12 Apr 2019

Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) stave off dementia, but multiple clinical trials have failed to bear that out. Now, the most recent and, the authors say, final effort has come up short. In the INTREPAD trial, led by John Breitner, McGill University in Montreal, asymptomatic people in their 60s at high risk of Alzheimer’s disease took daily naproxen for two years. As published online April 5 in Neurology, the regimen did not affect their cognition or imaging and CSF markers, and may have even made the primary outcome, a composite of all these measures, a bit worse. What’s more, and as predicted, the drugs caused significant side effects, including gastrointestinal and cardiovascular problems.

Epidemiology has suggested NSAIDs curb risk of AD.

New study finds naproxen does not slow cognitive decline in people at high risk.

Previous failures, dangerous side effects, doom NSAID use for prevention.

Taken together with previous trials, INTREPAD should mark the end of the road for NSAIDs and AD prevention, the authors and several commentators agreed. “This is a good and important study that allows us to conclude that NSAIDs are just not going to be effective in this condition,” said Lon Schneider, University of Southern California Keck School of Medicine, Los Angeles. Eric Larson of the Kaiser Permanente Washington Health Research Institute in Seattle expressed similar sentiments. “The drugs caused enough harm to be detectable in a trial, and they produced no benefit. School is out for NSAIDs for prevention,” Larson said.

Breitner sees it the same way. “I do not think there should be any more clinical trials of NSAIDs for prevention or treatment of AD,” he said. “There was a lot of hope, based on epidemiological data, that these drugs would prove to be beneficial, but we’ve learned over the last 10 to 15 years that when you test NSAIDs in trials, they are not beneficial and invariably, you make people sick,” he added.

A two-decade stream of epidemiological studies linked the use of NSAIDs for chronic inflammatory conditions to a lower incidence of Alzheimer’s disease. The data fit a biological theory that inflammation stokes AD pathogenesis, and led to a series of trials of various NSAIDs for prevention. In the largest of those, ADAPT, people at high risk of AD due to a family history of the disease took daily doses of naproxen or celecoxib, and were monitored for age-related cognitive decline or onset of AD. The trial was supposed to run for five to seven years, but was stopped early due to concerns about cardiovascular safety. The truncated trial revealed no evidence for efficacy, but the data held out the possibility that naproxen could stem cognitive decline in people treated in the earliest presymptomatic stages (Breitner et al., 2011).

INTREPAD, described by co-first authors Pierre-Francois Meyer and Jennifer Tremblay-Mercier, was designed specifically to test naproxen in this earliest-stage, at-risk, but cognitively normal group. To join the study, people had to have a strong family history of AD, including a parent or multiple siblings, or both, with the disease. The researchers rigorously screened participants, mostly in their 60s, for what Breitner termed “cognitive fragility,” or any signs of decline or incipient dementia. The participants took 220 mg naproxen twice daily, or placebo.

For the trial, the investigators developed a new composite primary endpoint to track disease progression in asymptomatic volunteers. The Alzheimer Progression Score (APS) comprised the RBANS battery to measure cognitive decline, along with assessments of olfactory function, brain structure, cerebral blood flow, and, in half the volunteers, cerebrospinal fluid total tau and Aβ42. An increase in the APS signaled disease progression.

Over the two-year treatment period, the APS composite worsened in the group as a whole, but there was no difference in the rate of change between treatment and placebo groups. On the contrary, there was a trend for naproxen to promote progression, as reported for people with memory impairment in earlier studies. None of the individual endpoints benefitted from treatment.

Naproxen did cause more side effects, and more severe adverse events. Gastrointestinal complaints, constipation, shortness of breath, high blood pressure, and petechiae—small lesions caused by bleeding under the skin—were the most common. Serious vascular or cardiac events were also more common in the naproxen group.

The trial had limitations. The CSF measures were expected to enhance its power to detect changes, but did not. As a result, the trial was underpowered. In addition, the baseline composite scores of the treatment and placebo groups differed. In an accompanying editorial, Linda Hershey at the University of Oklahoma Health Center in Oklahoma City and Richard Lipton, Albert Einstein College of Medicine, Bronx, New York, raised the prospect that another trial with a different dose of naproxen, another NSAID, or a different high-risk group might produce a different result. Breitner and colleagues disagree. They believe that due to the lack of apparent benefit, and the demonstrated harm, further trials with NSAIDs would raise ethical concerns.

This is not the first time AD epidemiological data has not panned out in subsequent clinical trials. Other examples include estrogen replacement, rosiglitazone, statins, and others. It is unclear why the trial results are at odds with the epidemiological data. In the case of NSAIDs, perhaps their use is merely an indicator for an underlying immune response that spares people from AD. “I don’t think we can exclude that possibility, based on everything we’ve done up to this point,” Breitner said.

Gregory Cole, University of California, Los Angeles, pointed out that the dosing regimen could be critical: Using NSAIDS intermittently, as many people do, versus the constant exposure in the trial, could modulate the immune system differently (see comment below).

Piet Eikelenboom, Vrije University in Amsterdam, has pioneered research into inflammatory processes in aging and Alzheimer’s. He argues that the original rationale for NSAID treatment may no longer hold, and noted a meta-analysis suggesting that the reported NSAID benefits may have resulted from recall, prescription, and publication bias (de Craen et al., 2005). In addition, Eikelenboom said, a growing understanding of the positive effects of inflammation on limiting AD pathogenesis supports the idea that NSAIDs would be detrimental early in disease (see comment below). See also ibuprofen, Flurizan.—Pat McCaffrey