Healthy Skepticism Library item: 7229

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Publication type: news

Herper M.
In Vioxx's Wake
Forbes.com 2006 Nov 14
http://www.forbes.com/2006/11/13/merck-vioxx-successor-biz-cz_mh_1114vioxx.html?partner=yahootix

Abstract:

Vioxx ignited a drug safety backlash. Now some doctors seem ready to revolt against the resulting hair-trigger safety environment—even as the debate about Vioxx and drugs like it rages on.

If either of two bills working their way through the Senate pass, it could lead to the largest reorganization of the Food and Drug Administration in decades. A first step will come on Thursday, as the Senate’s Committee on Health, Education, Labor and Pensions holds hearings on reforming the FDA. Meanwhile, Vioxx’s maker, Merck, faces some 20,000 product liability lawsuits related to the drug, potentially costing it many billions of dollars.

Into this climate, Merck on Monday released the full data set for a gigantic study of Arcoxia, its Vioxx follow-up, here at the annual meeting of the American Heart Association. Like Vioxx, it is an arthritis drug that works by inhibiting the enzyme known as COX-2, without knocking out another enzyme called COX-1. The upshot was that the newer drugs, including Celebrex and Bextra from rival Pfizer, did less damage to the stomach than older medicines like naproxen (sold as Aleve), ibuprofen (Motrin or Advil) or diclofenac (a Novartis drug called Voltaren).

But COX-2 inhibitors also appear to cause more heart attacks and strokes than placebo, a fact that led Merck to yank Vioxx from the market in 2004. Merck’s Arcoxia study, begun in 2002, followed 44,000 patients for a year and a half, on average. Patients received either Arcoxia or diclofenac, and there was no difference in the number of heart attacks, strokes or death, or major stomach bleeding. Arcoxia was linked to high blood pressure and fluid retention that can lead to heart failure, and diclofenac caused more ulcers.

Merck has submitted the new data to the FDA in the hope of getting Arcoxia approved as an arthritis treatment, but the Merck-funded study, known as MEDAL, is unlikely to change many minds. (See: “Vioxx, The Sequel.”) But it does give some important clues as to how the larger arguments about drug safety are likely to play out.

Christopher Cannon, the Brigham & Women’s Hospital cardiologist who ran the MEDAL study, says that to his mind, it settles a major question. Arcoxia was as safe as a widely used painkiller, and it (or drugs like it) could provide an option to the 46 million Americans who suffer from arthritis pain. Risks to the stomach and heart need to be balanced against one another. “One size won’t fit all,” he says. “We won’t come out of this with an absolute answer.”

Too much of what is known about Vioxx’s risks comes from so-called observational studies, which don’t randomize patients to two different drugs to compare them. Such studies often show benefits where none exist. Moreover, he says, based on data from other randomized, controlled trials, he doesn’t see big differences between any of the COX-2 drugs. “The full set of data makes Vioxx look pretty similar to all the other COX-2 inhibitors,” says Cannon, “Celebrex included.”

Steven Nissen, chairman of cardiology at the Cleveland Clinic, says that he “does not agree with the interpretation” that the data from MEDAL shows no cardiovascular risk for Arcoxia. The study, he says, “was fatally flawed from the beginning” because it compared Arcoxia to diclofenac, which may itself pose a risk to the heart.

In a statement, the American Heart Association maintained that COX-2 inhibitors like Arcoxia or Celebrex should be used only as a last resort in patients who cannot take other arthritis drugs. The AHA said that “more long-term data are needed to fully evaluate” the risks and benefits of these drugs. Raymond Gibbons, a professor at the Mayo Clinic and the AHA’s president, said that at the very least, Arcoxia’s single benefit in terms of reducing ulcers is likely to come with a big difference in financial cost.

Garret FitzGerald, the University of Pennsylvania pharmacologist who was a critic of the COX-2 inhibitors but is also one of the authors of the MEDAL study, says that he sees a great irony in the results. “All this evidence brings us back to where we began,” he says. From the start, the COX-2 drugs were designed for a limited number of patients—those who were at high risk for ulcers and other stomach problems. That is still where they should be used, he says.

How should patients figure out which drug to use? Researchers don’t agree. Cannon says only to weigh data from controlled clinical trials, which are expensive and are funded mostly from drug companies.

Nissen has said that observational data needs to be in the safety equation, but also favors big trials—he is conducting one, paid for by Pfizer, that will compare the heart safety of Celebrex, naproxen, and ibuprofen. FitzGerald favors a totally different approach, using small studies to try and understand how the drugs favor in individual patients.

Now legislators are about to wage into this scientific morass. At least they’re likely to be more thoughtful than plaintiffs’ lawyers.