ArticlesCombination of a 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
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) can induce ulcer complications such as bleeding and perforation that remain an important cause of hospital admissions and death worldwide. NSAIDs are thought to cause at least 7000 deaths every year in the USA1 and 1000 deaths every year in the UK in those aged 60 years or older.2 Patients with a history of ulcer bleeding are at the highest risk of NSAID-induced ulcer complications.3 We previously reported that about 19% of patients with a history of ulcer bleeding who took the NSAID naproxen developed recurrent bleeding within 6 months.4 Prophylaxis with a proton-pump inhibitor (PPI)4, 5, 6 or substitution of NSAIDs with a selective inhibitor of cyclo-oxygenase-2 (COX 2)7, 8, 9 reduces the risk of ulcer complications. The American College of Rheumatology guidelines for the management of osteoarthritis and an international working group on pain management recommend use of COX 2 inhibitors or the combination of NSAIDs and a PPI in patients at risk of ulcers whose symptoms cannot be relieved by simple analgesics.10, 11
However, emerging data suggest that these recommendations do not adequately protect patients at very high risk of gastrointestinal problems. In a randomised trial of patients who had had previous NSAID-induced ulcer bleeding, the COX 2 inhibitor celecoxib was shown to be as effective as a combination of the NSAID diclofenac and the PPI omeprazole for prevention of recurrent ulcer bleeding.12 However, about 5% of patients in either treatment group still had recurrent bleeding within 6 months.12 The rate of recurrent endoscopic or complicated ulcers was unacceptably high with either treatment in patients with previous ulcer bleeding; one study reported that the 6-month incidence of recurrent endoscopic ulcers was 18·7% with a COX 2 inhibitor and 25·6% with NSAIDs and a PPI.13 In another study, the 6-month incidence of recurrent complicated ulcers was 3·7% with celecoxib and 6·3% with NSAIDs and a PPI.14 Thus, neither a COX 2 inhibitor nor non-selective NSAIDs plus a PPI seem to be effective when used as a stand-alone strategy in patients at very high gastrointestinal risk.15, 16
Might a COX 2 inhibitor combined with a PPI provide the best protection in patients at very high gastrointestinal risk?17, 18 A 6-month endoscopic study showed that PPIs reduced the rate of ulcers in long-term users of NSAIDs, including a subgroup of patients given COX 2 inhibitors.19 However, that study was not randomised and was not powered to assess whether a COX 2 inhibitor with a PPI provided greater gastrointestinal protection than a non-selective NSAID with a PPI. No randomised gastrointestinal outcome trials have yet been designed to assess the benefit of combined treatment with a COX 2 inhibitor and a PPI. We aimed to test the hypothesis that combined treatment with celecoxib and esomeprazole would be better than celecoxib alone for prevention of recurrent ulcer bleeding in patients with previous NSAID-induced ulcer bleeding who continued to need anti-inflammatory analgesics.
Section snippets
Patients
Our single-centre, prospective, randomised, double-blind trial was based at the Prince of Wales Hospital in Hong Kong. The hospital's ethics committee approved the protocol. All patients gave written informed consent. We screened 441 patients who presented consecutively to the hospital with upper-gastrointestinal bleeding and were taking non-selective NSAIDs for arthritis. Endoscopy was used to confirm ulcer bleeding. Patients with Helicobacter pylori infection were given 1 week of a PPI-based
Results
Between August, 2002, and August, 2004, we screened 441 patients who had ulcer bleeding while taking non-selective NSAIDs. 273 patients were eligible for the intention-to-treat analysis: 137 were randomly assigned to a combined-treatment group, and 136 to a control group (figure 1). Table 1 shows demographic variables at baseline for the two groups. The median follow-up time was 13 months in both groups (range 0·4–13·0). Similar numbers in the combined-treatment group (129, 94%) and the control
Discussion
All patients enrolled in this study had a recent history of ulcer bleeding. Most also had additional risk factors such as old age and comorbid illnesses. None of these patients at very high risk for ulcer bleeding, who were assigned celecoxib plus esomeprazole had recurrent ulcer bleeding for 13 months, compared with 12 (8·9%) of patients given celecoxib alone. Our finding suggests that combination of a COX 2 inhibitor and a PPI is effective for prevention of recurrent ulcer bleeding in
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