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Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta-analytic approach
  1. F Richy1,
  2. O Bruyere1,
  3. O Ethgen1,
  4. V Rabenda1,
  5. G Bouvenot2,
  6. M Audran3,
  7. G Herrero-Beaumont4,
  8. A Moore5,
  9. R Eliakim6,
  10. M Haim7,
  11. J-Y Reginster1,
  12. on behalf of the WHO Collaborating Centre for Public Health Aspects of Osteoarticular Disorders, Liège, Belgium
  1. 1Department of Public Health, Epidemiology and Health Economics, University of Liège; WHO Collaborating Centre for Public Health Aspects of Osteoarticular Disorders, Liège, Belgium
  2. 2Department of Internal Medicine and Therapeutics, Centre Hospitalier Régional et Universitaire de Marseille, Hôpital Ste-Marguerite, Marseille, France
  3. 3Department of Rheumatology, CHRU Faculté d’Angers, Angers, France
  4. 4Department of Rheumatology, Madrid, Spain
  5. 5Pain Research, The Churchill, Oxford, UK
  6. 6Department of Gastroenterology, Rambam Medical Centre Haifa, Israel
  7. 7Merck & Co, Paris, France
  1. Correspondence to:
    Dr F Richy
    Santé Publique, Epidémiologie et Economie de la Santé, CHU, Bât B23, B-4000 Sart-Tilman, Belgium, Europe;


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.

  • ANOVA, analysis of variance
  • GI, gastrointestinal
  • NSAIDs, non-steroidal anti-inflammatory drugs
  • RCT, randomised controlled trial
  • RR, relative risk
  • evidence based medicine
  • non-steroidal anti-inflammatory drugs
  • adverse effects
  • meta-analysis

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