Interactions of Warfarin with Drugs and Food

  1. Philip S. Wells, MD, MSc, FRCP(C);
  2. Anne M. Holbrook, MD, PharmD, MSc, FRCP(C);
  3. N. Renee Crowther, BSc; and
  4. Jack Hirsh, MD, FRCP(C)
  1. From McMaster University; Centre for Evaluation of Medicines, St. Joseph's Hospital; the Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada. Grant Support: In part by Hamilton Civic Hospitals Research Centre and The Centre for Evaluation of Medicines, St. Joseph's Hospital, Ontario, Canada. Dr. Wells is the recipient of a McLaughlin scholarship from the University of Ottawa. Dr. Hirsh is a Distinguished Research Professor of the Heart and Stroke Foundation of Canada and is a Trillium Award recipient from the Ministry of Health.

    Abstract

    Purpose: To evaluate the quality of studies about drugs and food interactions with warfarin and their clinical relevance.

    Data Sources: MEDLINE and TOXLINE databases from 1966 to October 1993 using the Medical Subject Headings warfarin, drug interactions, and English only.

    Study Selection: All articles reporting original data on drug and food interactions with warfarin.

    Data Extraction: Each report, rated independently by at least two investigators (using causality assessment), received a summary score indicating the level of assurance (level 1 = highly probable, level 2 = probable, level 3 = possible, and level 4 = doubtful) that a clinically important interaction had or had not occurred. Inter-rater agreement was assessed using a weighted κ statistic.

    Results: Of 793 retrieved citations, 120 contained original reports on 186 interactions. The weighted κ statistic was 0.67, representing substantial agreement. Of 86 different drugs and foods appraised, 43 had level 1 evidence. Of these, 26 drugs and foods did interact with warfarin. Warfarin's anticoagulant effect was potentiated by 6 antibiotics (cotrimoxazole, erythromycin, fluconazole, isoniazid, metronidazole, and miconazole); 5 cardiac drugs (amiodarone, clofibrate, propafenone, propranolol, and sulfinpyrazone); phenylbutazone; piroxicam; alcohol (only with concomitant liver disease); cimetidine; and omeprazole. Three patients had a hemorrhage at the time of a potentiating interaction (caused by alcohol, isoniazid, and phenylbutazone). Warfarin's anticoagulant effect was inhibited by 3 antibiotics (griseofulvin, rifampin, and nafcillin); 3 drugs active on the central nervous system (barbiturates, carbamazepine, and chlordiazepoxide); cholestyramine; sucralfate; foods high in vitamin K; and large amounts of avocado.

    Conclusions: Many drugs and foods interact with warfarin, including antibiotics, drugs affecting the central nervous system, and cardiac medications. Many of these drug interactions increase warfarin's anticoagulant effect.

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    1. Ann Intern Med November 1, 1994 vol. 121 no. 9 676-683
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