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Analysis: Heart, Renal Risks Tied to Vioxx

Posted on: Tuesday, 12 September 2006, 21:00 CDT

By STEVE MITCHELL

Two studies released Tuesday indicate some COX-2 inhibitors and non-steroidal anti-inflammatory drugs increase the risk of cardiovascular and kidney problems, findings that could lead to a re-examination of these medications and impact Merck's efforts to fight Vioxx lawsuits.

In the first study, Patricia McGettigan and David Henry of the University of Newcastle in New South Wales, Australia, conducted a meta-analysis of studies in the medical literature and found COX-2 inhibitors and the older NSAID diclofenac increase the risk of cardiovascular events.

Controlled data from observational and randomized studies confirm a dose-related risk of cardiovascular events with selective COX-2 inhibitors, McGettigan and Henry wrote in the October 4 issue of The Journal of the American Medical Association. Both studies were released early due to their public health implications.

The observational data indicate that the risk increases early in treatment, the researchers added.

In regard to diclofenac, they noted that it appears harmful at doses commonly used to treat patients. We believe there are grounds for reviewing its regulatory status, they state in the journal.

Eric Ding, a doctoral candidate at the Harvard School of Public Health who was an author on the second study, told United Press International that even though two COX-2 inhibitors have been removed from the market -- Merck's Vioxx and Pfizer's Bextra -- the findings are important because there has been speculation that there might be a class effect and all COX-2 inhibitors, including two in development, could cause heart and renal problems.

It seems not necessarily true, Ding said. Vioxx stands out from all of them for adverse events related to renal problems and arrhythmia, he said.

However, he noted, that there was limited data for Merck's Arcoxia and Novartis' Prexige -- two COX-2 inhibitors in development -- so he does not feel comfortable drawing definitive conclusions about those medications from this analysis.

Ding's team conducted a meta-analysis of 114 randomized trials of COX-2 inhibitors and found that Vioxx, but not other drugs in this class, increased the risks of arrhythmia and renal events, including peripheral edema, renal dysfunction and hypertension.

The findings of arrhythmia could make it more difficult for Merck to prevail in some of the pending lawsuits involving people who died or claim they were injured after taking Vioxx. Merck has previously said the evidence did not indicate the drug increased the risk of arrhythmia.

FDA employee Dr. David J. Graham, who wrote an accompanying editorial that reflects his personal views and not that of the agency, told UPI the findings shoot down two other arguments Merck has previously advanced. One being that Vioxx did not the increase the risk of heart attack until after 18 months of use. The other being that Vioxx was not as dangerous to the heart as it appeared in one study because it was compared against naproxen, which somehow protected against heart attacks.

What we see now clearly is Vioxx increases the risk of heart attack at low and high doses, said Graham, who became a whistleblower against the FDA in 2004 and accused the agency of lax oversight on Vioxx and other medications. The drug is unsafe at any dose and the risk begins early, probably with the first dose, not 18 months later.

The findings also establish naproxen is safe as far as the heart is concerned, Graham said. It doesn't increase or decrease the risk.

He said the studies raise the question of whether the COX-2 inhibitors have an acceptable cost-benefit profile.

Economically, if I was a third party payer, why should I spend $3 a table knowing that it causes these side effects when for a fraction of that cost (for generic naproxen) I could get pain relief and no side effects on the heart? he said.

Graham said the findings on Vioxx highlight the problems with the agency's current method for approving drugs.

The problem is you have a system that is completely bankrupt and it's not working for the American people, he said. It's guaranteed there will be other major drug disasters.

Asserting that Vioxx should not have been approved in the first place and was responsible for the deaths of 60,000 Americans, he said FDA and Congress should share the blame.

FDA is not held accountable and Congress does nothing about it, he said. Thirty times the number of people were killed by Vioxx as were killed in 9/11, but what has Congress done? Absolutely nothing.

Ding said ongoing meta-analyses, such as the one his team performed, may be useful for monitoring the safety of drugs once they are on the market.

The passive reporting system the FDA uses has many limitations, he said. We believe an active accumulative system would have detected adverse events sooner.

The renal effects of Vioxx were apparent as early as 2000 and arrhythmia as early as 2004, the year Merck pulled it off the market, he noted.

Source: United Press International

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