Is Celebrex as Detrimental to the GI Tract as Non-selective NSAIDs and
Is There An Increased Risk of Cardiovascular Events With The Use of
Celebrex?
An Argument Paper for Pfizer Pharmaceutical Representatives
Akane Seki and Christine Ermak
Spring 2005
Issue
The recent controversy surrounding Vioxx has triggered many questions about the
safety of other COX-2 inhibitors such as Celebrex. Many studies have shown the
statistical significance in which Vioxx demonstrated the increased risk of acute
myocardial infarction (See Table 1). The incidence of stroke was greater with Vioxx than
with other anti-inflammatory prescription medications as well. Celebrex is in the same
COX-2 inhibitor class as Vioxx and is still being prescribed for similar purposes. Vioxx
was thought to be the most effective COX-2 inhibitor, but because of its discontinuation
many physicians have instead substituted Celebrex for Vioxx regimes.
It is important to investigate the safety of Celebrex because it is a widely
prescribed medication not only for arthritis patients, but for patients with severe
migraines, dysmennorhea and to treat post-surgical procedures. Although Celebrex and
Vioxx are in the same COX-2 class they have different functional groups within their
chemical structures (see Figure 2). They also differ in their potency, specificity of COX-2
inhibition, pharmacokinetics and metabolism. Thus, the question at hand is how much do
1
these differences actually affect the physiological mechanisms in which risks of heart and
gastrointestinal complications are increased?
An understanding that the effectiveness of Celebrex is not what has caused so
much controversy must be recognized. There were many studies reviewed by the FDA
concerning Celebrex before it ever was put on the shelf, which showed it was just as
effective as non-selective NSAIDs at decreasing inflammation (Crawford et al.2002 and
Nachimuthu et al. 2001). The argument here is concerning the safety of the drug in terms
of cardiovascular and gastrointestinal side effects. Despite studies that have inferred
risks of Celebrex use, after sifting through a large portion of the current research that has
been published about Celebrex, it is safe to say that this drug is gentler on the GI tract as
well as safe for cardiovascular health than non-selective NSAIDs that are available on the
market today.
Table 1. Evidence that the issue is unresolved
Celebrex Safe in
terms of
Cardiovascular
risks
Celebrex unsafe in
terms of
Cardiovascular
safety
Celebrex
safe on the
GI tract
Chenevard et al.
(2003)
Rabausch et al.
(2005)
Simon et al.
(1999)
Celebrex not
any safer on
the GI tract
than nonselective
NSAIDs
Crawford et
al. (2002)
Levesque et al.
(2005)
Solomon et al.
(2005)
Silverstein et
al. (2000)
Nachimuthu
et al. (2001)
Mamdani et
al. (2002)
Brief Overview of COX-2 Inhibitors
COX-2 inhibitors are manufactured with the specific purpose of gastrointestinal safety in
mind. The COX-2 inhibiting drugs, such as Vioxx and Celebrex, have proved to be
2
involved in directly alleviating inflammation with less gastrointestinal complications than
non-selective NSAIDs. Prostaglandin G/H synthase, the enzyme that catalyzes
prostaglandins and thromboxanes which specify pain and platelet aggregation, is
inhibited by both non-selective NSAIDs and COX-2 inhibitors. Inhibiting the COX-2
enzyme may be of therapeutic advantage, since this isoenzyme is almost certainly
involved in prostaglandin production at the site of inflammation but not at other sites
such as the gastrointestinal tract and kidney. Non-selective NSAIDs target the COX-1
enzyme activity in gastrointestinal mucosa and platelets as well as COX-2 enzyme
activity. However, COX-2 inhibitors such as Celebrex do not interfere with the COX-1
receptor. COX-1 enzymes are responsible for producing the protective mucous lining in
the GI tract as well as decreasing levels of HCl secretion in the stomach and stimulating
intestinal motility. It also is the constitutive isoform found in the blood vessels, stomach
and kidney. COX-2 enzymes on the other hand are induced in settings of inflammation
by cytokines and inflammatory mediators. Consequently, this inhibition of both COX
isoenzymes and prostaglandins has been related to gastrointestinal tract toxicity and the
long-term use of non-selective NSAIDs is therefore limited by gastrointestinal effects
such as abdominal pain, constipation, dyspepsia, nausea, vomiting and constipation (See
Table 2).
It is worth noting to hear that it is not the actual medication itself that is
responsible for eating a hole through the mucosal lining of the stomach. Rather the
COX-1 receptors are compromised with the use of the non-selective NSAID’s, which
significantly decreases resilience of the mucosal lining of the stomach. It is then the
individual’s own stomach acid which irritates the stomach wall and can cause an ulcer.
3
Table 2. Adverse events cccurring in ≥2% of Celebrex patients (From Celebrex
Premarketing Controlled Arthritis Trials)
Abdominal Pain
Diarrhea
Dyspepsia
Flatulence
Nausea
Celebrex
(100-200
mg BID
or 200
mg QD)
(n=4146)
Placebo
(n=1864)
Naproxen
500 mg
BID
(n=1366)
Diclofenac
75 mg BID
(n=387)
Ibuprofen
800 mg
TID
(n=345)
4.1%
5.6%
8.8%
2.2%
3.5%
2.8%
3.8%
6.2%
1.0%
4.2%
7.7%
5.3%
12.2%
3.6%
6.0%
9.0%
9.3%
10.9%
4.1%
3.4%
9.0%
5.8%
12.8%
3.5%
6.7%
Because prostaglandins are the most abundant chemical messenger in the body,
affecting activity in each body system, the pharmaceutical industry has long targeted
research involving selective control of them (See Figure 1).
Figure 1. Synthetic pathway and sites of actions of prostaglandins.
Studies Promoting the Cardiovascular Safety of Celebrex
Despite Celebrex’s being in the same COX-2 class as Vioxx, there are many
studies promoting the cardiovascular advantages of Celebrex (Silverstein et al. 2000,
4
Chenevard et al. 2003, Levesque et al. 2005, Sower et al. 2005, Aw et al. 2005).
Specifically, the study performed by Levesque et al. (2005) found that Vioxx increased
cardiovascular events, but this was not the case with Celebrex. The results of these
findings are able to be extrapolated to a larger population due to an extremely large
subject size (n=113,927) for an at risk elderly population. In addition, Sower et al. (2005)
and Aw et al. (2005) confirmed these findings when their results revealed that Vioxx
does increase blood pressure, but Celebrex does not.
The different chemical makeup of Celebrex and Vioxx may explain how these
two drugs can perform the same anti-inflammatory actions with very different
physiological outcomes such as increased cardiovascular risks. Celebrex and Vioxx differ
in their pharmacokinetics as a result of differing functional structural characteristics
which may provide an explanation for the safety of Celebrex. Both Celebrex and Vioxx
have two benzane rings, but have different functional groups (See Figure2). Celebrex is
97% bound to plasma protein and in turn the remaining 3% is distributed throughout the
body. On the other hand, Vioxx is 87% bound to plasma protein leaving 13% to be
released in the body. Celebrex also has a shorter half-life of 11 hours versus a half-life of
17 hours for Vioxx, leaving the duration of action of Vioxx in the body an additional 6
hours longer than Celebrex. Because of the shorter half-life of Celebrex it is easier to
control plasma levels because it is cleared from the blood more rapidly than Vioxx and
needs to be given in frequent doses in order to develop and maintain a sufficient
concentration in the blood to be therapeutically effective. In turn the possible side affects
Figure 2. Chemical Composition of Celebrex (left) and Vioxx (right)
5
due to Celebrex are easier to control because of its shorter half life.
Currently, Celebrex has been used in studies to find if there are any other
conditions in which Celebrex may not only be used as an inflammatory preventative but
as helping cardiovascular function. While Vioxx and Celebrex still act in a similar
manner in terms of inflammation, they do not necessarily act the same way when it
comes to platelet coagulation. A study that was performed recently found that Celebrex
actually improved endothelial-dependent vasodilation in high risk patients who had
advanced coronary artery disease (Chenevard et al. 2003). Celebrex can help lower risk
of heart complications by lowering oxidized LDL (ox-LDL), improving flow-mediated
dilation, lowering high-sensitivity C-reactive protein (hs-CRP) that aggregate
atherogenesis and lower oxidative stress and chronic inflammation in the arteries of the
heart (See Figure 3).
Figure 3. A. Flowmediated vasodilation
was significantly
increased after 14 days of
treatment with celecoxib
(P=0.026 vs placebo).
B.Endotheliumindependent function as
assessed by
nitroglycerine-induced
vasodilation remained
unchanged (P=0.75 vs
placebo).
C. High-sensitivity CRP
was lowered after 14 days
of treatment with
celecoxib (P=0.019).
D. COX-2 inhibition with
celecoxib decreased
oxidized LDL plasma
levels (P=0.028 vs.
placebo)
6
In turn Celebrex, reduces the oxidative stress placed on the arteries as is evident
by the decrease in the highly indicative oxidative stress markers CRP and oxidative LDL.
Studies Opposing the Cardiovascular Safety of Celebrex
Celebrex’s cardiovascular safety has been closely assessed and although most
studies promote its cardiovascular safety, there are a few studies that have not agreed
with the majority. There has been evidence in one study (Solomon et al., 2005) which
found that Celebrex actually increases the risk of cardiovascular events in patients who
were administered the drug. The idea behind their research was that Celebrex was
responsible for promoting a prothrombotic (platelet coagulation) state and would
therefore cause a higher incidence of heart attacks, strokes and/or heart failure. This is
good research, but it needs to be known that any patient with a family history or even a
personal history of such cardiovascular events would naturally be at a higher risk. In the
study performed by Solomon et al. (2005), Celebrex was found to increase the risk for a
cardiovascular event in comparison to a placebo group by 1.3% - 2.4% depending on the
dose administered (200 mg BID or 400 mg BID) (See Table 3).
End Point
Placebo
(n=679)
Celebrex 200
mg BID
(n=685)
Celebrex 400
mg BID
(n=671)
Both Celebrex
groups
(n=1,356)
Death from
cardiovascular
cause
1(0.1)
3(0.4)
6(0.9)
9(0.7)
Nonfatal
myocardial
infarction
3(0.4)
9(1.3)
9(1.3)
18(1.3)
Nonfatal stroke
3(0.4)
3(0.4)
5(0.7)
8(0.6)
Nonfatal heart
failure
2(0.3)
1(0.1)
4(0.6)
5(0.4)
Table 3. Incidence of Individual Cardiovascular and Fatal Events for different doses of Celebrex.
There is a dose-dependent increase in the risk of cardiovascular events. Number of Patients (percent)
7
It is more common for a doctor to treat a patient with a dose closer to 200 mg BID than it
is to treat a patient with the higher dose. Those higher doses (400 mg BID) are often
reserved for the patients afflicted with much more aggressive inflammation. In the case
of those patients, the benefits would most likely out weigh the risks. For these select
individuals, it comes down to one simple issue questioning a cost-benefit relationship of
Celebrex. What quality of life do I want?
On the other hand, there have been studies done that question the safety of COX-2
inhibitors as a whole class. Because class effects are placed on every drug in a class it is
difficult to overlook negative outcomes for one specific member of this class. A few
weeks after Vioxx was withdrawn from the market the National Cancer Institute
announced the premature termination of a Celebrex study, Adenoma Prevention with
Celecoxib (APC), because of significant excess of cardiovascular death, myocardial
infarction, and stroke (See Figure 4).
Figure 4. Event
Rates
of
Cardiovascular
Death,
Myocardial
Infarction, and
Stroke in the
Adenoma
Prevention
With Celecoxib
(APC)
Trial.
The difference
for
events
between
the
400mg and 800
mg dose was
not significant
but
was
significant
between
the
placebo
and
400 mg dose.
8
Rabausch et al. (2005) also found that COX-2 inhibitors as a class lowered the
levels of thrombodulin by inhibiting vascular formation of prostacyclin. However, this
study was not preformed in vivo, but rather on tissue samples and cannot be considered
strong enough evidence to pull Celebrex from the shelf. Just because other drugs in the
same class pose adverse cardiovascular affects, it does not mean others in the same class
necessarily will. Thus, the question of its safety must be resolved as soon as possible.
Studies Promoting the Gastrointestinal Safety of Celebrex
Several studies have reported a significantly lower incidence of ulcers in patients
who were treated with Celebrex rather than non-selective NSAIDs (Mamdani et
al.(2002), Emery (1999)., Ekenel et al (2003), Simon et al. 1999. Silverstein et al., 2000).
It has been found that even though Celebrex does not completely eliminate incidence of
ulcers, when it is compared to popular non-selective NSAID treatment it is obvious that
Celebrex greatly reduces the incidence of ulcers (See Figure 5). When compared to the
Figure 5. Incidence of Gastroduodenal
Ulcers Over 12 Weeks of Treatment. An
ulcer was defined as any break in the
mucosa at least 3 mm in diameter with
unequivocal depth. For each patient there
were 3 possible outcomes: known ulcer,
known no ulcer, and unknown. Any
endoscopic finding other than ulcer was
categorized as unknown if the data were
obtained before the 12-week visit. Naproxentreated patients had a significantly greater
incidence of gastroduodenal ulcers than did
patients treated with either celecoxib or
placebo (P<.001). The incidences of
gastroduodenal ulcers in the celecoxib
treatment groups were similar to that in
placebo-treated patients (P>.40. Celecoxib
and naproxen were both administered twice
daily for all dosages.
9
common rheumatoid arthritis treatment of Diclofenac, Celebrex takers revealed an 11%
decrease in the incidence of ulcers (Emery et al. 2003). When compared to Naproxen
Celebrex decreased the incidence of ulcers by 20% (Simon et al. 1999).
The Celecoxib Long-term Arthritis Safety Study (CLASS), consisting of two oneyear double-blind studies, performed by Fred E. Silverstein et al (2000) revealed that
Celebrex, at dosages greater than those indicated clinically, was associated with a lower
incidence of symptomatic ulcers and ulcer complications combined, as well as other
clinically important toxic effects, compared with non-selective NSAIDs at standard
dosages (See Figure 6). This study included a large subject pool consisting of subjects of
adults of all ages with any type of arthritis.
Figure 6. Data are pulled from 12-week placebo controlled trials. Celebrex significantly lower than
Naproxen.
Ulcer incidence in patients with rheumatoid arthritis
30
Patients with ulcers (%)
25
20
15
%
10
5
0
Placebo
50-400 mg Celebrex BID
500 mg Naproxen BID
Drug doses (mg)
Studies Opposing the Gastrointestinal Safety of Celebrex
When it comes down to the GI safety of Celebrex, it is virtually impossible to find
any completed research-based studies that found conclusive results to show Celebrex is
detrimental to the GI tract. This phenomenon is not surprising because Celebrex was
10
specifically designed to be gentler on the stomach and intestines than non-selective
NSAIDs. There have been a few case studies in which patients have been documented as
having developed severe ulcers which may be due in part to Celebrex use (Nachimuthu et
al. 2001, Crawford et al. 2002). While case studies are an excellent way to observe an
individual and provide research on a more personal level, the results from these studies
are not able to be extrapolated to a larger population. A perfect example of this is the
research report given by Nachimuthu et al (2001) that found Celebrex may actually be
harmful to the GI tract. The patient that was being observed in this particular study was a
67 year old woman who was admitted to the hospital for severe upper abdominal pain.
She had multiple medical problems such as hypertension, diabetes, congestive heart
failure and gastrointestinal bleeding secondary to peptic ulcer disease. Due to all of these
ailments, she was taking several prescription drugs everyday and Celebrex happened to
be one of them. Therefore, due to the incredibly high daily ingestion of several different
medications, it was no surprise when doctors found ulcers in this individual’s stomach.
However, it is impossible to be certain that Celebrex was the cause of the ulcerations
since several medications were taken on a regular basis and the patient had a history of
bleeding ulcers before ever taking Celebrex. An almost similar case was also reported in
a 67 year old man who was admitted to the hospital due to an adverse reaction to a
vaccination he had received a week prior to his admittance to the hospital (Crawford et
al., 2002). Similarly, this individual had a lengthy health history that included several
medical problems and he was taking seven different medications everyday to control his
ailments. Included in his mini-pharmacy were the drugs Celebrex and aspirin. It is
known that regularly taking aspirin can cause ulcerations and GI bleeding so it is
11
impossible to definitively conclude that Celebrex was the sole contributor in this
individual’s development of ulcers. It is worth noting that this older man was taking an
extremely large dose of Celebrex (600 mg daily) and for an extended period of time (14
weeks) which is rarely prescribed to any patient. If however, Celebrex is in fact
responsible for these ulcerations and has become so popular because of its so-called GI
advantages and these advantages do not exist, patients should merely stick to taking
traditional NSAIDs that do not pose additional problems.
Strengths and Limitations of Research
The biggest strength of the research supporting the safety of Celebrex was that we
had at least 1,000 participants in all of the studies except for one. A study performed on
fourteen males who had severe coronary artery disease (Chenevard et al. 2003) was the
smallest group of individuals we included. Although this study “broke” our rules by
having a very small subject size, it was decided that we would use the findings in our
research because the techniques used were very invasive an it would not be practical to
have an extremely large group of individual that were willing to participate in this type of
research. It is also important to include this research because it showed that Celebrex can
actually be cardiovascularly beneficial to some individuals.
Our research was also very inclusive and strong because we did not single out one
particular type of ailment. Because this is a drug that has many different uses, anyone
who is taking Celebrex would potentially be at risk for developing ulcers and
cardiovascular complications. If there were strong enough evidence to prove that there
were serious adverse side effects to this medication it would be important to look at every
type of individual who could be prescribed Celebrex. Included in our research were
12
studies that had participants who had rheumatoid as well as osteoarthritis, cancer patients,
patients with coronary artery problems and individuals with a history of colorectal
adenoma just to name a few.
Yet another strength of the research which has been conducted was that we also
chose to include an extremely large age range (18 - ≥ 66 years of age) which allowed us
to account for any age dependent risk factors such as increased cardiovascular risks in the
elderly population. Age also played a role in our decision making process. The youngest
subject that was included was 18 years old and we went clear past 66 years old on the
other end of the spectrum. This was important to us because the risks that may be
associated with taking this drug would be evident on or after the fifth day since this is
when the Celebrex obtains its highest concentration in the plasma. If we would have
narrowed our search down to one specific age group the potential of missing a population
that was at an increased risk of developing adverse side effects would have been ignored.
By including all of the research groups that we did, we were able to get a much better
idea of the true safety of Celebrex.
In terms of limitations, there was only one big setback. Since the cardiovascular
safety of Celebrex is a fairly new idea, there have not been a lot of long term studies
published concerning this topic. However, Vioxx was voluntarily pulled off the market
by its manufacturer Merck because on going research found that it was detrimental to
cardiovascular health after 18 months of continued use. Thus, in order to pursue safer
research it is understood that there should be stricter precautionary guidelines concerning
duration of studies on Celebrex. When it comes to the safety on the GI tract there is no
question that there is a decreased risk of developing ulcers while using Celebrex instead
13
of a non-selective NSAID. In order to mend this limitation more research is needed in
this particular area of interest in order to further reinforce our findings.
Additional benefits of COX-2 inhibitors
With the recent attention from the media on the COX-2 inhibitor drug family,
many new beneficial research conclusions are being overlooked. Not only is Celebrex
great in terms of reducing inflammation, but it has also proved to be useful in treating
other medical conditions such as cancer and traumatic brain injuries. Certain types of
cancer in which the patient was prescribed Celebrex found that its physiological
mechanisms actually aided patients’ bodies by not allowing the mutated cells
(hematopoietic and epithelial cells) to multiply (Waskewich et al. 2002). One mechanism
that researchers feel is responsible for these findings is that the COX-2 inhibitors are
helping the CD8+ t cells (killing cells) get into the actual tumor easier and are then able
to aid in the elimination of the growth.
Another hot topic that has been introduced to the medical community is the
benefits of using a COX-2 inhibitor in the treatment of traumatic brain injuries. In a rat
model, when a COX-2 inhibitor was given within six hours of the brain injury, there was
marked improvement in the outcome of the subject. Researchers believe that this is due
in part to the reduction in the inflammation of the tissue surrounding the neurons of the
brain and therefore oxygen was allowed to remain at high levels. If more studies can be
performed in these different areas of research, Celebrex may just be getting of the
ground.
14
Conclusion
After examining all aspects of Celebrex’s safety, it is clear that Celebrex is much
safer than Vioxx both in terms of GI safety and cardiovascular risks. There have been
more studies with strong results that exhibit the safety of Celebrex than the studies that
imply that it may be unsafe. The bigger issue that now needs to be looked at is the over
prescribing of the drug. Many physicians are impressed with the effectiveness of
Celebrex and it has quickly become the drug of choice when it comes to fighting
inflammation. Thus, Celebrex must remain dispensed for the patients it was originally
intended for-those with extensive gastrointestinal problems who are in dire need of an
anti-inflammatory medication regime. Obviously, it is important for all physicians to
become aware of their clients’ health history and make educated decisions accordingly,
but this problem is not solely a doctors’ responsibility. Patients must assume greater
responsibility for themselves and take medications the way they were intended to be
taken. Most importantly, the risks and benefits of taking any kind of medication must be
weighed very carefully.
15
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