title: Overanticoagulation associated with combined use of antifungal agents and coumarin anticoagulants.
abstract: BACKGROUND
  Several case reports have associated combined use of coumarins and antifungal agents with overanticoagulation. However, we are not aware of epidemiologic studies that quantify the risk of overanticoagulation caused by antifungal agents. We conducted a follow-up study in a large population-based cohort to investigate the antifungal agents that are associated with overanticoagulation during therapy with coumarins.
  
  
  METHODS
  All patients in the Rotterdam Study who were treated with acenocoumarol or phenprocoumon in the study period from April 1, 1991, through Dec 31, 1998, and for whom international normalized ratio data were available were followed up until an INR > or =6.0, the end of their treatment, death, or the end of the study period. Proportional hazards regression analysis was used to estimate the risk of an INR > or =6.0 in relation to concomitant use of an oral anticoagulant and antifungal agents, after adjustment for several potentially confounding factors such as age, gender, hepatic dysfunction, malignancies, and heart failure.
  
  
  RESULTS
  Of the 1124 patients in the cohort, 351 had an INR > or =6.0. The incidence rate was 6.9 per 10,000 treatment days. Oral miconazole most strongly increased the risk of overanticoagulation with an adjusted relative risk of 36.6 (95% confidence interval [CI], 12.4-108.0).
  
  
  CONCLUSIONS
  In this study among outpatients of an anticoagulant clinic who were on a regimen of coumarins, oral miconazole was especially strongly associated with overanticoagulation. Awareness of these drug interactions and more frequent monitoring of INR values during the initial stages of treatment with some antifungal drugs in patients taking coumarins may minimize the risk of bleeding complications. The concurrent use of miconazole and coumarins should be discouraged.
authors.affiliation: Pharmacoepidemiology Unit, Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Loes E
authors.initials: LE
authors.lastname: Visser
authors.forename: Fernie J A
authors.initials: FJ
authors.lastname: Penning-van Beest
authors.forename: A A Harrie
authors.initials: AA
authors.lastname: Kasbergen
authors.forename: Peter A G M
authors.initials: PA
authors.lastname: De Smet
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Vulto
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Bruno H Ch
authors.initials: BH
authors.lastname: Stricker
mesh_terms: D000074:Acenocoumarol / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D001777:Blood Coagulation / Q000187:drug effects*; D016001:Confidence Intervals; D003374:Coumarins / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010644:Phenprocoumon / Q000494:pharmacology; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D000935:Antifungal Agents; D003374:Coumarins; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D000074:Acenocoumarol; D010644:Phenprocoumon