Merck's VIOXX®

On September 30, 2004, Merck & Co. announced the immediate recall of one of its COX-2 inhibitors, the anti-inflammatory drug VIOXX®, because, in Merck's own words, a study it had been conducting showed that:

"there was an increased relative risk for confirmed cardiovascular events, such as heart attack and stroke, beginning after 18 months of treatment in the patients taking VIOXX compared to those taking placebo." 

This action crashed Merck's stock price, tumbled the Dow Jones Average, and led to more questions, among them:

For how long ago has it been known that VIOXX carried an increased risk of cardiac events and, if it was a while, why didn't Merck withdraw the drug sooner?

Do other drugs in the COX-2 class carry similar risks and, if so, why aren't they being recalled as well?

There's even the lingering question, much in the news a few years ago and in some quarters continuing to the present, of whether these COX-2 inhibitors are really as superior to the NSAIDs they attempted to supplant as their makers said they were.

A search of the publicly-available information on the Internet provided at least tentative answers to the first two questions, if not a definitive one to the third.

According to an article in the September 30, 2004, edition of USA TODAY, entitled "Merck halts Vioxx sales" :

"In November 2000, Merck published a study in The New England Journal of Medicine that found a higher rate of heart attacks in patients assigned to Vioxx than those assigned to naproxen (an NSAID sold as Aleve). Because of that finding, the FDA in April 2002 required a new warning on the Vioxx label."

In August, 2001, the Journal of the American Medical Association (JAMA) published an article entitled Risk of cardiovascular events associated with selective COX-2 inhibitors. The authors provide detailed statistical support (based on two major studies together involving more than 16,000 patients) for their conclusion that:

"The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors."

An article in the British Journal of Medicine, dated September 1, 2001, reporting on the same study that was covered in the previous month's JAMA, has a slightly more alarmist headline "COX 2 inhibitors may increase risk of heart attack."

An article appearing in the March/April 2002 edition of ScienceWatch®, picks up where the previous fall's piece 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."

The reason for this should be clear from an article published as long ago as August 29, 2000, in the 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."

In a November 21, 2002, article on the Pharmafocus web site, entitled "New Bextra warnings add to COX-II doubts," it says that:

"It is the latest in a series of safety issues to hit the COX-II inhibitor class, which is being investigated by the EMEA following concerns over cardiovascular complications.

"Recent data published in the BMJ [see above] has linked high-doses of Merck's Vioxx to an increased risk of coronary heart disease."

It's clear that the reports in August, 2004, about the results of the Kaiser Permanente study about the safety of VIOXX (and Celebrex®) showing an increased risk of cardiac events for patients on VIOXX and the APPROVe (Adenomatous Polyp Prevention on VIOXX) trial being run by Merck "to evaluate the efficacy of VIOXX 25 mg in preventing recurrence of colorectal polyps in patients with a history of colorectal adenomas," which also showed an elevated risk of cardiac events and which provided the final impetus to Merck to recall VIOXX, did not come out of the blue, but were merely the latest in a long series of concerns raised about VIOXX from the time it first came on the market.

Why did it come on the market, and why wasn't it recalled sooner, given this mass of evidence?

Here's a possibility, taken from the Merck press release announcing the recall:

"Worldwide sales of VIOXX in 2003 were $2.5 billion."

Given the apparent stampede of lawsuits now being contemplated against Merck, it remains to be seen if, overall, introducing VIOXX will prove to have been a net source of revenue.

As for VIOXX's COX-2 colleagues (Celebrex, Bextra®, Prexige®, and Arcoxia ®), if the suppression of prostaglandin production through the inhibition of cyclooxygenase-2 crucially changes prostacyclin levels in the blood vessel wall, increasing the risk of cardiac events, at the same time that it reduces inflammation in joints, then it's going to be hard for any of these drugs to avoid the problems that have now led Merck to recall VIOXX, years after the first evidence of these problems was widely published in the medical community.

It's hard to avoid comparisons between this state of affairs and what's been happening down the hall with selective serotonin uptake inhibitors (SSRIs). Also heralded as "breakthrough" drugs for the treatment of depression and related conditions, the SSRIs, like the COX-2 drugs, work by blocking the biochemical activity of an intimate physiological process, in their case, the re-uptake into the synapse of the neurotransmitter serotonin.

This can have profound effects on the brain, some apparently beneficial, others, such as the reported increases in suicidality, especially in children and adolescents, not so beneficial.

As with the COX-2 inhibitors, the market is full of many, mostly very similar, competing SSRIs. Cynical critics have argued that the minor differences among the competitors are more a function of patent requirements than ones of medical value. Also as with the COX-2 inhibitors, there are apparent differences in the efficacy, or reduced lethality, of the various products (e.g., Prozac® is seen as less dangerous for children and adolescents than Zoloft®, just as Celebrex is now being touted as less dangerous than VIOXX).

There remain critics, however, such as Judy Foreman and Emily Cox, PhD, of Express Scripts, who argue that the benefits claimed for COX-2 inhibitors may, in the words of Ms. Cox, "undermine the efficient allocation of scarce healthcare resources." Or as Ms. Foreman puts it in the title of the article here cited: "Expensive Arthritis Pills Have Not Lived Up to the Hype."

Similar criticisms have been leveled against the drug companies that market SSRIs, in those cases taking the form of allegations that these powerful chemical agents may have powerful effects on patient's brains, without necessarily curing or even successfully treating whatever is wrong with them.

The similar shape of these criticisms may be related to the fact that some SSRIs and some COX-2 inhibitors are made by the same corporations. The much-maligned SSRI Zoloft and the still relatively-esteemed Celebrex are both products of Pfizer, Inc.