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Time to Treatment Initiation in People With Alzheimer Disease: A Meta-Analysis of Randomized Controlled Trials

Published:September 18, 2015DOI:https://doi.org/10.1016/j.jamda.2015.08.007

      Abstract

      Background

      Alzheimer disease (AD) is a global health problem which afflicts millions of old age population worldwide. Acetylcholinesterase inhibitors and memantine are recognized drug treatments with limited clinical efficacy. It is uncertain if earlier initiation of these drugs will result in better outcomes in the longer term.

      Aim

      To evaluate the benefit of early treatment among people with AD.

      Methods

      Prospective randomized controlled trials were systematically searched from the OVID databases. The trials were eligible if study participants diagnosed with AD and were randomized to have early or late treatment. Any clinical assessment scales on cognitive function, physical function, behavioral problems, and the overall clinical status were the primary outcomes, and any reported adverse events were the secondary outcomes.

      Results

      Ten randomized trials were identified between 2000 and 2010. A total of 3092 participants with AD with mean age 75.8 years were randomly assigned to receive early treatment or treatment delayed by placebo intervention for around 6 months. Compared with late treatment, early AD drug treatment showed no significant benefit on cognitive function [mean difference (MD) of Alzheimer's Disease Assessment Scale- Cognitive Subscale = −0.49, 95% CI = −1.67 to 0.69], physical function (MD of Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory = 0.47, 95% CI = −1.44 to 2.39), behavioral problems (MD of Neuropsychiatric Inventory = −0.26, 95% CI = −2.70 to 2.18), and clinical status (MD of Clinician's Interview-Based Impression of Change plus Caregiver Input = 0.02, 95% CI = −0.23 to 0.27). Nausea was the most common adverse events in acetylcholinesterase inhibitor users, while memantine did not result in more side effects than the placebo group. For both drugs, early treatment had comparable adverse events when compared with late treatment.

      Conclusions

      Earlier AD drug treatment by around 6 months did not result in significant difference in cognitive function, physical function, behavioral problems, and clinical status. This study included relative high proportion of early AD with the follow-up less than 2 years. Future studies can be conducted to further investigate the long-term findings.

      Keywords

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      References

        • Le Couteur D.G.
        • Doust J.
        • Creasey H.
        • Brayne C.
        Political drive to screen for pre-dementia: Not evidenced based and ignores the harms of diagnosis.
        BMJ. 2013; 347: f5125
        • Lin J.S.
        • O'Connor E.
        • Rossom R.C.
        • et al.
        Screening for cognitive impairment in older adults: A systematic review for the U.S. Preventive Services Task Force.
        Ann Intern Med. 2013; 159: 601-612
        • Geldmacher D.S.
        • Provenzano G.
        • McRae T.
        • et al.
        Donepezil is associated with delayed nursing home placement in patients with Alzheimer's disease.
        J Am Geriatr Soc. 2003; 51: 937-944
        • Kavirajan H.
        • Schneider L.S.
        Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: A meta-analysis of randomised controlled trials.
        Lancet Neurol. 2007; 6: 782-792
        • Orgogozo J.M.
        • Rigaud A.S.
        • Stöffler A.
        • et al.
        Efficacy and safety of memantine in patients with mild to moderate vascular dementia: A randomized, placebo-controlled trial (MMM 300).
        Stroke. 2002; 33: 1834-1839
        • Gauthier S.
        Cholinergic adverse effects of cholinesterase inhibitors in Alzheimer's disease: Epidemiology and management.
        Drugs Aging. 2001; 18: 853-862
        • Jones R.W.
        A review comparing the safety and tolerability of memantine with the acetylcholinesterase inhibitors.
        Int J Geriatr Psychiatry. 2010; 25: 547-553
        • Doraiswamy P.M.
        • Krishnan K.R.R.
        • Anand R.
        • et al.
        Long-term effects of rivastigmine in moderately severe Alzheimer's disease. Does early initiation of therapy offer sustained benefits?.
        Prog Neuropsychoparmacol Biol Psychiatry. 2002; 26: 705-712
        • Farlow M.
        • Anand R.
        • Messina Jr., J.
        • et al.
        A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease.
        Eur Neurol. 2000; 44: 236-241
        • Raskind M.A.
        • Peskind E.R.
        • Wessel T.
        • Yuan W.
        Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group.
        Neurology. 2000; 54: 2261-2268
        • Bullock R.
        • Erkinjuntti T.
        • Lilienfeld S.
        • GAL-INT-6 Study Group
        Management of patients with Alzheimer's disease plus cerebrovascular disease: 12-month treatment with galantamine.
        Dement Geriatr Cogn Disord. 2004; 17: 29-34
        • Kurz A.F.
        • Erkinjuntti T.
        • Small G.W.
        • et al.
        Long-term safety and cognitive effects of galantamine in the treatment of probable vascular dementia or Alzheimer's disease with cerebrovascular disease.
        Eur J Neurol. 2003; 10: 633-640
        • Small G.
        • Erkinjuntti T.
        • Kurz A.
        • Lilienfeld S.
        Galantamine in the treatment of cognitive decline in patients with vascular dementia or Alzheimer's disease with cerebrovascular disease.
        CNS Drugs. 2003; 17: 905-914
        • Lyketsos C.G.
        • Reichman W.E.
        • Kershaw P.
        • Zhu Y.
        Long-term outcomes of galantamine treatment in patients with Alzheimer disease.
        Am J Geriatr Psychiatry. 2004; 12: 473-482
        • Reisberg B.
        • Doody R.
        • Stöffler A.
        • et al.
        A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease.
        Arch Neurol. 2006; 63: 49-54
        • Rockwood K.
        • Fay S.
        • Song X.
        • et al.
        Attainment of treatment goals by people with Alzheimer's disease receiving galantamine: A randomized controlled trial.
        CMAJ. 2006; 174: 1099-1105
        • Homma A.
        • Imai Y.
        • Tago H.
        • et al.
        Long-term safety and efficacy of donepezil in patients with severe Alzheimer's disease: Result from a 52-week, open-label, multicenter, extension study in Japan.
        Dement Geriatr Cogn Disord. 2009; 27: 232-239
        • Likitjaroen Y.
        • Meindl T.
        • Friese U.
        • et al.
        Longitudinal changes of fractional anisotropy in Alzheimer's disease patients treated with galantamine: A 12-month randomized, placebo-controlled, double-blinded study.
        Eur Arch Psychiatry Clin Neurosci. 2012; 262: 341-350
        • Winblad B.
        • Wimo A.
        • Engedal K.
        • et al.
        • for the Donepezil Nordic Study Group
        3-year study of donepezil therapy in Alzheimer's disease: Effects of early and continuous therapy.
        Dement Geriatr Cogn Disord. 2006; 21: 353-363
        • Ott B.R.
        • Blake L.M.
        • Kagan E.
        • Resnick M.
        • Memantine MEM-MD-11AB Study Group
        Open label, multicenter, 28-week extension study of the safety and tolerability of memantine in patients with mild to moderate Alzheimer's disease.
        J Neurol. 2007; 254: 351-358
        • Imbimbo B.
        • Verdelli G.
        • Martelli P.
        • Marchesini D.
        • the Eptastigmine Study Group
        Two-year treatment of Alzheimer's disease with eptastigmine.
        Dement Geriatr Cogn Disord. 1999; 10: 139-147
        • Doody R.S.
        • Geldmacher D.S.
        • Gordon B.
        • et al.
        • 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
        • Aupperle P.M.
        • Koumaras B.
        • Chen M.
        • et al.
        Long-term effects of rivastigmine treatment on neuropsychiatric and behavioral disturbances in nursing home residents with moderate to severe Alzheimer's disease: Results of a 52-week open-label study.
        Curr Med Res Opin. 2004; 20: 1605-1612
        • Pirttila T.
        • Wilcock G.
        • Truyen L.
        • Damaraju C.V.
        Long-term efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer's disease: Multicenter trial.
        Eur J Neurol. 2004; 11: 737-741
        • Burns A.
        • Gauthier S.
        • Perdomo C.
        Efficacy and safety of donepezil over 3 years: An open-label, multicenter study in patients with Alzheimer's disease.
        Int J Geriatr Psychiatry. 2007; 22: 806-812
        • McKhann G.
        • Drachman D.
        • Folstein M.
        • et al.
        Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.
        Neurology. 1984; 34: 939-944
        • American Psychiatric Association
        Diagnostic and statistical manual of mental disorders.
        4th ed. American Psychiatric Association, Washington, DC1994
        • Folstein M.F.
        • Folstein S.E.
        • McHugh P.R.
        “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician.
        J Psychiatr Res. 1975; 12: 189-198
        • Rosen W.G.
        • Mohs R.C.
        • Davis K.L.
        A new rating scale for Alzheimer's disease.
        Am J Psychiatry. 1984; 141: 1356-1364
        • Panisset M.
        • Roudier M.
        • Saxton J.
        • Boller F.
        Severe impairment battery: A neuropsychological test for severely demented patients.
        Arch Neurol. 1994; 51: 41-45
        • Galasko D.
        • Bennett D.
        • Sano M.
        • et al.
        An inventory to assess activities of daily living for clinical trials in Alzheimer's disease.
        Alzheimer Dis Assoc Disord. 1997; 11: S33-S39
        • Cummings J.L.
        • Mega M.
        • Gray K.
        • et al.
        The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia.
        Neurology. 1994; 44: 2308-2314
        • Reisberg B.
        • Schneider L.
        • Doody R.
        • et al.
        Clinical global measures of dementia: Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines.
        Alzheimer Dis Assoc Disord. 1997; 11: 8-18
        • Higgins J.P.
        • Altman D.G.
        • Gotzsche D.M.
        • et al.
        The Cochrane collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
        • Moher D.
        • Schulz K.F.
        • Altman D.G.
        The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomised trials.
        Lancet. 2001; 357: 1191-1194
      1. Review Manager (RevMan) (Computer program) version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.

        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
        Ann Intern Med. 2009; 151: 264-269
        • Tan C.C.
        • Yu J.T.
        • Wang H.F.
        • et al.
        Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer's disease: A systematic review and meta-analysis.
        J Alzheimers Dis. 2014; 41: 615-631
        • Ravina B.
        • Putt M.
        • Siderowf A.
        • et al.
        Donepezil for dementia in Parkinson's disease: A randomised, double blind, placebo controlled, crossover study.
        J Neurol Neurosurg Psychiatry. 2005; 76: 934-939
        • Woods R.T.
        • Moniz-Cook E.
        • Iliffe S.
        • et al.
        Dementia: Issues in early recognition and intervention in primary care.
        J R Soc Med. 2003; 96: 320-324