With safety concerns about rofecoxib (Vioxx®), celecoxib (Celebrex®), and now naproxen, it seems that nonsteroidal antiinflammatories (NSAIDs) are dropping like flies. On Monday last, the National Institute on Aging halted the Alzheimer’s Disease Antiinflammatory Prevention Trial (ADAPT), in part because “Preliminary information from the study showed some evidence of increased risk of cardiovascular events, when compared to placebo, to patients taking naproxen,” according to a statement released Monday by the FDA.

ADAPT began enrolling patients in early 2001 (see ARF related news story) based on evidence that certain NSAIDs may offer some protection against Alzheimer disease (AD). The trial was designed to evaluate the protective effects of two drugs, celecoxib and naproxen. When Merck recently withdrew Vioxx from the market because of safety concerns (see ARF related news story), the action sent ripples through the drug and healthcare industries and made many take a second look at celecoxib, a drug in the same class—designed to block the enzyme cyclooxygenase-2 (COX-2). Four days ago, Pfizer reported similar long-term safety issues with celecoxib—increased risk of cardiovascular disease—following evaluation of data from a clinical trial designed to test the drug’s ability to prevent adenomas (see Pfizer statement). Celebrex has not been withdrawn, but patients and doctors have been encouraged to consider alternative therapies (see FDA statement).

Last Friday's news from Pfizer may eventually have put an end to ADAPT, despite the fact that celecoxib doses (up to 200 mg) given to ADAPT patients are fourfold lower than those found to confer increased risk of cardiovascular disease (800 mg/day), and the fact that in another long-term trial, patients taking 400 mg/day of the drug had no evidence of adverse cardiovascular events. But the latest news, from ADAPT itself, that naproxen also confers risk for cardiovascular events signaled the end of the trial.

The results come as a surprise to many, especially since naproxen (better known to many as Aleve®) has been approved since the mid-1970s and is available over the counter. In addition, because it is not a selective COX-2 inhibitor, there was reason to doubt that it would be tainted with the same brush as the selective inhibitors.—Tom Fagan.

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  1. Without seeing the data, I cannot comment on the decision to halt
    ADAPT. But note that in 2000, the VIGOR trial showed greater risk of MI [myocardial infarction] with rofecoxib than naproxen (triggering concern about COX-2 inhibitors and cardiovascular risk). The recent NCI study showed increased cardiovascular risk with celecoxib. Now ADAPT apparently shows excess risk with naproxen, but not celecoxib. These findings are not consistent; I don't believe we yet have a clear understanding of the cardiovascular risks associated with selective or non-selective NSAIDs.

    It is unfortunate when a large clinical trial is stopped early because of safety concerns; it generally means that a huge effort by investigators and subjects will fail to reach a conclusion. In the case of ADAPT, it means we will probably never know whether NSAIDs are useful in reducing the risk of AD. Clearly, DSMBs [data and safety monitoring boards] must be diligent in overseeing trials, and some studies must be stopped early. Such decisions must be based on careful, deliberate consideration of all relevant information.

  2. The results showing increased cardiovascular risk of patients taking COX-2 inhibitors, or a non-selective COX inhibitor, may come as a surprise in the face of extensive research on role of macrophages in atherosclerosis. The results of current animal studies listed on PUBMED under "COX-2 inhibitors macrophage" have shown for example that COX-2 inhibitors decrease production of reactive oxygen intermediates, chemokines, and leukotrienes. These effects may be accompanied by decreased intimal hyperplasia. However,as shown in the amyloid-beta vaccine trial, effects on the human immune system and human neuropathology do not parallel those in lower animal forms, perhaps because of the rapid evolution of the human brain. Chemokines, cytokines and macrophages have both neurotoxic and neuroprotective roles in human nervous system.

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References

News Citations

  1. Major Prevention Trial Is Now Recruiting Participants
  2. Merck Withdraws Vioxx®

External Citations

  1. statement
  2. Pfizer statement
  3. FDA statement

Further Reading

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