Celecoxib: fierce debate and polarized opinions

[Guest guest]

Oct 16, 2002

Celecoxib: fierce debate and polarized opinions

London , UK -- The issue of whether or not celecoxib (Celebrex®, Pharmacia

and Pfizer) is safer on the gastrointestinal (GI) tract than conventional

nonsteroidal anti-inflammatory drugs (NSAIDs) continues to stir fierce

debate and has polarized opinions. The controversy spills over to the other

coxibs, and the question of whether the selective COX-2 inhibitors offer any

advantage over the much cheaper traditional NSAIDs has become one of the

most widely discussed issues in medicine today.

The extreme spectrum of opinions about the issue can be seen in recent

correspondence to the British Medical Journal, in response to a favorable

review published last month and to a critical editorial published earlier

this year. While some argue that the case for the coxibs is still not

proved, others maintain that the drugs are a breakthrough.

Criticism of favorable review of celecoxib clinical trials

The latest paper on the subject a systemic review of 17 clinical trials,

which concluded that celecoxib is significantly safer on the GI tract than

nonselective NSAIDs [1,2] attracted 10 rapid responses [3]. Many disagree

with the conclusion and pick holes in data.

Leeds, UK general practitioner Dr Arnold Zermansky points out that the

nonselective NSAIDs studied naproxen, ibuprofen, and diclofenac differ in

their capacity to cause GI harm and that the differences between the

orthodox NSAIDs in this " assorted basket " are greater than the small

difference between them and celecoxib. He maintains that the case for

celecoxib being safer is " not proven. " Another GP, Dr Alessandro Calderan

from Venice, Italy, says the review was misleading in concentrating only on

GI safety, because overall there was a significant difference in all adverse

events the results show that rates of withdrawal not due to GI events were

40% to 60% higher in the celecoxib group, he notes.

However, consultant rheumatologist Dr (Freeman Hospital,

Newcastle, UK) says the meta-analysis " really confirms what those of us who

have followed the story thought anyway, ie, that these drugs are a

breakthrough as far as GI side effects are concerned. " He adds that the

editorial that accompanied the review [4] " treads the usual skeptical line, "

whereas he believes that " offering to save a thousand lives a year, and not

[in the short term], should be greeted with more enthusiasm. "

Neither this review nor the observational study from Canada with similar

conclusions that was published at the same time [5] helps to resolve the

current difficulty in selecting which patients stand to benefit most from

taking the COX-2 selective inhibitors, says a group from the UK National

Prescribing Centre (Liverpool). They report their own analysis of 3 clinical

trials, which suggest that celecoxib is not as good an option as using an

NSAID with the gastroprotective agent misoprostol. And separately, another

correspondent says the review casts no new light on the question of

longer-term safety of celecoxib compared with the " standard treatment " of

using an NSAID with a proton pump inhibitor.

Controversy continues and spills over to other coxibs

The review " is more favorable than the data, " says Dr Pechlaner

(Innsbruck University Hospital, Austria). As more than half the patients

came from the Celecoxib Large Arthritis Safety Study (CLASS), the review is

based on " disputed data, " he says, adding that " flawed data yield flawed

conclusions. No computational or analytical efforts can remedy that. "

The CLASS trial has stirred up an unprecedented amount of controversy, as

already reported by rheumawire, and the fierce debate over how the study was

conducted and reported and what it actually shows continues unabated. Among

the harshest criticism directed at the study was an editorial in the British

Medical Journal earlier this year [6,7], and the flurry of responses that it

elicited again show a diversity of opinions [8].

Several correspondents agree with the editorial that promotional claims for

celecoxib being safer on the GI are misleading. But it's not only the claims

based on CLASS that are misleading, says Agnes Vitry, senior editor of the

Australian Medicines Handbook (Adelaide). She gives examples of

advertisements based on a flawed meta-analysis supported by Searle (part of

Pharmacia), which she points out does not contain long-term clinical data

reported to the FDA.

The promotional materials for celecoxib have repeatedly been found

misleading, Vitry says, but the absence of sanctions or imposition of

derisory fines is insufficient to deter companies from continuing. More

drastic action needs to be taken, she suggests: " It might be suspension of

the drug's marketing approval and/or fines, but of a size comparable to the

manufacturer's unjust enrichment. "

" Marketing by manipulated and falsified data [is] a rapidly growing drug

business, " say editorial staff on the German medical newsletter

arznei-telegramm (Berlin). The example of CLASS with celecoxib " showed the

success of suppressing and/or falsifying scientific data in deceiving the

medical profession and stimulating drug sales. " But they feel that the same

applies also to the Vioxx Gastrointestinal Outcomes Research (VIGOR) study

with rofecoxib (Vioxx®, Merck & Co), and the misleading presentation of data

from this study resembles the manipulation of data from CLASS, they say.

" Parallels are striking: in both cases, only the favorable findings were

selectively submitted for publication, while the complete data not favorable

for the products [were] suppressed and withheld from the scientific

community [and] only reported to the FDA. "

Are coxibs inferior to NSAIDs?

Turning the whole argument for coxibs on its head is the suggestion that

they may, in fact, be inferior in terms of overall safety from Prof

(University of British Columbia, Vancouver, BC). He points out that a

meta-analysis of all the data from CLASS and VIGOR reported to the FDA

demonstrates a statistically significant increase in serious adverse effects

for COX-2 inhibitors as compared with the nonselective NSAIDs (with relative

risk RR=1.19 [1.06-1.322], p=0.002). This increase exists despite a

reduction in complicated ulcers (1 category of adverse effects) by rofecoxib

in the VIGOR trial. " This analysis strongly suggests that COX-2 inhibitors

are inferior overall to nonselective NSAIDs, " he declares, and it

underscores the need for independent individual patient meta-analysis.

Quite the opposite view is aired by pharmaceutical analyst Stover

(Arnhold and S Bleichroeder Inc, New York). He argues that both CLASS and

VIGOR support the COX-2 hypothesis and, while acknowledging that CLASS had

flaws, points out that ulceration rate in the celecoxib patients was

considerably below 2% to 4% per year.

Yet the current US labeling for celecoxib, as well as for rofecoxib and the

latest member of this class of drugs, valdecoxib (Bextra®, Pharmacia and

Pfizer), carries the traditional NSAID-class warning of ulcer rates of 2% to

4% per year, which is not supported by any scientific or clinical data,

Stover says. He suggests that this represents " mislabeling of the cruelest

(to patients) sort " and points out that " in the US, it enables managed care

to deprive patients of the safer alternatives. "

But perhaps the most constructive comment comes too late. The massive debate

that has been stirred up by all this may have " created more clarity " had the

critical editorial last summer and the favorable review last month been

published side by side, says Dr Ebbe Englev, (Pharmacia, Copenhagen,

Denmark). From the dates that both papers were accepted for publication it

appears to have been possible, and it would have provided " a more balanced

view. "

Zosia Chustecka