NEJM：中重度阿尔茨海默病患者宜继续服用多奈哌齐

3月8日的《新英格兰医学杂志》(New England Journal of Medicine)上发表的一项随机试验显示，在接受多奈哌齐治疗后病情仍继续加重的中重度阿尔茨海默病(AD)患者中，与追加或转为美金刚以及停用AD药物治疗相比，继续多奈哌齐(爱忆欣)治疗显示出较小但显著的益处，表现为认知和功能性预后改善。该试验为期1年，名为DOMINO(多奈哌齐和美金刚治疗中重度阿尔茨海默病)研究，研究者为英国伦敦国王学院精神病学研究所的Robert Howard医生及其合作者。

当AD进展时，是继续原有治疗，还是更换治疗药物？注意到有关这一问题的证据很少，Howard医生及其同事对社区中居住的295例中重度AD患者进行了研究，这些患者已接受多奈哌齐治疗2-3年，其临床医生正在考虑更换治疗药物。所有患者的简易智力状态检查(SMMSE)评分介于5-13分之间，SMMSE的评分范围为0-30分；评分越高提示认知功能越好。研究者将患者随机分配到继续多奈哌齐治疗并加用安慰剂组(73例患者)、停用多奈哌齐并给予安慰剂组(73例患者)、停用多奈哌齐并改用美金刚组(76例患者)以及继续多奈哌齐治疗并加用美金刚组(73例患者)。

结果显示，在1年随访期间，137例患者(46%)退出研究，最常见的退出原因为感到继续治疗无效。继续多奈哌齐治疗者的SMMSE评分较停用多奈哌齐者高出1.9分。并且这些患者在护理者评估的60分Bristol日常生活活动量表(BADLS)评分方面也较停用多奈哌齐者高出3分，提示功能受损较少。与未使用美金刚的患者相比，接受美金刚治疗的患者SMMSE评分提高了1.2分，BADLS评分提高了1.5分。但从任何主要或次要终点来看，与单纯多奈哌齐治疗相比，联合治疗未提供任何有统计学意义的益处。

研究者总结认为，对于继续进展的AD患者，继续多奈哌齐治疗似乎是最好的选择，加用美金刚无显著的进一步获益。然而，相对于患者的认知和功能状态的降低，多奈哌齐和美金刚治疗的益处是很小的。（生物谷 bioon.com）

doi:10.1056/NEJMoa1106668
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Donepezil and Memantine for Moderate-to-Severe Alzheimer's Disease

Robert Howard, M.D., Rupert McShane, F.R.C.Psych., James Lindesay, D.M., Craig Ritchie, M.D., Ph.D., Ashley Baldwin, M.R.C.Psych., Robert Barber, M.D., Alistair Burns, F.R.C.Psych., Tom Dening, F.R.C.Psych., David Findlay, M.B., Ch.B., Clive Holmes, Ph.D., Alan Hughes, M.B., Ch.B., Robin Jacoby, D.M., Rob Jones, M.B., Ch.B., Roy Jones, M.B., Ian McKeith, F.Med.Sc., Ajay Macharouthu, M.R.C.Psych., John O'Brien, D.M., Peter Passmore, M.D., Bart Sheehan, M.D., Edmund Juszczak, M.Sc., Cornelius Katona, M.D., Robert Hills, D.Phil., Martin Knapp, Ph.D., Clive Ballard, M.D., Richard Brown, Ph.D., Sube Banerjee, M.D., Caroline Onions, P.G.Dip., Mary Griffin, R.G.N., Jessica Adams, B.Sc., Richard Gray, M.Sc., Tony Johnson, Ph.D., Peter Bentham, M.B., Ch.B., and Patrick Phillips, Ph.D.

Background Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. Methods We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini–Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. Results Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. Conclusions In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.)