NEWS - CV risks of anti-inflammatories discussed at cardiology meeting

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CV risks of anti-inflammatories discussed at cardiology meeting

Rheumawire

Mar 17, 2005

Sue

Orlando, FL - At a session on the cardiovascular effects of the COX-2

inhibitors/nonsteroidal anti-inflammatory drugs (NSAIDs) at last week's

American College of Cardiology (ACC) 2005 Scientific Sessions, Dr

Califf (Duke University, Durham, NC) attempted to summarize the state of

play regarding this issue and made some recommendations on how to move

forward.

He said there was very little evidence to assess the actual balance of

benefit (pain relief) and risk (cardiovascular/gastrointestinal events) with

either the COX-2 inhibitors or the regular NSAIDs and questioned why this

was the case. " Our system of drug development and postmarketing surveillance

has failed to produce a solid estimate of the balance of risks and benefits

for any patients taking chronic NSAIDs or coxibs. How can it be that,

despite all the money spent on these drugs, we still can't tell the consumer

what the balance of risks and benefits are for any of them? "

Califf pointed out that while cardiovascular disease may be the leading

cause of death in the Western world, arthritis is the leading cause of

disability. " Who among us does not have an aching joint? All of us have an

interest in this. " And NSAIDs will become more important as the population

ages, he pointed out. " I can guarantee that almost everyone over 65 takes

these drugs, and not just occasionally. But these drugs do cause GI

bleeding, which is a real big problem. "

While the new COX-2-selective drugs were hoped to block the pain without

causing bleeding and GI problems, they had another downside. " While

preserving the gut, they appear to increase cardiovascular eventswe are

always dealing with a trade-off. " Noting that all therapeutics represent a

balance of risk and benefit, he suggested that the doctor's old maxim should

be changed to from " Do no harm " to " On average, do more good than harm. "

Cardiovascular events: A class effect of the COX-2 inhibitors

He said that all the panelists to whom he had spoken at the recent FDA

meeting on the coxibs believed that cardiovascular adverse events were a

class effect with the COX-2 agents and that the more COX-2-selective the

agent, the greater the protective effect on the gut but also the greater the

risk of cardiovascular events. " Cardiotoxicity is a class effect of the

COX-2-selective drugs that may be dose dependent. It is likely that

cardiotoxicity is proportional to COX-2 specificity. COX-2 inhibitors also

cause GI toxicity, but this is probably inversely proportional to COX-2

specificity, " Califf summarized.

Dr Tilo Grosser (University of Pennsylvania School of Medicine,

Philadelphia) ordered the selectivity of the COX-2 inhibitors as follows:

Lumiracoxib (Prexige, Novartis) is the most COX-2 selective.

Then etoricoxib (Arcoxia, Merck), rofecoxib (Vioxx, Merck), and

valdecoxib (Bextra, Pfizer), which are all similar for selectivity.

Celecoxib (Celebrex, Pfizer) and diclofenac are less selective.

In an interview with rheumawire, Grosser noted that diclofenac

has been marketed for years as a regular NSAID, but it actually has a COX-2

selectivity similar to celecoxib. He pointed out that lumiracoxib, as the

most selective COX-2 inhibitor, should in theory have the highest risk of

cardiovascular events, but the TARGET trial of this drug (published last

year) did not show any increase in such events. While this argues against

the idea of cardiotoxicity being linked to COX-2 selectivity, Grosser said

the trial might not have been big enough or long enough to show an increase.

" The trial followed patients for only 1 year. In other studies of COX-2

drugs, it has taken 18 months for the effect to show up, " he commented. Dr

Juni (University of Berne, Switzerland), who recently published a

meta-analysis of rofecoxib trials, added: " Lumiracoxib has a short

half-lifethat may also make a difference. "

Califf said that in general NSAIDs are probably worse than neutral for

cardiovascular risk, but that naproxen is probably an exception, with a

modest reduction in thrombotic events. Califf agrees with the

recommendations made at the FDA last month that naproxen plus a proton pump

inhibitor (PPI) should be the regimen of first choice now for patients

needing an NSAID.

NIH statement on naproxen: Misguided

He said the National Institutes of Health (NIH) statement that it was

terminating the trial on naproxen in Alzheimer's disease after discovering

that the drug was associated with an increase in cardiovascular events vs

placebo was " terribly misguided. " " The results were preliminary, and only a

few details of the trial have been released. The observation with naproxen

was apparently statistically nonsignificant, and there are not enough data

to make any recommendations, " he commented.

Califf noted that there are an enormous number of people with acute or

chronic pain, and as many of these people are elderly, " the same patients

are at risk of GI ulceration from NSAIDs but may also have heart disease or

are at risk of getting heart disease. " So how to treat these people?

Clinical recommendations

Califf made the following recommendations:

Low-dose aspirin should be continued when indicated.

Alternatives to NSAIDs should be considered, such as acetaminophen and

topical therapies.

If an NSAID is used, naproxen plus a proton pump inhibitor (to protect

the gut) should be used first.

COX-2-selective drugs should be avoided unless the above strategies

fail.

Large-scale study of coxibs needed

Califf called for a large-scale study of COX-2-selective drugs that would

have naproxen plus a proton pump inhibitor as a control arm and at least 10

000 patients in each arm, with a mix of aspirin takers and patients at high

risk of heart disease enrolled. The primary end point should be 1 of net

clinical benefittaking into account pain relief, GI events, and

cardiovascular events.

Other speakers at the COX-2 session were not sure whether a trial in

patients at high risk of heart disease would be practical. In an interview

with rheumawire, Juni said he thought a large-scale trial was definitely

necessary but asked: " Whom do we do the trial in? To get events we need

patients who are likely to have a cardiovascular event, but these patients

are going to be reluctant to enroll. I certainly would be. "

Califf disagrees. " Since many patients with known coronary disease are

already taking these drugs, I think we'd have no trouble with enrollment, "

he told rheumawire.

But having recommended that an NSAID/PPI be the first-line choice and that

coxibs should be reserved for patients who cannot take this combination or

for whom it does not work, how can he recommend randomizing between an

NSAID/PPI and a coxib in a clinical trial?

Califf commented: " Faced with uncertainty, we have to make recommendations

using judgment and the data we have. The remarkable thing is that almost all

experts recommended naproxen/PPI based on what we know now. But the

uncertainty is so broad that we just don't know if the recommendation is

right. So, if there is no randomized controlled trial to enter, go with the

naproxen/PPI. If there is a randomized controlled trial, join it so we can

resolve the uncertainty! "

Juni said he thought it was essential for patients enrolled in new trials of

the coxibs to be carefully characterized. " It may always be a particular

characteristic of a patient that is making them susceptible to these adverse

effects. We must explore that. What we do not have is a large safety trial

in the population of patients who actually take these drugs in reality. This

is what we need. "

Should the coxibs remain available?

Most of the speakers at the ACC session believed the coxibs should remain on

the market. Califf said: " I think they should still be available for

patients as long as they know the risks. My mother took Vioxx for her aching

knees, as it was the only thing that worked. She ended up having a

knee-replacement operation last week, which is not without risk, because

Vioxx is no more. "

Juni agrees. " I think the FDA will restrict COX-2 inhibitors to patients who

can't take NSAIDs/PPI or in whom that combination is not effective and who

don't have a cardiovascular risk. " He added that while there is no

scientific evidence to support the idea that COX-2 inhibitors are more

effective than standard NSAIDs in reducing pain, there are many anecdotal

reports from patients who say they are better. " I think it may be patient

specific, " he said.

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