A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2–specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis

doi:10.1016/S0016-5085(99)70334-3

Gastroenterology

Volume 117, Issue 4, October 1999, Pages 776-783

https://doi.org/10.1016/S0016-5085(99)70334-3 Get rights and content

Abstract

Background & Aims: Prostaglandin production in the normal gastrointestinal tract, believed to be critical for mucosal integrity, is mediated by cyclooxygenase (COX)-1, whereas prostaglandin production at inflammatory sites seems to occur via induction of COX-2. We hypothesized that COX-2–specific inhibition with rofecoxib (25 mg once daily) in the treatment of patients with osteoarthritis would cause fewer gastroduodenal ulcers than an equally effective dose of ibuprofen (800 mg 3 times a day), a nonspecific COX inhibitor. Methods: A total of 742 osteoarthritis patients without ulcers on baseline endoscopy were randomly assigned to receive rofecoxib (25 or 50 mg once daily), ibuprofen (800 mg 3 times daily), or placebo. Endoscopy was repeated at 6, 12, and 24 weeks. At 16 weeks, by study design, 95% of the placebo group and 5% of the other groups were discontinued. Results: The cumulative incidence of gastroduodenal ulcers ≥3 mm with rofecoxib (25 or 50 mg once daily) was significantly (P < 0.001) lower than with ibuprofen and was statistically equivalent to placebo at week 12 (placebo, 9.9%; 25 mg rofecoxib, 4.1%; 50 mg rofecoxib, 7.3%; and ibuprofen, 27.7%). At 24 weeks, ulcer rates were 25 mg rofecoxib, 9.6%; 50 mg rofecoxib, 14.7%; and ibuprofen, 45.8% (P < 0.001, ibuprofen vs. 25 and 50 mg rofecoxib). Conclusions: Rofecoxib, at doses 2-4 times the dose demonstrated to relieve symptoms of osteoarthritis, caused significantly less gastroduodenal ulceration than ibuprofen, with ulcer rates comparable to placebo.

GASTROENTEROLOGY 1999;117:776-783

Section snippets

Patients

Patients with osteoarthritis ≥50 years old requiring NSAID treatment for at least 6 months were eligible. Patients were excluded if they had active duodenal, gastric, or esophageal ulcers; pyloric obstruction; or erosive esophagitis at baseline endoscopy. Patients with gastroduodenal erosions at baseline were eligible. Patients were excluded for past upper GI surgery; inflammatory bowel disease; serum creatinine level of >2.0 mg/dL; an estimated creatinine clearance of ≤30 mL/min; fecal occult

Results

Between December 1996 and August 1997, 1102 patients at 34 sites in the United States were screened and 742 were enrolled (Figure 1).

. Trial profile. AE, adverse experience; LOE, lack of efficacy. Abnormal baseline endoscopy includes 45 patients with erosive esophagitis, 25 with ulcers, 1 with prior gastric surgery, 1 with submucosal mass, and 2 with extensive erosive disease. Other causes of discontinuation include loss to follow-up, relocation of patient, withdrawal of consent, and protocol

Discussion

We set out to test the hypothesis that the COX-2–specific inhibition with rofecoxib would have a lower incidence of gastroduodenal ulcers than NSAIDs in a long-term endoscopy study. An in vivo study of rofecoxib showed no significant effect on prostaglandin synthesis in human gastric mucosal biopsy specimens,¹⁵ and previous clinical studies suggested little or no GI tract injury with rofecoxib. In a 1-week double-blind endoscopic study, 250 mg rofecoxib once daily (20 times the dose shown to

Acknowledgements

The authors thank Jan Redfern and Kathleen Guckert for help with preparation of the manuscript; and Monica Hoover, Angeline Cagliola, Michelle Shelko, Sophia Haralson, and Francis D'Anzi for help in study implementation as well as database construction and review.

References (35)

L Laine
Nonsteroidal anti-inflammatory drug gastropathy
Gastrointest Endosc Clin North Am
(1996)
EA Meade et al.
Dif ferential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs
J Biol Chem
(1993)
DY Graham
High-dose famotidine for prevention of NSAID ulcers?
Gastroenterology
(1997)
B Cryer et al.
Comparison of salsalate and aspirin on mucosal injury and gastroduodenal mucosal prostaglandins
Gastroenterology
(1990)
L Laine et al.
A randomized double-blind comparison of placebo, etodolac, and naproxen on gastrointestinal injury and prostaglandin production
Gastrointest Endosc
(1995)
NM Agrawal et al.
Comparison of the upper gastrointestinal safety of Ar throtec 75 and nabumetone in osteoarthritis patients at high risk for developing nonsteroidal anti-inflammatory drug–induced gastrointestinal ulcers
Clin Ther
(1999)
L Laine et al.
Has the impact of Helicobacter pylori therapy on ulcer recurrence in the United States been overstated: a meta-analysis of rigorously designed trials
Am J Gastroenterol
(1998)
L Laine
Helicobacter pylori and complicated ulcer diseases
Am J Med
(1996)
S Takahashi et al.
Localization of cyclooxygenase-2 and regulation of its expression in gastric ulcers in rats (abstr)
Gastroenterology
(1998)
JF Fries
NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal
J Rheumatol
(1991)

HE Paulus

FDA arthritis advisory committee meeting: postmarketing surveillance of nonsteroidal antiinflammatory drugs

Ar thritis Rheum

(1985)

FE Silverstein et al.

Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid ar thritis receiving nonsteroidal anti-inflammatory drugs

Ann Intern Med

(1995)

G Singh et al.

NSAID induced gastrointestinal complications: the ARAMIS perspective—1997

J Rheumatol

(1998)

B Cryer

Nonsteroidal anti-inflammatory drugs and gastrointestinal disease

E Fosslien

Adverse effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal system

Ann Clin Lab Sci

(1998)

JA Mitchell et al.

Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase

Proc Natl Acad Sci USA

(1994)

C Brideau et al.

A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors

Inflamm Res

(1996)

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This study aimed to investigate the protective effect of epiisopiloturine hydrochloride (EPI), an imidazole alkaloid, on NAP-induced gastrointestinal damage in rats.
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EPI pretreatment prevented NAP-induced macro and microscopic gastric damage with a maximal effect at 10 mg/kg. Histological analysis revealed that EPI decreased scores of damage caused by NAP. EPI reduced MPO (3.4 ± 0.3 U/mg of gastric tissue) and inhibited changes in MDA (70.4 ± 8.3 mg/g of gastric tissue) and GSH (246.2 ± 26.4 mg/g of gastric tissue). NAP increased TNF-α levels, and this effect was reduced by EPI pretreatment. Furthermore, EPI increased GMBF by 15% compared with the control group.
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This was a 24-week, multicenter, single-arm phase IV Study for the safety and efficacy of GCSB-5. A total of 761 patients were enrolled and 756 patients received at least one dose of GCSB-5. Among them, 629 patients (82.7%) completed the 24 week follow up. The primary goal was to determine the safety and efficacy of GCSB-5 for 24 weeks. The secondary goal was to compare the GI safety data of GCSB-5 with that of the previously reported Celecoxib Long-term Arthritis Safety Study (CLASS).
The incidence of GI disorders of GCSB-5 was 23.7%. The annual rate of perforation, ulcer obstruction, or bleeding (PUB) incidence was 0.0%. The drop-out rate due to GI disorders following GCSB-5 use was 4.8%. Compared to celecoxib data from CLASS, the incidence of GI disorders (23.7% vs. 31.4%, p<0.001), annual rate of PUB and gastroduodenal ulcers (0.0% vs 2.2%, p=0.004), and drop-out rate due to GI disorders following GCSB-5 use were significantly low (4.8% vs 8.7%, p<0.001). Efficacy was proven by significant improvements in Western Ontario McMaster Questionnaire (WOMAC) scale, Korean Knee Score (KKS), 100-mm pain visual analogue scale (VAS), and physician's global assessments of patient's response to therapy (PGART).
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^☆: Address requests for reprints to: Loren Laine, M.D., GI Liver Division, Department of Medicine (LAC 12-137), University of Southern California School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033. e-mail: [email protected]; fax: (323) 226-7573.

^☆☆: Supported by a grant from Merck & Co., Inc., Whitehouse Station, New Jersey.

^★: The following institutions and primary investigators participated in the Rofecoxib Osteoarthritis Endoscopy Group 044 Study. Hill Top Research, Ltd., Cincinnati, OH: R. Bath. Rush Center for Clinical Studies, Chicago, IL: J. Block. Metroplex Clinical Research Center, Dallas, TX: S. Cohen. William Beaumont Hospital, Birmingham, MI: M. Doyle. Garland and Associates, P.C., Lawrenceville, NJ: W. T. Garland. Veterans Administration Hospital, Houston, TX: M. Genta. Nashville Research Associates, Nashville, TN: D. Gremillion. University of California, San Diego, San Diego, CA: J. Isenberg. Rockford Gastroenterology Associates, Rockford, IL: J. Johanson. St. John's Health Center, Santa Monica, CA: W. Katkov. Medici Research Centers, LLC, Peoria, AZ: L. Kirby II. Northwestern Memorial Hospital/Northwestern Community Medical Group, Chicago, IL: J. Kopin. University of Southern California School of Medicine, Los Angeles, CA: L. Laine. Houston Institute for Clinical Research, Houston, TX: F. Lanza. New York Hospital–Cornell Medical Center, New York, NY: C. McDougall. The Penrose-St. Francis Medical Group, P.C., Colorado Springs, CO: E. Miller. Dayton Area Research Association, Kettering, OH: N. Patel. PSC Family Medicine, Louisville, KY: M. Peveler. Marshfield Medical Clinic, Marshfield, WI: C. Rall. Arizona Research and Education, Phoenix, AZ: S. Roth. Rush-Presbyterian–St. Luke's Medical Center, Chicago, IL: E. Ruderman. Cincinnati Gastroenterology, Cincinnati, OH: A. Safdi. California Research Foundation, San Diego, CA: B. Sahba. South Florida Center for Digestive Diseases, Miami, FL: H. Schwartz. Mid-Atlantic Medical Research Center, Hollywood, MD: U. Shah. Florida Medical Clinic, P.A., Zephyrhills, FL: D. Sikes. New Orleans Center for Clinical Research, New Orleans, LA: W. Smith. Clinical Interventions Research Institute, Mission Viejo, CA: D. Stanton. Northern California Medical Associates, Santa Rosa, CA: P. Stein. University of Louisville, Louisville, KY: S. Stern. Peninsula Gastroenterology Medical Group, Redwood City, CA: J. Torosis. Clinical Investigations Specialists, Inc., Little Rock, AK: L. Watkins. Mid-South Clinical Research Institute, Memphis, TN: L. Wruble. Physicians Quality Care Research, Baltimore, MD: T. Zizic.

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Alimentary TractA randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2–specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis☆,☆☆,★

Abstract

Section snippets

Patients

Results

Discussion

Acknowledgements

Gastrointest Endosc Clin North Am

J Biol Chem

Gastroenterology

Gastroenterology

Gastrointest Endosc

Clin Ther

Am J Gastroenterol

Am J Med

Gastroenterology

NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal

J Rheumatol

FDA arthritis advisory committee meeting: postmarketing surveillance of nonsteroidal antiinflammatory drugs

Ar thritis Rheum

Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid ar thritis receiving nonsteroidal anti-inflammatory drugs

Ann Intern Med

NSAID induced gastrointestinal complications: the ARAMIS perspective—1997

J Rheumatol

Nonsteroidal anti-inflammatory drugs and gastrointestinal disease

Adverse effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal system

Ann Clin Lab Sci

Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase

Proc Natl Acad Sci USA

A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors

Inflamm Res

Alimentary Tract
A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2–specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis☆,☆☆,★