Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Selegiline or α-tocopherol slowed the progression of Alzheimer disease

ACP J Club. 1997 Nov-Dec;127:67. doi:10.7326/ACPJC-1997-127-3-067


Source Citation

Sano M, Ernesto C, Thomas RG, et al., for the members of the Alzheimer's Disease Cooperative Study. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med. 1997 Apr 24;336:1216-22.


Abstract

Objective

To compare the effectiveness of selegiline, α-tocopherol, or a combination of both with placebo in slowing the clinical progression of Alzheimer disease (AD).

Design

Randomized, double-blind, placebo-controlled trial with 2-year follow-up.

Setting

23 clinical centers in the United States.

Patients

341 patients (mean age 73 y, 65% women) with probable AD of moderate severity who were free of other central nervous system diseases, were not taking psychoactive medications, and were living at home or in a supervised setting without skilled nursing attendants.

Intervention

87 patients were allocated to selegiline, 5 mg twice a day; 85 patients were allocated to α-tocopherol vitamin E, 1000 IU twice a day; 85 patients were allocated to a combination of the 2 agents; and 84 patients were allocated to placebo. Both agents were given in the morning and afternoon.

Main outcome measures

The primary outcome was the time to the occurrence of any 1 of the following: death, institutionalization, loss of the ability to perform ≥ 2 of the 3 basic activities of daily living, or severe dementia. Secondary outcome measures included cognition, activities of daily living, behavior, and the presence or absence of extrapyramidal signs.

Main results

Analysis was by intention to treat. In unadjusted analyses, no differences existed between the groups for the primary or secondary outcome measures. After adjustment for baseline score on the Mini-Mental State Examination and using the Cox proportional-hazards model, delays occurred in the time to the primary outcome for patients in the selegiline group (median delay 655 d, P = 0.012), α-tocopherol group (median delay 670 d, P = 0.001), and the combined therapy group (median delay 585 d, P = 0.049) when compared with the placebo group (median delay 440 d). The difference shown between the treatment groups primarily resulted from an increased need to institutionalize patients in the placebo group (P = 0.003 for placebo compared with α-tocopherol). A benefit with treatment was shown for improvement in cognitive and behavioral symptoms. No differences existed between the treatment groups for all other secondary outcome measures. Falls were increased for treatment groups (P < 0.005) compared with placebo.

Conclusion

Selegiline or α-tocopherol slowed the progression of Alzheimer disease in patients with moderate impairment.

Source of funding: National Institutes of Health.

For article reprint: Dr. M. Sano, 630 West 168th Street, Box 16, New York, NY 10032, USA. FAX 212-305-2426.


Commentary

The failure of neurotransmitter enhancers, exemplified by tacrine and donepezil, to alter the underlying process of AD has led researchers to investigate agents that interfere with neuronal degeneration. Mounting evidence suggests that neuronal loss in AD is mediated by inflammation (involving free radicals) and that anti-inflammatory drugs may delay the onset and progression of AD. Estrogen may play a neuroprotective role in women. However, concern about the efficacy, safety, and compliance problems of these agents currently precludes their prescription for AD. Robust evidence that a relatively inexpensive, nonprescription anti-oxidant vitamin slows the progression of AD could radically alter current treatment recommendations.

Sano and colleagues were able to show the beneficial effects of selegiline and high-dose α-tocopherol only after adjustment for the small difference in mental status between the control and treatment groups, a statistical manipulation that creates uncertainty about the validity of the results. The reduced institutionalization in the α-tocopherol group compared with the placebo group may be a proxy for an unknown treatment effect but is consistent with the slower decline on the Blessed Dementia Scale, which measures activities of daily living. Unanswered questions remain about which antioxidants to recommend, at what doses they should be taken, and whether supplements increase the benefit of a normal dietary intake. A longitudinal study of 442 elderly persons found a statistical association of serum levels of the antioxidants ascorbic acid and β-carotene—but not α-tocopherol—with better memory (1). No difference in memory existed between persons who received and those who did not receive supplemental vitamins.

It is premature to declare vitamin E an effective treatment for AD, but clinicians no longer should disapprove of the decision by nearly half of patients with AD and their families to take vitamin supplements as alternate therapy. Sano and colleagues make an important contribution by emphasizing the effect of treatment on functional independence rather than performance on cognitive scales, which have questionable clinical relevance in moderate-to-severe dementia.

Calvin H. Hirsch, MD
University of CaliforniaSacramento, California, USA


Reference

1. Perrig WJ, Perrig P, Stahelin HB. The relation between antioxidants and memory performance in the old and very old. J Am Geriatr Soc. 1997;45:718-24.