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Vioxx Most Dangerous Cox-2 Drug: Studies

Its heart-threatening effects emerge early and rise with dosage, research shows

TUESDAY, Sept. 12, 2006 (HealthDay News) -- Two studies suggest that the banned prescription painkiller Vioxx was more dangerous for users than its two cox-2 inhibitor rivals, Bextra, also withdrawn, and the still-available Celebrex.

Heart risks linked to Vioxx -- which was pulled from drug store shelves in 2004 -- began to emerge almost immediately, researchers say, and escalated along with the dose taken.

"Not all cox-2 inhibitors have the same adverse effects," said the co-author of one study, Eric Ding, a graduate student in the department of epidemiology and nutrition at the Harvard School of Public Health.

The Journal of the American Medical Association published the studies and an accompanying editorial early in its Sept. 12 online edition because of the findings' public-health implications. The articles will appear in the journal's Oct. 4 print edition.

Cox-2 inhibitors are part of a class of analgesics called non-steroidal anti-inflammatory drugs (NSAIDs), which also include widely used medications such as aspirin, ibuprofen and naproxen (Aleve). Cox-2 inhibitors were originally developed because they are safer on the stomach than other NSAIDs.

However, Celebrex is the only cox-2 inhibitor left on the market. Vioxx and Bextra were withdrawn in 2004 and 2005, respectively, following reports of heightened cardiovascular risks associated with their use.

As mandated by the U.S. Food and Drug Administration, Celebrex now carries a special "black box" warning that advises consumers of the potential heart dangers.

More data on the safety of cox-2 inhibitors continues to emerge.

In one of the two new studies, Ding and his colleagues at Harvard tracked the drugs' effects on kidney function. The team reviewed the results of 114 randomized trials involving more than 116,000 people.

They found that Vioxx increased risks for adverse kidney events and irregular heart rhythms. These problems were not apparent with Bextra and Celebrex, however, suggesting there is no "class effect" linking all cox-2 inhibiting drugs to kidney trouble and arrhythmias.

Based on the data, Ding's group said these effects may be unique to Vioxx.

More could have been done to ferret out Vioxx's harmful side effects before any real damage was done, Ding said.

"The risks of these drugs should have been made known to the public much earlier," he said. In addition, "tracking drug safety may be improved by adopting an active and continuous cumulative surveillance system."

In the second study, Australian researchers reviewed 17 studies comparing the use of painkillers for 86,000 people with a history of cardiovascular events to more than 500,000 healthy "control" participants. Six other studies included over 75,500 users of cox-2 inhibitors, more than 375,000 users of other NSAIDs, and nearly 600,000 people who used neither.

Researchers at the University of Newcastle found that heart-attack risk rose as the dose of Vioxx increased. This risk was most pronounced in the first month after users started taking the drug.

In addition, the team found that one non-cox-2 NSAID, diclofenac, also increased the risk of a heart attack and, "it appears to be harmful at commonly used doses. We believe there are grounds for reviewing its regulatory status."

One expert said he wasn't surprised by the findings.

"It is clear that Vioxx increases the risk of heart attack. And that increase in risk begins with the first tablet a patient takes," said Dr. David J. Graham, the associate director for science in the Office of Drug Safety at the U.S. Food and Drug Administration and author of the accompanying journal editorial.

Graham first came to prominence in the Vioxx debacle as an insider "whistleblower" when he delivered testimony to a special Senate hearing on the matter late in 2004.

Merck & Co., the maker of Vioxx, claimed that the drug did not increase the risk for heart attack but actually protected people from heart attack, Graham said. "That's not true," he said.

These drugs were designed to prevent bleeding in the intestines, which is always a danger with NSAIDs. "But for every serious intestinal bleed that they prevented with the drug, they caused a heart attack," Graham said.

Until recently, Merck had contended that Vioxx-linked heart risks only arose in users after they had taken the drug for 18 months or more. But research revealed that cardiovascular risks kicked in at four to six months of use.

An estimated 16,000 Vioxx-related lawsuits have been filed against Merck in state and federal courts. The third federal trial began Monday in New Orleans.

Graham noted that the public can reach for safe, cheap and equally effective alternatives to cox-2 drugs to relieve pain.

There's a lot of blame to go around -- starting with Merck, Graham said. He also cast some blame on the FDA. "In this case, they knew before the drug came on the market that Vioxx increased the risk of heart attack," he said.

In response to Graham's editorial, the FDA released a statement Tuesday that read, in part: "Dr. Graham's views expressed in the accompanying editorial are his own, and do not reflect the official positions of the FDA. Dr. Graham provides his personal views on the issue of what NSAID he would recommend to patients in need of long-term use of an analgesic, however, the FDA does not believe the available data rise to the level required to support an official FDA regulatory decision regarding comparative safety and efficacy of the available COX2-selective and non-selective NSAIDs."

More information

There's more on cox-2 inhibitors at the U.S. Food and Drug Administration.

SOURCES: Eric Ding, doctoral candidate, department of epidemiology and nutrition, Harvard School of Public Health, Boston; David J. Graham, M.D., M.P.H., associate director for science, Office of Drug Safety, U.S. Food and Drug Administration, Rockville, Md.; Sept. 12, 2006, online edition, Journal of the American Medical Association
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