Yanking Vioxx and Pfizer’s Bextra - both of which were Cox-2 inhibitors - to reduce the risk of heart attacks may have hurt plenty of stomachs, according to a study released this past week. The rate of gastrointestinal events serious enough to require hospitalization rose significantly since the meds were yanked in 2004 and 2005, HealthDay News reports.

“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,” says study author Gurkirpal Singh, a Stanford University School of Medicine professor. You may recall the Cox-2 inhibitors, which includes Celebrex, were pitched as safer than older NSAIDs, such as aspirin, ibuprofen and naproxen, because they relieved pain, while lowering GI risks.

In the 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 scrips for NSAIDs written for arthritis patients over 65. The rate of serious GI events - bleeding ulcers leading to hospitalization or death - declined steadily from 1999 to 2003 as sales of cox-2 painkillers surged, HealthDay writes.

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 But a year later - after Vioxx and Bextra were withdrawn - those levels had already climbed to 434 per 100,000, a 21 percent increase, the study found.

So, was the FDA’s decision to withdraw Vioxx and Bextra wrong? “I don’t have an answer to that,” Singh says. “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 (proton-pump inhibitor) use (which protect against GI bleeding). That’s the problem.”

Singh, you may recall, was bullied by Merck for criticizing Vioxx until his boss complained to Merck execs. In his 2004 testimony before the Senate Finance Committee, Singh was unequivocal that Vioxx was “not the proudest chapter in drug approval in the US.” He cited controversy over Merck’s handling of heart-risk data. So if the FDA was wrong to have approved Vioxx, why is Singh unclear now whether Vioxx should have been withdrawn?

UPDATE: We wrote Singh and this is what came back: “I was presenting my scientific research findings at the American College of Rheumatology when I was asked that question….

Our study was not designed to assess if the FDA decisions around Vioxx were correct or not. I was answering a question in a scientific forum of ACR, and tried not to get into a discussion on issues that our study did not directly address…

Later on, in my press conference, I pointed out that there are multiple ways to reduce GI bleeds, besides prescribing Vioxx. One cannot directly link Vioxx withdrawal to the increase in GI bleeds, as some of the news reports have suggested - there are multiple other ways to prevent GI bleeds. One fact appears clear - we did seem to have taken our eyes off the ball when it came to the risk of serious GI bleeds…But Vioxx withdrawal in and by itself need not have led to the increase in GI bleeds.”

Experts, meanwhile, 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,” Mark Fendrick, a professor of internal medicine at the University of Michigan School of Medicine, tells HealthDay News. He has followed the cox-2 saga closely, co-authoring a commentary on the drugs’ risks and benefits for The Lancet earlier this year.

Fendrick believes 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 says.

A study that compared both aspects in the same population might provide real guidance, but such studies haven’t been conducted. “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,’” he says, adding that patients still have options. “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. 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 meds such as proton pump inhibitors, such as Nexium and Prilosec, which protect against bleeding. “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 says.

Another expert agreed, but says docs 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, says 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.”

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 adds.