from one health state to another (stroke, systemic embolism, bleeding, death) for the drugs under comparison were obtained from the ARISTOTLE clinical trial16 and from other sources when necessary.20–27 According to the model, each patient can experience only 1 complication per cycle and only 1 recurrence of stroke (ischemic or hemorrhagic) is permitted. The simulation of avoided episodes was modeled throughout the patient's lifespan, based on the intention-to-treat analysis in the ARISTOTLE trial. Table 1 shows the rate of complications/100 person-years and the hazard ratio of these complications with acenocoumarol vs apixaban, adjusted according to the CHADS2 (congestive heart failure, hypertension, age, diabetes, stroke [doubled]) score, and the international normalized ratio (INR) quality control index according to the time in therapeutic range (TTR).

Table 1.

Population and Risks Considered in the Markov Model

Item  Mean  Range  References 
Population characteristics
Patients with an indication for VKA  Yes  —  Granger et al16 
Women  35.3%  —  Granger et al16 
Mean age, years  70  63-76  Granger et al16 
CHADS2, mean  2.1  —  Granger et al16 
Complication rates/100 person-yearsa
Stroke, excluding hemorrhagic stroke
Apixaban  0.981  —  Granger et al16 
Acenocoumarol  1.077  —  Granger et al16 
Myocardial infarction
Apixaban  0.530  —  Granger et al16 
Acenocoumarol  0.610  —  Granger et al16 
Systemic embolism
Apixaban  0.090  —  Granger et al16 
Acenocoumarol  0.100  —  Granger et al16 
Other CV-related hospitalizationsb
Apixaban  10.460c  —  Connolly22 
Acenocoumarol  10.460c  —  Connolly22 
Other reasons for discontinuing AC therapyb
Apixaban  13.177  —  Granger et al16 
Acenocoumarol  14.405  —  Granger et al16 
ICH
Apixaban  0.330  —  Granger et al16 
Acenocoumarol  0.800  —  Granger et al16 
Other major bleeding
Apixaban  1.790  —  Granger et al16 
Acenocoumarol  2.270  —  Granger et al16 
CRNM bleeding
Apixaban  2.083  —  Granger et al16 
Acenocoumarol  2.995  —  Granger et al16 
Recurrence of ischemic stroke  4.100  —  Mohan26 
Recurrence of hemorrhagic stroke  2.996  —  Mohan26 
Hazard ratios of apixaban vs acenocoumarol
Stroke  0.79  0.65-0.95  Granger et al16 
Myocardial infarction  0.88  0.66-1.17  Granger et al16 
Systemic embolism  0.87  0.44-1.75  Granger et al16 
ICH  0.51  0.35-0.75  Granger et al16 
Other major bleeding  0.79  0.68-0.93  Granger et al16 
Major and CRNM bleeding  0.68  0.61-0.75  Granger et al16 
Additional risk of mortality with acenocoumarol vs apixaban
NVAF  1.34  —  Granger et al16 
Stroke, minor/moderate/severe  3.18/5.84/15.75  —  Granger et al16 
Myocardial infarction (men/women)  4.16/2.56  —  Friberg et al23 
Systemic embolism  1.34  —  Henriksson et al24 
Other factors
Adjustment factor for stroke risk for each decade of life  1.40  —  Huybrechts et al25 
Adjustment factor for risk of hemorrhage for each decade of life  1.97  —  Bronnum et al21 
Hemorrhagic stroke in ICH (apixaban), %  77  —  No authors listed27 
Hemorrhagic stroke in ICH (acenocoumarol), %  64  —  Ariesen et al20 
GI hemorrhage in the other major bleeding (apixaban), %  38  —  Granger et al16 
GI hemorrhage in the other major bleeding (acenocoumarol), %  35  —  Granger et al16 
Treatment with ASA following discontinuationd
Rate of ischemic stroke/100 person-years  3.453  —  Connolly et al22 
Rate of myocardial infarction/100 person-years  1.110  —  Connolly et al22 
rate of ICH/100 person-years  0.322  —  Connolly et al22 
Rate of other major bleeding/100 person-years  0.887  —  Connolly et al22 
Rate of CRNM bleeding/100 person-years  2.936  —  Connolly et al22 

AC, anticoagulants; ASA, acetylsalicylic acid; CHADS2, congestive heart failure, hypertension, age, diabetes, stroke (double); CRNM, clinically relevant nonmajor; CV, cardiovascular; GI, gastrointestinal; ICH, intracranial hemorrhage; NVAF, nonvalvular atrial fibrillation; VKA, vitamin K antagonists.

a

Adjusted for CHADS2 (congestive heart failure, hypertension, age, diabetes, stroke [doubled]).

b

Not due to stroke or myocardial infarction.

c

The same rate observed in patients with a contraindication for vitamin K antagonists is assumed.

d

Treatment with acetylsalicylic acid after discontinuation of the previous anticoagulation therapy was considered to be due to major bleeding or other causes; it was also considered that the distribution according to severity of the ischemic or hemorrhagic stroke would be the same as that observed with acetylsalicylic acid in the first-line treatment (AVERROES study).

Overall mortality in women and men older and younger than 75 years was obtained by adjusting published Spanish mortality data19 to a Gompertz function, for the purpose of predicting all-cause mortality and excluding that due to stroke and hemorrhage in order to avoid counting them twice. Treatment with acetylsalicylic acid was considered after interruption of previous anticoagulation therapy (acenocoumarol or apixaban) due to major bleeding or other causes.22

For example, with respect to the method of extrapolating the results for acute myocardial infarction from the ARISTOTLE clinical trial16 to the patient's entire lifespan, calculations were based on the risks of having an infarction with apixaban and with warfarin obtained in the clinical trial, with a rate of 100 person-years of 0.53 and 0.61, respectively. These annual risks were transformed into a risk model for a 6-week period (the duration of the cycles of the Markov model). Thus, every 6 weeks, a percentage of patients with NVAF from a hypothetical cohort of 1000 will have an infarction. Some of these patients will die as a consequence of this complication and the remainder will survive. Those patients who have had an infarction complete the simulation at this time and are counted as failures in prevention, with the costs and utilities associated with the state of acute myocardial infarction.

Differences in the effectiveness of the treatments were measured in life years gained and in quality-adjusted life years (QALY) gained. The utilities of the different health states used to calculate the QALY were obtained from a study performed in the United Kingdom based on the EQ-5D (EuroQol 5D) questionnaire in patients with AF28,29 (Table 2). Determination of the loss of quality of life associated with the need for monitoring required by the use of acenocoumarol was based on a study by Gage et al30 (Table 2).

Table 2.

Utilities Considered in the Markov Model

Item  Mean  References 
Utilities of the Markov states
Nonvalvular atrial fibrillation, baseline  0.7270  Sullivan et al28 
Minor strokea  0.6151  Sullivan et al28 
Moderate strokea  0.5646  Sullivan et al28 
Severe strokea  0.5142  Sullivan et al28 
Systemic embolism  0.6265  Sullivan et al28 
Myocardial infarction  0.6098  Sullivan et al28 
Loss of utilities, duration
Intracranial hemorrhage  0.1511 (6 weeks)  Sullivan et al28 
Other major bleeding  0.1511 (2 weeks)  Sullivan et al28, Freeman et al29 
CRNM bleeding  0.0582 (2 days)  Sullivan et al28, Freeman et al29 
Hospitalization for other CV-related causes  0.1276 (6 days)  Sullivan et al28 
Use of acenocoumarol, INR monitoring  0.0130 (treatment)  Sullivan et al28 
Use of apixaban  Assumptionb 

CV, cardiovascular; INR, international normalized ratio; CRNM, clinically relevant nonmajor.

a

Ischemic or hemorrhagic.

b

A sensitivity analysis was performed, considering that, improbably, the loss of utilities with the use of apixaban was the same as that assumed for acenocoumarol.

Health Care Costs and Resources

The per unit use and cost of resources were obtained from Spanish sources (in 2012 euros). The analysis was carried out from the perspective of the Spanish National Health System (considering only the direct health care costs) and of society (including direct nonhealth care costs, as well). The cost of the medications (RRP [recommended retail price] + VAT [value added tax], with a 7.5% reduction)31 was calculated by considering 10 mg/day (5-mg doses twice daily) of apixaban32 and 5mg/day of acenocoumarol (the daily dose recommended by the World Health Organization). The cost of INR monitoring was estimated to be € 320 a year, according to a study by De Solà-Morales Serra and Elorza Ricart.33 It was considered that all the patients, regardless of their treatment, visited their primary care physician every 3 months for routine follow-up of the AF. The cost of the complications of NVAF during the acute phase was obtained by taking the mean of the retail prices corresponding to diagnosis-related groups in the Spanish autonomous communities; the cost of treatment after the acute phase of the complications was obtained from other Spanish sources7,34–38 (Table 3). The direct nonhealth care costs included in the analysis from the societal perspective consisted of those derived from informal care (aid to the dependent patient and home adaptations) of patients who have had an ischemic or hemorrhagic stroke7 (Table 3). An annual discount rate of 3.5% was applied for health care costs and results.

Table 3.

Costs Considered in the Markov Model

  Cost (€)  Unit  Duration  Source 
Annual cost of monitoring*  320.00  Annual  NA  De Solà-Morales et al33 
Systematic control  35.32  Per visit  NA  Retail prices in the ACs 
Stroke
Direct costs
Minor
Acute phase  5970.09  Per episode  2 weeks  Retail prices in the ACs 
Maintenance  120.01  Monthly  For life  Mar et al36 
Moderate
Acute phase  6281.38  Per episode  2 weeks  Retail prices in the ACs 
Maintenance  742.59  Monthly  For life  Mar et al36 
Severe
Acute phase  6951.01  Per episode  2 weeks  Retail prices in the ACs 
Maintenance  2081.85  Monthly  For life  Mar et al36 
Fatal  5910.08  Per episode  NA  Retail prices in the ACs 
Direct nonhealth care costs
Minor
Acute phase  252.39  Per episode  2 weeks  Beguiristain et al7 
Maintenance  1367.57  Monthly  For life  Beguiristain et al7 
Moderate
Acute phase  666.11  Per episode  2 weeks  Beguiristain et al7 
Maintenance  1789.53  Monthly  For life  Beguiristain et al7 
Severe
Acute phase  1031.69  Per episode  2 weeks  Beguiristain et al7 
Maintenance  1942.61  Monthly  For life  Beguiristain et al7 
Hemorrhagic stroke
Direct costs
Minor
Acute phase  7575.44  Per episode  2 weeks  Retail prices in the ACs 
Maintenance  120.01  Monthly  For life  Mar36 
Moderate
Acute phase  7886.73  Per episode  2 weeks  Retail prices in the ACs 
Maintenance  742.59  Monthly  For life  Mar36 
Severe
Acute phase  8556.36  Per episode  2 weeks  Retail prices in the AC 
Maintenance  2081.85  Monthly  For life  Mar36 
Fatal  7515.44  Per episode  NA  Retail prices in the ACs 
Direct nonhealth care costs
Minor
Acute phase  252.39  Per episode  2 weeks  Beguiristain et al7 
Maintenance  1367.57  Monthly  For life  Beguiristain et al7 
Moderate
Acute phase  666.11  Per episode  2 weeks  Beguiristain et al7 
Maintenance  1789.53  Monthly  For life  Beguiristain et al7 
Severe
Acute phase  1031.69  Per episode  2 weeks  Beguiristain et al7 
Maintenance  1942.61  Monthly  For life  Beguiristain et al7 
Other intracranial bleeding  7515.44  Per episode  NA  Retail prices in the ACs 
Other major bleeding
GI hemorrhage  3431.91  Per episode  NA  Monreal et al37 
Non intracranial/GI  3431.91  Per episode  NA  Monreal et al37 
CRNM hemorrhages  2304.66  Per episode  NA  Monreal et al37 
Myocardial infarction
Acute phase  10 513.37  Per episode  NA  Retail prices in the AC 
Maintenance  164.81  Monthly  For life  Mar36 
Systemic embolism
Acute phase  2846.50  Per episode  2 weeks  Retail prices in the ACs 
Maintenance  116.84  Monthly  For life  Mar et al36 
Other CV-related hospitalizations  4729.67  Per episode  NA  Retail prices in the ACs 
Dyspepsia-related costs  27.39  Monthly  NA  Ariza-Ariza et al34 
Costs of renal monitoring  14.76  Annual  NA  Navarrete-Navarro et al38 
Monthly costs related todyspepsia and renal monitoring
Apixaban  1.69  Monthly  NA  Calculated: according to renal monitoring and dyspepsia-related costs 
Acenocoumarol  0.50  Monthly  NA   
Mean daily pharmacy costs(RRP – 7.5% of discount + VAT)
Apixaban  2.80  Daily  NA  BOT PLus32 
Acenocoumarol  0.15  Daily  NA  BOT PLus32 

ACs, autonomous communities; CRNM, clinically relevant nonmajor; CV, cardiovascular; GI, gastrointestinal; NA, not applicable; RRP, recommended retail price; VAT, value added tax.

*

Applicable only to acenocoumarol.

Base Case and Sensitivity Analysis

We analyzed a base case with the mean values of all the parameters. To confirm the stability of the results, simple univariate sensitivity analyses were performed (in each sensitivity analysis, the baseline value of a variable was modified, applying its extreme values) for the main variables of the model (Table 1). One of those analyzed was the percentage of TTR of the study population. According to the ARISTOTLE trial,16 in the base case of the analysis, 25% of the patients were equally distributed among the 4 established TTR intervals (< 52.38%; from ≥ 52.38% to < 66.02%; from ≥ 66.02% to < 76.51%, and ≥ 76.51%). In this respect, sensitivity analysis of the extreme values considering that 100% of the patients were in the worst (< 52.38% in TTR) or best (≥ 76.51% in TTR) of the intervals was carried out. Sensitivity analyses were also performed for acenocoumarol and apixaban, taking the extreme values of variables such as risk of stroke and intracranial hemorrhage, the probability of hospital admission, the cost of each visit for INR monitoring for acenocoumarol, and the loss of utilities associated with the use of acenocoumarol or apixaban (Figure 3). As the reduction in the risk of myocardial infarction vs warfarin was not statistically significant, a sensitivity analysis was carried out considering that apixaban did not reduce the number of myocardial infarctions vs warfarin, that is, taking the same rate of infarctions (0.530/100 person-years) for apixaban and warfarin. Finally, a probabilistic analysis was performed (Monte Carlo simulation with 2000 simulations in the 1000-patient cohort) which included, at the same time, all the variables of the analysis, adjusted for the appropriate statistical distributions in each case (beta for the transition probabilities and the utilities and gamma for costs). When the model simulated the course of a hypothetical cohort of 1000 patients with NVAF, the course of each patient in that cohort was different, since the modifications in all the variables of each patient (eg, the hazard ratio of stroke, myocardial infarction, systemic embolism, intracranial hemorrhage, costs, utilities, etc) occurred randomly in accordance with the previously defined statistical distributions. Thus, an attempt was made to imitate the real clinical course of the patients.

Figure 3.

Deterministic sensitivity analysis from the perspective of the Spanish National Health System. Tornado diagram (the extreme values used are indicated to one side). Ratio of incremental cost-effectiveness (euros per quality-adjusted life years gained with apixaban vs acenocoumarol) (in 2012 euros). The figure shows the values of the base case and the extreme values used in the sensitivity analysis. The risks are expressed as rate/100 patient-years. Mortality is the rate of death during the clinical trial. CV, cardiovascular; ICER, incremental cost-effectiveness ratio; ICH, intracranial hemorrhage; TTR, time in therapeutic range.

(0.38MB).
RESULTSEpisodes Avoided

According to the results produced by the model applied to a cohort of 1000 patients with NVAF, apixaban would prevent a considerable number of complications compared with acenocoumarol: 18 strokes (4 ischemic and 14 hemorrhagic), 71 hemorrhages (12 of which would be intracranial and 16 would be cases of major bleeding), 1 systemic embolism, and 2 myocardial infarctions. In contrast, apixaban would prevent 23 deaths related to thromboembolic or hemorrhagic episodes (Table 4).

Table 4.

Number of Complications Predicted in the Life-long Follow-up of a Cohort of 1000 Patients With Nonvalvular Atrial Fibrillation

Complication  Apixaban  Acenocoumarol  Difference 
Ischemic strokes*  263  267  –4 
Hemorrhagic strokes*  29  43  –14 
Intracranial hemorrhages  13  25  –12 
Systemic embolisms  25  26  –1 
Other major hemorrhages  169  185  –16 
CRNM bleeding  295  338  –43 
Myocardial infarctions  87  89  –2 
Other CV-related hospitalizations  1219  1188  31 
Other discontinuations of the treatment  644  640 
Deaths per episodes (acute phase)  62  74  –12 
Deaths per episodes (maintenance)  318  329  –11 

CRNM, clinically relevant nonmajor; CV, cardiovascular.

*

Indicates both a first stroke and recurrent strokes.

Cost-effectiveness

Consequently, for each patient treated with apixaban rather than acenocoumarol we would obtain more life years (0.187 life years gained) and an increase in QALY (0.194 gained). The incremental costs per patient treated with apixaban would be € 2488 for the Spanish National Health System and € 1826 for society. This difference in costs is mainly due to the more marked decrease in mortality obtained with apixaban and its higher purchase price. The cost per life years gained for the Spanish National Health System and for society was € 13 305 and € 9765, respectively. The cost per QALY gained was € 12 825 and € 9412, respectively (Table 5). These results indicate that, compared with acenocoumarol, apixaban is cost-effective in the prevention of stroke in patients with NVAF in Spain, as the costs per life years gained or for QALY gained are below € 30 000, which is the threshold that is generally accepted in Spain.39

Table 5.

Results of the Cost-effectiveness Analysis of Apixaban vs Acenocoumarol

  Apixaban  Acenocoumarol  Difference 
Perspective of the Spanish NationalHealth System
Life years  9.037  8.850  0.187 
QALY  6.424  6.230  0.194 
Total costs (€)  18 029  15 541  2488 
Costs per LYG (€)  13 305     
Costs of gaining 1 QALY (€)  12 825     
Societal perspective*
Life years  9.037  8.850  0.187 
QALY  6.424  6.230  0.194 
Total costs (€)  29 193  27 367  1826 
Costs per LYG (€)  9765     
Costs of gaining 1 QALY (€)  9412     

LYG, life year gained; QALY, quality adjusted life year.

*

Includes the direct non-health care costs for aid to the patient who is dependent due to stroke.

Sensitivity Analysis

The sensitivity analyses confirmed that apixaban is a cost-effective treatment compared with acenocoumarol. The changes in the most sensitive parameters of the study, such as the risks of complications with one treatment or the other, the loss of utilities associated with INR monitoring with acenocoumarol, and the costs of follow-up visits, do not affect the results of the analysis since, in every case, the costs of gaining 1 life year and the cost of gaining 1 QALY with the most effective treatment (apixaban) were below the threshold of € 30 000 (Figure 3).

Considering that 100% of the patients were in the lowest percentage of TTR (< 52.38%), the cost of gaining 1 QALY would be € 7054. In the opposite case (≥ 76.51% in TTR), the cost per QALY gained would increase to € 12 404, in both cases, from the perspective of the Spanish National Health System (Figure 3). Should apixaban fail to reduce the number of myocardial infarctions compared with warfarin, the cost of gaining 1 QALY would be € 14 150.

According to the probabilistic sensitivity analysis, the probability of apixaban being cost-effective vs acenocoumarol was 87% (Figure 4).

Figure 4.

Probabilistic sensitivity analysis. The probability that apixaban is cost-effective (cost per quality-adjusted life year gained < € 30 000) compared with acenocoumarol is 87%.

(0.39MB).
DISCUSSION

Although acenocoumarol and warfarin are the usual treatments for AF, their use has limitations owing to their narrow therapeutic margin, the risk of bleeding, and drug-drug and drug-food interactions.40,41 Patients treated with VKA require frequent INR monitoring and resulting dose adjustments. According to a meta-analysis by Baker et al,42 patients treated with warfarin remain in the therapeutic INR range only 55% of the time. Of anticoagulated patients who have a cardioembolic stroke, 67.6% have an INR below the therapeutic range at the time of the stroke.43

Apixaban is a new anticoagulant that produces a statistically significant reduction in the risks of stroke, bleeding, and death due to these episodes compared with VKA.40 In this respect, a study by Banerjee et al,44 based on patients treated in real-world clinical practice, indicates that the net clinical benefit (balance between the risk of ischemic stroke and the risk of intracranial hemorrhage) of apixaban is greater than that of warfarin, for different CHADS2 scores and risk of bleeding.

According to the present model and the adopted premises, apixaban can be a cost-effective treatment compared with acenocoumarol in the prevention of stroke in NVAF patients in Spain.

Limitations of the Model

In the assessment of these results, we must take into account the fact that this is a theoretical model that is, by definition, a simplified simulation of reality. Pharmacoeconomic models enable the creation of economic simulations of complex drug-related health care processes. They are especially useful when the intention is to simulate the course of a disease beyond the period of clinical tests.17 Markov models with Monte Carlo simulation are preferred over deterministic models when dealing with chronic diseases like NVAF, as they are better at simulating the course of the disease over the long term. The Markov deterministic model is based on the course of a hypothetical patient cohort. However, the Monte Carlo probabilistic analysis simulates the course of individual patients, based on the values of randomly chosen variables, which more closely resembles clinical reality. The data on efficacy and on adverse effects utilized in the model were obtained from a randomized clinical trial involving 18 201 patients with NVAF,16 providing a high level of evidence.

One of the main suppositions of the model is the therapeutic equivalence between warfarin and acenocoumarol. Thus, we adopted the effectiveness values obtained for acenocoumarol in the ARISTOTLE clinical trial, which compared it with warfarin.16 This assumption can be considered a limitation of the study, given that, although the 2 drugs could have similar effectiveness in clinical practice,12 an observational study found no significant differences in the quality of INR control, but did report a longer duration of the TTR in the patients treated with acenocoumarol than in those treated with warfarin (37.6% vs 35.7%; P = .0002).13 Nevertheless, in other previously published Spanish economic studies, acenocoumarol and warfarin were considered to be perfect substitutes for each other, both in efficacy and safety and the in the resource use associated with each.45,46

The costs assumed for the acute phase of the strokes and hemorrhages in the model were obtained from the diagnosis-related groups published by the Spanish autonomous communities, prices that could differ from the real direct costs of the processes.

The cost of the drugs was calculated considering a dose of 5mg/d of acenocoumarol, the daily dose recommended by the World Health Organization. Nevertheless, it should be considered that this premise serves only for the calculation of the cost of treatment with acenocoumarol, a variable that does not significantly affect the result because of the low price of the drug.

The utilities of the model were obtained from a study performed in the United Kingdom based on the EQ-5D questionnaire in patients with AF.28,29 Concerning the validity of these utility data corresponding to the Spanish population, a study based on 83 000 evaluations of 44 health states, with the EQ-5D applied in 6 European countries (including Spain) observed wider variability between individuals than between countries.47

Despite the aforementioned limitations of the model, the results obtained concur, as the result favoring apixaban is maintained both in deterministic sensitivity analyses and in the Monte Carlo analysis, with a high probability (87%) that apixaban is more cost-effective than acenocoumarol.

The present report is the first analysis of the cost-effectiveness of apixaban in NVAF performed in Spain. Two analyses comparing the cost-effectiveness of apixaban and warfarin in NVAF have recently been published in the United States.48,49 These studies found that apixaban would be cost-effective in 98% and 62% of the simulations for primary and secondary stroke prevention, respectively.

Two economic analyses of oral anticoagulants vs acenocoumarol in the prevention of stroke in patients with NVAF in Spain have recently been published.45,46 From the perspective of the Spanish National Health System, the cost per QALY gained would be € 17 581 with dabigatran5 and € 11 274 with rivaroxaban.46 The results of the economic models of apixaban, dabigatran, and rivaroxaban are not directly comparable, since they differ in the structure of the Markov models used; however, they reflect the fact that the oral anticoagulants available in Spain are cost-effective options in the current Spanish health care context.

CONCLUSIONS

According to the premises assumed in this model, it can be concluded that it is highly probable (probability of 87% according to the probabilistic analysis) that apixaban could be a cost-effective treatment compared with acenocoumarol in the prevention of stroke in patients with NVAF, in accordance with the cost-effectiveness threshold generally accepted in Spain.39 The stability of the results obtained in the base case of the analysis were confirmed in the deterministic and probabilistic sensitivity analyses.

CONFLICTS OF INTEREST

This study was jointly financed by Bristol-Myers Squibb S.A. and Pfizer S.L.U. Lourdes Betegón and Cristina Canal are employees of Bristol-Myers Squibb S.A. and Marina De Sales is employed by Pfizer S.L.U. The remaining authors have been remunerated by Bristol-Myers Squibb S.A. and Pfizer S.L.U. for their collaboration in matters of consultancy and editorial opinion.

Acknowledgments

The authors wish to thank Teresa Lanitis and Thitima Kongnakorn for their work in the development of the model used as the basis for the adaptation of the study to Spain.

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