Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer's dementia: a pooled area under the curve analysis

被引:49
作者
Atri, Alireza [1 ,2 ,3 ,4 ]
Hendrix, Suzanne B. [5 ]
Pejovic, Vojislav [6 ]
Hofbauer, Robert K. [7 ]
Edwards, John [7 ]
Luis Molinuevo, Jose [8 ,9 ]
Graham, Stephen M. [7 ]
机构
[1] Ray Dolby Brain Hlth Ctr, San Francisco, CA 94114 USA
[2] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94114 USA
[3] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA
[4] Harvard Univ, Sch Med, Boston, MA USA
[5] Pentara Corp, Salt Lake City, UT USA
[6] Prescott Med Commun Grp, Chicago, IL USA
[7] Forest Res Inst Inc, Jersey City, NJ USA
[8] Hosp Clin Barcelona, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain
[9] Barcelona Beta Brain Res Ctr, Barcelona, Spain
关键词
SEVERE IMPAIRMENT BATTERY; RECEIVING DONEPEZIL; CONTROLLED-TRIAL; DISEASE; VALIDITY; INVENTORY; EFFICACY; SAFETY; DRUGS;
D O I
10.1186/s13195-015-0109-2
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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-ADL(19)), 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-alpha = 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-ADL(19) (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.
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页数:12
相关论文
共 32 条
[1]   Longitudinal changes in functional disability in Alzheimer's disease patients [J].
Arrighi, H. Michael ;
Gelinas, Isabelle ;
McLaughlin, Trent P. ;
Buchanan, Jacqui ;
Gauthier, Serge .
INTERNATIONAL PSYCHOGERIATRICS, 2013, 25 (06) :929-937
[2]  
Atri A., 2011, J NUTR HEALTH AGING, V15, pS2
[3]  
Atri A., 2014, Dementia comprehensive principles and practice, P360, DOI 10.1093/med/9780199928453.003.0016
[4]   Long-term course and effectiveness of combination therapy in Alzheimer disease [J].
Atri, Alireza ;
Shaughnessy, Lynn W. ;
Locascio, Joseph J. ;
Growdon, John H. .
ALZHEIMER DISEASE & ASSOCIATED DISORDERS, 2008, 22 (03) :209-221
[5]   Memantine in patients with Alzheimer's disease receiving donepezil: new analyses of efficacy and safety for combination therapy [J].
Atri, Alireza ;
Molinuevo, Jose L. ;
Lemming, Ole ;
Wirth, Yvonne ;
Pulte, Irena ;
Wilkinson, David .
ALZHEIMERS RESEARCH & THERAPY, 2013, 5 (01)
[6]   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 [J].
Atri, Alireza ;
Rountree, Susan D. ;
Lopez, Oscar L. ;
Doody, Rachelle S. .
NEURODEGENERATIVE DISEASES, 2012, 10 (1-4) :170-174
[7]   Cholinesterase inhibitors for Alzheimer's disease [J].
Birks, J .
COCHRANE DATABASE OF SYSTEMATIC REVIEWS, 2006, (01)
[8]   Summary measures were a useful alternative for analyzing therapeutic clinical trial data [J].
Carusone, SC ;
Goldsmith, CH ;
Smieja, M ;
Loeb, M .
JOURNAL OF CLINICAL EPIDEMIOLOGY, 2006, 59 (04) :387-392
[9]  
Cummings Jeffrey L, 2006, Alzheimers Dement, V2, P263, DOI 10.1016/j.jalz.2006.07.001
[10]   The neuropsychiatric inventory: Assessing psychopathology in dementia patients [J].
Cummings, JL .
NEUROLOGY, 1997, 48 (05) :S10-S16