NEWS - Rofecoxib (Vioxx) withdrawn because of CV side effects

[Guest guest]

Rofecoxib (Vioxx) withdrawn because of CV side effects

Rheumawire

Sep 30, 2004

Zosia Chustecka

The COX-2 selective inhibitor rofecoxib (Vioxx, Merck & Co) has been

withdrawn worldwide by the manufacturer, after a new prospective

clinical trial showed an increase in cardiovascular events in patients

taking the drug compared with those on placebo. The withdrawal is

effective immediately, and Merck says all patients taking the drug

should contact their healthcare provider to discuss discontinuing the

drug and possible alternative treatments.

The data that prompted the move come from a 3-year cancer prevention

trial and show for the first times a higher risk than placebo. The

APPROVE study involved 2600 patients with a history of colorectal

adenomas taking either rofecoxib 25 mg or placebo to see whether the

selective COX-2 inhibitor would prevent the occurrence of colorectal

polyps (this indication is similar to that already approved for another

selective COX-2 inhibitor, celecoxib (Celebrex, Pfizer).

After 18 months of continuous treatment (but not before), there was an

increased risk of confirmed cardiovascular events, such as myocardial

infarction and stroke, in the group taking rofecoxib. Merck tells

rheumawire that the figures for confirmed cardiovascular events were 45

in the rofecoxib group vs 25 in the placebo group, giving rates of 1.48%

vs 0.75%, respectively. There was no difference in the incidence of

mortality, with 5 deaths in each group. This is the first time that a

prospective study has shown more harm with rofecoxib than with placebo,

and it was this finding that prompted the withdrawal, the company said.

Rheumatologists contacted by rheumawire were said they were surprised by

the news and concerned that it may spell trouble for this whole class of

drugs. Dr Pisetsky (Duke University, Durham, NC) says the news

will prompt reevaluation of the overall safety of these products, as the

improved gastrointestinal safety compared with nonselective nonsteroidal

anti-inflammatory drugs (NSAIDs) now has to be weighed against an

increased risk of cardiovascular events. " It alters the balance, " he

says, as it now appears that " we were accepting more risk than we

thought we were. "

Dr Lou Bridges (University of Alabama, Tuscaloosa) says, " Although there

are no data to support it at present, I am worried that this finding may

be a class effect that might apply to other coxibs. " He says all

patients on chronic therapy should stop taking rofecoxib. " I believe

that the drug is safe in short-term use, but the long-term results are

alarming. "

Both doctors praised Merck for its action. " I give great credit to

Merck, I think this is an important step in response to concerns about

safety. they could have restricted the drug, or added new warnings, so

they deserve credit for reacting like this, " says Pisetsky.

" We are taking this action because we believe it best serves the best

interests of the patients, " says Ray Gilmartin, chair, president, and

chief executive officer of Merck. " Given the availability of alternative

therapies and the questions raised by the data, we concluded that a

voluntary withdrawal is the responsible course to take. "

Vioxx had sales of $2.3 billion in 2003 and was among the top-20

best-selling drugs in the world. Merck shares plummeted in reaction to

the news, falling by 26% within hours of the announcement.

Pharmaceutical analyst Jo Walton at Lehman Brothers (London, UK) tells

rheumawire that the announcement of a withdrawal came as a " complete

surprise . . . it's a major shock. " The new data suggest the drug is

causing harm and change the story, she commented, as until now Merck has

always maintained that the increased risk of cardiovascular events that

have been seen with rofecoxibi n comparison with nonselective NSAIDs

have been due to an absence of cardioprotective effects rather than an

adverse effect of the drug itself.

The finding that the cardiovascular risks increased after 18 months of

continuous therapy (but not before that time) may lead to delays in the

approvals of new drugs in this class, says Walton. Newly released data

from the TARGET trial with lumiracoxib (Prexige, Novartis) show no

evidence of a cardiovascular risk, but the data so far are for 1 year.

Regulatory agencies may now want to see 3-year data before agreeing to

approve new products, she suggested.

Merck noted that 2 previous placebo-controlled trials with rofecoxib,

both of which are included in the Vioxx product labeling, showed no

increased risk of cardiovascular events, but both of these studies

lasted only 18 months. The increased risk in the APPROVE study appeared

after that time.

Dr Tom Huizinga (Leiden University Medical Center, the Netherlands)

comments that it's not clear why rofecoxib was associated with an

increased risk of cardiovascular eventsthere are not enough data to know

whether it's an intrinsic effect of the drug or if it results from an

increase in blood pressure. " It is interesting to see that the dose of

Vioxx was relatively high, which opens up the possibility that

inhibition of COX-2 in the kidney leads to fluid retention and a rise in

blood pressure, " he tells rheumawire, adding that it would be useful to

compare the blood pressure in both groups. " If this last option is the

case, then this trial emphasizes the need to be careful with COX

inhibition, especially in patients with borderline hypertension. "

The withdrawal of rofecoxib leaves a dilemmawhat to prescribe for these

patients in its place?

Pisetsky says patients must be considered on an individual basis, with a

focus being on why they were taking rofecoxib in the first place and

whether they are they at high risk of gastrointestinal toxicity. There

are a lot of questions that need to be asked, he says. Many of these

patients are also taking aspirin for cardioprotection, but does this

negate the GI safety advantage of the selective COX-2 inhibitors? Should

they be taking a nonselective NSAID instead, as well as the aspirin?

Should they also have gastroprotective therapy such as a proton pump

inhibitor or an H2-antagonist?

When the coxibs first appeared, the decision of when to use them was

geared originally by considerations of GI toxicity, but more and more

over the past few years, the cardiovascular issues have been creeping

into the equation " we haven't been blind to this, this has been talked

about in the past few years, and we've been trying to balance this out, "

Pisetsky says.

" The new data really complicate the risk/benefit analysis, " he says. " I

worry about side effects, and I think we need caution. " His own

immediate reaction will be to " think twice, " especially about writing

new prescriptions for the selective COX-2 inhibitors.

************************************

Reaction mixed from cardiologists

One cardiologist who has long maintained that rofecoxib had an

unacceptable cardiovascular safety profile is Dr Topol (Cleveland

Clinic, OH). He commented to rheumawire that " Merck has finally got it

right, " although it was " too bad it took so long for them to accept the

truth. " He added: " Ironically, the validation of our concern came from a

colon polyp trial in patients without any known heart disease. " He said

the other COX-2 inhibitors seemed safer, but " it was hard to know. "

Another high-profile cardiologist has a somewhat different opinion on

this issue. Dr Califf (Duke Clinical Research Institute, Durham,

NC) commented to rheumawire that rofecoxib caused a small but measurable

increase in risk of cardiovascular events, but that other ongoing

placebo-controlled trials do not show the same effect. " From what we can

piece together from the poor studies that are available, it looks like

naproxen may be the only one that reduces riskwe just don't know about

celecoxib, etc. Any chronically given drug that affects inflammation

will have cardiovascular effects. Not doing long-term trials to inform

the public about the balance of risks and benefits is like playing

Russian rouletteyou just don't know which chambers have bullets unless

you look. "

He added that: " It's a shame the drug has to pulled from the market. It

would be best to inform doctors and patients of the risk and let them

make a choice, but because of the dominance of lawsuits in therapeutics,

obviously Merck can't afford to do that. "

-Sue

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org