Cambridge, UK - The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) of naproxen and celecoxib (Celebrex, Pfizer), which attracted much controversy when it was stopped prematurely almost two years ago, has now been published online November 17, 2006 in the Public Library of Science journal PLoS Clinical Trials [1].

The trial, which was comparing naproxen, celecoxib, and placebo in the prevention of Alzheimer's disease, was stopped in December 2004 after it was found that the naproxen group was showing an increase in cardiovascular events compared with placebo, and a public warning was issued about the safety of naproxen. But this decision has been criticized by many, as the data suggesting harm with naproxen were far from definitive.

One of the most vocal critics of the decision to stop the trial, Dr Steven Nissen (Cleveland Clinic, OH), is the author of an editorial accompanying the paper [2]. In the editorial, Nissen continues his attack, saying: "Both the termination of this trial and the issuance of a public warning about naproxen were inappropriate and reflected faulty logic."

ADAPT was an National Institutes of Health (NIH)-sponsored study designed to evaluate whether anti-inflammatory drugs might prevent or delay the onset of Alzheimer's disease. The 2528 participants were aged 70 years or older with a family history of Alzheimer's. They were randomized to celecoxib (200 mg twice daily), naproxen sodium (220 mg twice daily), or placebo.

The trial was stopped after a median follow-up of 23 months. The ADAPT investigators note that the results do not show increased or decreased risk for cardiovascular harm among people taking celecoxib, as compared with placebo. The data do, however, suggest some evidence of risk among people taking naproxen, as compared with placebo, they report.

In the paper, the ADAPT investigators explain why the trial was stopped early. They note that on December 17, 2004, increased cardiovascular risks with celecoxib were reported from the National Cancer Institute-sponsored APC trial, and the ADAPT trial was stopped on the same day. They say the termination of both the celecoxib and naproxen arms of the ADAPT 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."

They agree that the ADAPT results with either drug are not definitive due to the early termination of the trial and that under ordinary circumstances, these results would not have warranted suspension of the study. But they continue: "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 also point out that ADAPT was a primary-prevention trial and as such would have a lower tolerance for risk associated with the treatments being evaluated, as "the only benefit of the intervention is the possibility of later protection from a condition they might have avoided in any case" and that this is different from the clinical setting, where these drugs are used for pain relief and the potential risks can be weighed against the known immediate benefits of treatment.

They say that the naproxen data from ADAPT provide some support to the theory that all nonsteroidal anti-inflammatory drugs (NSAIDs) may have some degree of cardiovascular risk but add that without adequate evidence from long-term, placebo-controlled trials, the measure of this risk remains a matter of speculation.

In a press release, ADAPT investigator Dr Barbara Martin (John Hopkins Bloomberg School of Public Health, Baltimore, MD) comments: "Because ADAPT stands alone as a large, long-term, placebo-controlled trial of NSAIDs in the elderly, we believe the data are an important contribution to the medical literature. Particularly for safety data, 'truth' may come in small doses. We firmly believe that results from trials should be published regardless of the direction, magnitude, or statistical significance of the observed results."

In his editorial, Nissen points out that for the standard composite end point of cardiovascular death, MI, and stroke, there were 17 events in celecoxib treatment group, 23 in the naproxen arm, and 22 in the placebo group, giving a hazard ratio for naproxen compared with placebo of 1.57 (95% CI 0.87-2.81; p=0.13). When heart failure and transient ischemic attack are added in, the p value becomes marginally significant, he adds.

He notes that the trial was not stopped by the data safety monitoring board (DSMB), but by NIH officials concerned about revelations regarding the safety of coxibs in the colon-polyps studies. Nissen explains that during clinical trials, hazard ratios are often unstable, sometimes drifting over time into marginal levels of ''significance," but that these ''signals'' are not reliable, and to avoid inappropriate premature termination of trials, rigorous ''stopping rules'' have been developed that, if followed, would have "precluded early stopping of ADAPT and avoided the generation of spurious findings."

In answer to the question: "Who shares responsibility for the improper termination of ADAPT?" he says: "In my opinion, a major factor was the inappropriate unblinding of the trial by leadership at the NIH. Allowing unrestricted access to the study data by NIH officials represents an unwise policy and can only lead to errors of this kind." He adds that the trial's principal investigator, steering committee, and DSMB should have also refused premature examination of the trial data or, alternatively, explained that the reasons for termination did not include the finding of a hazard for naproxen treatment.

"Management of clinical trials is a major public responsibility. It takes self-discipline and a precise understanding of statistical methods. For ADAPT, accepted scientific procedures were not followed, resulting in an inappropriate public warning. Accordingly, the trial results cannot be reliably interpreted."

Nissen also points out that there are many sources of evidence that refute the notion that naproxen increases the risk of adverse cardiovascular outcomes, including a recent meta-analysis of 23 studies of NSAIDs and COX-2 inhibitors that found a relative risk for naproxen of 0.97 [3].

Another expert in the field, Dr Garrett FitzGerald (University of Pennsylvania, Philadelphia) agrees with Nissen's stance. He told heartwire: "I concur with Dr Nissen's concerns about the circumstances surrounding the premature conclusion of this trial. Along with this, the small number of events, all of them unadjudicated, renders the result essentially uninterpretable. It is akin to publishing an experiment that you know has failed for technical reasons."

Writing in theheart.org's forum, Dr Chris Cannon (Brigham and Women's Hospital, Boston), who presented the MEDAL study with etoricoxib and diclofenac at last week's American Heart Association 2006 Scientific Sessions, agrees that the ADAPT trial was inappropriately stopped but points out that it was still a randomized trial of 2500 patients and it is important to try to learn from the information reported. He notes that ADAPT is one of the first studies of low-dose naproxen; while high-dose naproxen is known to have a sustained antiplatelet effect (one possible explanation as to why it shows a lower cardiovascular risk than COX-2 inhibitors), this study could be showing that low-dose naproxen has the same increased cardiovascular risk that has been seen with other COX-2 inhibitors and NSAIDS, he suggests.