This paper provides a comprehensive review of studies examining adherence and (or) persistence with dementia pharmacotherapy during the past decade, including a summary of the key patient-, drug-, system-, and provider-level factors associated with these measures. Estimates of adherence and 1-year persistence to these drugs have ranged from 34% to 94% and 35% to 60%, respectively. Though many studies reported nonsignificant associations, there are data suggesting that patient age, sex, ethnoracial background, socioeconomic status, and region-specific reimbursement criteria, as well as the extent and quality of interactions among patients, caregivers, and providers, may influence persistence with pharmacotherapy. As many studies relied on administrative data, limited information was available regarding the relevance of patient's cognitive and functional status or the importance of caregiver involvement or assistive devices to adherence or persistence.
World Health Organization (WHO) and Alzheimer's Disease International. Dementia: A public health priority. Geneva (CH): WHO; 2012.
2.
Alzheimer Society of Canada. Rising tide: The impact of dementia on Canadian Society. Toronto (ON): Alzheimer Society of Canada; 2010.
3.
HoganDBBaileyPBlackSDiagnosis and treatment of dementia: 5. Nonpharmacologic and pharmacologic therapy for mild to moderate dementia. CMAJ. 2008;179:1019–1026.
4.
HerrmannNGauthierS.Diagnosis and treatment of dementia: 6. Management of severe Alzheimer disease. CMAJ. 2008;179:1279–1287.
5.
HerrmannNLanctôtKLHoganDB. Pharmacological recommendations for the symptomatic treatment of dementia: The Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimer Res Ther. 2013;5(Suppl 1):S5.
6.
BurnsAGauthierSPerdomoC.Efficacy and safety of donepezil over 3 years: An open-label, multicentre study in patients with Alzheimer's disease. Int J Geriatr Psychiatry. 2007;22:806–812.
7.
WinbladBWimoAEngedalK3-year study of donepezil therapy in Alzheimer's disease: Effects of early and continuous therapy. Dement Geriatr Cogn Disord. 2006;21:353–363.
8.
DoodyRSGeldmacherDSGordonB, For the Donepezil Study Group. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer's disease. Arch Neurol. 2001;58:427–433.
9.
RogersSLDoodyRSPrattRDLong-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: Final analysis of a US multicentre open-label study. Eur Neuropsychopharmacol. 2000;10:195–203.
10.
HowardRMcShaneRLindesayJDonepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med. 2012;366:893–903.
11.
ScarpiniEBrunoGZappalàGCessation versus continuation of galantamine treatment after 12 months of therapy in patients with Alzheimer's disease: A randomized, double blind, placebo controlled withdrawal trial. J Alzheimers Dis. 2011;26:211–220.
12.
SeltzerB.Cholinesterase inhibitors in the clinical management of Alzheimer's disease: Importance of early and persistent treatment. J Int Med Res. 2006;34:339–347.
13.
DaielloLAOttBRLapaneKLEffect of discontinuing cholinesterase inhibitor therapy on behavioral and mood symptoms in nursing home patients with dementia. Am J Geriatr Pharmacother. 2009;7:74–83.
14.
BirksJ.Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006;1:CD005593.
15.
McShaneRSastreA AreosaMinakaranN.Memantine for dementia. Cochrane Database Syst Rev. 2006;2:CD003154.
16.
RolinskiMFoxCMaidmentICholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease. Cochrane Database Syst Rev. 2012;3:CD006504.
17.
KaduszkiewiczHZimmermanTBeck-BornholdtH-PCholinesterase inhibitors for patients with Alzheimer's disease: Systematic review of randomised clinical trials. Br Med J. 2005;331:321–327.
18.
RainaPSantaguidaPIsmailaAEffectiveness of cholinesterase inhibitors and memantine for treating dementia: Evidence review for a clinical practice guideline. Ann Intern Med. 2008;148:379–397.
19.
KnappMIemmiVRomeoR.Dementia care costs and outcomes: A systematic review. Int J Geriatr Psychiatry. 2013;28:551–561.
20.
BondMRogersGPetersJThe effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of Technology Appraisal No 111): A systematic review and economic model. Health Technol Assess. 2012;16:1–470.
21.
CappellJHerrmannNCornishSThe pharmacoeconomics of cognitive enhancers in moderate to severe Alzheimer's disease. CNS Drugs. 2010;24:909–927.
22.
CourtneyCFarrellDGrayRLong-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): Randomized double-blind trial. Lancet. 2004;363:2105–2115.
23.
RosenblattASamusQMOnyikeCUAcetylcholinesterase inhibitors in assisted living: Patterns of use and association with retention. Int J Geriatr Psychiatry. 2008;23:178–184.
24.
LopezOLBeckerJTSaxtonJAlteration of a clinically meaningful outcome in the natural history of Alzheimer's disease by cholinesterase inhibitors. J Am Geriatr Soc. 2005;53:83–87.
25.
GeldmacherDSProvenzanoGMcRaeTDonepezil is associated with delayed nursing home placement in patients with Alzheimer's disease. J Am Geriatr Soc. 2003;51:937–944.
26.
AcriTGrossR.Studies of medication adherence. In: StromBLKimmelSEHennessyS, editors. Textbook of pharmacoepidemiology. 2nd ed.Hoboken (NJ): John Wiley & Sons, Ltd; 2013.
27.
CampbellNLBoustaniMASkopeljaENMedication adherence in older adults with cognitive impairment: A systematic evidence-based review. Am J Geriatr Pharmacother. 2012;10:165–177.
28.
ArltSLindnerRRöslerAAdherence to medication in patients with dementia: Predictors and strategies for improvement. Drugs Aging. 2008;25:1033–1047.
29.
SmallGDuboisB.A review of compliance to treatment in Alzheimer's disease: Potential benefits of a transdermal patch. Curr Med Res Opin. 2007;23:2705–2713.
30.
BradyRWeinmanJ.Adherence to cholinesterase inhibitors in Alzheimer's disease: A review. Dement Geriatr Cogn Disord. 2013;35:351–363.
31.
ThiruchselvamTNaglieGMoineddinRRisk factors for medication nonadherence in older adults with cognitive impairment who live alone. Int J Geriatr Psychiatry. 2012;27:1275–1282.
32.
GelladWFGrenardJLMarcumZA. A systematic review of barriers to medication adherence in the elderly: Looking beyond cost and regimen complexity. Am J Geriatr Pharmacother. 2011;9:11–23.
33.
VikSAHoganDBPattenSBMedication nonadherence and subsequent risk of hospitalization and mortality in older adults. Drugs Aging. 2006;23:345–356.
34.
TaipaleHTanskanenAKoponenMAntidementia drug use among community-dwelling individuals with Alzheimer's disease in Finland: A nationwide register-based study. Int Clin Psychopharmacol. 2014;29:216–223.
35.
HaiderBSchmidtRSchweigerCMedication adherence in patients with dementia: An Austrian cohort study. Alzheimer Dis Assoc Disord. 2014;28:128–133.
36.
GardetteVLapeyre-MestreMPiauAA 2-year prospective cohort study of antidementia drug non-persistency in mild-to-moderate Alzheimer's disease in Europe: Predictors of discontinuation and switch in the ICTUS study. CNS Drugs. 2014;28:157–170.
37.
SalehSKirkAMorganDGLess education predicts anticholinesterase discontinuation in dementia patients. Can J Neurol Sci. 2013;40:684–690.
38.
BrewerLBennettKMcGreevyCA population-based study of dosing and persistence with anti-dementia medications. Eur J Clin Pharmacol. 2013;69:1467–1475.
39.
OlazaranJNavarroERojoJM. Persistence of cholinesterase inhibitor treatment in dementia: Insights from a naturalistic study. Dement Geriatr Cogn Dis Extra. 2013;3:48–59.
40.
Le CouteurDGRobinsonMLevertonAAdherence, persistence and continuation with cholinesterase inhibitors in Alzheimer's disease. Australas J Ageing. 2012;31:164–169.
41.
van den BusscheHKaduszkiewiczHKollerDAntidementia drug prescription sources and patterns after the diagnosis of dementia in Germany: Results of a claims data-based 1-year follow-up. Int Clin Psychopharmacol. 2011;26:225–231.
42.
MansourDWongRKuskowskiMDiscontinuation of acetylcholinesterase inhibitor treatment in the nursing home. Am J Geriatr Pharmacother. 2011;9:345–350.
43.
KrögerEvan MarumRSouvereinPDiscontinuation of cholinesterase inhibitor treatment and determinants thereof in the Netherlands: A retrospective cohort study. Drugs Aging. 2010;27:663–675.
44.
AmuahJEHoganDBEliasziwMPersistence with cholinesterase inhibitor therapy in a population-based cohort of patients with Alzheimer's disease. Pharmacoepidemiol Drug Saf. 2010;19:670–679.
45.
ParienteAPinetMMorideYFactors associated with persistence of cholinesterase inhibitor treatments in the elderly. Pharmacoepidemiol Drug Saf. 2010;19:680–686.
46.
GadzhanovaSRougheadLMacksonJ.Anticholinesterase duration in the Australian veteran population. Aust N Z J Psychiatry. 2010;44:469–474.
47.
GardetteVAndrieuSLapeyre-MestreMPredictive factors of discontinuation and switch of cholinesterase inhibitors in community-dwelling patients with Alzheimer's disease: A 2-year prospective, multicentre, cohort study. CNS Drugs. 2010;24:431–442.
48.
HerrmannNBinderCDalzielWPersistence with cholinesterase inhibitor therapy for dementia: An observational administrative health database study. Drugs Aging. 2009;26:403–407.
49.
UmegakiHItohASuzukiYDiscontinuation of donepezil for the treatment of Alzheimer's disease in geriatric practice. Int Psychogeriatr. 2008;20:800–806.
50.
MassoudFDoraisMCharbonneauCDrug utilization review of cholinesterase inhibitors in Quebec. Can J Neurol Sci. 2008;35:508–509.
51.
AbughoshSMKogutSJ. Comparison of persistence rates of acetylcholine-esterase inhibitors in a state Medicaid program. Patient Prefer Adherence. 2008;2:79–85.
52.
MuchaLShaohungSCuffelBComparison of cholinesterase inhibitor utilization patterns and associated health care costs in Alzheimer's disease. J Manag Care Pharm. 2008;14:451–461.
53.
SunYLaiM-SLuC-JHow long can patients with mild or moderate Alzheimer's dementia maintain both the cognition and the therapy of cholinesterase inhibitors: A national population-based study. Eur J Neurol. 2008;15:278–283.
54.
HerrmannNGillSSBellCMA population-based study of cholinesterase inhibitor use for dementia. J Am Geriatr Soc. 2007;55:1517–1523.
55.
SuhD-CThomasSKValiyevaEDrug persistency of two cholinesterase inhibitors: Rivastigmine versus donepezil in elderly patients with Alzheimer's disease. Drugs Aging. 2005;22:695–707.
56.
MauskopfJAParamoreCLeeWCDrug persistency patterns for patients treated with rivastigmine or donepezil in usual care settings. J Manag Care Pharm. 2005;11:231–239.
57.
SinghGThomasSKArconaSKTreatment persistency with rivastigmine and donepezil in a large state Medicaid program. J Am Geriatr Soc. 2005;53:1269–1270.
58.
DybiczSBKeohaneDJErwinWGPatterns of cholinesterase inhibitor use in the nursing home setting: A retrospective analysis. Am J Geriatr Pharmacother. 2006;4:154–160.
59.
KogutSJEl-MaoucheDAbughoshSM. Decreased persistence to cholinesterase inhibitor therapy with concomitant use of drugs that can impair cognition. Pharmacotherapy. 2005;25:1729–1735.
60.
RoeCMAndersonMJSpivackB.How many patients complete an adequate trial of donepezil?Alzheimer Dis Assoc Disord. 2002;16:49–51.
61.
BlaisLKettaniFZPerreaultSAdherence to cholinesterase inhibitors in patients with Alzheimer's disease. J Am Geriatr Soc. 2009;57(2):366–368.
62.
BorahBSaccoPZarotskyV.Predictors of adherence among Alzheimer's disease patients receiving oral therapy. Curr Med Res Opin. 2010;26:1957–1965.
63.
PoonILalLSFordMERacial/ethnic disparities in medication use among veterans with hypertension and dementia: A national cohort study. Ann Pharmacother. 2009;43:185–193.
64.
TianHAbouzaidSChenWPatient adherence to transdermal rivastigmine after switching from oral donepezil: A retrospective claims database study. Alzheimer Dis Assoc Disord. 2013;27:182–186.
65.
Lopez-PousaSArranzFJ. Characteristics of patients with Alzheimer's disease who switch to rivastigmine transdermal patches in routine clinical practice. Patient Prefer Adherence. 2013;7:47–54.
66.
SchwalbeOScheeransCFreibergICompliance assessment of ambulatory Alzheimer patients to aid therapeutic decisions by healthcare professionals. BMC Health Serv Res. 2010;10:232.
SchneiderLSInselPSWeinerMW, For the Alzheimer's Disease Neuroimaging Initiative. Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer's Disease Neuroimaging Initiative. Arch Neurol. 2011;68:58–66.
69.
MaxwellCJVuMHoganDBPatterns of dementia pharmacotherapy in a population-based cohort of home care clients. Drugs Aging. 2013;30:569–585.
70.
GillSSBronskillSEMamdaniMRepresentation of patients with dementia in clinical trials of donepezil. Can J Clin Pharmacol. 2004;11:e274–e285.
71.
BelleSHZhangSCzajaSJUse of cognitive enhancement medication in persons with Alzheimer disease who have a family caregiver: Results from the Resources for Enhancing Alzheimer's Caregiver Health (REACH) project. Am J Geriatr Psychiatry. 2004;12:250–257.
72.
SeitzDPGruneirAConnDKCholinesterase inhibitor use in US nursing homes: Results from the National Nursing Home Survey. J Am Geriatr Soc. 2009;57:2269–2274.
73.
HaywoodWMMukaetova-LadinskaEB. Sex influences on cholinesterase inhibitor treatment in elderly individuals with Alzheimer's disease. Am J Geriatr Pharmacother. 2006;4:273–286.
74.
HöerAGotheHKhanZMPersistence and adherence with antihypertensive drug therapy in a German sickness fund population. J Hum Hypertens. 2007;21:744–746.
75.
ErkensJAPannemanMMKlungelOHDifferences in antihypertensive drug persistence associated with drug class and gender: A PHARMO study. Pharmacoepidemiol Drug Saf. 2005;14:795–803.
76.
HernandezSMcClendonMJZhouX-HPharmacological treatment of Alzheimer's disease: Effect of race and demographic variables. J Alzheimers Dis. 2010;19:665–672.
77.
GilliganAMMaloneDCWarholakTLRacial and ethnic disparities in Alzheimer's disease pharmacotherapy exposure: An analysis across four state Medicaid populations. Am J Geriatr Pharmacother. 2012;10:303–312.
78.
OsterbergLBlaschkeT.Adherence to medication. N Engl J Med. 2005;353:487–497.
79.
GoldmanPDJoyceGFZhengY.Prescription drug cost sharing: Associations with medication and medical utilization and spending and health. JAMA. 2007;298:61–69.
80.
PietteJDHeislerMWagnerTH. Medication characteristics beyond cost alone influence decisions to underuse pharmacotherapy in response to financial pressures. J Clin Epidemiol. 2006;59:739–746.
81.
ParienteAFourrier-RéglatADucruetTAntipsychotic use and myocardial infarction in older patients with treated dementia. Arch Intern Med. 2012;172:648–653.
82.
HernandezRKFarwellWCantorMDCholinesterase inhibitors and incidence of bradycardia in patients with dementia in the Veterans Affairs New England Healthcare System. J Am Geriatr Soc. 2009;57:1997–2003.
83.
GillSSAndersonGMFischerHDSyncope and its consequences in patients with dementia receiving cholinesterase inhibitors. A population-based cohort study. Arch Intern Med. 2009;169:867–873.
84.
CarnahanRMLundBCPerryPJThe concurrent use of anticholinergics and cholinesterase inhibitors: Rare event or common practice?J Am Geriatr Soc. 2004;52:2082–2087.
85.
AdlerGMuellerBArticusK.The transdermal formulation of rivastigmine improves caregiver burden and treatment adherence of patients with Alzheimer's disease under daily practice conditions. Int J Clin Pract. 2014;68:465–470.
86.
BoadaMArranzFJ. Transdermal is better than oral: Observational research of the satisfaction of caregivers of patients with Alzheimer's disease treated with rivastigmine. Dement Geriatr Cogn Disord. 2013;35:23–33.
87.
WinbladBCummingsJAndreasenNA six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease—rivastigmine patch versus capsule. Int J Geriatr Psychiatry. 2007;22:456–467.
88.
WinbladBKawataAKBeusterienKMCaregiver preference for rivastigmine patch relative to capsules for treatment of probable Alzheimer's disease. Int J Geriatr Psychiatry. 2007;22:485–491.
89.
HoganDBGoldlistBNaglieGComparison studies of cholinesterase inhibitors for Alzheimer's disease. Lancet Neurol. 2004;3:622–626.
90.
BrookhartMAPatrickARSchneeweissSPhysician follow-up and provider continuity are associated with long term medication adherence. A study of the dynamics of statin use. Arch Intern Med. 2007;167:847–852.
91.
DhallaIAAndersonGMMamdaniMMInappropriate prescribing before and after nursing home admission. J Am Geriatr Soc. 2002;50:995–1000.
92.
WatanabeNYamamuraKSuzukiYPharmacist-based donepezil outpatient consultation service to improve medication persistence. Patient Prefer Adherence. 2012;6:605–611.
93.
Barro-BelayguesNvan KanGARollandYPatterns of dementia treatment use in assisted living facilities: A cross-sectional study of 1975 demented residents. J Am Med Dir Assoc. 2011;12:648–654.
94.
CherubiniARuggieroCDell'AquilaGUnderrecognition and undertreatment of dementia in Italian nursing homes. J Am Med Dir Assoc. 2012;13:759.e7–e13. doi: 10.1016/j.jamda.2012.05.015. Epub 2012 Jun 23.
95.
HoganDB. Long-term efficacy and toxicity of cholinesterase inhibitors in the treatment of Alzheimer's disease. Can J Psychiatry. 2014;59(12):618–623.
96.
RitchieCWZhinchinG.Low dose, high dose, or no dose: Better prescribing of cholinesterase inhibitors for Alzheimer's disease. Int Psychogeriatr. 2013;25:511–515.
97.
MassoudF.Persistence with cholinesterase inhibitor treatment in Alzheimer disease. Can J Neurol Sci. 2013;40:623–624.
98.
ParsonsCHughesCMPassmoreAPWithholding, discontinuing and withdrawing medications in dementia patients at the end of life: A neglected problem in the disadvantaged dying?Drugs Aging. 2010;27:435–449.
99.
Park-WyllieLYMamdaniMMLiPCholinesterase inhibitors and hospitalization for bradycardia: A population-based study. PLoS Med. 2009;6:e1000157.
100.
GrayHLJimenezDECucciareMAEthnic differences in beliefs regarding Alzheimer disease among dementia family caregivers. Am J Geriatr Psychiatry. 2009;17:925–933.
101.
RobertsJSConnellCMCisewskiD, et el. Differences between African Americans and whites in their perceptions of Alzheimer disease. Alzheimer Dis Assoc Disord. 2003;17:19–26.
102.
JacklinKMWalkerJDShawandeM.The emergence of dementia as a health concern among First Nations populations in Alberta, Canada. Can J Public Health. 2013;104:e39–e44.
103.
FinkelsteinSAForbesDARichmondCAM. Formal dementia care among First Nations in Southwestern Ontario. Can J Aging. 2012;31:257–270.
104.
WinbladBEngedalKSoininenHA 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology. 2001;57:489–495.
