Pearls of Wisdom: Warfarin for Atrial Fibrillation
Atrial fibrillation is serious business, since it is associated with an increased risk of stroke and death. Fortunately, numerous clinical trials have shown that anticoagulant therapy—specifically, warfarin—reduces the risk of stroke by about 66%; additionally, mortality among patients treated with warfarin for atrial fibrillation is reduced by about 25%. But as in most other situations, there is no free lunch. Although warfarin is an excellent drug, its many drug, food, and herbal interactions can lead to trouble: Supratherapeutic international normalized ratios (INRs) lead to increased bleeding risk, or subtherapeutic INRs eliminate the stroke-reducing benefits of treatment.
A patient has been successfully taking warfarin for atrial fibrillation for 1 year. His INR has been consistently within the therapeutic range. Today, however, his INR is dramatically supratherapeutic (>10.0). Which of the following medications could be the culprit?
A. Sertraline
B. Topical miconazole cream
C. Topical mometasone cream
D. Canagliflozin
What is the correct answer?
(Answer and discussion on next page)
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Answer: Topical miconazole cream
Because warfarin has been used for decades, there are probably few surprises about its use left to discover. However, drugs that are newly marketed are routinely tested for potential interaction with warfarin, and that list of agents continues to grow.
Probably the most common problematic interaction with warfarin occurs through the hepatic CYP450 system, specifically the CYP450 2C9 pathway. Because 2C9 is a major metabolic pathway for warfarin, anything that inhibits 2C9 can lead to problematic elevations in warfarin levels—and a substantially increased risk of bleeding.
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RELATED CONTENT
Potential Interactions with Warfarin Treatment
Warfarin and Atrial Fibrillation
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Although the plasma levels of a topical agent are generally substantially less than those of the same agent administered orally, that does not guarantee universal safety. Even when administered topically, the systemic inhibition of 2C9 by miconazole is sufficient to have a meaningful impact upon warfarin metabolism through inhibition of CYP 2C9.
Topical Miconazole & Coumadin Interaction: A Case1
In one reported case1, an 80-year-old man taking warfarin was admitted for a marked increase in INR. He hadno change in medications, except recent use of topical miconazole. The administration of fresh frozen plasma restored coagulation factors, and the elimination of miconazole from the regimen once again allowed for continued maintenance of a therapeutic INR.
Topical Miconazole & Coumadin Interaction: Treatment1
What’s the “Take Home”?
Because CYP450 2C9 is a primary metabolic pathway for warfarin, any agent that inhibits 2C9 can lead to supratherapeutic INR levels and a risk for bleeding. Most clinicians are aware that systemic medications (oral or parenteral) can cause meaningful interaction with warfarin but are much less aware that topical agents (eg, miconazole) can also result in problematic interactions.
Reference:
1. Devaraj A, O’Beirne JP, Veasey A, Dunk AA. Interaction between warfarin and topical miconazole cream. BMJ. 2002;325(7355):77.