Vioxx and Bextra: Out of the frying pan into the fire? (BMJ 2004)

Some time ago in a discussion about possible future projects Iain Chalmers mentioned to me that he would like to see more work done around the question of whether new treatments were better than older established ones. It seems that the general impression conveyed by the marketers and advertisers is that new is better than old (which may have more than a little to do with the fact that manufacturers make much of their profit when new products are protected by patent).

Whilst I was in Canada at the 12th Annual Cochrane Colloquium the news broke that rofecoxib (Vioxx) had been withdrawn by the manufacturers and on my return I discovered that this was due to the results from a large long-term study on Vioxx to see what effect it had on polyps in the large bowel. The absolute increase in serious thromboembolic events was about 1% over 18 months, which was a doubling of the risk in the placebo group.

The problem is that these events are not very common and short-term trials looking at how well Vioxx performs as an anti-inflammatory agent would not have sufficient power to detect differences of this magnitude.

So in 2004 we had to decide what to do with patients who had been taking Vioxx? The crucial question is whether this is a class effect (which represents an increased thromboembolic risk in all Cox-2 inhibitors) or whether it is a particular problem with Vioxx. Two different questions could be asked:

1.Have other Cox-2 drugs been shown to increase thromboembolic risk?

2.Have other Cox-2 drugs been shown to be better than Vioxx for thromboembolic risk?

We did not know the answer to either question, but my guess it that those with a vested interest in the other Cox-2 inhibitors will major on the fact that we do not know the answer to question one, and those who are more concerned about safety will focus on the second question. The latter will also remember the issues related to delayed publication of adverse effects from SSRIs in adolescents mentioned in my last newsletter.

One alternative to Vioxx is Bextra (valdecoxib) and I was interested to read in today’s BMJ that concern has been voiced about delay in releasing information about Bextra following the withdrawal of Vioxx. Guess what one of the members of the FDA’s Safety and Risk Management committee has found?

“The first of the two trials was published but in a manner that obscured the risks, according to Dr Furberg. He said,’ They listed each [adverse] event individually and said the numbers were too small to analyse. But I added up heart attacks, strokes, and deaths and found a statistically significant fourfold increase over placebo.’” ‘ .

So do you think a class effect is likely? If you do then changing patients from Vioxx to another Cox-2 inhibitor may not be the right thing to do. This may be an instance where new is not better after all.