More evidence of how painkillers called COX-2 inhibitors can raise the risk of heart disease was published Monday, showing Pfizer Inc.'s Bextra can triple the risk of heart attack and stroke in certain patients.

A second study shows how older drugs such as aspirin work to prevent heart disease. Both appear in this week's issue of the American Heart Association journal Circulation.

The COX-2 inhibitors were designed to help treat arthritis pain and similar long-term conditions without the serious stomach side-effects of aspirin and related drugs such as ibuprofen, and other non-steroidal anti-inflammatory drugs or NSAIDS.

But in September Merck & Co. Inc. pulled its COX-2 inhibitor Vioxx from the market after clear evidence its use could raise the risk of heart attacks. And in December, the National Institutes of Health halted a study involving Pfizer's COX-2 inhibitor Celebrex.

The U.S. Food and Drug Administration cautioned patients and doctors to limit their use of such drugs and will hold a meeting next month to discuss them. The European Medicines Agency is holding a similar meeting this week.

Dr. Garret FitzGerald of the University of Pennsylvania School of Medicine and colleagues used a statistical approach called meta-analysis to combine the findings of two trials to estimate the risk of heart attack and stroke in people taking Bextra, another COX-2 inhibitor made by Pfizer.

Their analysis, first presented at a Heart Association meeting last November and published this week in Circulation, suggests Bextra tripled the combined incidence of heart attack and stroke in heart bypass surgery patients.

NSAIDS work by suppressing two enzymes called COX-1 and COX-2. But they can cause gastrointestinal bleeding, and research had suggested that suppressing COX-1 caused this damage.

So drug companies worked to make drugs that only affect COX-2, the enzyme associated with pain and inflammation.

But in the second study, the researchers studied mice genetically prone to hardening of the arteries or atherosclerosis and found that a compound called thromboxane or TxA2, produced by COX-1, accelerates atherosclerosis.

"This is of particular interest, as low-dose aspirin prevents heart attack and stroke by blocking COX-1 formation of TxA2 in blood cells called platelets," FitzGerald said in a statement.

When a COX-2 inhibitor was added, something happened that may help explain why the COX-2 inhibitors raise the risk of a heart attack, said FitzGerald's colleague, Karine Egan.

"Addition of the COX-2 inhibitor caused changes that, if they occurred in humans, would result in a loss of stability of the plaque, making it more likely to rupture and activate clotting, causing heart attack or stroke," she said.

"These results would have disturbing implications for patients at high cardiovascular risk treated with aspirin and a coxib (COX-2 inhibitor)," FitzGerald said.