The Finnish population offers many advantages for evaluating the impact of anti-dementia medication on mortality in Alzheimer’s disease (AD) due to broad range of individual-level data collected in national health and social care registries and the fact that Finland has one of the highest mortality rates for dementia globally.
Objective:
The aim of this study was to investigate the association of anti-dementia medication with 2-year risk of death and all-cause mortality in patients with AD.
Methods:
This was a retrospective, non-interventional registry study based on individual-level data using Finnish national health and social care registries. An incident cohort of 9,204 AD patients (first AD diagnosis in 2012) was formed from a population of 316,470 individuals ≥74 years of age. The main outcome measure was overall 2-year risk of death. Statistical modelling was used to assess mortality (Kaplan-Meier) and adjusted hazard ratios (HR) (Cox proportional hazard model).
Results:
Early start of anti-dementia medication (treatment started ≤3 months from AD diagnosis) reduced significantly the risk of all-cause death compared to AD patients who had late medication initiation (defined as treatment started >3 months from AD diagnosis/no medication; HR, 0.51; 95% confidence interval (CI), 0.46–0.57). Dementia was the most common recorded cause of death in both groups.
Conclusion:
This study places importance on early diagnosis of AD and subsequent early initiation of drug treatment in decreasing 2-year risk of death.
(2016) 2016 Alzheimer’s disease facts and figures., Alzheimers Dement12, 459–509.
2.
PrinceM, WimoA, GuerchetM, AliGC, WuY PA (2015) World Alzheimer Report 2015: The global impact of dementia. An analysis of prevalence, incidence, costs and trends., Alzheimer’s Disease International, London.
3.
WinbladB, AmouyelP, AndrieuS, BallardC, BrayneC, BrodatyH, Cedazo-MinguezA, DuboisB, EdvardssonD, FeldmanH, FratiglioniL, FrisoniGB, GauthierS, GeorgesJ, GraffC, IqbalK, JessenF, JohanssonG, JonssonL, KivipeltoM, KnappM, MangialascheF, MelisR, NordbergA, RikkertMO, QiuC, SakmarTP, ScheltensP, SchneiderLS, SperlingR, TjernbergLO, WaldemarG, WimoA, ZetterbergH (2016) Defeating Alzheimer’s disease and other dementias: A priority for European science and society. Lancet Neurol15, 455–532.
4.
LarsonEB, ShadlenM-F, WangL, McCormickWC, BowenJD, TeriL, KukullWA (2004) Survival after initial diagnosis of Alzheimer disease. Ann Intern Med140, 501–509.
5.
LonnroosE, KyyronenP, BellJS, van der CammenTJM, HartikainenS (2013) Risk of death among persons with Alzheimer’s disease: A national register-based nested case-control study. J Alzheimers Dis33, 157–164.
6.
FoleyNC, AffooRH, MartinRE (2015) A systematic review and meta-analysis examining pneumonia-associated mortality in dementia. Dement Geriatr Cogn Disord39, 52–67.
7.
WattmoC, LondosE, MinthonL (2014) Response to cholinesterase inhibitors affects lifespan in Alzheimer’s disease. BMC Neurol14, 173.
8.
WattmoC, LondosE, MinthonL (2014) Risk factors that affect life expectancy in Alzheimer’s disease: A 15-year follow-up. Dement Geriatr Cogn Disord38, 286–299.
9.
MesulamM, ShawP, MashD, WeintraubS (2004) Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann Neurol55, 815–828.
10.
ZhuCW, LivoteEE, ScarmeasN, AlbertM, BrandtJ, BlackerD, SanoM, SternY (2013) Long-term associations between cholinesterase inhibitors and memantine use and health outcomes among patients with Alzheimer’s disease. Alzheimers Dement9, 733–740.
11.
HagerK, BasemanAS, NyeJS, BrashearHR, HanJ, SanoM, DavisB, RichardsHM (2014) Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer’s disease. Neuropsychiatr Dis Treat10, 391–401.
12.
BlackCM, FillitH, XieL, HuX, KariburyoMF, CityY, CunyT, YorkN (2018) Economic burden, mortality, and institutionalization in patients newly diagnosed with Alzheimer’s disease. J Alzheimers Dis61, 185–193.
13.
Krolak-SalmonP, DuboisB, SellalF, Delabrousse-MayouxJ-P, VandelP, AmievaH, JeandelC, AndrieuS, Perret-LiaudetA (2018) France will no more reimburse available symptomatic drugs against Alzheimer’s disease. J Alzheimers Dis66, 425–427.
14.
VersijptJ (2014) Effectiveness and cost-effectiveness of the pharmacological treatment of Alzheimer’s disease and vascular dementia. J Alzheimers Dis42 Suppl 3, S19–25.
15.
PouryamoutL, DamsJ, WasemJ, DodelR, NeumannA (2012) Economic evaluation of treatment options in patients with Alzheimer’s disease: A systematic review of cost-effectiveness analyses. Drugs72, 789–802.
16.
LovemanE, GreenC, KirbyJ, TakedaA, PicotJ, PayneE, CleggA (2006) The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease, Health Technol Assess10, iii-iv, ix-xi, 1–160.
17.
ZalaD, ChanD, McCroneP (2018) The cost-effectiveness implications of suboptimal treatment for different severities of Alzheimer’s disease in the UK. Int J Geriatr Psychiatry33, 307–315.
18.
Lenox-SmithA, ReedC, LebrecJ, BelgerM, JonesRW (2018) Potential cost savings to be made by slowing cognitive decline in mild Alzheimer’s disease dementia using a model derived from the UK GERAS observational study. BMC Geriatr18, 57.
19.
Helsinki: The Finnish Medical Society Duodecim, Dementia. Current Care Guidelines. Working group set up by the Finnish Medical Society Duodecim, Finnish Neurological Society, Finnish Psychogeriatric Society, and Finnish Association for General Practice., Last updated 2017, Accessed on 2017.
20.
Statistics Finland 2016: Population.
21.
NordstromP, ReligaD, WimoA, WinbladB, EriksdotterM (2013) The use of cholinesterase inhibitors and the risk of myocardial infarction and death: A nationwide cohort study in subjects with Alzheimer’s disease. Eur Heart J34, 2585–2591.
22.
TanECK, JohnellK, Garcia-PtacekS, HaaksmaML, FastbomJ, BellJS, EriksdotterM (2018) Acetylcholinesterase inhibitors and risk of stroke and death in people with dementia. Alzheimers Dement14, 944–951.
23.
MuellerC, PereraG, HayesRD, ShettyH, StewartR (2018) Associations of acetylcholinesterase inhibitor treatment with reduced mortality in Alzheimer’s disease: A retrospective survival analysis. Age Ageing47, 88–94.
24.
HowesLG (2014) Cardiovascular effects of drugs used to treat Alzheimer’s disease. Drug Saf37, 391–395.
25.
GillSS, BronskillSE, MamdaniM, SykoraK, LiP, ShulmanKI, AndersonGM, HillmerMP, WodchisWP, RochonPA (2004) Representation of patients with dementia in clinical trials of donepezil, Can J Clin Pharmacol11, e274–85.
26.
Park-WyllieLY, MamdaniMM, LiP, GillSS, LaupacisA, JuurlinkDN (2009) Cholinesterase inhibitors and hospitalization for bradycardia: A population-based study, PLoS Med6, e1000157.
27.
HernandezRK, FarwellW, CantorMD, LawlerEV (2009) Cholinesterase inhibitors and incidence of bradycardia in patients with dementia in the veterans affairs new England healthcare system. J Am Geriatr Soc57, 1997–2003.
28.
FosbolEL, PetersonED, HolmE, GislasonGH, ZhangY, CurtisLH, KoberL, IwataI, Torp-PedersenC, SetoguchiS (2012) Comparative cardiovascular safety of dementia medications: A cross-national study. J Am Geriatr Soc60, 2283–2289.
29.
GillSS, AndersonGM, FischerHD, BellCM, LiP, NormandS-LT, RochonPA (2009) Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: A population-based cohort study. Arch Intern Med169, 867–873.
30.
McCainKR, SawyerTS, SpillerHA (2007) Evaluation of centrally acting cholinesterase inhibitor exposures in adults. Ann Pharmacother41, 1632–1637.
31.
PoluzziE, RaschiE, MorettiU, De PontiF (2009) Drug-induced torsades de pointes: Data mining of the public version of the FDA Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf18, 512–518.
32.
TanakaA, KogaS, HiramatsuY (2009) Donepezil-induced adverse side effects of cardiac rhythm: 2 cases report of atrioventricular block and Torsade de Pointes. Intern Med48, 1219–1223.
33.
LeitchA, McGinnessP, WallbridgeD (2007) Calculate the QT interval in patients taking drugs for dementia. BMJ335, 557.
34.
FisherAA, DavisMW (2008) Prolonged QT interval, syncope, and delirium with galantamine. Ann Pharmacother42, 278–283.
35.
MasudaY (2004) Cardiac effect of cholinesterase inhibitors used in Alzheimer’s disease–from basic research to bedside. Curr Alzheimer Res1, 315–321.
36.
BarnettJH, LewisL, BlackwellAD, TaylorM (2014) Early intervention in Alzheimer’s disease: A health economic study of the effects of diagnostic timing. BMC Neurol14, 101.
37.
BlackCM, LiptonRB, ThielE, BrouilletteM, KhandkerR (2019) Relationship between treatment initiation and healthcare costs in Alzheimer’s disease. J Alzheimers Dis68, 1575–1585.
38.
IsikAT, SoysalP, StubbsB, SolmiM, BassoC, MaggiS, SchofieldP, VeroneseN, MuellerC (2018) Cardiovascular outcomes of cholinesterase inhibitors in individuals with dementia: A meta-analysis and systematic review. J Am Geriatr Soc66, 1805–1811.
39.
LinY-T, WuP-H, ChenC-S, YangY-H, YangY-H (2016) Association between acetylcholinesterase inhibitors and risk of stroke in patients with dementia. Sci Rep6, 29266.
40.
SeltzerB (2006) Cholinesterase inhibitors in the clinical management of Alzheimer’s disease: Importance of early and persistent treatment. J Int Med Res34, 339–347.
41.
LojkowskaW, RyglewiczD, JedrzejczakT, MincS, JakubowskaT, JaroszH, BochynskaA (2003) The effect of cholinesterase inhibitors on the regional blood flow in patients with Alzheimer’s disease and vascular dementia. J Neurol Sci216, 119–126.
42.
GetsiosD, BlumeS, IshakKJ, MaclaineG, HernandezL (2012) An economic evaluation of early assessment for Alzheimer’s disease in the United Kingdom. Alzheimers Dement8, 22–30.
43.
WinbladB, Cedazo-MinguezA, GraffC, JohanssonG, JönssonL, KivipeltoM, SakmarTP, TjernbergLO, WinbladB, AmouyelP, AndrieuS, BallardC, BrayneC, BrodatyH, Cedazo-MinguezA, DuboisB, EdvardssonD, FeldmanH, FratiglioniL, FrisoniGB, GauthierS, GeorgesJ, GraffC, IqbalK, JessenF, JohanssonG, JönssonL, KivipeltoM, KnappM, MangialascheF, MelisR, NordbergA, RikkertMO, QiuC, SakmarTP, ScheltensP, SchneiderLS, SperlingR, TjernbergLO, WaldemarG, WimoA, ZetterbergH (2016) The Lancet Neurology Commission Defeating Alzheimer’s disease and other dementias: A priority for European science and society. Lancet Neurol15, 455–532.
44.
DuboisB, PadovaniA, ScheltensP, RossiA, Dell’AgnelloG (2016) Timely diagnosis for Alzheimer’s disease: A literature review on benefits and challenges. J Alzheimers Dis49, 617–631.
