Validity, Significance, Strengths, Limitations, and Evidentiary Value of Real-World Clinical Data for Combination Therapy in Alzheimer’s Disease: Comparison of Efficacy and Effectiveness Studies

Atri, Alireza; Rountree, Susan; López, Oscar L.; Doody, Rachelle S.

doi:10.1159/000335156

Cited by 22 publications

(29 citation statements)

References 64 publications

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“…Our conclusions are similar to those reached by NICE in 2010 [41], of no additional benefit of the combination memantine plus AChE/ChE-Is versus memantine monotherapy, and to those of another study covering 1 year [42]. Opposite conclusions for the cognition domains, everyday functions, and global status were reported by a post hoc metanaalysis [43, 44]. Unfortunately, due to the heterogeneity of conditions explored by RCTs and of the cognitive assessment tools used, it is not possible to compare properly the different trials.…”

Section: Discussionsupporting

confidence: 89%

Efficacy of Memantine, Donepezil, or Their Association in Moderate‐Severe Alzheimer’s Disease: A Review of Clinical Trials

Molino

Colucci

Fasanaro

et al. 2013

The Scientific World Journal

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Background. Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer's disease (AD), respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage. Objectives. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD. Method. Double-blind, placebo-controlled randomized trials (RCTs) using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007–2012. Results and Conclusion. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of “adequacy and representativeness.” Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24–52 weeks), and the different cognitive assessment tools used did not allow comparing properly different trials.

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Section: Discussionsupporting

confidence: 89%

Efficacy of Memantine, Donepezil, or Their Association in Moderate‐Severe Alzheimer’s Disease: A Review of Clinical Trials

Molino

Colucci

Fasanaro

et al. 2013

The Scientific World Journal

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“…These results, when considered together with evidence from long-term observational studies (in patients with existing ChEI therapy), support that memantine allows patients to remain independent for longer - alleviating caregiver burden and delaying the time to placement in a nursing home [51,52,53,54]. …”

Section: Discussionmentioning

confidence: 72%

Memantine in Patients with Moderate to Severe Alzheimer's Disease: Meta-Analyses Using Realistic Definitions of Response

Wilkinson

Wirth²,

Goebel

2013

Dement Geriatr Cogn Disord

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Background/Aims: We aimed to develop realistic definitions of clinical worsening in advanced Alzheimer's disease (AD) and to use them in a post hoc responder analysis of memantine. Methods: 2,340 patients with moderate to severe AD (Mini-Mental State Examination <20) were included from 9 multicentre, 16- to 28-week, randomised, double-blind, placebo-controlled studies of memantine 20 mg/day versus placebo. Responder meta-analyses were performed, with definitions of response based on minimally important differences (MIDs) on cognitive, functional, and global assessment scales. Validated or established MIDs were used where available; otherwise, MIDs were estimated by a data-driven approach, using data from our moderate to severe AD population. Results: Patients with moderate to severe AD treated with memantine had a lower incidence of worsening from baseline to endpoint than patients treated with placebo, in cognition [24.4 vs. 35.0%; odds ratio (OR) = 0.60; p < 0.001], function (38.1 vs. 43.4%; OR = 0.81; p = 0.01), global status (39.8 vs. 48.6%; OR = 0.70; p < 0.001), and in a combined ‘triple' worsening measure (9.4 vs. 16.1%; OR = 0.54; p < 0.001). Conclusions: New definitions of clinical worsening based on MIDs represent a more realistic functional decline in advanced stages of AD. Results of this new analysis show that memantine reduces the incidence of clinical worsening in key symptomatic domains in moderate to severe AD.

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“…While longer-term observational clinical cohort studies also support the clinical effectiveness of combination therapy above and beyond stable ChEI monotherapy [32-34], the recently published 52-week, randomised, placebo-controlled DOMINO-AD study in patients with moderate to severe AD (mean baseline standardised MMSE = 9.1), receiving stable donepezil therapy for at least 6 weeks, and whose clinician was considering a change in drug treatment, did not report similar effects [35]. This was an important study that had substantial methodological limitations, which may have particularly affected reliability and validity of results regarding detecting potential group differences over the full course of the 52-week study; these limitations included a study re-design due to delayed and insufficient recruitment, subsequently not meeting re-adjusted sample size requirements, high and imbalanced attrition causing non-ignorable missing data, and reporting of mixed effects modelling results based on difference testing, as opposed to equivalence testing, performed without a posteriori power analysis (when required sample sizes were not achieved).…”

Section: Discussionmentioning

confidence: 99%

Memantine in patients with Alzheimer's disease receiving donepezil: new analyses of efficacy and safety for combination therapy

et al. 2013

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IntroductionMemantine and cholinesterase inhibitors potentially offer additional benefits in Alzheimer's disease (AD) when used together. This study assessed the efficacy and safety of combination treatment with memantine added to stable donepezil in patients with moderate to severe AD, and in a subset with moderate AD.MethodsPost hoc meta-analyses of data combined from two 24-week, randomised, double-blind, placebo-controlled trials of memantine 20 mg/day versus placebo, added to a stable cholinesterase inhibitor, were conducted. Data were included for all patients receiving donepezil 10 mg/day with Mini-Mental State Examination (MMSE) scores < 20 (n = 510). Efficacy was assessed using measures of cognition, function, and global status. Furthermore, marked clinical worsening, defined as concurrent deterioration from baseline in the three main efficacy domains, and safety, measured by treatment-emergent adverse events, were assessed. Analyses were performed for patients with moderate to severe AD (MMSE 5-19; MOD-SEV subgroup), and also for patients with moderate AD (MMSE 10-19; MOD subgroup; n = 367).ResultsAt week 24, in the MOD-SEV subgroup, patients receiving memantine added to donepezil significantly outperformed those receiving placebo added to donepezil in measures of cognition (P < 0.0001), function (P = 0.02), and global status (P = 0.010), with standardised mean differences (SMDs) of 0.36, 0.21, and 0.23, respectively (all last observation carried forward). Similarly, in the MOD subgroup, significant benefits were observed for cognition (P = 0.008), function (P = 0.04) and global status (P = 0.008), with SMDs of 0.28, 0.21, and 0.28, respectively. Significantly fewer patients receiving memantine added to donepezil showed marked clinical worsening than those receiving placebo added to donepezil, in both subgroups (MOD-SEV: 8.7% versus 20.4%, P = 0.0002; MOD: 5.9% versus 15.0%, P = 0.006). The incidence of adverse events was similar between treatment groups.ConclusionsThese results support and extend previous evidence that combination treatment with memantine added to stable donepezil in patients with moderate AD, and in those with moderate to severe AD, is associated with significant benefits in reducing 24-week decline in cognition, function and global status. Combination treatment produces substantially reduced rates of marked clinical worsening, has good safety and tolerability, and generates effect sizes that are both statistically significant and clinically meaningful.

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Validity, Significance, Strengths, Limitations, and Evidentiary Value of Real-World Clinical Data for Combination Therapy in Alzheimer’s Disease: Comparison of Efficacy and Effectiveness Studies

Cited by 22 publications

References 64 publications

Efficacy of Memantine, Donepezil, or Their Association in Moderate‐Severe Alzheimer’s Disease: A Review of Clinical Trials

Efficacy of Memantine, Donepezil, or Their Association in Moderate‐Severe Alzheimer’s Disease: A Review of Clinical Trials

Memantine in Patients with Moderate to Severe Alzheimer's Disease: Meta-Analyses Using Realistic Definitions of Response

Memantine in patients with Alzheimer's disease receiving donepezil: new analyses of efficacy and safety for combination therapy

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