INFO - The CV risk with coxibs: is it really proven, how big is it, and are traditional NSAIDs any safer in this regard?

March 11, 2005

The CV risk with coxibs: is it really proven, how big is it, and are

traditional NSAIDs any safer in this regard?

Rheumawire

March 10, 2005

Zosia Chustecka

London, UK - The increased cardiovascular risk with rofecoxib (Vioxx, Merck

& Co) that led to this drug's withdrawal now appears to be a class effect of

the COX-2 inhibitors, but as the data are analyzed, they are throwing up

more questions than answers. Some question whether the CV risk has really

been proven, others how large this risk really is, while others still point

out that some of the traditional nonsteroidal anti-inflammatory drugs

(NSAIDs) also have a CV signal and so may also carry an increased CV risk.

One consequence of the growing belief that the CV risk is a class effect of

the coxibs is Merck considering the return of rofecoxib to the market. This

proposal is " astonishing " and " a mockery to the international medical

community, " says Dr Osvaldo Messina (Dr Cosme Argerich Hospital, Buenos

Aires, Argentina), commenting in the email forum of www.jointandbone. All of

these COX-2 inhibitors share the same mechanism of action and the hence same

increased cardiovascular risk, and so " we should be thinking about taking

them all off the market, " he argues.

The COX-2-selective inhibitors allow the effects of COX-1 to predominate,

creating clinical conditions that lead to a trend to arterial thrombosis

(vasoconstriction, platelet aggregation, and endothelial proliferation),

Messina explains. " This is the biochemical reality, " he tells rheumawire.

There are strong interests other than medical at work here, he says, and

proposing that rofecoxib should return is saying that " 1 more member of a

questionable pharmaceutical class should be marketed because there are

others already being sold. "

But has the increased CV risk of rofecoxib really been proven? Dr

Mann, a retired physician from Salt Lake City, UT, suggests that it hasn't.

A former emergency-medicine doctor, he has a particular interest in clinical

trials and runs a medical education website on which he publishes detailed

critiques of clinical trials, including a recent 1 about the Adenomatous

Polyp Prevention on Vioxx (APPROVE) study [1]. This showed nearly a doubling

of CV risk for rofecoxib compared with placebo.

However, Mann points out that the increase in CV risk was seen only 18

months into the trial and " primarily reflects the fact that the placebo

group had an unexpectedly low control event rate during the last 18 months

of the trial. " The Kaplan-Meier curves for cumulative adverse CV events in

the placebo group show a dramatic flattening in the second half of the

study, he points out; if it had remained similar to what it had been in the

first half of the study, the difference between rofecoxib and placebo would

probably have been deemed not to be clinically significant. " I cannot think

of any intrinsic reason why the rate of adverse events should vary markedly

from month to month other than due to the play of chance. "

A problem with this trial, and many other clinical studies, is the

heterogeneity of patients when the control event rate is low. " Many clinical

researchers believe that randomization will ensure that there is a balance

of patients in the control and treatment group, but common sense tells us

this is not necessarily true, " Mann commented in an interview with

rheumawire. Normally, a slight difference between the 2 groups in pattern

distribution of baseline prognostic variables should not affect a study's

results, but when the control event rate is low, it can have a significant

confounding effect, he explains. However, in the case of the APPROVE study,

the most likely explanation is unrelated to any pattern-distribution

imbalance: the placebo patients had a low risk of an adverse event (around

2%) over the 36-month study time period, and it was " pure chance " that very

few of those events occurred during the second half of the study, he says.

Hence, Mann suggests that the conclusion that rofecoxib increases CV risk is

" scientifically invalid " and says he was " quite amazed " that this 1 finding

led to the drug's withdrawal. In his opinion, it is " foolish to definitively

state that rofecoxib increases the risk of adverse CV events based on a

single trial that has a low signal/noise ratio. "

Mann expresses similar disquiet about the conclusions of the Adenoma

Prevention with Celecoxib (APC) trialthe only study so far to show an

increased CV risk with celecoxib (Celebrex, Pfizer). The APC trial also has

a low control event rate, and it is difficult for randomized trials that

recruit low-risk individuals to generate a strong signal, he comments.

Science demands repeatable results, and the fact that the findings of both

the APPROVE and APC studies differ from that of many other trials is in

itself a cause for suspicion, he adds.

Allow patients to choose what risks to take

Also, the increased CV risk should be placed into context, says Mann. If

rofecoxib does double the risk of a CV eventwhich Mann emphasizes isn't

proventhen whether or not this is clinically significant depends on " one's

mind-set. . . . If the patient in question has a 1% chance of a heart

attack, and rofecoxib raises this to 2%, well, many patients would be

prepared to accept this in exchange for the benefits they derive from the

drug, especially if it's put to them that they have a 98% chance of not

having a heart attack, as opposed to a 99% chance. " And there are many other

factors that need to be taken into account, he adds; for example, smoking is

believed to double CV risk.

" My patients have the right to accept whatever risks they choose in light of

the individual benefits and their own informed consent, " says Dr

Hardy (University of Mississippi Medical Center, ). He argues

strongly in favor of bringing back Vioxx in the email forum of

www.jointandbone.org and describes patients now crippled with arthritis who

would be willing to take the risk to gain the benefit of this drug.

Hardy objects to what he sees as the hijacking of this issue by an

out-of-control media and legal system and a result as well of paranoia and

loathing of industry wealth and power, all of which " have clouded our

otherwise good clinical judgment. " He says: " Rheumatologists are among the

most thorough of all internists " and should be left " the hell alone to deal

with the medicines and the patients we know best. "

Hysteria is unfair to physicians and patients

" The reason for all this coxib/NSAID/CV-risk hysteria is that we are all

unwittingly wallowing in confusion at the bottom of a statistical barrel, "

says Hardy. " The CV risks, while admittedly real, are so small that earlier

studies simply couldn't statistically and/or reliably detect them at all. In

fact, everyone currently agrees that large, prospective trials with multiple

cohorts over many years will be needed before we can truly understand whatif

anydifferences in CV risk exist between specific (rofecoxib, valdecoxib),

selective (meloxicam, celecoxib, etodolac, etc), and nonspecific (ie,

traditional) NSAIDs. The risks and differences are simply too small to be

reliably interpreted from our available clinical trials. "

Hardy makes the point that naproxen has come out showing different effects

in different studiessome show it to have a decreased CV risk, but some show

it to increase the CV risk, and some show no effect at all. " We have scraped

the bottom of the statistical barrel looking for meaningful information and

received instead controversial, variable, and highly sensationalized data of

minimal practical value to anyone other than trial attorneys and the media, "

says Hardy.

This is " grossly inappropriate and unfair to physicians and their patients, "

he argues. " Huge numbers of patients have benefited enormously, and safely,

especially from the coxibs. . . . Armed with practical information, patients

and their physicians should be the ones to discuss risk/benefit on an

individualized basis. "

Does problem extend to all NSAIDs?

One of the fears of practicing clinicians is that the publicity about the

" dangers " of the increased CV risk with the coxibs will lead doctors and

patients to older drugs that do not have any better safety records and that

in fact may be worse. This is already being advocated in some areasas

reported by rheumawire, New Zealand recently ruled that the risks of COX-2

inhibitors outweigh the benefits in the general population and advised using

" alternative therapeutic options " while listing available traditional NSAIDs

(including diclofenac, ibuprofen, sulindac, tiaprofenic acid, ketoprofen,

naproxen, tenoxicam, and piroxicam).

But the safety of many of these older drugs hasn't been thoroughly

documented, a point that came out strongly at the recent US FDA hearing on

the safety of NSAIDs. " We are worried about some of the other NSAIDs, and I

hope that message came through, " says 1 of the FDA advisory panel members,

Dr Nissen (Cleveland Clinic Cardiovascular Coordinating Center, OH).

Some of the older drugs are also relatively COX-2 selective, he points out,

and " we aren't so sure that agents like diclofenac and meloxicam don't have

the same cardiovascular risks. And we're not so sure about ibuprofen,

either. " [2] His comments appear in a report of the FDA hearing on

AMednews.com, and he adds: " My concern is that if we are going to push

people to a different pattern of use, that pattern ought to reduce risk, but

we don't really know if these drugs are going to reduce the risk of

cardiovascular complications. "

The same point is highlighted in the latest hotline on the safety of COX-2

inhibitors from the American College of Rheumatology (ACR), which summarizes

deliberations at the FDA hearing [3]. As already reported by rheumawire, the

ACR comments that the data on CV risks of traditional NSAIDs are

" incomplete, but concerning. " It notes that trials of celecoxib using

diclofenac and ibuprofen as comparators fielded comparable rates of CV

events but adds that this " does not confirm the safety of the coxib, as

these nonselective NSAIDs may also share an increased CV risk. " Unpublished

observational studies reported at the meeting by Dr Graham using 2

large US databases suggest there is an increased CV risk for many NSAIDs

(indomethacin, meloxicam, sulindac), and preliminary data from a Norwegian

study (Sudbo et al) showed increased CV risks with traditional NSAIDs, with

CV hazard ratios ranging from 1.70 for naproxen to 2.86 for ibuprofen.

The mechanism behind the increased CV risk is not entirely clear, comments

Dr Laster, a rheumatologist in private practice in Charlotte, NC and

an editorial consultant to www.jointandbone.org. " We have assumed until now

that COX-2 drugs are implicated because they block prostacyclin and allow

thromboxane to work unopposed, " he comments. However, aspirin is a selective

COX-1 inhibitor, and yet a subset analysis of the coxib trials that have

shown a CV signal indicates that the increased CV risk occurred both in

patients who were taking aspirin and in those who weren't. " So if aspirin

was unable to block this response, does this mean that an alternate

mechanism is in effect? Is this why some NSAIDs that are nonselective may

also be associated with increased CV risk? "

So if aspirin was unable to block this response, does this mean

that an alternate mechanism is in effect?

Dr Pisetsky (Duke University, Durham, NC), an editorial consultant to

www.jointandbone.org, says that there are several important issues that need

to be considered. He points out that the trials showing an increased CV risk

with the coxibs were long-duration cancer-prevention studies where patients

were taking the drug every day and asks whether it is reasonable to

extrapolate from them to the arthritis population and the more common

situation where people take NSAIDs periodically1 estimate suggests for 60

days per year.

" I agree that all drugs have side effects and that patients need to evaluate

for themselves the relative risks and benefits, " he says. " And like many

physicians, I have patients who claim unique benefits from 1 or another

NSAID or coxib. " But while alternatives should be available for these

individuals, this need should not equate with widespread use of a class of

drugs that potentially has more side effects, he adds. However, he also

wonders whetherby nowthe media and direct-to-consumer advertising have

clouded the discussion to such an extent that a reasonable middle ground

will be hard to achieve.

Sources

Mann J. Questioning the validity of the APPROVe study's

official interpretation. Accessed March 10, 2005.

Landers SJ. FDA ponders future for -2 drugs.

AMNews.com, March 14, 2005. Available at:

http://www.ama-assn.org/amednews/2005/03/14/hlsa0314.htm.

Kavanaugh A, Matteson EL, Cush JJ. The safety of COX-2

inhibitors: Deliberations from the February 16-18, 2005 FDA meeting.

American College of Rheumatology Hotline. Available at:

http://www.rheumatology.org/publications/hotline/0305NSAIDs.asp. Accessed

March 10, 3005.

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org

March 11, 2005

I made the decision today to go back on Bextra. I called the rheumy

Fellow and got his okay. The salsalate just is not doing anything for

my pain. While on Enbrel and Bextra, I had very little pain at all.

Since I've been taking sulsalate instead of Bextra, for a little over

three weeks, I've had pretty much continual pain, in the hips, knees,

and feet primarily, as far as my joints go. But in addition, I'm having

considerable stomach discomfort, which is all I felt before when I had

the bleeding ulcer from taking Aleve. I did take the salsalate after

meals, and took an acid reducer 30 minutes beforehand. My dose of

Bextra is small, only 10 mg. I decided that the benefits outweigh the

risks for me. At least I did try something else. Now I don't know

whether I need to go to my PCP to see about my stomach. Oh, well, it's

the weekend, anyway, so I'll decide next week.

Sue

On Friday, March 11, 2005, at 03:57 PM, wrote:

>

> " I agree that all drugs have side effects and that patients need to

> evaluate

> for themselves the relative risks and benefits, " he says. " And like

> many

> physicians, I have patients who claim unique benefits from 1 or another

> NSAID or coxib. "

March 11, 2005