Celebrex Is A Big Risk At High Doses
8 CommentsBy Ed Silverman // March 31st, 2008 // 12:02 pm
Patients taking the largest dose of 400 mg twice a day tripled their chance of a heart attack or stroke, compared with people taking a placebo, according to a study presented today at the American College of Cardiology meeting. The study confirms earlier concerns that prompted the FDA three years ago to warn that Celebrex and other painkillers, including ibuprofen and naproxen, should be prescribed at the lowest dose possible, Bloomberg News writes.
“There is clearly an increased risk with increased dose and because this tends to be with the higher doses it probably provides some level of comfort at the lower end of the Celebrex spectrum,” Scott Solomon, director of noninvasive cardiology at Brigham and Women’s Hospital in Boston and the author of the study, tells Bloomberg.
This is the abstract, this is the analysis, and this is Solomon’s presentation.
Patients taking 200 mg twice a day doubled their risk of a heart attack, but there was no increase in patients taking 400 mg once a day. That could be a result of chance because the number of patients studied was relatively small, Solomon tells Bloomberg. There was also an increased risk in people with heart disease, high cholesterol, diabetes or who smoked. Most arthritis patients are believed to take a total of 200 mg or less of Celebrex a day, according to Pfizer. The study didn’t examine risk for those lower doses, he adds.
Pfizer later removed Bextra and kept Celebrex should remain on the market, arguing there was no data showing a risk at the most commonly prescribed doses. The issue is being fought in court. A federal judge ruled last November that plaintiffs didn’t present scientifically reliable evidence that Celebrex caused heart attacks or strokes when taken at a daily dose of 200 mg. There are more than 3,000 lawsuits, but the ruling by US Districrt Court Judge Charles Breyer in San Francisco kept alive lawsuits involving the 400 mg dose.
Justice in Michigan
I am assuming we still don’t know the comparative CV risk of 400 mg. Celebrex bid, as compared with, say, 600 mg. ibuprofen, tid or qid.
Or do we?
Atlex
Ed, does the study show that these very high doses are a “big” risk as indicated in your headline; or, does it say that the risk is much higher than lower doses or placebo, but still a “very small” risk?
M Helm, MD
A piece of the answer to the question of cardiovascular risk and celebrex may be in Canada. Back in 2002, A Dr. Mamadani published a study examining risk of upper GI bleeding for celecoxib, rofecoxib, non-selective NSAIDs comparing to an incredible 100,000 strong control group selected from the provencial health claims files. Here’s the citation: BMJ. 2002 Sep 21;325(7365):62. He also published a similar study looking at risks of CHF hospitalization. More lately there has been an analysis of hypertension risks.
The original study methods permited identification of the low risks of upper GI bleeding. Though the absolute risks were very small, the design and size of the study allowed comparison of the risks between the different treatments. These methods could have been (and yet can be) adapted to answer the question of heart attack and other CV risks. However, Pfizer was so impressed with the original published reports that Dr. Mamdani got a plum job offer in International Outcomes Research. I understand from the nice folks at ICES in Toronto that he is no longer at Pfizer - don’t know if that is true or not.
In my experience, PhRMA companies don’t usually ask questions which don’t have relatively certain answers. If an unexpected result is found, you can be fairly sure the results won’t be public until the damage control plan is in place.
It is sad that now we know the predictable outcome that higher doses are more risky than lower doses. We actually already knew this from the discontinued colon cancer prevention trial. Sadder still is that we treat it as news simply because it is at the ACC. I can’t see how this gives us any assurances of safety (absolute or relative) of lower doses of celecoxib.
We are left with this question: Given all of the available, reasonable treatments are the cardiovascular risks of celecoxib lower, equal to or higher than any of the other agents?
The folks in Ontario could help us find an answer - even if it is with administrative data. This could have happened a long time ago if Pfizer had really wanted to know. They had the guy who could have done it with a few changes in some SAS code.
Ed Silverman
Hi Dr. Helm,
I appreciate your thoughtful comment. And you raise a good question. One thing I would like to note, however, is that I decided to post this item not merely because it popped up at the ACC, but because the issue concerning the high doses was fought in court just a few months ago, which I noted.
Thanks for stopping by,
ed
M Helm, MD
Ed,
Please understand, I’m glad you posted the piece. I appreciate the larger legal implications which you higlighted. I didn’t see that in Ms. Pettypiece’s story which seemed to be more about leveraging a presentation at ACC into increase sales of a product we should regard with some suspicion. I wasn’t at the ACC and didn’t see the data, but it seems that Dr. Solomon is reaching in the quote in the second paragraph above.
My interpretation would be simply: “the higher the dose, the greater the risk.” We don’t know the lowest safe dose of celecoxib. It may be zero milligrams.
My compliments on your site. It rivals the “Pink Sheets” of olden days, but much less expensive. The bonus is no need for a stupid distribution list stapled to the front of it to save a buck or two.
Bruce
Ah, the Pink sheets. That brought back a bit of nostalgia!
Ed Silverman
Hi Dr. Helm,
Understood. And thanks for the kind words. And I continue to appreciate your observations.
all best
ed
Larry
What was the change in absolute risk vs relative risk? Double and triple sounds dramatic in the press, however, how many events per 1000 pts are we talking about?