¹ Department of Public Health, Epidemiology and Health Economics, University of Liège; WHO Collaborating Centre for Public Health Aspects of Osteoarticular Disorders, Liège, Belgium
² Department of Internal Medicine and Therapeutics, Centre Hospitalier Régional et Universitaire de Marseille, Hôpital Ste-Marguerite, Marseille, France
³ Department of Rheumatology, CHRU Faculté d’Angers, Angers, France
⁴ Department of Rheumatology, Madrid, Spain
⁵ Pain Research, The Churchill, Oxford, UK
⁶ Department of Gastroenterology, Rambam Medical Centre Haifa, Israel
⁷ Merck & Co, Paris, France

Correspondence to:
Correspondence to:
Dr F Richy
Santé Publique, Epidémiologie et Economie de la Santé, CHU, Bât B23, B-4000 Sart-Tilman, Belgium, Europe; florent.richy{at}ulg.ac.be

ABSTRACT
Objectives: To provide an updated document assessing the global, NSAID-specific, and time dependent risk of gastrointestinal (GI) complications through meta-analyses of high quality studies.

Methods: An exhaustive systematic search was performed. Inclusion criteria were: RCT or controlled study, duration of 5 days at least, inactive control, assessment of minor or major NSAID adverse effects, publication range January 1985 to January 2003. The publications retrieved were assessed during a specifically dedicated WHO meeting including leading experts in all related fields. Statistics were performed conservatively. Meta-regression was performed by regressing NSAID adjusted estimates against study duration categories.

Results: Among RCT data, indolic derivates provided a significantly higher risk of GI complications related to NSAID use than for non-users: RR = 2.25 (1.00; 5.08) than did other compounds: naproxen: RR = 1.83 (1.25; 2.68); diclofenac: RR = 1.73 (1.21; 2.46); piroxicam: RR = 1.66 (1.14; 2.44); tenoxicam: RR = 1.43 (0.40; 5.14); meloxicam: RR = 1.24 (0.98; 1.56), and ibuprofen: RR = 1.19 (0.93; 1.54). Indometacin users had a maximum relative risk for complication at 14 days. The other compounds presented a better profile, with a maximum risk at 50 days. Significant additional risk factors included age, dose, and underlying disease. The controlled cohort studies provided higher estimates: RR = 2.22 (1.7; 2.9). Publication bias testing was significant, towards a selective publication of deleterious effects of NSAIDs from small sized studies.

Conclusion: This meta-analysis characterised the "compound" and "time" aspects of the GI toxicity of non-selective NSAIDs. The risk/benefit ratio of such compounds should thus be carefully and individually evaluated at the start of long term treatment.

Abbreviations: ANOVA, analysis of variance; GI, gastrointestinal; NSAIDs, non-steroidal anti-inflammatory drugs; RCT, randomised controlled trial; RR, relative risk

Keywords: evidence based medicine; non-steroidal anti-inflammatory drugs; adverse effects; meta-analysis