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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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« We Have Ways of Keeping You Safe | Main | Prices and Innovation »

October 7, 2004

How Bad Are the Cox-2 Inhibitors, Anyway?

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Posted by Derek

Since Merck pulled Vioxx (rofecoxib) off the market, the big question has been whether its cardiovascular problems are specific or general. Do all COX-2 inhibitors have this liability? If so, do they all have it to the same extent? The analogy that comes to mind is the statins - all of them have been shown, at high enough dosages, to be associated with a potential for rhabdomyolosis, a serious muscle side effect. But Bayer's entry into the class, Baycol, showed it more than the others and had to be pulled.

Pfizer's been saying that they have seen no evidence of trouble for their Celebrex (celecoxib). But there's an interesting perspective in the latest New England Journal of Medicine. (That link will allow you to download a free PDF of the article.) The author, Garret Fitzgerald of U Penn, suggests that there could be trouble enough to go around.

The story involves two signaling molecules formed from the COX enzymes, thromboxane A2 and prostaglandin I2. Aspirin inhibits both COX-1 and COX-2, and suppresses the formation of both of them. The thromboxane, formed by COX-1, causes vasoconstriction and platelet aggregation, while the prostaglandin causes the opposite - it dilates blood vessels and inhibits platelet aggregation.

Neither Vioxx and Celebrex touch the thromboxane A2 pathway, naturally, but they both suppress the formation of prostaglandin I2 in humans. This was a weird result when it came out, because it was assumed that this molecule was made via COX-1 too, which these drugs don't inhibit. It later turned out that it's also made by COX-2 - which at least made sense from the drug standpoint - but that was still odd, because that enzyme wasn't supposed to be in the blood vessels at all.

But it seems that COX-2 can be induced there, especially when the vessel walls are subject to shear stress from blood flow. Problem is, when you inhibit that prostaglandin's formation, you've taken off a brake to platelet aggregation and you've probably caused some vasoconstriction, too. They're trying to make more of the prostaglandin, but the drug is preventing that from happening.

FitzGerald doesn't put any sugar on it:

"We now have clear evidence of an increase in cardiovascular risk that revealed itself in a manner consistent with a mechanistic explanation that extends to all the coxibs. (Emphasis mine - DL) It seems to be time for the FDA urgently to adjust its guidance to patients and doctors to reflect this new reality. . .The burden of proof now rests with those who claim that this is a problem for rofecoxib alone and does not extend to the other coxibs."

Over to you, Pfizer! Uh, Pfizer? Oh. . .I see. . .

Comments (6) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Toxicology


1. Chris on October 8, 2004 2:47 PM writes...

Why is Searle (a division of Pfizer) marketing both Bextra and Celebrex? What's the difference?

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2. Brent M Krupp on October 10, 2004 12:50 AM writes...

Interesting. Back when I was in medical school and these drugs were on the horizon (mid-late 90s), we speculated that folks might do worse from a cardiac standpoint by switching away from various NSAIDs that at least theoretically have a bit of anticlotting protection (nothing like aspirin, but perhaps still helping). I always wondered if this hypothesis was investigated, but I've been to lazy to actually look at the research on these drugs.

Little did I know that they might have a directly harmful effect. Poor Pfizer.

[P.S. this comment form needs a preview function, IMO]

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3. Old Patriot on October 10, 2004 11:03 PM writes...

I'm a former user of Vioxx, and a current user of Bextra (I was switched over to that from the Vioxx when the military pharmacy system stopped carrying Vioxx). I can't take Celebrex at all - I have a problem with nosebleeds, some of which last for a day or more.

I take pain medication for a bad back - cervical annular growths, osteoarthritic spurs, degenerative disk problems, damage to facet joints and interconnecting tissue, a couple of herniated disks, and a few other, less serious but just as painful problems. Pain is something I live with daily, ranging in that oh-so-wonderful physician's reference from a three to a nine, BUT ALWAYS PRESENT, regardless of medication. Better medications such as Vioxx brought it down on a general level, sometimes by as much as two or three levels.

If we take the better non-narcotic pain medications out of the mix, what are we left with but a tranked-up herd of zombies? I cannot, and will not, live like that. I took that kind of medication, and I'd rather be in pain.

It seems that the government is trying to make medical treatment absolutely safe for everyone. In so doing, they are denying relief from symptoms for millions. Which is better, a treatment that works and the potential of a shortened lifefspan, or a longer life lived in a virtual hell of pain?

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4. Cory on October 11, 2004 3:23 PM writes...

Interestingly, the selective COX2 inhibitors have never been shown to provide better pain relief than the non-selective NSAIDs, such as ibuprofen and naproxen. The only benefit to the COX2's was that they were supposed to provide a safer GI side effect profile. According to the FDA, only Vioxx had demonstrated significant reduction in GI events compared to the nonselective NSAIDs. Again, none of the COX2's have demonstrated superior pain relief compared to the non-selective NSAIDs.

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5. Lawrence B. Ebert on October 13, 2004 1:16 PM writes...

I had a quick question on the Merck study on Vioxx. According to the New York Times, the incidence of stroke in the control population was 7.5 per 1000, and in the Vioxx population 15 per 1000. The incidence of stroke in the US population would seem to be about 1/3 the level of the control. If correct, why was the control so high and if not correct what are the right numbers?

The point about pain relief is well-taken. Dr. Thomas Schnitzer of Northwestern University noted that some 96 percent of high-dose NSAID users don't develop ulcers, "If you're an elderly person with a history of gastrointestinal problems, the new drugs make sense," he says. "If you're a 30-year-old athlete with a sprained ankle, why should an insurer spend $ 4 to $ 5 a pill to get you the same relief you get safely for a few cents?"

Separately, of the inquiry about Celebrex (as distinct from Vioxx), didn't an early study by Dr. Ganet A. FitzGerald in the Proceedings of the National Academy of Science, 1999, 96:272-277, talk about Celebrex?

Lawrence B. Ebert

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6. Cory on October 13, 2004 3:29 PM writes...

In reponse to the above comments, the numbers I have seen are acutally a bit fuzzy. I have not been able to find the actual data from the APPROVe trial, and so we are stuck with just sound bites to go by. The New York Times reported the risk to be increased from 7.5 per 1000 up to 15 per 1000. However, I have seen other reports stating that the risk was increased from 3 per 1000 to 7.5 per 1000. Until the data is published from the APPROVe study, it is hard to determine what the actual risk is. In response to the question about why the risk in the control group was higher than the risk of stroke in the general US population, the risk in this trial was reported as the COMBINED risk of heart attack, stroke, or blood clot. So you would need to find out the baseline US population risk for each of these three events in order to compare the US population to the control group. Also, remember that the patients in this study were sicker than the general population. They were all patients with a history of colorectal cancer.

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