Fred E. Silverstein, Gerald Faich, Jay L. Goldstein, Lee S. Simon, Theodore Pincus, Andrew Whelton, Robert Makuch, Glenn Eisen, Naurang M. Agrawal, William F. Stenson, Aimee M. Burr, William W. Zhao, Jeffrey D. Kent, James B. Lefkowith, Kenneth M. Verburg, G. Steven Geis. Gastrointestinal Toxicity With Celecoxib vs Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid ArthritisThe CLASS Study: A Randomized Controlled Trial. JAMA. 2000;284(10):1247–1255. doi:10.1001/jama.284.10.1247
Author Affiliations: Department of Medicine, University of Washington, and Partner Frazier & Co, Seattle (Dr Silverstein); Pharmaceutical Safety Assessments Inc, Narberth, Pa (Dr Faich); Department of Medicine, Section of Digestive and Liver Diseases, College of Medicine, University of Illinois at Chicago, Chicago, Ill (Dr Goldstein); Division of Rheumatology and Metabolic Bone Disease, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (Dr Simon); Divisions of Rheumatology and Immunology (Dr Pincus) and Gastroenterology (Dr Eisen), Vanderbilt University School of Medicine, Nashville, Tenn; Department of Medicine, Johns Hopkins University, Baltimore, Md (Dr Whelton); Department of Biostatistics, Yale University, New Haven, Conn (Dr Makuch); Division of Gastroenterology, Duke University, Durham, NC (Dr Agrawal); Division of Gastroenterology, Washington University, St Louis, Mo (Dr Stenson); and Clinical Research and Development, Pharmacia, Skokie, Ill (Ms Burr and Drs Zhao, Kent, Lefkowith, Verburg, and Geis).
Context Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated
with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because
of inhibition of cyclooxygenase (COX)-1. Whether COX-2–specific inhibitors
are associated with fewer clinical GI toxic effects is unknown.
Objective To determine whether celecoxib, a COX-2–specific inhibitor, is
associated with a lower incidence of significant upper GI toxic effects and
other adverse effects compared with conventional NSAIDs.
Design The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind,
randomized controlled trial conducted from September 1998 to March 2000.
Setting Three hundred eighty-six clinical sites in the United States and Canada.
Participants A total of 8059 patients (≥18 years old) with osteoarthritis (OA)
or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received
at least 1 dose of study drug. A total of 4573 patients (57%) received treatment
for 6 months.
Interventions Patients were randomly assigned to receive celecoxib, 400 mg twice per
day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987);
ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per
day (n = 1996). Aspirin use for cardiovascular prophylaxis (≤325 mg/d)
Main Outcome Measures Incidence of prospectively defined symptomatic upper GI ulcers and ulcer
complications (bleeding, perforation, and obstruction) and other adverse effects
during the 6-month treatment period.
Results For all patients, the annualized incidence rates of upper GI ulcer complications
alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76%
vs 1.45% (P = .09) and 2.08% vs 3.54% (P = .02), respectively. For patients not taking aspirin, the annualized
incidence rates of upper GI ulcer complications alone and combined with symptomatic
ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P
= .04) and 1.40% vs 2.91% (P = .02). For patients
taking aspirin, the annualized incidence rates of upper GI ulcer complications
alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01%
vs 2.12% (P = .92) and 4.70% vs 6.00% (P = .49). Fewer celecoxib-treated patients than NSAID-treated patients
experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal
toxicity. No difference was noted in the incidence of cardiovascular events
between celecoxib and NSAIDs, irrespective of aspirin use.
Conclusions In this study, celecoxib, 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
NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest
among patients not taking aspirin concomitantly.
For patients with musculoskeletal disorders, conventional nonsteroidal
anti-inflammatory drugs (NSAIDs) are a mainstay of clinical care.1- 3 Well-established limitations
of NSAID therapy, however, include the risk of developing significant injury
to the upper gastrointestinal (GI) tract.4- 10
The annualized incidence rate of symptomatic GI ulcers and ulcer complications
in NSAID users ranges from 2% to 4% (1%-2% for ulcer complications alone).11- 15
NSAID-related ulcer complications are estimated to lead to 107,000 hospitalizations
and 16,500 deaths yearly in the United States.10
NSAIDs inhibit cyclooxygenase (COX), the enzyme responsible for conversion
of arachidonic acid to prostaglandins.16 COX
exists in 2 isoforms.17 COX-1 is a ubiquitous
constitutive isozyme producing prostaglandins responsible for homeostatic
functions such as maintenance of GI mucosal integrity.17
COX-2 is largely a cytokine-induced isozyme producing prostaglandins that
mediate pain and inflammation.17 NSAIDs inhibit
both COX-1 and COX-2 to varying degrees.18,19
Thus, the therapeutic effects of conventional NSAIDs are derived from inhibition
of COX-2, while the adverse effects of these agents, particularly in the upper
GI tract, arise from inhibition of COX-1 activity.
Celecoxib, a COX-2–specific inhibitor, recently was approved by
the US Food and Drug Administration (FDA) for symptomatic treatment of rheumatoid
arthritis (RA) and osteoarthritis (OA). To determine whether the COX-2 specificity
of celecoxib is associated with lower COX-1–related adverse effects,
we compared celecoxib administered at 2 and 4 times the maximum FDA-approved
effective dosages for RA and OA, respectively, with commonly used therapeutic
dosages of ibuprofen and diclofenac. The dosage of celecoxib exceeded the
maximum dosage approved by the FDA for OA and RA to permit a safety assessment
of the higher dosages. However, based on previous studies,20,21
exceeding the dosages approved by the FDA would not improve patients' symptom
relief. The dosages of ibuprofen and diclofenac were based on prescription
data; 48% and 60% of OA and RA patients, respectively, who received ibuprofen
were prescribed a dosage of at least 2400 mg/d, and 36% and 57% of OA and
RA patients, respectively, who received diclofenac were prescribed a dosage
of at least 150 mg/d.22
Outpatients aged 18 years or older were eligible to participate in the
study if, on screening, they were diagnosed as having RA or OA evident for
at least 3 months and were expected to require continuous treatment with an
NSAID for the duration of the trial. Patients were excluded from study participation
if at screening they had active GI, renal, hepatic, or coagulation disorders;
malignancy (unless removed surgically with no recurrence within 5 years);
esophageal or gastroduodenal ulceration within the previous 30 days; history
of gastric or duodenal surgery other than an oversew; or known immediate-type
hypersensitivity to COX-2 inhibitors, sulfonamides, ibuprofen, or diclofenac.
Women were excluded if they were pregnant, might have become pregnant, or
This prospective, randomized double-blind trial was conducted at 386
centers in the United States and Canada from September 1998 to March 2000
in accordance with the principles of good clinical practice and the Declaration
of Helsinki. The protocol was approved by the institutional review board at
each study site, and all patients provided written informed consent. Prior
to enrollment, patients completed a physical examination and clinical laboratory
testing. After a baseline visit, follow-up clinic visits took place at weeks
4, 13, and 26 after the initial dose of medication, and every 13 weeks thereafter.
All patients were provided an opportunity to complete a minimum of 6 months
Patients withdrawing from study participation prior to 6 months were
classified as follows: preexisting violation of entry criteria, protocol noncompliance
(investigator-defined failure to comply with the requirements of the protocol,
eg, failure to take at least 70% of the study medication in any 13-week interval),
treatment failure (investigator-defined failure of study medication to control
arthritis signs and symptoms), or adverse effect (investigator-defined signs
or symptoms unrelated to arthritis; see "Clinical Assessments" herein). These
patients nonetheless were followed up for end-point evaluation for 2 months
or until study termination.
Patients were randomly assigned to receive treatments (celecoxib, 400
mg twice per day; ibuprofen, 800 mg 3 times per day; or diclofenac, 75 mg
twice per day) on a 2:1:1 basis by an interactive voice response system (ClinPhone,
Nottingham, England) according to a computer-generated randomization schedule.
All treatment regimens were blinded and double dummy. Treatment assignment
for 3 patients was unblinded by study site personnel during trial conduct
(1 at the investigation site, 2 via the interactive voice response system).
None of these patients experienced a study outcome event. One celecoxib patient
experienced diverticular bleeding; 2 patients (1 celecoxib and 1 diclofenac)
experienced non–GI-related adverse events; and in no instance was the
treatment assignment made known to personnel of the drug company (Pharmacia,
Skokie, Ill) or to members of the oversight committees prior to final review
of all end points by a GI events committee.
NSAIDs (except for stable dosages of aspirin up to 325 mg/d); antiulcer
drugs (except for occasional antacid use); antibiotics used alone or in combination
with omeprazole, lansoprazole, and ranitidine for treatment of Helicobacter pylori infection; and antineoplastics (except methotrexate
or azathioprine for RA) were prohibited during the study. Use of oral, intramuscular,
and intra-articular glucocorticoids and disease-modifying antirheumatic drugs
Investigators were instructed to identify and report all potential upper
GI ulcer complications. Evaluation of such events was outlined in a prespecified
algorithm structured to reproduce clinical practice norms. Evaluation was
required for any of the following presentations: hematemesis; melena; acute
hypovolemia/hypotension; development of postural dizziness, lightheadedness,
or syncope; history of dark stool, hematochezia, or anal or rectal bleeding;
development of new anemia (defined as a hematocrit level outside of the reference
range) or a decrease in hematocrit of at least 5 percentage points; development
of dyspepsia, abdominal pain, or nausea or vomiting; or development of occult
blood-positive stools. Endoscopy was encouraged to document bleeding lesions
but could also be performed if indicated by the investigator's clinical judgment.
All documentation relating to potential ulcer complications was forwarded
to a GI events committee (J.L.G., G.E., N.M.A., and W.F.S). The committee
collectively reviewed each case in a treatment-blinded fashion and assigned
it by unanimous consensus as either meeting or not meeting the definition
of an upper GI ulcer complication (Table
1). Symptomatic ulcers consisted of cases that did not meet the
definition of an ulcer complication but did have endoscopic or x-ray evidence
of a gastric or duodenal ulcer as judged by the committee. All patients with
symptomatic ulcers or ulcer complications were withdrawn from the study and
included in the analysis as having had a study end point.
Adverse effect data were collected at each visit (and as reported spontaneously)
using the following question: "Since your last visit, have you experienced
or do you currently have any symptoms that are not associated with your arthritis?"
All affirmative responses were recorded regardless of severity or relationship
to study drug. Laboratory data were also collected at each visit and as indicated
according to the investigators' discretion. Clinically significant changes
in hematocrit and hemoglobin were predefined as decreases of at least 10 percentage
points and 20 g/L, respectively. Clinically significant changes in serum urea
nitrogen and creatinine were predefined as values at 6-month follow-up of
at least 40 mg/dL (14.3 mmol/L) and 1.8 mg/dL (159 µmol/L), respectively.
Clinically significant changes in alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) were predefined as increases to at least 3 times the
upper limit of normal. Trial safety (eg, serious adverse effects) was monitored
in a treatment-blinded fashion during the study by the data safety monitoring
board (G.F., T.P., A.W., and R.M.).
Sample size calculations were based on the assumption that the annualized
incidence of upper GI ulcer complications would be 0.3% for celecoxib and
1.2% for NSAIDs. To detect this difference with a 2-sided .05 significance
level with statistical power of 85% and assuming a 35% withdrawal rate, a
sample size of approximately 4000 patients was required for the celecoxib
group and 2000 patients were needed for each of the 2 NSAID groups.
Homogeneity of the treatment groups at baseline was analyzed using the χ2 test for categorical data and 2-way analysis of variance with treatment
and center effects for continuous-valued data. Statistical analyses were conducted
on the intent-to-treat population, defined a priori in the protocol as consisting
of all patients who received at least 1 dose of assigned study medication.
An additional prespecified analysis was performed on the population of patients
not taking aspirin (since aspirin use was a predefined risk factor for GI
events). Time-to-event analyses of upper GI ulcer complications alone or combined
with symptomatic ulcers were performed based on cumulative event rates (symptomatic
ulcers and/or ulcer complications) for the 6-month study period and are expressed
as annualized incidence rates (number of events per 100 patient-years of exposure
or percentage). The log-rank test was used to compare time-to-event curves
among treatment groups. Based on the recommendation of the GI events committee
and as specified by the protocol a priori, upper GI ulcer complications were
defined as a study end point (ie, an uncensored event) if they occurred within
the 6-month treatment period and occurred 48 hours after the first dose day
or before 14 days after the last known dose of study drug (to avoid confounding
due to prestudy or poststudy NSAID use). Patients who had upper GI ulcer complications
outside of the specified time frame were censored for purposes of time-to-event
analysis. This recommendation was based on the pharmacologic washout period
for most common NSAIDs and evidence in the literature of carryover effects
of NSAIDs in terms of GI toxic effects.8,23
Analyses were conducted with and without these censored patients. The effects
of potential risk factors for the development of an ulcer complication (including
but not limited to concurrent aspirin use) were analyzed by Cox proportional
hazards models. The incidences of treatment-emergent adverse effects or clinical
laboratory changes in the different treatment groups during the 6 months were
compared using the Fisher exact test. All P values
and 95% confidence intervals (CIs) are 2-sided. No significant differences
in adverse events were noted by sex, so results are presented with women and
men combined. Adverse events for diclofenac and ibuprofen were similar except
for liver enzyme elevations, for which results are presented separately.
A total of 8059 patients were randomized (Figure 1). Ninety-one patients did not receive study drug (32 were
randomized and found to be ineligible prior to administration of study drug;
59 withdrew consent prior to taking study drug). Of these 91 patients, 44
were randomized to celecoxib and 47 were randomized to NSAIDs.
A total of 7968 patients received at least 1 dose of medication. Of
these, 3987 patients were treated with celecoxib, 400 mg twice per day, and
3981 patients were treated with NSAIDs (1985 received ibuprofen, 800 mg 3
times per day, and 1996 received diclofenac, 75 mg twice per day). The celecoxib
and NSAID groups had 1441 and 1384 total patient-years of exposure, respectively.
Baseline characteristics did not differ significantly between groups (Table 2). More than 20% of the patients
were taking low-dosage aspirin (≤325 mg/d). Approximately 57% of the patients
(n = 4573) completed 6 months of treatment (Figure 1). More patients in the NSAID treatment group withdrew from
the study for either adverse effects (n = 822 [20.6%]) or lack of therapeutic
efficacy (n = 589 [14.8%]) than did celecoxib-treated patients (n = 732 [18.4%]
and n = 503 [12.6%], respectively; P = .01 and P = .005; Figure 1).
No patients were lost to follow-up (ie, a cause of withdrawal was determined
for all patients who withdrew).
A total of 260 cases were selected by the GI events committee for adjudication.
The committee identified 35 upper GI ulcer complications and another 48 cases
that represented symptomatic but uncomplicated gastroduodenal ulcers (Table 3). Four upper GI ulcer complications
(2 in celecoxib-treated patients and 2 in NSAID-treated patients) were censored
according to predetermined criteria (see "Methods" section). The remaining
177 cases not meeting the definition of gastroduodenal ulcer or ulcer complication
were assigned a diagnosis from the categories listed in Table 3.
The annualized incidence of upper GI ulcer complications in celecoxib-treated
patients was 0.76% (11 events/1441 patient-years) vs an incidence of 1.45%
(20 events/1384 patient-years) for patients taking NSAIDs (P = .09; Figure 2A). The
relative risk (RR) for celecoxib compared with NSAIDs was 0.53 (95% CI, 0.26-1.11).
The annualized incidence of upper GI ulcer complications plus symptomatic
ulcers with celecoxib was 2.08% (30 events/1441 patient-years) vs 3.54% (49
events/1384 patient-years) for patients taking NSAIDs (P = .02; Figure 2A). The
RR for celecoxib compared with NSAIDs was 0.59 (95% CI, 0.38-0.94).
Inclusion of the 2 censored events in each group did not alter the interpretation
of results. For upper GI ulcer complications, the rates without censoring
were 0.90% (13 events/1441 patient-years) and 1.59% (22 events/1384 patient-years)
for celecoxib and NSAIDs, respectively (P = .11).
For upper GI ulcer complications plus symptomatic ulcers, the rates were 2.22%
(32 events/1441 patient-years) and 3.68% (51 events/1384 patient-years) for
celecoxib and NSAIDs, respectively (P = .03).Corticosteroid
use was not significantly associated with the incidence of upper GI ulcer
complications in either treatment group (RR, 0.2 and 0.6 for patients treated
with celecoxib and NSAIDs, respectively; P = .13
and P = .27).
Based on time-to-event analyses using a Cox proportional hazard model,
low-dosage aspirin use was found to have a significant effect on the incidence
of upper GI ulcer complications in celecoxib-treated patients. Within the
celecoxib treatment group, the RR of an upper GI ulcer complication was 4.5
with low-dosage aspirin use: 6 events in 833 patients taking low-dosage aspirin
vs 5 events in 3154 non–aspirin users (P =
.01). Low-dosage aspirin use did not have a significant effect on the rate
of upper GI ulcer complications in patients receiving NSAIDs (RR, 1.7; P = .29).
When the non–aspirin-using cohort was examined, 2 upper GI ulcer
complications were censored (1 in each group). The annualized incidence of
upper GI ulcer complications in non–aspirin users was significantly
lower with celecoxib vs NSAIDs (0.44% [5 events/1143 patient-years] vs 1.27%
[14 events/1101 patient-years]; P = .04; Figure 2B). The RR for celecoxib compared
with NSAIDs was 0.35 (95% CI, 0.14-0.98). The annualized incidence of upper
GI ulcer complications plus symptomatic ulcers in patients not taking aspirin
was also significantly lower with celecoxib than with NSAIDs (1.40% [16 events/1143
patient-years] vs 2.91% [32 events/1101 patient-years]; P = .02; Figure 2B). The
RR for celecoxib compared with NSAIDs was 0.48 (95% CI, 0.28-0.89).
Inclusion of the 1 censored event in each group did not alter the interpretation
of results. For upper GI ulcer complications, the rates without censoring
were 0.52% (6 events/1143 patient-years) and 1.36% (15 events/1101 patient-years)
for celecoxib and NSAIDs, respectively (P = .05).
For upper GI ulcer complications plus symptomatic ulcers, the rates were 1.49%
(17 events/1143 patient-years) and 3.00% (33 events/1101 patient-years) for
celecoxib and NSAIDs, respectively (P = .02).
For patients taking aspirin (Figure
2C), the annualized incidences of symptomatic ulcers and/or upper
GI complications were not significantly different in patients taking celecoxib
vs NSAIDs. For upper GI complications, the observed rates were 2.01% for patients
taking celecoxib vs 2.12% for patients taking NSAIDs (6 events/298 patient-years
vs 6 events/283 patient-years, respectively; P =
.92). For upper GI ulcer complications plus symptomatic ulcers, the observed
rates were 4.70% for patients taking celecoxib vs 6.00% for patients taking
NSAIDs (14 events/298 patient-years vs 17 events/283 patient-years, respectively; P = .49). Including the 2 censored events (1 in each group),
the rates were 2.35% and 2.47%, respectively, for upper GI ulcer complications
and 5.03% and 6.36%, respectively, for upper GI ulcer complications plus symptomatic
Adverse effects with an incidence of at least 5% in either treatment
group during the 6-month treatment period were GI symptoms, upper respiratory
tract infection or related symptoms, headache, and rash. Adverse effects causing
withdrawal with an incidence of at least 1% in either treatment group were
GI symptoms, rash, and elevated transaminase levels. For these categories,
celecoxib was associated with equivalent or lower incidences of adverse effects
and withdrawals compared with NSAID therapy, with the exceptions of rash and
pruritus (Table 4).
Serious adverse effects (representing hospitalizations or malignancies
detected during the 6-month treatment period) were reported for 4.3% of celecoxib
patients (172 events/3987 patients) and 4.2% of NSAID patients (168 events/3981
patients). The most common serious adverse effects in patients taking celecoxib
and NSAIDs were accidental fractures (7 and 8 events, respectively), back
pain (8 and 8 events, respectively), pneumonia (9 and 9 events, respectively),
cardiac failure (9 and 10 events, respectively), myocardial infarction (10
and 10 events, respectively), and coronary artery disease (9 and 7 events,
respectively). No serious rashes or unexpected serious adverse events were
observed in patients taking celecoxib.
The overall incidence of GI symptoms experienced by patients taking
celecoxib was significantly lower than by those taking NSAIDs, as was the
rate of withdrawal due to GI intolerability (Table 4). Of the most commonly reported GI adverse effects, dyspepsia,
abdominal pain, nausea, and constipation were significantly less common with
celecoxib than with NSAIDs, although there was no difference in the incidence
of diarrhea (Table 4).
The overall incidence of bleeding-related adverse events, and specifically,
anemia and hematochezia, experienced by patients taking celecoxib was significantly
lower than that among patients taking NSAIDs for all patients and for those
not taking aspirin (Table 4).
Similar results were noted for patients taking aspirin; the incidences of
all bleeding-related adverse events were 4.0% and 8.3% for patients taking
celecoxib and NSAIDs, respectively, and for anemia were 2.6% and 6.4%, respectively
(P<.001 for both comparisons). Celecoxib was also
associated with a lower incidence (P<.001) of
clinically meaningful reductions in hematocrit and/or hemoglobin for the entire
patient cohort than NSAIDs (Figure 3).
A lower incidence was noted both in patients not taking aspirin (1.3% vs 3.4%
in patients taking celecoxib and NSAIDs, respectively; P<.001) and patients taking aspirin (2.6% vs 4.9% in the 2 groups,
respectively; P = .02). This difference persisted
when all cases selected by the GI events committee for adjudication were excluded
from the analysis, thus removing all patients with ulcer complications, symptomatic
ulcers, or other diagnosed GI disease (Figure
3). Mean serum iron–iron binding capacity ratios increased
in patients taking celecoxib and decreased in patients taking NSAIDs (1.4%
vs − 2.3%; P = .007).
As shown in Figure 4, the
incidence of serum ALT or AST elevations that exceeded 3 times the upper limit
of normal was several-fold and statistically significantly higher in patients
receiving NSAIDs than those receiving celecoxib. The incidence of ALT elevation
for diclofenac was 3.2% vs 0.3% for ibuprofen; for AST, it was 1.8% vs 0.1%,
respectively. Similarly, investigators reported a significantly higher incidence
of adverse effects related to elevated ALT and AST with NSAID treatment (Table 4). Study withdrawals due to such
elevations were also higher in patients receiving NSAIDs (Table 4). Overall, 97% of ALT and AST abnormalities occurred in
patients receiving diclofenac.
The overall incidence of renal adverse effects, and the incidence of
increased creatinine and hypertension in particular, were significantly lower
in patients receiving celecoxib than in those receiving NSAIDs (Table 4). Also, significantly more patients receiving NSAIDs exhibited
clinically significant elevations in serum creatinine and/or serum urea nitrogen
levels than with celecoxib (Figure 4).
The overall incidence of cardiovascular events, and the incidences of
cerebrovascular events and myocardial infarction in particular, were similar
in the 2 treatment groups (Table 4).
No treatment-related differences in such events were apparent in the cohort
of patients not taking aspirin for cardiovascular prophylaxis (Table 4). Incidence of myocardial infarction in patients taking
either celecoxib or NSAIDs was 0.3%, with 95% CIs of 0.12% to 0.46% and 0.14%
to 0.49%, respectively. For patients not taking aspirin, incidence of myocardial
infarction in patients taking celecoxib was less than 0.10% (95% CI, 0.02%-0.28%)
and was also 0.10% (95% CI, 0.03%-0.32%) in patients taking NSAIDs.
This study determined that celecoxib, a COX-2–specific inhibitor,
when used for 6 months in a dosage 2 to 4 times the maximum therapeutic dosage,
is associated with a lower incidence of combined clinical upper GI events
than comparator NSAIDs (ibuprofen and diclofenac) used at standard therapeutic
In this study, patients taking NSAIDs had significantly higher rates
of symptomatic ulcers or ulcer complications than did patients taking celecoxib,
but the rate for ulcer complications did not differ. The statistically indistinguishable
rate of ulcer complications associated with celecoxib and NSAIDs appears to
be a function of the higher-than-expected event rate observed in the celecoxib
group. The previously reported annualized incidence rate for ulcer complications
in patients taking celecoxib (used for the sample size determination) was
0.2%, obtained from pooled analyses of 14 randomized controlled trials.15
This increased ulcer complication rate was likely attributable to higher-than-anticipated
concurrent low-dosage aspirin use. The percentage of patients using low-dosage
aspirin for cardiovascular prophylaxis was nearly double that seen in other
clinical trials that we have conducted recently, albeit within the range reported
for the general population.24 Low-dosage aspirin
therapy has clearly been associated with serious GI ulcer complications.25- 29
In contrast, analysis of non–aspirin users alone demonstrated
that celecoxib was associated with a significantly lower incidence of symptomatic
ulcers and/or ulcer complications compared with NSAIDs. The rate of ulcer
complications in non–aspirin users taking celecoxib (0.44%) is similar
to the background rate of ulcer complications observed in patients not taking
NSAIDs or aspirin in the general population (0.1%-0.4%).8,9,11,12,30- 33
The observed incidences of symptomatic ulcers and/or ulcer complications
were not significantly different in patients taking celecoxib vs NSAIDs who
were also taking concomitant low-dosage aspirin. Data from endoscopic trials
suggest that there may be a significant but smaller risk reduction in patients
taking low-dosage aspirin, but this remains to be proven in terms of clinical
In addition to the assessment of GI effects, the present study determined
that the increased dosage of celecoxib used in this study did not change the
adverse effect profile observed at lower dosages.20,21,35
Of note, celecoxib-treated patients had a significantly lower incidence
of clinically significant decreases in hemoglobin and/or hematocrit compared
with NSAID-treated patients, even when patients with upper GI ulcer complications,
symptomatic ulcers, and other GI diseases were excluded. Celecoxib was also
better tolerated than NSAIDs, as evidenced by the decreased incidence of GI
symptoms and withdrawals for such symptoms.
The clinical consequences of NSAIDs on kidneys are heterogeneous, and,
at present, the relative importance of COX-1 and COX-2 in the human kidney
is not well defined.36 Regardless, celecoxib
appeared to be associated with significantly less renal toxicity compared
with NSAID therapy in this study.
Although it has been hypothesized that COX-2–specific inhibitors
might increase the risk of cardiovascular thromboembolic events via inhibition
of vascular prostacyclin synthesis without a corresponding inhibition of platelet
thromboxane, no such increase was evident in the current study.37
In both the entire study population and the cohort not taking aspirin (who
would conjecturally be at greatest risk of such an effect), the incidence
of cardiovascular events, particularly myocardial infarction, was comparable
between the celecoxib and NSAID groups.
Despite the size and duration of this trial, the populations of patients
with OA and RA are much larger and therapy continues for substantially longer
than 6 months.38 Moreover, many patients with
OA and RA have comorbid illnesses (eg, active GI disease) that would have
excluded them from the current study. Consequently, the results of this study
do not address the occurrence of rare adverse events, nor can they be extrapolated
to all patients seen in general clinical practice.
Despite these caveats, however, our results demonstrate that celecoxib,
at a dosage 2- to 4-fold greater than the maximum therapeutic dosages and
those approved for labeling for RA and OA, is associated with a lower rate
of upper GI toxic effects compared with standard therapeutic dosages of NSAIDs.
This finding supports the COX-2 hypothesis that COX-2–specific agents
exhibit decreased GI toxic effects.17,39
Despite the high dosage used, other adverse effects did not emerge. Our findings
thus have significant implications with respect to drug therapy for the symptomatic
treatment of RA and OA.