title: Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer's dementia: a pooled area under the curve analysis.
abstract: BACKGROUND
  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.
authors.affiliation: Ray Dolby Brain Health Center and California Pacific Medical Center Research Institute, CPMC Davies Campus, 45 Castro Street, Suite 220, San Francisco, CA 94114 USA ; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA.
authors.forename: Alireza
authors.initials: A
authors.lastname: Atri
authors.affiliation: Pentara Corporation, Salt Lake City, UT USA.
authors.forename: Suzanne B
authors.initials: SB
authors.lastname: Hendrix
authors.affiliation: Prescott Medical Communications Group, Chicago, IL USA.
authors.forename: Vojislav
authors.initials: V
authors.lastname: Pejović
authors.affiliation: Forest Research Institute Inc., Jersey City, NJ USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hofbauer
authors.affiliation: Forest Research Institute Inc., Jersey City, NJ USA.
authors.forename: John
authors.initials: J
authors.lastname: Edwards
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit Hospital Clínic, Barcelona, Spain ; Barcelona Beta Brain Research Centre, Barcelona, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Molinuevo
authors.affiliation: Forest Research Institute Inc., Jersey City, NJ USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Graham