Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: Many drugs and foods interact with warfarin

ACP J Club. 1995 Mar-April;122:44. doi:10.7326/ACPJC-1995-122-2-044


Source Citation

Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med. 1994 Nov 1;121:676-83.


Abstract

Objective

To determine the clinical relevance of drug and food interactions with warfarin and to evaluate the quality of the studies reporting on these interactions.

Data sources

English-language studies were identified by searching the MEDLINE and TOXLINE databases from 1966 to the end of October 1993 using the Medical Subject Headings warfarin and drug interactions. Additional studies were identified by scanning the bibliographies of retrieved articles.

Study selection

Studies were selected if they contained original data about food and drug interactions with warfarin in humans. Reports on drugs not available in the United States or Canada were excluded.

Data extraction

Data pertaining to the participants, the drug or food affected by the interaction, and the type and mechanism of interaction were recorded. The quality of evidence reported was rated independently by 2 investigators. Studies received a summary score indicating the level of evidence (assurance) that showed a clinically important interaction had or had not occurred (level 1 = highly probable, level 2 = probable, level 3 = possible, and level 4 = doubtful).

Main results

Of 793 citations retrieved, 120 contained original data on 186 interactions. 43 of 86 different drug and food interactions appraised were judged to have level 1 evidence. Of these, 16 had a potentiating effect, 10 had an inhibiting effect, and 17 had no effect. The anticoagulant effect of warfarin was potentiated by 6 antibiotics (cotrimoxazole, erythromycin, fluconazole, isoniazid, metronidazole, and miconazole) and by 5 cardiac drugs (amiodarone, clofibrate, propafenone, propranolol, and sulfinpyrazone). Other drugs with a potentiating effect were phenylbutazone, piroxicam, alcohol (only with concomitant liver disease), cimetidine, and omeprazole. Only 3 patients had a hemorrhage at the time of a potentiating interaction (caused by alcohol, isoniazid, and phenylbutazone). The anticoagulant effect of warfarin was inhibited by 3 antibiotics (griseofulvin, rifampin, and nafcillin) and by 3 drugs active on the central nervous system (barbiturates, carbamazepine, and chlordiazepoxide). Other drugs and foods with an inhibiting effect were cholestyramine, sucralfate, foods and enteral feeds 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 the anticoagulant effect of warfarin.

Sources of funding: In part, Hamilton Civic Hospitals Research Centre; The Centre for Evaluation of Medicines, St. Joseph's Hospital; S.R. Samuel McLaughlin Foundation.

For article reprint: Dr. P.S. Wells, Fourth Floor, Civic Parkdale Clinic, Ottawa Civic Hospital, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada. FAX 613-761-5340.


Commentary

Growing evidence exists to support the use of anticoagulation with warfarin for many conditions, including atrial fibrillation (1). Despite these benefits from treatment, the antithrombotic effect of warfarin must be carefully regulated, both to maximize protection and to minimize the risk for hemorrhage. Most patients receiving warfarin therapy have important comorbidities or advanced age, placing them at a higher risk for treatment complications, which include adverse interactions with food or other drugs.

These interactions are hard to prove and frequently involve a degree of subjectivity. As shown in this review, the process of critically evaluating possible interactions may be thwarted by several factors. First, most reported studies of interactions had small samples of patients (only one third of the cited studies with the strongest evidence about the interactions of warfarin involved ≥ 10 persons). Second, despite explicit and standardized criteria, the 2 evaluators initially disagreed about the strength of the evidence for causation in 20% (38 of 186) of the interactions. Third, most patient-based reports on interactions lack control or comparison groups, making confounding factors difficult to exclude.

Despite these obstacles, Wells and colleagues provide a useful compendium of situations when food or drugs may interfere with the activity of warfarin. Their evaluative criteria are robust, although the authors acknowledge that failure to show an interaction with warfarin cannot exclude this possibility. With this review, one may rationally select agents not affected by warfarin cotherapy from among drugs in the same class, for example, avoiding propranolol (among β-blockers) or cimetidine (among histamine-2 antagonists). Finally, the review reminds the conscientious clinician to educate patients treated with warfarin about the need to report any changes in drug therapy (including over-the-counter preparations) or dietary changes linked to vitamin K.

Peter Rudd, MD
Stanford UniversityStanford, California, USA


Reference

1. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154:1449-57.