Scientists study whether cox-2 inhibitors cause threaten heart attacks in some people

WASHINGTON (AP) _ There's growing suspicion that switching from aspirin to a more stomach-friendly arthritis drug could increase some people's risk of heart attacks _ and a study suggests the reason:

Thursday, April 18th 2002, 12:00 am

By: News On 6

WASHINGTON (AP) _ There's growing suspicion that switching from aspirin to a more stomach-friendly arthritis drug could increase some people's risk of heart attacks _ and a study suggests the reason: a drug-caused chemical imbalance that spurs blood clots.

The new research was in mice, not people. But the evidence is prompting scientists to study users of new painkillers called cox-2 inhibitors to determine whether their hearts are at risk.

At issue is whether people with heart disease _ not healthy people _ increase their risk of heart attacks even more by taking the popular arthritis pain relievers Vioxx or Celebrex.

The study by University of Pennsylvania researchers, in Friday's edition of the journal Science, suggests, biologically, how the drugs could cause such side effects.

Vioxx maker Merck & Co. dismisses the study as irrelevant, because it is in mice and presumes an effect in the human body far larger than the drug actually causes.

A leading heart expert, however, called the new research a very important step in explaining an earlier study that found certain Vioxx users suffered twice the risk of heart attacks as users of an older painkiller.

``Now the only thing we're really missing is quantifying the magnitude of the risk,'' said Dr. Eric Topol of the Cleveland Clinic, who wants more research quickly to settle the issue.

Meanwhile, he said, ``If you have heart disease, it ought to be with particular care and concern that you take these medications, ... because there could be some risk.''

People's bodies harbor two forms of an enzyme that plays a role in pain-causing inflammation and blood clotting. One of the enzymes, Cox-1, makes thromboxane, which causes blood vessels to constrict and platelets to become sticky, steps important in a heart attack or stroke. The other, Cox-2, is a major source of prostacyclin, which dilates blood vessels and prevents platelets from clumping together.

In a healthy person, the two coxes are thought to balance each other so blood doesn't excessively clot.

In people at risk of heart attack, aspirin helps because it thins the blood by blocking cox-1; it also slightly blocks cox-2.

Vioxx and Celebrex, in contrast, block only cox-2. Could that action let cox-1's clotting tendencies run amok? The drugs' makers long dismissed that idea, because other body chemicals also control clotting.

Then last summer, Topol and other doctors reported more Vioxx users than users of the older painkiller naproxen suffered heart attacks. Vioxx maker Merck & Co. argued Vioxx didn't cause illness, but naproxen, like aspirin, thins the blood so naproxen users got an extra benefit.

The new study bolsters suspicion that Vioxx could play an active role.

In genetically engineered mice, researchers irritated an artery to spur release of both clotting chemicals. Mice resistant to prostacyclin's effects, a model of cox-2 inhibition, experienced more thromboxane-caused clotting activity.

That's not proof people would be endangered, stressed lead scientist Dr. Garret Fitzgerald, a University of Pennsylvania pharmacologist. After all, he said, ``Mice aren't people.''

Still, ``the credibility of the hypothesis is enhanced'' enough that he plans to begin studies in people to try to settle the issue.

But the study looked at mice that had completely inhibited prostacyclin, while cox-2 drugs inhibit the chemical only half as much, said Merck scientist Dr. Alise Reicin.

She said the study contributed no new information to the debate, but Merck plans further safety studies to deal with the issue, although she would not provide details.

Settling the issue is crucial because millions use cox-2 inhibitors. That means, Topol said, that even if the risk is very small, it could result in lots of heart attacks.