Merck's VIOXX®

Now that Merck & Co.'s $2.5 billion annual revenues from anti-inflammatory COX-2 inhibitor VIOXX® are history, the next question is what happens to the even greater amount of money ($3.5 billion) generated by sales of rival drugmaker Pfizer's anti-inflammatory COX-2 inhibitors Celebrex® and Bextra®, not to mention the fate of "second-generation" COX-2 inhibitors Arcoxia® (from Merck) and Prexige® (from Novartis).

In an article published today in the New York Times, entitled "New Scrutiny of Drugs in Vioxx's Family", reporter Andrew Pollack reports that Pfizer is trying to avoid being tarred by the VIOXX brush by spinning that its best-known and biggest selling COX-2 inhibitor is positively good for cardiovascular health, rather than something, like VIOXX, that puts patients using it at higher risk for "cardiac events."

As Pollack puts it: "Pfizer says it is looking into whether its somewhat similar drug, Celebrex, may actually help prevent heart attacks." He goes on to say that Dr. Mitch Gandelman, a Pfizer vice president, has "acknowledged that evidence for this is scant and inconclusive."

Pollack summarizes last week's main development in this area:

"Merck said last week that it would no longer sell Vioxx because a study showed a higher risk of heart attacks and strokes among patients who had taken it for longer than 18 months. The reason for the greater risk is not known." (italics added)

Saying that the "reason for the greater risk is not known" is not completely accurate. And the most-likely reason is not good news for Pfizer, or Novartis, or Merck.

As pointed out in an October 3, 2004, article Etopia Media Medical News Network #18: "VIOXX® risks have been known for years, other COX-2 inhibitors may be equally dangerous",

An article appearing in the March/April 2002 edition of ScienceWatch®, picks up where a previous study on the subject leaves off. Entitled "Safety Scrutiny for New Class of Musculoskeletal Pain Drugs", the article's author, Mr. David Sharpe, suggests a mechanism of action to explain how COX-2 inhibitors may reduce joint inflammation while simultaneously weakening the cardiovascular system, thereby predisposing patients taking the drug, especially for extended periods, to a higher incidence of cardiac events. He writes:

"Two-edged swords are often encountered in clinical pharmacology, and with the cyclooxygenases [cyclooxygenases put the "COX" in "COX-2 inhibitors"] the further complication, in cardiovascular terms, is that COX-2 inhibitors interfere with prostacyclin production in vessel walls, providing a possible explanation for any increase in cardiovascular risk with such drugs, were that to be confirmed. The other explanation offered for the VIGOR data is that naproxen (the control drug) was cardioprotective but a recent retrospective study of non-aspirin NSAIDs, including naproxen (see W.A. Ray, et al., Lancet, 359[9301]:118-23, 12 January 2002), casts some doubt on this."

In an article published in the February 15, 2002, edition of American Family Physician, writer Bill Zepf says this about a study comparing COX-2 inhibitors and NAISDs:

"FitzGerald and Patrono present an in-depth review of the pharmacology and clinical effects of selective COX-2 inhibitors, including a discussion of a possibly increased incidence of cardiovascular and renal disease among patients using these agents."
There follows a re-iteration of the same theory about the mechanism whereby COX-2 inhibitors also inhibit the maintenance of optimal prostacyclin levels in the cardiovascular system:

"A predisposition to thrombosis may be possible with the use of coxib agents because of changes in prostacyclin levels in the blood vessel wall. The Vioxx Gastrointestinal Outcomes Research trial, which compared rofecoxib with naproxen in patients with rheumatoid arthritis, also monitored cardiovascular outcomes. The combined rate of nonfatal myocardial infarction, nonfatal stroke, and death from a vascular event was significantly higher in the rofecoxib group than in the naproxen group; however, the absolute difference was small (0.8 percent versus 0.4 percent, respectively). The Celecoxib Long-Term Arthritis Safety Study trial, comparing celecoxib to ibuprofen and diclofenac, did not detect a significant difference in the incidence of major cardiovascular events."

On that basis,

"The authors conclude that celecoxib and rofecoxib have fewer adverse gastrointestinal effects compared with nonselective NSAIDs but may be associated with small elevations in the risk of cardiovascular and adverse renal effects."

A possible explanation of these facts can be found in an article published four years ago, in the August 29, 2000, Proceedings of the National Academy of Science of the United States of America, entitled "Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits," which includes the finding that "this study identifies COX-2 as a cardioprotective protein." The study also makes the point that "the recognition that COX-2 mediates the antistunning and antiinfarct effects of late PC impels a reassessment of current views regarding this enzyme, which is generally regarded as detrimental."

To say it again: "A predisposition to thrombosis may be possible with the use of coxib agents because of changes in prostacyclin levels in the blood vessel wall."

COX-2 inhibitors, which suppress the production of prostaglandins by the cyclooxygenase-2 enzyme, in order to diminish inflammation and pain, thereby also deprive the cardiovascular system of the prostacyclin levels needed for optimal cardioprotection.

You can read more about prostacyclin (a type of prostaglandin) and prostaglandins generally by clicking here.

You can be sure that Pfizer, which had to pay $430 million earlier this year to settle the Neurontin "off-label" marketing abuse case, and is facing litigation regarding the alleged addictiveness of Zoloft, bad press regarding its possible liability in a case of young person who killed his grandparents after taking Zoloft, and increased suicidality in children and adolescents taking Zoloft, in no way wants to give up selling its cash cow Celebrex, even if it is eventually shown to cause the same "cardiodetrimental" effects as its former competitor VIOXX.

So it may not be completely accurate to say that the reason for the increased cardiovascular risk with VIOXX is not known.  It's not proven yet, but the mechanism consistently elucidated by all these medical scientists and recounted here may very well prove in fact to be what is causing the elevated risk of cardiac events among VIOXX users, and, if so, it may very well prove to be the mechanism endemic to all COX-2 inhibitors, with far-reaching consequences for patients, drug companies, the stock market and the health care delivery system itself.

In some cases, like this one, it's neither nice, nor is it possible, to fool Mother Nature, or at least that part of Mother Nature embodied in the formation of prostaglandins by cyclooxygenase-2.