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Therapeutics

Celecoxib was as effective as diclofenac plus omeprazole in reducing recurrent ulcer bleeding in arthritis

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ACP J Club. 2003 Jul-Aug;139:12. doi:10.7326/ACPJC-2003-139-1-012


Clinical Impact Ratings

GIM/FP/GP: 5 stars

Rheumatology: 5 stars


Source Citation

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;347:2104-10. [PubMed ID: 12501222] (All 2003 articles were reviewed for relevancy, and abstracts were last revised in 2009.)


Abstract

Question

In patients with arthritis at high risk for ulcer bleeding, is celecoxib noninferior (i.e., similar) to diclofenac plus omeprazole in reducing the risk for recurrent ulcer bleeding?

Design

Randomized {allocation concealed*}†, blinded {clinicians, patients, outcome assessors, data collectors, and data analysts}†,* controlled trial with 6-month follow-up.

Setting

The Endoscopy Center of the Prince of Wales Hospital in Hong Kong, China.

Patients

290 patients who had rheumatoid arthritis, osteoarthritis, or other forms of arthritis; confirmed ulcer healing; a negative test result for Helicobacter pylori or successful eradication of H. pylori; and anticipated regular use of nonsteroidal antiinflammatory drugs (NSAIDs) during the trial. Exclusion criteria were concomitant use of anticoagulant agents or corticosteroids, gastric or duodenal surgery other than a patch repair, erosive esophagitis, gastric-outlet obstruction, renal failure, terminal illness, or cancer. 287 patients (99%) (mean age 68 y, 56% women) were included in the analysis.

Intervention

Patients were allocated to celecoxib, 200 mg twice daily, plus omeprazole placebo daily (n = 144) or extended-release diclofenac, 75 mg twice daily, plus omeprazole, 20 mg daily (n = 143) for 6 months. Patients were permitted to take antacids, acetaminophen or other non-NSAID analgesics, and disease-modifying antirheumatic drugs.

Main outcome measures

Recurrent ulcer bleeding (hematemesis or melena with ulcers [a circumscribed mucosal break ≥ 0.5 cm in diameter with a perceptible depth] or bleeding erosions [a flat mucosal break of any size that occurred in the presence of blood in the stomach] confirmed by endoscopy, or a decrease in the hemoglobin level ≥ 2 g/dL in the presence of endoscopically proven ulcers or bleeding erosions). Secondary endpoints were efficacy (patients’ assessment of global disease activity and arthritis pain); recurrent ulcer bleeding if not taking low-dose aspirin (≤ 325 mg/d); and other adverse gastrointestinal, renal, and cardiovascular events.

Main results

Analysis was by intention to treat. The groups did not differ for recurrent ulcer bleeding (Table) or for any of the secondary endpoints.

Conclusion

In patients with arthritis at high risk for ulcer bleeding, celecoxib was noninferior to diclofenac plus omeprazole in reducing the risk for recurrent ulcer bleeding.

*See Glossary.

†Information provided by author.

Sources of funding: Chinese University of Hong Kong and Health Services Research Committee of Hong Kong.

For correspondence: Dr. F.K. Chan, Prince of Wales Hospital, Hong Kong, China. E-mail fklchan@cuhk.edu.hk.


Table. Celecoxib vs diclofenac plus omeprazole for arthritis at 6 months‡

Outcome Celecoxib Diclofenac plus omeprazole Difference (95% CI)
Recurrent ulcer bleeding 4.9% 6.4% −1.5% (−6.8 to 3.8)

‡CI defined in Glossary; difference is not statistically significant.


Revised Commentary 2009

Serious upper gastrointestinal (GI) complications, such as bleeding or perforation, occur in about 1% to 1.5% of NSAID users annually. Previous GI events, older age, and steroid or warfarin use can substantially increase this risk. Furthermore, serious lower GI events occur at an annual incidence of ≤ 0.9.

2 strategies are commonly used to decrease complications, especially in high-risk patients: use of COX-2 specific inhibitors (coxibs) or co-therapy with proton-pump inhibitors (PPIs). Compared with standard NSAIDs, coxibs have been shown to decrease upper and lower GI complications and ulcer development (1, 2). Once-daily PPI co-therapy also decreases endoscopic ulcers. 2 randomized trials have shown that PPIs decrease recurrent ulcer bleeding in patients taking nonselective NSAIDs (3, 4).

The well-executed study by Chan and colleagues is the first to compare these 2 strategies. At first glance, the difference of only 1.5% between the 2 groups suggests that they are similar. However, in a noninferiority or equivalence study, the 95% CI of the difference should be carefully examined. The results are consistent with a relatively wide range of outcomes, from the coxibs being 7% better to PPI co-therapy being 4% better. The authors defined noninferiority as an absolute difference < 6% in rebleeding between therapies, but many clinicians would not consider this difference an indicator of equivalence or noninferiority when the rebleeding rate itself is 5% to 6%.

A subsequent study (Lai), with a similar objective, population, and design, also showed no significant difference between a coxib and a traditional NSAID plus a PPI, but a relatively high rate of recurrent ulcer complications was found in both groups (~4% to 6% at 24 wk median follow-up).

Other factors to consider when choosing a therapy include cost, whether PPIs are already prescribed (e.g., for reflux), the fact that PPIs decrease upper GI symptoms and coxibs decrease lower GI complications, and that compliance may be better with 1 medication (coxib) rather than 2 (PPIs plus NSAIDs). Cardiovascular risk should also be considered when prescribing these medications. Coxibs have been documented to increase risk for cardiovascular events such as myocardial infarction, although nonselective NSAIDs, with the probable exception of naproxen, also appear to increase cardiovascular risk (Kearney).

In the study by Chan and colleagues, the rebleeding rate at 6 months (5% to 6%) suggests that neither strategy alone is adequate in very high-risk patients. For these patients, I recommend a coxib plus a PPI. This recommendation is supported by a randomized trial showing that combination PPI plus coxib led to significantly less recurrent ulcer bleeding than coxib alone in NSAID users who had recently presented with a bleeding ulcer (Chan).

Loren Laine, MD
University of Southern California
Los Angeles, California, USA


References

1. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343:1520-8. [PubMed ID: 11087881]

2. Laine L, Connors LG, Reicin A, et al. Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. Gastroenterology. 2003;124:288-92. [PubMed ID: 12557133]

3. Chan FK, Chung SC, Suen BY, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med. 2001;344:967-73. [PubMed ID: 11274623]

4. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med. 2002;346:2033-8. [PubMed ID: 12087138]

1. Lai KC, Chu KM, Hui WM, et al. Celecoxib compared with lansoprazole and naproxen to prevent gastrointestinal ulcer complications. Am J Med. 2005;118:1271-8. [PubMed ID: 16271912]

2. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomized trials. BMJ. 2006;332:1302-8. [PubMed ID: 16740558]

3. Chan FK, Wong VW, Suen BY, et al. Combination of cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet. 2007;369:1621-6. [PubMed ID: 17499604]