Memantine and cholinesterase inhibitor combination therapy for Alzheimer's disease: a systematic review

Lucy E Farrimond, Emmert Roberts, Rupert McShane, Lucy E Farrimond, Emmert Roberts, Rupert McShane

Abstract

Background: Memantine is licensed for moderate-to-severe Alzheimer's disease (AD). National Institute for Clinical Excellence (NICE) guidance does not recommend the use of memantine in combination with cholinesterase inhibitors (acetylcholinesterase inhibitor (AChEI)). The underpinning meta-analysis was disputed by the manufacturer.

Objectives: To compare the efficacy of AChEI monotherapy with combination memantine and AChEI therapy in patients with moderate-to-severe AD and to examine the impact of including unpublished data on the results.

Design: Systematic review and meta-analysis of randomised controlled trials.

Data sources: The Cochrane Dementia Group trial register, ALOIS, searched for the last time on 3 May 2011.

Data synthesis: Data from four domains (clinical global, cognition, function, behaviour and mood) were pooled. Sensitivity analyses examined the impact on the NICE-commissioned meta-analysis of restricting data to patients with moderate-to-severe AD and of including an unpublished trial of an extended release preparation of memantine.

Results: Pooled data from the trials, which were included in the NICE-commissioned meta-analysis but which were restricted to moderate-to-severe AD only, showed a small effect of combination therapy on cognition (standardised mean difference (SMD)=-0.29, 95% CI -0.45 to -0.14). Adding data from an unpublished trial of an extended release memantine (total three trials, 1317 participants) showed a small benefit of combination therapy on global scores (SMD=-0.20, 95% CI -0.31 to -0.09), cognition (SMD=-0.25, 95% CI -0.36 to -0.14) and behaviour and mood (SMD=-0.17, 95% CI -0.32 to -0.03) but not on function (SMD=-0.04, 95% CI -0.21 to 0.13) at 6 months. No clinical data have been reported from a 1-year trial, although this found 'no significant benefit' on any clinical measures at 1 year.

Conclusions: These results suggest that there may be a small benefit at 6 months of adding memantine to AChEIs. However, the impact on clinical global impression depends on exactly which studies are included, and there is no benefit on function, so its clinical relevance is not robustly demonstrated. Currently available information from randomised controlled trails indicates no benefit of combination therapy over monotherapy at 1 year. Legislation on the form and content of registry posted results is needed in Europe.

Conflict of interest statement

Competing interests: None.

Figures

Figure 1
Figure 1
Clinical global (CIBIC-plus). ChEI, cholinesterase inhibitor; ER, extended release; LOCF, last observation carried forward; OC, observed case; SMD, standardised mean difference.
Figure 2
Figure 2
Cognition (ADAS-Cog and SIB). ChEI, cholinesterase inhibitor; ER, extended release; LOCF, last observation carried forward; OC, observed case; SMD, standardised mean difference.
Figure 3
Figure 3
Function (ACDS-ADL19 and ADCS-ADL23). ChEI, cholinesterase inhibitor; ER, extended release; LOCF, last observation carried forward; OC, observed case; SMD, standardised mean difference.
Figure 4
Figure 4
Behaviour and mood (NPI). ChEI, cholinesterase inhibitor; ER, extended release; LOCF, last observation carried forward; OC, observed case; SMD, standardised mean difference.

References

    1. EMEA Committee for Medicinal Products for Human Use October 2005 Plenary Meeting Monthly Report. European Medicines Agency Website. (accessed 17 Nov 2005).
    1. National Institute for Clinical Excellence (NICE) Donepezil, Galantamine, Rivastigmine and Memantine for the Treatment of Alzheimer's Disease. NICE Technology Appraisal Guidance 217 (Review of NICE Technology Appraisal Guidance 111). National Institute for Clinical Excellence, 2011. (accessed 23 Mar 2012).
    1. Institute for Quality and Efficiency in Healthcare (IQWiG) Memantine in Alzheimer's Disease. Executive Summary of Final Report A05–19C. Institute for Quality and Efficiency in Healthcare (IQWiG), 2009. (Translation of the executive summary of the final report “Memantin bei Alzheimer Demenz”) (accessed 23 Mar 2012).
    1. Institute for Quality and Efficiency in Health Care (IQWiG) Federal Joint Committee. Responder Analyses on Memantine in Alzheimer's Disease: Executive Summary of Rapid Report A10–06. Institute for Quality and Efficiency in Healthcare (IQWiG), 2011. (accessed 23 Mar 2012).
    1. Institute for Quality and Efficiency in Healthcare (IQWiG) Press Release: Memantine in Alzheimer's Disease: Reliable Analyses are Required. Institute for Quality and Efficiency in Healthcare (IQWiG), 2010. (accessed 23 Mar 2012).
    1. Patel L, Grossberg GT. Combination therapy for Alzheimer's disease. Drugs Aging 2011;28:539–46
    1. Schneider LS, Dagerman KS, Higgins JPT, et al. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol 2011;68:991–8
    1. Bond M, Rogers G, Peters J, et al. The Effectiveness and Cost-Effectiveness of Donepezil, Galantamine, Rivastigmine and Memantine for the Treatment of Alzheimer's Disease (Review of TA111): A Systematic Review and Economic Model. NIHR HTA Programme Project Number 09/87/01. National Institute for Clinical Excellence, 2010. (accessed 23 Mar 2012).
    1. Tariot P, Farlow M, Grossberg T, et al. For the memantine study group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donopezil. A randomized controlled trial. JAMA 2004;291:317–24
    1. Porsteinsson AP, Grossberg GT, Mintzer J, et al. 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;5:83–9
    1. Winblad B, Jones RW, Wirth Y, et al. Memantine in moderate to severe Alzheimer's disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn 2007;24:20–7
    1. The Cochrane Dementia and Cognitive Improvement Group (CDCIG) ALOIS: A Comprehensive Register of Dementia Studies. ALOIS; (accessed 23 Mar 2012).
    1. McShane R, Marcus S; Cochrane Dementia and Cognitive Improvement Group About The Cochrane Collaboration (Cochrane Review Groups (CRGs). Cochrane Dementia and Cognitive Improvement Group (CDCIG), 2010:4 (accessed 23 Mar 2012).
    1. Review Manager (RevMan) [Computer Program]. Version 5.0. Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008
    1. Forest Laboratories Study No MEM-MD-50: A Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Memantine in Patients with Moderate-to-Severe Dementia of the Alzhiemer's Type. Forest Laboratories Clinical Trials Registry, 2008. (accessed 23 Mar 2012).
    1. Lundbeck Trials Clinical Trial Report Summary: Study 10112. A 1-Year Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Effects of Memantine on the Rate of Brain Atrophy in Patients With Alzheimer's Disease. H. Lundbeck A/S, 2012. (accessed 23 Mar 2012).
    1. Study ID: NCT00866060 Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD). . (accessed 14 Aug 2011).
    1. Forest Laboratories Forest and Merz Announce FDA Approval of NAMENDA XR for the Treatment of Moderate to Severe Dementia of the Alzheimer's Type. Forest Laboratories, Inc, 2010. (accessed 23 Mar 2012).
    1. Wilkinson D, Fox N, Barkhof F, et al. Evaluating the effect of memantine on the rate of brain atrophy in patients with Alzheimer's disease: a multicentre imaging study using a patient enrichment strategy. Poster Presented at: 14th International Congress of the International Psychogeriatric Association; 1–5 September 2009, Montréal, Canada: H. Lundbeck A/S, 2009.
    1. Peninsula Technology Assessment Group (PenTAG), University of Exeter AChEIs and Memantine for Alzheimer's Disease: PenTAG Responses to Consultee Comments. National Institute for Clinical Excellence; (accessed 17 Aug 2010).
    1. Periclou A, Hu Y. Extended-release memantine capsule (28 mg, once daily): a multiple dose, open-label study evaluating steady-state pharmacokinetics in healthy volunteers [abstract from poster presentation]. Presented at the 11th International Conference on Alzheimer's Disease; 26–31 July 2008. Chicago, IL, USA: Forest Laboratories Inc; 2008
    1. Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 2010;11:682–96
    1. Lovera JF, Frohman E, Brown TR, et al. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Mult Scler 2010;16:715–23
    1. Villoslada P, Arrondo G, Sepulcre J, et al. Memantine induces reversible neurologic impairment in patients with MS. Neurology 2009;72:1630–3
    1. Reisberg B, Doody R, Stoffler A, et al. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol 2006;63:49–54
    1. Forest Laboratories Inc An Open-Label Evaluation of the Safety of Memantine in Patients with Moderate-to-Severe Dementia of the Alzheimer's Type. Forest Laboratories Clinical Trials Registry, 2005. (accessed 23 Mar 2012).
    1. Forest Laboratories Inc An Open-Label Extension Study Evaluating the Safety and Tolerability of Memantine in Patients with Moderate-to-Severe Dementia of the Alzheimer's Type. Forest Laboratories Clinical Trials Registry, 2009. (accessed 23 Mar 2012).

Source: PubMed

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