Experts debate house of coxibs

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Experts debate " house of coxibs "

Dec 29, 2004 Gandey

Cleveland, OH - The deliberations over cyclooxygenase-2 inhibitors rage on

in an early-release article in the Journal of the American Medical

Association and this week's issue of the New England Journal of Medicine,

where experts debate the value of coxibs, the conduct of Merck & Co, and the

role of the US Food and Drug Administration.

With the considerably higher cost, marginal efficacy, and known

cardiovascular risks of the remaining agents on the market, valdecoxib and

celecoxib, it would seem prudent, at the least, to avoid using these agents

as first-line therapy.

In an editorial published in JAMA, Dr Topol (Cleveland Clinic

Foundation, OH and editor-in-chief of www.jointandbone.org's sibling

website, www.theheart.org) writes there has hardly been a day without

significant news on COX-2 inhibitors since rofecoxib (Vioxx, Merck) was

withdrawn from the market [1]. " In the wake of the high density of new data

on coxibs, several important issues now need to be confronted, " he writes.

" First, is there any continuing role for coxibs? "

Topol points out that only rofecoxib has been shown to reduce

gastrointestinal complications compared with naproxen, but valdecoxib

(Bextra, Pfizer) and celecoxib (Celebrex, Pfizer) have never been

definitively confirmed to protect against gastrointestinal complications.

" Importantly, there have not been any direct comparative (head-to-head)

trials of 1 of the agents vs another, which is the only way to definitively

establish likeness or difference between the drugs, " he writes.

Topol notes that while coxib superiority over nonsteroidal anti-inflammatory

drugs (NSAIDs) for relief of arthritic pain has not been shown, many

individual patients report pain relief with a coxib but not an NSAID. " With

the considerably higher cost, marginal efficacy, and known cardiovascular

[CV] risks of the remaining agents on the market, valdecoxib and celecoxib,

it would seem prudent, at the least, to avoid using these agents as

first-line therapy, " he argues.

From the outset, the coxib class of medicines seemed destined for

potential collapse.

" There are major concerns about how an entire drug class has gone awry with

respect to unleashing significant cardiovascular hazard, " Topol writes.

" From the outset, the coxib class of medicines seemed destined for potential

collapse. These drugs were mass-marketed from the moment they were

commercially available in the new world of direct-to-consumer advertising,

with unrealistic expectations about pain relief, marked gastrointestinal

protection, and safety. " Topol argues that rather than a sufficient waiting

period after approval to firmly establish safety in the large,

representative real-world population, " the unbridled promotion exacerbated

the public-health problem. "

Topol points out that in recent weeks, there has been considerable

speculation on how the FDA can be bolstered to preempt a coxiblike problem

in the future. " An independent drug safety agency or center that

compartmentalizes the vital functions of approval and surveillance seems to

be gathering broad support, " he writes. " [P]roviding more authority to the

FDA to shape and require the execution of vital trials is perhaps the most

important lesson from the coxibs. "

Merck responds

Replying to another article by Topol, this 1 published in the October 21,

2004 issue of the New England Journal of Medicine and previously reported by

rheumawire [2], Drs Kim and Alise Reicin (Merck Research Laboratories,

West Point, PA) write in a letter, " Merck has been proactive and

conscientious in evaluating the cardiovascular profile of rofecoxib; Dr

Topol's remarks to the contrary in his Perspective article are false " [3].

Kim and Reicin argue that Topol's description of the drug's time line

" obfuscates the facts. " They explain that the FDA approved Vioxx in May 1999

and the clinical data then existing did not suggest an adverse

cardiovascular effect. " Nevertheless, because the literature suggested a

hypothetical possibility of both cardioprotective and prothrombotic effects

of COX-2 inhibitors, Merck initiated adjudication of cardiovascular events

by an external expert panel at the end of 1998 (before the Vioxx

Gastrointestinal Outcomes Research [VIGOR] trial began) for future studies

of Merck's COX-2 inhibitors. "

Kim and Reicin point out that Merck learned the preliminary VIGOR results in

March 2000, which showed more cardiovascular events over a period of 1 year

in patients receiving Vioxx than in those receiving naproxen [4]. They

explain that the company promptly disclosed this finding to the FDA, other

regulators, and the media.

Merck has been proactive and conscientious in evaluating the

cardiovascular profile of rofecoxib; Dr Topol's remarks to the contrary in

his Perspective article are false.

" Dr Topol neglects to mention that beginning in 2000, Merck undertook 3

prospective, randomized, placebo-controlled trials of Vioxx in more than 24

000 patients with or without known cardiovascular disease, " they write,

adding that after deliberations with numerous consultants, Merck finalized a

protocol in 2002, which prespecified the analysis of adjudicated

cardiovascular-event data from these studies as a hypothesis-testing end

point. Two of these studies, Adenomatous Polyp Prevention on Vioxx

(APPROVE), with approximately 2600 patients, and Vioxx in Colorectal

Therapy, Definition of Optimal Regimen (VICTOR), a study of 7000 patients

with a history of colon cancer, had already begun, and the third, a study of

15 000 patients at risk for prostate cancer, was initiated after

consultation with regulatory agencies.

Kim and Reicin argue that before the results of the APPROVE study were

available, completed and ongoing randomized trials involving more than 28

000 patients with more than 14 000 patient-years of exposure showed an

incidence of cardiovascular events among patients taking Vioxx that was

similar to the incidence among those taking placebo and those taking NSAIDs

other than naproxen. " Because naproxen inhibits platelet aggregation in

similar fashion to low-dose aspirin, we concluded that the VIGOR results

were most likely due to the effects of naproxen. "

Kim and Reicin note that the APPROVE study began 9 months after the FDA

approved Vioxx and 1 month before the results of the VIGOR study were known.

Because the study was designed to examine the effects of long-term use of

rofecoxib on gastric polyps, they were able to detect an increase in

cardiovascular risk that began after 18 months of continuous Vioxx therapy,

they explain. " At that time, September 2004, Merck moved promptly and

voluntarily to remove Vioxx from the market. The record, in short, is one of

careful analysis at every stage, a continued commitment to research, and

prompt and decisive action in response to clinical-study results. "

The FDA responds

" Dr Topol shows a lack of understanding of the FDA's regulatory authority, "

write Drs Lourdes Villalba and Witter (Food and Drug Administration,

Rockville, MD) [5]. " The FDA cannot 'mandate' postmarketing clinical trials.

Dr Topol also fails to appreciate the successful efforts by the FDA to

negotiate ongoing evaluation of cardiovascular safety in several multiyear

clinical trials, 1 of which helped to resolve the cardiovascular questions

first noted in the postmarketing VIGOR study. "

Dr Topol shows a lack of understanding of the FDA's regulatory

authority. The FDA cannot 'mandate' postmarketing clinical trials.

Villalba and Witter note that the FDA convened an advisory committee (on

February 8, 2001) to review the data from VIGOR. " The study showed a 50%

decreased risk of gastroduodenal perforations, symptomatic ulcers, and

bleeding with Vioxx (50 mg daily), but twice the risk of cardiovascular

thrombotic events (mostly myocardial infarctions [MIs], with no differences

in strokes or cardiovascular deaths), as compared with naproxen, " they

write, explaining that the study had several limitations that hampered the

generalization of these findings.

" After careful review, " the doctors write, " the expert panel (which included

cardiologists) recommended that the label for Vioxx should include the

unquestionable gastrointestinal advantage as well as the negative

cardiovascular safety information. "

Villalba and Witter argue that the finding of an increased risk of MIs and

strokes in Merck's APPROVE study was unexpected, but not an accident. " The

FDA worked vigorously with Merck to inform the public of the potential

cardiovascular risks associated with Vioxx and to ensure adequate

ascertainment and analyses of these cardiovascular events in Merck's

prevention trials. "

Topol replies

" In response to Drs Kim and Reicin, " Topol writes, " I believe that many

vital steps were not taken to evaluate the cardiovascular safety of

rofecoxib properly " [6]. He points out that in 2000, along with the VIGOR

trial, a second trial conducted by Merck, known as Study 090, also showed a

significant excess of heart attacks and strokes among patients taking

rofecoxib, as compared with controls [7]. " Together with the results of the

VIGOR trial, there was indeed replication in an independent, randomized,

controlled trial of an excess of the cardinal cardiovascular end point of

death, heart attack, and stroke. "

Topol shows that 1.3% of patients in the rofecoxib group of the 2 trials and

0.6% of patients from the control group experienced death, MI, or stroke

(odds ratio 2.1, 95% CI 1.4-3.3, p=0.001).

Cardiovascular events and deaths in 2 trials of rofecoxib

Outcome VIGOR Study 090

Rofecoxib Control Rofecoxib Control

Patients, n 4047 4029 390 588

Death, n 22 15 0 0

MI, n 20 4 3 1

Stroke, n 11 9 2 0

Total, n (%) 53 (1.3) 28 (0.7) 5 (1.3) 1 (0.2)

Topol notes that not only was Study 090 never published and available solely

through a subsequent FDA memorandum, but the data presented in the VIGOR

article also suffered from errors of omission, along with erroneous

information and lack of completeness. " In the VIGOR article, " Topol writes,

" the actual deaths were not reported, but it is stated in the article in 3

places that the overall mortality rate was similar in the 2 groups. The

heart-attack rate for rofecoxib was erroneous. More than half of the

thrombotic events are not presented in the VIGOR article but appear in the

FDA report. " Topol says the updated cardiovascular-event data from VIGOR

were submitted to the FDA on October 13, 2000six weeks before the VIGOR

study was published.

Not only was Study 090 never published and available solely through a

subsequent FDA memorandum, but the data presented in the VIGOR article also

suffered from errors of omission, along with erroneous information and lack

of completeness.

" Drs Villalba and Witter are incorrect in suggesting that the FDA cannot

influence postmarketing clinical trials that a sponsor performs, " Topol

argues, noting that their claim that the 50% decreased risk of

gastroduodenal perforations outweighed the cardiovascular risk in the VIGOR

trial is not substantiated by the data. " There were no differences in the

rate of perforation (0.1% in both the rofecoxib and naproxen groups). It is

hard to imagine that the small protection from gastric or duodenal ulcers in

the VIGOR trial is an acceptable trade-off as compared with twice the

incidence of death, heart attacks, and strokes. "

Topol charges that it took 14 months after the expert FDA panel convenedfrom

February 2001 to April 2002to minimally change the cardiovascular safety

information for rofecoxib in the package insert. " After their cumulative

meta-analysis, Juni et al correctly stated, 'Our findings indicate that

rofecoxib should have been withdrawn several years earlier' " [8].

Sources

1. Topol EJ. Arthritis medicines and cardiovascular events " house of

coxibs. " JAM

http://jointandbone.org/viewArticle.do?primaryKey=377281