The Cox-2 Inhibitors Controversy
Dr. Shiel is a a practicing rheumatologist, and Chief Medical Editor of
MedicineNet.com, and Dr. Smith is
Senior Medical Editor, WebMD, Inc.
- Question: Dr. Smith
Are Cox-2 inhibitors less likely to irritate the stomach than older
antiinflammatory drugs?
Answer:
Dr. Shiel
Selective
Cox-2 inhibitors (such as Celebrex and Bextra) NOTE: April 7, 2005, Pfizer has agreed to suspend sales and marketing of Bextra in the U.S., pending further discussions with the with the FDA. For more information, please read the
FDA press release.
, do not inhibit the
Cox-1 enzyme in the stomach and are thus felt to be less toxic to the stomach
than traditional antiinflammatory drugs (such as aspirin,
ibuprofen, or
naproxen). These traditional anti-inflammatory drugs, called nonselective
Cox-1/Cox-2 inhibitors, inhibit both Cox-1 and Cox-2 enzymes. While inflammation
is reduced by blocking Cox-2, the protective mucus lining of the stomach is also
reduced when Cox-1 is blocked, which can cause stomach upset, ulcers, and
bleeding.
Current evidence suggests that the selective Cox-2 inhibitors are less toxic
to the stomach than traditional antiinflammatory drugs. This effect is
especially significant in persons who are at risk of stomach bleeding, such as
those with a history of prior stomach bleeding or patients on blood thinning
medications.
- Question: Dr. Smith
There are studies on Cox-2 inhibitors showing heart risks for elderly
people. Is the concern only in elderly people?
Answer: Dr.
Shiel
Actually, while there have been studies demonstrating a heart risk in persons in
the Medicare age group, the issues raised pertain to any patient with underlying
risk factors for heart disease or stroke. This means not only the elderly may be
at risk, but also those who have underlying known heart disease (either coronary
artery disease or congestive heart failure) or known blood vessel disease
(atherosclerosis or calcification of blood vessels).
Caution might be also be used for those with
high blood pressure and a
tendency toward fluid retention (edema). It has been shown that ALL
antiinflammatory drugs (traditional and Cox-2 inhibitors) can worsen blood
pressure or cause fluid retention and patients should be monitored for such side
effects. Similarly, in the elderly who are at risk for kidney impairment, or in
any patient with known kidney disease, antiinflammatory drugs should be used
cautiously with close monitoring of kidney function.
- Question: Dr. Smith
Do the new Cox-2 inhibitors relieve pain better than older traditional
anti-inflammatory drugs, like ibuprofen and naproxen?
Answer:
Dr. Shiel
No. As a group, the benefit of these drugs lies in their lower incidence of
gastrointestinal side effects not in their effectiveness. Clinical research has
shown that the Cox-2 inhibitors are essentially equivalent to traditional
antiinflammatory drugs in effectiveness. Improved effectiveness has never been
the point of these medications, nor have their respective manufacturers marketed
them for that purpose.
Having said that, doctors are well aware that determining which patient is
going to respond to which antiinflammatory drug to a certain degree involves
some trial and error. Therefore, it is convenient to have options when treating
chronic pain or inflammation.
- Question: Dr. Smith
Do older anti-inflammatory drugs, like ibuprofen and naproxen (Aleve),
have the same heart risks as the Cox-2 inhibitors?
Answer: Dr.
Shiel
We don't
know. Recently, the National Institutes of Health (NIH) was conducting a study
for Alzheimer's disease prevention and was comparing naproxen (Aleve) in
low doses (220 mg twice daily) to celecoxib (Celebrex) and a placebo. The trial
was stopped as a precaution because of an "apparent" increase in
heart attack
and stroke in participants taking naproxen as compared to the placebo. This
report, in my opinion, is completely inconclusive.
In order to determine if there are heart attack and stroke risks associated
with naproxen and ibuprofen, much larger and longer term studies that are geared
(preprogrammed) to look specifically at this issue will be necessary. Moreover,
the doses evaluated will need to be in line with the doses commonly prescribed
by doctors (375-500 mg twice daily) in order to provide adequate guidance
information.
- Question: Dr. Smith
Are Celebrex and Bextra likely to be removed from the market like Vioxx?
Answer: Dr. Shiel
I have absolutely no idea. And, this is after reviewing most major research
reports about these drugs as well as attending a major symposium on them at the
2004 national arthritis meeting (American College of Rheumatology). The results
of current studies are conflicting and incomplete. As a practicing clinician, it
is my hope that as a result of an upcoming FDA review of research data, doctors
will have clearer guidelines as to the use of all antiinflammatory drugs (both
traditional and Cox-2 inhibitors).
I can say that if Celebrex and Bextra are removed from the market, there is
some good news for those patients requiring antiinflammatory drugs who have
underlying gastrointestinal risks. There is significant data that demonstrates a
decreased risk of stomach bleeding in persons taking traditional
antiinflammatory drugs who simultaneously take stomach protection drugs, called
proton pump inhibitors. Examples of proton pump inhibitors include
omeprazole
(Prilosec), lansoprazole (Prevacid),
esomeprazole (Nexium),
pantoprazole
(Protonix), and rabeprazole (Aciphex).
I might add that if these drugs are removed from the market, it will
undoubtedly have serious consequences in patient care. A recent
MedicineNet survey found
that over half of former Vioxx users took matters into their own hands, stopping
their drug and either taking no drug or substituting over-the-counter pain
medications without contacting their doctor's office!
- Question: Dr. Smith
Some studies have shown that Cox-2 inhibitors have been over-prescribed.
To whom should these drugs be prescribed?
Answer: Dr. Shiel
In particular, a recent study published in Archives of Internal Medicine
(January, 2005), showed that doctors were using Cox-2 drugs in a wide variety of
patients instead of specifically selecting patients at risk for stomach bleeding
as the ideal candidates. It was suggested that marketing and promotion of the
drugs lead to their use in an unnecessarily large group of patients. Moreover,
patients may have requested them because of perceived benefits.
Drug treatment is always based on a risk vs. benefit analysis. In clinical
practice, Cox-2 inhibitors are considered after weighing the benefits vs. the
risks. As more research clarifies the risks and the groups of patients who are
more prone to these risks, it will become easier for patients and doctors to
choose medications optimally.
Currently, Cox-2 drugs are most suited for patients who have a history of
gastrointestinal bleeding or who are at risk for bleeding. Persons who are
taking the blood thinning medication
warfarin (Coumadin) cannot take traditional
antiinflammatory drugs because of high bleeding risks. When an antiinflammatory
drug is necessary, Cox-2 inhibitors are permissible for this group of patients.
The risks and benefits of taking a medication must be evaluated in an
individualized fashion for each patient. The decision to take a medication
requires knowledge of the severity of the condition treated, risks of
alternatives, underlying medical conditions, past medication experiences,
affordability of the drug, and the patient's age to adequately appreciate the
risks.
- Question: Dr. Smith
Is a lower dose of Celebrex or Bextra safer?
Answer: Dr.
Shiel
In general, in order to minimize side effects, ALL medications should be used in
the lowest dose and for the least amount of time as is reasonable for the
particular condition being treated. But, is using a lower dose of Celebrex or
Bextra safer than using a higher dose?
The answer is: We don't yet know.
For example, the studies that have demonstrated an increased risk of heart
attack and stroke in patients taking Celebrex were in patients taking high doses
(400-800 mg per day). This does not mean that taking 200 mg is free from risk or
poses less risk. While many side effects can relate directly to the amount of
the daily dose, some simply are associated with taking ANY of the medication. We
need to have more research to clarify these issues.
- Question: Dr. Smith
If a Cox-2 drug is discontinued, is the adverse risk of heart attack or
stroke permanent?
Answer: Dr. Shiel
No. There is no evidence of a sustained adverse effect. The risk would only be
expected to be present while taking the drug, not after it has been
discontinued.
It is interesting to note that the heart attack and stroke risk detected in
the Vioxx study (which led to its manufacturer to pull it from the market) did
not present in study participants until the drug was taken for at least 18
months. There was no increased risk of heart attack or stroke detected in study
participants who took Vioxx for less than 18 months. This suggests the
possibility of some metabolism or enzyme change that takes time to occur in the
body.
For more, please read Dr. Shiel's recent article,
"Cox-2 Inhibitors Dilemma, What
Patients Should Do."
Last Editorial Review: 4/7/2005
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