Are the GI Benefits of Etoricoxib Worthwhile?

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MEDAL: Are the GI Benefits of Etoricoxib Worthwhile?

http://www.medscape.com/viewarticle/551975?src=mp

Laine L, Curtis S P, Cryer B et al. Assessment of upper gastrointestinal

safety of etoricoxib and diclofenac in patients with osteoarthritis and

rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac

Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2007;

369:465-73.

Drenth JPH, Verheugt FWA. Do COX-2 inhibitors give enough gastrointestinal

protection? Lancet 2007; 369:439-40.

Sue Heartwire 2007. © 2007 Medscape

February 9, 2007 - Detailed gastrointestinal (GI) results from the

Multinational Etoricoxib and Diclofenac Arthritis Long-Term (MEDAL) trial,

comparing Merck's new COX-2 inhibitor etoricoxib (Arcoxia) with diclofenac,

have been published in the February 10, 2007 issue of the Lancet and show

significantly fewer uncomplicated upper-GI clinical events with etoricoxib,

a benefit that was maintained in patients taking proton pump inhibitors

(PPIs) or low-dose aspirin [1]. But there was no difference in complicated

GI events.

While the authors claim this reduction in uncomplicated upper-GI events is

important, an accompanying editorial disagrees [2], saying the GI benefits

of etoricoxib are " certainly not large and might not be clinically

relevant. "

The MEDAL study's main results, which focused on cardiovascular safety, were

published late last year and found the two drugs to be similar with respect

to thrombotic cardiovascular events, the subject surrounding the whole COX-2

controversy. But there has been much discussion about the choice of the

comparator drug--diclofenac--in MEDAL, with critics pointing out that this

agent has more COX-2 selectivity than other nonsteroidal anti-inflammatory

drugs (NSAIDs) and may therefore itself be associated with an increased rate

of cardiovascular events.

Is the GI benefit worthwhile?

The GI results from MEDAL are important in that the COX-2 inhibitors were

developed for the specific purpose of reducing GI side effects associated

with traditional NSAIDs, and this trial provides a mass of new data on this

issue as well as the question of cardiac safety. Whether or not the GI

benefits seen are actually worthwhile is now the subject of debate.

In an interview with heartwire, lead author of the GI MEDAL paper, Dr Loren

Laine (University of Southern California Keck School of Medicine, Los

Angeles), stressed that although complicated upper-GI effects were not

decreased with etoricoxib, reducing uncomplicated upper-GI effects is still

desirable. " These events may not be life-threatening, but they do have an

impact on a patient in that they need extra follow-up and changes to

treatment, and they may need an endoscopy. This may not be as clinically

relevant as a life-threatening bleed but it is still relevant--it is just a

matter of degree. "

But the authors of the accompanying editorial, Drs Joost Drenth and Freek

Verheugt (Nijmegen Medical Centre, the Netherlands) disagree. From the MEDAL

data they have calculated that 259 patients would need to be treated with

etoricoxib instead of diclofenac for 18 months to prevent one uncomplicated

gastrointestinal event. Drenth commented to heartwire: " I'm not sure that

this is worth the effort. The generally accepted figure that we consider

worthwhile is treating around 8 to 15 people to save one event. "

He added. " The advantage of COX-2 inhibitors was supposed to be fewer GI

side effects than traditional NSAIDs. But I haven't seen any good evidence

that they actually do reduce GI side effects in any meaningful way, and this

trial doesn't change that. The MEDAL program is a combination of three

different trials in almost 35 000 patients, and still we are seeing only a

very moderate effect on GI complaints. I don't think this is very hopeful. "

In the current paper, Laine et al note that while clinical trials have shown

fewer upper-GI clinical events with COX-2 inhibitors than traditional

NSAIDs, none of these trials simulated real-world practice because

GI-protective therapies such as PPIs were not allowed. In addition, it is

not known for sure what effect the addition of low-dose aspirin has on the

GI effects of COX-2 inhibitors. More information on these issues can be

gleaned from the MEDAL trial, which compared etoricoxib and diclofenac in 34

701 osteoarthritis and rheumatoid arthritis patients followed for a mean

duration of 18 months, in which patients with GI risk factors were

encouraged to use protective PPI therapy and those with cardiovascular risk

were encouraged to use low-dose aspirin.

Results showed that overall upper-GI clinical events were significantly less

common with etoricoxib than with diclofenac, but while there were

significantly fewer uncomplicated GI events with the new COX-2 inhibitor,

there was no difference in complicated events.

GI event Hazard ratio with etoricoxib vs diclofenac 95% CI p

All upper-GI events0.690.57-0.830.0001

Uncomplicated upper-GI events 0.570.45-0.74<0.0001

Complicated upper-GI events0.910.67-1.240.561

PPIs were used concomitantly for at least 75% of the study period by 40% of

patients and low-dose aspirin by 33% of patients, and treatment effects did

not differ significantly in these individuals. But they note that further

analysis of the results with regard to how regularly patients took low-dose

aspirin suggested that " etoricoxib reduces the risk of uncomplicated

upper-gastrointestinal events compared with the traditional NSAID diclofenac

in patients taking low-dose aspirin regularly, but the magnitude of the

gastrointestinal benefit might be decreased with low-dose-aspirin use. "

Reduction in dyspepsia

Laine et al also report that significantly fewer patients discontinued

etoricoxib than they did diclofenac due to dyspepsia. They point out that

this decrease was similar in patients who took PPIs, suggesting that the

COX-2-selective inhibitor provides symptomatic benefit even in patients

already taking a PPI. In addition, the reduction in dyspepsia

discontinuations was not affected by whether or not patients took

concomitant low-dose aspirin. " Dyspepsia is the most common side effect that

occurs with NSAID use and the most common side effect leading to

discontinuation of NSAID therapy. Not only is dyspepsia far more common than

upper-gastrointestinal clinical events, but medications for gastrointestinal

side effects probably account for most gastrointestinal costs--exceeding the

expensive but uncommon hospitalizations for gastrointestinal complications, "

they write.

Editorial cautious

In their editorial, Drenth and Verheugt point out some other caveats about

the study. They note that GI toxicity was not the primary end point in the

MEDAL program and that " to attribute benefits to secondary outcomes in a

trial can be problematic. " They explain that the groups of patients in the

MEDAL program were allocated according to cardiovascular risk factors rather

than upper-gastrointestinal risk factors, introducing a possible source of

bias. " The MEDAL program allowed patients to take proton-pump inhibitors or

low-dose aspirin, and as a consequence, groups were not randomly allocated.

.. . . The pragmatic nature mirrors the real-life situation in clinical

practice but confuses the interpretation of the results, " they write. They

add that as use of PPIs was encouraged in patients at high risk of a GI

clinical event, this might have led to confounding.

The editorialists also question why there was no benefit in complicated GI

events with etoricoxib. " Peptic-ulcer disease is a continuum from discrete

mucosal defect to frank disease with peptic ulceration with bleeding or even

perforation. A drug that prevents uncomplicated disease might be expected to

also reduce serious side effects such as bleeding and perforation; however,

it does not, " they write. But they add that peptic-ulcer complications are

relatively rare, and the MEDAL program might have been underpowered to

detect an actual treatment effect.

They say that the real question is whether a COX-2 inhibitor, such as

etoricoxib, is safer than a PPI added to a standard NSAID. " The advantage of

the PPI option is that it is less expensive, potentially less cardiotoxic,

and advantageous in terms of reducing dyspepsia, but confirmation of this

needs a new randomized trial. . . . The MEDAL program, however, does not

allow a definitive answer to that question, " they write.

Laine responded to heartwire: " Yes, this is a good question, but we didn't

address it as that would have necessitated randomizing to PPI plus a regular

NSAID vs a COX-2 inhibitor alone, and this trial was designed as a

cardiovascular safety trial for etoricoxib vs diclofenac. You can't address

all questions in one trial. "

Which drug to use?

heartwire asked Laine and Drenth (both gastroenterologists) to sum up how

they believed etoricoxib or other COX-2 inhibitors now fit into clinical

practice. While Laine can still see a role for these agents in patients with

GI risk factors, Drenth says he would rather use a regular NSAID with a PPI.

Laine commented: " At the end of the day, our results suggest etoricoxib does

have some GI benefits over diclofenac and that the thrombotic risk is

similar. As the GI benefits become greater in patients at higher GI risk, I

would advocate that a COX-2 inhibitor be used in patients who have a history

of GI problems. It appears that all NSAIDs may have some cardiovascular

risk, possibly apart from naproxen, so I would veer away from using any

NSAID or COX-2 inhibitor in patients at high cardiovascular risk such as

those with a prior MI, apart from maybe naproxen. "

But Drenth argued: " If I had a patient with a high risk of GI events and I

had a choice between a COX-2 inhibitor and diclofenac plus a PPI, I would

choose the diclofenac/PPI option, as PPIs reduce dyspepsia. The GI results

of MEDAL are not going to convince me to use COX-2 inhibitors at the

moment. "

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can be found at www.theheart.org, a Web site for cardiovascular healthcare

professionals.