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

Department of Neurology, Massachusetts General Hospital, Boston, Mass 02114, USA.
Neurodegenerative Diseases (Impact Factor: 3.51). 02/2012; 10(1-4):170-4. DOI: 10.1159/000335156
Source: PubMed


Randomized controlled efficacy trials (RCTs), the scientific gold standard, are required for regulatory approval of Alzheimer's disease (AD) interventions, yet provide limited information regarding real-world therapeutic effectiveness.
To compare the nature of evidence regarding the combination of approved AD treatments from RCTs versus long-term observational controlled studies (LTOCs).
Comparisons of strengths, limitations, and evidence level for monotherapy [cholinesterase inhibitor (ChEI) or memantine] and combination therapy (ChEI + memantine) in RCTs versus LTOCs.
RCTs examined highly selected populations over months. LTOCs collected data across multiple AD stages in large populations over many years. RCTs and LTOCs show similar patterns favoring combination over monotherapy over placebo/no treatment. Long-term combination therapy compared to monotherapy reduced cognitive and functional decline and delayed time to nursing home admission. Persistent treatment was associated with slower decline. While LTOCs used control groups, adjusted for multiple covariates, had higher external validity, and favorable ethical, practical and cost considerations, their limitations included potential selection bias due to lack of placebo comparisons and randomization.
Naturalistic LTOCs provide complementary long-term level II evidence to complement level I evidence from short-term RCTs regarding therapeutic effectiveness in AD that may otherwise be unobtainable. A coordinated strategy/consortium to pool LTOC data from multiple centers to estimate long-term comparative effectiveness, risks/benefits, and costs of AD treatments is needed.

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Available from: Susan Rountree, Aug 19, 2014
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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. "
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    ABSTRACT: 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.
    Full-text · Article · Oct 2013 · The Scientific World Journal
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    • "Long-term observational clinical cohort studies performed in naturalistic settings with prospectively collected data show similar patterns to RCTs, and demonstrate Level II grade, generalisable evidence that favours combination treatment over monotherapy, and monotherapy over placebo/no anti-dementia medication treatment [32-34]. Long-term combination therapy with memantine added to a ChEI has, in the clinical setting, been observed to significantly reduce cognitive and functional decline, and to delay time to nursing home admission compared to ChEI monotherapy and to standard care without a ChEI or memantine [32,33]. "
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    ABSTRACT: Introduction Memantine 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. Methods Post 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). Results At 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. Conclusions These 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.
    Full-text · Article · Jan 2013 · Alzheimer's Research and Therapy
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    ABSTRACT: Accurate measurement of cognitive function is critical for understanding the disease course of Alzheimer's disease (AD). Detecting cognitive change over time can be confounded by level of premorbid intellectual function or cognitive reserve and lead to under- or over-diagnosis of cognitive impairment and AD. Statistical models of cognitive performance that include cognitive reserve can improve sensitivity to change and clinical efficacy. We used confirmatory factor analysis to test a four-factor model composed of memory/language, processing speed/executive function, attention, and cognitive reserve factors in a group of cognitively healthy older adults and a group of participants along the spectrum of amnestic mild cognitive impairment to AD (aMCI-AD). The model showed excellent fit for the control group (χ2 = 100; df = 78; CFI = .962; RMSEA = .049) and adequate fit for the aMCI-AD group (χ2 = 1750; df = 78; CFI = .932; RMSEA = .085). Although strict invariance criteria were not met, invariance testing to determine if factor structures are similar across groups yielded acceptable absolute model fits and provide evidence in support of configural, metric, and scalar invariance. These results provide further support for the construct validity of cognitive reserve in healthy and memory impaired older adults. (JINS, 2012, 18, 1-10).
    No preview · Article · Oct 2012 · Journal of the International Neuropsychological Society
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