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Adverse Upper Gastrointestinal Effects of Rofecoxib Compared With NSAIDs
Michael J. Langman, MD;
Dennis M. Jensen, MD;
Douglas J. Watson, PhD;
Sean E. Harper, MD;
Peng-Liang Zhao, PhD;
Hui Quan, PhD;
James A. Bolognese, MS;
Thomas J. Simon, MD
JAMA. 1999;282:1929-1933.
ABSTRACT
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Context Nonsteroidal anti-inflammatory drug (NSAID)–induced gastrointestinal (GI) toxic effects, such as upper GI tract perforations, symptomatic gastroduodenal ulcers, and upper GI tract bleeding (PUBs), are thought to be attributable to cyclooxygenase 1 (COX-1) inhibition. Rofecoxib specifically inhibits COX-2 and has demonstrated a low potential for causing upper GI injury.
Objective To compare the incidence of PUBs in patients with osteoarthritis treated with rofecoxib vs NSAIDs.
Design Prespecified analysis of all 8 double-blind, randomized phase 2b/3 rofecoxib osteoarthritis trials conducted from December 1996 through March 1998, including one 6-week dose-ranging study, two 6-week efficacy studies vs ibuprofen and placebo, two 1-year efficacy studies vs diclofenac, two 6-month endoscopy studies vs ibuprofen and placebo, and one 6-week efficacy study vs nabumetone and placebo.
Setting Multinational sites.
Participants Osteoarthritis patients (N = 5435; mean age, 63 years [range, 38-94 years]; 72.9% women).
Interventions Rofecoxib, 12.5, 25, or 50 mg/d (n = 1209, 1603, and 545, respectively, combined) vs ibuprofen, 800 mg 3 times per day (n = 847), diclofenac, 50 mg 3 times per day (n = 590); or nabumetone, 1500 mg/d (n = 127) (combined).
Main Outcome Measure Cumulative incidence of PUBs for rofecoxib vs NSAIDs, based on survival analysis of time to first PUB diagnosis, using PUBs that met prespecified criteria judged by a blinded, external adjudication committee.
Results The incidence of PUBs over 12 months was significantly lower with rofecoxib vs NSAIDs (12-month cumulative incidence, 1.3% vs 1.8%; P = .046; rate per 100 patient-years, 1.33 vs 2.60; relative risk, 0.51; 95% confidence interval, 0.26-1.00). The cumulative incidence of dyspeptic GI adverse experiences was also lower with rofecoxib vs NSAIDS over 6 months (23.5% vs 25.5%; P = .02), after which the incidence rates converged.
Conclusion In a combined analysis of 8 trials of patients with osteoarthritis, treatment with rofecoxib was associated with a significantly lower incidence of PUBs than treatment with NSAIDs.
INTRODUCTION
Two isoforms of cyclooxygenase (COX), COX-1 and COX-2,1-4 catalyze human prostaglandin synthesis. Almost all currently available nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both COX isoforms.5 COX-1 is constitutively expressed and generates prostaglandins believed to be involved in gastrointestinal (GI) mucosal protection,6 while COX-2 is induced at sites of inflammation throughout the body and generates prostaglandins that mediate inflammation and pain.7 Therefore, the anti-inflammatory effects of NSAIDs appear to be mediated via inhibition of COX-2,8 while the deleterious GI effects, a significant source of morbidity and mortality, are believed to occur primarily via inhibition of COX-1.5 These GI-related adverse effects (AEs)9-11 are estimated to be responsible for 107,000 hospitalizations and 16,500 deaths annually in the United States alone.12
Rofecoxib (Vioxx, Merck & Co, Inc, Whitehouse Station, NJ) specifically inhibits COX-213-14; at dosages of up to 375 mg/d for 12 days15 and up to 1000 mg in single doses,13 it had no effect on COX-1 isoenzyme activity. In vitro studies of rofecoxib showed no significant effect on prostaglandin synthesis in human gastric biopsies.16 In addition, rofecoxib demonstrated low potential for GI injury (at dosages of 25 and 50 mg/d) as measured by intestinal permeability17 and fecal red blood cell loss,18 and by assessment of endoscopic gastroduodenal mucosal injury in both healthy volunteers (at 250 mg/d)19 and patients with osteoarthritis (at 25 and 50 mg/d).20
This study was a planned, blinded, combined analysis of 8 randomized, double-blind, phase 2b/3 clinical trials performed from December 1996 through March 1998 of rofecoxib inpatients with osteoarthritis to examine the incidence of upper GI perforations, symptomatic gastroduodenal ulcers, and upper GI bleeding (PUBs). We hypothesized that the incidence of PUBs would be lower with rofecoxib (12.5-, 25-, and 50-mg combined treatment groups) than with NSAIDs (ibuprofen, diclofenac, and nabumetone combined treatment groups).
METHODS
The plan used to analyze the incidence of PUBs with rofecoxib compared with NSAIDs was prespecified. PUBs are rare and large numbers of patients are necessary to evaluate the rate of incidence with precision; therefore, in this analysis, we pooled patients from all 8 phase 2b/3 osteoarthritis trials of rofecoxib and their blinded extensions (Table 1). All patients gave signed informed consent and an institutional review board approved each study.
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Table 1. Features of Studies Included in the Combined Analysis
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The analysis plan prespecified that patients with asymptomatic ulcers diagnosed within a 7-day window surrounding the scheduled procedure dates in the 2 surveillance endoscopy studies would be excluded from the analysis. Eleven additional patients with asymptomatic ulcers confirmed by investigators to have been detected at surveillance endoscopies scheduled outside the 7-day window for a variety of reasons were also excluded.
Investigators were instructed to report all laboratory and clinical AEs, including upper GI dyspepsia and PUBs, that occurred during treatment and within 14 days of study drug discontinuation. In all the studies, a final patient contact and/or evaluation was scheduled for the 14th day following study completion or study drug discontinuation. Patients were followed up in each study until final evaluation after completion of study therapy or after early discontinuation for any reason (eg, diagnosis of PUB, other AE, lack of treatment efficacy, withdrawal of consent), death, or loss to follow-up.
Clinical source documentation for suspected PUBs was reviewed by a blinded, external adjudication committee. Only PUBs judged as confirmed, according to prespecified definitions (Table 2), were analyzed. PUBs that occurred more than 14 days after the last dose of study drug were not included in the analysis (as prespecified).
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Table 2. Definitions and Adjudication Criteria for Upper Gastrointestinal (GI) Perforations, Gastroduodenal Ulcers, and GI Bleeding*
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Adverse events, including PUBs, were coded blind to treatment with a standard automated dictionary that classified AEs into broader categories grouped by body system. We also compared discontinuations due to any GI AE and discontinuations due to a prespecified subset of GI AEs typical of upper GI symptoms associated with NSAIDs.21-23 The latter category (hereafter referred to as "dyspeptic-type GI AEs") consists of all AEs mapped by the dictionary to the categories of acid reflux, dyspepsia, epigastric discomfort, heartburn, nausea, or vomiting.
Analyses were based on all patients treated in the 8 trials, with exceptions as follows. Patients from the placebo and 5-mg rofecoxib groups of Protocol 029 (Table 1) were switched after 6 weeks to diclofenac, 12.5 mg of rofecoxib, or 25 mg of rofecoxib in an extension phase. Similarly, patients from the placebo group of Protocol 058 were switched after 6 weeks to nabumetone, 12.5 mg of rofecoxib, or 25 mg of rofecoxib in an extension phase. To avoid double-counting patients in the analyses, it was prespecified that the data from patients randomized to the placebo or 5-mg rofecoxib groups in the 6-week placebo-controlled phase of both studies would be excluded from analyses, while the data from these patients' extension phase would be included. However, 117 such patients (2.1% of the total population) did not continue into extensions or did not have extension data at the time of the analysis and were therefore excluded.
A survival analysis of the time to first PUB diagnosis date was used for between-treatment comparisons. This method is appropriate because it takes into account the varying lengths of treatment in the 8 studies. For PUBs diagnosed in inpatients, the hospital admission date was used as the diagnosis date. For PUBs diagnosed in outpatients, the date of the diagnostic procedure or clinical observation was used. The log-rank test was the primary method used to compare time-to-first-event distributions between groups. The cumulative incidence difference between rofecoxib and NSAIDs was assessed at 6 weeks and at 4, 6, 12, and 24 months, using the method of Breslow and Crowley.24 Results are reported at 4 months (maximum duration of placebo) and 12 months (no PUBs occurred beyond 12 months). Differences between groups were considered significant when P<.05. The Cox proportional hazards model was used to estimate overall relative risks (RRs) and 95% confidence intervals (CIs) of rofecoxib vs NSAIDs. Treatment by type of protocol interactions were evaluated in the Cox model. Analyses stratified by type of protocol and analyses in which each type of protocol was removed from the analysis 1 at a time were performed to assess possible confounding.
RESULTS
The analysis included 5435 patients. Of these, 3357 patients were treated with rofecoxib (1209, 1603, and 545 patients received 12.5, 25, and 50 mg, respectively, once daily), 1564 patients were treated with NSAIDs (847 received ibuprofen, 800 mg 3 times daily; 590 received diclofenac, 50 mg 3 times daily; and 127 received nabumetone, 1500 mg once daily) and 514 patients were treated with placebo. Total patient-years of exposure were 1428, 615, and 112, in the rofecoxib, NSAID, and placebo groups, respectively. The average dosage of rofecoxib was 24.7 mg once daily.
There were no clinically meaningful differences in baseline characteristics between groups (Table 3). Mean age overall was 63 years (range, 38-94 years); 45% of patients were 65 years or older, and 73% were women. Most (90%) patients had previously used NSAIDs for their osteoarthritis. Approximately 10% of the patients in each group had a prior medical history of PUB.
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Table 3. Baseline Patient Characteristics*
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Rofecoxib was generally well tolerated and fewer patients overall discontinued rofecoxib compared with the NSAIDs (Table 4); 9.4% of rofecoxib patients vs 10.7% of NSAID patients discontinued the study drug because of any clinical AE, and 3.5% of the rofecoxib patients discontinued the study drug due to a GI AE, compared with 4.8% of NSAID patients (Table 4). The cumulative incidence of dyspeptic-type GI AEs up to 6 months was significantly lower with rofecoxib than with NSAIDs (23.5% vs 25.5%; P = .02), after which the incidence rates converged. The 12-month cumulative incidences of study drug discontinuation due to GI AEs were 5.7% vs 7.8% for the rofecoxib and NSAID groups. The difference was significantly lower (P = .02) in the rofecoxib group compared with the NSAID group over 12 months (8.2 vs 12.0 per 100 patient-years, respectively; RR = 0.70; 95% CI, 0.52-0.94).
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Table 4. Exposure to Study Drug and Number of Patients Who Completed and Who Were Discontinued From the Study Populations*
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Forty-nine potential PUBs were submitted by investigators and adjudicated; 5 (3 in the rofecoxib and 2 in the NSAID group) did not meet the prespecified case definition because they occurred more than 14 days after study drug discontinuation. Of the remaining 44 cases, 38 (19 in the rofecoxib, 16 in the NSAID, 3 in the placebo group) were adjudicated as having at least 1 confirmed PUB, and 6 (all in the NSAID group) were adjudicated as having unconfirmed PUBs. Nine patients had more than 1 PUB (2, 3, and 4 in the placebo, placebo, refecoxib, and NSAID groups respectively); all of these patients had 2 PUBs each, except for 1 patient (NSAID group) with 3 PUBs. Only the first PUB in a given patient was included in the analysis. There were no PUBs during the small amount of patient exposure (25 patient-years) to nabumetone in the 1 study that included this treatment.
The cumulative incidence of confirmed PUBs over 12 months with rofecoxib was significantly lower (1.3% vs 1.8%, P = .046) than with NSAIDs (Figure 1). The rates per 100 patient-years over 12 months were 1.33 and 2.60 for rofecoxib and NSAIDs, respectively. The overall RR over 12 months for rofecoxib vs NSAIDs was 0.51 (95% CI, 0.26-1.00). Analyses stratified by type of protocol yielded very similar results to the unstratified analyses (RR = 0.53; 95% CI, 0.27-1.03; P =.06), and analyses that sequentially removed each protocol type also yielded consistent results, demonstrating a lack of confounding by type of protocol. No statistically significant treatment by type of protocol interaction was present (P>.10) in the unstratified Cox model. The difference between rofecoxib and NSAIDs in the incidence of confirmed PUBs became statistically significant as early as 6 weeks (RR for rofecoxib vs NSAIDs, 0.21; 95% CI, 0.06-0.67; P = .004), and remained so up to 12 months.
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Figure. 12-Month Survival Analysis of Confirmed Upper Gastrointestinal (GI) Perforations, Symptomatic Ulcers, and Upper GI Bleeding by Combined Treatment Groups
Relative risk with rofecoxib vs nonsteroidal anti-inflammatory drugs (NSAIDs) is 0.51 (95% confidence interval, 0.26-1.00; P = .046 by log-rank test).
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In analyses confined to placebo-controlled protocols, which were up to 4 months in duration, the cumulative incidence rates of confirmed PUBs were 0.9%, 0.9%, and 1.6% for placebo, rofecoxib, and NSAIDs, respectively. The corresponding rates per 100 patient-years over 4 months were 2.68, 2.50, and 7.21. The RR over 4 months for NSAIDs vs placebo was 2.50 (95% CI, 0.68-9.24), while that for rofecoxib vs placebo was 0.94 (95% CI, 0.25-3.60).
COMMENT
Because PUBs are rare, we carried out a prespecified analysis of data obtained from 8 randomized, double-blind phase 2b/3 osteoarthritis trials with rofecoxib to determine whether COX-2 specific inhibition would be associated with a lower incidence of PUBs than nonspecific COX inhibition. The combined population included patients at high risk of PUBs (eg, those with a history of PUB and/or age  65 years), as reported previously.25 The analysis demonstrated a significantly lower incidence of confirmed PUBs with rofecoxib than with NSAIDs over 12 months. In addition, the total rate of study drug discontinuations due to GI AEs was significantly lower in the group receiving rofecoxib than in the group receiving NSAIDs.
The analysis has particular strengths. It was prospectively designed and used prespecified adjudication criteria, hypotheses, and data analysis plans, and an external, blinded committee adjudicated all reported PUBs. It included all phase 2b/3 osteoarthritis trials of rofecoxib and a broad range of patients, including those with prior PUB history. The primary hypothesis involved a biologically meaningful comparison of GI safety with COX-2 specific inhibition vs nonspecific COX-1/COX-2 inhibition, and the doses of NSAID comparators for the included studies were chosen to be within the clinical dose range for treatment of osteoarthritis. The average dosage of rofecoxib in this study was 24.7 mg/d, which corresponds to the highest recommended daily dose (25 mg) for osteoarthritis. Both the 12.5-mg and 25-mg doses of rofecoxib have been shown, using prespecified criteria, to be therapeutically equivalent, in terms of osteoarthritis symptom relief, to the doses of the main comparator NSAIDs (diclofenac and ibuprofen) used in this study.26-27 The analytic methods took account of the varying lengths of the studies. Analyses stratified by type of protocol demonstrated that difference in study design was not a confounding variable in the assessment of PUB risk with treatment. Statistical tests of treatment by type of protocol interaction in the unstratified COX model indicated that the assumption of a common RR was appropriate. Because PUBs are uncommon, there were generally too few within any 1 study to provide precise study-specific RR estimates. However, the variation that did occur was compatible with the assumption of a common, study-specific incidence rate ratio. Analyses in which each type of protocol was removed from the analysis 1 at a time showed consistent results.
The analysis also had limitations. First, there were only enough patient-years of exposure to compare pooled rofecoxib and NSAID comparators, rather than individual treatments. Second, inclusion of studies with scheduled endoscopies mandated in their protocols may have caused a bias against rofecoxib. Patients in these studies were systematically discontinued from treatment when they developed endoscopically evident gastroduodenal ulcers 3 mm or more in diameter, and a much higher rate of endoscopically detected ulceration was observed in the ibuprofen than in the rofecoxib group.21 If patients discontinued from the study had greater potential to develop a PUB (eg, because of an endoscopic ulcer or a prior history of PUB), then the inclusion of these 2 studies may have reduced the observed incidence of PUBs in the ibuprofen groups.
Our analysis shows that COX-2 specific inhibition with rofecoxib was associated with a significantly lower risk of PUBs relative to NSAIDs. These findings are consistent with the results of studies of intestinal permeability,17 fecal red blood cell loss,18 and upper GI endoscopy19-20 with rofecoxib and indicate that risks of GI toxic effects associated with NSAIDs can be reduced by COX-2 specific inhibition.
AUTHOR INFORMATION
Financial Disclosures: Drs Langman and Jensen are consultants to Merck & Co Inc. Drs Watson, Harper, Zhao, Quan, and Simon and Mr Bolognese are employees of Merck & Co Inc.
Funding/Support: This work was supported by Merck & Co Inc, Whitehouse Station, NJ.
Acknowledgment: We thank Marie R. Griffin, MD, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tenn, for her leadership as chair of the Clinical Event Case Review Committee and for her thoughtful review and critique of the manuscript. We also thank Maryanne Plesher, MS, and Carrie Schmidt, BA, for their assistance in conducting the study.
Corresponding Author: Michael J. Langman, MD, University of Birmingham, Department of Medicine, Birmingham B15 2TH, England. Reprints: Douglas J. Watson, PhD, Merck Research Laboratories, 10 Sentry Pkwy (BL1-7), Blue Bell, PA 19422.
Author Affiliations: Department of Medicine, University of Birmingham, Birmingham, England (Dr Langman); Department of Medicine, University of California, Los Angeles Center for the Health Sciences (Dr Jensen); and Merck Research Laboratories, Merck & Co Inc, West Point, Pa (Drs Watson, Harper, Zhao, Quan, Simon, and Mr Bolognese).
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The overexpression of cyclo-oxygenase-2 in chronic periodontitis
ZHANG et al.
Journal of the American Dental Association 2003;134:861-867.
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Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre, randomised, double blind study
Hawkey et al.
Gut 2003;52:820-826.
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Characterization of Etoricoxib, a Novel, Selective COX-2 Inhibitor
Dallob et al.
J Clin Pharmacol 2003;43:573-585.
ABSTRACT
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Cyclooxygenase-2 Inhibitors
Gajraj
Anesth. Analg. 2003;96:1720-1738.
FULL TEXT
The Cost-Effectiveness of Cyclooxygenase-2 Selective Inhibitors in the Management of Chronic Arthritis
Spiegel et al.
ANN INTERN MED 2003;138:795-806.
ABSTRACT
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Comparison of the incidence rates of selected gastrointestinal events reported for patients prescribed rofecoxib and meloxicam in general practice in England using prescription-event monitoring data
Layton et al.
Rheumatology (Oxford) 2003;42:622-631.
ABSTRACT
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Acute pain management for patients undergoing thoracotomy
Soto and Fu
Ann. Thorac. Surg. 2003;75:1349-1357.
ABSTRACT
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Non-steroidal anti-inflammatory drugs: overall risks and management. Complementary roles for COX-2 inhibitors and proton pump inhibitors
Hawkey and Langman
Gut 2003;52:600-608.
ABSTRACT
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COX-2 Inhibition for Postoperative Analgesia * Response
Schwarz et al.
Anesth. Analg. 2003;96:1235-1235.
FULL TEXT
Single- and Multiple-Dose Pharmacokinetics of Etoricoxib, a Selective Inhibitor of Cyclooxygenase-2, in Man
Agrawal et al.
J Clin Pharmacol 2003;43:268-276.
ABSTRACT
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Effect of Rofecoxib on Prednisolone and Prednisone Pharmacokinetics in Healthy Subjects
Schwartz et al.
J Clin Pharmacol 2003;43:187-192.
ABSTRACT
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Ulcerogenic Influence of Selective Cyclooxygenase-2 Inhibitors in the Rat Stomach with Adjuvant-Induced Arthritis
Kato et al.
J. Pharmacol. Exp. Ther. 2002;303:503-509.
ABSTRACT
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Ankylosing spondylitis: an overview
Sieper et al.
Ann Rheum Dis 2002;61:iii8-18.
ABSTRACT
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Conventional treatments for ankylosing spondylitis
Dougados et al.
Ann Rheum Dis 2002;61:iii40-50.
ABSTRACT
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Paracetamol toxicity: epidemiology, prevention and costs to the health-care system
SHEEN et al.
QJM 2002;95:609-619.
ABSTRACT
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Primary prevention of diclofenac associated ulcers and dyspepsia by omeprazole or triple therapy in Helicobacter pylori positive patients: a randomised, double blind, placebo controlled, clinical trial
Labenz et al.
Gut 2002;51:329-335.
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Results of a randomized, dose-ranging trial of etoricoxib in patients with osteoarthritis
Gottesdiener et al.
Rheumatology (Oxford) 2002;41:1052-1061.
ABSTRACT
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Cyclooxygenase Inhibition for Postoperative Analgesia
McCrory and Lindahl
Anesth. Analg. 2002;95:169-176.
FULL TEXT
Fatal haemorrhagic pulmonary oedema and associated angioedema after the ingestion of rofecoxib
Kumar et al.
Postgrad. Med. J. 2002;78:439-440.
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Association Between Naproxen Use and Protection Against Acute Myocardial Infarction
Rahme et al.
Arch Intern Med 2002;162:1111-1115.
ABSTRACT
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Balancing the Risks of Stroke and Upper Gastrointestinal Tract Bleeding in Older Patients With Atrial Fibrillation
Man-Son-Hing and Laupacis
Arch Intern Med 2002;162:541-550.
ABSTRACT
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Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues
Thun et al.
JNCI J Natl Cancer Inst 2002;94:252-266.
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Cyclooxygenase-2---10 Years Later
Hinz and Brune
J. Pharmacol. Exp. Ther. 2002;300:367-375.
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Commentary: Peptic ulcer, Susser and Stein and the cohort phenomenon
Langman
Int J Epidemiol 2002;31:27-28.
FULL TEXT
Efficacy of Rofecoxib, Celecoxib, and Acetaminophen in Osteoarthritis of the Knee: A Randomized Trial
Geba et al.
JAMA 2002;287:64-71.
ABSTRACT
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Osteoarthritis: New Insights
Palmer
ANN INTERN MED 2002;136:87-88.
FULL TEXT
Management of gastrointestinal haemorrhage
Ghosh et al.
Postgrad. Med. J. 2002;78:4-14.
ABSTRACT
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Treatment of low back pain with a herbal or synthetic anti-rheumatic: a randomized controlled study. Willow bark extract for low back pain
Chrubasik et al.
Rheumatology (Oxford) 2001;40:1388-1393.
ABSTRACT
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Clinical case study.
Haglund et al.
AM J HOSP PALLIAT CARE 2001;18:429-431.
Quality Indicators for the Management of Osteoarthritis in Vulnerable Elders
MacLean
ANN INTERN MED 2001;135:711-721.
FULL TEXT
Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors
Mukherjee et al.
JAMA 2001;286:954-959.
ABSTRACT
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The Coxibs, Selective Inhibitors of Cyclooxygenase-2
FitzGerald and Patrono
NEJM 2001;345:433-442.
FULL TEXT
Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen
Fernandez et al.
NEJM 2001;344:1398-1399.
FULL TEXT
Etoricoxib (MK-0663): Preclinical Profile and Comparison with Other Agents That Selectively Inhibit Cyclooxygenase-2
Riendeau et al.
J. Pharmacol. Exp. Ther. 2001;296:558-566.
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Guest Editorial: The Use of COX-2-Specific Inhibitors: Is It All Hype or Is It Evidence Based?
Ince
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2001;56:136M-137.
FULL TEXT
The Year in Review: Rheumatology
Rozenfeld et al.
Journal of Pharmacy Practice 2001;14:54-69.
ABSTRACT
Cyclooxygenase-2 Is Overexpressed in Human Cervical Cancer
Kulkarni et al.
Clin. Cancer Res. 2001;7:429-434.
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THE OPTIMAL ANALGESIC DOSE OF ROFECOXIB: OVERVIEW OF SIX RANDOMIZED CONTROLLED TRIALS
MORRISON et al.
Journal of the American Dental Association 2000;131:1729-1737.
ABSTRACT
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Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis
Bombardier et al.
NEJM 2000;343:1520-1528.
ABSTRACT
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Are {blacktriangledown}rofecoxib and {blacktriangledown}celecoxib safer NSAIDS?
DTB 2000;38:81-86.
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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
Saag et al.
Arch Fam Med 2000;9:1124-1134.
ABSTRACT
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Gastrointestinal Tolerability of the Selective Cyclooxygenase-2 (COX-2) Inhibitor Rofecoxib Compared With Nonselective COX-1 and COX-2 Inhibitors in Osteoarthritis
Watson et al.
Arch Intern Med 2000;160:2998-3003.
ABSTRACT
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Regular review: Medical management of osteoarthritis
Walker-Bone et al.
BMJ 2000;321:936-940.
FULL TEXT
Recent advances: Rheumatology
Madhok et al.
BMJ 2000;321:882-885.
FULL TEXT
COX-2-Selective NSAIDs: New and Improved?
Lichtenstein and Wolfe
JAMA 2000;284:1297-1299.
FULL TEXT
COX-1 and COX-2 products in the gut: therapeutic impact of COX-2 inhibitors
WHITTLE
Gut 2000;47:320-325.
FULL TEXT
Selective Cox-2 inhibition in man--therapeutic breakthrough or cosmetic advance?
Wollheim
Rheumatology (Oxford) 2000;39:935-938.
FULL TEXT
Outcomes studies of drug induced ulcer complications: do we need them and how should they be done?
Hawkey
BMJ 2000;321:291-293.
FULL TEXT
An evidence-based approach to the management of uninvestigated dyspepsia in the era of Helicobacter pylori
van Zanten et al.
CMAJ 2000;162:s3-23.
ABSTRACT
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Anti-TNFalpha : a new dimension in the pharmacotherapy of the spondyloarthropathies !?
BRAUN and SIEPER
Ann Rheum Dis 2000;59:404-407.
FULL TEXT
Rofecoxib caused fewer endoscopic gastroduodenal ulcers than ibuprofen in osteoarthritis
Henry and McGettigan
Evid. Based Med. 2000;5:74-74.
FULL TEXT
Celecoxib was similar to naproxen for rheumatoid arthritis with fewer endoscopic ulcers
Henry and McGettigan
Evid. Based Med. 2000;5:75-75.
FULL TEXT
Rofecoxib and the Risk of Adverse Upper Gastrointestinal Effects
Freston et al.
JAMA 2000;283:1960-1961.
FULL TEXT
Effect of COX-2 Specific Inhibitors on GI Symptoms
JWatch Gastroenterology 2000;2000:4-4.
FULL TEXT
Do Cyclooxygenase-2 Inhibitors Provide Benefits Similar to Those of Traditional Nonsteroidal Anti-Inflammatory Drugs, with Less Gastrointestinal Toxicity?
Feldman and McMahon
ANN INTERN MED 2000;132:134-143.
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How Important Is the Benefit from COX-2 Inhibitors?
JWatch General 1999;1999:1-1.
FULL TEXT
COX-1-Sparing NSAIDs--Is the Enthusiasm Justified?
Peterson and Cryer
JAMA 1999;282:1961-1963.
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Cardiovascular Thrombotic Events in Controlled, Clinical Trials of Rofecoxib
Konstam et al.
Circulation 2001;104:2280-2288.
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