for personal use only reproduction ...con apixaban se generarían más costes por paciente que con...

Atención Farmacéutica

Volume 16

Number 5

September - October 2014

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ORIGINALS

Effectiveness of posaconazole and voriconazole in primary and secondary prophylaxis of invasive fungal infection in hematological patients: Retrospective observational studyChamorro de Vega E, Gil Navarro MªV, Bautista Paloma FJ

Cost-effectiveness analysis of apixaban versus dabigatran for prevention of stroke in patients with non-valvular atrial fibrillation in SpainBetegón Nicolás L, Canal Fontcuberta C, Escolar Albaladejo G, De Salas Cansado M, Rubio-Rodríguez D, Rubio-Terrés C, Fernández Gallego V

Chemotherapy induced-anemia treated with erythropoietin alpha or darbopoetin in non-small cell lung cancer patientsGasent Blesa JM, Poquet Jornet J, Giner Bosch V, Cuesta Grueso C, Munilla Das A, Garde Noguera J, Fonfría Esparza Mª, Olmo Ortega P, Alberola Candel V

Role of teleneurology in health and social care centresIglesias Barreira R, Albiñana Pérez MªS, De la Fuente Fernández R, Taboada López RJ, López Sandomingo L, Rodríguez Penín I, Meizoso López MªD, Pérez Hermida P, Díaz López E, Sicre Romero I

Enzalutamide: New alternative for treatment of prostate cancer metastaticGómez Valbuena I, Alioto D, Serrano Garrote O, Ferrari Piquero JM

Use of nephrotoxic drugs in chronic kidney disease patientsCabello Muriel A, Urbieta Sanz E, Iniesta Navalón C, Gascón Cánovas JJ, Fernández Pardo J

REVIEWS

Linaclotide: Pharmacology and clinical perspectiveLópez Tricas JM, Álvarez de Toledo Bayarte Á

SHORT REPORTS

Paclitaxel administration in a patient with hyperbilirubinemiaDo Pazo Oubiña F, Amorós Reboredo P, Bastida Fernández C, Creus Baró N

Defibrotide for treatment of veno-occlusive disease. A single center experienceRuiz Ramos J, Company Albir MªJ, Favieres Puigcerver C, Megías Vaericat JE, López Briz E, Poveda Andres JL

Successful prasugrel therapy in frail elderly patients: A case reportDuero M, Pérez-Ricart A, Mestre L, Martínez J

Mushroom poisoningSaavedra Quirós V, García Sanz E, Torralba Arranz A

Effectiveness and tolerance of 0.02% chlorhexidine eye drops with an Acanthamoeba keratitisRizo Cerdá ÁMª, Espuny Miró A, Lucas Elio G, Selvi Sabater P

JOURNAL EDITED BY RASGO EDITORIAL, S. L,SINCE 1983

EDITORIAL

Administration of insulin inhalation

López Tricas JM

FOR PERSONAL USE ONLY

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COPYRIGHT RASGO EDITORIAL,S.L

Cost-effectiveness analysis of apixaban versus dabigatran for prevention of stroke EUR J CLIN PHARMVOL 16 NUM 5 SEP-OCT 2014 325

BETEGÓN NICOLÁS L. MHEcon.1

CANAL FONTCUBERTA C. MHEcon.1

ESCOLAR ALBALADEJO G. MD.2

DE SALAS CANSADO M. BChem.3

RUBIO-RODRÍGUEZ D. MHEcon.4

RUBIO-TERRÉS C. MPharmacol.4

FERNÁNDEZ GALLEGO V. MD.2

1 Bristol-Myers Squibb España. Madrid.2 Hospital Clínic. Barcelona.3 P er España. Madrid.4 Health Value. Madrid.Spain.

his study has been ointly nanced by Bris-tol-Myers Squibb S. . and P er S. . .

ourdes Bete n Cristina Canal and Víctor ern nde alle o are employees o Bristol-

Myers Squibb, S.A. Marina de Salas is an em-ployee o P er S. . . he rest o the authors ha e recei ed payment rom Bristol-Myers Squibb, S.A. and P er S. . . or their par-ticipation in the study.

Eur J Clin Pharm 2014; 16(5): 325-38.

Received: 13/03/2014.Accepted: 14/05/2014.

ORIG INAL

COST-EFFECTIVENESS ANALYSIS OF APIXABAN VERSUS DABIGATRAN FOR PREVENTION OF STROKE IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION IN SPAINBETEGÓN NICOLÁS LOURDES, CANAL FONTCUBERTA CRISTINA, ESCOLAR ALBALADEJO GINÉS, DE SALAS CANSADO MARINA, RUBIO-RODRÍGUEZ DARÍO, RUBIO-TERRÉS CARLOS, FERNÁNDEZ GALLEGO VÍCTOR

ABSTRACTb ective: o assess the cost-e ectiveness o api aban vs. dabi atran in stro e

prevention in patients ith non-valvular atrial brillation VA in Spain.Method: A Mar ov model as developed, ith cycles o si ee s, throu h-

out the patient s li e and 10 health states. he analysis as done rom the Spanish ational Health System S S and societal perspective. he sa ety and e cacy

o the dru s ere obtained rom a meta-analysis o pair ise indirect compari-sons. Dru costs api aban 10 m /day 5 m bid dabi atran: 220 110 m bid or 300 150 m bid m /day , VA complications and disease mana ement costs

ere obtained rom Spanish sources. An annual discount rate o 3.5 or costs and health outcomes was applied.

Results: n a cohort o 1,000 patients with VA durin their li etime, api aban were pro ected to avoid numerous complications versus dabi atran 24 ischemic stro es and 2 related deaths vs. dabi atran 110 m bid 11 ischemic stro es, 2 bleed-in s and 1 deaths vs. dabi atran 150 m bid . Consequently, each patient treated with api aban could obtain more years o li e 0.12 and 0.0 4 , respective-ly and more quality-ad usted li e-years 0.10 and 0.0 1 A , respectively .

Api aban enerated hi her overall costs per patient vs. dabi atran 110 m bid rom the S S perspective 13 but savin s would arise rom the socie-tal perspective 524 , with a cost per and A ained o 1,103 and

1,2 or the S S, and api aban bein dominant more e ective with less cost than dabi atran 110 m bid or the Society. he cost per A ained, rom the S S and societal perspective, compared with dabi atran 150 m bid would be ,5 1 and 10, , respectively. Deterministic and probabilistic sensitivity analyses con rmed the stability o these results.

Conclusion: Accordin to the model outcomes, api aban would be cost-e -ective versus dabi atran or the prevention o stro e in patients with VA in

Spain.

APIXABAN – DABIGATRAN – COST-EFFECTIVENESS – NON-VALVULAR ATRIAL FIBRILLATION

RESUMENObjetivo: Llevar a cabo un análisis de coste-efectividad de apixaban frente a

valvular (FANV) en España.Método: Modelo de Markov, con ciclos de seis semanas, durante toda la vida

del paciente y 10 estados de salud como ictus, sangrados y otras complicacio-




Betegón Nicolás L, Canal Fontcuberta C, Escolar Albaladejo G, De Salas Cansado M, Rubio-Rodríguez D, et alEUR J CLIN PHARMVOL 16 NUM 5 SEP-OCT 201432

INTRODUCTIONAtrial brillation A is a cardiac arrhythmia associated to a in , arterial hypertension, valve disease and other heart disorders.1 Atrial brillation is associated to an in-creased mortality ris 2- old compared with the absence o A , cerebrovascular disease 5- old and systemic embolism.1

Atrial brillation has an important impact in Spain, with an estimated prevalence o 2 in the eneral popu-lation 1 and a mean annual cost per patient o 2,3 5.2 The economic impact o the disease is moreover increased by the hi h cost o its associated complications in both the acute phase and at lon term. As an e ample, the esti-mated cost o cardioembolic stro e in the rst 3 days a ter the event is 13, 4 o which 4 .2 is enerated by hospital stay and 24. by rehabilitation .3

The vitamin anta onists acenocoumarol and war-arin, vitamin anta onists V A are currently the

standard treatment or the prevention o stro e in patients with AF.4 However, despite the recommendations o the treatment uides, appro imately 30-50 o all patients with AF and at moderate to hi h ris o su erin stro e receive ine ective treatment or even no treatment.5, On the other hand, the use o V A is limited by bleedin ris , a narrow therapeutic mar in and inconveniences or the patient derived rom the need or monitorin and interac-tions with dru s and oods. Althou h dose-ad usted V A reduce the ris o stro e by 4 versus placebo, they also double the ris o additional and intracranial bleedin .

Since 2011 a new amily o oral anticoa ulants has become available, with indications or the prevention o

stro e and systemic embolism in patients with non-valvu-lar atrial brillation VAF in Europe. At present there are three new oral anticoa ulants OA : dabi atran a direct thrombin inhibitor , api aban and rivaro aban direct inhibitors o coa ulation actor a .

Accordin to the recommendations o the European Society o Cardiolo y, the OA api aban, rivaro aban and dabi atran are pre erable to the V A in treatin most cases o VAF, since they are comparatively not in erior in terms o e cacy and moreover reduce the number o intracranial bleedin episodes.

Two clinical trials have compared api aban and da-bi atran, respectively, versus war arin. The AR STOT E study, a randomi ed, double-blind clinical trial, com-pared the e cacy and sa ety o api aban versus war-arin in 1 ,201 patients with VAF. The results o

this study showed api aban 5 m administered twice a day to be superior to war arin in preventin stro e and systemic embolism HR 0. 5 C , 0. -0. 5 p 0.001 , with ewer ma or bleedin episodes HR 0.

5 C , 0. -0. p 0.001 , and lesser mortality due to any cause HR 0. 5 C , 0. -0. p 0.04 . The RE- study, another randomi ed, double-blind clinical trial, compared the e cacy and sa ety o two dabi atran doses 150 or 110 m , both administered twice a day, versus war arin in 1 ,113 patients with VAF.10 Da - bi atran 150 m administered twice a day showed reater e cacy than war arin in preventin stro e and systemic embolism relative ris reduction RRR 35 , with a si ni cant decrease in the ris o intracranial bleedin RRR 5 . Dabi atran 110 m administered twice a

un metaanálisis de comparaciones indirectas por parejas. Las perspectivas del análisis consideradas fueron la del Sistema Nacional de Salud (SNS) y de la sociedad. El cálculo del coste de los medicamentos se realizó según las dosis recomendadas (apixaban: 10 mg/día [5 mg bid]; dabigatrán: 220 [110 mg bid] y 300 [150 mg bid] mg/día). El coste de las complicaciones de la FANV y del ma-nejo de la enfermedad se obtuvo de fuentes españolas. Para costes y resultados sanitarios se aplicó una tasa de descuento del 3,5% anual.

Resultados: En una cohorte de 1.000 pacientes con FANV, con apixaban se evi-tarían un gran número de complicaciones (24 ictus isquémicos y 28 muertes rela-cionadas en comparación con dabigatrán 110 mg bid; 11 ictus isquémicos, 29 sangrados y 19 muertes frente a dabigatrán 150 mg bid). Así mismo, en cada paciente tratado con apixaban se obtendrían más años de vida (0,126 y 0,084 AVG, respec-tivamente) y más años de vida ajustados por calidad (0,107 y 0,071 AVAC gana-dos, respectivamente). Con apixaban se generarían más costes por paciente que con dabigatrán 110 mg bid para el SNS (139 €), pero se producirían ahorros desde la perspectiva social (–524 €), con un coste por AVG y AVAC ganado de 1.103 €

que dabigatrán 110 mg bid) desde la perspectiva de la sociedad. El coste por AVAC ganado, desde la perspectiva del SNS, en comparación con dabigatrán 150 mg bid es de 6.591 €. Los análisis de sensibilidad determinísticos y probabilísticos con-

Conclusión: Según el presente estudio, se puede llegar a la conclusión de que apixaban es un tratamiento coste-efectivo en comparación con dabigatrán en la prevención del ictus en pacientes con FANV.

APIXABAN – DABIGATRÁN – COSTE-EFECTIVIDAD – FIBRILACIÓN AURICULAR NO VALVULAR




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day was not ound to be superior to war arin in prevent-in stro e and systemic embolism, thou h it was asso-ciated with a si ni cantly lesser ris o ma or bleed-in RRR 20 . The results re erred to api aban were there ore the only data showin statistically si ni cant di erences in the ollowin three e cacy variables: prevention o stro e or systemic embolism, reduction o ma or bleedin ris , and reduction o mortality due to any cause. , 10

To date, no clinical trials have directly compared the OA. However, there are several indirect comparison meta-analyses which in eneral do not su est relevant di erences in e cacy amon the OA 11-14 thou h the requency o ma or bleedin appears to be lower with api -

aban 5 m twice a day bid and with dabi atran 110 m bid. , 11, 14 A recent networ meta-analysis 15 su ests that api aban 5 m bid and dabi atran 110 m bid may o er the best bene t-ris ratio in the prevention o stro e in VAF.

TABLE 1. Population and risks considered in the Markov model.

Item Mean Interval References

Population characteristics Patients in which V A are indicated es Females 35.3 Mean a e years 0

— Mean CHADS2 score 2.1

Hazard ratios of dabigatran versus apixaban— Stro e e cludin hemorrha ic stro e Dabi atran 110 m bid 1.1 0. -1. 35 20 Dabi atran 150 m bid 0. 23 0.5 3-1.141 20— Myocardial in arction Dabi atran 110 m bid 1.4 4 0. 5 -2.2 20 Dabi atran 150 m bid 1.45 0. 4 -2.23 20— Systemic embolism Dabi atran 110 m bid 1 Assumption*

Dabi atran 150 m bid 1 Assumption*

— Other CV hospitali ations 1 Dabi atran 110 m bid 1 Assumption*

Dabi atran 150 m bid 1 Assumption*

— Other AC treatment suspensions 1 Dabi atran 110 m bid 1.452 1.30 -1. 11 20 Dabi atran 150 m bid 1.505 1.35 -1. 20— C bleedin Dabi atran 110 m bid 0. 33 0.42 -1.25 20 Dabi atran 150 m bid 1.02 0. 1 -1. 1 20— Other ma or bleedin Dabi atran 110 m bid 1.205 0. 5-1.504 20 Dabi atran 150 m bid 1.3 1 1.102-1. 05 20— Clinically relevant non-ma or bleedin Dabi atran 110 m bid 1.155 0. -1.354 20 Dabi atran 150 m bid 1.303 1.113-1.52 20— Anticoa ulant treatment suspension Dabi atran 110 m bid 1.452 1.30 -1. 11 20 Dabi atran 150 m bid 1.505 1.35 -1. 20— Additional mortality ris VAF 1.34 }{ 24 Stro e mild/moderate/severe 3.1 /5. 4/15. 5 25 M males/ emales 4.1 /2.5 22 Systemic embolism 1.34 22— Stro e ris ad ustment actor per decade o li e 1.4 2— Bleedin ris ad ustment actor per decade o li e 1. 21— hemorrha ic stro e in C bleedin Dabi atran 110 m bid 4 10 Dabi atran 150 m bid 41 10— bleedin in other ma or bleedin Dabi atran 110 m bid 41 10 Dabi atran 150 m bid 4 10

ASA treatment after suspension 2

— schemic stro e rate per 100 persons-year 3.453 23— M rate per 100 persons-year 1.11 23— ntracranial bleedin rate per 100 persons-year 0.322 23— Other ma or bleedin rate per 100 persons-year 0. 23— CR M bleedin rate per 100 persons-year 2. 3 231: ot due to stro e or M . 2: Treatment with ASA was considered a ter suspension o the previous AC treatment due to ma or bleedin or other reasons. t was also considered that the severity distribution o ischemic or hemorrha ic stro e would be equal to that observed with ASA in rst-line treatment AVERROES study . *: Due to the lac o data, the same ris as observed with api aban is assumed. Abbreviations: AC: anticoa ulant ASA: acetylsalicylic acid CR M: Clinically Relevant on-Ma or bleedin CV: Cardiovascular : astrointestinal HR: Ha ard Ratio C: ntracranial M : Myocardial n arction V A: anta onists o vitamin acenocoumarol .





The present study aims to conduct a cost-e ectiveness analysis o the prevention o stro e and systemic embo-lism with api aban or dabi atran in patients with VAF.

METHODCost-e ectiveness analysis is a particularly use ul instru-ment that acilitates decision ma in by the policy ma ers o the Spanish ational Health System Sistema Nacional de Salud, S S , since it allows inte ration and compari-son o the e ectiveness and cost o two dru s in a sin le e ciency variable: the cost per li e year ained or the cost per quality-ad usted li e year ained A with the most e ective o the comparator treatments. These analyses are enerally made based on economic models, which allow us to simulate the lon -term evolu-tion o hypothetical patient cohorts usin the e cacy and sa ety data obtained rom clinical trials in real patients. These models moreover allow introduction o the Spanish

healthcare costs and resources associated to the mentioned patient evolution.1

The characteristics o the present model have been published elsewhere.1 , 1 t was desi ned to compare the e ciency o api aban and dabi atran in patients with

VAF, analy in the li etime course with a li e e pectan-cy o 0.4 years or both se es o a hypothetical cohort o 1,000 patients with VAF and e hibitin the charac-teristics o those sub ects included in the AR STOT E trial, which compared the e cacy and sa ety o api aban and war arin in application to AF. These characteristics were: patients in which V A are indicated 35.3 e-males mean a e 0 years and a mean CHADS2 score o 2.1 Table 1 . t should be underscored that these characteristics are very similar to those o the patients included in the RE- trial patients in which V A are indicated 3 . emales mean a e 1.5 years and a mean CHADS2 score o 2.1 .10

FIG. 1. Markov economic model for stroke prevention in patients with NVAF.

SE

IschemicStroke

Other ACdiscontinuation

Other deaths

MI

Bleeding

Non-fatal

Fatal

Non-fatal

Fatal

Mild

Moderate

Severe

Non-fatal

Fatal

Non-fatal

Fatal

Non-fatal

Fatal

Non-fatal

Fatal

Stay on current AC

Discontinue AC (1)

ICH Treatment interruption(6 weeks)

Discontinue AC (1)

Mild

Moderate

Severe

(1) Treatment adjustment to ASA

Abbreviations:AC: Anticoagulant; ASA: Acetylsalicylic acid; CRNM: Clinically Relevant Non-Major bleeding; HS: Hemorrhagic Stroke; ICH: Intracranial hemorrhage; NVAF: Non-Vasvular Atrial Fibrillation; MI: Myocardial Infarction; SE: Systemic Embolism.

A) Evolution of patients with NVAF

B) Evolution of patients with stroke (ischemic or hemorrhagic)

Moderate stroke

Death

Death

Death

Severe stroke

Death

Moderate stroke

Death

Severe recurrent stroke

Moderate recurrent stroke

Fatal recurrent stroke

Mild recurrent stroke

Moderate stroke

Mild stroke

Death

Death

Death

Severe stroke

Death

Moderate stroke

Death





Mildstroke

Severe stroke

Death

Death

Death

Severe stroke

Death

Severe stroke

Death





Severe stroke

NOTE: Patients progressing to MI or SE can subsequently die as a result of these complications.

NVAF

NVAF

SE

Death

Death

Mild stroke

Moderate stroke

Severe stroke

Major Bleeding

CRNM

Death

MI

Death

NVAF w/o original AC

HS

Other ICH

Death

Death

Death

Mild HS

Moderate HS

Severe HS

(1)

NVAF


NVAF







The model used is the Mar ov desi n the best type o model or simulatin chronic diseases 1 Fi . 1 , with cycles o wee s and 10 main health states: i VAF ii ischemic stro e iii hemorrha ic stro e iv other in-

tracranial bleedin v other ma or bleedin vi clinically relevant non-ma or bleedin vii myocardial in arction viii systemic embolism i VAF with suspension o

anticoa ulant therapy and death due to other causes di erent rom the above complications. Stro e ischemic or hemorrha ic was classi ed as mild, moderate or se-vere. The entire patient cohort starts in VAF, and in each cycle the sub ects either remain in VAF or pro ress towards the other states, accordin to certain transition probabilities. These probabilities o transition amon the di erent health states, re erred to the e cacy prevention o stro e and o other vascular complications or recur-rences and sa ety bleedin , deaths o the comparator dru s, were mainly collected rom an ad hoc indirect com-parisons meta-analysis 20 and rom other sources where necessary.10, 21-2 Accordin to the model, in each patient only one complication can occur per cycle, and only one recurrence o stro e ischemic or hemorrha ic is al-lowed. The rate o complications per 100 persons-year and the ha ard ratios HR o these complications with dabi atran versus api aban, which were ad usted ac-cordin to the CHADS2, and the quality o R inter-national normali ed ratio control accordin to the TTR time in therapeutic ran e , are shown in Table 1.

The eneral mortality amon emales and males un-der or over 5 years o a e was obtained by ad ustin the published Spanish mortality data www.mortality.or 2 to a ompert unction in order to predict mortality due to all causes and e clude mortality due to stro e and bleedin —thereby avoidin double counts. t was as-sumed that a ter suspendin anticoa ulant therapy da-bi atran or api aban due to ma or bleedin or or other reasons, the patients would switch to acetylsalicylic acid ASA, aspirin . n the event o such a chan e in treat-

ment, we applied the severity distribution o the cases o stro e produced durin treatment with ASA as observed with ASA in rst-line treatment AVERROES study .23

The di erences in treatment e cacy were measured in terms o li e years ained and quality-ad usted li e years ained A . The utilities o the di erent health states accordin to patient perception used to calculate the correspondin A were obtained rom a study conducted in the nited in dom, based on an E -5D type questionnaire amon patients with AF.2 The utilities o the health conditions and the loss o utilities associated to the complications considered in the model, indicated in Table 2, were li ewise obtained rom the literature.30 These utilities are identical or both treat-ments, and no utility loss associated to the use o da-bi atran and api aban was assumed.

The data re erred to resource utili ation and the unit costs were obtained rom Spanish sources o 2012 Table 3 . The cost-e ectiveness analysis was per ormed rom two perspectives: that o the Spanish ational

Health system S S considerin only the direct health-care costs and that o society includin also the direct non-healthcare costs . The ollowin direct healthcare costs were included: purchasin cost o the anticoa u-lants dabi atran and api aban havin the same cost per day o treatment cost o the acute episodes and posterior treatment o the vascular complications cost associated to the dyspepsia which may be enerated by anticoa u-lant therapy 1. , 3. and 4.5 with api aban and dabi atran 110 m and 150 m bid, respectively , 10 and to the renal monitorin required by the treatment one control a year or both treatments and the cost o

the routine control visits o the patients with VAF. The cost o the medications —retail price with VAT applyin the .5 deduction contemplated by Spanish Royal Decree /2010— was calculated on the basis o the doses recommended in the respective Summaries o Product Characteristics api aban: 10 m /day, administered as

TABLE 2. Utilities considered in the Markov model.

Item Mean References

Utilities of the Markov states— on-valvular atrial brillation basal 0. 2 2— Mild stro e 1 0. 151 2— Moderate stro e 1 0.5 4 2— Severe stro e 1 0.5142 2— Systemic embolism 0. 2 5 2— Myocardial in arction 0. 0 2

Loss of utilites (duration)— ntracranial bleedin 0.1511 wee s 2— Other ma or bleedin 0.1511 2 wee s 2 , 30— CR M bleedin 0.05 2 2 days 2 , 30— CV hospitali ation due to other causes 0.12 days 2— se o api aban and dabi atran 0 Estimate1: schemic or hemorrha ic CV: cardiovascular CR M: Clinically Relevant on-Ma or bleedin .




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TABLE 3. Costs considered in the Markov model.

Cost (€) Unit Duration Source

Routine control 35.32 Per visit A AC public prices

Ictus — Direct costs Mild Acute phase 5, 0.0 Per episode 2 wee s AC public prices Maintenance 120.01 Monthly For li e 35 Moderate Acute phase ,2 1.3 Per episode 2 wee s AC public prices Maintenance 42.5 Monthly For li e 35 Severe Acute phase , 51.01 Per episode 2 wee s AC public prices Maintenance 2,0 1. 5 Monthly For li e 35 Fatal 5, 10.0 Per episode A AC public prices— ndirect costs Mild Acute phase 252.3 Per episode 2 wee s 33 Maintenance 1,3 .5 Monthly For li e 33 Moderate Acute phase .11 Per episode 2 wee s 33 Maintenance 1, .53 Monthly For li e 33 Severe Acute phase 1,031. Per episode 2 wee s 33 Maintenance 1, 42. 1 Monthly For li e 33

Hemorrhagic stroke — Direct costs Mild Acute phase ,5 5.44 Per episode 2 wee s AC public prices Maintenance 120.01 Monthly For li e 35 Moderate Acute phase , . 3 Per episode 2 wee s AC public prices Maintenance 42.5 Monthly For li e 35 Severe Acute phase ,55 .3 Per episode 2 wee s AC public prices Maintenance 2,0 1. 5 Monthly For li e 35 Fatal ,515.44 Per episode A AC public prices— ndirect costs Mild Acute phase 252.3 Per episode 2 wee s 33 Maintenance 1,3 .5 Monthly For li e 33 Moderate Acute phase .11 Per episode 2 wee s 33 Maintenance 1, .53 Monthly For li e 33 Severe Acute phase 1,031. Per episode 2 wee s 33 Maintenance 1, 42. 1 Monthly For li e 33

Other intracranial bleeding ,515.44 Per episode A AC public prices

Other major bleeding — bleedin 3,431. 1 Per episode A 3— on-intracranial/ bleedin 3,431. 1 Per episode A 3

CRNM 2,304. Per episode A 3— M Acute phase 10,513.3 Per episode A AC public prices Maintenance 1 4. 1 Monthly For li e 35— SE Acute phase 2, 4 .5 Per episode 2 wee s AC public prices Maintenance 11 . 4 Monthly For li e 34

Other CV hospitalizations 4, 2 . Per episode A AC public prices

Cost of dyspepsia 2 .3 Monthly A 32

Cost of renal monitoring 14. Annually A 3

Monthly cost of anticoagulant management — Api aban 1. Monthly A Calculated usin the cost o— Dabi atran 110 m bid 2.24 Monthly A dyspepsia and the o patients— Dabi atran 150 m bid 2.24 Monthly A with dyspepsia and the cost o renal monitorin and the o patients with renal monitorin

Mean daily drug cost (retail price with VAT –7.5% discount)— Api aban 2. Daily A 31— Dabi atran 110 m bid 2. Daily A 31— Dabi atran 150 m bid 2. Daily A 31AC: Autonomous Community ASA: acetylsalicylic acid CR M: Clinically Relevant on-Ma or bleedin CV: cardiovascular : astrointestinal M : Myocardial n arction A: ot Applicable SE: Systemic Embolism.





two 5-m doses dabi atran: 300 and 220 m /day, ad-minis tered as two doses o 150 m and 110 m , respec-tively .31 Dose selection is based on the data obtained rom the individuali ed assessment o thromboembolic

ris and bleedin ris in each patient. The patient charac-teristics are: a e between 5- 0 years, individuals with moderate renal ailure, astritis, esopha itis or astroe-sopha eal re u , or other sub ects with increased bleedin ris . On the basis o e pert opinion, it was considered that all the patients, independently o the treatment received, would report or a routine AF ollow-up visit every three months in the clinical practice settin . The cost o the complications o VAF in the acute phase based on dia nosis-related roups DR , includin all the costs o the period in which the patient is hospitali ed was obtained rom the mean o the public prices in the di -erent Spanish Autonomous Communities. The cost o

the treatment o the complications a ter the acute phase, estimated in terms o the monthly cost or li e, was ob-tained rom other Spanish sources 32-3 Table 3 . Re ardin the direct non-healthcare costs included in the analysis rom the perspective o society, we included those de-

rived rom in ormal care help or dependent patients and adaptation o the home o individuals who su er ischemic or hemorrha ic stro e 33 Table 3 . ith the purpose o convertin the healthcare costs and outcomes

e pected in uture over the entire li e o the patients to values correspondin to the current year, we applied an annual 3.5 discount rate to the healthcare costs and outcomes.

A base case with the mean values o all the parame-ters was analy ed rom the perspective o the S S and society. n order to corroborate the stability o the results obtained in the base case, we conducted simple univari-ate sensitivity analyses modi yin the baseline value o a variable in each sensitivity analysis, applyin its e treme values or all the variables considered in the model —presentin only those results o the variables with the

reatest impact. astly, we per ormed a probabilistic analysis Monte Carlo simulation with 2,000 simulations in the cohort o 1,000 patients simultaneously includin all the variables o the analysis, ad usted to the statistical distributions pertinent in each case beta or the transition and utility probabilities, and amma or the costs .3

RESULTSEpisodes avoided. Considerin a cohort o 1,000 patients with VAF, api aban would avoid many complications in the course o the patient li etime 24 cases o ischemic stro e and 2 related deaths compared with dabi atran 110 m bid 11 cases o ischemic stro e, 2 cases o bleedin includin intracranial bleedin , ma or bleedin ,

TABLE 4. Expected number of episodes during follow-up for life in a cohort of 1,000 pa-tients with NVAF. Comparisons with dabigatran (110 and 150 mg bid).

Complication Apixaban Dabigatran 110 mg bid Difference

schemic stro e * 2 3 2 24Hemorrha ic stro e * 2 1 10ntracranial bleedin 13 13 0

Systemic embolism 25 2 2Other ma or bleedin 1 1 0 CR M 2 5 2 5 0Myocardial in arction 12Other CV hospitali ations 1,21 1,210 Other treatment suspensions 44 21 Deaths per episodes acute phase 2 5Deaths per episodes maintenance 31 341 23

Complication Apixaban Dabigatran 150 mg bid Difference

schemic stro e * 2 3 2 4 11Hemorrha ic stro e * 2 1 10ntracranial bleedin 13 1

Systemic embolism 25 2 3Other ma or bleedin 1 1 4 5CR M 2 5 313 1Myocardial in arction 100 13Other CV hospitali ations 1,21 1,22 Other treatment suspensions 44 3 2Deaths per episodes acute phase 2 5Deaths per episodes maintenance 31 332 14Abbreviations: CR M: Clinically Relevant on-Ma or bleedin . * ndicates both initial and recurrent stro e.





and clinically relevant non-ma or bleedin and 1 deaths compared with dabi atran 150 m bid Table 4 .

Cost-effectiveness. Consequently, or each patient treated with api aban we would obtain more li e years 0.12 and 0.0 4 compared with dabi atran 110 m bid and 150 m bid, respectively and more quality-ad usted li e years 0.10 and 0.0 1 A , respectively Table 5 .

From the perspective o the S S, api aban would enerate more costs 13 and 4 , respectively . This

is mainly due to the act that on avera e, patients treated with api aban live lon er than patients treated with da-bi atran consequently the duration o treatment with api aban is comparatively lon er. The additional cost o api aban versus dabi atran 150 m bid is reater than with the 110 m bid dose, undamentally because o the lesser requency o ischemic stro e and the reater inci-dence o treatment suspension related to bleedin with the lar er dabi atran dose Tables 4 and 5 . The cost per

and A associated with api aban respectively would be 1,103 and 1,2 low dabi atran dose and

5,5 1 and ,5 1 hi h dabi atran dose Table 5 . n all cases this is less than the 30,000 threshold or cuto

point enerally accepted in Spain, below which a new treatment is considered to be cost-e ective.

From the perspective o society, api aban would be the dominant treatment more e ective and with ewer costs versus dabi atran 110 m bid, and the cost per

and A versus dabi atran 150 m bid would be ,024 and 10, , respectively Table 5 .

Sensitivity analysis. The sensitivity analyses con rmed that api aban is cost-e ective compared with dabi atran. Accordin to the deterministic sensitivity analysis, the variation o the most sensitive study variables ris o is-chemic stro e, ris o cardiovascular hospital admission durin treatment with api aban or ASA in second-line therapy, cost o hemorrha ic stro e, etc. e erted no rele-vant e ect upon the analytical results, since in all cases the cost o one or the cost o one A with the most e ective treatment api aban was below the men-tioned cuto point o 30,000 Fi . 2 .

Accordin to the probabilistic sensitivity analysis, the probability that api aban is cost-e ective would be .3 versus the low dabi atran dose and 1. versus the hi h dabi atran dose Fi . 3 .

TABLE 5. Results of the cost-effectiveness analysis of apixaban versus dabigatran.

Comparison with dabigatran 110 mg bid Apixaban Dabigatran Difference

Perspective of the SNS— i e years .03 . 11 0.12— uality-ad usted li e years .424 .31 0.10 — Total costs 1 ,02 1 , 0 13— Cost per 1,103— Cost per A 1,2

Perspective of society *

— i e years .03 . 11 0.12— uality-ad usted li e years .424 .31 0.10 — Total cost 2 ,1 3 2 , 1 524— Cost per Api aban dominantes **

— Cost per A Api aban dominantes **

Comparison with dabigatran 150 mg bid Apixaban Dabigatran Difference

Perspective of the SNS— i e years .03 . 53 0.0 4— uality-ad usted li e years .424 .353 0.0 1 — Total costs 1 ,02 1 ,5 1 4— Cost per 5,5 1— Cost per A ,5 1

Perspective of society *

— i e years .03 . 53 0.0 4— uality-ad usted li e years .424 .353 0.0 1 — Total costs 2 ,1 3 2 ,435 5— Cost per ,024— Cost per A 10,* ncludin the direct non-healthcare costs correspondin to the help o patients with dependency due to stro e. ** Api aban is more e ective and with ewer costs than dabi atran. Abbreviations: : i e- ear ained A : uality-Ad usted i e ears S S: Spanish ational Health System.





DISCUSSIONPharmacoeconomic models allow us to conduct economic simulations o comple healthcare processes related to dru s. Such models are use ul when no pra matic clinical trials are available, than s to their reat e ternal validity, and in simulatin the evolution o a disease beyond the duration o clinical trials.1 Mar ov models are pre era-ble to deterministic constructs, particularly in the case o chronic disorders such as VAF, since they are better able to simulate the lon -term clinical course o the disease.1

Accordin to our economic model, api aban would avoid a considerable number o complications stro e, bleedin , treatment suspensions and deaths, and consti-

tutes a cost-e ective treatment compared with dabi atran or the prevention o stro e in Spanish patients with VAF.

From the perspective o society, api aban would be the dominant treatment more e ective, with ewer costs ver-sus dabi atran 110 m bid, due to inclusion o the costs correspondin to in ormal care.

n evaluatin these results, a number o study limita-tions and consistency actors must be ta en into account. Firstly, this is a theoretical model, i.e., by de nition it constitutes a simpli ed simulation o reality. On the other hand, the data re erred to e cacy and adverse e ects have been obtained rom an ad hoc indirect comparisons meta-analysis,20 due to the lac o clinical trials estab-

B) € per QALY gained with apixaban 5 mg bid versus dabigatran 150 mg bid

1.2

3.45

10.46

13.57

€742.59

1

€2,081.85

70

1.47

1.45

0.27

1.64

5.34

5.98

20.98

€1,148.24

1.1

€3,219.09

63

2.27

1.31

0.21

0.88

1.97

16.17

7.76

€424.45

0.9

€1,189.96

77

0.96

1.61

0.34

5,088

4,288

3,476

2,950

2,787

2,851

2,135

1,980

2,263

2,069

2,115

–675

–497

–423

–796

–608

–257

222

72

444

251

407

Stroke HR

ASA 2nd line ischemic stroke risk*

CV hospitalization risk for apixaban*

CV hospitalization risk for 2nd line ASA*

Mild hemorrhagic stroke cost

CV hospitalization HR

Severe hemorrhagic stroke cost

Mean age for females (years)

MI HR

Treat. discontinuation HR

Ischemic stroke mortality

ASA 2nd line ischemic stroke risk*

Stroke HR

Apixaban stroke risk*

MI HR

CV hospitalization risk for 2nd line ASA*

CV hospitalization risk for apixaban*

CV HR mortality

CV hospitalization HR

Hemorrhagic IC risk for apixaban*

IC hemorrhagic HR

Ischemic stroke mortality

3.45

0.82

0.98

1.47

13.57

10.46

1

1

0.33

1.02

1.4

5.34

1.14

0.56

2.27

20.98

5.98

1.1

1.1

0.19

1.68

0.8

1,993

2,860

3,917

3,664

2,754

3,816

5,311

4,238

5,006

4,549

5,043

19,804

14,566

11,781

10,821

9,556

10,021

10,095

8,866

9,500

8,400

8,793

1.97

0.59

1.52

0.96

7.76

16.17

0.9

0.9

0.51

0.62

2.16

* Rate per 100 Person-Years.ASA: acetylsalicylic acid; CT: Clinical Trial; CV: Cardiovascular; HR: Hazard Ratio; IC: Intracranial; ICER: Incremental Cost-Effectiveness Ratio; MI: Myocardial Infarction.

Base case

Extremevalues

ICER(base case)

€1,299Extremevalues

Base case

Extremevalues

ICER(base case)

€6,591Extremevalues

A) € per QALY gained with apixaban 5 mg bid versus dabigatran 110 mg bid

FIG. 2. Deterministic sensitivity analysis conducted from the perspective of the National Health Sys-tem. Tornado chart. (€ in 2012).





lishin direct comparisons o the di erent treatments. evertheless, provided they are conducted with ri or and

usin adequate methodolo y, indirect comparisons meta- analyses are use ul tools, as reco ni ed by dru evalua-tion a encies such as the ational nstitute or Health and Clinical E cellence 3 or the E ES S roup,40 in those cases in which studies directly comparin the alter-natives are not available. On the other hand, the stability o the results obtained in the base case o the analysis has been con rmed by deterministic and probabilistic sensi-tivity analyses, indicatin a hi h probability that api aban is cost-e ective versus dabi atran .3 and 1. compared with the 110 m bid and 150 m bid doses, respectively .

The present study represents the rst cost-e ective-ness analysis o api aban versus dabi atran in VAF conducted in Spain. e have identi ed an economic analy sis Mar ov model carried out in the nited States, in which the cost-e ectiveness o api aban, dabi atran and rivaro aban versus war arin was compared in

VAF.41 Accordin to the Monte Carlo simulation made in this study, the probability o bein cost-e ective ver-sus war arin 50,000 SD would be 45.1 or api -aban, 40 or dabi atran, and 14. or rivaro aban. This model is very di erent in terms o its structure and premises rom our own model, and the results are there ore not comparable. Other economic analy-ses have compared the cost-e ectiveness o api aban

Cost

e in

crem

enta

l

Incremental effectiveness

Incr

emen

tal c

ost

Incremental effectiveness

Incr

emen

tal c

ost

A) € per QALY gained with apixaban versus dabigatran 110 mg bid

5,000

4,000

3,000

2,000

1,000

0

–1,000

–2,000

B) € per QALY gained with apixaban versus dabigatran 150 mg bid

For a cost-effectiveness cutoff point of < €30,000 per QALY, the probability that apixaban is cost-effective was 99.3% (A) and 91.6% (B)

0.05 0.10 0.15 0.20 0.25 0.30 –0.05

FIG. 3. Probabilistic sensitivity analysis conducted from the perspective of the National Health System. Incremental cost-effectiveness ratio (€ in 2012).





versus war arin 42 and ASA,43 and o dabi atran versus war arin,30, 44-53 ASA 54 and rivaro aban,54 in the primary prevention o stro e in VAF. However, these analyses are o scant interest or the comparison o api aban and dabi atran. The litera ture also o ers an e ectiveness model based on microsimulations and indirect com-parisons between api aban AR STOT E study , dabi-

atran RE- study and rivaro aban ROC ET-AF study , with war arin as common comparator dru , in the mana ement o patients with VAF. The results indicate that or a li e-lon time hori on, 0.130, 0.10 and 0.0 5 A would be ained per patient, respec-tively. Thus, accordin to these analyses, api aban would be the most e ective treatment.55

Accordin to our ndin s, it can be concluded that api aban constitutes a cost-e ective treatment compared with dabi atran or the prevention o stro e in patients with

VAF, on the basis o the cost-e ectiveness cuto point enerally accepted in Spain.5 CP

ACKNOWLEDGMENTSThe authors than Teresa anitis and Thitima on na orn or their wor in the development o the cost-e ective-

ness model that has served as the basis or the present study, adapted to Spain.

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