As reported by The Hartford Courant, November 20, 2004.

Warning About Painkiller Splits Drug Experts

Report of Bextra's Dangers Sharply Disputed

By William Hathaway

For anyone looking for certitude in the assessment of a drug's safety, the story of the painkiller Bextra is a cautionary tale.

Like its cousin Vioxx, Bextra has been labeled as a potential threat to a healthy heart.

How that happened is a mystery to Dr. William White at the University of Connecticut Health Center, the author of a study that found that arthritis patients who take Pfizer's Bextra have no additional risk of heart problems.

But to other scientists who study a family of drugs called Cox-2 inhibitors - including Vioxx, Bextra and Celebrex - warnings about the drugs are overdue.

During testimony to Congress on Thursday, David Graham, associate director of the Office of Drug Safety at the Food and Drug Administration, listed Bextra as one of five potentially dangerous drugs that the FDA has approved.

Others retort that such comments are unscientific fear-mongering.

Graham's testimony was "disgusting," said Dr. Lee Simon, a former FDA official and now professor of medicine at Harvard Medical School who has investigated Cox-2 drugs.

"Congress, if they knew or understood, would not be giving him a platform," Simon said. "What we don't need is inadequate science being passed off as fact."

The controversy over this class of painkillers began Sept. 30 when Merck recalled its bestselling drug, Vioxx. In a colon cancer prevention study, people taking the Cox-2 inhibitor were shown to have twice the risk of having a heart attack or stroke.

Merck and the FDA since have come under criticism that they ignored warning signs that Vioxx might represent a health threat. Some scientists have asked whether the whole class of Cox-2 inhibitors, which provide pain relief with a lower risk of stomach bleeding than aspirin, might also increase the risk of heart attacks and stroke.

Some basic science research supports the idea. Friday, the prestigious journal Science published a study that suggests that the activation of Cox-2 protects female mice from heart disease. The author of the paper, Dr. Garret FitzGerald of the University of Pennsylvania, has suggested that drugs that inhibit the action of Cox-2 might also increase the risk of cardiovascular disease in people.

While there have been no major health risks associated with Pfizer's Celebrex, which has been used by 27 million patients since 1998, Bextra has not been so lucky since it was introduced in 2001.

In his own review of literature on Cox-2 safety, Simon wrote that the limited available data reveal no significant risk of cardiovascular problems in patients taking Bextra. Simon did note, however, that the drug was associated with a higher incidence of hypertension.

However, earlier this month, a study by FitzGerald and Dr. Curt Furberg, a professor of public health at Wake Forest University, claimed that people who took Bextra had about twice the risk of having a heart attack or stroke.

When the study results were reported by some news outlets, it angered White, professor and chief of the division of hypertension and clinical pharmacology at UConn. The new study had not been reviewed by other scientists for accuracy and was not reported by any medical journal, White said. It also relied on data from an unpublished Pfizer study and also misused data from his own study, which came to the opposite conclusion on Bextra's safety.

"They cherry-picked the data for their own convenience," White said. "This was very improper."

The Pfizer study found increased risk for heart problems in patients who had undergone bypass surgery and only among those patients who took both the intravenous and oral form of Bextra, White said. There was no increased risk in bypass patients who took the oral form of Bextra alone, he said.

"And you wouldn't prescribe Bextra to heart bypass patients in the first place," said White, who has received fees from Pfizer in the past to conduct clinical investigations.

White's study, published earlier this year in the American Journal of Therapeutics and paid for in part by Pfizer, found no increased risk of heart problems when Bextra was given to patients with osteoarthritis and rheumatoid arthritis.

When using his data, the authors of the new Bextra study also did not take proper steps to ensure statistical validity of their work, White argued.

Both FitzGerald and Furberg were out of the country Friday and unavailable for comment, according to spokeswomen at their schools. Attempts to reach Graham were unsuccessful.

In a statement released Friday, Pfizer officials said Bextra has been shown to be a safe and effective pain reliever and the company is committed to long-term safety studies.

Simon said that for now he would continue to prescribe Bextra in low dosage for arthritis, but to avoid its use in patients undergoing vascular surgery.

White agrees more study needs to be done on Bextra, but he believes that evidence suggests that the Cox-2 story may turn out like the controversy surrounding the cholesterol-lowering drugs called statins. While one statin drug called Baycol had to be withdrawn from the market for safety reasons, other statins have proven to be safe and effective.

"We shouldn't be throwing out the baby with the bath water and assume that all these drugs will act the same way," White said. "We just don't know that right now."