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Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment

Background: Amnestic mild cognitive impairment is a transitional state to Alzheimer’s disease. Cholinesterase inhibitors are recommended for use in patients with mild to moderate Alzheimer’s disease and may be an effective option to slow progression to Alzheimer’s disease in patients with mild cognitive impairment.

Objective: The study was designed to determine if treatment with vitamin E or donepezil could delay a clinical diagnosis of Alzheimer’s disease in patients with amnestic mild cognitive impairment.

Methods: This represented a randomized, double-blind, placebo controlled, parallel group study, collecting data for 3 years. Seven hundred sixty nine subjects were enrolled from 69 Alzheimer’s Disease Cooperative Study sites. Inclusion criteria consisted of a diagnosis of degenerative amnestic mild cognitive impairment, age 55 to 90 years, Mini Mental Status Exam (MMSE) score of 24-30, impaired memory, a logical memory delayed recall score below normal, adequate vision and hearing, normal vitamin B12 and thyroid function, normal electrocardiogram, and an appropriate Clinical Dementia Rating (CDR) score. Exclusion criteria consisted of significant cerebral vascular disease, depression (Hamilton Depression rating Scale >12), central nervous system infarct, medical diseases or psychiatric disorders that could possibly interfere with study participation, pregnancy, lactation, taking vitamin supplements, and restrictions on concomitant medication usage. Subjects were randomized to three difference treatment regimens: 2000IU Vitamin E, donepezil placebo, and a multivitamin (257 subjects) , or 10 mg donepezil, Vitamin E placebo, and a multivitamin (253 subjects), or vitamin E and donepezil placebo and a multivitamin (259 subjects). The primary outcome was the time to the development of possible or probable Alzheimer’s disease. Secondary measures included scores for the MMSE, Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog), global CDR, CDR sum of boxes, ADCS Mild Cognitive Impairment Activities of Daily Living Scale, Global Deterioration Scale, and the neuropyschological battery test. The intention to treat principle was used for the primary analysis. The Cox proportional-hazards model was used to derive hazard ratios, Hochberg method was used to adjust the two p values for multiple comparisons, Schoenfeld residual test was used to test for nonproportional hazards, and the z-test was used to compare estimated survival rates at various points on the Kaplan-Meier curves.

Results: Due to deaths, adverse events, and withdrawal of consent only 522 subjects completed the study, 180 in the vitamin E group, 154 in the donepezil group, and 188 in the placebo group. There were no significant differences between placebo and Vitamin E at any time during the study. For the first 12 months of the study, the risk of progression to AD was lower in the donepezil group than in the placebo group (p=0.004 at 6 months, p=0.04 at 12 months) with 16 patients in the donepezil group and 18 patients in the placebo group developing Alzheimer’s disease. However, at 36 months there were no significant differences between vitamin E and placebo (hazard ratio 1.02, 95% CI 0.74-1.41, p=0.91) or donepezil and placebo (hazard ratio 0.80, 95% CI 0.57-1.13, p=0.42). The number of subjects progressing to AD after 36 months was 73 in the placebo group, 76 in the vitamin E group, and 63 in the donepezil group. Few significant differences were reported between vitamin E and placebo for secondary outcome measures. Exceptions included executive, language, and overall cognition. Significant differences in secondary outcomes were seen with donepezil compared to placebo including MMSE scores, CDR sum of boxes, Global Deterioration Scale, modified ADAS-COG, memory, language, and overall cognitive scores. For both vitamin E and donepezil compared to placebo, these differences were significant only within the first 18 months. This study has shown preliminary evidence that the APO e4 allele is a predictor of progression to AD. Seventy six percent of the subjects that progressed to AD were carriers of this gene and donepezil appeared to reduce their risk of progression to AD by one-third at year three. The authors concluded that over the three-year study, there were no significant difference between vitamin E or donepezil compared to placebo. Analysis of the study results at six-month intervals showed donepezil had a lower rate of progression to AD in the first 12 months.

Strengths: The study design was appropriate to help minimize bias, to determine if the effects of the active drugs were significant over placebo, and to reinforce balanced groups. The dose of donepezil was standardized to current treatment guidelines and both donepezil and vitamin E were titrated up appropriately. Given that the study centered on nominal data, the Cox proportional-hazard model was used effectively.

Weaknesses: No power was given in the study, thus making it more difficult to examine Type II error. In addition, a sub analysis of the APOE4 was conducted, however because power was not addressed, in this group, we have an even greater possibility of Type II error. Compliance was not addressed which could have a profound effect on the study results. In future studies compliance should be implemented. The intention to treat analysis was used, however given this study design, per protocol, or a combination of per protocol and intention to treat should be used due to the large drop out rate. Unblinding was not addressed, however due to the side effect profile of donepezil, unblinding could have occurred. In the inclusion/exclusion criteria no mention was given to family history of AD in the subjects. This should be addressed due to the genetic prevalence of AD. Also, a treatment group combining vitamin E and donepezil compared to placebo should be added to determine the added benefit of the drugs together.

Conclusions: The study did not report sufficient data supporting the use of donepezil or vitamin E in the overall progression from amnestic mild cognitive impairment to AD. Donepezil did have a significant difference for the first 12 months of the study, however vitamin E was insignificant throughout the entire course of the treatment. Future studies should be done addressing the effectiveness of a fourth treatment group including both donepezil and vitamin E compared to placebo, as well as compliance and the correlation between AD, APOE e4, and donepezil.

Petersen RC, Thomas RG, Grundman M, Benneett D, Doody R, Ferris S, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379-2387

Emily DeVault, Pharm.D. Candidate