Elsevier

The Lancet

Volume 376, Issue 9736, 17–23 July 2010, Pages 173-179
The Lancet

Articles
Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial

https://doi.org/10.1016/S0140-6736(10)60673-3Get rights and content

Summary

Background

Cyclo-oxygenase (COX)-2-selective non-steroidal anti-inflammatory drugs (NSAIDs) and non-selective NSAIDs plus a proton-pump inhibitor (PPI) have similar upper gastrointestinal outcomes, but risk of clinical outcomes across the entire gastrointestinal tract might be lower with selective drugs than with non-selective drugs. We aimed to compare risk of gastrointestinal events associated with celecoxib versus diclofenac slow release plus omeprazole.

Methods

We undertook a 6-month, double-blind, randomised trial in patients with osteoarthritis or rheumatoid arthritis at increased gastrointestinal risk at 196 centres in 32 countries or territories. Patients tested negative for Helicobacter pylori and were aged 60 years and older or 18 years and older with previous gastroduodenal ulceration. We used a computer-generated randomisation schedule to assign patients in a 1:1 ratio to receive celecoxib 200 mg twice a day or diclofenac slow release 75 mg twice a day plus omeprazole 20 mg once a day. Patients and investigators were masked to treatment allocation. The primary endpoint was a composite of clinically significant upper or lower gastrointestinal events adjudicated by an independent committee. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00141102.

Findings

4484 patients were randomly allocated to treatment (2238 celecoxib; 2246 diclofenac plus omeprazole) and were included in intention-to-treat analyses. 20 (0·9%) patients receiving celecoxib and 81 (3·8%) receiving diclofenac plus omeprazole met criteria for the primary endpoint (hazard ratio 4·3, 95% CI 2·6–7·0; p<0·0001). 114 (6%) patients taking celecoxib versus 167 (8%) taking diclofenac plus omeprazole withdrew early because of gastrointestinal adverse events (p=0·0006).

Interpretation

Risk of clinical outcomes throughout the gastrointestinal tract was lower in patients treated with a COX-2-selective NSAID than in those receiving a non-selective NSAID plus a PPI. These findings should encourage review of approaches to reduce risk of NSAID treatment.

Funding

Pfizer Inc.

Introduction

Present approaches to reduce risk of upper gastrointestinal adverse events associated with non-steroidal anti-inflammatory drugs (NSAIDs) recommend use of a non-selective NSAID plus a proton-pump inhibitor (PPI) or a cyclo-oxygenase (COX)-2 selective NSAID alone.1, 2, 3 Although these guidelines, which are based on previous work by ourselves and others,4, 5, 6, 7 suggest that both strategies reduce risk to the upper gastrointestinal tract, they do not address gastrointestinal adverse events originating beyond the duodenum. Although NSAID use is associated with injury to the small bowel and colon,4, 8, 9, 10 leading to overt bleeding, ulceration, occult blood loss, or development of anaemia, evidence suggests that COX-2 selective NSAIDs are associated with fewer mucosal lesions of the small bowel than are non-selective NSAIDs plus a PPI.11, 12 Prespecified prospective trials directly comparing clinically relevant sequelae of these strategies throughout the gastrointestinal tract are not available.

To address the absence of a comprehensive yet clinically practical endpoint, we proposed a composite endpoint of clinically significant events throughout the gastrointestinal tract (referred to in the protocol as clinically significant upper or lower gastrointestinal events) as a common platform for comparison of future clinical trials of gastrointestinal safety.13 This endpoint was designed to assess several potential outcomes relevant to clinical practice, ranging from discontinuation of treatment due to presumed significant occult blood loss to admission to hospital for life-threatening complications. We also included presumed significant occult gastrointestinal blood loss in the definition of the endpoint because this outcome is relevant in view of the number of patients at risk and the potential downstream clinical implications and economic effect.

Since damage to the small bowel and colon is not acid-dependent,14, 15 we postulated that the risk of clinical outcomes across the entire gastrointestinal tract associated with celecoxib would be lower than that associated with diclofenac plus omeprazole. To address this hypothesis, we aimed to compare treatment with celecoxib and diclofenac plus omeprazole in patients with osteoarthritis and rheumatoid arthritis at increased gastrointestinal risk.

Section snippets

Study design and patients

We undertook a double-blind, triple-dummy, parallel-group randomised trial at 196 active (having recruited more than one patient) centres in 32 countries or territories. One site was excluded because it did not comply with International Conference on Harmonisation Good Clinical Practice guidelines. The protocol was approved by local institutional review boards; all participants provided written informed consent.

Patients with a clinical diagnosis of osteoarthritis or rheumatoid arthritis were

Results

Between Oct 31, 2005, and May 11, 2009, 8098 potentially eligible patients were screened; 4484 patients were enrolled and were included in intention-to-treat analyses (2238 celecoxib, 2246 diclofenac plus omeprazole; figure 1, table 1). Predominant reasons for screening failure were H pylori infection (2476 patients, 75%) and low baseline haemoglobin (217, 6%). 876 patients initially infected with H pylori were successfully treated and then randomly allocated to celecoxib (444, 51%) and

Discussion

In this population of patients with osteoarthritis or rheumatoid arthritis who were not using antiplatelet and anticoagulant drugs, the rate of clinically significant gastrointestinal events was four times higher in those receiving diclofenac plus omeprazole than in those receiving celecoxib. As in our previous trial, rates of upper gastrointestinal bleeding did not differ between treatment groups.4 However, we noted large differences for the likelihood of clinically significant blood loss from

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