Future of coxibs being deliberated

Allison Gandey

January 17, 2005

Jan 17, 2005

London, UK - This week the European Medicines Agency will review cyclooxygenase-2 inhibitors, and next month the US Food and Drug Administration will follow suit, studying growing concerns about the drug class. Many are anticipating changes to existing marketing authorizations and a call for further study.

The European meeting starts today, and the agency says it will issue an update at the end of the review Thursday. The FDA's meeting will take place February 16-18, 2005 and will study the overall benefit-to-risk considerations of COX-2 nonsteroidal anti-inflammatory drugs (NSAIDs) and related agents. Among the considerations will be whether COX-2 inhibitors should continue to be marketed.

After the withdrawal of rofecoxib (Vioxx, Merck & Co), there are now only 2 coxibs on the market in the US— celecoxib (Celebrex, Pfizer) and valdecoxib (Bextra, Pfizer)—but these are joined by 2 others in Europe— etoricoxib (Arcoxia, Merck & Co) and the intravenous product parecoxib sodium (Dynastat, Rayzon, Pfizer).

Last month, the FDA issued a caution urging limited use of coxibs. "We're not saying definitively that these should be second-line therapies," John Jenkins, director of the FDA's Office of New Drugs, told the media. "But we're advising that physicians take all of this available information into mind as they're weighing what product to use for their patients."

Jenkins suggested that COX-2s may be most appropriate for patients with a history of gastrointestinal adverse events associated with nonselective NSAID use and patients not responding to or intolerant of those agents.


Withdrawal of whole class unlikely?

Datamonitor, a company specializing in industry analysis, predicts that both regulatory agencies will recommend a black-box warning be placed on the labeling of these products to inform patients of the potential cardiovascular risks associated with taking high doses. Withdrawal of the whole class would be an unprecedented move and unlikely, it suggests. Regardless of what the FDA decides, confidence in the COX-2s has now been dented. Several high-profile physicians have been quoted as saying that they can no longer prescribe COX-2s to their patients due to the uncertainty regarding their cardiovascular safety. Despite this, Datamonitor believes that the level of anxiety that has been witnessed regarding the COX-2s and subsequent threats of "class withdrawal" from the FDA are somewhat unwarranted. In patient populations where the products are used according to their labeling, they provide safe and effective relief from the symptoms of both rheumatoid arthritis (RA) and osteoarthritis (OA), it argues.

But there are calls for withdrawal of the whole coxib class, most vocally from the US consumer group Public Citizen. The group, led by Dr Sidney Wolfe, says evidence of the cardiovascular risk of COX-2 inhibitors was evident early on, but drug makers misled the public. "In the April 2001 issue of our newsletter Worst Pills, Best Pills News, we urged patients not to use [COX-2s] because there are safer alternatives," Wolfe said in a statement to the press.

The story about coxibs and NSAIDs remains very confusing.

"The story about coxibs and NSAIDs remains very confusing," said Dr David Pisetsky (Duke University, Durham, NC and editorial consultant for www.jointandbone.org). He points out that signals from the different drugs show up variably in studies. "While naproxen was viewed as having little or no CV risk, 1 study suggested otherwise. Similarly, celecoxib, which previously did not show a signal, shows one in a study."

Editorial consultant Dr David Felson (Boston University, MA) told rheuma wire , "My opinion is that the naproxen scare is ridiculous." Felson argues that many studies have already been conducted showing naproxen is safe. "This study was stopped prematurely and rashly and the NIH was irresponsible in scaring people," he said. "As for celecoxib, I'm not sure what to make of these results. My suspicion is that it's a dose-related problem. The doses that caused problems were 800 mg per day (not used clinically) and 400 mg per day (the highest dose we ever use). Previous studies, which have not shown any risk, were generally done at a lower dose."

Pisetsky says that many questions are currently being raised about what amount and type of data signaling a CV risk should be considered sufficient to restrict the use of a product. He notes that physicians have good reason to think twice before increasing the use of NSAIDs simply because they have not shown a CV signal. "It is quite possible that they have simply been studied less and therefore there are data on fewer patients," Pisetsky warns. "For many patients, it appears likely that low-dose ASA will be used for CV protection, thereby increasing GI risk. Therapy will have to be individualized based on assessment of multiple risk factors as well as efficacy of the different agents," he said. "This is a vexing issue, and there are no simple answers."

I am using all NSAIDs, including coxibs, at as low a dose as possible and for as short a period of time as possible.

In the meantime, many physicians are opting to err on the side of caution. "I am using all NSAIDs, including coxibs, at as low a dose as possible and for as short a period of time as possible," said Dr Louis Bridges (University of Alabama at Birmingham and editorial consultant for the site).

In a posting on www.jointandbone.org's forum, Dr Osvaldo Messina argues that all coxibs will follow rofecoxib's fate. "Considering that the mechanism of action of all the coxibs is the same—inducing the accumulation of thromboxane and inhibiting prostacyclin I2—it is reasonably expected that the rest of the coxibs follow the same route as rofecoxib," he writes. "Expectations [to the contrary] reveal a profound ignorance about the mechanisms of action and the aim of preserving strong commercial interests."

Dr Josef Smolen (University of Vienna, Austria and editorial consultant to www.jointandbone.org) notes that while the coxibs may have class effects, it has been suggested that the degree to which they exhibit these class effects will depend on how selective they are for COX-2. "However, if now naproxen is afflicted with CV issues, I wonder if it is not the whole class of NSAIDs; after all edema, hypertension, and renal failure, etc, are all induced by them, and it may have just taken placebo-controlled studies of tens of thousands of patients to pick up differences."


Why weren't appropriate trials performed?

In an online rapid response in BMJ [ 1 ], retired physician Dr Jeffrey Mann (Salt Lake City, UT) writes that as early as 2001, researchers were calling for large randomized-controlled trials (RCTs) of coxibs in people at higher-than-normal risk of MI (such as elderly osteoarthritis patients who have a higher baseline risk of MI) [ 2 ].

I think that Merck was highly delinquent because it did not perform that much-needed RCT during the past few years. I think that the FDA was also highlydelinquent. . . . and the Lancet editor (and other mainstream medical journal editors) . . . because they did not insist that it be performed.

"I think that this suggestion was very rational and an appropriate solution to this dilemma," Mann writes. "I think that Merck was highly delinquent because it did not perform that much-needed RCT during the past few years. I think that the FDA was also highly delinquent because it did not insist that it be performed. And, finally, I think that the Lancet editor (and other mainstream medical journal editors) were also highly delinquent because they did not repeatedly insist, during the past four years, that this RCT be performed."

Mann also critiques a recent meta-analysis of clinical trial data of rofecoxib by Dr Peter Jueni (University of Berne, Switzerland and University of Bristol, UK) and colleagues [ 3 ]. The analysis shows that a doubling of the risk of MI with rofecoxib could be seen by 2000, and the researchers suggest that the drug could and should have been withdrawn then—4 years before it was taken off the market.

But despite his assertion that the "medical research community obviously missed a golden opportunity" to demonstrate an increased risk of MI with rofecoxib, Mann slams the Jueni report, calling it "unscientific" and "flawed" and accusing the authors of "misrepresenting a number of facts."


Preliminary data "causing anxiety"

The American College of Rheumatology says that for patients with arthritis and the physicians who treat them "it remains critical to consider factors that affect the risk-to-benefit ratio when determining whether to continue or discontinue any pharmaceutical product, including those NSAIDs that are under scrutiny for potential increased health risks." In a press release issued after the news about cardiovascular signals with celecoxib and naproxen, the ACR said, "It is unfortunate that physicians and patients have preliminary data, some of it in direct conflict with existing conclusions, causing anxiety that, at this time, cannot be definitively confirmed or refuted." The ACR is now working on another hotline to address the COX-2 NSAID issue, and notes that it has been facilitating interviews with rheumatologists for many media outlets on this issue.



Details of the celecoxib study showing CV signal

The study demonstrating a cardiovascular risk with celecoxib was the Adenoma Prevention with Celecoxib (APC) trial, and it contrasts with the lack of such a signal in a similar trial, the Prevention of Spontaneous Adenoma Polyps (PreSAP) trial. The European Medicines Agency, which will begin reviewing the data today, has stated publicly that these preliminary data show inconsistent results. "The reason for the different results between these 2 studies is not apparent. One possible reason could be a difference in the presence of risk factors for cardiovascular disease between the 2 trial populations," the agency explains. "To further explore possible reasons, detailed data from the studies are being obtained and will be further assessed."

Adenoma Prevention with Celecoxib: trial of 2400 patients with an average duration of 33 months of treatment


Outcome
Celecoxib 400 mg bid (n=671), n (%)
Celecoxib 200 mg bid (n=685), n (%)
Placebo (n=679), n (%)
Increased CV risk
20 (3)
15 (2.2)
6 (0.9)

An increase in risk overall and for the two dosage groups was noticeable after 10 to 12 months of celecoxib treatment


Prevention of Spontaneous Adenoma Polyps: trial of more than 1500 patients over approximately 36 months of treatment


Outcome
Celecoxib 400 mg (n=933), n (%)
Placebo (n=628), n (%)
Serious CV event
16 (1.7)
11 (1.8)


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Sources

  1. Mann J. Vioxx controversy—Lancet publishes unscientific meta-analysis of rofecoxib studies. BMJ rapid response November 7, 2004. Available at: http://bmj.bmjjournals.com/

  2. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286:954-959.

  3. Jueni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: Cumulative meta-analysis. Lancet 2004; 364:2021-2029.




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