Findings on the Effect of COX-2 Inhibitors on Gastrointestinal Events
Claire Bombardier, MD*
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of
drugs developed to treat inflammation and pain. NSAIDs work by inhibiting
cyclo-oxygenase activity, which in turn is responsible for generating
prostaglandins at the site of tissue injury. While they effectively reduce
inflammation and pain, the widespread use of traditional NSAIDs has been
associated with various adverse events, including serious gastrointestinal (GI)
toxic effects (eg, ulceration, hemorrhage, and perforation). Utilization of
traditional NSAIDs has reportedly resulted in a 2% to 4% annualized incidence
rate of symptomatic GI ulcers and ulcer complications that subsequently resulted
in approximately 107,000 hospitalizations and 16,500 deaths in the United States.
Recent pharmaceutical findings have encouraged the development of a new class
of medications (ie, COX-2 inhibitors, such as rofecoxib and celecoxib). This
new family of NSAIDs is designed to provide the beneficial reduction of
inflammation and pain, with a better GI safety profile.
All NSAIDs inhibit cyclo-oxygenase (COX) isozymes to
different extents, which accounts for their anti-inflammatory and analgesic
activities, as well as their GI side effects. Two distinctive forms of
cyclo-oxygenase have been identified. Cyclo-oxygenase-1 (COX-1) exists in every
organ system, including the stomach, intestines, kidneys, and platelets.
Cyclo-oxygenase-2 (COX-2) is not expressed under baseline conditions (except in
the kidneys and brain, where it is constitutive), but is rapidly unregulated
during inflammation. The therapeutic effects of NSAIDs are largely the result
of inhibition of the enzyme COX-2, whereas effects on GI cytoprotection
activity and platelet activity are primarily due to the inhibition of COX-1.
Inhibition of COX-1 results in reduced cytoprotective prostaglandins (PGE2 and
PG12). Selective inhibitors of COX-2 subsequently result in reduced incidence
of gastrointestinal, renal, and platelet side effects (Figure 1). Rofecoxib is indicated
for relief of the signs and symptoms of osteoarthritis, management of acute
pain in adults, and the treatment of primary dysmenorrheal. Celecoxib is
indicated for relief of the signs and symptoms of osteoarthritis and rheumatoid
arthritis, and to reduce the number of adenomatous colorectal polyps in
familial adenomatous polyposis (FAP) as an adjunct to usual care.
Since serious GI events have been associated with NSAID
treatment, these medications should be avoided in patients who present with
various pre-existing conditions (Table). Extreme caution should be practiced
when prescribing NSAIDs for patients with a prior history of peptic ulcer
disease of GI bleeding. These patients have an increased risk for developing a
GI event (eg, perforation, obstruction, bleed) compared to patients without
these risk factors.
Patients who may be
at higher risk for serious gastrointestinal events while taking NSAIDs includes
- With a
history of ulcer disease
therapy with anticoagulants
poor general health status
A prospective study presented at the American College of
Rheumatology (ACR) 64th Annual Scientific Meeting compared the rates
of GI protective agents (eg, proton pump inhibitors, cytoprotective agents, and
H2 blockers), GI diagnostic procedures (eg, UGI series and
endoscopy), and hospitalizations for upper GI perforation, ulcer, or bleeding
following treatment with rofecoxib and naproxen. Approximately 82% of these
patients were treated with NSAIDs at baseline and 56% used concomitant
steroids. The results of this investigation indicated that patients treated
with rofecoxib required a significantly reduced amount of treatment with new GI
protective agents (11.2% with rofecoxib versus 14.5% with naproxen, P<0.001). Fewer gastrointestinal
procedures were required for patients treated with rofecoxib (5.6% versus 6.9%,
p=0.02), and the subjects treated with this medication were hospitalized less
frequently for GI perforation, ulcer, or bleeding (0.4% versus 0.9%, p=0.01). A
double-blind investigation presented at the same symposium indicated that
patients treated with rofecoxib had a significantly decreased incidence of
clinically important and complicated gastrointestinal events compared to
patients treated with a nonselective NSAID. A recent randomized controlled
investigation (the CLASS study) also determined that utilization of a COX-2
specific inhibitor was associated with a lower incidence of combined clinical
upper GI events than comparator NSAIDs.
Severe pain as a result of arthritic, dental, or other
inflammatory related events is extremely uncomfortable for the patient. While
the proven efficacy and pain management provided by nonselective NSAIDS is
undeniable, COX-1 inhibition can result in serious negative side effects and
even death. Selective inhibition of COX-2 provided by both rofecoxib and
celecoxib facilitates the successful achievement of pain suppression, with a
significantly lower rate of adverse gastrointestinal events. Reduced stomach
ulceration and GI bleeding are only some of the benefits associated with this
new class of medications, and the clinical efficacy of COX-2 inhibitors
continues to be evaluated.
*Senior Scientist and Head of the Division of Clinical Decision-making & Health Care, Toronto General Research Institute, Toronto, Ontario
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