Therapeutics

Review: Cholinesterase inhibitors do not prevent dementia in patients with mild cognitive impairment

Cooper C, Li R, Lyketsos C, Livingston G. Treatment for mild cognitive impairment: systematic review. Br J Psychiatry. 2013; 203:255-64.

Clinical impact ratings: F ★★★★★★✩ G ★★★★★★✩ N ★★★★★★✩ Question

Main results

What is the effectiveness of interventions for mild cognitive impairment (MCI)?

Results for study-reported primary outcomes are shown in the Table.

Review scope

Conclusions

Included studies evaluated ≥ 1 intervention for MCI. Outcomes included cognition and incident dementia.

In mild cognitive impairment, cholinesterase inhibitors do not prevent dementia; evidence is insufficient for improved cognition. Evidence is insufficient for other interventions.

Review methods MEDLINE, CINAHL, PsycINFO, Web of Science, AMED, and Cochrane Database of Systematic Reviews to Jan 2013; and reference lists were searched for randomized controlled trials (RCTs). Experts were contacted. 42 RCTs {n = 7803}* met the selection criteria; 17 were rated as high quality (≥ 4 of 5 criteria). 9 RCTs evaluated cholinesterase inhibitors (ChEIs); 5 exercise therapy; 4 group psychological interventions; 3 computer-assisted cognitive training; and 2 each of nonsteroidal antiinflammatory drugs, ginkgo biloba, B vitamins, vitamin E, and omega-3 polyunsaturated fatty acids. Other interventions were evaluated in single trials and are not reported here. 25 RCTs defined MCI using Petersen criteria; other RCTs used other MCI definitions, Mini-Mental State Examination criteria and subjective or objective memory impairments, or other measures.

*Based on information provided by author.

Source of funding: No external funding. For correspondence: Dr. C. Cooper, University College London, London, England, UK. E-mail [email protected]. ■

Commentary

Of the 42 RCTs evaluated by Cooper and colleagues, 25 met < 4 of the 5 criteria for validity. The authors standardized outcomes to compare the magnitude of effect of diverse pharmacologic and nonpharmacologic interventions; however, such standardization may conceal important clinical differences in effects. Most RCTs used outcome measures of questionable clinical relevance. Some, such as the Alzheimer Disease Assessment Scale–Cognitive subscale (ADAS-Cog), were developed for patients with Alzheimer disease (AD) and Interventions for mild cognitive impairment† may have ceiling effects or insensitivity to change (1). The Interventions Selected findings for study-reported primary outcomes failure of many RCTs to differentiate MCI subtypes, Cholinesterase No benefit with donepezil at 3 y (1 RCT, n = 516), galantamine which have different prognoses, complicates comparisons. inhibitors at 2 y (2 RCTs, n = 2048), or rivastigmine at Cooper and colleagues’ review supports the conclusion of a 2 y (1 RCT, n = 1018) vs placebo for incident AD/dementia recent Cochrane analysis (2) that ChEIs do not reduce the Donepezil improved cognitive function at 48 wk incidence of dementia. Intolerance to ChEIs seems to be (1 RCT, n = 757, ADAS-Cog SMD 0.10, 95% CI 0.03 to 0.20) greater in MCI than in AD trials, with discontinuation rates but not delayed recall at 24 wk (1 RCT, n = 270) vs placebo of 18% vs 10% (1). Although ChEIs were associated with No benefit with rivastigmine vs placebo on a cognitive better scores on the ADAS-Cog than with placebo in 1 RCT test battery at 2 y (1 RCT, n = 1018) in MCI, the magnitude of response was clinically meaningless NSAIDs Rofecoxib increased risk for incident AD at < 4 y vs placebo (1). Some nonpharmacologic interventions for MCI were (1 RCT, n = 257, hazard ratio 1.46, CI 1.09 to 1.94) promising. For example, a 6-month cognitive intervention in No benefit with triflusal vs placebo for cognitive function at a small trial of patients with amnestic MCI (3) had a 10-fold 13 mo (1 RCT, n = 257) greater relative improvement on the ADAS-Cog than that seen in a 48-week trial of donepezil (1). The cognitive interGinkgo biloba No benefit vs placebo for preventing incident AD/dementia vention also improved symptoms of depression, which often at 6 y (1 RCT, n = 482) accompany MCI and are associated with twice the risk for Improved memory (SMC 0.42, CI 0.05 to 0.80) and nonsense dementia than MCI without depression (2). picture recognition (SMC 0.46, CI 0.09 to 0.84) at 6 mo vs usual care (1 RCT, n = 120) Whether starting ChEIs during MCI can change the trajecVitamin E No benefit vs placebo for preventing incident AD at 3 y (1 RCT, n = 512) tory of symptoms after AD has begun is unknown. Limited evidence from an open-label follow-up of an RCT in patients B vitamins No benefit vs placebo for immediate memory at 6 mo (1 RCT, n = 152) with early AD suggested that continuous treatment with Omega-3 PUFAs Improved cognition (ADAS-Cog) at 6 mo vs placebo in donepezil led to better cognitive and functional abilities after adjusted analysis (1 RCT, n = 23) 3 years than delaying donepezil for 1 year (4). Exercise interventions No benefit with moderate-intensity group walking program vs a low-intensity active control for word recall at 1 y (1 RCT, n = 152) Group psychological interventions

6-mo mixed intervention improved cognition vs a placebo intervention (ADAS-Cog SMD 1.00, CI 0.60 to 1.90, 1 RCT, n = 22) 6-wk targeted intervention improved processing speed (P < 0.001) and reasoning (P < 0.05) but not memory at 2 y vs no treatment (1 RCT, n = 193)

Computer-assisted cognitive training

No benefit with a mixed training strategy vs a no-training group on a cognitive test battery at 6 wk (1 RCT, n = 47)

†AD = Alzheimer disease; ADAS-Cog = Alzheimer’s Disease Assessment Scale–Cognitive subscale; NSAID = nonsteroidal antiinflammatory drug; PUFA = polyunsaturated fatty acid; RCT = randomized controlled trial; SM(C/D) = standardized mean (change/difference).

15 April 2014 | ACP Journal Club | Volume 160 • Number 8

Calvin Hirsch, MD University of California, Davis Medical Center Sacramento, California, USA References 1. Doody RS, Ferris SH, Salloway S, et al. Neurology. 2009;72:1555-61. 2. Russ TC, Morling JR. Cochrane Database Syst Rev. 2012;9: CD009132. 3. Buschert VC, Friese U, Teipel SJ, et al. J Alzheimers Dis. 2011;25: 679-94. 4. Winblad B, Wimo A, Engedal K, et al. Dement Geriatr Cogn Disord. 2006;21:353-63. © 2014 American College of Physicians

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ACP Journal Club. Review: Cholinesterase inhibitors do not prevent dementia in patients with mild cognitive impairment.

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