Warfarin With Fluoroquinolones, Sulfonamides, or Azole Antifungals: Interactions and the Risk of Hospitalization for Gastrointestinal Bleeding

The aim of this study was to determine whether a potential pharmacokinetic interaction between warfarin and orally administered anti‐infectives increases the risk of hospitalization for gastrointestinal (GI) bleeding in warfarin users. We conducted a nested case–control and case–crossover study using US Medicaid data. Logistic regression was used to determine the association between GI bleeding and prior use of ciprofloxacin, levofloxacin, gatifloxacin, co‐trimoxazole, or fluconazole vs. no exposure and also vs. use of cephalexin, which would not be expected to interact with warfarin. All of the anti‐infectives examined were associated with elevated odds ratios (ORs) when compared to no exposure to these drugs. With cephalexin data as the reference, the ORs for co‐trimoxazole (OR: 1.68 (95% confidence interval (CI): 1.21–2.33) in the prior 6–10 days) and fluconazole (OR: 2.09 (95% CI: 1.34–3.26) in the prior 11–15 days) were significantly elevated. Warfarin users who had received an anti‐infective agent showed a substantially increased risk of GI bleeding. However, a drug–drug interaction with warfarin was evident only for co‐trimoxazole and fluconazole.

[1]  R. Herings,et al.  Main comedications associated with major bleeding during anticoagulant therapy with coumarins , 2005, European Journal of Clinical Pharmacology.

[2]  R. J. Artymowicz,et al.  Possible interaction between gatifloxacin and warfarin. , 2002, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[3]  Mark Crowther,et al.  Systematic overview of warfarin and its drug and food interactions. , 2005, Archives of internal medicine.

[4]  J. Lipsky.  Antibiotic-associated hypoprothrombinaemia. , 1988, Journal of Antimicrobial Chemotherapy.

[5]  D. Wysowski,et al.  Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. , 2007, Archives of internal medicine.

[6]  J. Berger,et al.  Administrative Claims Analysis of the Relationship Between Warfarin Use and Risk of Hemorrhage Including Drug-Drug and Drug-Disease Interactions , 2006, Journal of managed care pharmacy : JMCP.

[7]  C. Bell,et al.  The safety of levofloxacin in elderly patients on warfarin. , 2005, The American journal of medicine.

[8]  W. Linn,et al.  Potential Warfarin‐Ciprofloxacin Interaction in Patients Receiving Long‐Term Anticoagulation , 1992, Pharmacotherapy.

[9]  W. Flanders,et al.  The exposure odds ratio in nested case-control studies with competing risks. , 1986, American journal of epidemiology.

[10]  S Greenland,et al.  The impact of confounder selection criteria on effect estimation. , 1989, American journal of epidemiology.

[11]  Flanders Wd,et al.  THE EXPOSURE ODDS RATIO IN NESTED CASE-CONTROL STUDIES WITH COMPETING RISKS , 1986 .

[12]  J. Robins,et al.  Control sampling strategies for case-crossover studies: an assessment of relative efficiency. , 1995, American journal of epidemiology.

[13]  L. G. García Rodríguez,et al.  Positive Predictive Value of ICD‐9 Codes in the Identification of Cases of Complicated Peptic Ulcer Disease in the Saskatchewan Hospital Automated Database , 1996, Epidemiology.

[14]  P W Curreri,et al.  The Medicare Payment Advisory Commission. , 1998, Bulletin of the American College of Surgeons.

[15]  J. E. Harris,et al.  Interaction of dietary factors with oral anticoagulants: review and applications. , 1995, Journal of the American Dietetic Association.

[16]  P. Petersen,et al.  Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation. , 1999, Archives of internal medicine.

[17]  J. D'Elia,et al.  Bleeding in patients with infections. Are antibiotics helping or hurting? , 1982, Archives of internal medicine.

[18]  T. Grasela,et al.  Adverse reaction reporting of interaction between warfarin and fluoroquinolones. , 1991, Archives of internal medicine.

[19]  M L Dourson,et al.  Genetic polymorphisms in assessing interindividual variability in delivered dose. , 2002, Regulatory toxicology and pharmacology : RTP.

[20]  M. Rich,et al.  Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). , 2006, American heart journal.

[21]  A. Prochazka,et al.  The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens. , 2005, Journal of general internal medicine.

[22]  Valentin Fuster,et al.  American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. , 2003, Circulation.

[23]  J. Lettieri,et al.  Effect of ciprofloxacin on the pharmacokinetics and pharmacodynamics of warfarin. , 1996, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[24]  Valentin Fuster,et al.  AHA/ACC Scientific StatementAmerican Heart Association/American College of Cardiology Foundation guide to warfarin therapy1 , 2003 .

[25]  A. Prochazka,et al.  Brief report: The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens , 2005, Journal of General Internal Medicine.

[26]  J. Black.  Diarrhoea, vitamin K, and warfarin , 1994, The Lancet.

[27]  Charles E. Leonard,et al.  Quality of Medicaid and Medicare Data Obtained Through Centers for Medicare and Medicaid Services (CMS) , 2007, Medical care.

[28]  Heather L. Heiman,et al.  Contributions Acetaminophen and Other Risk Factors for Excessive Warfarin Anticoagulation , 2001 .

[29]  H. G. Anderson,et al.  Retrospective Evaluation of a Possible Interaction Between Warfarin and Levofloxacin , 2005, Pharmacotherapy.

[30]  E N Jonsson,et al.  A PK–PD Model for Predicting the Impact of Age, CYP2C9, and VKORC1 Genotype on Individualization of Warfarin Therapy , 2007, Clinical pharmacology and therapeutics.

[31]  F. McAlister,et al.  Why do patients with atrial fibrillation not receive warfarin? , 2000, Archives of internal medicine.