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: 3.45). 02/2012; 10(1-4):170-4. DOI: 10.1159/000335156
Source: PubMed

ABSTRACT 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.


Available from: Susan Rountree, Aug 19, 2014
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    ABSTRACT: Introduction Treatment in moderate or severe Alzheimer’s disease (AD) often involves adding memantine to a cholinesterase-inhibitor (ChEI: donepezil, galantamine, rivastigmine). Evidence from six-month randomized trials and long-term observational studies supports superiority of memantine-ChEI combination to ChEI monotherapy. We utilized area-under-the-curve (AUC) analysis to assess six-month cumulative treatment efficacy of memantine-donepezil combination versus component monotherapies on individual clinical domains and on a composite index. Methods Data were pooled from 1,408 individuals with moderate to severe AD from four six-month randomized trials of memantine monotherapy (n = 570) or add-on therapy (donepezil-only subset: n = 847). AUC changes from baseline on measures of cognition (SIB), function (ADCS-ADL19), behavior (NPI), global status (CIBIC-Plus), and a composite index (4D-CI: equally weighted composite of four domain measures) were calculated using the trapezoidal rule and evaluated via analysis of covariance (ANCOVA) (2-sided-α = 0.05). AUC results were contrasted with visit-by-visit changes from baseline (“snapshot analysis”), performed using a mixed-effects model with repeated measures (MMRM). Results Over the entire six-month period, placebo-only treatment was associated with significant cumulative worsening on all outcomes. Memantine-donepezil combination showed significantly greater AUC improvements (point x week) on the SIB, NPI, and CIBIC-Plus than placebo-donepezil (SIB: 68.4 versus 32.0, P = 0.019; NPI: −74.3 versus −28.2, P = 0.003; CIBIC-Plus: −2.5 versus 1.4, P = 0.006) and memantine-only monotherapies (SIB: 68.4 versus 12.0, P <0.001; NPI: −74.3 versus −7.4, P <0.001; CIBIC-Plus: −2.5 versus 2.7, P <0.001), whereas these comparisons were not significant for the ADCS-ADL19 (memantine-donepezil (1.4) versus placebo-donepezil (−0.9), P = 0.407; versus memantine-only (−12.2), P = 0.310). Composite index analysis demonstrated significant cumulative advantages of memantine-donepezil combination (630.0) over placebo-donepezil (344.7, P <0.001) and memantine-only (152.1, P <0.001) treatments. Combining memantine and donepezil had an additive effect. Compared with AUC analysis, baseline-to-endpoint change-score analysis underestimated effects of combination therapy, monotherapies, or both. Conclusions This large pooled area-under-the-curve analysis of randomized-trial data in moderate to severe AD provides ecologically valid support that adding memantine to stable donepezil results in overall clinical benefits that are additive compared with individual monotherapies, continue to accumulate through six-month treatment, and are at least 50% greater than those of monotherapies.
    Alzheimer's Research and Therapy 12/2015; 7(1). DOI:10.1186/s13195-015-0109-2 · 3.50 Impact Factor
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    The Scientific World Journal 10/2013; 2013:925702. DOI:10.1155/2013/925702 · 1.73 Impact Factor
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