Gastrointestinal Side Effects of Etoricoxib in Patients with Osteoarthritis: Results of the Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) Trial HERBERT S.B. BARAF, CARLOS FUENTEALBA, MARIA GREENWALD, JAN BRZEZICKI, KATHERINE O’BRIEN, BETH SOFFER, ADAM POLIS, STEVEN BIRD, AMARJOT KAUR, and SEAN P. CURTIS, for the EDGE Study Group ABSTRACT. Objective. To compare the gastrointestinal (GI) tolerability, safety, and efficacy of etoricoxib and diclofenac in patients with osteoarthritis (OA). Methods. In total, 7111 patients (mean age 64 yrs) diagnosed with OA were enrolled in a randomized, double-blind trial. Patients received etoricoxib 90 mg qd (n = 3593) or diclofenac sodium 50 mg tid (n = 3518). Gastroprotective agents and low-dose aspirin were prescribed per treatment guidelines. The primary endpoint was the cumulative rate of discontinuations due to clinical and laboratory GI adverse experiences (AE). General safety was assessed, including adjudication of thrombotic cardiovascular (CV) safety data. Efficacy was evaluated using the least-square (LS) mean change from baseline patient global assessment of disease status (PGADS; 0–4 point scale). Results. Mean (SD, maximum) duration of treatment was 9.3 (4.4, 16.5) and 8.9 (4.5, 16.6) months in the etoricoxib and diclofenac groups, respectively. The cumulative discontinuation rate due to GI AE was significantly lower with etoricoxib than diclofenac [9.4 vs 19.2 events per 100 patient-years (PY), respectively; hazard ratio (HR) 0.50 (95% CI 0.43, 0.58; p < 0.001). Rates of thrombotic CV events were similar with etoricoxib and diclofenac [1.25 vs 1.15 events per 100 PY, respectively; HR 1.07 (95% CI 0.65, 1.74)]. The incidence of patients who discontinued due to hypertension-related AE was significantly higher with etoricoxib compared to diclofenac (2.3% vs 0.7%; p < 0.001), although few AE were severe (3 etoricoxib, 1 diclofenac). Etoricoxib and diclofenac treatment resulted in similar improvements in PGADS from baseline of –0.78 (95% CI –0.80, –0.75) and –0.75 (95% CI –0.77, –0.72), respectively. Conclusion. Treatment with etoricoxib 90 mg was associated with significantly better GI tolerability compared to diclofenac in this population of patients with OA. Etoricoxib 90 mg, a dose 50% higher than indicated for OA, resulted in more discontinuations due to hypertension-related AE. (J Rheumatol 2007;34:408–20) Key Indexing Terms: ETORICOXIB DICLOFENAC OSTEOARTHRITIS GASTROINTESTINAL TOLERABILITY Osteoarthritis (OA) is one of the most common disabilities year 20201. The primary objective of treatment for patients present in the elderly population and is projected to be the with OA is to manage symptoms, including pain and inflam- fourth leading cause of disability on a worldwide basis by the mation, and to improve quality of life2,3. For patients who From the Center for Rheumatology and Bone Research, Wheaton, Merck & Co., Ortho-McNeill, Pfizer, Procter and Gamble, Roche, Wyeth, Maryland, USA; Hospital San Borja Arriarán, Santiago, Chile; Desert and Zelos Therapeutics. J. Brzezicki has received research support from Medical Advances, Palm Desert, California, USA; Oddzial Reumatologii and served as a speaker and consultant for Merck & Co. K. O’Brien, – Wojewodzki Szpital Zespolony, Elblag, Poland; and Merck & Co., Inc., B. Soffer, A. Polis, S. Bird, A. Kaur, and S.P. Curtis are employees of West Point, Pennsylvania, and Rahway, New Jersey, USA. Merck & Co. and own stock and/or hold stock options in the Company. Supported by Merck & Co., Inc., Whitehouse Station, NJ, USA. Clinical H.S.B. Baraf, MD, The Center for Rheumatology and Bone Research; study protocol registered at http://www.clinicaltrials.gov/ct/show/ C. Fuentealba, MD, Hospital San Borja Arriarán; M. Greenwald, MD, NCT00092703. H.S.B. Baraf serves as a consultant for Merck & Co. and Desert Medical Advances; J. Brzezicki, MD, Oddzial Reumatologii– Savient Pharmaceuticals. He has received research grant support from Wojewodzki Szpital Zespolony; K. O’Brien, BS; B. Soffer, BA, Med, RA; Merck & Co., Pfizer, Amgen, Centocor, Abbott Laboratories, TAP A. Polis, MA; S. Bird, MS; A. Kaur, PhD; S.P. Curtis, MD, Merck & Co., Pharmaceutical Products, GlaxoSmithKline, Sanofi-Aventis, and Savient Inc. Pharmaceuticals. He has served as a speaker for Merck & Co., Pfizer, Address reprint requests to Dr. H.S.B. Baraf, The Center for Amgen, Centocor, Abbott, and TAP Pharmaceutical Products. C. Rheumatology and Bone Research, 2730 University Boulevard West, Suite Fuentealba has received research support from and served as a speaker 306, Wheaton, MD 20902, USA, E-mail: [email protected] for Merck & Co. M. Greenwald has received research support from Abbott Laboratories, Allelix, Amgen, Sanofi-Aventis, Biogen Idec, Bristol-Myers Accepted for publication August 23, 2006. Squibb, Boehringer Mannheim, Genentech, GlaxoSmithKline, Eli Lilly, Personal non-commercial use only. The Journal of Rheumatology Copyright © 2007. All rights reserved. 408 The Journal of Rheumatology 2007; 34:2 Downloaded on September 30, 2021 from www.jrheum.org require effective pain and symptom relief, nonsteroidal antiin- malignancy within the past 5 years that had not been successfully treated; flammatory drugs (NSAID) are often prescribed. Lack of effi- required therapy with warfarin, heparin, high-dose aspirin (> 100 mg/day), nonstudy NSAID or coxib, or the combination of ticlopidine or clopidogrel cacy is the leading cause for switching treatment to other 4 plus low-dose aspirin; or allergy or hypersensitivity to aspirin, other tradi- members of the NSAID class . The use of traditional NSAID tional NSAID, or coxibs. In addition, patients who used H2-receptor antago- can be limited due to their inherent toxicity to the upper and nists, antacids, or proton pump inhibitors at prescription or over-the-counter lower gastrointestinal (GI) tract5,6. Specifically, use of tradi- doses for more than 4 consecutive days within 1 month prior to the screening tional NSAID is associated with upper GI intolerance (often visit were excluded. Patients were also excluded who used misoprostol or sucralfate within 3 days prior to study start. characterized under the general term of dyspepsia), which is Study design. This was a randomized, double-blind, active-comparator-con- not necessarily related to GI mucosal injury or serious upper 7-9 trolled, multicenter study (Sponsor protocol number 061) to compare the GI GI events (i.e., perforations, ulcers, or bleeds) . Dyspeptic tolerability of etoricoxib and diclofenac. The EDGE trial is a component of symptoms can occur in a significant proportion (~25%) of the larger MEDAL Program, which consists of 3 studies: EDGE; EDGE II 19 patients being treated with traditional NSAID7. Patients expe- (NCT00250445); and MEDAL (NCT00092742) . The trial was designed to riencing GI symptoms may be prescribed gastroprotective run for about 18 months with an enrollment period of about 5 months. Based on the predefined end-of-study period for all patients and time between agents (GPA) to alleviate their symptoms, or may discontinue 10,11 screening and enrollment, the maximum duration of treatment for a patient and/or switch treatment . Hepatotoxicity due to NSAID could range from 11 to 16 months. therapy occurs at a much lower rate than dyspeptic symptoms, Following screening, patients discontinued their prestudy OA medication but is also associated with treatment switching12. and returned to the clinical research center within 2 to 10 days. Patients who Selective inhibitors of COX-2 (coxibs) such as etoricoxib completed this prestudy washout period were stratified according to low-dose aspirin use and randomized using a computer-generated randomization sched- were developed to reduce the risk of GI adverse experiences ule, in a 1:1 ratio, to etoricoxib 90 mg qd or diclofenac sodium 50 mg tid. 13,14 (AE) . A combined analysis of 9 randomized, double- Study medication was supplied in 2 coded study bottles, labeled bottle A (con- blind, efficacy studies of the coxib etoricoxib, across its devel- taining etoricoxib 90 mg tablets or matching placebo) and bottle B (contain- opment program, suggested reduced rates of discontinuation ing diclofenac sodium 50 mg tablets or matching placebo). Patients were instructed to take one tablet in the morning from bottles A and B and one of etoricoxib or of GPA use due to dyspeptic symptoms dur- tablet in the afternoon and evening from bottle B. Acetaminophen (up to 2600 ing the first 6 months of use compared to traditional mg per day) served as rescue pain medication. If acetaminophen failed, non- 15,16 NSAID . To further evaluate this, our current study was aspirin, non-NSAID analgesic alternatives (e.g., narcotic analgesic) could be designed with the primary objective of evaluating the GI “tol- taken for a maximum of 3 doses per day for up to 7 days per month. erability” of etoricoxib 90 mg qd compared to diclofenac 50 Safety and efficacy data were collected during clinic visits (screening, randomization, and at 1, 4, 8, and 12 months of therapy, and at end of study). mg tid, in patients with OA, using the primary endpoint of The investigators identified and evaluated AE based on patient reports, phys- treatment discontinuations due to clinical and laboratory GI ical examination, and laboratory assessments. Telephone contacts to monitor AE. GI tolerability was assessed by determining the rates of compliance and facilitate patient retention occurred monthly between visits treatment discontinuation arising from the development of the (Months 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, and 16 for patients remaining in the study). Pill counts furnished a measure of compliance. Patients contacted GI signs, symptoms, or laboratory abnormalities associated the investigator if they desired to discontinue treatment, or an investigator with NSAID use. The trial was not designed to formally test could recommend discontinuation. Study sites contacted patients who dis- treatment differences related to GI safety (i.e., rates of perfo- continued early by telephone every 4 months, at 12 months, and at the prede- rations, ulcers, or bleeds).