Monday, March 16, 2009

Celebrex--What Don't We Know Yet about Its Risks?

As summarized in HOOKED, Celebrex (celecoxib) is the only COX-2 selective nonsteroidal antiinflammatory drug left standing in the marketplace, though its sales are way down from its heyday, before its cousins Vioxx and Bextra got yanked. As you no doubt know, the other COX-2s bit the dust due to their excessive risks of cardiovascular disease due to increased blood clotting--the downside of the beneficial mechanism of the COX-2s by which they were supposed to have prevented bleeding from the gastrointestinal tract (a fond hope that was never realized in practice to the extent predicted in the lab).

Pfizer, who makes Celebrex, would love to believe, and to have us believe, that because it's chemically different from Vioxx and Bextra, the big-time cardiovascular risks attendant upon those drugs are either much reduced, or virtually non-existent, with Celebrex. The position I took in HOOKED was that the bulk of the evidence showed that the CV risk is a class effect, and that while Celebrex might be relatively safer than Vioxx or Bextra, it's still riskier than the non-COX-2s like ibuprofen and naproxen. Given that Celebrex has never been shown to have superior pain-relieving properties, and given that it costs ten times as much as the generic nonsteroidals, it seems a no-brainer not to prescribe it. So who's right--me or Pfizer?

The Dynamic Duo of journalists Jeanne Lenzer and Shannon Brownlee recently weighed on the Center for Public Integrity website: Their cogent analysis is well worth reading in its entirety. Here are some highlights.

Quite independent of the scientific question of whether Celebrex is heart-risky or not, Pfizer has managed to stage two major public relations coups. The first was handed to them by the FDA. The FDA's scientific advisory panel agreed with my point of view back in 2005. The FDA bigwigs then caved to commercial interests and obscured the issue, by demaning that all nonsteroidals (even naprosyn and ibuprofen who were not part of this dogfight in the first place) carry a warning of increased heart risk. If, by virtue of equal labeling, Celebrex appears to be no more risky than over-the-counter Motrin, then that seems to send a strong message to physicians and the public that whatever low risk Celebrex might carry is not worth worrying about. This, L&B quote an insider, is standard industry strategy. If you can't get the FDA label you want for your own drug, then at least be sure that the bad label is slapped on all your competitor drugs too.

The other big coup for Pfizer, Lenzer and Brownlee continue, is a study called PRECISION. Its lead investigator is Dr. Steve Nissen, cardiologist at the Cleveland Clinic, who is often a hero to the skeptical-of-Pharma crowd, as he was for his work in exposing the heart risks of the diabetes drug Avandia (rosiglitazone). Here he gets to be the goat. PRECISION is designed to answer the question of the relative cardiovascular risks of Celebrex, ibuprofen, and naprosyn, by enrolling 20,000 subjects at 637 international sites (at a cost of a whopping $100M). Subjects will be selected from groups known to be at high risk for heart disease, to make sure that enough adverse events occur to be able to get a good read on which drug causes the most.

Dr. Nissen's take on this according to L&B: there remains a valid open question as to which drug is the lowest risk and so should be preferred in practice. L&B's rejoinder: this issue was settled by the FDA advisory committee back in 2005. The only advantage to doing the PRECISION study now is Pfizer marketing. While the study is ongoing, Pfizer can claim in rebuttal to anyone who accuses Celebrex of carrying excess heart risks, "the data are not in yet." When the data finally are in, and even if PRECISION then shows that Celebrex clearly has higher risks, guess what--that's just about the time that Celebrex is scheduled to go off patent, so the study is low-risk for Pfizer marketing (even if high-risk for the hapless research subjects).

L&B's most telling criticism: the consent form for PRECISION (which Pfizer, Dr. Nissen, and the Cleveland Clinic all refused to release, but which the journalists obtained via a leak) says flat out, “At this time, no studies have shown that celecoxib [Celebrex] causes more heart attacks or strokes than prescription ibuprofen or naproxen in the treatment of patients with chronic arthritis.” That statement, as L&B document and as I showed in HOOKED a couple of years ago, is simply not accurate. If you have to falsify the data to get people to enroll in your study, that says something about how valid the study is.


Anonymous said...

Ay caramba! Why would a responsible physician prescribe anyone Celebrex, let alone a failed gastric bypass pt who takes hydrocodone/APAP like she's eating M&Ms? (Never mind that the hydrocodone is ototoxic and the APAP causes liver damage...)

Anonymous said...

According to, numerous PRECISION study sites terminated after the article was published. Check out NCT00346216 "History of Changes" on 4/8/09 and 5/2/09. You will need to uncheck "Hide non-essential portions."