Arthritis Advisor

Amid still-swirling controversy, alternative strategies emerge.

The recent Vioxx recall is having ripple effects at many levels. Regulators in the U.S. and Europe are reviewing the status of all other COX-2 medications on the market, as well as those under development. The makers of these same drugs are launching new clinical trials to try to show conclusively that their particular COX-2 drug poses less cardiovascular risk than Vioxx. And people with arthritis who had relied on Vioxx for pain relief have been forced to find new alternatives for managing their chronic pain.

If you had been taking Vioxx, or are still taking one of the other COX-2s still on the market—celecoxib (Celebrex) or valdecoxib (Bextra)—it’s time to talk to your doctor to find out if it makes sense to stay with your current medication, or switch to an alternative. Exactly what that alternative may be will largely depend upon why you are taking a COX-2 in the first place, your tolerance for stomach or gastrointestinal irritation, and your risk or level of heart disease.

Since a cloud of suspicion now hangs over all COX-2 drugs, and conclusive studies on their comparative heart risks won’t be complete for several years, your doctor will likely err on the side of caution when suggesting an alternative for you.

As long as you can handle the stomach irritation, your doctor may recommend that you switch to an analgesic or non-steroidal anti-inflammatory drug (NSAID), either alone or in combination with a medication that can block stomach acid.

Group suspicion
One of the key questions that regulators and researchers have yet to answer is whether the problems with Vioxx are specific to this particular drug, or are symptomatic of a wider problem that all COX-2 inhibitors may pose.

Celebrex and Bextra are similar to Vioxx in that they reduce inflammation by blocking the cyclo-oxygenase-2 enzyme, but they don’t interfere with the COX-1 enzyme that protects the stomach lining.

“Since they are members of the same class of drugs with similar mechanisms of action, and given what’s happened with Vioxx, it’s reasonable to be suspicious about them all,” says Steven Nissen, M.D., the Cleveland Clinic cardiologist who was among the first to call attention to the possible heart risks of Vioxx.

However, the specific reasons why Vioxx causes cardiovascular problems are unclear. There are several molecules, in addition to the COX-2 enzyme, that play a role in platelet stickiness and blood clotting. And researchers can only speculate on how each COX-2 drug may differ in its effects upon these key molecules.

Vioxx on trial
In designing the clinical trials needed to get their drugs approved by the Food and Drug Administration, manufacturers typically limit the focus of the study to compare specific benefits and side effects. The initial safety trials on Vioxx, Celebrex, and Bextra largely excluded patients with known heart disease (previous heart attack, bypass, or stroke). The studies focused on possible risks to the stomach, not the heart.

However, when Dr. Nissen and other experts reviewed the data from the Vioxx trial, they saw signals of cardiovascular risk that, though relatively rare, were deemed serious enough to require follow-up testing. Whether such a follow-up study is done before the FDA approves a drug, is a judgment call made by the FDA.

In the case of Vioxx, the FDA did not ask for a follow-up study, but instead instructed that an additional warning be added to the drug label. Vioxx remained on the market until September 2004, when a study to see if the drug could reduce the reoccurrence of colon polyps found that people taking a low dose (25mg) of the drug for 18 months were almost twice as likely to have a heart attack or stroke as those taking a placebo.  

What about Celebrex?
Though Celebrex, like Vioxx, has never been specifically tested for cardiac safety, many experts think it doesn’t pose the same risk as Vioxx.

“Celebrex has been on the market just as long, and we haven’t yet seen any signal of cardiac risk,” says Dr. Nissen. “But then, we don’t have the clinical trials to confirm this.”

At least not yet. In early November, Canadian health officials discovered evidence potentially linking Celebrex to 14 deaths and numerous heart-related side effects in a study of 100 adverse-reaction reports on the drug. However, both Health Canada and Pfizer, the maker of Celebrex, said that the study was limited in scope and that any conclusions based on it would be premature. In the meantime, Pfizer has announced it will launch a two-year clinical study in 2005 that will look specifically at the drug’s impact on heart attack and stroke risk among 4,000 patients with osteoarthritis and a history of heart disease.

Bextra: Questions still loom
The suspicions about Bextra are stronger than those about Celebrex. In October 2004, Pfizer, the maker of Bextra, said its own clinical trials showed that heart-bypass patients who took the drug in the weeks after surgery seemed to have a higher risk of stroke and heart attack.

Then, in early November, preliminary results of a study of 5,930 patients undergoing coronary artery bypass surgery revealed that more than twice as many heart attacks or strokes were experienced among patients given Bextra.The study was later questioned by medical experts as being “irrelevant” to the chronic use of lower doses of the drug by arthritis patients.

The next generation
With the cloud of suspicion hanging over the entire COX-2 class of drugs, the FDA is likely to demand a higher order of safety data before it admits any new members to the class. There are currently two next-generation COX-2 drugs in the development pipeline—etoricoxib (Arcoxia) and lumiracoxib (Prexige).

In October 2004, the FDA told Merck, the maker of Arcoxia, that it needed more data on the proposed drug’s safety and effectiveness before it would consider approval. Preliminary findings, announced by Merck, suggested that those who took the drug for a year had no higher risk of heart attack and stroke than those who took the NSAID diclofenac.

Novartis, the maker of Prexige, is being even more cautious. Though the drug is in late-stage development, the company has decided to hold off on seeking approval for the time being. This delay may be due in part to a panel of independent experts that the FDA is convening to review all COX-2 drugs (see “In the News” this issue). The recommendations that emerge from this body could call for significant changes in how these drugs are used and labeled, at least until new clinical trials that quantify their cardiac risk are complete.

The following are not meant as specific recommendations, but rather as options to be discussed with your doctor.

• If you only need pain relief. Try acetaminophen (Tylenol), which is inexpensive and safe. It will not cause ulcers or bleeding if you use less than 4,000mg a day. Other over-the-counter pain relievers include tramadol (Ultram) and non-aspirin salsalate products (Disalcid, Trilisate).
• If inflammation is also a problem. For both pain relief and anti-inflammatory action, try one of the NSAIDs—ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn). They are just as effective as a COX-2 but cost one-tenth as much.
• If your stomach irritation is real, but not critical. Try combining a NSAID with one of the drugs that block acid formation in the stomach, such as esomeprazole (Nexium). More expensive options include the combination drug Arthrotec, which is a mix of the NSAID diclofenac and misoprostol, a synthetic prostaglandin that helps protect the stomach lining.
• If you suffer from stomach ulcers or bleeding. Consider switching to Celebrex. After several years of public use, it has shown the least indication of cardiac risk of all the COX-2s.