Vioxx Ban Tied to Rise in Serious GI Trouble

THURSDAY Nov. 8, 2007 -- Pulling the painkillers Vioxx and Bextra off the market to spare patients' hearts may have ended up harming their stomachs, a new study suggests.

Rates of gastrointestinal events serious enough to require hospitalization have risen significantly since the cox-2 inhibitor medications were ordered off the market in 2004-2005, researchers say.

"It's like our focus shifted from the reason that we were using these drugs -- against GI bleeds -- and onto something else. We left our eye off the ball, and this is what has happened," said study author Dr. Gurkipal Singh, a rheumatologist and a clinical professor of medicine at Stanford University School of Medicine.

His team presented its findings Thursday at the American College of Rheumatology annual meeting, in Boston.

Cox-2 inhibitors such as Vioxx, Bextra and Celebrex are a subset of a larger group of painkillers called non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs such as aspirin, ibuprofen (Advil, Motrin) and naproxen (Aleve) relieve pain, but they also raise risks for GI tract complications, including bleeding.

Cox-2 inhibitors were heralded as a safer alternative to other NSAIDs precisely because they offered users a much lower risk of these side effects.

In their heyday, millions of Americans took the drugs. However, beginning in late 2004, the U.S. Food and Drug Administration called for the withdrawal of Vioxx and then Bextra, after studies suggested higher rates of serious cardiac events in long-time users. Only Celebrex remains on the market.

The Vioxx and Bextra withdrawals may have come at a cost, however, as Americans battling pain reached again for NSAIDs.

In their study, Singh's team tracked the use of cox-2 inhibitors from their introduction in 1999 until the end of 2005. In total, they looked at almost 4.5 million prescriptions for NSAIDs written for American arthritis patients over 65.

The Stanford team found that the rate of serious gastrointestinal events -- bleeding ulcers leading to hospitalization or death -- declined steadily from 1999 to 2003 as sales of cox-2 painkillers surged.

In 2004, the last year in which all three cox-2 drugs were still on the market, the incidence of serious ulcerations hit an all-time low of 357 cases per 100,000 NSAID prescriptions filled.

But a year later -- after the Vioxx/Bextra withdrawals and attendant controversy -- those levels had already climbed to 434/100,000, a 21 percent increase, the study found.

Experts said they aren't shocked by the findings.

"With decreasing use of gastroprotective therapies, it comes as no surprise to see a substantial increase in NSAID-related GI adverse events," said Dr. Mark Fendrick, a professor of internal medicine at the University of Michigan School of Medicine. He has followed the cox-2 saga closely, co-authoring a commentary on the drugs' risks and benefits for The Lancet earlier this year.

According to Fendrick, it's unclear whether the cardiovascular health gains achieved by removing Vioxx and Bextra from the market have now been outweighed by a surge in serious gastrointestinal events.

"What's always bothered me as a general internist is that every study that you ever read on this either looks at the GI side or the cardiovascular side -- never both," he said. A study that compared both aspects in the same population might provide real guidance, he said.

"Then I might be able to say 'Oh, if we saved 1,000 lives from heart disease by increasing GI adverse events by X percent, then maybe we are doing the right thing,'" Fendrick said. So far, no such study has been done, he added.

Fendrick believes patients still have relatively safe treatment options, however.

"We got into this mess in the first place, because we had known for a long time that non-steroidals of all types have a well-documented increase in GI adverse events," he said. "So, we created two strategies to prevent them."

One strategy was to use a cox-2 inhibitor to help relieve pain. The other was to "buffer" an NSAIDs effect on the GI tract by giving patients medications such as proton pump inhibitors (PPIs), which protect against bleeding. PPIs include drugs such as Nexium and Prilosec.

The second strategy remains useful, he noted. "In patients who have known GI risk factors and are taking aspirin, most experts now suggest that you have to have additional gastroprotective therapy [such as a PPI] whether you are on a cox-2 inhibitor or not," Fendrick said.

Another expert agreed, but said doctors are often in a bind when a patient taking an NSAID comes to them with gastrointestinal problems.

Switching to the remaining cox-2, Celebrex, is an option, but many drug plans won't pay for it, said Joe Biskupiak, a research associate professor of pharmacology at the University of Utah in Salt Lake City.

"The easier solution is clearly taking a gastroprotective agent," he said.

Unfortunately, the blockbuster drug Prilosec has been sold over-the-counter since 2003, meaning that most drug plans won't pay for it, either.

"This creates a problem for physicians. They know what the right thing is to do -- just tell the patient to go to the store and buy [Prilosec]," Biskupiak said. "But many patients aren't going to do that."

The result is patients wind up with little protection against gastrointestinal troubles, he said.

So, was the FDA's decision to withdraw Vioxx and Bextra wrong?

"I don't have an answer to that," Singh said. "To my own mind, the whole noise around this issue has just led to a dramatic decrease in cox-2 inhibitor use but not a concomitant increase in PPI use. That's the problem."

More information

There's more on painkillers at Medline Plus.

Posted: November 2007


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