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Thromb Haemost. 2018 Mar;118(3):461-470. doi: 10.1055/s-0038-1627100. Epub 2018 Feb 12.

Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach.

Author information

Spanish Centre for Pharmacoepidemiologic Research (CEIFE), Madrid, Spain.
Department of Neurology, Odense University Hospital, Odense, Denmark.
Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
Clinical Pharmacology Unit, University Hospital Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.
Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.
Pharmacoepidemiology Group, Institute of Health Research IRYCIS, Madrid, Spain.



To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels.


Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3).


Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%).


Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users.


Conflict of interest statement

D. Gaist received honoraria from AstraZeneca (Sweden) for participation as a co-investigator in a research project. L.A. García Rodríguez and M. Martín-Pérez work at CEIFE, which has received research grants from Bayer Pharma AG (Germany); L.A. García Rodríguez has also served as an advisory board member for Bayer Pharma AG (Germany). F.J. de Abajo declares no conflicts of interest.

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