Naproxen, Celecoxib Do Not Prevent Alzheimer's Disease

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April 27, 2007 — Primary-end-point results from the controversial AD Anti-inflammatory Prevention Trial (ADAPT) show no protection from Alzheimer's disease (AD) among undemented patients with a family history of the disease from treatment with either naproxen or celecoxib (Celebrex, Pfizer), at least in the first few years.

The results do not support the hypothesis generated by observational studies suggesting that sustained use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a protective effect against the disease, the authors note.

"Although our study was conducted to test the hypothesis that celecoxib or naproxen would reduce the incidence of Alzheimer's disease, these results indicate no such effect, at least within the first few years after treatment begins," said study author Constantine Lyketsos, MD, from Johns Hopkins Bayview Hospital and Johns Hopkins School of Medicine, in Baltimore, Maryland, in a statement from the American Academy of Neurology (AAN).

Results of ADAPT were published online April 25 in Neurology.

Decision Under Fire

The ADAPT trial was stopped in December 2004 after it was found that there was an increase in cardiovascular events in the naproxen group vs placebo, and a public warning was issued about the safety of naproxen. At the same time, increased cardiovascular risks with celecoxib were reported from another trial, the Adenoma Prevention with Celecoxib (APC) trial looking at the use of celecoxib to prevent colon polyps.

In a previous publication examining the cardiovascular safety end points in ADAPT, the researchers noted that the termination of both the celecoxib and naproxen groups of their trial "reflected the ADAPT investigators' reluctance to imply, by continuing the trial, that naproxen was safer than celecoxib, when ADAPT data did not support this conclusion." (ADAPT Research Group. PLoS Clin Trials 2006;1:e33.)

However, the decision was widely criticized because the data suggesting harm with naproxen was not definitive. The ADAPT investigators acknowledged that, under ordinary circumstances, the safety results with naproxen would not have warranted stopping the study. "Nonetheless, after the APC announcements, the ADAPT investigators were fundamentally uncomfortable with continuing naproxen simply because highly publicized external circumstances had spotlighted risks with celecoxib, but not with naproxen," they wrote.

Their decision was roundly criticized, however, perhaps most vocally by Steven Nissen, MD, from the Cleveland Clinic, in Ohio, who was the author of an editorial accompanying the paper and wrote: "Both the termination of this trial and the issuance of a public warning about naproxen were inappropriate and reflected faulty logic." (Nissen SE. PLoS Clin Trials 2006;1: e35.)

The researchers had further pointed out that ADAPT was a primary prevention trial and as such would have a lower tolerance for risks associated with the treatments. The only benefit of the intervention "is the possibility of later protection from a condition that they might have avoided in any case."

In this paper, the researchers examine the efficacy end points in ADAPT, the main outcome being a diagnosis of AD after randomization, and in the end, found no benefit from either treatment, at least in the early years after treatment initiation prior to stopping the trial.

Primary-End-Point Results

ADAPT was a randomized, double-blind trial comparing celecoxib 200 mg twice a day or naproxen 220 mg twice per day with placebo. Some 2538 subjects were enrolled from 6 US dementia research clinics; eligible participants were above designated cutoffs on cognitive screening scores but had a family history of AD. Median follow-up was about 730 days in each group.

The main outcome measure, a diagnosis of AD after randomization, was not significantly reduced by treatment with either agent compared with placebo over that period.

ADAPT: AD Risk With Celecoxib or Naproxen vs Placebo
Comparison Hazard Ratio 95% CI P 
Celecoxib vs placebo 1.99 0.80 – 4.97 .14
Naproxen vs placebo 2.35 0.95 – 5.77 .06


"Imperfect screening measures led to enrollment of 7 individuals with dementia and 46 others with milder cognitive syndromes," the authors note. Their prevalent disease was detected at enrollment and diagnosed within 6 months of randomization, they add. Secondary analyses that excluded these 7 patients showed increased hazard ratios for AD with both of the study agents.

"These results do not suggest a reduction in the occurrence of AD with either NSAID but, if anything, the reverse," they write. Neither treatment had any effect on the incidence of milder cognitive syndromes.

The authors conclude by urging that continued masked observation of the ADAPT cohort be undertaken. "Because the observational data suggest NSAIDs may have protective effects for individuals with 'healthier' brains (ie, for those whose onset of AD would be some years in the future), continued observations in the ADAPT cohort could show mitigation — or even reversal — of the treatment effects that presently appear null or negative."

For now, they write, these treatments are not indicated for the prevention of AD. "By contrast, our findings are too limited to be considered evidence that persons at risk for AD should avoid these or other NSAIDs when used for their approved indication."

More Questions Than Answers

Ronald Petersen, MD, from the Mayo Clinic in Rochester, Minnesota, was asked for comment on these findings by Medscape. "The NSAID story has been a sort of a mixed one over the years, with some pretty good epidemiologic data supporting the possibility that in fact some of the NSAIDs may be protective against developing AD," he said. "And yet virtually all of the treatment trials, either in the mild cognitive impairment stage or in mild AD, have virtually been negative."

Because of this divergent finding, the authors have speculated that to be beneficial, NSAID treatment may have to come at a more specific point in the disease process, similar to speculation that has been put forward about the risks and benefits of estrogen treatment.

"I think those are interesting speculations," he said. "Of course, the study itself doesn't give you the answers as such, but as is often the case, it raises these interesting questions."

The challenge with continued follow-up of this cohort, though, relates to its being prematurely stopped due to safety concerns, he noted. "Trying to keep the cohort together to allow long-term observation and follow-up is kind of a challenge when the study is halted, and in tough funding times that everybody's experiencing at [the National Institutes of Health], that's just compounding the situation."
 
The study was supported by the National Institute on Aging.

Neurology. Published online April 25, 2007.