Merck's Vioxx Replacement Gets Mixed Reviews

Patient Expert

On November 13th, the Associated Press released an article showing mixed reviews of Arcoxia, the cox-2 inhibitor drug that Merck is hoping to market as a replacement for its drug Vioxx. Merck pulled Vioxx off the market in late 2004 because of studies showing an increased risk of heart attack / cardiovascular events when taking the drug.

The results of 3 studies were due to be published this week in the British journal called the Lancet and also presented at an American Heart Association conference. The studies, sponsored by Merck, compare Arcoxia to diclofenac. Diclofenac is sold in the U.S. by Novaris AG as both Cataflam and Voltaren. Merck is hoping that the studies will help persuade the FDA to give approval for Arcoxia in the U.S. Arcoxia has been approved for use in other countries for several years.

Merck pooled the results of the 3 studies. In total there were more than 34,000 arthritis patients, with an average age of 63, in the U.S. and 37 other countries. One third had heart disease or multiple risk factors for heart disease. Results reported are as follows:

  • After an average of 18 months on either drug, clot-related heart problems were statistically similar 320 among the 17,412 who started the study on Arcoxia, and 323 among the 17,289 on diclofenac.
  • About one percent of each group suffered a heart attack, stroke or death within a year of starting on their drug. That rose to about 2.5 percent three years later.
  • Arcoxia users were 30 percent less likely to have ulcers, stomach bleeding or other gastrointestinal problems (176 cases versus 246 on diclofenac), but the rate of serious problems was similar.
  • Slightly more than half of each group stopped taking whichever drug they had been assigned. Side effects were the reason for 20 percent of the discontinuations. More people quit Arcoxia because of high blood pressure; more stopped diclofenac because of stomach or liver problems. Congestive heart failure was rare but more common among those receiving a higher dose of Arcoxia than among those on a lower dose or diclofenac.

However, some scientists say the results do not make a case for the medication's approval. The critics cite both Arcoxia's side effects and the fact that Merck tested it against diclofenac, which is an older painkiller known to raise heart risks. Some say that a fairer comparison would have been to a medicine that does not do that, such as naproxen, sold as Aleve. They therefore believe that the development program for Arcoxia is "fatally flawed" and that the FDA should not approve Arcoxia.

Critics include Dr. Steven Nissen, a Cleveland Clinic cardiologist who formerly headed the Food and Drug Administration's cardiac drug advisory panel. Dr. Nissen is currently heading a large study for Merck rival, Pfizer, but is not receiving salary from Pfizer. All of the research revenue goes to the Cleveland Clinic Foundation. Another critic quoted in the article is Dr. David Graham, an FDA drug safety expert who criticized his agency's handling of the Vioxx approval. He was quoted in the article as saying that he believes the Merck study was intentionally designed to minimize the possibility of what happened in the trial related to Vioxx, which showed that Vioxx was more likely to cause heart attacks than its comparison drug. Therefore, for the Arcoxia trial they deliberately chose an older medication known to have heart-related side effects.

One of the co-authors of the Arcoxia research, Dr. Garret Fitzgerald of the University of Pennsylvania, believes that all cox-2 inhibitors (including Arcoxia, Vioxx, Celebrex and others) cause additional heart and stroke risk because they all work by the same mechanism. However, other medications such as naproxen are more likely to cause GI problems. So he sees it as a spectrum and prescriptions for the drugs should depend on each patient's symptoms and risk factors; doctors should prescribe drugs at the naproxen end of the spectrum to persons with heart disease (or with risk factors for it), and should prescribe cox-2 inhibitors to patients with known GI problems.