Variability Among Nonsteroidal Antiinflammatory Drugs in Risk of Upper Gastrointestinal Bleeding

Objective. Traditional nonsteroidal anti-inflammatory drugs ( NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX-1) and COX-2 in vitro. Methods. We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX-1 and COX-2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation. Results. The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82-5.31) for traditional NSAIDs and 1.88 ( 95% CI 0.96-3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [ 95% CI 2.17-3.33]), rofecoxib (2.12 [ 95% CI 1.59-2.84]), aceclofenac (1.44 [ 95% CI 0.65-3.2]), and celecoxib (1.42 [ 95% CI 0.85-2.37]), while higher RRs were observed for ketorolac (14.54 [ 95% CI 5.87-36.04]) and piroxicam (9.94 [ 95% CI 5.99-16.50). Estimated RRs were 5.63 ( 95% CI 3.83-8.28) for naproxen, 5.57 ( 95% CI 3.94-7.87) for ketoprofen, 5.40 ( 95% CI 4.16-7.00) for indomethacin, 4.15 ( 95% CI 2.59-6.64) for meloxicam, and 3.98 ( 95% CI 3.36-4.72) for diclofenac. The degree of inhibition of whole blood COX-1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r(2) = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half-life and with a slow-release formulation were associated with a greater risk than NSAIDs with a short half-life. Conclusion. The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half-life or slow-release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation.