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Requests for reprints should be addressed to Gurkirpal Singh, MD, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Institute of Clinical Outcomes Research and Education (ICORE), 100 Hamilton Avenue, Suite 225 #22, Palo Alto, CA 94301
To evaluate the efficacy and upper gastrointestinal (UGI) safety of celecoxib, compared with nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs), among patients with osteoarthritis.
Methods
A total of 13274 osteoarthritis patients from 39 countries were randomly assigned to double-blind treatment with either celecoxib 100 mg twice daily (BID), celecoxib 200 mg BID, or nonselective NSAID therapy (diclofenac 50 mg BID or naproxen 500 mg BID) for 12 weeks. Standard validated measures were used to assess osteoarthritis efficacy. Serious UGI events were evaluated by 2 blinded, independent, gastrointestinal events committees.
Results
Results from all primary efficacy assessments showed that both dosages of celecoxib were as effective as NSAIDs in treating osteoarthritis. Significantly more ulcer complications occurred within the nonselective NSAID group (0.8/100 patient-years) compared with the celecoxib group (0.1/100 patient-years) (odds ratio = 7.02; 95% confidence interval [CI], 1.46 to 33.80; P =.008). There were fewer ulcer complications in the celecoxib group compared with the NSAID group, both in patients taking concomitant aspirin and those not taking aspirin, but the difference reached statistical significance only in the latter comparison. The number of cardiovascular thromboembolic events was low and not statistically different between the groups (eg, myocardial infarction rates: celecoxib 10 events [0.55/100 patient-years] vs NSAIDs 1 event [0.11/100 patient-years], (P =.11), but the study was not powered to detect such differences.
Conclusions
In the treatment of osteoarthritis, celecoxib is as effective as the nonspecific NSAIDs naproxen and diclofenac, but has significantly fewer serious upper gastrointestinal events.
It has been estimated that serious gastrointestinal complications related to NSAID therapy result in approximately 103000 hospitalizations and 16500 deaths per year in the United States (US).
The cyclooxygenase-2 (COX-2)-specific inhibitors, which have demonstrated equivalent efficacy to nonspecific NSAIDs in the management of arthritis and pain,
Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis systematic review of randomised controlled trials.
Osteoarthritis Studies Group Rofecoxib, a new cyclooxygenase 2 inhibitor, shows sustained efficacy, comparable with other nonsteroidal anti-inflammatory drugs a 6-week and a 1-year trial in patients with osteoarthritis.
Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis systematic review of randomised controlled trials.
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.
Three large, randomized, clinical trials compared the rates of serious upper gastrointestinal events in patients taking COX-2-specific inhibitors and nonspecific NSAIDs but came to different conclusions. The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, which compared rofecoxib with naproxen in rheumatoid arthritis patients, and the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), which compared lumiracoxib with naproxen and ibuprofen in osteoarthritis patients, found a significantly lower incidence of serious upper gastrointestinal events in patients treated with the COX-2-inhibitor compared with patients treated with nonspecific NSAIDs.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.
The Celecoxib Long-term Arthritis Safety Study (CLASS), which compared celecoxib with ibuprofen and diclofenac in patients with osteoarthritis and rheumatoid arthritis, did not conclusively demonstrate a significant reduction in the primary endpoint of upper gastrointestinal ulcer complications, although significant differences were observed when symptomatic ulcers were also considered with ulcer complications.
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
An unexpected finding from the VIGOR trial was a significantly increased risk of serious thromboembolic events in rofecoxib-treated patients compared with those taking naproxen;
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.
Several questions remain about the safety advantage of COX-2-specific inhibitors compared with nonspecific NSAIDs, including whether they have a lower risk of serious gastrointestinal events and whether their potential gastrointestinal advantage is negated by an increased risk of thromboembolic complications. Additionally, the impact of concomitant low-dose aspirin use on gastrointestinal events is still uncertain. The VIGOR trial excluded all patients requiring concomitant aspirin,
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.
In an attempt to answer some of these questions, we present data from the SUccessive Celecoxib Efficacy and Safety Study-1 (SUCCESS-1), a large, multinational, “real-world,” randomized, and controlled clinical trial in patients with osteoarthritis.
Celecoxib 100 or 200 mg twice daily is as effective as diclofenac 50 mg BID and naproxen 500 mg BID in treating osteoarthritis.
•
Significantly less ulcer complications occur with celecoxib as compared to NSAIDs both in patients taking concomitant aspirin and in those who are not.
•
The number of cardiovascular thromboembolic events is low and not statistically different between the groups.
Methods
Patients
The SUCCESS-1 study was specifically designed with inclusion and exclusion criteria that would yield a study population representative of osteoarthritis patients in community-based, outpatient, clinical practices in each of the participating countries. Eligible patients were aged 18 years or older; had osteoarthritis of the hip, knee, or hand (meeting American College of Rheumatology classification criteria) of at least 6 months duration before randomization; required daily anti-inflammatory agents or other analgesic therapy to control arthritis symptoms; and had a Functional Capacity Classification ranging from I to III.
Major exclusion criteria were a history of 2 or more episodes of active peptic ulceration; gastrointestinal bleeding, or recurrent gastric or duodenal ulcers; an esophageal, gastric, or duodenal ulcer within 30 days before randomization; or active gastrointestinal disease or any condition precluding NSAID therapy. Additional criteria for exclusion were intra-articular or intramuscular corticosteroid or intra-articular hyaluronic acid joint injection within 8 weeks before randomization; required daily use of anti-ulcer medications, including misoprostol, histamine H2-receptor antagonists, proton-pump inhibitors, or antacids; or required daily acetaminophen or other analgesics (in addition to NSAID therapy) for arthritis pain relief. The use of other NSAIDs (except aspirin up to 325 mg daily for cardioprotection), oral corticosteroids, and disease modifying antirheumatic drugs were not permitted, and patients enrolled in the study were not thought to require these agents by their treating physician. The ethics committees or institutional review boards in all participating centers approved the study protocol, and all patients gave written informed consent.
Procedures
The study was a multicenter, multinational, randomized, double-blind, 3-arm, active-comparator trial. Patients were randomly assigned to receive either celecoxib (Celebrex; Pfizer, New York, New York) 100 mg twice daily; celecoxib 200 mg twice daily; or non-specific NSAID therapy (diclofenac [Voltaren; Novartis, Basel, Switzerland] 50 mg twice daily or naproxen [Naprosyn; Roche, Nutley, New Jersey] 500 mg twice daily) for 12 weeks. Naproxen was administered to patients in the U.S. and Canada, and diclofenac was administered to patients in all other countries. Double-blind, central computer-generated, interactive voice response system (IVRS) randomization was in a 1:1:1 ratio, with block sizes of 3, using 2 randomization schedules: 1 for celecoxib treatment groups and naproxen, and the other for the celecoxib treatment groups and diclofenac. Study drug treatment was initiated either on the day of or the day following randomization, and no washout period was required before study drug administration.
The objectives of the study were to evaluate the overall efficacy, safety, and tolerability of celecoxib, as compared with nonspecific NSAIDs. At each visit (pretreatment, week 6, and week 12 [or final]), efficacy and safety were assessed and patients were queried as to what medications were taken. Efficacy was measured by: 1) Patient’s Assessment of Arthritis Pain-Visual Analog Scale, graded on a scale of 0 mm (no pain) to 100 mm (very severe pain);
and 3) the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, a 24-component patient assessment of osteoarthritis pain, joint stiffness, and physical function.
Validation study of WOMAC a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
Patients with osteoarthritis of the hand also completed the WOMAC questionnaire, even though it has not been validated in patients with this disease classification. The primary efficacy analysis was a comparison of these endpoints among the treatment groups in prespecified countries or geographic sub-regions; an assessment of homogeneity of efficacy between various countries or geographic regions was also planned. The primary safety analysis included an adjudication of serious upper gastrointestinal events, as well as an overall evaluation of investigator-reported adverse events, including cardiovascular events.
Investigators were required to report any possible serious upper gastrointestinal adverse event, and to investigate those events according to local standard-of-care procedures, ie, there were no predetermined requirements for any gastrointestinal investigations, including endoscopy. Investigator-identified serious upper gastrointestinal events were reviewed and adjudicated to consensus by 2 independent committees (both blinded to patient randomization), using 2 different methodologies and definitions. The first committee used criteria that required endoscopic confirmation of all lesions (“adjudication based on endoscopic lesions”). Each case was classified as 1 of 5 distinct outcomes—categories 1 through 4 (perforations, ulcer bleeding, obstructions, and symptomatic ulcers, respectively) were upper gastrointestinal outcomes, and category 5 was “other” gastrointestinal events. Categories 1, 2 and 3 were designated “ulcer complications” and Categories 1 through 4 “significant upper gastrointestinal events” (Appendix A). The second committee (post hoc) used criteria based on clinical presentation, and did not always require endoscopic documentation of lesions (“adjudication based on clinical presentation”); patients were classified as having “complicated” or “confirmed” upper gastrointestinal outcomes (Appendix B).
All efficacy and safety analyses were conducted in the intention-to-treat cohort, defined as all patients who received at least 1 dose of study medication. The primary efficacy analysis was a comparison of efficacy in prespecified countries, groups of countries, or geographic regions. A treatment difference of ±9% (95% confidence interval [CI]) between the celecoxib and NSAID groups was anticipated. Clinical comparability was declared when the 95% CI of the difference in the mean treatment response between 2 treatments was ±10 mm on a 100-mm visual analog scale (VAS).
All prespecified efficacy analyses compared each dose of celecoxib with the combined NSAID group. Changes from baseline were compared using the Cochran-Mantel-Haenszel test for categorical variables and a general linear model for continuous variables. For continuous variables, the baseline value was included as a covariate. In addition, an assessment of homogeneity was performed to compare treatment effect across the different regions.
All prespecified gastrointestinal safety analyses compared the combined celecoxib group with the combined NSAID group. Specifically concerning upper gastrointestinal safety, the prespecified power calculation required a comparison of the combined celecoxib and the combined NSAID groups. The rates of serious gastrointestinal events in the combined celecoxib group and in the combined NSAID group were compared using time-to-event analyses (log-rank test) and Fisher’s exact test. A post hoc analysis of upper gastrointestinal safety according to aspirin use was also performed. Treatment differences in the incidence of adverse events were compared using the Fisher’s exact test or the Cochran-Mantel-Haenszel test. Additionally, because of current interest, a post hoc analysis of cardiovascular event rates (which were investigator-reported) among the treatment groups was also performed. The odds ratio (OR) was calculated comparing events in the NSAID group to those in the celecoxib group. A significant P value of ≤.05 was designated for all assessments.
Results
A total of 13274 patients from 1142 study centers in 39 countries were randomized. Of these patients, 13194 received at least 1 dose of study medication (intention-to-treat cohort): 4393 celecoxib 100 mg twice daily, 4407 celecoxib 200 mg twice daily, 905 naproxen 500 mg twice daily, and 3489 diclofenac 50 mg twice daily. Geographically, 6511 patients were from Europe and South Africa, 2873 from Latin America, 2736 from the U.S. and Canada, 681 from Asia, and 393 from Australia and New Zealand. Baseline characteristics were similar between the celecoxib and NSAID treatment groups, including cardiovascular history and risk factors for gastrointestinal events (Table 1). The majority of patients were Caucasian (80%) and women (76%). In both treatment groups, the mean age of patients was 62 years and the mean duration of osteoarthritis was 8 years. Results from all primary efficacy assessments showed that both dosages of celecoxib were as effective as NSAIDs in treating the signs and symptoms of osteoarthritis, including Patient’s Assessment of Arthritis Pain – VAS (Table 2). Although in some instances the differences were statistically significant, they were not clinically significant according to the prespecified criteria (>10 mm difference on a 100-mm VAS). Homogeneity assessments also showed no difference in treatment response across the geographic areas. In addition, celecoxib 100 mg twice daily demonstrated efficacy similar to celecoxib 200 mg twice daily. Separate analyses of osteoarthritis of the hip, knee, or hand showed that all treatments were similarly efficacious in all joints.
Table 1Baseline Characteristics of the 13194 Randomized Participants, According to Treatment Group
In the U.S. and Canada, celecoxib was compared with naproxen, and in all other countries, celecoxib was compared with diclofenac. BID = twice daily, NSAID = nonsteroidal anti-inflammatory drug. Patient global assessment of arthritis was based on a scale of 1-5. Confidence intervals (CIs) notated in italics represent a significant difference between groups. These differences were small and not clinically meaningful.
Celecoxib 100 mg BID vs NSAID
Celecoxib 200 mg BID vs Celecoxib 100 mg BID
Mean Treatment Difference (95% Confidence Interval)
Although the CI does not include 0, a difference of <10 mm on a VAS of 100 mm is clinically insignificant.
0.12 (−0.03 to 0.26)
Assessment not collected
−3.04 (−6.91 to 0.83)
−0.06 (−0.21 to 0.08)
Assessment not collected
In the U.S. and Canada, celecoxib was compared with naproxen, and in all other countries, celecoxib was compared with diclofenac. BID = twice daily, NSAID = nonsteroidal anti-inflammatory drug. Patient global assessment of arthritis was based on a scale of 1-5. Confidence intervals (CIs) notated in italics represent a significant difference between groups. These differences were small and not clinically meaningful.
† Although the CI does not include 0, a difference of <10 mm on a VAS of 100 mm is clinically insignificant.
‡ Belgium, Netherlands, Luxembourg.
§ Czech Republic, Hungary, Poland, Slovakia.
∥ Denmark, Finland, Norway, Sweden.
¶ Colombia, Ecuador, Peru, Venezuela.
# Hong Kong, Malaysia, People’s Republic of China, Philippines, Singapore, Taiwan, Thailand.
The most commonly reported adverse events are shown in Table 3. Overall, a significantly smaller proportion of patients treated with celecoxib (37.2%) than with NSAIDs (40.3%) experienced at least 1 adverse event (P <.001). The most commonly reported events were abdominal pain and dyspepsia, both of which were experienced by significantly more NSAID patients than celecoxib patients. A total of 10 deaths were reported, 5 in the celecoxib group (0.06%) and 5 in the NSAID group (0.11%); the difference between groups was not statistically significant. In the investigators’ opinions, 9 deaths were considered not related to study medication, and 1 was categorized as having an uncertain relationship to study medication. Adverse events requiring study withdrawal occurred in a smaller proportion of celecoxib-treated (9.2 %) than NSAID-treated patients (10.3%) (P =.05). The most common event leading to withdrawal was abdominal pain (2.1% in the celecoxib group and 2.8% in the NSAID group, P =.02).
Table 3Comparison of Adverse Events with ≥1% Incidence Between the Treatment Groups
Investigators identified 144 potential serious upper gastrointestinal events, and these were submitted for adjudication (Table 4). In the adjudication “by lesion” analysis, 36 events were judged as significant upper gastrointestinal events, including 9 events classified as “ulcer complications” (gastric or duodenal perforations, gastric outlet obstruction, or upper gastrointestinal bleeding, confirmed by endoscopy). Significantly more ulcer complications occurred within the NSAID group (0.8 per 100 patient-years) compared with celecoxib (0.1 per 100 patient-years) (OR = 7.02; 95% CI, 1.46 to 33.80; P =.008). In the adjudication “by clinical presentation” analysis, 37 events were judged as confirmed upper gastrointestinal events, including 12 events classified as complicated upper gastrointestinal events. Again, significantly more complicated upper gastrointestinal events were seen with the NSAID group (1.0 per 100 patient-years) compared with celecoxib (0.2 per 100 patient-years) (OR = 6.02; 95% CI, 1.50 to 34.57; P =.004). Figure 1 shows the time-to-event analysis for complicated upper gastrointestinal events, and Figure 2 shows a similar analysis for confirmed upper gastrointestinal events. Log-rank tests for comparison of celecoxib and the NSAID group were statistically significant for both analyses. SUCCESS-1 was not powered for comparisons between celecoxib and each of the two NSAIDs individually. However, a post hoc analysis showed that patients on celecoxib had numerically fewer events (2 events, 0.1/100 patient-years) than either NSAID comparator (naproxen, 4 events [1.83/100 patient-years]; diclofenac, 3 events, [0.41/100 patient-years]). There was no statistically significant difference because of the small numbers, as anticipated.
Table 4Summary of Upper Gastrointestinal (UGI) Event Data Using Both Adjudication Methodologies
Figure 1Cumulative probability of complicated upper gastrointestinal events in patients treated with celecoxib and nonsteroidal anti-inflammatory drugs (naproxen and diclofenac). Log-rank test for difference P value =.002.
Figure 2Cumulative Probability of Confirmed Upper Gastrointestinal Events in Patients Treated with Celecoxib and Nonsteroidal Anti-inflammatory Drugs (Naproxen and Diclofenac). Log-rank Test for Difference P Value =.019.
As shown in Table 5, a post hoc analysis of upper gastrointestinal events found that among nonaspirin users, the incidence of ulcer complications (adjudication “by lesion”) was significantly higher in the NSAID group compared with the celecoxib group (OR = 12.05; 95% CI, 1.45 to 100.09). Among aspirin users (7% of the study population), the overall event rate was low. Although the incidence of ulcer complications was numerically lower in the celecoxib group than in the NSAID group, this difference was not statistically significant (OR = 1.98; 95% CI, 0.12 to 31.72). Similar results were obtained using the adjudication “by clinical presentation” endpoints.
Table 5Clinically Significant Upper Gastrointestinal Events (UGI) in Concurrent Users and Nonusers of Aspirin for Cardiovascular Protection
The analysis of cardiovascular events was based upon investigator-reported events (ie, there was no preplanned adjudication). Investigators were masked to treatment assignment and all reported events were analyzed. There was no significant difference between celecoxib and the NSAID group in any cardiovascular adverse event rate, with the exception of investigator-reported cardiac failure (Table 6). The rate of cardiac failure was 0.22/100 patient-years with celecoxib and 1.00/100 patient-years with the NSAID group (OR = 4.51, 95% CI, 1.26 to 20.06, P =.01). The incidence of cerebrovascular disorders was low and statistically similar between the groups. A post hoc analysis of selected adverse events by treatment group across the geographic regions also showed no significant differences, except for the incidence of peripheral edema (celecoxib 100 mg twice daily 6.45/100 patient-years vs diclofenac 3.79/100 patient-years, P =.03). The risk of myocardial infarction (MI) was low and statistically similar among the treatment groups. The incidence of MI was 0.89/100 patient-years in the combined celecoxib 100 mg twice daily groups, 0.22/100 patient-years in the combined celecoxib 200 mg twice daily groups, and 0.61/100 patient-years for naproxen. There were no cases of MI in diclofenac users.
Table 6Incidence of Selected Investigator-Reported Cardiovascular and Renal Events
Event
NSAID Groups (n = 4394) 901.5 pt-years
Celecoxib Groups (n = 8800) 1806.7 pt-years
Odds Ratio (95%CI)
P Value
Number (Rate/100 pt-yrs)
Coronary artery disorder
1 (0.11)
5 (0.28)
0.40 (0.05, 3.43)
.67
Angina pectoris
7 (0.78)
13 (0.72)
1.08 (0.43, 2.70)
.82
Myocardial infarction
1 (0.11)
10 (0.55)
0.20 (0.03, 1.56)
.11
Cerebrovascular disorders
6 (0.67)
14 (0.74)
0.86 (0.33, 2.23)
1.00
Cardiac failure
9 (1)
4 (0.22)
4.51 (1.39, 14.62)
.01
Peripheral edema
63 (6.99)
129 (7.14)
0.98 (0.73, 1.32)
.94
Hypertension
55 (6.1)
94 (5.2)
1.17 (0.84, 1.63)
.38
Odds ratios represent a comparison of the NSAID group with the celecoxib group.
We found that celecoxib 100 mg twice daily was comparable to naproxen and diclofenac for relief of the signs and symptoms of osteoarthritis of the knee, hip, or hand. Additionally, celecoxib 100 mg twice daily and 200 mg twice daily were similar in efficacy. We found a significant reduction in serious upper gastrointestinal events in celecoxib-treated patients compared with patients on naproxen or diclofenac.
These results are important considering that differing conclusions with regard to serious upper gastrointestinal events were found in the CLASS, VIGOR, and TARGET trials.
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.
The VIGOR trial showed that patients treated with rofecoxib 50 mg/day had a significantly lower risk of serious upper gastrointestinal complications compared with patients treated with naproxen 1000 mg per day.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.
However, the CLASS trial failed to show a statistically significant difference between patients treated with celecoxib 800 mg/day and those treated with ibuprofen or diclofenac, although significant differences were observed when symptomatic ulcers were also considered with ulcer complications.
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
The reason(s) for these differences may be related to several factors, including study design and methodology of evaluating gastrointestinal outcomes, unexpectedly high withdrawal rates in the CLASS trial, or a higher than expected rate of aspirin use in the CLASS trial. It may also reflect a true difference in the gastrointestinal safety profiles of these agents; however, other studies show that this is unlikely.
Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis systematic review of randomised controlled trials.
Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs.
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.
the 12-week SUCCESS-1 study had a withdrawal rate of less than 20% and provides strong evidence of the upper gastrointestinal safety profile of celecoxib in a prospective, randomized, double-blinded, controlled setting.
There is no definitive consensus regarding the most appropriate methodology for evaluating upper gastrointestinal outcomes. In event trials with a high degree of monitoring (such as CLASS, VIGOR, and TARGET),
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.
criteria requiring direct visualization of lesions may be appropriate, whereas in a more “real-world” study, the use of clinical criteria may be more suitable. Although SUCCESS-1 had a “real-world” design (few strict inclusion or exclusion criteria and little protocol-mandated monitoring in a broad range of patients worldwide under different healthcare systems), we used both evaluation criteria. The risk reduction seen with celecoxib compared with the NSAID group was consistent across both methodologies, thus reinforcing the robustness of our conclusions. Furthermore, the dose of diclofenac used (50 mg twice daily) is lower than the highest approved dose for osteoarthritis in the participating countries, and this would be expected to have biased the study against finding any safety advantage of celecoxib over the combined NSAID group (diclofenac n = 3489; naproxen, n = 905).
Low-dose aspirin increases the risk of upper gastrointestinal complications.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.
the SUCCESS-1 study was not stratified by aspirin use and did not have a prespecified sample size to study this issue. In our analysis of nonusers and users of aspirin, celecoxib was associated with a lower numerical rate of serious upper gastrointestinal events compared with NSAIDs. Although, the observed odds ratios were not significant in the aspirin subgroup, where the number of patients taking concomitant aspirin was too small (Table 5). Further controlled studies are required to more clearly define the benefit of COX-2-specific inhibitors compared with nonspecific NSAIDs in this population.
Concern has arisen regarding a potential increase in thromboembolic events in patients taking COX-2-specific inhibitors, as compared with those taking nonspecific NSAIDs.
More recently, the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, which evaluated the incidence of adenomatous polyps in patients treated with rofecoxib 25 mg daily compared with placebo, showed a doubling of MI risk in the rofecoxib-treated patients.
Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.
Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.
Following the release of these results, rofecoxib was voluntarily withdrawn from the worldwide market on September 30, 2004. In 2 studies of the investigational use of parecoxib/valdecoxib for postoperative pain relief following coronary artery bypass graft surgery, a significantly greater incidence of cardiovascular/thromboembolic events was detected in the parecoxib/valdecoxib treatment group compared with the placebo treatment group.
Subsequently, valdecoxib was voluntarily withdrawn from the worldwide market on April 7, 2005, based on its overall risk-benefit assessment. The data with other COX-2-specific inhibitors are mixed. In the TARGET study, patients treated for 1 year with lumiracoxib had a higher, but statistically nonsignificant, increased risk of MI compared with those taking naproxen.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.
Comparable results were also seen for etoricoxib in the Etoricoxib Diclofenac Gastrointestinal Evaluation (EDGE) trial, which had a follow-up of approximately 1 year.
Baraf HSB, Fuentealba C, Greenwald M, et al. Gastrointestinal tolerability and effectiveness of etoricoxib compared to diclofenac sodium in patients with osteoarthritis: a randomized, blinded clinical study (EDGE Trial). Poster presented at the American College of Rheumatology annual meeting, October 19, 2004.
The data with celecoxib are controversial. As with other COX-2-specific inhibitors, there are no studies that were designed or powered to evaluate cardiovascular adverse events. In our 12- week study of average risk osteoarthritis patients, the incidences of cardiovascular adverse events, including hypertension, coronary artery disease, as well as stroke and transient ischemic attacks, were low, as expected, and similar between treatment groups (Table 6). In our post hoc analysis, we observed a higher, but nonsignificant difference in the incidence of MI in patients treated with celecoxib 100 mg twice daily compared with either naproxen or diclofenac. The incidence of MI in the celecoxib 200 mg twice daily group, however, was lower than that seen in patients on naproxen. Overall, there were few MI events in our study, and because of differences within the celecoxib group (ie, 4 times higher rate at the lower dose vs. the higher dose), it is difficult to draw robust conclusions from these data. Several studies of celecoxib (including the CLASS trial,
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
) have not shown an increase in cardiovascular event rates with celecoxib. Some observational studies comparing celecoxib and rofecoxib have shown a dose-dependent increase in MI in patients treated with rofecoxib, but not celecoxib, thus suggesting a significant difference in the cardiovascular adverse event profile of these 2 drugs.
In a recent study on the use of celecoxib to prevent colon polyps (treatment duration 2.8-3.1 years), patients treated with celecoxib 400 mg twice daily had a 3.4 times greater risk of cardiovascular events compared with placebo, and the risk for patients treated with celecoxib 200 mg twice daily was 2.3 times greater than placebo.
Adenoma Prevention with Celecoxib (APC) Study Investigators Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.
In a similarly designed trial, with a similar treatment duration (average of 33 months), celecoxib 400 mg once daily did not show any significantly increased risk of serious cardiovascular events compared with placebo (preliminary data).
It is possible that the increased risk of MI is related to a long-term sustained suppression of the COX-2 enzyme, and thus is seen only in patients treated with high-dose celecoxib (400 mg) taken twice daily for a long period of time. Preliminary information from another long-term study, the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT), showed an increased risk of thromboembolic events in naproxen-treated patients compared with placebo.
Other data have suggested that celecoxib may provide a beneficial cardiovascular effect by suppressing inflammation in vulnerable atherosclerotic plaques. A 2-week treatment with celecoxib improved endothelial function and reduced high-sensitivity C-reactive protein and oxidized low-density lipoproteins (LDL) in patients with coronary artery disease.
Sulfone COX-2 inhibitors increase susceptibility of human LDL and plasma to oxidative modification comparison to sulfonamide COX-2 inhibitors and NSAIDs.
In light of concerns regarding COX-2-specific inhibitors and thromboembolic events, further studies in patients with higher cardiovascular risk are needed to elucidate the precise mechanism(s) involved and to evaluate whether true differences exist among the COX-2-specific inhibitors and nonspecific NSAIDs.
Because a limitation of our study is the short treatment duration (3 months), it can be argued that our results cannot be extrapolated to longer time periods. However, most previous studies, including the VIGOR and TARGET trials, have suggested that the risk of serious upper gastrointestinal complications with NSAIDs is linearly dependent on time, displaying a constant hazard function.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.
Thus, considering our large study population (>13000 patients), it is probable that our conclusions can be extrapolated to longer time-periods.
In summary, our study shows that the COX-2-specific inhibitor celecoxib is as effective as the nonspecific NSAIDs naproxen and diclofenac but has significantly fewer serious upper gastrointestinal events. The number of cardiovascular thromboembolic events in our study was low, and, although numeric differences were noted, these did not reach statistical significance. Because current clinical osteoarthritis treatment guidelines vary in their recommendations regarding the appropriate therapeutic role of COX-2-specific inhibitors, clinicians should consider a number of factors, including the risk for upper gastrointestinal events, duration of therapy, as well as costs, before deciding upon individual patient treatment.
Acknowledgments
We are indebted to the SUCCESS-1 investigators for their participation in the study, Suzanne P. Boots for her dedication and invaluable assistance in managing the study, and Lorraine R. Baer, PharmD for editorial contributions and assistance in the preparation of the manuscript.
APPENDIX A.
Tabled
1Gastrointestinal Events Committee Classification of Serious Upper Gastrointestinal Events for Adjudication Based on Endoscopic Lesions
UGI = upper gastrointestinal. Categories 1, 2 and 3 were designated “ulcer complications” and included perforations, ulcer bleeding, and obstruction. Category 4 was symptomatic ulcers and other UGI events. Categories 1 through 4 were designated “significant upper gastrointestinal events.”
Classification
Description of Primary Diagnosis
1
UGI perforation: An opening in the wall of the stomach or duodenum requiring surgery or laparoscopic repair, but only if the evidence was unequivocal (free air, peritoneal irritation signs, etc.).
2
UGI bleeding: 1 of 7 traditional clinical presentations (2a-2d4).
2a
Hematemesis with gastric or duodenal ulcer or large erosion proven by endoscopy or UGI barium radiograph.
2b
A gastric or duodenal ulcer or large erosion proven by endoscopy with evidence of active bleeding or stigmata of a hemorrhage (visible vessel or attached clot to base of an ulcer).
2c
Melena with a gastric or duodenal ulcer or large erosion proven by endoscopy or UGI barium radiograph.
2d-1
Hemoccult positive stools with a gastric or duodenal ulcer or large erosion proven by endoscopy or UGI barium radiograph and with bleeding as evidenced by a fall in hematocrit of ≥5% or a reduction of hemoglobin of >1.5 g/dL from baseline.
2d-2
Hemoccult positive stools with a gastric or duodenal ulcer or large erosion proven by endoscopy or UGI barium radiograph and with bleeding as evidenced by orthostasis (changes to postural vital signs; increase in pulse rate of ≥20 beats/min or a decrease in systolic blood pressure of ≥20 mmHg or diastolic blood pressure of ≥10 mmHg).
2d-3
Hemoccult positive stools with a gastric or duodenal ulcer or large erosion proven by endoscopy or UGI barium radiograph and with bleeding as evidenced by a need for blood transfusion of 2 or more units.
2d-4
Hemoccult positive stools with a gastric or duodenal ulcer or large erosion proven by endoscopy or UGI barium radiograph and with bleeding as evidenced by blood in the stomach as determined by endoscopy or nasogastric aspiration.
3
Gastric Outlet Obstruction: Opinion of clinician with endoscopic or UGI barium radiograph documentation. Endoscopic evidence would include tight edematous pylorus with an ulcer in the pyloric channel, inability to pass the endoscope tip into the duodenal bulb or descending duodenum, or retained fluid/food in the stomach. UGI barium radiograph evidence of obstruction would include: (1) a dilated stomach, (2) a slowly emptying stomach in a patient with clinical evidence of outlet obstruction, and in some instances, with an ulcer seen in the channel or duodenal bulb or (3) severe narrowing and edema obstructing the outlet of the stomach.
4
Other UGI Event: Symptomatic ulcers documented by endoscopy or UGI barium radiograph and with no evidence of GI bleeding were summarized separately as were other symptomatic UGI complaints.
UGI = upper gastrointestinal. Categories 1, 2 and 3 were designated “ulcer complications” and included perforations, ulcer bleeding, and obstruction. Category 4 was symptomatic ulcers and other UGI events. Categories 1 through 4 were designated “significant upper gastrointestinal events.”
Gastrointestinal Events Committee Classification of Serious Upper Gastrointestinal Events for Adjudication Based on Clinical Presentation (adapted)16
Tabled
1
Event
Criteria for Confirmed Event
Criteria for Complicated Event
Gastric or duodenal perforation due to active gastric ulcer or duodenal ulcer
Report of gastric or duodenal perforation (excluding perforation caused by a malignant ulcer) confirmed by one or more of the following:
All gastric or duodenal perforations are classified as complicated.
1. Endoscopy
2. Surgery
3. Unequivocal radiographic results consistent with free intraperitoneal air or extravasation of contrast media
4. Autopsy
Obstruction due to active gastric ulcer or duodenal ulcer
Postprandial nausea and vomiting lasting for at least 24 hours AND evidence of narrowing of the distal stomach, pylorus, or duodenum due to a nonmalignant ulcer documented by:
All obstructions are classified as complicated.
1. Endoscopy
2. Surgery
3. Radiography
4. Autopsy
Development of active gastric ulcer or duodenal ulcer
Report of gastric ulcer or duodenal ulcer confirmed by one or more of the following:
1. Endoscopy
2. Surgery
3. Unequivocal radiological evidence of active gastric ulcer or duodenal ulcer on upper gastrointestinal series with contrast
4. Autopsy
Gastric ulcer or duodenal ulcer associated with a confirmed upper gastrointestinal hemorrhage as defined under Development of Upper Gastrointestinal Hemorrhage, criteria 1, 2, or 3.
Development of upper gastrointestinal (esophageal, gastric, or duodenal) hemorrhage
Report of upper gastrointestinal hemorrhage fulfilling one or more of the following:
1. Healthcare provider documented frank hematemesis (distinguished from blood tinged or streaked emesis), including coffee-grounds vomitus, OR healthcare provider-witnessed frank blood or coffee grounds by gastric aspiration or lavage (distinguished from scant coffee-grounds that clear rapidly).
2. Healthcare provider documented frank melena (distinguished from other dark stool eg, that due to bismuth salts).
3. Active upper gastrointestinal bleeding documented by endoscopy, angiography, or surgery.
4. Heme-positive stool associated with a documented upper gastrointestinal lesion judged by the healthcare provider to be the source of the bleeding AND associated with either of the following:
a) Significant bleeding/volume loss
b) Stigmata of recent bleeding (visible vessel, pigmented spot or clot on ulcer base) on endoscopy.
5. Patient reported hematemesis or melena associated with a documented upper gastrointestinal lesion judged by the healthcare provider to be the source of the bleeding AND associated with one or more of the following:
a) Significant bleeding/volume loss
b) Stigmata of recent bleeding (visible vessel, pigmented spot or clot on ulcer base) on endoscopy.
1. Upper gastrointestinal hemorrhage associated with significant bleeding/volume loss.
Criteria for significant bleeding/volume loss: One or more of the following (a, b, c, or d) is temporally related to the event: a. Decrease in hemoglobin ≥2 gm/dL (or ≥6% decrease in hematocrit if hemoglobin not available). b. Evidence of orthostatic (sitting to standing, or lying to sitting) changes; one or more of: i) pulse rate increase of >20 beats/minute, ii) decrease in systolic blood pressure >20 mmHg, iii) decrease in diastolic blood pressure >10 mmHg. c. Other evidence of significantly reduced circulatory volume (eg, significant hypotension corrected by volume replacement). d. Transfusion of blood or packed red blood cells.
Criteria for significant bleeding/volume loss: One or more of the following (a, b, c, or d) is temporally related to the event: a. Decrease in hemoglobin ≥2 gm/dL (or ≥6% decrease in hematocrit if hemoglobin not available). b. Evidence of orthostatic (sitting to standing, or lying to sitting) changes; one or more of: i) pulse rate increase of >20 beats/minute, ii) decrease in systolic blood pressure >20 mmHg, iii) decrease in diastolic blood pressure >10 mmHg. c. Other evidence of significantly reduced circulatory volume (eg, significant hypotension corrected by volume replacement). d. Transfusion of blood or packed red blood cells.
Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.
Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications.
Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs.
Baraf HSB, Fuentealba C, Greenwald M, et al. Gastrointestinal tolerability and effectiveness of etoricoxib compared to diclofenac sodium in patients with osteoarthritis: a randomized, blinded clinical study (EDGE Trial). Poster presented at the American College of Rheumatology annual meeting, October 19, 2004.
This study was supported by a grant from Pharmacia Corporation and Pfizer, Inc. The study design as well as data analysis and interpretation were performed by the study design committee, of which the sponsor was a member. The study sponsors were responsible for data collection and management, in collaboration with the authors. Two independent Gastrointestinal Events adjudication committees performed the data analysis and interpretation of gastrointestinal events. The authors had full access to all the data and had final responsibility for data analysis, interpretation, manuscript preparation and the decision to submit for publication.
Conflict of Interest Statement: Gurkirpal Singh received research support from Searle, Pharmacia, Pfizer, Merck, Boehringer Ingelheim, TAP Pharmaceuticals, Wyeth, Altana, Glaxo Smith Kline, Novartis, and Centocor; consultancies, travel grants, speakers bureau from Searle, Pharmacia, Pfizer, Merck and Boehringer Ingelheim. John G. Fort and Carl Wallmark were employees of Pharmacia/Pfizer and own stock in Pfizer, Inc. Jay L. Goldstein: consultancies, honoraria, travel grants, travel expenses, speakers bureau, and research grants from Searle, Pharmacia, Pfizer, TAP Pharmaceuticals, and Astra-Zeneca. Roger A. Levy: Investigator and Speakers bureau (Pfizer, Aventis, Wyeth and Schering-Plough); Advisory board (Pfizer and Novartis). Patrick S. Hanrahan: travel grants from Pfizer. Alfonso E. Bello: former employee of Pharmacia/Pfizer. Lilia Andrade-Ortega: Advisory board (Pfizer); travel grants (Schering Plough). Naurang M. Agrawal: honoraria (Pharmacia and Pfizer); advisory board (Pfizer). Glenn M. Eisen: consultancies and honoraria (Pfizer). William F. Stenson: consultancies (Pharmacia and Pfizer). George Triadafilopoulos: research support from Pfizer, Astra-Zeneca and TAP Pharmaceuticals; consultant to Pfizer, Merck, Boerhinger-Ingelheim, Astra-Zeneca, TAP Pharmaceuticals, Janssen and Wyeth; honoraria and travel support for lectures and meetings from Pfizer, Merck, Boerhinger-Ingelheim, Astra-Zeneca, TAP Pharmaceuticals, Janssen and Wyeth.
All P values are from Exact methods, except for age, duration of osteoarthritis, and VAS pain scale, which are from the t test.
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