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Randomised double blind placebo controlled trial.
40 ambulatory treatment centres associated with the Alzheimer’s Disease Cooperative Study, USA; December 1999 to November 2000.
351 people, aged 51 years or more, with mild to moderate Alzheimer’s disease (mini-mental state examination score 13 to 26). Concomitant use of cholinesterase inhibitors, oestrogen, aspirin and vitamin E were permitted. Those allergic to rofecoxib or naproxen, or with peptic ulcer, liver or kidney disease, poorly controlled hypertension, heart failure or bleeding disorder, or who were being treated with other antiinflammatory drugs or treatments for Alzheimer’s disease (other than those listed above), were excluded.
Rofecoxib 25 mg daily or naproxen 220 mg twice daily or placebo for 1 year.
Main outcome measures
The primary outcome was the change in the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) after 1 year. The ADAS-Cog is scored from 0 (no impairment) to 70 (profound impairment). Secondary outcomes included activities of daily living, quality of life, time to institutionalisation or death.
At 1 year, there were no significant differences in either cognitive decline (see table⇓) or any of the secondary outcome measures among groups.
The results show that neither naproxen nor rofecoxib slow cognitive decline in people with mild to moderate Alzheimer’s disease.
The role of estrogens and NSAIDs in the putative prevention or treatment of Alzheimer’s disease remains to be clarified. There is evidence that non-steroidal anti-inflammatory agents (NSAIDs) might affect both the metabolism of amyloid beta protein,1 and the incidence of Alzheimer’s disease.2 This paper describes an RCT in which participants with probable Alzheimer’s disease were randomised to a Cox-2 inhibitor (rofecoxib), a non-selective NSAID (naproxen), or placebo. The aim of the study was to determine whether NSAIDs slow disease progression. The primary outcome was performance on the Alzheimer’s Disease Assessment Scale, cognitive sub-score. Secondary outcomes included measures of activities of daily living and quality of life. The treatment period was one year.
In essence, the result of this trial was negative. Neither the primary nor secondary outcomes demonstrated any significant effect from NSAIDs. Since the study was probably powered adequately, and data were analysed on an intention to treat basis, it provides no support for the efficacy of these drugs in the treatment of Alzheimer’s disease over a 1 year period. It is possible that a longer period of treatment might be needed3 but difficult to see that this is likely. Given the epidemiological indication that NSAIDs might reduce the incidence of Alzheimer’s disease, research effort would, as the authors point out, now be better directed at a prevention study. For the time being there is no reason to change current clinical practice and begin to prescribe NSAIDs for treatment of Alzheimer’s disease. NSAIDs have significant adverse effects on the gastrointestinal and cardiovascular systems, especially in older people (the people who get Alzheimer’s disease), so that very clear evidence is needed before they are prescribed. These authors deserve credit for adding a little clarity to the debate.
Source of funding: This work was funded by the National Institute on Aging, from the General Clinical Research Center Program of the National Center for Research Resources, National Institutes of Health.
For correspondence: P Aisen. Department of Neurology, Georgetown University Medical Center, Bldg D, Suite 207, 4000 Reservoir Rd, NW, Washington, DC 20057. E-mail:
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