The hepatic safety and tolerability of the cyclooxygenase-2 selective NSAID celecoxib: pooled analysis of 41 randomized controlled trials

ABSTRACT

Objective: To assess the hepatic safety and tolerability of celecoxib versus placebo and three commonly prescribed nonselective nonsteroidal anti-inflammatory drugs (NSAIDs).

Research design and methods: This was a retrospective, pooled analysis of a 41-study dataset involving patients with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, chronic low back pain, and Alzheimer's disease. Criteria for selection of studies were:

(1) Randomized, parallel-group design and planned treatment duration of ≥2 weeks

(2) ≥1 placebo or NSAID comparator

(3) ≥1 arm with celecoxib at total daily dose of ≥200 mg

(4) Data available as of October 31, 2004

Data were pooled by treatment and subject from the safety analysis population of included studies. Treatment-emergent hepatobiliary adverse events (AEs) were compared for celecoxib <200 mg/day (943 patients), 200 mg/day (12 008 patients), 400 mg/day (7380 patients), and 800 mg/day (4602 patients); placebo (4057 patients); diclofenac 100–150 mg/day (7639 patients); naproxen 1000 mg/day (2953 patients); and ibuprofen 2400 mg/day (2484 patients). Hepatobiliary laboratory abnormalities were also analyzed.

Results: There were no cases of liver failure, treatment-related liver transplant, or treatment-related hepatobiliary death. Incidence of serious hepatic AEs was low, with 13 (0.05%) serious hepatic AEs among 24 933 celecoxib-treated patients, and 16 (0.21%) among 7639 diclofenac-treated patients. No patients receiving celecoxib or any nonselective NSAID met criteria for Hy's rule (alanine aminotransferase [ALT] ≥3 × upper limit of normal [ULN] with bilirubin ≥2 × ULN). The incidence of notable (≥5 × ULN) and severe (≥10 × ULN) ALT elevations was similar for all treatment groups except diclofenac. Significantly fewer hepatobiliary AEs were reported for celecoxib (any dose; 1.11%) than for diclofenac (vs. 4.24%, p < 0.0001); for ibuprofen (vs. 1.53%, p = 0.06) and placebo (vs. 0.89%, p = 0.21) the incidence of AEs was comparable to celecoxib.

Limitations: A number of limitations should be considered when evaluating the results: findings were limited by the quality and reporting of the studies selected; difficulty in estimating the incidence of AEs due to the low frequency of events; acetaminophen not included as an active comparator.

Conclusions: In this pooled analysis, the incidence of hepatic AEs in patients treated with celecoxib was similar to that for both placebo-treated patients and patients treated with ibuprofen or naproxen, but lower than for diclofenac.

Key words: :

• Celecoxib
• Hepatic safety
• NSAIDs
• Pooled analysis

Transparency

Declaration of funding

This study and the editorial support for this paper was sponsored by Pfizer Inc.

Declaration of financial/other relationships

P.S., B.S., G.C., C. L. and H.M. are full time employees of Pfizer Inc.

All peer reviewers received honoraria for peer reviewing for CMRO. Reviewer 1 disclosed that he/she has received grants from Sbinsa and has been a consultant to Ocera Therapeutics, Sinexus and Pfizer. Reviewer 2 disclosed that he/she has no significant relationships with this study or the study sponsor nor any significant competing financial interests or relationships with other commercial entities relevant to the reviewed manuscript's content.

Acknowledgment

Statistical analysis was carried out by Ha Nguyen and Jim Huang of Pfizer. P.S., B.S., G.C., C.L. and H.M. have disclosed that they are full time employees of Pfizer Inc. Editorial support was provided by M. Berrington, PhD, of PAREXEL and was funded by Pfizer. The authors thank Willis Maddrey of the University of Texas Southwestern for his review of an early draft of this manuscript.