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Systematic review

Vol. 149 No. 2526 (2019)

Acetylcholinesterase inhibitors combined with memantine for moderate to severe Alzheimer's disease: a meta-analysis

  • Dominik Glinz
  • Viktoria L. Gloy
  • Andreas U. Monsch
  • Reto W. Kressig
  • Chandni Patel
  • Kimberly Alba McCord
  • Zanfina Ademi
  • Yuki Tomonaga
  • Matthias Schwenkglenks
  • Heiner C. Bucher
  • Heike Raatz
DOI
https://doi.org/10.4414/smw.2019.20093
Cite this as:
Swiss Med Wkly. 2019;149:w20093
Published
30.06.2019

Summary

BACKGROUND

The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with Alzheimer’s disease is inconclusive.

AIMS OF THE STUDY. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the clinical efficacy and safety of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate to severe Alzheimer's disease (Mini-Mental State Examination score is <20).

METHODS

We systematically searched EMBASE, Medline and CENTRAL until February 2018 for eligible RCTs. We pooled the outcome data using inverse variance weighting models assuming random effects, and assessed the quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE).

RESULTS

We included nine RCTs (2604 patients). At short-term follow-up (closest to 6 months), combination therapy compared to AChEI monotherapy had a significantly greater effect on cognition than AChEI monotherapy (standardised mean difference [SMD] 0.20, 95% confidence interval [CI] 0.05 to 0.35, 7 RCTs, low QoE) and clinical global impression (SMD −0.15, 95% CI −0.28 to −0.01, 4 RCTs, moderate QoE), but not on activities of daily living (SMD 0.09, 95% CI −0.01 to 0.18, 5 RCTs, moderate QoE) or behavioural and psychological symptoms of dementia (mean difference −3.07, 95% CI −6.53 to 0.38, 6 RCT, low QoE). There was no significant difference in adverse events (relative risk ratio 1.05, 95% CI 0.98 to 1.12, 4 RCTs, low QoE). Evidence for long-term follow-up (≥ 9 months) or nursing home placement was sparse. Only two studies compared combination therapy with memantine monotherapy.

CONCLUSIONS

Combination therapy had statistically significant effects on cognition and clinical global impression. The clinical relevance of these effects is uncertain. The overall QoE was very low. With the current evidence, it remains unclear whether combination therapy adds any benefit. Large pragmatic RCTs with long-term follow-up and focus on functional outcomes, delay in nursing home placement and adverse events are needed.

References

  1. Maier WB. UB. Neurokognitive Störungen im DSM-5: Durchgreifende Änderungen in der Demenzdiagnostik. Nervenarzt. Berlin Heidelberg: Springer-Verlag, 2014:564–70.
  2. Siberski J. Dementia and DSM-5: Changes, Cost, and Confusion. Secondary Dementia and DSM-5: Changes, Cost, and Confusion 2012. http://www.todaysgeriatricmedicine.com/archive/110612p12.shtml.
  3. WHO World Health Organization. Dementia. Secondary Dementia March 2015 http://www.who.int/mediacentre/factsheets/fs362/en/.
  4. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;(1):CD005593.
  5. Birks JS, Chong LY, Grimley Evans J. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev. 2015;9:CD001191.
  6. Loy C, Schneider L. Galantamine for Alzheimer’s disease and mild cognitive impairment. Cochrane Database Syst Rev. 2006;(1):CD001747. doi:.https://doi.org/10.1002/14651858.CD001747.pub3
  7. Matsunaga S, Kishi T, Iwata N. Memantine monotherapy for Alzheimer’s disease: a systematic review and meta-analysis. PLoS One. 2015;10(4):e0123289. doi:.https://doi.org/10.1371/journal.pone.0123289
  8. Monsch AU, Büla C, Hermelink M, Kressig RW, Martensson B, Mosimann U, et al., Alzheimer Forum Schweiz. Konsensus 2012 zur Diagnostik und Therapie von Demenzkranken in der Schweiz [Consensus 2012--diagnosis and treatment of patients with dementia in Switzerland]. Praxis (Bern 1994). 2012;101(19):1239–49. doi:.https://doi.org/10.1024/1661-8157/a001085
  9. European Medicines Agency (EMA). Refusal of the marketing authorisation for Acrescent (memantine hydrochloride / donepezil hydrochloride). http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002424/WC500134080.pdf, accessed 05.03.2018. EMA 2012.
  10. European Medicines Agency (EMA). Refusal of the marketing authorisation for Balaxur (memantine hydrochloride / donepezil hydrochloride). http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002708/WC500134081.pdf, accessed 05.03.2018. EMA 2012.
  11. Schmidt R, Hofer E, Bouwman FH, Buerger K, Cordonnier C, Fladby T, et al. EFNS-ENS/EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer’s disease. Eur J Neurol. 2015;22(6):889–98. doi:.https://doi.org/10.1111/ene.12707
  12. Tsoi KK, Chan JY, Leung NW, Hirai HW, Wong SY, Kwok TC. Combination Therapy Showed Limited Superiority Over Monotherapy for Alzheimer Disease: A Meta-analysis of 14 Randomized Trials. J Am Med Dir Assoc. 2016;17(9):863.e1–8. doi:.https://doi.org/10.1016/j.jamda.2016.05.015
  13. Chen R, Chan PT, Chu H, Lin YC, Chang PC, Chen CY, et al. Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: A meta-analysis. PLoS One. 2017;12(8):e0183586. doi:.https://doi.org/10.1371/journal.pone.0183586
  14. Swiss Medical Board. Combination therapy compared to monotherapy for moderate to severe Alzheimer's Disease - Assessment report published 2017. https://www.swissmedicalboard.ch/fileadmin/public/news/2017/assessment_report_smb_antidementia_long_2017.pdf, accessed April 3rd, 2018.
  15. Wong SS, Wilczynski NL, Haynes RB. Developing optimal search strategies for detecting clinically sound treatment studies in EMBASE. J Med Libr Assoc. 2006;94(1):41–7.
  16. Cochrane Work. The Cochrane highly sensitive search strategies for identifying randomized trials in PubMed, sensitivity- and precision-maximizing version (2008 revision), http://workcochraneorg/pubmed.
  17. Guyatt G, Oxman AD, Kunz R, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol. 2011;64(4):395–400.
  18. Guyatt G, Oxman AD, Akl E, et al. GRADE guidelines 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94.
  19. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88. doi:.https://doi.org/10.1016/0197-2456(86)90046-2
  20. da Costa BR, Nüesch E, Rutjes AW, Johnston BC, Reichenbach S, Trelle S, et al. Combining follow-up and change data is valid in meta-analyses of continuous outcomes: a meta-epidemiological study. J Clin Epidemiol. 2013;66(8):847–55. doi:.https://doi.org/10.1016/j.jclinepi.2013.03.009
  21. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. www.cochrane.org/training/cochrane-handbook The Cochrane Collaboration last edited 20 March 2011
  22. Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64(4):380–2. doi:.https://doi.org/10.1016/j.jclinepi.2010.09.011
  23. Araki T, Wake R, Miyaoka T, Kawakami K, Nagahama M, Furuya M, et al. The effects of combine treatment of memantine and donepezil on Alzheimer’s disease patients and its relationship with cerebral blood flow in the prefrontal area. Int J Geriatr Psychiatry. 2014;29(9):881–9. doi:.https://doi.org/10.1002/gps.4074
  24. Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med. 2012;366(10):893–903. doi:.https://doi.org/10.1056/NEJMoa1106668
  25. Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, et al. Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease (DOMINO-AD) trial: secondary and post-hoc analyses. Lancet Neurol. 2015;14(12):1171–81. doi:.https://doi.org/10.1016/S1474-4422(15)00258-6
  26. Choi SH, Park KW, Na DL, Han HJ, Kim EJ, Shim YS, et al.; EXPECT Study Group. Tolerability and efficacy of memantine add-on therapy to rivastigmine transdermal patches in mild to moderate Alzheimer’s disease: a multicenter, randomized, open-label, parallel-group study. Curr Med Res Opin. 2011;27(7):1375–83. doi:.https://doi.org/10.1185/03007995.2011.582484
  27. Yoon SJ, Choi SH, Na HR, et al. Effects on agitation with rivastigmine patch monotherapy and combination therapy with memantine in mild to moderate Alzheimer’s disease: a multicenter 24-week prospective randomized open-label study (the Korean EXelon Patch and combination with mEmantine Comparative Trial study). Geriatr Gerontol Int. 2017;17(3):494–9.
  28. Grossberg GT, Manes F, Allegri RF, Gutiérrez-Robledo LM, Gloger S, Xie L, et al. The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer’s disease taking cholinesterase inhibitors. CNS Drugs. 2013;27(6):469–78. doi:.https://doi.org/10.1007/s40263-013-0077-7
  29. Herrmann N, Gauthier S, Boneva N, Lemming OM ; 10158 Investigators. A randomized, double-blind, placebo-controlled trial of memantine in a behaviorally enriched sample of patients with moderate-to-severe Alzheimer’s disease. Int Psychogeriatr. 2013;25(6):919–27. doi:.https://doi.org/10.1017/S1041610213000239
  30. Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT ; Memantine MEM-MD-12 Study Group. Memantine treatment in patients with mild to moderate Alzheimer’s disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res. 2008;5(1):83–9. doi:.https://doi.org/10.2174/156720508783884576
  31. Cummings JL, Schneider E, Tariot PN, Graham SM ; Memantine MEM-MD-02 Study Group. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology. 2006;67(1):57–63. doi:.https://doi.org/10.1212/01.wnl.0000223333.42368.f1
  32. Feldman HH, Schmitt FA, Olin JT ; Memantine MEM-MD-02 Study Group. Activities of daily living in moderate-to-severe Alzheimer disease: an analysis of the treatment effects of memantine in patients receiving stable donepezil treatment. Alzheimer Dis Assoc Disord. 2006;20(4):263–8. doi:.https://doi.org/10.1097/01.wad.0000213859.35355.59
  33. Schmitt FA, van Dyck CH, Wichems CH, Olin JT ; Memantine MEM-MD-02 Study Group. Cognitive response to memantine in moderate to severe Alzheimer disease patients already receiving donepezil: an exploratory reanalysis. Alzheimer Dis Assoc Disord. 2006;20(4):255–62. doi:.https://doi.org/10.1097/01.wad.0000213860.35355.d4
  34. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I ; Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291(3):317–24. doi:.https://doi.org/10.1001/jama.291.3.317
  35. van Dyck CH, Schmitt FA, Olin JT ; Memantine MEM-MD-02 Study Group. A responder analysis of memantine treatment in patients with Alzheimer disease maintained on donepezil. Am J Geriatr Psychiatry. 2006;14(5):428–37. doi:.https://doi.org/10.1097/01.JGP.0000203151.17311.38
  36. Shao Z-Q. Comparison of the efficacy of four cholinesterase inhibitors in combination with memantine for the treatment of Alzheimer’s disease. Int J Clin Exp Med. 2015;8(2):2944–8.
  37. Wilkinson D, Fox NC, Barkhof F, Phul R, Lemming O, Scheltens P. Memantine and brain atrophy in Alzheimer’s disease: a 1-year randomized controlled trial. J Alzheimers Dis. 2012;29(2):459–69. doi:.https://doi.org/10.3233/JAD-2011-111616
  38. Robert P, Ferris S, Gauthier S, Ihl R, Winblad B, Tennigkeit F. Review of Alzheimer’s disease scales: is there a need for a new multi-domain scale for therapy evaluation in medical practice? Alzheimers Res Ther. 2010;2(4):24. doi:.https://doi.org/10.1186/alzrt48
  39. Cohen J. Statistical power analysis for the behavioral sciences. 2nd edition. Hillsdale, NJ: Lawrence Earlbaum Associates; 1988.
  40. King MT. A point of minimal important difference (MID): a critique of terminology and methods. Expert Rev Pharmacoecon Outcomes Res. 2011;11(2):171–84. doi:.https://doi.org/10.1586/erp.11.9
  41. Institut für Qualität and Wirtschaftlichkeit im Gesundheitswesen (IQWiG). Cholinesterasehemmer bei Alzheimer Demenz: Ergänzungsauftrag Rivastigmin-Pflaster und Galantamin. Bericht Nr. 18. https://www.iqwig.de/download/A09-05_Abschlussbericht_Cholinesterasehemmer_Ergaenzungsauftrag_Rivastigmin_Pflaster_Galantamin.pdf, accessed 16.05.2018. IQWiG 2012.
  42. Rodda J, Walker Z. Ten years of cholinesterase inhibitors. Int J Geriatr Psychiatry. 2009;24(5):437–42. doi:.https://doi.org/10.1002/gps.2165
  43. Blanco-Silvente L, Castells X, Saez M, Barceló MA, Garre-Olmo J, Vilalta-Franch J, et al. Discontinuation, Efficacy, and Safety of Cholinesterase Inhibitors for Alzheimer’s Disease: a Meta-Analysis and Meta-Regression of 43 Randomized Clinical Trials Enrolling 16 106 Patients. Int J Neuropsychopharmacol. 2017;20(7):519–28. doi:.https://doi.org/10.1093/ijnp/pyx012
  44. Lemstra AW, Richard E, van Gool WA. Cholinesterase inhibitors in dementia: yes, no, or maybe? Age Ageing. 2007;36(6):625–7. doi:.https://doi.org/10.1093/ageing/afm117
  45. Haute Autorité de Santé (HAS). Alzheimer – Zoom sur les travaux de la HAS: parcours, évaluation des médicaments. Published 29.05.2018. https://www.has-sante.fr/portail/jcms/c_2680920/fr/medicaments-alzheimer-interet-medical-insuffisant, accessed June 5th, 2018.
  46. Institut für Qualität and Wirtschaftlichkeit im Gesundheitswesen (IQWiG). Memantin bei Alzheimer Demenz. Bericht Nr. 59. https://www.iqwig.de/download/A05-19C_Abschlussbericht_Memantin_bei_Alzheimer_Demenz.pdf, accessed 17.01.2017. IQWiG 2009.
  47. Institut für Qualität and Wirtschaftlichkeit im Gesundheitswesen (IQWiG). Responderanalysen zu Memantin bei Alzheimer Demenz - Rapid Report. Bericht Nr. 84. https://www.iqwig.de/de/projekte-ergebnisse/projekte/arzneimittelbewertung/2010-oder-frueher/a10-06-responderanalysen-zu-memantin-bei-alzheimer-demenz-rapid-report.1349.html, accessed 18.06.2018. IQWiG 2011.
  48. European Medicines Agency (EMA). Guideline on mdicinal products for the treatment of Alzheimer's disease and other dementias. Committee for medicinal products for human use (CHMP). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003562.pdf, accessed 09.05.2018. EMA 2008.
  49. Dworkin RH, Turk DC, McDermott MP, Peirce-Sandner S, Burke LB, Cowan P, et al. Interpreting the clinical importance of group differences in chronic pain clinical trials: IMMPACT recommendations. Pain. 2009;146(3):238–44. doi:.https://doi.org/10.1016/j.pain.2009.08.019
  50. Geldmacher DS, Provenzano G, McRae T, Mastey V, Ieni JR. Donepezil is associated with delayed nursing home placement in patients with Alzheimer’s disease. J Am Geriatr Soc. 2003;51(7):937–44. doi:.https://doi.org/10.1046/j.1365-2389.2003.51306.x
  51. Riepe MW, Mittendorf T, Förstl H, Frölich L, Haupt M, Leidl R, et al. Quality of life as an outcome in Alzheimer’s disease and other dementias--obstacles and goals. BMC Neurol. 2009;9(1):47. doi:.https://doi.org/10.1186/1471-2377-9-47
  52. Kahle-Wrobleski K, Ye W, Henley D, Hake AM, Siemers E, Chen YF, et al. Assessing quality of life in Alzheimer’s disease: Implications for clinical trials. Alzheimers Dement (Amst). 2017;6:82–90. doi:.https://doi.org/10.1016/j.dadm.2016.11.004
  53. Kishi T, Matsunaga S, Oya K, Nomura I, Ikuta T, Iwata N. Memantine for Alzheimer’s Disease: An Updated Systematic Review and Meta-analysis. J Alzheimers Dis. 2017;60(2):401–25. doi:.https://doi.org/10.3233/JAD-170424
  54. Zheng Y, Yu J. The efficacy and safety of combination therapy of memantine and donepezil among old Alzheimer’s disease patients (Translated from Chinese). Modern Practical Medicine. 2011;4:415–6.
  55. IE2201 (after 2001). Phase I study of SUNY7017 (memantine hydrochloride) in patients with dementia of Alzheimers type. Industry trial. Year published unknown.
  56. Nakamura Y, Kitamura S, Nagakubo T, et al. Study of memantine hydrochloride in combination with donepezil hydrochloride in patients with moderate-to-severe alzheimer’s disease. Jpn J Geriatr Med. 2016;54:1147–58.
  57. Tricco AC, Ashoor HM, Soobiah C, Rios P, Veroniki AA, Hamid JS, et al. Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer’s Disease: Systematic Review and Network Metaanalysis. J Am Geriatr Soc. 2018;66(1):170–8. doi:.https://doi.org/10.1111/jgs.15069
  58. European Medicines Agency (EMA). Consultation on revised guideline on medicines to treat Alzheimer’s disease. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/02/WC500200830.pdf accessed 19.01.2017. EMA 2016.
  59. Bennett DA. Lack of Benefit With Idalopirdine for Alzheimer Disease: Another Therapeutic Failure in a Complex Disease Process. JAMA. 2018;319(2):123–5. doi:.https://doi.org/10.1001/jama.2017.19700
  60. Simpson I. An industry update: the latest developments in therapeutic delivery. Ther Deliv. 2018;9(1):9–15. doi:.https://doi.org/10.4155/tde-2017-0109
  61. Cummings J, Lee G, Mortsdorf T, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2017. Alzheimers Dement (N Y). 2017;3(3):367–84. doi:.https://doi.org/10.1016/j.trci.2017.05.002