The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019

Celecoxib and Diclofenac Plus Omeprazole are Similarly Effective in the Treatment of Arthritis in Patients at High GI Risk in the CONDOR Trial§



Herbert L. Kellner*, 1, Chunming Li2, Margaret N. Essex2
1 Division of Rheumatology, Center for Inflammatory Joint Diseases, Munich, Germany
2 Pfizer Inc, New York, NY, USA

Abstract

Objective:

Compare effectiveness of celecoxib versus diclofenac plus omeprazole in improving arthritis signs and symptoms in patients at high gastrointestinal (GI) risk who were enrolled in the CONDOR (Celecoxib vs Omeprazole and Diclofenac in Patients With Osteoarthritis and Rheumatoid Arthritis) trial.

Methods:

CONDOR was a 6-month, prospective, double-blind, triple-dummy, parallel-group, randomized, multicenter trial comparing celecoxib 200 mg twice daily versus diclofenac slow release (SR) 75 mg twice daily plus omeprazole 20 mg daily. Patients were Helicobacter pylori negative, had osteoarthritis (OA) or rheumatoid arthritis (RA), were aged ≥60 years, were with or without a history of gastroduodenal ulceration, or were ≥18 years with previous gastroduodenal ulceration. Patients’ Global Assessment of Arthritis was determined at each study visit.

Results:

A total of 4484 patients were randomized to treatment (2238 celecoxib, 2246 diclofenac SR) and included in the intention-to-treat analyses. Least squares mean (LSM) (standard error [SE]) for Patients’ Global Assessment of Arthritis was 3.219 (0.017) and 3.221 (0.017) at baseline for celecoxib and diclofenac SR (p=0.90). Improvement in both groups was similar in months 2, 4, and 6; at month 1 the LSM (SE) was 2.647 (0.017) and 2.586 (0.017) for celecoxib and diclofenac (p=0.0025). LSM difference (SE) from baseline to final visit demonstrated an improvement of 0.75 (0.02) in celecoxib-treated patients and 0.77 (0.02) in diclofenac SR-treated patients (p=0.42).

Conclusions:

Celecoxib and diclofenac plus omeprazole were shown to have similar efficacy in patients with OA and/or RA at increased GI risk who were enrolled in the CONDOR trial.

Trial Registry:

Trial was registered under ClinicalTrials.gov identifier NCT00141102.

Keywords: : Arthritis, GI, NSAIDs..


Article Information


Identifiers and Pagination:

Year: 2013
Volume: 7
First Page: 96
Last Page: 100
Publisher Id: TORJ-7-96
DOI: 10.2174/1874312901307010096

Article History:

Received Date: 19/3/2013
Revision Received Date: 9/9/2013
Acceptance Date: 14/9/2013
Electronic publication date: 13/11/2013
Collection year: 2013

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© Kellner et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Division of Rheumatology, Center for Inflammatory Joint Diseases, KH Neuwittelsbach, Romanstr. 9, 80639 München, Germany; Tel: 089 / 13 959-100; Fax: 089 / 13 959-102; E-mail: hk@prof-dr-kellner.de§ These data were presented at the European League Against Rheumatism annual congress, London, UK, 27 May 2011. Abstract No. FRI0125. Ann Rheum Dis 2011; 70(suppl 3): 386.





INTRODUCTION

Treatment goals in patients with arthritis focus on reducing pain and inflammation, and on improving functional activity [1Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand hip and knee. Arthritis Care Res 2012; 64(4): 465-74., 2Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010; 69(4): 631-7.]. Nonsteroidal anti-inflammatory drugs (NSAIDs), including nonselective NSAIDs and cyclooxygenase-2 (COX-2) selective NSAIDs, are used widely in the management of pain and inflammation associated with osteoarthritis (OA) and rheumatoid arthritis (RA) [3Dai C, Stafford RS, Alexander GC. National trends in cyclooxygenase-2 inhibitor use since market release: nonselective diffusion of a selectively cost-effective innovation. Arch Intern Med 2005; 165(2): 171-7.].

Although the efficacy of nonselective NSAIDs in arthritis is well established, use of these agents is associated with numerous adverse events, including upper and lower gastrointestinal (GI) toxicity [4Lanas A, Sopena F. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications. Gastroenterol Clin North Am 2009; 38(2): 333-52.-9Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343(8905): 1075-8.]. All prescription NSAIDs have the same warning for serious GI events from the US Food and Drug Administration [10U S Food and Drug Administration COX-2 selective (includes Bextra Celebrex and Vioxx) and non-selective non-steriodial anti-inflammatory drugs (NSAIDs) April 2005 US FDA website. Available at http://wwwfdagov/Drugs/DrugSafety/PostmarketDr ugSafetyInformationforPatientsandProviders/ucm103420htm Ac-cessed March 9 2012.]. Physicians are faced with a difficult clinical decision in selecting the best treatment option for individual patients, particularly those at high risk of GI events, that balances effectiveness against arthritis signs and symptoms alongside the potential for adverse events.

COX-2 selective NSAIDs were developed to potentially reduce the GI adverse events caused by nonselective NSAIDs [11Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition therapeutic challenges and opportunities. J Clin Invest 2006; 116(1): 4-15.] while retaining similar efficacy [12Laine L. The gastrointestinal effects of nonselective NSAIDs and COX-2-selective inhibitors. Semin Arthritis Rheum 2002; 32(3 )(Suppl 1 ): 25-32.]; several lines of evidence suggest that use of COX-2 selective NSAIDs may confer a reduced GI risk, particularly in the lower GI tract [13Goldstein JL, Eisen GM, Lewis B, et al. Small bowel mucosal injury is reduced in healthy subjects treated with celecoxib compared with ibuprofen plus omeprazole as assessed by video capsule endoscopy. Aliment Pharmacol Ther 2007; 25(10): 1211-22.-15Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG. Video capsule endoscopy to prospectively assess small bowel injury with celecoxib. naproxen plus omepraole.and placebo. Clin Gastroenterol Hepatol 2005; 3(2): 133-41.]. These observations have led to the publication of clinical guidelines that recommend the use of a nonselective NSAID plus a proton-pump inhibitor (PPI) or a COX-2 selective NSAID in patients with arthritis at risk of GI adverse events [1Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand hip and knee. Arthritis Care Res 2012; 64(4): 465-74., 16American College of Rheumatology Subcommittee on Osteoarthritis Guidelines.Recommendations for the medical management of osteoarthritis of the hip and knee 2000 update American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000; 43(9): 1905-5.-20Zhang W, Doherty M, Arden N, et al. EULAR evidence based recommendations for the management of hip osteoarthritis report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2005; 64(5): 669-81.].

However, while there are a limited number of studies comparing the efficacy and safety of celecoxib versus diclofenac [7Chan FK, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet 2010; 376(9736): 173-9., 21Emery P, Zeidler H, Kvien TK, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis randomised double-blind comparison. Lancet 1999; 354(9196): 2106-11.-25Chan FK, Hung LC, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002; 347(26): 2104-10.], there are very few studies in patients at high risk of GI adverse events. The CONDOR (Celecoxib versus Omeprazole and Diclofenac in Patients With Osteoarthritis and Rheumatoid Arthritis) trial, was the first prospective, large-scale clinical trial that showed that the risk of clinical outcomes across the entire GI tract was significantly reduced in patients with arthritis at high GI risk treated with celecoxib compared with those treated with diclofenac slow release (SR) plus omeprazole [7Chan FK, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet 2010; 376(9736): 173-9.]. Treatment efficacy of celecoxib versus diclofenac SR plus omeprazole was also determined as a secondary outcome [7Chan FK, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet 2010; 376(9736): 173-9.]. The aim of the present analysis was therefore to compare the effectiveness of celecoxib versus diclofenac plus omeprazole in improving arthritis signs and symptoms in patients at high GI risk who were enrolled in CONDOR.

METHODOLOGY

Patients and Study Design

CONDOR was a 6-month, prospective, double-blind, triple-dummy, parallel-group randomized trial conducted across 32 countries or territories. Patients with OA and/or RA with an increased risk of GI events were randomized 1:1 to receive either celecoxib 200 mg twice daily (bid) or diclofenac SR 75 mg bid plus omeprazole 20 mg once daily (qd) for 6 months. The detailed inclusion and exclusion criteria, study design, and methods have been published previously [7Chan FK, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet 2010; 376(9736): 173-9.] and are briefly discussed.

Patients with a clinical diagnosis of OA or RA were eligible for study entry if they were aged ≥60 years, with or without a history of gastroduodenal ulceration, or were aged ≥18 years and had documented evidence of gastroduodenal ulceration 90 days or more before screening. Patients also had to test negative for Helicobacter pylori at screening or have confirmed eradication of infection at a rescreening visit. Patients were excluded if they had a GI hemorrhage or active gastroduodenal ulceration within 90 days of screening and if they were concomitantly using antiplatelet (including aspirin) or anticoagulant therapy. Eligible patients were randomized to treatment at the baseline study visit and returned to the clinic at months 1, 2, 4, and 6 for assessments.

The study was conducted in accordance with Good Clinical Practice and the protocol was approved by local institutional review boards. All patients provided written informed consent.

Efficacy Assessments

The primary efficacy assessment was the Patients’ Global Assessment of Arthritis; this efficacy assessment provides good test-retest reliability in arthritis [26Rohekar G, Pope J. Test-retest reliability of patient global assessment and physician global assessment in rheumatoid arthritis. J Rheumatol 2009; 36(10): 2178-82.]. The Patients’ Global Assessment of Arthritis was determined at each study visit (screening, baseline, and months 1, 2, 4, and 6) by asking the following question: “Considering all the ways the OA or RA affects you, how are you doing today?” Patients rated their arthritis on a 5-point Likert scale, where 1 was very good and 5 very poor.

Statistical Analyses

All analyses in the study were based on the intention-to-treat (ITT) population (unless otherwise stated); the ITT population included all patients who were randomized to treatment. Baseline demographics and characteristics were summarized using descriptive statistics. Treatment comparisons based on the Patients’ Global Assessment of Arthritis were analyzed using a general linear model, including geographic region and history of gastroduodenal ulceration as fixed effects and Patients’ Global Assessment of Arthritis at baseline as a covariate. A last observation carried forward approach was applied to the final visit. Responses were also summarized by category and compared between treatment groups using a Cochran-Mantel-Haenszel (CMH) method. A p value <0.05 was considered statistically significant.

RESULTS

Patients

A total of 4484 patients were included in the ITT population (2238 celecoxib, 2246 diclofenac plus omeprazole). 1730 (77.3%) patients treated with celecoxib and 1621 (72.2%) patients treated with diclofenac SR plus omeprazole completed the study. Compliance with study medication was similar in both treatment groups (0.99 [0.03] celecoxib, 0.99 [0.05] diclofenac plus omeprazole).

The mean age of the study population was 65 years and the majority of patients were female (82%). There were no major differences between treatment groups with respect to demographic or baseline characteristics (Table 1). The majority of patients had a diagnosis of OA (84% [3774/4484] of patients versus 16% [710/4484] of patients with RA). The mean disease duration of OA was 7.6 years and 7.8 years in the celecoxib and diclofenac plus omeprazole groups, respectively. Mean disease duration of RA was 10.2 years for patients treated with celecoxib and 9.9 years for those treated with diclofenac plus omeprazole.

Table 1

Baseline Demographics and Characteristics in Patients with Arthritis Enrolled in the CONDOR Trial (ITT Population)




Table 2

Categorical Summary of Patients’ Global Assessment of Arthritis Scores in Patients Enrolled in the CONDOR Trial Receiving Celecoxib or Diclofenac Plus Omeprazole




Patients’ Global Assessment of Arthritis

Patients’ Global Assessment of Arthritis was similar between treatment groups at baseline, with a least squares mean (LSM) (standard error [SE]) of 3.219 (0.017) for the celecoxib group and 3.221 (0.017) for the diclofenac SR plus omeprazole group (p=0.90) (Fig. 1). Improvement in both treatment arms was similar in months 2, 4, and 6; at month 1 the LSM (SE) was 2.647 (0.017) and 2.586 (0.017) for celecoxib and diclofenac SR, respectively (p=0.0025). The LSM (SE) of Patients’ Global Assessment of Arthritis at final visit or early termination (last observation carried forward) was 2.474 (0.02) in the celecoxib group and 2.455 (0.02) in the diclofenac group.

Fig. (1)

Improvements in the least squares mean of the Patients’ Global Assessment of Arthritis from baseline to final visit or early termination in patients enrolled in the CONDOR study receiving celecoxib or diclofenac plus omeprazole



The LSM difference (SE) from baseline to last observation carried forward demonstrated an improvement of 0.75 (0.02) in celecoxib-treated patients and 0.77 (0.02) in diclofenac plus omeprazole–treated patients (p=0.42). These findings were reflected in the categorical summary of Patients’ Global Assessment of Arthritis score; compared with baseline, more patients scored their arthritis as good or very good following 6 months of treatment with celecoxib or diclofenac plus omeprazole (Table 2). There was no significant difference in the categorical summary of Patients’ Global Assessment of Arthritis score at the final visit between treatment groups using CMH (p=0.9053).

DISCUSSION

When considering appropriate NSAID treatment strategies for individuals with arthritis, physicians must balance the efficacy alongside safety of the NSAIDs. This secondary analysis of data from the CONDOR trial demonstrates that celecoxib and diclofenac SR plus omeprazole have comparable efficacy in patients with OA and RA who are at increased GI risk. Patients in both treatment groups experienced an improvement in arthritis during the 6 months of the study as evidenced by a reduction in scores on the Patients’ Global Assessment of Arthritis. Compared with baseline, more patients rated their arthritis as good or very good following 6 months of treatment with either intervention.

This study has shown that celecoxib and the non-selective NSAID diclofenac are equally efficacious in the treatment of OA and RA. These findings further support previous studies and meta-analyses in which celecoxib was consistently found to have similar efficacy to nonselective NSAIDs, including diclofenac and naproxen, in patients with OA or RA [21Emery P, Zeidler H, Kvien TK, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis randomised double-blind comparison. Lancet 1999; 354(9196): 2106-11., 24Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients. SUCCESS-I Study Am J Med 2006; 119(3): 255-66., 27Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib a cyclooxygenase-2 inhibitor a randomized controlled trial. Mayo Clin Proc 1999; 74(11): 1095-5.-30McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol 2001; 30(1): 11-8.].

It should be noted that the dose of celecoxib (200 mg bid) studied in the CONDOR trial is the maximum licensed dose for the treatment of OA and RA [31 Celebrex [package insert]. In: Inc New York NY: Pfizer 2013.], and, as such, may not accurately reflect the dose commonly used in current clinical practice. However, earlier studies assessing escalating doses of celecoxib indicate that 100-mg bid and 200-mg bid doses of celecoxib are similarly efficacious to one another and to nonselective NSAIDs in patients with OA or RA [27Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib a cyclooxygenase-2 inhibitor a randomized controlled trial. Mayo Clin Proc 1999; 74(11): 1095-5., 29Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999; 282(20): 1921-8.].

Data from the CONDOR trial have demonstrated that, in patients at high GI risk, celecoxib is as efficacious as diclofenac SR plus omeprazole in improving the signs and symptoms of arthritis but it is associated with significantly fewer GI events. COX-2 selective NSAIDs and nonselective NSAIDs remain an important component of the therapeutic armamentarium for arthritis, provided the relative benefits and risks are assessed in individual patients.

AUTHOR’S CONTRIBUTIONS

H.L. Kellner – conduct of study, analysis and interpretation of data, critical revision/drafting of the manuscript, final approval to submit.

C. Li – statistical analysis and interpretation, critical revision/drafting of the manuscript, final approval to submit.

M.N. Essex – analysis and interpretation of data, critical revision/drafting of the manuscript, final approval to submit.

CONFLICT OF INTEREST

H.L. Kellner – consultant/advisor for Pfizer and member of Pfizer’s speakers’ bureau.

C. Li – Pfizer Inc. full-time employee and shareholder.

M.N. Essex – Pfizer Inc. full-time employee and shareholder.

ACKNOWLEDGEMENTS

The study was sponsored by Pfizer Inc, New York, NY, USA. Editorial support was provided by K. Bradford, PhD, and C. Campbell, PhD, of PAREXEL, UK and was funded by Pfizer Inc.

REFERENCES

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[2] Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010; 69(4): 631-7.
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[25] Chan FK, Hung LC, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002; 347(26): 2104-10.
[26] Rohekar G, Pope J. Test-retest reliability of patient global assessment and physician global assessment in rheumatoid arthritis. J Rheumatol 2009; 36(10): 2178-82.
[27] Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib a cyclooxygenase-2 inhibitor a randomized controlled trial. Mayo Clin Proc 1999; 74(11): 1095-5.
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[29] Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999; 282(20): 1921-8.
[30] McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol 2001; 30(1): 11-8.
[31] Celebrex [package insert]. In: Inc New York NY: Pfizer 2013.

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"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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