title: Risk of upper gastrointestinal bleeding from different drug combinations.
abstract: OBJECTIVE
  Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin increases the risk of upper gastrointestinal bleeding (UGIB). Guidelines suggest avoiding certain drug combinations, yet little is known about the magnitude of their interactions. We estimated the risk of UGIB during concomitant use of nonselective (ns)NSAIDs, cyclooxygenase -2 selective inhibitors (COX-2 inhibitors), and low-dose aspirin with other drugs.
  
  
  METHODS
  We performed a case series analysis of data from 114,835 patients with UGIB (930,888 person-years of follow-up) identified from 7 population-based health care databases (approximately 20 million subjects). Each patient served as his or her own control. Drug exposure was determined based on prescriptions of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin, alone and in combination with other drugs that affect the risk of UGIB. We measured relative risk (incidence rate ratio [IRR] during drug exposure vs nonexposure) and excess risk due to concomitant drug exposure (relative excess risk due to interaction [RERI]).
  
  
  RESULTS
  Monotherapy with nsNSAIDs increased the risk of diagnosis of UGIB (IRR, 4.3) to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of UGIB; concomitant nsNSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and also produced the greatest excess risk (RERI, 5.5). Concomitant use of nsNSAIDs and aldosterone antagonists produced an IRR for UGIB of 11.0 (RERI, 4.5). Excess risk from concomitant use of nsNSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from use of COX-2 inhibitors with SSRIs was 1.9 and that for use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of nsNSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9.
  
  
  CONCLUSIONS
  Based on a case series analysis, concomitant use of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with SSRIs significantly increases the risk of UGIB. Concomitant use of nsNSAIDs or low-dose aspirin, but not COX-2 inhibitors, with corticosteroids, aldosterone antagonists, or anticoagulants produces significant excess risk of UGIB.
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: g.masclee@erasmusmc.nl.
authors.forename: Gwen M C
authors.initials: GM
authors.lastname: Masclee
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Vera E
authors.initials: VE
authors.lastname: Valkhoff
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Preciosa M
authors.initials: PM
authors.lastname: Coloma
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: de Ridder
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Silvana
authors.initials: S
authors.lastname: Romio
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: Schuemie
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands; PHARMO Institute, Utrecht, The Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Herings
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands; Agenzi Regionali di Sanità della Toscana, Florence, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Gini
authors.affiliation: Health Search, Italian College of General Practitioners, Florence, Italy.
authors.forename: Giampiero
authors.initials: G
authors.lastname: Mazzaglia
authors.affiliation: Pedianet, Societá Servizi Telematici SRL, Padova, Italy.
authors.forename: Gino
authors.initials: G
authors.lastname: Picelli
authors.affiliation: Università degli Studi di Milano-Bicocca, Milan, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Scotti
authors.affiliation: Clinical Epidemiology, Aarhus University Hospital, Århus Sygehus, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Pedersen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Kuipers
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Lei
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Miriam C J M
authors.initials: MC
authors.lastname: Sturkenboom
mesh_terms: D000305:Adrenal Cortex Hormones / Q000009:adverse effects; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D000925:Anticoagulants / Q000009:adverse effects; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005060:Europe; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced*; D006801:Humans; D000451:Mineralocorticoid Receptor Antagonists / Q000009:adverse effects; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D000305:Adrenal Cortex Hormones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D016861:Cyclooxygenase Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D001241:Aspirin
keywords: Prostaglandin; Side Effects; Stomach; Treatment