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Combination Therapy in Moderate to Severe Alzheimer’s Disease


In both RCTs, combination therapy was safe and well tolerated, with a similar incidence of adverse events to the ChEI and placebo group.6,10 Furthermore, the addition of memantine to a ChEI reduced the gastrointestinal adverse effects associated with ChEIs.2,12


Reduced Occurrence of Clinical Worsening Patients with AD deteriorate over time and stabilising the patient, or even reducing the amount of clinical worsening, is a useful outcome. Based on the two combination therapy RCTs, two pooled analyses have been conducted to assess clinical worsening, where clinical worsening was defined as concurrent decline in cognition, function and global status. Both pooled analyses considered the subgroup of patients with moderate to severe AD (MMSE <20); the first analysis permitted any concurrent ChEI, while the second permitted only concurrent donepezil.13,14


with memantine and a ChEI almost halved the occurrence of marked clinical worsening in comparison with a ChEI and placebo (9.8 versus 18.3 %; p<0.01; OC).13


In the second analysis, fewer than half of


the patients receiving combination therapy with memantine and donepezil showed marked clinical worsening compared with those receiving donepezil and placebo (7.9 versus 18.5 %; p<0.001; OC).15


Long-term, Real-world Benefits


In addition to the benefits seen in RCTs, combination therapy has shown real-world effectiveness. A US study followed 943 probable AD patients, with a mean (SD) follow-up time of 62.3 (35.8) months, to determine the time to nursing home admission.16


Compared with


1. Birks J, Cholinesterase inhibitors for Alzheimer’s disease, Cochrane Database Syst Rev, 2006;(1):CD005593.


2. McShane R, Areosa Sastre A, Minakaran N, Memantine for dementia, Cochrane Database Syst Rev, 2006;(2):CD003154.


3. 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 Disord, 2007;24:20–7.


4. Molinuevo JL, [Memantine: the value of combined therapy], Rev Neurol, 2011;52:95–100. Article in Spanish.


5. Gauthier S, Molinuevo JL, Benefits of combined cholinesterase inhibitor and memantine treatment in moderate–severe Alzheimer’s disease, Alzheimers Dement, [submitted].


6. Tariot PN, Farlow MR, Grossberg GT, et al., for the Memantine Study Group, Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil. A randomized controlled trial, JAMA, 2004;291:317–24.


7. Cummings JL, Schneider E, Tariot PN, Graham SM, for the Memantine MEM-MD-02 Study Group, Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment, Neurology, 2006;67:57–63.


8. Schmitt FA, van Dyck CH, Wichems CH, Olin JT, for the Memantine MEM-MD-02 Study Group, Cognitive response to


patients who received ChEI monotherapy, patients who received memantine and ChEI combination therapy were more than seven times less likely to be admitted to a nursing home (relative hazard 0.13; 95 % confidence interval 0.03–0.56).16


A second real-world study


followed 382 subjects with probable AD over a mean treatment time of 22.5 months.17


significantly slower rates of deterioration in cognition and ability to perform activities of daily living compared with patients receiving ChEI monotherapy (both p<0.001), and these benefits appeared to increase with treatment duration.17


Conclusions In the first analysis, combination therapy


In RCTs of patients with moderate to severe AD, combination therapy with memantine and a ChEI produces symptomatic benefits in cognition, function, behaviour and global outcome. Evidence from observational studies suggests that the benefits of combination therapy are sustained over the long term and appear to increase with time. Based on the available data and drug licensing, patients with mild AD should be started on a ChEI, with memantine added when the disease reaches the moderate stages (MMSE <20). For patients first diagnosed in the moderate stages of AD, combination therapy could be initiated, although the treatments should be started and titrated one at a time. In the future, the optimal treatment is likely to consist of disease-modifying therapy with concurrent symptomatic therapies. However, at present, memantine and ChEI combination therapy is the optimal treatment option, since it allows patients with AD to retain cognitive abilities and to remain functional and in home care, for longer. n


memantine in moderate to severe Alzheimer disease patients already receiving donepezil: an exploratory reanalysis, Alzheimer Dis Assoc Disord, 2006;20:255–62.


9. Feldman HH, Schmitt FA, Olin JT, for the 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;20:263–8.


10. Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT, for the 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;5:83–9.


11. Gauthier S, Molinuevo JL, Lemming O, Effects of memantine in patients with moderate to severe Alzheimer’s disease receiving stable doses of donepezil: a meta-analysis, Presented at the 10th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD), Barcelona, Spain, 9–13 March 2011, Poster P 233.


12. Olin JT, Bhatnagar V, Reyes P, et al., Safety and tolerability of rivastigmine capsule with memantine in patients with probable Alzheimer’s disease: a 26-week, open-label, prospective trial (Study ENA713B US32), Int J Geriatr Psychiatry,


2010;25:419–26.


13. Wilkinson D, Andersen HF, Analysis of the effect of memantine in reducing the worsening of clinical symptoms in patients with moderate to severe Alzheimer’s disease, Dement Geriatr Cogn Disord, 2007;24:138–45.


14. Molinuevo JL, Lemming O, Wilkinson D, Effect of memantine in reducing the worsening of clinical symptoms in patients with moderate to severe Alzheimer’s disease receiving stable doses of donepezil, Eur J Neurology, 2011;18(Suppl. 2):79.


15. Molinuevo JL, Lemming O, Wilkinson D, Effect of memantine in reducing the worsening of clinical symptoms in patients with moderate to severe Alzheimer’s disease receiving stable doses of donepezil, Presented at the 15th Congress of the European Federation of Neurological Societies (EFNS), Budapest, Hungary, 10–13 September 2011, Poster P 1030.


16. Lopez OL, Becker JT, Wahed AS, et al., Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease, J Neurol Neurosurg Psychiatry, 2009;80:600–7.


17. Atri A, Shaughnessy LW, Locascio JJ, Growdon JH, Long-term course and effectiveness of combination therapy in Alzheimer disease, Alzheimer Dis Assoc Disord, 2008;22:209–21.


Patients receiving combination therapy had


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