European Journal of Clinical Pharmacology

, Volume 74, Issue 11, pp 1503–1511 | Cite as

Only full adherence to proton pump inhibitors protects against drug-induced upper gastrointestinal bleeding

  • Borja Ruiz
  • Urko Aguirre
  • Ana Estany-Gestal
  • Luca Rodella
  • Pablo Ruiz
  • Adolfo Figueiras
  • Alfonso Carvajal
  • Luisa Ibáñez
  • Anita Conforti
  • Marian M. de Pancorbo
  • Xavier Vidal
  • Luis H. Martin
  • Carmelo AguirreEmail author
Pharmacoepidemiology and Prescription



The use of gastroprotective agents has allowed significant progress in the prevention of upper gastrointestinal bleeding (UGIB) associated with non-steroidal anti-inflammatory drugs (NSAIDs) and antiplatelet agents. Nevertheless, some concerns remain regarding the gastroprotective dosage and treatment duration. Our aim was to study the effect of gastroprotective agents in UGIB induced by NSAIDs and single- or dual-antiplatelet therapy.


A multicenter case-control study was conducted including 577 cases diagnosed with UGIB and 1343 sex-, age-, and hospital-matched controls. To estimate exposure to NSAIDs and gastroprotective agents, consumption was calculated for the 4 weeks prior to hospital admission in terms of defined daily doses (DDDs). Risk groups for UGIB induced by NSAIDs and single- or dual-antiplatelet therapy were defined as a function of each drug dose, use of gastrointestine-damaging drugs, and risk factors for UGIB. Odds ratios (ORs) with 95% confidence intervals (CIs) were adjusted for single- (model 1) and dual- (model 2) antiplatelet therapy.


Full adherence (> 0.80DDD) to proton pump inhibitors (PPIs) was the only gastroprotective therapy that significantly reduced the risk of UGIB, considering NSAID risk (OR: 0.53; 95% CI: 0.30–0.95) and dose (OR: 0.48; 95% CI: 0.27–0.87) with ORs adjusted for single-antiplatelet therapy (model 1) and NSAID risk (OR: 0.55; 95% CI: 0.31–0.98) and dose (OR: 0.49; 95% CI: 0.28–0.89) with ORs adjusted for dual-antiplatelet therapy (model 2).


These results reinforce the recommendation of adding a PPI at effective doses (full adherence) to prevent UGIB induced by NSAIDs, or single- or dual-antiplatelet therapy.


Upper gastrointestinal Hemorrhage Acid-suppression therapy Prospective case-control 


Guarantor of the article

C Aguirre and B Ruiz.

Author’s contributions

A Figueiras, A Carvajal, L Ibañez, A Conforti, and C Aguirre: design of the research study, obtained funding; critical revision of the manuscript for important intellectual content. B Ruiz, A Estany-Gestal, L Rodella, P Ruiz: acquisition of data. B Ruiz, U Aguirre, C Aguirre: statistical analysis. B Ruiz and C Aguirre: drafting of the manuscript. MM de Pancorbo, X Vidal, and LH Martin: critical revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript.


In Spain, this study was funded by the national Health Research Fund (Fondo de Investigación Sanitaria) (Ministry of Economy and Competitiveness), grant numbers PI 02/1512, 02/0661/, 02/1364, and 02/1572 and by the Department of Health of the Basque Country, grant numbers 03/11092 and 11/111103; as well as supported in part in Catalonia by the Novartis, Pfizer and Dr. Esteve pharmaceutical companies. In Italy, the study was funded by unrestricted grants from Pfizer Italy and Department of Medicine and Public Health, University of Verona. The funders had no role in the study design, data-collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

The study protocol was approved by the institutional review boards of all participating hospitals. All patients were provided with information about the study and gave written informed consent.

Conflict of interests

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Borja Ruiz
    • 1
  • Urko Aguirre
    • 2
  • Ana Estany-Gestal
    • 3
  • Luca Rodella
    • 4
  • Pablo Ruiz
    • 5
  • Adolfo Figueiras
    • 3
  • Alfonso Carvajal
    • 6
  • Luisa Ibáñez
    • 7
  • Anita Conforti
    • 8
  • Marian M. de Pancorbo
    • 9
  • Xavier Vidal
    • 7
  • Luis H. Martin
    • 6
  • Carmelo Aguirre
    • 1
    • 10
    Email author
  1. 1.Unidad de Farmacovigilancia del Pais VascoGaldakao-Usansolo HospitalGaldakaoSpain
  2. 2.Research Unit, Research Network of Health Services in Chronic Diseases (REDISSEC)Galdakao-Usansolo HospitalGaldakaoSpain
  3. 3.Department of Preventive Medicine and Public Health, Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Pública–CIBERESP)University of Santiago de CompostelaSantiago de CompostelaSpain
  4. 4.1st Department of Surgery, Surgical Endoscopy UnitUniversity of VeronaVeronaItaly
  5. 5.Department of Digestive DiseasesBasurto University HospitalBilbaoSpain
  6. 6.Pharmacoepidemiology Institute, Department of Pharmacology, School of MedicineUniversity of ValladolidValladolidSpain
  7. 7.Catalan Institute of Pharmacology, Clinical Pharmacology Service, University Hospital Vall d’Hebron, Department of Pharmacology, Therapeutics and ToxicologyAutonomous UniversityBarcelonaSpain
  8. 8.Clinical Pharmacology Unit, Department of Medicine and Public HealthUniversity of VeronaVeronaItaly
  9. 9.General Service of Genomic Research: DNA Bank, School of PharmacyUniversity of the Basque CountryVitoria-GasteizSpain
  10. 10.Pharmacology Department, School of Medicine and NursingUniversity of the Basque CountryLeioaSpain

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