Jeffrey R. Lisse, MD; Monica Perlman, MD, MPH; Gunnar Johansson, MD; James R. Shoemaker, DO; Joy Schechtman, DO; Carol S. Skalky, BA; Mary E. Dixon, BS; Adam B. Polis, MA; Arthur J. Mollen, DO; Gregory P. Geba, MD, MPH; for the ADVANTAGE Study Group*
Acknowledgments: The authors thank Drs. John Yates, Thomas Dobbins, Desmond Thompson, Richard Petruschke, Douglas Watson, and Walter Straus for reviewing this manuscript and for providing helpful comments. They also thank Dr. Nicholas Bellamy for providing the AUSCAN Osteoarthritis Hand Index and Drs. Thomas Schnitzer, Marc Hochberg, Arthur Weaver, Walter Straus, and Glenn Gormley for their input into study design. In addition, they gratefully acknowledge the contribution of Kathy O'Brien for assistance with manuscript preparation and for comonitoring this trial and Dr. Martino Laurenzi for comonitoring sites outside the United States.
Grant Support: By Merck & Co., Inc.
Potential Financial Conflicts of Interest: Employment: C.S. Skalky (Merck and Co., Inc.), M.E. Dixon (Merck and Co., Inc.), A.B. Polis (Merck and Co., Inc.), G.P. Geba (Merck and Co., Inc.); Consultancies: J.R. Lisse (Merck and Co., Inc.); Honoraria: J.R. Lisse (Merck and Co., Inc.); Stock ownership (other than mutual funds): C.S. Skalky (Merck and Co., Inc.), M.E. Dixon (Merck and Co., Inc.), A.B. Polis (Merck and Co., Inc.), G.P. Geba (Merck and Co., Inc.).
Requests for Single Reprints: Gregory P. Geba, MD, MPH, Merck & Co., Inc., HM-202, PO Box 4, West Point, PA 19486-0004; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Lisse: Department of Rheumatology, University of Arizona, 1501 North Campbell, Tuscon, AZ 85724.
Dr. Perlman: Scripps Clinic and Research Foundation, 10666 North Torrey Pines, La Jolla, CA 92037.
Dr. Johansson: Uppsala University, Nyby vrdcentral, Topeliusgatan 18, 754 41 Uppsala, Sweden.
Dr. Shoemaker: Ormond Medical Arts, 77 West Granada Boulevard, Ormond Beach, FL 32174.
Dr. Schechtman: Sun Valley Arthritis Center, Ltd., 6525 West Sack Drive, Glendale, AZ 85308.
Ms. Dixon: Merck & Co., Inc., HM-220, PO Box 4, West Point, PA 19486-0004.
Mr. Polis: Merck & Co., Inc., HM-601, PO Box 4, West Point, PA 19486-0004.
Dr. Mollen: Southwest Health Institute, 4602 North 16th Street, Phoenix, AZ 85016.
Ms. Skalky and Dr. Geba: Merck & Co., Inc., HM-202, PO Box 4,West Point, PA 19486-0004.
Author Contributions: Conception and design: G. Johansson, M.E. Dixon, A.B. Polis, G.P. Geba.
Analysis and interpretation of the data: J.R. Lisse, G. Johansson, C.S. Skalky, A.B. Polis, G.P. Geba.
Drafting of the article: G. Johansson, J. Schechtman, C.S. Skalky, G.P. Geba.
Critical revision of the article for important intellectual content: J.R. Lisse, M. Perlman, G. Johansson, J.R. Shoemaker, J. Schechtman, A.B. Polis, A.J. Mollen, G.P. Geba.
Final approval of the article: J.R. Lisse, M. Perlman, G. Johansson, J.R. Shoemaker, J. Schechtman, A.B. Polis, A.J. Mollen, G.P. Geba.
Provision of study materials or patients: J.R. Lisse, M. Perlman, G. Johansson, J. Schechtman, C.S. Skalky, M.E. Dixon, A.J. Mollen.
Statistical expertise: A.B. Polis, G.P. Geba.
Obtaining of funding: M.E. Dixon.
Administrative, technical, or logistic support: C.S. Skalky, M.E. Dixon.
Collection and assembly of data: G. Johansson, J.R. Shoemaker, C.S. Skalky, M.E. Dixon, A.J. Mollen.
Gastrointestinal (GI) toxicity mediated by dual cyclooxygenase (COX)-1 and COX-2 inhibition of nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious alterations of mucosal integrity or, more commonly, intolerable GI symptoms that may necessitate discontinuation of therapy. Unlike NSAIDs, rofecoxib targets only the COX-2 isoform.
To assess the tolerability of rofecoxib compared with naproxen for treatment of osteoarthritis.
Randomized, controlled trial.
600 office and clinical research sites.
5557 patients (mean age, 63 years) with a baseline diagnosis of osteoarthritis of the knee, hip, hand, or spine.
Rofecoxib, 25 mg/d, or naproxen, 500 mg twice daily. Use of routine medications, including aspirin, was permitted.
Discontinuation due to GI adverse events (primary end point) and use of concomitant medication to treat GI symptoms (secondary end point). Efficacy was determined by patient-reported global assessment of disease status and the Australian/Canadian Osteoarthritis Hand Index, as well as discontinuations due to lack of efficacy. Patients were evaluated at baseline and at weeks 6 and 12.
Rates of cumulative discontinuation due to GI adverse events were statistically significantly lower in the rofecoxib group than in the naproxen group (5.9% vs. 8.1%; relative risk, 0.74 [95% CI, 0.60 to 0.92]; P = 0.005), as were rates of cumulative use of medication to treat GI symptoms (9.1% vs. 11.2%; relative risk, 0.79 [CI, 0.66 to 0.96]; P = 0.014]). Subgroup analysis of patients who used low-dose aspirin (13%) and those who previously discontinued using arthritis medication because of GI symptoms (15%) demonstrated a relative risk similar to the overall sample for discontinuation due to GI adverse events (relative risk, 0.56 [CI, 0.31 to 1.01] and 0.53 [CI, 0.34 to 0.84], respectively). No statistically significant difference was observed between treatments for efficacy in treating osteoarthritis or for occurrence of other adverse events.
In patients with osteoarthritis treated for 12 weeks, rofecoxib, 25 mg/d, was as effective as naproxen, 500 mg twice daily, but had statistically significantly superior GI tolerability and led to less use of concomitant GI medications. Benefits of rofecoxib in subgroup analyses were consistent with findings in the overall sample.
*For members of the ADVANTAGE (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness) Study Group, see the Appendix.
Jeffrey R. Lisse, Monica Perlman, Gunnar Johansson, James R. Shoemaker, Joy Schechtman, Carol S. Skalky, et al. Gastrointestinal Tolerability and Effectiveness of Rofecoxib versus Naproxen in the Treatment of Osteoarthritis: A Randomized, Controlled Trial. Ann Intern Med. 2003;139:539–546. doi: 10.7326/0003-4819-139-7-200310070-00005
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Published: Ann Intern Med. 2003;139(7):539-546.
Gastroenterology/Hepatology, Osteoarthritis, Rheumatology.
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