Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial
ADAPT Research Group , Lyketsos CG, Breitner JC, Green RC, Martin BK, Meinert C, et al.;
Commented by , 19 Jun 2007
Aim of the study
To evaluate the efficacy and safety of naproxen and celecoxib for the primary prevention of Alzheimer’s disease (AD).
Methods
In six US sites, volunteers recruited through mailings to Medicare beneficiaries age 70+ with cognitive scores above designated cut-offs and a family history of AD in one first-degree relative were randomized to celecoxib 200mg BID, to naproxen sodium 220mg BID or to placebo.
Screening for eligibility included the Mini Mental state Examination, the Hopkins Verbal Learning test-Revised and the informant-based Dementia Severity Rating Scale. Randomization was stratified by age groups (70-74, 75-79, 80+) and by six sites. The primary outcome was incident AD, diagnosed following DSM-IV and NINCDS-ADRDA criteria. Secondary outcomes included a Cognitive Assessment Battery (CAB). Visits or phone contacts were every 3 months, the CAB being done annually.
Results
The study was stopped at the end of its 4th year because of concern about the safety of celecoxib. At that time 2,528 participants had been recruited up to that time and 2,128 contributed to the analysis of cognitive outcomes. There was a trend for an increase risk of AD on active treatment: hazard ratio versus placebo of 1.99 (95% CI 0.80 to 4.97; p = 0.14) for celecoxib and 2.35 (95% CI 0.95 to 5.77; p = 0.06) for naproxen.
Professor Gauthier's comments
The conclusion from the authors of this study is that these two anti-inflammatory drugs do not appear to have a protective action in asymptomatic persons over age 69 with family history of AD as risk factor.
The design of this study is important because there will be other primary prevention studies in the future using non-pharmacological (physical and mental exercises with or without antioxidant and omega-3 diet enrichment) and pharmacological (possibly anti-amyloid agents such as tramiprosate and R-flurbiprofen). Furthermore there are on-going studies in US and Europe using Ginkgo Biloba.
Variations in entry criteria (family history of AD, subjective complaints, neither) will likely influence the incidence of AD, e.g. the likelihood of cases emerging from the cohort under study.
Does the failure of this study indicate that NSAIDS are not effective in the prevention of AD? No, because other agents such as ibuprofen still have to be tested in high enough doses and in the appropriate populations. Perhaps the new definition of "Predementia stage of AD" that will be proposed by Dubois et al. in Lancet Neurology later this year will facilitate research in this at risk population with studies of less than 3 years duration.