More Skeptical Voices Join the Cox-2 Inhibitor Debate

Arcoxia was launched in a number of foreign markets in 2002, and it is now available in 48 countries. Merck submitted an application to the FDA in 2003. In October 2004, the agency gave conditional approval with major conditions attached -- Merck must conduct additional safety and efficacy tests. Merck is seeking to have Arcoxia approved for osteoarthritis, rheumatoid arthritis, acute pain, menstrual pain and several other uses.

The FDA staff report said the Merck application for Arcoxia makes overall comparisons of the drug's cardiovascular impact difficult to assess. The staff was especially critical of a 7,000-patient study, nicknamed Edge, which examined a narrow group of patients, failed to heed an FDA recommendation to compare more drugs and used a lower dose of Arcoxia vs. a higher dose of another pain reliever.

However, when Arcoxia was compared against placebo or older pain relievers, "the results appear to demonstrate that etoricoxib is worse than each comparator" in terms of cardiovascular safety. Etoricoxib is the generic name for Arcoxia, which was compared vs. placebo and several older pain relievers.

"For cardiovascular-related deaths, there appears to be an excess of cases due to etoricoxib compared to placebo although the exposure to placebo is limited," the report said.

"The data related to naproxen clearly shows an excess of cardiovascular mortality related to etoricoxib," the report said. "The explanation for these results is not clear and may or may not be related to a protective effect of naproxen, [which is] not demonstrated."

(In defending its handling of Vioxx, Merck has said that a test four years ago showing a greater cardiovascular risk for patients taking the drug vs. patients taking naproxen might be explained by an alleged heart-protective effect of naproxen rather than a heart-impairing effect of Vioxx. Merck said it pulled Vioxx from the market only after the heart risk for Vioxx patients was measured vs. patients taking a placebo.)

The report added that "superficially, the rates for cardiovascular related deaths" between patients taking Arcoxia and patients taking non-naproxen pain relievers are similar.

"There appears to be an increase in the incidence of hypertension" among Arcoxia users, the FDA staff report said. But this evaluation depends on which drug is being tested against Arcoxia. This difference in high blood pressure "is clear" vs. patients receiving diclofenac, an older painkiller, now generic, which is sold under the brand name Voltaren from Novartis. "This is less so" when comparing Arcoxia to naproxen, the report said.

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