ARTHRITIS & RHEUMATISM Vol. 62, No. 6, June 2010, pp 1592–1601 DOI 10.1002/art.27412 © 2010, American College of Rheumatology Variability Among Nonsteroidal Antiinflammatory Drugs in Risk of Upper Gastrointestinal Bleeding Elvira L. Masso ´ Gonza ´lez, 1 Paola Patrignani, 2 Stefania Tacconelli, 2 and Luis A. Garcı ´a Rodrı ´guez 1 Objective. Traditional nonsteroidal antiinflam- matory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the mag- nitude 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 correla- tion 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 inhibi- tion 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]), rofe- coxib (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 keto- profen, 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 demon- strate 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 associ- ated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation. Traditional nonaspirin nonsteroidal antiinflam- matory drugs (NSAIDs) have been shown to increase the risk of upper gastrointestinal (GI) bleeding/perforation (1). Because of the widespread use of NSAIDs as anal- gesic, antiinflammatory, and antipyretic drugs, their serious upper GI complications are a major public health con- cern. To reduce the morbidity associated with NSAIDs it is necessary to establish specific estimates for individual drugs and individual groups of patients with different risk profiles. The biochemistry study was supported by a grant from the European Community’s Sixth Framework Program (Eicosanox, grant LSMH-CT-2004-005033 to Dr. Patrignani). Ms Masso ´ Gonza ´lez re- ceived fellowship support from Real Colegio Complutense at the Harvard School of Public Health. 1 Elvira L. Masso ´ Gonza ´lez, MSc (current address: AstraZeneca, Madrid, Spain), Luis A. Garcı ´a Rodrı ´guez, MD: Spanish Centre for Pharmacoepidemiological Research, Madrid, Spain; 2 Paola Patrig- nani, PhD, Stefania Tacconelli, PhD: G. d’Annunzio University, School of Medicine, Centro Studi dell’Invecchiamento, Chieti, Italy. Ms Masso ´ Gonza ´lez and Dr. Patrignani contributed equally to this work. Dr. Garcı ´a Rodrı ´guez has received consulting fees from AstraZeneca (less than $10,000) and research grants from Novartis and Bayer. Address correspondence and reprint requests to Luis A. Garcı ´a Rodrı ´guez, MD, Spanish Centre for Pharmacoepidemiological Research, Almirante 28, 2, 28004 Madrid, Spain. E-mail: lagarcia@ ceife.es. Submitted for publication August 12, 2009; acepted in revised form February 12, 2010. 1592