Overall Study Question
Is treatment with celecoxib (200 mg po twice daily) inferior to combined therapy with diclofenac (75 mg po twice daily) and omeprazole (20 mg po daily) in reducing the risk of recurrent ulcer bleeding in H.pylori negative arthritis patients with endoscopically confirmed ulcers?
What was the declared relationship between authors and sponsors for this study?
The study was supported by research grants from the Chinese University of Hong Kong and the Health Services Research Committee of Hong Kong. Dr. Chan reports having received a consulting fee from Pfizer (maker of celecoxib). Dr. W.K. Leung reports having received a consulting fee from Novartis. None of the authors were industry employees.
Are the Results of the Study Valid?
1. Was assignment of patients randomized?
Yes. One hundred and forty-two patients were randomized to the celecoxib group; 143 patients were randomized to the diclofenac plus omeprazole group.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
Yes. Ninety-two percent of the patients in the two treatment groups took at least 70% of the study drugs. The rates of discontinuation of medications were similar in the two groups: 13.3% in the celecoxib group and 11.9% in the diclofenac-plus-omeprazole group.
3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Yes, although no formal assessment of blinding maintenance was reported.
4. Were the groups similar at the start of the trial?
The baseline characteristics of the groups appeared substantially similar. Notable differences existed in the use of low dose ASA at entry (6.2% celecoxib vs. 12.6% combination) and the proportion of patients with:
1) both gastric and duodenal bleeding ulcers at entry (4.2% celecoxib vs. 10.5% combination);
2) elevated serum creatinine (25.7% celecoxib vs. 18.9% combination); and
3) a requirement for blood transfusions to manage the initial bleeding episode (46.5% celecoxib vs. 37.8% combination).
5. Aside from the experimental intervention, were the groups treated equally?
What were the Results?
1. How large was the treatment effect?
The primary outcome variable (recurrent ulcer bleeding at six months) was observed in 4.9% of celecoxib patients versus 6.4% of patients receiving diclofenac plus omeprazole. Adverse effects included renal dysfunction (24.3% celecoxib vs. 30.8% combination), dyspepsia (15.3% celecoxib vs. 8.4% combination), medication discontinuation (4.9% celecoxib vs. 4.9% combination).
2. How precise was the estimate of the treatment effect?
For recurrent ulcer bleeding at six months, the 95% confidence intervals around the 1.5% absolute difference found were -6.8 to 3.8%. This means that the result found is consistent with celecoxib being up to 6.8% superior to diclofenac plus omeprazole through to diclofenac plus omeprazole being 3.8% superior to celecoxib for the endpoint of recurrent ulcer bleeding.
This trial was carefully designed as a “non-inferiority” trial, meaning that it was powered simply to show that celecoxib was not worse (defined as a absolute difference of 6% for this study) to a clinically meaningful degree than diclofenac plus omeprazole in terms of the primary endpoint. The difference that was found confirms this non-inferiority of celecoxib, and even suggests that celecoxib might be superior to the combination therapy.
Will the Results Help Me in Caring for My Patients?
1. Can the results be applied to my patient care?
Yes. This well-conducted trial is the first specific evidence that using celecoxib (or any COX-2 inhibitor) is a viable alternative to using the well-established combination of diclofenac plus proton pump inhibitor in arthritis patients who have already experienced a gastrointestinal (GI) bleed due to NSAID therapy. The drugs and dosages used in the combination therapy arm were consistent with those normally used in practice. The 400 mg/day of celecoxib used is the maximum recommended dose for any condition. This was appropriate since it purposely biases this study against the celecoxib arm. Despite this “rigging”, celecoxib was deemed non-inferior to diclofenac plus omeprazole, which strengthens the conclusion that celecoxib used in lower doses is probably not inferior to the combination therapy used.
2. Were all clinically important outcomes considered?
Generally speaking, yes. It would have been appropriate to combine the lower GI bleeding events in the overall analysis, since it is now clear that NSAIDs cause lower GI events as well.
3. Are the likely treatment benefits worth the potential harms and costs?
Probably. There appeared to be more renal toxicity in the combination therapy group (e.g. hypertension, peripheral edema, renal failure), but less dypepsia when compared to the celecoxib recipients. The drug cost of celecoxib may be less than diclofenac plus omeprazole, although the actual cost to the patient would be dependent upon their health insurance situation.
Following publication of the CLASS (2) and VIGOR (3) trials which showed very small absolute risk reductions for serious GI events with celecoxib and rofecoxib as compared to typical NSAIDs, many commentators and clinicians recommended that COX-2 inhibitors be reserved for patients at “high risk” of serious GI events, despite the lack of any clinical trial evidence demonstrating the safety of COX-2 inhibitors in such patients. Because of this, other clinicians preferred to simply add a proton pump inhibitor to the NSAID therapy to minimize the risk of recurrent GI events, a practice which is supported by the OMNIUM trial. (4) The prototypical “high risk” patient is one who has had a previous symptomatic ulcer or upper GI bleed on a typical NSAID.
This trial represents the first randomized trial evidence that using a COX-2 inhibitor is a reasonable alternative to using the more cumbersome, possibly more nephrotoxic, and sometimes more expensive combination of traditional NSAID plus proton pump inhibitor. The only real advantage to diclofenac plus omeprazole which surfaced in this trial was less dyspepsia, although the overall incidence was fairly low.
It is probable that these GI bleeding results can be extrapolated to other COX-2 inhibitors and other traditional NSAIDs in combination with other proton pump inhibitors when used at comparable doses. Of course, the cost and toxicity profiles of these other combinations may be different than those characterized in this trial.
It must be emphasized that NSAIDs (including COX-2 inhibitors) should only be used in high risk patients when no suitable alternatives exist, since the bleeding rates are unacceptably high, as evidenced in both groups in this trial. It is currently unknown whether combining COX-2 inhibitors with proton pump inhibitors would further reduce this risk.
Chan FK, Hung LC, Suen BY, Wu JC, Lee KC, Leung VK, Hui AJ, To KF, Leung WK, Wong VW, Chung SC, Sung JJ. 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.