Thromb Haemost 2020; 120(07): 1066-1074
DOI: 10.1055/s-0040-1710592
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Risk of Bleeding with Exposure to Warfarin and Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review and Meta-Analysis

Lorenzo Villa Zapata
1  Skaggs School of Pharmacy and Pharmaceutical Sciences, Center for Pharmaceutical Outcomes Research, University of Colorado, Denver, Colorado, United States
Philip D. Hansten
2  School of Pharmacy, University of Washington, Seattle, Washington, United States
Jennifer Panic
3  Marshfield Clinic Health System, Marshfield, Wisconsin, United States
John R. Horn
4  Department of Pharmacy Practice, School of Pharmacy, Pharmacy Services UW Medicine, University of Washington, Seattle, Washington, United States
Richard D. Boyce
5  Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Sheila Gephart
6  Community and Health Systems Science, College of Nursing, The University of Arizona, Tucson, Arizona, United States
Vignesh Subbian
7  Department of Biomedical Engineering, College of Engineering, The University of Arizona, Tucson, Arizona, United States
Andrew Romero
8  Department of Pharmacy, Banner–University Medical Center Tucson, Tucson, Arizona, United States
Daniel C. Malone
9  College of Pharmacy, L. S. Skaggs Research Institute, University of Utah, Salt Lake City, Utah, United States
› Author Affiliations
Funding This project was funded by the Agency for Healthcare Research and Quality, grant numbers R01HS025984 and R21HS023826.
Further Information

Publication History

21 November 2019

15 April 2020

Publication Date:
26 May 2020 (online)


Background Warfarin use can trigger the occurrence of bleeding independently or as a result of a drug–drug interaction when used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs).

Objectives This article examines the risk of bleeding in individuals exposed to concomitant warfarin and NSAID compared with those taking warfarin alone (Prospero Registry ID 145237).

Methods PubMed, EMBASE, Scopus, and Web of Science were searched. The primary outcome of interest was gastrointestinal bleeding and general bleeding. Summary effects were calculated to estimate average treatment effect using random effects models. Heterogeneity was assessed using Cochran's Q and I 2. Risk of bias was also assessed using the Agency for Healthcare Research and Quality bias assessment tool.

Results A total of 651 studies were identified, of which 11 studies met inclusion criteria for meta-analysis. The odds ratio (OR) for gastrointestinal bleeding when exposed to warfarin and an NSAID was 1.98 (95% confidence interval [CI]: 1.55–2.53). The risk of gastrointestinal bleeding was also significantly elevated with exposure to a COX-2 inhibitor and warfarin relative to warfarin alone (OR = 1.90, 95% CI: 1.46–2.46). There was an increased risk of general bleeding with the combination of warfarin with NSAIDs (OR = 1.58, 95% CI: 1.18–2.12) or COX-2 inhibitors (OR = 1.54, 95% CI: 0.86–2.78) compared with warfarin alone.

Conclusion Risk of bleeding is significantly increased among persons taking warfarin and a NSAID or COX-2 inhibitor together as compared with taking warfarin alone. It is important to caution patients about taking these medications in combination.

Authors' Contributions

D.C.M. and L.V. conceived and designed the study. P.H., J.R.H., S.G., R.B., V.S., A.R., and J.P. assisted in the identification of relevant studies and comparators. All authors reviewed clinical evidence of harm and participated in interpretation of findings. L.V. compiled the database of eligible studies and performed the analysis. All authors critically revised the manuscript, interpreted the results, and performed a critical review of the manuscript for intellectual content. L.V. and D.C.M. produced the final version of the submitted article, and all coauthors approved it. L.V. and D.C.M. had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the analysis. L.V. and D.C.M. are the guarantors.


The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality.

Data Sharing

Data extracted from relevant studies is made available on request.

Supplementary Material