Vioxx, Celebrex, and Naproxen:

A level-headed analysis of the available information

December 21, 2004

Today the news is full of chatter about the possible side-effects of the commonly prescribed anti-inflammatory drugs Vioxx, Celebrex, and naproxen* (aka Naprosyn and Aleve). The pharmaceutical manufacturer Merck discontinued the sale and distribution of Vioxx several weeks ago when its link to cardiovascular disease was publicized. (Apparently Merck was aware of this for some time.) Today on the news I heard that Celebrex and naproxen may also be linked to increased risk of heart disease and stroke. In a typical fear-provoking announcement, the news reporter blurted, "Is ibuprofen next?" (I'm not aware of any studies suggesting that ibuprofen — aka Advil, Motrin IB, etc. — increases one's risk of heart attack or stroke.)

So, in an attempt to present the information now known about these drugs and their potential for causing cardiovascular disease, here is a calm, rational review of current knowledge.

In light of the recent concern about Vioxx, the National Institutes of Health (NIH) looked at several long-term studies currently in progress in which Celebrex and naproxen were being evaluated for their ability to prevent certain diseases. In one three year study Celebrex was being evaluated for its potential ability to prevent colon polyps. In another study both Celebrex and naproxen where used to determine if there was a role for either drug in the prevention of Alzheimer's disease. Both studies were halted when it was determined that the incidence of adverse cardiovascular (CV) events was increased in those subjects taking Celebrex or naproxen compared to the subjects taking a placebo. In the Alzheimer's study, the incidence of CV events was 50% greater than the group taking a placebo. In other words, half again as many people suffered an adverse CV event in the naproxen group than the control group. This study did not suggest that there was a greater risk in the group taking Celebrex. It has not been revealed at this time how many people in either group actually suffered a CV event during the course of the study.

In the other study, the risk of an adverse CV event was determined to be between 2.5 and 3.4 times as great in the group taking Celebrex than in the control group. The difference in risk factors was dose related; the higher risk was associated with a higher dose of Celebrex. Naproxen was not used in this study.

In evaluating these reports, it is important to understand the meanings of the terms incidence and risk. The incidence of CV events in the Alzheimer's study was 1.5 times that of the placebo or control group. This means that more people in the group taking naproxen developed some sort of heart disease or stroke than in the group not taking the drug. (An incidence of 1 time would mean that the rate at which the disease occurred was the same.) In the other study, the report I reviewed (see links at the end of this article) did not discuss the incidence at which the unintended CV effects occurred but talked about the increased risk in the subjects taking Celebrex. However, I would interpret this to mean that the occurrence of adverse CV events was 2.5 times as great in the group taking 200 mg Celebrex per day and 3.4 times as great in the group taking 400 mg per day compared to the control group.

A risk factor is a hypothesis that is derived from the incidence of a particular condition in a group being studied. Thus, from this information one can hypothesize that the use of these NSAIDs may increase the risk of cardiovascular disease. If the hypothesis is correct, then one's increased risk is going to depend on how much risk already exists in each individual. For example, a healthy guy like me who doesn't smoke and grazes at the bottom of the food pyramid (I'll admit this is a bit of an exaggeration) is already at less risk than a 300 pound 3-pack a day meat-and-potatoes couch potato (I again take some literary license here). If you take any of these drugs, your particular risk of stroke or heart attack may differ from the groups in these studies. We do not know from the available information what the risk factors for the research populations were to begin with. The studies were intended to determine the preventive effects of these drugs for colon polyps and Alzheimer's disease, so it is possible or even likely that the people chosen were older and at higher risk for CV disease than the "average" person. Furthermore, with respect to the disparate results between the one study that indicated adverse effects with Celebrex and two other studies which did not, it is likely that the varying results are also due to differences in the populations being studied. Comparing the risks between the groups in the different studies is like comparing kumquats and kiwi fruit, or Apples and PCs. Like it says on the label, "Your results may vary."

My advice is this (now would be a good time to read our disclaimer, if you have not done so already): Avoid taking any drug, prescription or over-the-counter, if there are other, safer alternatives. If you have to take a drug, take the smallest dose necessary for the desired result for the shortest time. For many musculoskeletal problems, chiropractic care can be a safe and effective treatment and should be considered before resorting to drugs with a higher risk of unintended and possibly adverse effects.

Here are links to current information (as of 12/21/04) on these drugs:

http://www.medscape.com/viewarticle/496301

http://www.medscape.com/viewarticle/496403

* Vioxx, Celebrex, and naproxen are all NSAIDs, or nonsteroidal anti-inflammatory drugs. They are widely used in the treatment of various arthritic conditions from osteoarthritis (the common wear-and-tear arthritis associated with aging) to rheumatoid arthritis and other less common varieties. Vioxx and Celebrex are COX-2 inhibitors, referring to their ability to inhibit a certain enzyme which contributes to the inflammatory process. When these drugs were first released a few years ago it was thought that they are less likely than COX-1 inhibitors to cause harm to the stomach and intestines. (There is now evidence suggesting that they also cause gastrointestinal damage.) The COX-1 NSAIDs include naproxen and ibuprofen which have been prescribed for many years: some COX-1 NSAIDs are also available over the counter. top