As reported by The Hartford Courant, December 18, 2004.

A Second Look at an Entire Class of Pain Relievers

By William Hathaway

The withdrawal of the popular pain reliever Celebrex from a cancer prevention trial may mean that an entire class of widely prescribed drugs increases the risk of cardiovascular disease - or it may simply serve as a warning not to take Celebrex in high doses.

Different scientists have different opinions on which lesson should be drawn from Friday's announcement by Pfizer Inc. about Celebrex, one of a class of drugs known as Cox-2 inhibitors that includes Bextra and Vioxx.

"This result ends the controversy as to whether there is a class effect. We now have clear-cut evidence of a cardiovascular risk from controlled trials of Vioxx, Bextra and Celebrex," said Dr. Garret FitzGerald, a University of Pennsylvania scientist whose animal studies have shown that Cox-2 drugs increase the risk of heart disease.

But Dr. William White at the University of Connecticut Health Center notes that a different study of Celebrex showed no ill effects when the drug dosage was 400 milligrams. The increased risk of heart problems did not occur until dosage was increased to 800 milligrams - four to eight times the dose typically prescribed by doctors.

"What the new study suggests is that at higher doses there may be, over a period of a few years, an increased risk for a small percentage of patients," said White, who has conducted clinical trials of Cox-2 inhibitors for Pfizer and other pharmaceutical companies.

The National Cancer Institute's prevention trial did, however, find a higher likelihood of heart attack or stroke in patients taking 400 milligrams of Celebrex.

Ernest Hawk, the NCI's chief of gastrointestinal research, said patients on the 400 milligram dosage were 2.5 times more likely to have a heart attack or stroke than the group taking a placebo.

White concedes that he was surprised to see any health risk at all associated with the use of Celebrex, which has been widely studied and prescribed to more than 27 million patients since it was approved for use in 1998.

"I think 800 milligrams might just be high enough to cause an increase in blood pressure," White said.

High blood pressure was also a side effect of Vioxx, but at doses close to those normally prescribed to arthritis patients White said.

"That didn't happen with Celebrex," he said.

Merck, the maker of Vioxx, pulled the drug from the market earlier this year because people participating in a cancer prevention trial had about double the risk of a heart attack or stroke. Merck and the U.S. Food and Drug Administration have been accused of ignoring warning signs that Vioxx might represent a health threat.

Pfizer did not say Friday it had plans to withdraw Celebrex from the market.

FitzGerald said the FDA should look closely at the drug. His studies have shown that the Cox-2 enzyme protects female mice from heart disease, he said, and he suspects that drugs that inhibit Cox-2 will be likely to increase the risk of heart disease in humans.

"As we strive to retain the value of this class of drugs, there are serious lessons to be learned concerning the way we approve and advertise drugs and the way in which pharmaceutical companies react to the emerging evidence of risk," he said.

While some Cox-2 inhibitors have been proven to reduce gastrointestinal complications caused by long-term use of other pain-relievers, such as aspirin, Celebrex has not, FitzGerald said.

FitzGerald said he would personally choose a cheaper, non-steroidal, anti-inflammatory drug such as ibuprofen.

White, however, said that over-the-counter medication such as ibuprofen or naproxen taken at high doses over long periods of time might also cause cardiovascular problems.

"We just don't know," White said.