Acetylcholinesterase inhibitors combined with memantine for moderate to severe Alzheimer's disease: A meta-analysis

Glinz Dominik, L. Gloy Viktoria, U. Monsch Andreas, W. Kressig Reto, Patel Chandni, McCord Kimberly Alba, Ademi Zanfina, Tomonaga Yuki, Schwenkglenks Matthias, C. Bucher Heiner, Raatz Heike

Research output: Contribution to journalReview ArticleResearchpeer-review

29 Citations (Scopus)


BACKGROUND: The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with Alzheimer's disease is inconclusive. AIMS OF THE STUDY. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the clinical efficacy and safety of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate to severe Alzheimer's disease (Mini-Mental State Examination score is <20). METHODS: We systematically searched EMBASE, Medline and CENTRAL until February 2018 for eligible RCTs. We pooled the outcome data using inverse variance weighting models assuming random effects, and assessed the quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included nine RCTs (2604 patients). At short-term follow-up (closest to 6 months), combination therapy compared to AChEI monotherapy had a significantly greater effect on cognition than AChEI monotherapy (standardised mean difference [SMD] 0.20, 95% confidence interval [CI] 0.05 to 0.35, 7 RCTs, low QoE) and clinical global impression (SMD -0.15, 95% CI -0.28 to -0.01, 4 RCTs, moderate QoE), but not on activities of daily living (SMD 0.09, 95% CI -0.01 to 0.18, 5 RCTs, moderate QoE) or behavioural and psychological symptoms of dementia (mean difference -3.07, 95% CI -6.53 to 0.38, 6 RCT, low QoE). There was no significant difference in adverse events (relative risk ratio 1.05, 95% CI 0.98 to 1.12, 4 RCTs, low QoE). Evidence for long-term follow-up (= 9 months) or nursing home placement was sparse. Only two studies compared combination therapy with memantine monotherapy. CONCLUSIONS: Combination therapy had statistically significant effects on cognition and clinical global impression. The clinical relevance of these effects is uncertain. The overall QoE was very low. With the current evidence, it remains unclear whether combination therapy adds any benefit. Large pragmatic RCTs with long-term follow-up and focus on functional outcomes, delay in nursing home placement and adverse events are needed.

Original languageEnglish
Article numberw20093
Number of pages12
JournalSwiss Medical Weekly
Issue number25-26
Publication statusPublished - 17 Jun 2019


  • Alzheimer's
  • Cholinesterase inhibitor
  • Dementia
  • Drug treatment
  • Memantine

Cite this