NEWS - Future of COX-2s being deliberated

[Guest guest]

Rheumawire

Future of coxibs being deliberated

Jan 17, 2005 Gandey

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 non-steroidal anti-inflammatory drugs (NSAIDs) and

related agents. Among the considerations will be whether or not

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 UScelecoxib (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, "

, 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. "

suggested that COX-2s may be most appropriate for patients with a

history of gastrointestinal adverse events associated with non-selective

NSAID use and patients not responding or intolerant to those agents.

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 RA and 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, " said Dr

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, one study suggested otherwise. Similarly, celecoxib, which

previously did not show a signal, shows one in a study. "

Editorial consultant, Dr Felson (Boston University, MA) told

rheumawire, " 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. "

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 sameinducing the accumulation of thromboxane

and inhibiting prostacyclin I2it 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 f 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. "

In an online rapid response in the British Medical Journal, retired

physician Dr 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) [1, 2].

" 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 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 then4 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. "

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 is 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.

The two studies demonstrating a cardiovascular risk with

celecoxib were the Adenoma Prevention with Celecoxib (APC) trial and 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 two studies is not apparent. One

possible reason could be a difference in the presence of risk factors for

cardiovascular disease between the two trial populations, " the agency

explains. " To further explore possible reasons, detailed data from the

studies are being obtained and will be further assessed. "

-AG

Sources

Mann J. Vioxx controversyLancet publishes unscientific

meta-analysis of rofecoxib studies. BMJ rapid response November 7, 2004.

Available at: http://bmj.bmjjournals.com/

Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular

events associated with selective COX-2 inhibitors. JAMA 2001; 286:954-959.

Jueni P, Nartey L, Reichenbach S, et al. Risk of

cardiovascular events and rofecoxib: Cumulative meta-analysis. Lancet 2004;

364:2021-2029.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org