CLINICAL QUESTION

What are the safest and most effective cognitive enhancers for patients with different stages of Alzheimer dementia?

BOTTOM LINE

The study found much larger improvements in the Mini-Mental State Examination (MMSE) score (some that exceed the minimal clinically important difference [MCID]) with older drugs. For patients with mild to moderate dementia, donepezil (Aricept) or transdermal rivastigmine (Exelon) is the best initial choice; for patients with moderate to severe dementia, the combination of donepezil and memantine is most effective. Although new anti-amyloid monoclonal antibodies slow the decline of Alzheimer dementia, they do not come close to achieving clinically meaningful change in the MCID after 18 to 24 months. (Level of Evidence = 1a–)

SYNOPSIS

Cognitive enhancers are in an older category of medication intended to improve function in patients with Alzheimer dementia; these include three cholinesterase inhibitors (galantamine [Razadyne], donepezil, rivastigmine) and the N-methyl-d-aspartate receptor antagonist memantine. The authors of this network meta-analysis identified 80 randomized trials with 21,138 patients for aggregate meta-analysis. They were able to obtain individual patient data for 12 trials. Studies had to report the change in the MMSE score as the primary benefit outcome. The MCID is the minimum change that a patient or caregiver would be likely to notice; the authors used 1.4 points for the MMSE, although others have used a range of 1 to 3 points. The authors report the results in several different ways, but the findings were generally consistent. Most studies enrolled patients with mild to moderate (n = 44) or moderate to severe (n = 11) dementia. For the overall analysis, donepezil (mean difference [MD] = 1.41 points; 95% CI, 0.51 to 2.32) and donepezil plus memantine (MD = 2.57 points; 95% CI, 0.07 to 5.07) had improvements that exceeded the MCID. For studies of mild to moderate dementia, donepezil significantly improved the MMSE score (MD = 1.68 points; 95% CI, 0.31 to 3.06), and transdermal rivastigmine showed a larger improvement (MD = 2.74; 95% CI, −0.68 to 6.16). The latter was not statistically significant but had the highest probability of being the most effective based on the P value (the P value is the probability that a given therapy is likely to be the most effective). For studies of moderate to severe dementia, the combination of donepezil plus memantine was most effective (MD = 2.49; 95% CI, 1.55 to 3.44). Donepezil (MD = 1.31 points) and memantine (MD = 0.69 points) also significantly improved the MMSE score, but the change did not exceed the MCID. In terms of harms, oral rivastigmine significantly worsened the MMSE score for patients with moderate to severe dementia and shared the worst adverse event profile with donepezil, although confidence intervals were wide. Most studies were relatively short in duration (most commonly 24 weeks), and these drugs are not known to affect the progression of the disease.