Cox-2 Clot Problems

Arthritis drugs may raise risk for heart problems for some, says study

TUESDAY, Aug. 21, 2001 (HealthDayNews) -- A new class of powerful arthritis drugs may increase the risk of dangerous blood clots, new research says.

An analysis of roughly 18,000 people taking so-called cox-2 inhibitors shows a marked increase in cardiovascular trouble and heart-related deaths linked to clotting, report Cleveland Clinic researchers. They say their results are worrisome, and more study should be undertaken. The findings are published in this week's Journal of the American Medical Association

"There's now theoretical data; there's animal data and some suggestive human data that all leads to the conclusion that there is probably an effect here," says study co-author Dr. Steven Nissen, a Cleveland Clinic cardiologist.

A second paper, published earlier this week in the journal Circulation, also shows a link between cox-2 drugs and blood clotting in dogs.

Nissen says the findings don't mean people should avoid cox-2 inhibitors to relieve arthritis pain, but they do suggest that doctors consider the compounds' safety in light of their patients' cardiovascular risk factors. "For an 18-year-old with a football injury, there isn't a problem. But if you're 73 and have had a couple of [heart attacks], then we think that physicians would want to be careful," he says.

Cox-2 inhibitors, including rofecoxib (or Vioxx), and celecoxib (or Celebrex), block an enzyme involved in the inflammation pathway and are thought to be gentler on the gastric tract than common non-steroidal anti-inflammatory medications (NSAIDs) like aspirin.

The two companies that make the drugs say their products are safe on the heart and blood vessels.

Merck & Co., which makes Vioxx, says the latest study fails to include the company's own recent analysis of more than 28,000 patients showing that the drug does not increase the risk of cardiovascular problems. "That assessment was very reassuring to us," says Dr. Laura Demopoulos, a cardiologist at Merck.

Demopoulos says doctors have written some 40 million prescriptions for Vioxx since it went on the market in June of 1999, and follow-up shows that heart complications in users is "extremely low." "There's no clear signal for a suspicion of an elevated risk," she says.

Pharmacia, whose G.D. Searle division makes Celebrex, says it, too, hasn't detected a problem. "We don't believe we're seeing a signal" for an increased cardiovascular risk, says Dr. Steve Geis, group vice president for clinical research. An estimated 21.5 million patients worldwide have taken Celebrex since its launch in early 1999, Pharmacia reports.

Nissen, however, says follow-up research is notoriously poor at picking up adverse events that aren't unusual to begin with, and it tends to understate the true scope of a problem by a factor of 10 to 100.

Nissen and his colleagues reviewed two major studies of Vioxx and Celebrex that included more than 16,000 patients. They also looked at two smaller trials involving about 1,000 patients each.

In one large study, called VIGOR, Vioxx users had about a 2.4-fold greater risk of clot-related heart problems, such as heart attack, stroke, chest pain and sudden cardiac death, than people taking the anti-inflammatory pill naproxen. And in both large trials, patients on cox-2 drugs were more likely to suffer heart attacks over a year of treatment than subjects taking placebos.

"When we saw that there was an increase [in clotting problems] in the VIGOR trial, and really a rather large increase, we had to ask ourselves the question, 'Is it because naproxen is beneficial or is it because Vioxx is really increasing the event rate?'" Nissen says.

He says the answer based on the entire analysis seems to be that cox-2 inhibitors do boost the odds of clot-related heart problems, but by how much and in which patients isn't certain.

Nor is it clear whether taking a low dose of aspirin each day in addition to a cox-2 inhibitor can lower the increased risk of cardiovascular complications. Nissen says it probably would but perhaps with a loss of benefits of the cox-2 drugs in the gut.

Dr. Domenico Pratico, a pharmacologist at the University of Pennsylvania, says the matter is still an open question. "I don't think that there is a clear answer, yes, or a clear answer, no," says Pratico.

In work published earlier this year, Pratico and his colleagues showed that the cox-2 drugs carry at least a theoretical ability to increase the risks of cardiovascular trouble in mice with established vessel disease.

By blocking the cox-2 enzyme, the drugs reduce swelling and pain from osteoarthritis and rheumatoid arthritis, two conditions which together affect some 20 million Americans. But the drugs also suppress a hormone-like molecule called prostacyclin that is essential in the body's ability to break up blood clots.

For the average person with arthritis, the effect might be trivial, Pratico says. "But if they have a risk factor for cardiovascular disease, they could have problems from inhibiting prostacyclin," he says.

What To Do

If you're taking a cox-2 drug, talk with your doctor about your cardiovascular risk. For more on the drugs, try Johns Hopkins University.

To learn more about arthritis, try the Arthritis Foundation.

Celebrex also has been approved for the treatment of a rare form of hereditary colon cancer. For more on that condition, try the Celebrex Web site.

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