Largest coxib trial ever stirs more debate

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Largest coxib trial ever stirs more debate

Rheumawire

Aug 19, 2004

Nainggolan

Chicago, IL - The largest trial to date of a COX-2 inhibitor in this

case, lumiracoxib (Prexige, Novartis Pharmaceuticals)shows a reduction

in ulcer complications with the coxib compared with 2 comparator

nonsteroidal anti-inflammatory drugs (NSAIDs), naproxen and ibuprofen,

in patients with osteoarthritis (OA) [1]. There was also no difference

in the incidence of myocardial infarction between the different drugs.

But the trial has attracted criticism. An accompanying commentary says

the benefit of expensive coxibs is marginal, at best, over traditional

NSAIDs and nonexistent in those also taking low-dose aspirin for

cardiovascular prophylaxis. Also, the study did not enroll enough

patients with a history of cardiovascular disease to help determine the

real risk of MI with this class of drugs, it says.

The reductions in ulcer complications of the Therapeutic Arthritis

Research and Gastrointestinal Event Trial (TARGET) in 18 000 patients

with osteoarthritis are published in the August 21, 2004 issue of the

Lancet [1], by a team led by Dr J Schnitzer (Northwestern

University Feiberg School of Medicine, Chicago, IL). The cardiovascular

outcomes of TARGET also appear in the same issue, in a paper by

cardiologist Dr E Farkouh (New York University School of

Medicine, NY) and colleagues [2].

The commentary entitled: " A coxib a day won't keep the doctor away " is by

Drs J Topol and W Falk (Cleveland Clinic Foundation,

Cleveland, OH) [3].

Lumiracoxib is the latest in a line of coxibs, although it differs

structurally from other drugs in this class. It has the highest

selectivity for COX-2 and a fairly short half-life (3-6 hours) compared

with other coxibs. It is licensed in the UK and a few other countries,

at doses of 100 mg or 200 mg a day, but not in the USglobal rollout of

the product has been on hold pending US approval. The FDA has requested

submission of the final results of TARGET as part of further information

it requires on the drug.

TARGET randomized 18 325 patients who were 50 years or older with OA to

lumiracoxib 400 mg once daily (n=9156), naproxen 500 mg twice daily

(n=4754), or ibuprofen 800 mg 3 times daily (n=4415) in 2 substudies of

identical design. Approximately one quarter of the patients in TARGET

were taking low-dose aspirin for cardiovascular prophylaxis. Analysis

was done by intention to treat.

The primary end point in the reduction in ulcer complications study was

difference in time-to-event distribution of definite or probable

upper-gastrointestinal-ulcer complications (clinically significant

bleeding, perforation, or obstruction from erosive or ulcer disease).

Overall, the cumulative 1-year incidence of ulcer complications was

significantly reduced among patients given lumiracoxib compared with

patients using nonselective NSAIDs and not taking aspirin (hazard ratio

0.21; p=0.0001); however, this benefit did not apply for patients who

were also taking aspirin, although there was a trend in favor of

lumiracoxib (hazard ratio 0.79; p=0.4876).

In the other paper, the primary cardiovascular end point of TARGET was

the Antiplatelet Trialists Collaboration end point of nonfatal and

silent MI, stroke, or cardiovascular death. This part of the study was

conducted because of the concerns about cardiovascular safety with

currently marketed COX-2 inhibitors, most notably rofecoxib (Vioxx,

Merck & Co), which in the VIGOR trial was associated with a 5-fold

increase in MIs compared with naproxen in patients with rheumatoid

arthritis.

As Topol and Falk point out in their editorial: " It has remained unclear

whether this striking increase in MIs was related to rofecoxib directly,

or [whether] the comparator agent, naproxen, had significant

antithrombotic effects. "

In TARGET, at 1-year follow-up, incidence of the primary cardiovascular

end point was lowboth with lumiracoxib and the NSAIDs.

Although there was an excess of lumiracoxib-associated MIs in TARGET,

this " was not statistically significant; it was only present compared

with naproxen and was not evident in the ibuprofen substudy, " Topol and

Falk say in their editorial. In fact, lumiracoxib was associated with

fewer MIs compared with ibuprofen, they note.

However, " unfortunately, this trial, like all others in the clinical

development of coxibs, purposefully excluded patients with known and

significant preexisting coronary artery disease " less than 2% of the

TARGET study population had had a previous MI or revascularization

procedure, Topol told rheumawire.

He added: " This study does nothing to help determine whether there is

any cardiovascular risk with coxibs. However, based on TARGET,

lumiracoxib doesn't look nearly as bad as rofecoxib. "

But Farkouh, lead author of the cardiovascular outcomes study, maintains

that the TARGET population was chosen to reflect a " real-world'

osteoarthritis population " 50% of the patients in TARGET had

hypertension, 20% had hyperlipidemia, and 10% had a history of vascular

disease, " he told rheumawire.

Coauthor on the reduction in ulcer complications paper, Dr

Doherty (University of Nottingham, UK), agrees. " I believe Topol and

Falk are overplaying this caveat, " he told rheumawire. " One in 10 of the

patients in TARGET had a history of cardiovascular disease or was

defined as 'at risk' by Framingham criteria. "

Topol remains unconvinced, however. " The companies developing COX-2

inhibitors should be required to do trials in cardiovascular patients.

But they are frightened. They don't want to put their money on the

line. "

None of the doctors, however, were able to give rheumawire a reliable

estimate of what percentage of OA patients would normally be expected to

have some evidence of cardiovascular disease.

Doherty points out that lumiracoxib showed a 3- to 4-fold reduction in

ulcer complications compared with NSAIDs, without an increase in the

rate of serious cardiovascular events, suggesting that lumiracoxib is an

appropriate treatment for patients with osteoarthritis. " The GI paper is

very strong, " he commented to rheumawire.

But Topol and Falk say that despite the claims of large reductions in

ulcer complications, there is an absolute reduction of just 0.72% in

this end point with lumiracoxib in patients not taking aspirin, and for

those taking aspirin " it is hard to justify the coxib: there is no

benefit in ulcer complication reduction but the risk of MI and

hepatotoxicity persist. "

Topol told rheumawire: " If patients are taking low-dose aspirin they

should not be taking a coxib because it does not confer any ulcer

protection and it costs $4 to $5 a day . . . the aspirin seems to

neutralize any benefit of the COX-2 inhibitor. These patients should

probably be taking naproxen. "

Doherty commented to rheumawire: " ibs are not the only drug you can

give to patients with OA. " There are plenty of other options, he says,

such as acetaminophen, topical NSAIDs, and opioids. He also believes

strongly in using proton pump inhibitors (PPIs) to protect against

gastrointestinal bleeding and says that in a patient with OA at high

risk of GI bleeding who also has to take low-dose aspirin for

cardiovascular prevention, he would begin by giving them a PPI such as

omeprazole, which would protect against the bleeding associated with

that dose of aspirin.

The hepatotoxicity referred to by Topol and Falk was an excess of 2.0%

of asymptomatic liver function test (LFT) abnormalities among those

taking lumiracoxib compared with those taking the NSAIDs in TARGET,

although this was reversible on drug discontinuation. Doherty says 1 of

the reasons for this could be that TARGET used a " supratherapeutic " dose

of lumiracoxib2 or 4 times the chronic OA dose, something that is usual

practice in a safety study of this kind. In CLASS and VIGORthe safety

studies for celecoxib (Celebrex, Pfizer) and rofecoxib

respectivelysupratherapeutic doses were also used.

He adds that the incidence of probable or possible drug-induced clinical

hepatitis was much lower than abnormal liver-function tests 0.07% in

those taking lumiracoxib compared with 0.05% in those taking ibuprofen

and 0.02% in those on naproxen. Also, abnormal LFTs affect around 4% of

those taking diclofenac, a widely used traditional NSAID, but this does

not stop people from taking it, he notes.

The editorialists continue: " The coxib field has been marked by

intensive direct-to-consumer (DTC) advertising in the US, and sales of

these drugs exceed $7 billion per year. Yet it is hard to imagine the

justification for this extraordinary adoption of coxibs in light of

marginal efficacy, heightened risk, and excessive cost compared with

traditional NSAIDs.

" The coxib debate will not go away until safety and efficacy questions

are answered: if only a small fraction of the DTC advertising costs or

revenues were appropriately channeled for clinical trials, we might be

able to have an enhanced perspective and make sound recommendations for

our patients, " they conclude.

Doherty points out that Novartis has not yet done any direct-to-consumer

advertising with lumiracoxib and that he hopes they will not go down

this road in the US. " This is the first time that the safety paper for a

coxib has come before the launch, and I think Novartis is being quite

responsible . . . it has a good track record of integrity, " he

concludes.

Sources

Schnitzer TJ, Burmester GD, Mysler E, et al.

Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic

Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction

in ulcer complications: randomised controlled trial. Lancet 2004;

364:665-674.

Farkouh ME, Kirshner H, Harrington RA, et al.

Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic

Arthritis Research and Gastrointestinal Event Trial (TARGET),

cardiovascular outcomes: randomised controlled trial. Lancet 2004;

364:675-684.

Topol EJ and Falk GW. A coxib a day won't keep the

doctor away. Lancet 2004; 364:639-640.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org