FDA Says Naproxen, Sold Over-the-Counter as Aleve, Might Increase Risk for Heart Attack, Stroke

The pain medication naproxen might increase patient risk for heart attack and stroke based on the preliminary results of a National Institute on Aging study that found a 50% higher risk among participants who took naproxen compared with those who took a placebo, FDA said on Monday, the Los Angeles Times reports (Alonso-Zaldivar, Los Angeles Times, 12/21). Lead study author John Breitner of the University of Washington and the Veterans Affairs Puget Sound Health Care System said that although researchers must conduct additional analysis to determine whether the higher risk is statistically significant, the current evidence is "enough to cause some concerns" (Weiss, Washington Post, 12/21).

The study -- which began in 2001 and involved about 2,400 healthy adults ages 70 and older who had family histories of Alzheimer's disease -- sought to determine whether naproxen, sold over the counter by Bayer as Aleve, or Celebrex, a COX-2 inhibitor manufactured by Pfizer, could prevent the disease (Los Angeles Times, 12/21). Participants received either the recommended OTC dose of naproxen -- 220 milligrams twice daily -- 200 milligrams of Celebrex twice daily or a placebo. Seventy participants experienced heart attacks or strokes during the study, but researchers have not released data on which medications those participants received. Researchers said that 23 participants died during the study, with no significant difference in death rates among those who received naproxen, Celebrex or a placebo (Wilde Mathews/Winslow, Wall Street Journal, 12/21). The study found no increased risk for cardiovascular events among participants who took Celebrex.

Breitner said that researchers decided to suspend the study after Pfizer on Friday announced that Celebrex might increase patient risk for heart attack and stroke. According to the New York Times, "news of problems with Celebrex had led many of the patients to threaten to drop out" of the study. Breitner said that although the "safety data for some time has been giving a weak signal of possible increased risk of cardiovascular and cerebrovascular problems with naproxen," researchers did not end the study for that reason (Harris, New York Times, 12/21). A committee that reviewed safety data from the study on Sept. 10 presented preliminary results that indicated participants who took naproxen had a higher risk for heart attack and stroke, but researchers decided to continue the study (Bor, Baltimore Sun, 12/21). NIH and the researchers decided to suspend the study as a "precautionary measure" (Washington Post, 12/21).

Although study participants have ended treatment with naproxen, researchers will continue to monitor them, according to Breitner (Rubin, USA Today, 12/21). NIH Director Elias Zerhouni said, "In the context of naproxen, this is the first preliminary evidence that reaches a level of concern for us to do further study" (Los Angeles Times, 12/21). He added that for study participants who took naproxen, "the (potential) benefit did not warrant taking the risk. That's very different than advising patients who really need the drug for pain control" (Washington Post, 12/21).

FDA recommended that patients who take Aleve, generic naproxen or the prescription forms Naprosyn and Anaprox to consult their physicians and follow instructions on the labels. In addition, FDA said that patients should not take more than 440 milligrams of Aleve in a 24-hour period and should not take the medication for more than 10 days without a physician consultation (Los Angeles Times, 12/21).

According to Dr. Sandra Kweder, deputy director in the FDA office of new drugs, the agency will review the data from the study and consider "what regulatory actions are appropriate over the next day or two" (New York Times, 12/21). FDA officials said that they currently have not begun to consider any specific actions related to naproxen, such as a ban on direct-to-consumer advertisements (Henderson/Dembner, Boston Globe, 12/21).

Kweder called the results of the study "confusing" because "[w]e are not aware of any previous studies looking at the long-term risk associated with older" pain medications. According to the Los Angeles Times, "The latest developments could raise questions" about the use of nonsteroidal anti-inflammatory drugs, a class that also includes ibuprofen (Los Angeles Times, 12/21). Kweder said, "We know that there are other phenomena that occur across these class of drugs, including gastrointestinal bleeding," adding that increased risk for cardiovascular events "may be another class phenomenon" (New York Times, 12/21).

Gregg Fonarow, professor of cardiovascular medicine at the University of California-Los Angeles, said that "these medicines were originally studied in the short term for treatment of pain, and their cardiovascular effects were never really well scrutinized. ... Now they're being used in higher doses longer term, and we're seeing they indeed can increase the risk for myocardial infarction and strokes" (Los Angeles Times, 12/21). However, the "latest results could prove beneficial to Pfizer, which has been arguing that last week's findings about Celebrex should be placed in the context that similar pills may be just as hurtful to the heart and that other studies of Celebrex have shown no such worries," the New York Times reports.

"This is a very confusing situation," Kweder said, adding, "Every doctor and patient is going to have to have a conversation about their unique risks" (New York Times, 12/21). Dr. Roger Blumenthal, director of preventive cardiology at the Johns Hopkins School of Medicine, said, "My feeling is that many times we tend to exaggerate both what appear to be beneficial findings and what appear to be detrimental findings" (Baltimore Sun, 12/21).

Health care consultant David Webster said, "There's a heightened sensitivity about safety, particularly in this class of drugs. So any drug that's associated either directly or tangentially with these concerns will experience a dose of bad publicity." He added that the results of the study likely will have a long-term financial effect on Bayer.

Bayer spokesperson William O'Donnell said in a statement, "The company has not yet seen the data and therefore is unable to comment on the study at this time. We are investigating the matter and in the meantime we are in agreement with the FDA's recommendation that consumers carefully follow instructions on the label" (Los Angeles Times, 12/21).

Several broadcast programs reported on the naproxen study:

• ABCNews' "World News Tonight": ABCNews Medical Editor Tim Johnson discusses the results of the study (Johnson, "World News Tonight," ABCNews, 12/20).
  


• NBC's "Nightly News": NBC medical correspondent Robert Bazell discusses the results of the study findings (Bazell, "Nightly News," NBC, 12/20). The complete segment is available online in Windows Media.
  


• NPR's "Morning Edition": The segment includes comments from Kweder; Daniel Solomon of Brigham and Women's Hospital; Elizabeth Tindall, president of the American College of Rheumatology; Zerhouni; and a Celebrex patient who had planned to switch to naproxen (Knox, "Morning Edition," NPR, 12/21). The complete segment is available online in RealPlayer.