Vioxx, the anti-inflammatory drug taken off the market last fall because of safety concerns, could have caused thousands of heart problems and even deaths in the United States, a controversial study suggests.

The U.S. Food and Drug Administration study, published online Tuesday in the British medical journal The Lancet, says Vioxx could have caused up to 140,000 cases of serious heart disease in the United States since 1999.

• INDEPTH: Arthritis drug concerns

Merck & Co. halted worldwide sales of Vioxx in September 2004 after it was linked to an increased risk of heart attacks and strokes. (AP photo)

The lead researcher, Dr. David Graham of the FDA's office of drug safety, had previously disclosed his findings and the medical journal originally planned to publish them on Nov. 17.

The Lancet withheld the study after Graham accused his superiors of threatening to dismiss him if it were published.

COX-2 inhibitors were advertised for arthritis pain relief.

• FROM DEC. 17, 2004: Arthritis drug Celebrex linked to higher heart risk

Vioxx was recalled in September by its manufacturer, Merck and Co., after studies linked it to an increased risk of heart attacks and strokes.

34% higher risk of heart disease, study suggests

The study by Graham and his colleagues compares the incidence of coronary heart disease in patients taking Vioxx and other non-steroidal anti-inflammatory drugs known as COX-2 inhibitors.

They analyzed information from 1.4 million Californians who had used Vioxx (rofecoxib), Pfizer Inc.'s Celebrex (celecoxib) or similar drugs from 1999 to September 2004.

They found 8,143 people suffered coronary heart disease in the study, including 1,508 of who had sudden cardiac deaths.

When they examined the risk attached to each drug, they concluded that people taking Vioxx were nearly a third more likely to develop coronary heart disease – and many of these cases were likely fatal.

"An estimated 88,000-140,000 excess cases of serious coronary heart disease probably occurred in the U.S.A. over the market life of rofecoxib," Graham wrote.

"The U.S. national estimate of the case-fatality rate ... was 44 per cent, which suggests that many of the excess cases attributable to rofecoxib use were fatal."

• FROM DEC. 7, 2004: Review of arthritis drugs raises questions about role of regulators

In a commentary published in The Lancet, Simon Maxwell and David Webb of the University of Edinburgh urged researchers to study the risks of similar drugs.

"It now falls to the manufacturers, under the careful review of the regulatory authorities, to provide all the evidence that this class of drugs is safe, if necessary including studies that directly address cardiovascular morbidity as a primary outcome," Webb wrote.

FDA superiors questioned study's data

Graham has said his superiors at the FDA threatened him with "severe consequences" if his paper were published.

The acting director of the agency's Center for Drug Evaluation and Research, Dr. Steven Galson, contacted The Lancet in November to raise questions about the study.

"Some of the questions involve basic data integrity. [Graham] has declined to address these issues, and we think it's important that your readers know this," Galston wrote in an e-mail to Lancet editor Richard Horton.

Merck has also questioned some estimates by the researchers and said high blood pressure, smoking and other factors increase the risk of heart problems.

More studies flag Vioxx safety concerns

Just a day earlier, several other studies were published in the Archives of Internal Medicine that linked health concerns to Vioxx and Celebrex.

One paper in the U.S. medical journal echoes earlier research suggesting that the drugs might not provide older patients with as much protection as thought against gastrointestinal problems.

Another study suggests they have been overprescribed, often to patients who faced a low risk of developing stomach ailments.

Other research supported evidence that Vioxx raises blood pressure in some patients.

Scientists also wrote in the journal that Merck ordered one of its researchers to remove her name from a study linking Vioxx to heart attacks, then criticized the findings before pulling the drug.

Merck spokesperson Anita Larsen confirmed the action, but said the company believed the study's conclusions "were not supported by the data."

The FDA is meeting in mid-February to discuss the safety of all COX-2 drugs.