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. . .