As of November 30, 2004
Life After Vioxx
By Denise Mann and Donna Siegfried

A top arthritis drug was pulled off the market. What should you take instead? 

The headlines came fast and furious starting Sept. 30, 2004, the day Merck dramatically pulled its blockbuster painkiller Vioxx off the market, citing increased risk of heart attack and stroke. Since the introduction of the COX-2 inhibitor Vioxx in 1999, 91 million prescriptions have been written in the United States alone -- making its withdrawal the biggest drug turnabout in history. 

The most immediate question: What medication should Vioxx users switch to? But that question begged a host of others: Do the risks associated with Vioxx linger after discontinuation? Is taking another COX-2 equally risky?

Answering the Hard Questions 
Doctors are using their patients' health status, medical and family histories and experience with other patients to decide how to treat those who had been taking rofecoxib (Vioxx). Options are another COX-2 drug, either celecoxib (Celebrex) or valdecoxib (Bextra), which are designed to have a gastroprotective advantage like Vioxx, or a traditional NSAID, like diclofenac (Cataflam, Voltaren), ibuprofen (Advil, Motrin), meloxicam (Mobic) and naproxen (Aleve, Naprosyn). 

Doctors have long known that NSAIDs are effective anti-inflammatory medications, but in some people they can lead to potentially serious problems, such as stomach pain, ulcers and gastrointestinal bleeding. They have caused more than 100,000 hospitalizations and an estimated 16,500 deaths annually, according to the U.S. Department of Health and Human Services. 

Stomach protection is why COX-2s have been so widely used. The body produces two COX enzymes; only one, COX-2, contributes to pain and inflammation, and the other, COX-1, acts as a stomach protectant. NSAIDs wipe out both in order to ease pain and inflammation, two hallmark arthritis symptoms. The COX-2 drugs suppress only the COX-2 enzyme, relieving symptoms, while leaving the gastroprotective COX-1 enzyme in place. 

Since the withdrawal of Vioxx, however, the potential for other drugs in the COX-2 class to be similarly associated with cardiovascular problems has been questioned. "COX-2 inhibitors, which are no better at relieving pain than traditional NSAIDs, were developed for people at high risk of gastrointestinal complications," says Mark Fendrick, MD, a professor of internal medicine at the University of Michigan, Ann Arbor. "Now, given concerns regarding the cardiovascular safety of COX-2s, they are also only for people who are at low risk of heart disease, with no previous history of heart disease, diabetes or hypertension." Ultimately, many older people may be better off taking traditional NSAIDs, given that risk of heart disease and stroke increases with advancing age, he says. 

Pfizer, the manufacturer of Bextra and Celebrex, is distancing its products from the brouhaha over the cardiovascular risk of Vioxx. Those two drugs, though in the same class, are slightly different chemically from each other and from Vioxx. Pfizer believes that Celebrex may actually have cardiovascular benefits, and is launching a study to prove its hypothesis. 

Shortly after the Vioxx withdrawal, however, Pfizer announced to physicians that two small trials showed Bextra increases risk of heart attack and stroke in patients after bypass surgery, but maintains the risk is only to that subset of patients, not the general population. Another study by University of Pennsylvania researchers indicated Bextra more than doubled the risk of heart attack and stroke, though a Pfizer spokesperson has said the results are not valid, because of the study's methodology. 

Doctors wonder whether the cardiovascular risk seen with Vioxx -- and starting to be seen in Bextra -- will eventually be seen in all the COX-2 drugs, even perhaps the ones yet to be approved or in development. So how exactly does Vioxx increase risk of heart attack and stroke? Scientists are not yet certain, but several recently published studies have shown that Vioxx increased blood pressure, a known risk factor for cardiovascular disease, and increased clotting. Mason has a different theory. "Vioxx makes LDL [a type of cholesterol] susceptible to oxidative damage, which can trigger inflammation in the vessel wall -- an important contributor for heart attack and stroke. We did not see this effect with Celebrex or traditional NSAIDs," he says. "These findings corroborate other studies that showed Vioxx has an increased risk compared with Celebrex." 

In the study that prompted the withdrawal of Vioxx, 15 heart attacks, strokes or blood clots occurred for every 1,000 people taking the drug for three years, compared with 7.5 such events in those taking placebo. Several weeks before that study prompted the withdrawal, an FDA-funded study showed that people taking Vioxx had a 50-percent greater chance of heart attacks and sudden cardiac death than individuals using Celebrex. The cardiovascular risk seems small, until you consider that 1.3 million people in the United States and 700,000 people abroad take Vioxx. The latest report by the FDA projects that the widespread use of Vioxx may have already led to more than 27,000 heart attacks and sudden cardiac deaths. 

John Klippel, MD, president and CEO of the Arthritis Foundation and former clinical director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, a component of the National Institutes of Health (NIH), urges caution in the use of these drugs in people at risk for cardiovascular complications.

What You Can Do 
The full picture on how Vioxx and all COX-2s affect heart health is emerging. Data safety monitoring boards will meet again in February to determine if any additional events occurred among people after they stopped taking Vioxx. 

Until such results are available, you can expect your doctor to try one of several strategies to treat your pain and inflammation, while lessening gastrointestinal or cardiovascular risks. (See "Your Options for Safe Relief" below.) Dr. Fendrick recommends avoiding the seemingly win-win approach some doctors have tried, prescribing a COX-2 drugs along with a daily aspirin to protect the heart. "Aspirin either markedly diminishes, if not completely eliminates, the gastroprotection of COX-2's," he says. 

Kathleen W. Wilson, MD, a senior internal medicine doctor at the Ochsner Clinic in New Orleans, suggests that if you are taking either a COX-2 blocker or a traditional NSAID, you should monitor your blood pressure once a month -- more often if your ankles start to swell. "If blood pressure starts creeping up, see your doctor and be sure to mention that you are taking an NSAID or a COX-2 for your arthritis," she says. "If this occurs, see your doctor for a blood pressure check and a kidney function test." 

Managing arthritis means doing more than taking drugs, says Dr. Klippel. "Most people don't pay attention to exercise or diet, and both can help relieve arthritis pain," he says. In addition, heat wraps, ice packs, elastic bandages or braces to support the joint, and supplements like glucosamine can add to the relief.

Updated December 22, 2004
New reports over the safety of celecoxib (Celebrex) were raised when the National Institutes of Health (NIH), Bethesda, Md., halted two cancer prevention studies when results from one of the studies began to show a more than doubled increase of heart attacks and strokes. The other study did not show an increased cardiovascular risk. The NIH is reviewing all studies involving COX-2s.