Report Links Arthritis Drugs To Heart Attack
Excerpt By Merritt McKinney, Reuters Health

NEW YORK (Reuters Health) - Popular anti-inflammatory drugs that were designed to be easier on the stomach than aspirin and other arthritis drugs may increase the risk of heart attack, researchers caution.

The report raises a red flag about the use of these drugs, known as COX-2 inhibitors, or coxibs, one of the investigators told Reuters Health.

``The coxibs, while extremely popular, appear to carry a small risk of heart attack, somewhere in the range of 0.3% to 0.5%,'' said Dr. Eric J. Topol of the Cleveland Clinic Foundation in Ohio. This translates to about 1 in 300 patients, he noted.

``Patients with heart disease should either take low-dose aspirin in conjunction with the coxibs or switch to a (traditional) nonsteroidal medicine instead of a coxib,'' Topol advised.

But more research is needed, according to Topol, ``because little is known to assert whether taking aspirin in conjunction with a coxib cancels out the heart attack risk or is safe from the standpoint of gastrointestinal bleeding.''

COX-2 inhibitors, like older drugs such as ibuprofen and naproxen, are nonsteroidal anti-inflammatory drugs, or NSAIDs. Older NSAIDs reduce inflammation by blocking an enzyme called COX-2, but they also block another enzyme called COX-1. This enzyme helps protect the lining of the stomach, so blocking COX-2 can cause stomach irritation. COX-2 inhibitors only block COX-2, leaving the stomach-protecting COX-1 alone.

To see what effect, if any, COX-2 inhibitors have on cardiovascular health, Topol and his colleagues analyzed the results of several clinical trials of the drugs. The results of the review are published in the August 22/29 issue of The Journal of the American Medical Association (JAMA).

In a study of more than 8,000 patients that compared the COX-2 inhibitor rofecoxib (Vioxx) with the traditional NSAID naproxen, the risk of cardiovascular problems, including heart attack, chest pain related to heart disease, stroke, sudden death and blood clots, was more than two times higher in the rofecoxib group than in the naproxen group.

Another study, which also included more than 8,000 patients, compared the COX-2 inhibitor celecoxib (Celebrex) with ibuprofen. Unlike the rofecoxib study, this trial allowed patients to be treated with aspirin as well.

There was no statistically significant difference in the rate of heart attack and other cardiovascular events between patients taking celecoxib and ibuprofen, the researchers report.

However, the annual rates of heart attack in both the celecoxib and rofecoxib studies were increased compared to a review of studies containing a total of more than 48,000 patients. In those studies, 0.52% of patients taking an inactive placebo pill had a heart attack each year. The annual rate of heart attack was 0.74% for patients taking rofecoxib and 0.80% for those taking celecoxib.

According to Topol and his colleagues, determining whether rofecoxib actually increases the risk of cardiovascular complications is tricky. They point out that the drug went head-to-head with naproxen, which acts on platelets in the blood to reduce the risk of clotting.

But the rate of cardiovascular complications in patients taking COX-2 inhibitors may be increased not only because the drugs lack the anti-clotting properties of other NSAIDs, according to the researchers. The fact that patients taking one of the COX-2 inhibitors were more likely to have a heart attack than patients taking placebo suggests that the drugs may actually promote blood clotting, they state.

Even though the anti-inflammatory effects of COX-2 inhibitors may alleviate the artery disease atherosclerosis, the possibility that the drugs increase the risk of cardiovascular complications needs to be studied, Topol and his colleagues suggest.

``Given the remarkable exposure and popularity of this new class of medications, we believe that it is mandatory to conduct a trial specifically assessing cardiovascular risk and benefit of these agents,'' they conclude.

But according to an official at Merck & Co., the maker of rofecoxib, the Food and Drug Administration has already been presented with additional research that shows that the drug does not pose an extra cardiovascular risk.

``What they don't review is a lot of other information that we have that addresses the same question'' of whether rofecoxib affects the risk of cardiovascular complications, Dr. Laura Demopoulos, the senior director of cardiovascular clinical research at the Whitehouse Station, New Jersey-based company, told Reuters Health in an interview.

In a review of studies including more than 28,000 patients, there was no difference in the rates of heart attack among patients taking rofecoxib, other NSAIDs or placebo, Demopoulos said.

That information is ``very reassuring,'' she said.

The additional data will be presented this week at the European League Against Rheumatism's annual meeting, according to a Merck press release.

In a statement released in response to the report, Merck also pointed out that the researchers compared the rofecoxib study, which enrolled patients with rheumatoid arthritis, with the placebo groups from studies that did not include patients with rheumatoid arthritis.

``To compare a group of patients taking Vioxx for rheumatoid arthritis with a placebo group of patients who do not have rheumatoid arthritis is inappropriate and misleading because one would expect a higher rate of cardiovascular events in the rheumatoid arthritis group, regardless of any medications,'' according to the statement.

In a new release issued by Pharmacia and Pfizer, the makers of celecoxib, the two companies ``strongly support the cardiovascular safety profile of Celebrex.''

``The article in JAMA is not based upon any new clinical study,'' according to the release. ``The companies believe it is essential to exercise extreme caution in drawing any conclusions from this type of analysis.''

Pharmacia and Pfizer assert that the analysis is ''misleading,'' since some of the patients in the celecoxib study were taking aspirin, too, but patients in the placebo groups were not taking aspirin. When the analysis is limited to celecoxib patients not taking aspirin, the heart attack rate is lower than of patients taking placebo, according to the two companies.

SOURCE: The Journal of the American Medical Association 2001;286:954-959.

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