Patient-level pooled analysis of adjudicated gastrointestinal outcomes in celecoxib clinical trials: meta-analysis of 51,000 patients enrolled in 52 randomized trials

Abstract

Introduction: Although the safety of celecoxib has been investigated, limited data are available on complications affecting the entire (upper and lower) gastrointestinal (GI) tract, with no patient-level pooled analyses of upper and lower GI outcomes available. We therefore evaluated the upper and lower GI safety of celecoxib by using patient-level data from randomized controlled trials (RCTs).

Methods: This patient-level pooled analysis included 52 prospective, randomized, double-blind parallel-group studies from the Celecoxib Clinical Database. Each study had a planned duration of continuous treatment with celecoxib or a nonselective nonsteroidal antiinflammatory drug (nsNSAID), rofecoxib, or the placebo comparator arm for at least 4 weeks. All studies with final reports completed by 1 October 2007 were included. The primary end point was the combined incidence of clinically significant upper and lower GI events (CSULGIEs). An independent blinded committee reviewed and adjudicated all end points by using predefined criteria and all available reported adverse events, laboratory data, and case narratives. All doses of celecoxib and all doses of all nsNSAIDs were pooled for analysis.

Results: The pooled analysis involved 51,048 patients; 28,614 were randomized to celecoxib; 15,278 to nsNSAIDs (including 3,248 patients taking naproxen, 2,640 taking ibuprofen, 8,066 taking diclofenac, 1,234 taking loxoprofen, and 90 taking ketoprofen); 5,827 to placebo and 1,329 to rofecoxib. The mean age was 60 years, and 65% were women. Data on 1,042 patients with potential GI events were reviewed for end-points adjudication; the adjudication committee confirmed 89 patients with CSULGIEs. The majority were in the celecoxib and nsNSAID groups (with raw incidence proportions of 37 (0.1%) and 40 (0.3%), respectively). The incidence rates were 0.3, 0.9 and 0.3 per 100 patient-years in the celecoxib, nsNSAID, and placebo groups, respectively. The time to incidence of CSULGIEs was significantly longer with celecoxib than with nsNSAIDs (P=0.0004).

Conclusions: When compared with nsNSAIDs, celecoxib is associated with a significantly lower risk of all clinically significant GI events throughout the entire GI tract. This pooled analysis of 52 RCTs significantly advances the understanding of the upper and lower GI safety profile of celecoxib and its potential benefits to patients.

Figure 1

Incidence of CSULGIEs. AEs, adverse events; CSULGIEs, clinically significant upper and lower GI events; GI, gastrointestinal; nsNSAID, nonselective nonsteroidal antiinflammatory drug.

Figure 2

Incidence rate (per 100 patient-years) of CSULGIEs. Hb, hemoglobin; nsNSAID, nonselective nonsteroidal antiinflammatory drug; SU, symptomatic ulcer.

Figure 3

Kaplan-Meier plot of time to incidence of CSULGIEs. nsNSAID, nonselective nonsteroidal antiinflammatory drug.

Figure 4

CSULGIE incidence rates in the meta-analysis and subsequent large RCTs. *Incidence rate based on 100 patient-years of exposure to drug. CONDOR, Celecoxib vs Omeprazole and Diclofenac in Patients with Osteoarthritis and Rheumatoid Arthritis study; GI-REASONS, Gastrointestinal Randomized Event And Safety Open-Label NSAID Study; nsNSAID, nonselective nonsteroidal antiinflammatory drug.