title: Combination Therapy Showed Limited Superiority Over Monotherapy for Alzheimer Disease: A Meta-analysis of 14 Randomized Trials.
abstract: Acetylcholinesterase inhibitor (AChEI) and memantine are recognized drug treatments with limited clinical efficacy. Combination therapy for patients with Alzheimer disease (AD) was suggested, but the additional benefit of combination therapy is still controversial.
  
  
  
  To evaluate the additional benefit of combination therapy over monotherapy with either AChEI or memantine.
  
  
  
  Prospective randomized controlled trials were searched from the OVID databases. The trials were eligible if study subjects were diagnosed with AD, and were randomized to compare combination therapy with monotherapy. Any clinical assessment measured using validated scales on cognitive function, activities of daily living, behavioral problems, and global changes were the primary outcomes, and any reported adverse events were the secondary outcomes. Quality of studies and risk of bias were evaluated.
  
  
  
  Fourteen randomized trials were identified between 2004 and 2015 from the United States, Canada, Germany, Japan, China, and Korea. A total of 5019 patients with AD were randomly assigned to receive combination therapy of AChEI and memantine or monotherapy with AChEI or memantine. Combination therapy showed no significant benefit on cognitive function (mean difference [MD] of MMSE = 0.06, 95% CI -0.52 to 0.65), activities of daily living (MD of ADCS-ADL = -0.15, 95% CI -1.08 to 0.78), neuropsychiatric symptoms and behavioral problems (MD of NPI = -1.85, 95% CI -4.83 to 1.13), and global changes (MD of CIBIC-plus = 0.01, 95% CI -0.25 to 0.28). In subgroup analyses, combination therapy can improve cognitive function more than memantine alone; and it can significantly relieve neuropsychiatric symptoms and behavioral problems when concomitantly used with donepezil. No additional adverse event was reported in the combination therapy.
  
  
  
  Combination therapy only showed the benefit on neuropsychiatric symptoms and behavioral problems in moderate-to-severe AD, but no other superiority in terms of cognitive function, activities of daily living, and global changes. Although reported adverse events were comparable, the additional cost for combination therapy may be unnecessary.
authors.affiliation: Jockey Club School of Public Health and Primary Care, Hong Kong; Stanley Ho Big Data Decision Analytics Research Centre, Hong Kong.
authors.forename: Kelvin K F
authors.initials: KK
authors.lastname: Tsoi
authors.affiliation: Jockey Club School of Public Health and Primary Care, Hong Kong.
authors.forename: Joyce Y C
authors.initials: JY
authors.lastname: Chan
authors.affiliation: Jockey Club School of Public Health and Primary Care, Hong Kong.
authors.forename: Nelson W Y
authors.initials: NW
authors.lastname: Leung
authors.affiliation: Jockey Club School of Public Health and Primary Care, Hong Kong; Stanley Ho Big Data Decision Analytics Research Centre, Hong Kong.
authors.forename: Hoyee W
authors.initials: HW
authors.lastname: Hirai
authors.affiliation: Jockey Club School of Public Health and Primary Care, Hong Kong.
authors.forename: Samuel Y S
authors.initials: SY
authors.lastname: Wong
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong. Electronic address: tkwok@cuhk.edu.hk.
authors.forename: Timothy C Y
authors.initials: TC
authors.lastname: Kwok
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy*; D005260:Female; D006801:Humans; D038622:Internationality; D008297:Male; D019338:Polypharmacy; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
keywords: AChEI; Alzheimer disease; Combination; memantine; monotherapy