Upper Gastrointestinal Bleeding Associated with the Use of NSAIDs
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Aim: The relative gastrointestinal toxicity of NSAIDs in normal clinical practice is unknown. The aim of this study was to estimate the risk of upper gastrointestinal bleeding associated with NSAIDs and analgesics, with special emphasis on those agents that have been introduced in recent years.
Design: Multicentre case-control study.
Patients: All incident community cases of upper gastrointestinal bleeding from a gastric or duodenal lesion in patients aged >18 years of age (4309 cases). After secondary exclusions, 2813 cases and 7193 matched controls were included in the analysis.
Setting: Eighteen hospitals in Spain and Italy with a total study experience of 10 734 897 person-years.
Main Outcome Measure: Odds ratios of upper gastrointestinal bleeding for each drug, with adjustment for potential confounders. For each individual drug the reference category was defined as those not exposed to the drug.
Results: The incidence of upper gastrointestinal bleeding was 401.4 per million inhabitants aged >18 years. Thirty-eight percent of cases were attributable to NSAIDs. Individual risks for each NSAID were dose dependent. Ketorolac was associated with the highest risk estimate (24.7; 95% CI 8.0, 77.0). For newer NSAIDs, the risks were as follows: aceclofenac 1.4 (95% CI 0.6, 3.3), celecoxib 0.3 (95% CI 0.03, 4.1), dexketoprofen 4.9 (95% CI 1.7, 13.9), meloxicam 5.7 (95% CI 2.2, 15.0), nimesulide 3.2 (95% CI 1.9, 5.6) and rofecoxib 7.2 (95% CI 2.3, 23.0). The risk was significantly increased in patients with a history of peptic ulcer and/or upper gastrointestinal bleeding, and in those taking antiplatelet drugs.
Conclusions: NSAID-induced upper gastrointestinal bleeding is a common cause of hospital admission. Apart from the patient’s history of peptic ulcer, its risk depends on the particular drug and its dose, and on concomitant treatments. Our results do not confirm that greater selectivity for COX-2 confers less risk of upper gastrointestinal bleeding.
KeywordsPeptic Ulcer Celecoxib Naproxen Gastrointestinal Bleeding Piroxicam
The Spanish-Italian Collaborative Group for the Epidemiology of Upper Gastrointestinal Bleeding consists of the following individuals
Central Management and Coordinating Group: L Ibáñez, X Vidal, L Vendrell, J-R Laporte; Fundació Institut Català de Farmacologia, Barcelona, Spain.
Coordinating team in Italy: R Leone, U Moretti, A Conforti; Servizio di Farmacologia Medica, Università di Verona, Verona, Italy.
Investigators: E Vargas, M Ateinza, Hospital Clínico San Carlos, Madrid, Spain; J Torelló, O Belda, Hospital Virgen del Rocío, Sevilla, Spain; A Obrador, J Gayà, Hospital Son Dureta, Palma de Mallorca, Spain; F Guarner, JR Armengol, JR Malagelada, Hospital Universitari Vall d’Hebron, Barcelona, Spain; C Aguirre, J Cabriada, Hospital de Galdakao, Bizkaia, Spain; X Carné, F Feu, Hospital Clínic, Barcelona, Spain; T Caro-Patón, ML Goyeneche, Hospital Río Hortega, Valladolid, Spain; A Carvajal, Instituto de Farmacoepidemiología de Castilla-León; L del Olmo, Hospital Clínico, Valladolid, Spain; P Salvàt, J Costa, Hospital Germans Trias i Pujol, Badalona, Spain; J Balanzó, C Villanueva, Hospital Santa Creu i Sant Pau, Barcelona, Spain; G Angelini, A Castagnini, Policlinico GB Rossi, Verona, Italy; C Cordiano, G Guglielmi, Ospedale Civile Maggiore, Verona, Italy; S Loperfido, Ospedale Cà Foncello, Treviso, Italy; D Bernardini, L Milan, Presidio Ospedaliero S Bortolo, Vicenza, Italy; S Adamo, GM Bulighin, Ospedale Magalini, Villafranca di Verona, Italy; M Azzurro, Ospedale Orlandi, Bussolengo, Italy; F Chilovi, L Piazzi, Ospedale Generale Regionale, Bolzano, Italy; R Musola, M Azzini, Presidio Ospedaliero, Legnago, Italy.
Quality control and data entry in Spain: L Vendrell, X Barroso, Fundació Institut Català de Farmacologia, Barcelona, Spain.
Quality control and data entry in Italy: S Bisi, T Camerlengo, Servizio di Farmacologia Medica, Università di Verona, Verona, Italy.
Statistical support and analysis: X Vidal, Fundacio Institut Català de Farmacologia, Barcelona, Spain.
Data collection: A Terleira, S Fernández, I Navarro, Hospital Clinico San Carlos, Madrid, Spain; A Mengíbar, Hospital Virgen del Rocío, Sevilla, Spain; R Soto, Hospital Son Dureta, Palma de Mallorca, Spain; MJ de las Heras, Hospital Universitari Vall d’Hebron, Barcelona, Spain; M García, A Ajuria, Hospital de Galdakao, Bizkaia; G Santana, Hospital Clínic, Barcelona, Spain; A García, Hospital Río Hortega, Valladolid, Spain; N Alonso, Hospital Clínico, Valladolid, Spain; E Roldán, Hospital Germans Trias i Pujol, Badalona, Spain; ML Gálvez, Hospital Santa Creu i Sant Pau, Barcelona, Spain; B Rapanà, Policlinico GB Rossi, Verona; M Casoni, Ospedale Civile Maggiore, Verona, Italy; E Heras, D Nardi, Ospedale Cà Foncello, Treviso, Italy; S Gasparotto, Presidio Ospedaliero San Bortolo, Vicenza, Italy; G Franzon, Ospedale Magalini, Villafranca di Verona, Italy, and Ospedale Orlandi, Bussolengo, Italy; T Grasso, Ospedale Generale Regionale, Bolzano, Italy; R Pasqualini, Presidio Ospedaliero, Legnago, Italy.
In Spain, Almirall Prodesfarma, Aventis, Bayer, Boehringer Ingelheim, Ferrer Internacional, J Uriach y Cía, Knoll, Laboratorios del Dr Esteve, Lácer, Menarini, Merck Sharp and Dohme, Monsanto España, Novartis, Roche, Sanofi- Synthélabo, and Vita-Invest.
In Italy, Boehringer Ingelheim, Helsinn, and Roche.
The design, conduct, analysis and interpretation of the study were totally independent from the sponsoring companies. These were approached for potential funding after approval of the protocol by the study group.
Conflict of interest statement: The Fundació Institut Català de Farmacologia (FICF) and the Servizio di Farmacologia Medica (SFMV) have research contracts with the pharmaceutical companies supporting the present study. Personnel at these institutions do not receive any premium related to these contracts.
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