On December 20, 2004, the National Institutes of Health (NIH) issued a press release suspending the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT). This study compared naproxen (Aleve®) at 220 mg twice a day (a low dose) to placebo and to celecoxib (Celebrex®) at 200 mg twice daily (a high dose) in 2400 patients over the age of 70. The Data Safety Monitoring Board acting on previous signals from other recently halted trials (see http://www.hss.edu/Conditions/Osteoarthritis/Pfizer---Safety-of-Celecoxib) stopped the trial "as a precautionary measure" because the data "indicated an apparent [emphasis added] increase in cardiovascular and cerebrovascular events among the participants taking naproxen when compared with those on placebo". This was followed with another press release from the FDA advising patients not to exceed the recommended over-the-counter dose of 220 mg naproxen twice daily for no more than ten days (see http://www.fda.gov/bbs/topics/news/2004/NEW01148.html).
Left out of these press releases about naproxen (Aleve®) was the fact that Celebrex taken at 200mg twice daily did not result in more cardiovascular or cerebrovascular events when compared to placebo, a finding that directly contradicts what was reported on December 17, 2004, about another NIH study on colon polyps. In addition, in the recently reported study naproxen (Aleve®) was used at a dose (220 mg twice daily) below the dose that most rheumatologists have used to treat arthritis patients since the drug was released in 1976 (500 mg twice daily is the usual prescription strength). In the last 25+ years, although not formally studied in a prospective fashion, naproxen has not shown evidence of adverse cardiovascular or cerebrovascular events, as reported to the FDA. In fact, in two recent studies[1][2], there was no increase in cardiovascular events with naproxen compared to Celebrex® and Vioxx®, even though both studies showed an increase in cardiovascular events for rofecoxib (Vioxx®). Valdecoxib (Bextra®), the other drug mentioned in recent press releases, was not looked at in these particular studies.
Unfortunately, publication of these findings through press release, without the simultaneous provision to the public or to physicians of complete actual data has only added to the confusion. Contributing to the confusion has been the announcement of "apparent increases", that is, suggestions rather than facts, coupled with lack of information regarding specific numbers of patients affected. Additionally, there is a large interest on the part of media to hype bad news, calling this unbiased reporting of medical events, while ignoring a large body of data accumulated from other clinical trials, with large numbers of patients, from pharmaceutical companies, FDA, NIH, and academic investigators, published and unpublished, and well known to physicians, which contradicts these warnings.
Nevertheless, we, as clinicians and leaders in our field, are being asked to comment on the validity of the reports and advise our patients.
We feel strongly that we have a mandate of primum non nocere (first, do no harm). We emphasize that any medication for any indication always carries risks and benefits. There is no totally safe medication, just as there are few benign illnesses. Each illness in and of itself carries the potential for harm. These are considerations that we, as clinicians, weigh each time we prescribe a medicine.
We suggest that, until the answers become clear, and until we, the FDA, and other opinion leaders have an opportunity to review and critically examine the full data relating to the recent announcements, each physician should continue to weigh carefully the risks and benefits of prescribing Cox-2 inhibitors and traditional NSAIDS for each patient.
Many people with the more than 100 types of arthritis live with chronic pain that limits function, at times severely, and makes any activity a burden. These people yearn for relief and take NSAIDs and pain medications to help them get through the day. Because they constantly need medication, they make daily cost-benefit decisions about treatment, trying to balance their ability to carry out activities of living with the potential side effects of the medication. In close partnership with their doctors, and with direct personal research, they arrive at important decisions about their own care. Every medication has side effects, some more than others. Given all the new information about NSAIDs, both traditional and COX-2, patients will ask their physicians for guidance regarding whether or not to stop Celebrex®, Bextra® and now naproxen (Aleve®).
Your physician, as always, needs to balance this decision about you by employing knowledge about your life, medical problems, family history and medication risks. If you have a personal or strong family history of coronary artery disease, you and your doctor should discuss how the new information relates to you, taking into consideration that the results are conflicting and incomplete at this time. If you have been on many other NSAIDs without relief, have a low risk profile of coronary artery disease, and have been taking one of these medications safely for years, these factors may move you toward a decision to stay on the medication, possibly adding low dose aspirin for cardiac protection.
For the patient whose activities of daily living are impaired if they do not take these medications and who have not had side effects, the medications should be continued, presuming there has been a careful discussion between doctor and patient, including discussion of the limitation of available data. For the patient who is not clearly benefiting from the drug, the drug should be discontinued or another anti-inflammatory medication substituted.
We at Hospital for Special Surgery remain committed to the best treatment for our patients weighing benefits versus risk and utilizing the best medications presently available to us. We are always available for consultation (see http://www.hss.edu/Newsroom/Celebrex-and-Aleve). We will continue to review new data as they become available and to provide advice to our patients and colleagues.
Resources:
American College of Rheumatology Press Release on Arthritis Pain Medications:
http://www.rheumatology.org/press/2004/cox_2_news.asp
FDA statement on Aleve:
http://www.fda.gov/bbs/topics/news/2004/NEW01148.html
FDA Statement on Celebrex for patients:
http://www.fda.gov/cder/drug/infopage/celebrex/celebrex-ptsk.htm
FDA statement on Celebrex for practitioners:
http://www.fda.gov/cder/drug/infopage/celebrex/celebrex-hcp.htm
posted 12/27/2004