Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment
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《新英格兰医药杂志》
To the Editor: Petersen et al. (June 9 issue)1 report in their randomized, controlled trial of vitamin E, donepezil, and placebo in subjects with amnestic mild cognitive impairment that apolipoprotein E (APOE) 4 status had "a major modifying effect" and that "the benefit of donepezil was evident throughout the three-year follow-up" among carriers of APOE 4 alleles. This finding differs from those of prior studies in patients with Alzheimer's disease, which suggest that there is either no difference in the effect of cholinesterase inhibitors according to APOE 4 status2,3 or that there is a stronger treatment effect among noncarriers of APOE 4 alleles than among carriers.4,5 To determine whether APOE 4 status truly modified the effect in this study, it would be useful to know whether the APOE 4 subgroup analysis was prespecified or exploratory, what the hazard ratio was for donepezil among APOE 4 noncarriers, and the P value for the interaction between APOE 4 status and treatment group. We also commend the authors' sensitivity analysis and are curious to know the results of a more conservative, worst-case-scenario approach, in which all of the excess dropouts are assumed to have had progression to dementia.
Deborah E. Barnes, Ph.D., M.P.H.
Kristine Yaffe, M.D.
University of California, San Francisco
San Francisco, CA 94121
barnes@medicine.ucsf.edu
Dr. Yaffe reports having received research support from Pfizer.
References
Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379-2388.
Rigaud AS, Traykov L, Latour F, Couderc R, Moulin F, Forette F. Presence or absence of at least one epsilon 4 allele and gender are not predictive for the response to donepezil treatment in Alzheimer's disease. Pharmacogenetics 2002;12:415-420.
Rigaud AS, Traykov L, Caputo L, et al. The apolipoprotein E epsilon4 allele and the response to tacrine therapy in Alzheimer's disease. Eur J Neurol 2000;7:255-258.
Poirier J, Delisle M-C, Quirion R, et al. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci U S A 1995;92:12260-12264.
Farlow MR, Lahiri DK, Poirier J, Davignon J, Schneider L, Hui SL. Treatment outcome of tacrine therapy depends on apolipoprotein genotype and gender of the subjects with Alzheimer's disease. Neurology 1998;50:669-677.
The authors reply: We believe that our data do not necessarily imply that donepezil is effective for mild cognitive impairment only in APOE 4 carriers. The APOE 4 subset analysis over 36 months of follow-up was prespecified in the statistical-analysis plan. The additional 12-month and 24-month analyses were exploratory. The hazard ratios for the APOE 4 noncarriers were as follows: at 12 months, 0.66 (P=0.44); at 24 months, 1.02 (P=0.97); and at 36 months, 1.37 (P=0.37).
As stated in the article, in the sensitivity analysis, we used a very conservative assumption that the rate of progression to Alzheimer's disease among the 24 excess dropouts was approximately 25 percent per year (6 of 24), which is quite high. Therefore, it is not surprising that an analysis of the worst-case scenario, in which the rate of progression would be 100 percent (24 of 24), would not demonstrate a statistically significant difference between the two groups. In summary, although no effect would be found under this set of circumstances, the likelihood of this scenario is extremely low.
Ronald C. Petersen, Ph.D., M.D.
Mayo Clinic College of Medicine
Rochester, MN 55905
peter8@mayo.edu
Ronald G. Thomas, Ph.D.
Leon J. Thal, M.D.
University of California, San Diego
La Jolla, CA 92093
Deborah E. Barnes, Ph.D., M.P.H.
Kristine Yaffe, M.D.
University of California, San Francisco
San Francisco, CA 94121
barnes@medicine.ucsf.edu
Dr. Yaffe reports having received research support from Pfizer.
References
Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379-2388.
Rigaud AS, Traykov L, Latour F, Couderc R, Moulin F, Forette F. Presence or absence of at least one epsilon 4 allele and gender are not predictive for the response to donepezil treatment in Alzheimer's disease. Pharmacogenetics 2002;12:415-420.
Rigaud AS, Traykov L, Caputo L, et al. The apolipoprotein E epsilon4 allele and the response to tacrine therapy in Alzheimer's disease. Eur J Neurol 2000;7:255-258.
Poirier J, Delisle M-C, Quirion R, et al. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci U S A 1995;92:12260-12264.
Farlow MR, Lahiri DK, Poirier J, Davignon J, Schneider L, Hui SL. Treatment outcome of tacrine therapy depends on apolipoprotein genotype and gender of the subjects with Alzheimer's disease. Neurology 1998;50:669-677.
The authors reply: We believe that our data do not necessarily imply that donepezil is effective for mild cognitive impairment only in APOE 4 carriers. The APOE 4 subset analysis over 36 months of follow-up was prespecified in the statistical-analysis plan. The additional 12-month and 24-month analyses were exploratory. The hazard ratios for the APOE 4 noncarriers were as follows: at 12 months, 0.66 (P=0.44); at 24 months, 1.02 (P=0.97); and at 36 months, 1.37 (P=0.37).
As stated in the article, in the sensitivity analysis, we used a very conservative assumption that the rate of progression to Alzheimer's disease among the 24 excess dropouts was approximately 25 percent per year (6 of 24), which is quite high. Therefore, it is not surprising that an analysis of the worst-case scenario, in which the rate of progression would be 100 percent (24 of 24), would not demonstrate a statistically significant difference between the two groups. In summary, although no effect would be found under this set of circumstances, the likelihood of this scenario is extremely low.
Ronald C. Petersen, Ph.D., M.D.
Mayo Clinic College of Medicine
Rochester, MN 55905
peter8@mayo.edu
Ronald G. Thomas, Ph.D.
Leon J. Thal, M.D.
University of California, San Diego
La Jolla, CA 92093