Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis

Abstract

Pharmacologic treatments for Alzheimer's disease include the cholinesterase inhibitors donepezil, galantamine, and rivastigmine. We reviewed their evidence by searching MEDLINE, Embase, The Cochrane Library, and the International Pharmaceutical Abstracts from 1980 through 2007 (July) for placebo-controlled and comparative trials assessing cognition, function, behavior, global change, and safety. Thirty-three articles on 26 studies were included in the review. Meta-analyses of placebo-controlled data support the drugs' modest overall benefits for stabilizing or slowing decline in cognition, function, behavior, and clinical global change. Three open-label trials and one double-blind randomized trial directly compared donepezil with galantamine and rivastigmine. Results are conflicting; two studies suggest no differences in efficacy between compared drugs, while one study found donepezil to be more efficacious than galantamine, and one study found rivastigmine to be more efficacious than donepezil. Adjusted indirect comparison of placebo-controlled data did not find statistically significant differences among drugs with regard to cognition, but found the relative risk of global response to be better with donepezil and rivastigmine compared with galantamine (relative risk = 1.63 and 1.42, respectively). Indirect comparisons also favored donepezil over galantamine with regard to behavior. Across trials, the incidence of adverse events was generally lowest for donepezil and highest for rivastigmine.

Figure 1

Meta-analysis of cognitive outcomes (ADAS-cog) for active treatment compared with placebo. Notes: ^aLimited to doses recommended by product labeling. Abbreviations: WMD, Weighted Mean Difference; PRC, Prolonged Release Capsule; CI, Confidence Interval; ADAS-cog, Alzheimer’s Disease Assessment Scale-Cognitive section.

Figure 2

Meta-analysis of functional outcomes for active treatment compared with placebo. Notes: ^aLimited to doses recommended by product labeling. Abbreviations: SMD, Standardized Mean Difference; PRC, Prolonged Release Capsule; CI, Confidence Interval; ADCS/ADL, Alzheimer’s Disease Cooperative Studies Activities of Daily Living Inventory; ADFACS, Alzheimer’s Disease Functional Assessment and Change Scale; BADLS, Bristol Activities of Daily Living Scale; CMCS, Caregiver-rated Modified Crichton Scale; DAD, Disability Assessment for Dementia; IDDD, Interview for Deterioration in Daily living activities in Dementia; NOSGER-IADL, Nurses Observation Scale for Geriatric Patients Activities of Daily Living; PDS, Progressive Deterioration Scale.

Figure 3

Meta-analysis of behavior outcomes for active treatment compared with placebo. Notes: ^aLimited to doses recommended by product labeling. Abbreviations: WMD, Weighted Mean Difference; PRC, Prolonged Release Capsule; CI, Confidence Interval; NPI, Neuropsychiatric Inventory.

Figure 4

Meta-analysis of clinical global assessment of change for active treatment compared with placebo. Notes: ^aLimited to doses recommended by product labeling. Abbreviations: RR, Relative Risk; PRC, Prolonged Release Capsule; CI, Confidence Interval; CIBIC+, Clinician Interview-Based Impression of Change Incorporating Caregiver Information.

Figure 5

Comparative evidence for donepezil, galantamine, and rivastigminea. Notes: ^aLimited to comparisons with sufficient data for a single outcome measure and to doses recommended by product labeling. Abbreviations : WMD, Weighted Mean Difference (reflects the pooled difference for Drug A – Drug B); RR, Relative Risk (reflects the relative risk of responding with Drug B/Drug A); CI, Confidence Interval; ADAS-cog, Alzheimer’s Disease Assessment Scale-Cognitive section; NPI, Neuropsychiatric Inventory; CIBIC+, Clinician Interview-Based Impression of Change Incorporating Caregiver Information.

Appendix I

Literature review flow diagram.