Abstract

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder that causes dementia with gradual loss of cognitive function, leading to declines in social and functional activities of daily living. Up to 75% of cases of dementia involve AD.¹1.QiuC,KivipeltoM,Von StraussE. Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention.Dialogues Clin Neurosci.2009;11:111-28.

The World Health Organization (WHO) and Alzheimer’s Disease International (ADI) report that the global prevalence of dementia will rise from 35 million in 2012 to 115 million by 2050.²2.World Health Organization/Alzheimer’s Disease International (WHO/ADI). Dementia: a public health priority [Internet].2012[cited 2018 May 23]. www.who.int/mental_health/publications/dementia_report_2012/en/
www.who.int/mental_health/publications/d... In Latin America, the prevalence of dementia in the population over age 65 is 7.1%, increasing with advancing age.³3.GrinbergLT,NitriniR,SuemotoCK,Lucena Ferretti-RebustiniRE,LeiteRE,FarfelJM, et al. Prevalence of dementia subtypes in a developing country: a clinicopathological study.Clinics (São Paulo).2013;68:1140-5.

4.NitriniR,BottinoCM,AlbalaC,Custodio CapuñayNS,KetznoianC,Libre RodriguezJJ, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts.Int Psychogeriatr.2009;21:622-30.-⁵5.BottinoCM,LaksJ,BlaySL. Demência e transtornos cognitivos em idosos.In:MachadoJCB. Diagnóstico clínico na doença de Alzheimer.Rio de Janeiro: Guanabara Koogan;2006. p.173-6. In Brazil, the incidence of dementia ranges from 13.8 to 34.2 per 1,000 population/year.⁴4.NitriniR,BottinoCM,AlbalaC,Custodio CapuñayNS,KetznoianC,Libre RodriguezJJ, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts.Int Psychogeriatr.2009;21:622-30.,⁶6.MeguroK,ChubaciRY,MeguroM,KawamoridaK,GotoN,CaramelliP. Incidence of dementia and cause of death in elderly Japanese emigrants to Brazil before World War II.Arch Gerontol Geriatr.2011;52:75-8. Despite the scarcity of further data on the prevalence and incidence of AD in Brazil, studies have reported incidence rates between 7.7 new cases/year in São Paulo to 14.8 new cases/year in Rio Grande do Sul.⁴4.NitriniR,BottinoCM,AlbalaC,Custodio CapuñayNS,KetznoianC,Libre RodriguezJJ, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts.Int Psychogeriatr.2009;21:622-30.,⁷7.ChavesML,CamozzatoAL,GodinhoC,PiazenskiI,KayeJ. Incidence of mild cognitive impairment and Alzheimer disease in Southern Brazil.J Geriatr Psychiatry Neurol.2009;22:181-7.

The impacts of AD can be observed at different levels in society. Disease progression and the consequent demential process cause loss not only of cognitive and functional abilities but also of quality of life. In addition to the social impact, there is an economic impact caused by the care needs that result from AD progression.⁸8.BergvallN,BrinckP,EekD,GustavssonA,WimoA,WinbladB, et al. Relative importance of patient disease indicators on informal care and caregiver burden in Alzheimer's disease.Int Psychogeriatr.2011;23:73-85. The economic burden of AD is also felt by governments, as the social cost of AD has risen to become one of its most significant chronic effects in recent decades.⁹9.da CostaRD,Osorio-de-CastroCG,da SilvaRM,Maia AdaA,Ramos MdeC,CaetanoR. [The acquisition of medication to treat Alzheimer's disease in Brazil: an analysis of federal purchases, 2008-2013].Cienc Saude Colet.2015;20:3827-38.,¹⁰10.Alzheimer’s Disease International (ADI). World Alzheimer Report 2010. The Global Economic Impact of Dementia [Internet].2010Sep 21 [cited 2018 May 23]. www.alz.co.uk/research/files/WorldAlzheimerReport2010.pdf
www.alz.co.uk/research/files/WorldAlzhei...

To date, only two countries in Latin America have specific policies for dementia. Bolivia approved Law No. 4034, Creación de Centros de Apoyo a Enfermos de Alzheimer y otras Demencias (Creation of Support Centers for Patients with Alzheimer and Other Dementias) in 2009, while Peru implemented Law No. 30020 in 2013, which establishes the Plan Nacional para la Enfermedad de Alzheimer y otras Demencias (National Plan for Alzheimer’s Disease and other Dementias). Despite pushes by the Pan American Health Organization (PAHO)/WHO and ADI for the development of plans of action for mental health, the current Brazilian policy for dementia care is largely based on pharmacotherapy and compliance with the Brazilian Ministry of Health’s corresponding clinical practice guideline (Protocolo Clínico e Diretrizes Terapêuticas, PCDT).¹¹11.Brasil, Ministério da Saúde. Portaria n° 843, de 31 de outubro de 2002. Aprova o Protocolo Clínico e Diretrizes Terapêuticas da Doença de Alzheimer [Internet]. Diário Oficial da União, 4 novembro 2013.[cited2018May 24]. www.lex.com.br/doc_5930363_PORTARIA_N_843_DE_31_DE_OUTUBRO_DE_2002.aspx
www.lex.com.br/doc_5930363_PORTARIA_N_84...

Medications currently approved for the treatment of AD are still purely symptomatic, and produce only modest effects.¹²12.FlickerL. Eficácia do tratamento farmacológico da demência.Rev Bras Psiquiatr.2002;24:11-4. Anticholinesterase agents are the mainstay of AD pharmacotherapy, and there is some evidence that they work to slow disease progression.¹³13.MancaA,DaviesL,BuernsA. Cost-effectiveness of therapeutics for Alzheimer disease.In:DavisKL,CharneyD,CoyleJT,NemeroffC, editors. Neuropsychopharmacology: the fifth generation of progress.Philadelphia: Lippincott, Williams, & Wilkins;2002. p.1267-79. Among these agents, donepezil, galantine, and rivastigmine are listed in the Brazilian PCDT.

In an analysis of anticholinesterase agent procurement data available through the Outpatient Information System (Sistema de Informações Ambulatoriais, SIA) of the Brazilian Unified Health System, Lima & Coradi¹⁴14.LimaMG,CoradiCO. Gastos com medicamentos para tratamento da Doença de Alzheimer pelo Ministério da Saúde, 2007-2011 [Internet]. [cited2018May 24]. http:/docplayer.com.br/4406495-Gastos-com-medicamentos-para-tratamento-da-doenca-de-alzheimer-pelo-ministerio-da-saude-2007-2011.html
http:/docplayer.com.br/4406495-Gastos-co... reported a 109% increase in expenditures over a 5-year period, from BRL 75.6 million in 2007 to BRL 157.8 million in 2011. From 2008-2013, more than 47 million unit doses of these medicines were purchased, at a total cost exceeding BRL 90 million. Rivastigmine, in its various dosage forms, was the most commonly used drug (46.4% of all purchases). Drugs not indicated in the PCDT accounted for 3% of expenditures, with a negligible percentage of purchases⁹9.da CostaRD,Osorio-de-CastroCG,da SilvaRM,Maia AdaA,Ramos MdeC,CaetanoR. [The acquisition of medication to treat Alzheimer's disease in Brazil: an analysis of federal purchases, 2008-2013].Cienc Saude Colet.2015;20:3827-38. occurring as the result of legal action. The trend for increased donepezil purchasing continued until 2012, at which time a decline occurred. Rivastigmine purchases presented a fluctuating trend in the period of analysis, with significant reductions in the volumes purchased in 2012 and 2013, when Productive Development Partnership (PDP) agreements were implemented.⁹9.da CostaRD,Osorio-de-CastroCG,da SilvaRM,Maia AdaA,Ramos MdeC,CaetanoR. [The acquisition of medication to treat Alzheimer's disease in Brazil: an analysis of federal purchases, 2008-2013].Cienc Saude Colet.2015;20:3827-38. Given this context, to what extent can a cost-effective AD care policy be sought from the standpoint of medications?

The objective of this work is to perform an analysis of the cost-effectiveness of donepezil and rivastigmine, the drugs most commonly prescribed for mild and moderate AD,¹⁵15.Almeida-BrasilCC,Costa JdeO,AguiarVC,MoreiraDP,MoraesEM,Acurcio FdeA, et al. [Access to medicines for Alzheimer's disease provided by the Brazilian Unified National Health System in Minas Gerais State, Brazil].Cad Saude Publica.2016;32:e00060615. from the perspective of the Unified Health System.

Method

A Markov chain simulation was used to carry out cost-effectiveness analysis of pharmacological treatment strategies for AD. Therapeutic scenarios for the treatment of AD were modeled according to the corresponding PCDT.¹¹11.Brasil, Ministério da Saúde. Portaria n° 843, de 31 de outubro de 2002. Aprova o Protocolo Clínico e Diretrizes Terapêuticas da Doença de Alzheimer [Internet]. Diário Oficial da União, 4 novembro 2013.[cited2018May 24]. www.lex.com.br/doc_5930363_PORTARIA_N_843_DE_31_DE_OUTUBRO_DE_2002.aspx
www.lex.com.br/doc_5930363_PORTARIA_N_84... The transition stages of the disease according to the Mini Mental State Examination (MMSE)¹⁶16.FolsteinMF,FolsteinSE,MchughPR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician.J Psychiatr Res.1975;12:189-98. were also included, with death as an absorptive stage (Figure 1).

The Markov simulation model was calculated using TreeAge Pro^® software version 2011. A hypothetical cohort of 1,000 individuals diagnosed with AD according to the PCDT criteria¹¹11.Brasil, Ministério da Saúde. Portaria n° 843, de 31 de outubro de 2002. Aprova o Protocolo Clínico e Diretrizes Terapêuticas da Doença de Alzheimer [Internet]. Diário Oficial da União, 4 novembro 2013.[cited2018May 24]. www.lex.com.br/doc_5930363_PORTARIA_N_843_DE_31_DE_OUTUBRO_DE_2002.aspx
www.lex.com.br/doc_5930363_PORTARIA_N_84... was considered. The study population consisted of men and women aged 65 years and older – the age group with the highest incidence of AD, which is consistent with the natural history of the disease.¹1.QiuC,KivipeltoM,Von StraussE. Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention.Dialogues Clin Neurosci.2009;11:111-28.,³3.GrinbergLT,NitriniR,SuemotoCK,Lucena Ferretti-RebustiniRE,LeiteRE,FarfelJM, et al. Prevalence of dementia subtypes in a developing country: a clinicopathological study.Clinics (São Paulo).2013;68:1140-5.,⁴4.NitriniR,BottinoCM,AlbalaC,Custodio CapuñayNS,KetznoianC,Libre RodriguezJJ, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts.Int Psychogeriatr.2009;21:622-30.,⁶6.MeguroK,ChubaciRY,MeguroM,KawamoridaK,GotoN,CaramelliP. Incidence of dementia and cause of death in elderly Japanese emigrants to Brazil before World War II.Arch Gerontol Geriatr.2011;52:75-8.,⁷7.ChavesML,CamozzatoAL,GodinhoC,PiazenskiI,KayeJ. Incidence of mild cognitive impairment and Alzheimer disease in Southern Brazil.J Geriatr Psychiatry Neurol.2009;22:181-7. The onset of the cycle was established with an initial distribution of subjects without the disease and patients with AD in the mild or moderate stages. Transition probabilities were used recursively over time to simulate the progression of patients through the stages of illness. Disease progression was established through MMSE scores for each stage in the three scenarios studied.

The treatment strategies being compared were pharmacotherapy with (1) donepezil 5 mg/day and 10 mg/day and (2) rivastigmine according to the PCDT dosage scheme (3 mg/day, 6 mg/day, and 9 mg/day). As noted above, the proposed scenarios, as well as dose escalation procedures for both drugs, were based on the PCDT.¹¹11.Brasil, Ministério da Saúde. Portaria n° 843, de 31 de outubro de 2002. Aprova o Protocolo Clínico e Diretrizes Terapêuticas da Doença de Alzheimer [Internet]. Diário Oficial da União, 4 novembro 2013.[cited2018May 24]. www.lex.com.br/doc_5930363_PORTARIA_N_843_DE_31_DE_OUTUBRO_DE_2002.aspx
www.lex.com.br/doc_5930363_PORTARIA_N_84... We assumed a 10-year time horizon, with 1-year cycles, corresponding to the natural history of AD.¹⁷17.IkedaS,YamadaY,IkegamiN. Economic evaluation of donepezil treatment for Alzheimer’s disease in Japan.Dement Geriatr Cogn Disord.2002;13:33-9.

Transition probabilities were derived from randomized clinical trials and from international economic assessments.¹⁷17.IkedaS,YamadaY,IkegamiN. Economic evaluation of donepezil treatment for Alzheimer’s disease in Japan.Dement Geriatr Cogn Disord.2002;13:33-9.

18.SpackmanDE,KadiyalaS,NeumannPJ,VeenstraDL,SullivanDS. Measuring Alzheimer disease progression with transition probabilities: estimates from NACC-UDS.Curr Alzheimer Res.2012;9:1050-8.

19.HauberAB,GnanasakthyA,MauskopfJA. Savings in the cost of caring for patients with Alzheimer's disease in Canada: an analysis of treatment with rivastigmine.Clin Ther.2000;22:439-51.

20.FennP,GrayA. Estimating long-term cost savings from treatment of Alzheimer's disease. A modelling approach.Pharmacoeconomics.1999;16:165-74.

21.JonssonL,LindgrenP,WimoA,JonssonB,WinbladB. The cost-effectiveness of donepezil therapy in Swedish patients with Alzheimer's disease: a Markov model.Clin Ther.1999;21:1230-40.

22.NeumannPJ,HermannRC,KuntzKM,ArakiSS,DuffSB,LeonJ, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease.Neurology.1999;52:1138-45.

23.MorrisJC,HeymanA,MohsRC,HughesJP,van BelleG,FillenbaumG, et al. The consortium to establish a registry for Alzheimer's disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer's disease.Neurology.1989;39:1159-65.-²⁴24.StewartA,PhillipsR,DempseyG. Pharmacotherapy for people with Alzheimer's disease: a Markov-cycle evaluation of five years' therapy using donepezil.Int J Geriatr Psychiatry.1998;13:445-53. Three summative outcomes of AD were included in the simulation model, with probabilities were taken from national and international studies: a) depression and agitation²⁵25.BerghS,SelbækG. The prevalence and the course of neuropsychiatric symptoms in patients with dementia.Nor Epidemiol.2012;22:225-32.

26.CamelliP,BottinoCMC. Tratando os sintomas comportamentais e psicológicos da demência (SCPD).J Bras Psiquiatr.2007;56:83-7.

27.SilbermanCD,LaksJ,CapitãoCF,RodriguesCS,MoreiraI,VasconcellosLF, et al. Frontal functions in depressed and nondepressed Parkinson's disease patients: impact of severity stages.Psychiatry Res.2007;149:285-9.

28.SteinbergM,CorcoranC,TschanzJT,HuberC,Welsh-BohmerK,NortonMC, et al. Risk factors for neuropsychiatric symptoms in dementia: the cache county study.Int J Geriatr Psychiatry.2006;21:824-30.

29.TatschMF,BottinoCM,AzevedoD,HototianSR,MoscosoMA,FolquittoJC, et al. Neuropsychiatric symptoms in Alzheimer disease and cognitively impaired, nondemented elderly from a community-based sample in Brazil: prevalence and relationship with dementia severity.Am J Geriatr Psychiatry.2006;14:438-45.-³⁰30.AaltenP,De VugrME,JaspersN,JollesJ,VertheyFR. The course of neuropsychiatric symptoms in dementia. Part I: findings from the two-year longitudinal Maasbed study.Int J Geriatr Psychiatry.2005;20:523-30.; b) hospitalization for femoral fracture³¹31.WangJ,YuJT,WangHF,MengXF,WangC,TanCC, et al. Pharmacological treatment of neuropsychiatric symptoms in Alzheimer's disease: a systematic review and meta-analysis.J Neurol Neurosurg Psychiatry.2015;86:101-9.

32.MaloneDC,McLaughlinTP,WahlPM,LeibmanC,ArrighiHM,CzirakyMJ, et al. Burden of Alzheimer's disease and association with negative health outcomes.Am J Manag Care.2009;15:481-8.-³³33.TinettiME,BakerDI,McAvayG,ClausEB,GarrettP,GottschalkM, et al. A multifactorial intervention to reduce the risk of falling among elderly people living in the community.N Engl J Med.1994;331:821-7.; and c) pneumonia.³⁴34.PiuvezamG,FreitasMR,CostaJV,FreitasPA,CardosoPMO,MedeirosACM, et al. Fatores associados ao custo das internações hospitalares por doenças infecciosas em idosos em hospital de referência na cidade do Natal, Rio Grande do Norte.Cad Saude Colet.2015;23:63-8.

The effectiveness of treatment was measured in quality-adjusted life years (QALYs).¹⁷17.IkedaS,YamadaY,IkegamiN. Economic evaluation of donepezil treatment for Alzheimer’s disease in Japan.Dement Geriatr Cogn Disord.2002;13:33-9.,¹⁸18.SpackmanDE,KadiyalaS,NeumannPJ,VeenstraDL,SullivanDS. Measuring Alzheimer disease progression with transition probabilities: estimates from NACC-UDS.Curr Alzheimer Res.2012;9:1050-8. This measure was calculated based on the transition probability of the mild and moderate stages, in the different scenarios, multiplied by the utility scores of the corresponding states, as described in the international literature.³⁵35.OremusM,TarrideJE,ClaytonN, Raina P; Canadian Willingness-to-Pay Study Group, Raina P. Health utility scores in Alzheimer’s disease: differences based on calculation with American and Canadian preference weights.Value Health.2014:17:77-83.

36.MestertonJ,WimoA,ByA,LangworthS,WinbladB,JonssonL. Cross sectional observational study on the societal costs of Alzheimer’s disease.Curr Alzheimer Res.2010;7:358-67.

37.JonssonL,AndreasenN,KilanderL,SoininenH,WaldemarG,NygaardH, et al. Patient- and proxy-reported utility in Alzheimer disease using the EuroQoL.Alzheimer Dis Assoc Disord.2006;20:49-55.-³⁸38.NaglieG,TomlinsonG,TanseyC,IrvineJ,RitvoP,BlackSE, et al. Utility-based quality of life measures in Alzheimer’s disease.Qual Life Res.2006;15:631-43. The main outcomes used in the model are shown in Table 1

The direct costs included in the study were those of the diagnostic tests recommended in the Brazilian AD PCDT¹¹11.Brasil, Ministério da Saúde. Portaria n° 843, de 31 de outubro de 2002. Aprova o Protocolo Clínico e Diretrizes Terapêuticas da Doença de Alzheimer [Internet]. Diário Oficial da União, 4 novembro 2013.[cited2018May 24]. www.lex.com.br/doc_5930363_PORTARIA_N_843_DE_31_DE_OUTUBRO_DE_2002.aspx
www.lex.com.br/doc_5930363_PORTARIA_N_84... (complete blood count, electrolytes, blood glucose, urea, creatinine, TSH, computed tomography and magnetic resonance imaging, neuropsychological tests) and pharmacological treatment (donepezil and rivastigmine). Costs were evaluated from the perspective of the Brazilian health system and were accounted for in U.S. dollars and Brazilian reais (BRL). Indirect costs were not considered.

The estimated drug cost was based on the mean unit price and duration of treatment. Prices were obtained from the System of Management of the Table of Procedures and Medications (SIGTAP), for the year 2016,⁴⁰40.Brasil, Departamento de Informática do Sistema Único de Saúde (DATASUS), Sistema de Gerenciamento da Tabela de Procedimentos (SIGTAP). Medicamentos e OPM do SUS [Internet]. [cited2016Apr 14].sigtap.datasus.gov.br/
sigtap.datasus.gov.br/... and the Federal Government Purchasing Portal (COMPRASNET), for the years 2015/2016.⁴¹41.Brasil, Portal de compras do Governo Federal [Internet]. [cited2016Apr 14]. www.comprasnet.gov.br/
www.comprasnet.gov.br/... For diagnostic tests, the reference date for SIGTAP values was December 2016. The frequency and cost of tests were defined for: a) four annual medical appointments; b) hospitalization according to the prevalence of the outcomes of interest and treatment of the AD summative outcomes, i.e., medical conditions resulting from the disease; c) depression; d) pulmonary infection; and e) femoral fracture, which was included in the simulation because such fractures make treatment of AD more expensive and bring the model closer to reality. These costs are represented in Table 2.

The perspective adopted was that of the SUS. The comparative efficiencies of alternative treatment strategies were measured by the incremental cost-effectiveness ratio. The discount rate was 5% per year for both costs and outcomes, and a sensitivity analysis was performed.⁴²42.Brasil, Ministério da Saúde, Secretaria de Ciência, Tecnologia e Insumos Estratégicos, Departamento de Ciência e Tecnologia.Diretrizes metodológicas, diretriz de avaliação econômica [Internet].2014[cited 2018 May 21]. bvsms.saude.gov.br/bvs/publicacoes/diretrizes_metodologicas_diretriz_avaliacao_economica.pdf
bvsms.saude.gov.br/bvs/publicacoes/diret...

The following assumptions were used in the simulation model: a) the probability of severity transition depended on the severity of the disease at the onset of treatment; b) the probability of death used in the model was set according to the stage of the disease; c) the model did not use the severe stage of AD in its analysis because the SUS does not offer treatment for this condition – i.e., patients leave the model as they progress from moderate to severe AD; d) drug treatment does not alter disease mortality, but rather its progression to more severe stages; e) the 12-mg dose of rivastigmine was excluded in the model because of its restricted use in the public sector; and f) the cost of institutionalization was not included in the model due to the scarcity of cost information in the SUS databases.

Results

The average cost of AD diagnosis was BRL 248.68/patient (standard deviation [SD] = BRL 74.47). According to SIGTAP, the annual cost of follow-up for a patient with AD was BRL 94.02 (SD = BRL 8.63). The mean costs of outpatient follow-up (BRL 27.05/person), emergency-department hospitalization (BRL 189.043/day) and other types of special care for patients with this condition were similar in both scenarios. The annual cost of pharmacological treatment with donepezil and rivastigmine was estimated at BRL 154.70 and BRL 1,003.45, respectively.

Using a Markov model, we were able to simulate scenarios of treatment with donepezil and rivastigmine versus a baseline of untreated AD. This simulation yielded the costs of pharmacological treatment and the overall cost of AD care, including the cost of the summative outcomes of the mild and moderate stages. Moderate AD was the most costly phase of the disease, especially with rivastigmine treatment. Compared with other drug interventions, the use of rivastigmine is less supported than treatment with donepezil, which has the best cost-effectiveness ratio (Table 3).

Sensitivity analysis

The sensitivity analysis aimed to test the robustness and results of the variations between the parameters used in the model. Brazil does not have a formal threshold of acceptability for the incorporation of health technologies. In this scenario, i.e., health systems that do not have a formal threshold, a value of three times the per capita gross domestic product (GDP) is recommended.⁴³43.BertramMY,LauerJA,De JoncheereK,EdejerT,HutubessyR,KienyMP, et al. Cost-effectiveness thresholds: pros and cons.Bull World Health Organ.2016;94:925-30. For the year 2016, the value adopted was BRL 91,221/QALY; using this threshold, the likelihood of donepezil not being cost-effective was 2.8% when compared to rivastigmine (Figure 2).

Discussion

In our analysis of overall AD treatment scores, there was a difference between letting the disease run its course (natural history) and administering anticholinesterase therapy, as well as between different stages of AD. The cost of donepezil and rivastigmine treatment was lower than that of no treatment. A similar finding was reported by Ikeda et al.¹⁷17.IkedaS,YamadaY,IkegamiN. Economic evaluation of donepezil treatment for Alzheimer’s disease in Japan.Dement Geriatr Cogn Disord.2002;13:33-9. Despite the similarity of the results, it is not possible to explain the difference in cost between pharmacological treatment and no treatment because the authors did not adequately discriminate among the costs of the resources used to calculate treatment. Differences between costs were also observed in a study by Hartz³⁹39.HartzS,GetsiosD,TaoS,BlumeS,MaclaineG. Evaluating the cost effectiveness of donepezil in the treatment of Alzheimer’s disease in Germany using discrete event simulation.BMC Neurol.2012;12:2. which evaluated donepezil and memantine at the more advanced stages of AD.

Regarding the effectiveness of the technologies for mild AD, the study reported a QALY increase of 0.61/BRL 21,907.38 for patients treated with donepezil and a QALY increase of 0.58/BRL 24,683.33 for patients treated with rivastigmine in the mild stage; in the moderate stage, the increases observed were 0.05 QALY/BRL 27,414.96 for patients treated with donepezil and 0.06 QALY/BRL 34,222.96 for patients treated with rivastigmine. The results of the present study are thus consistent with the international literature, where QALY gains in AD have been shown to be more significant in the mild phase of the disease than at the moderate stage.¹⁷17.IkedaS,YamadaY,IkegamiN. Economic evaluation of donepezil treatment for Alzheimer’s disease in Japan.Dement Geriatr Cogn Disord.2002;13:33-9.,¹⁹19.HauberAB,GnanasakthyA,MauskopfJA. Savings in the cost of caring for patients with Alzheimer's disease in Canada: an analysis of treatment with rivastigmine.Clin Ther.2000;22:439-51.,²²22.NeumannPJ,HermannRC,KuntzKM,ArakiSS,DuffSB,LeonJ, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease.Neurology.1999;52:1138-45.

Ikeda et al.¹⁷17.IkedaS,YamadaY,IkegamiN. Economic evaluation of donepezil treatment for Alzheimer’s disease in Japan.Dement Geriatr Cogn Disord.2002;13:33-9. conducted an economic evaluation of the use of donepezil (3 mg/day) in the treatment of mild and moderate AD in Japan. Efficacy data were obtained from Japanese studies published in 1995 and 2000, and the unit costs of drugs were based on year-2000 prices. A Markov model was simulated to characterize the progression of patients between the stages of AD. At the mild stage, a QALY increase of 0.58/BRL 82,944.00 was observed, whereas at the moderate phase, the QALY increase was 0.31/BRL 148,716.00, indicating donepezil is a cost-effective treatment for AD when compared to natural history of disease. Neumann et al.²²22.NeumannPJ,HermannRC,KuntzKM,ArakiSS,DuffSB,LeonJ, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease.Neurology.1999;52:1138-45. conducted a cost-effectiveness analysis of the economic impact of donepezil treatment of mild and moderate AD in the United States. The cost of donepezil was partially offset by the reduction in care costs related to improved cognitive function and delayed onset of the costlier stages of the disease. The cost-effectiveness of donepezil treatment was $32,000.00 per QALY at the mild stage and $140,000.00 per QALY at the moderate stage of AD.

Hauber et al.¹⁹19.HauberAB,GnanasakthyA,MauskopfJA. Savings in the cost of caring for patients with Alzheimer's disease in Canada: an analysis of treatment with rivastigmine.Clin Ther.2000;22:439-51. estimated the potential cost savings per patient using rivastigmine for the treatment of AD in Canada. Their research suggested that this drug may delay onset of the most severe stage of AD for up to 188 days in patients with mild AD after 2 years of treatment. For patients with mild-to-moderate and moderate AD, the estimated delays were 106 and 44 days, respectively. The mean cost saved per patient was $0.45 per day at 6 months and $6.44 per patient after 2 years for mild AD. Although these results are promising, there is uncertainty about the cost-effectiveness of rivastigmine because data on the natural history of disease were not available in the study, making interpretation difficult. In a systematic review, Loveman et al.⁴⁴44.LovemanE,GreenC,KirbyJ,TakedaA,PicotJ,PayneE, et al. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease.Health Technol Assess.2006;10:iii-iv, ix-xi,1-160. evaluated cost-effectiveness studies of pharmacological treatments for AD. Four economic evaluations of rivastigmine, all sponsored by pharmaceutical industries, were analyzed. According to the review, reducing treatment costs does not offset the treatment cost with rivastigmine enough for it to be considered cost-effective at levels acceptable to the UK National Health Service (<£50,000 per QALY).

The present study has several limitations that merit discussion. Some are inherent to the modeling process, which might oversimplify the process of disease progression because of its divergence from real-world circumstances. In addition, international data were used, given the scarcity of information about AD in the Brazilian context. Different data sources were used to obtain probabilities for AD stage transitions.¹⁷17.IkedaS,YamadaY,IkegamiN. Economic evaluation of donepezil treatment for Alzheimer’s disease in Japan.Dement Geriatr Cogn Disord.2002;13:33-9.

18.SpackmanDE,KadiyalaS,NeumannPJ,VeenstraDL,SullivanDS. Measuring Alzheimer disease progression with transition probabilities: estimates from NACC-UDS.Curr Alzheimer Res.2012;9:1050-8.

19.HauberAB,GnanasakthyA,MauskopfJA. Savings in the cost of caring for patients with Alzheimer's disease in Canada: an analysis of treatment with rivastigmine.Clin Ther.2000;22:439-51.

20.FennP,GrayA. Estimating long-term cost savings from treatment of Alzheimer's disease. A modelling approach.Pharmacoeconomics.1999;16:165-74.

21.JonssonL,LindgrenP,WimoA,JonssonB,WinbladB. The cost-effectiveness of donepezil therapy in Swedish patients with Alzheimer's disease: a Markov model.Clin Ther.1999;21:1230-40.

22.NeumannPJ,HermannRC,KuntzKM,ArakiSS,DuffSB,LeonJ, et al. Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease.Neurology.1999;52:1138-45.-²³23.MorrisJC,HeymanA,MohsRC,HughesJP,van BelleG,FillenbaumG, et al. The consortium to establish a registry for Alzheimer's disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer's disease.Neurology.1989;39:1159-65. The differences between these probabilities may be related to the timing of publication of the original studies; other values might have modified the results of our simulation. The cost of institutionalization was not included in the model due to the scarcity of such information. Finally, the social costs involved in the treatment of AD, which, according to the literature, account for a large part of disease-related costs,⁴⁵45.WimoA,WinbladB,EngedalK,SoininenH,VerheyF,WaldemarG, et al. An economic evaluation of donepezil in mild to moderate Alzheimer's disease: results of a 1-year, double-blind, randomized trial.Dement Geriatr Cogn Disord.2003;15:44-54. were not considered, despite their potential impact on the cost-effectiveness analysis.

Finally, it is worth noting that economic health assessments are not intended to exhaust all existing technological alternatives. The analysis performed herein, for example, included the alternatives most prevalent in the SUS. Thus, we did not consider use of the anticholinesterase agent galantamine, which is also approved and dispensed in the SUS for mild to moderate AD, nor of the 12-mg dose of rivastigmine, due to its restricted use in the public sector.

In conclusion, this is one of the first cost-effectiveness studies of AD treatment in the mild and moderate stages and, to our knowledge, is the first to use a Markov model. No Brazilian studies had ever estimated the costs of diagnosis, follow-up, and treatment of AD.

The purpose of pharmacological treatment is to treat symptoms and slow the progression of AD, thereby reducing its burden on society and postponing the care-related expenditures that accompany the more advanced stages of the disease. From this perspective, our findings suggest that donepezil is the most cost-effective option for the SUS. In this sense, current practice in Brazil represents a worst-case scenario. The most common pharmacological treatment option, based on treatment with rivastigmine, has a lower effectiveness (0.39 QALYs/BRL 32,685.77) than donepezil.

Probabilistic analysis indicates that donepezil is the most cost-effective treatment for mild and moderate AD. The results of this study can help inform political decisions to establish the best treatment strategy for AD in its initial and moderate stages, as well as suggest pathways to a comprehensive policy for dementia care in Brazil.

Acknowledgements

This study was financed in part by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; grant 001).

References

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