Warfarin and Cranberry Juice: Time to Lose the Warnings?

Expert Interview With Jack E. Ansell, MD

Linda Brookes, MSc

Disclosures

September 02, 2010

In This Article

Background to the Interview

In the United States, current prescribing information for warfarin (Coumadin®) lists cranberry (Vaccinium macrocarpon) products as one of the botanical (herbal) medicines associated with an increase in the effects of the anticoagulant warfarin.[1] Patients receiving warfarin are advised to avoid intake of cranberry juice or any other cranberry products. This warning of a potential interaction was originally approved by the US Food and Drug Administration (FDA) in 2006.[2] It followed an advisory issued by the UK Medicines and Healthcare Products Regulatory Agency (MHRA)/Committee on Safety of Medicines (CSM) in 2004 stating that patients taking warfarin should avoid cranberry products unless the health benefits clearly outweigh the risks and that product information for warfarin should be updated to reflect this advice.[3,4] This advice was based on 12 poorly documented reports of suspected interactions involving warfarin and cranberry juice, 8 involving increases in international normalized ratio (INR) and/or bleeding episodes, 3 cases in which INR was unstable, and 1 case in which the INR decreased. An earlier warning to limit or avoid cranberry consumption concurrent with warfarin use had been issued by the MHRA/CSM in 2003 after the first 5 reports of interactions were received.[5] Since none of the reports defined a safe quantity or brand of cranberry juice or noted any difference between cranberry juice and other cranberry products with concurrent warfarin, similar caution was advised with all cranberry products. In Canada, Health Canada announced in 2004 that following the UK advisory, it would continue to monitor this and other potential warfarin interactions,[6] and in 2005, it placed cranberry juice on a list of food products that "may affect warfarin levels" as opposed to products for which evidence suggested that they "may change levels of warfarin in the bloodstream or may directly affect blood clotting on their own.[7]" None of these warnings about the potential warfarin-cranberry interaction has been modified since the warnings were first issued.

Few studies have been carried out to determine a possible mechanism for this potential interaction. Because warfarin is a racemic mixture of the R- and S-enantiomers, with the S-enantiomer having 2-5 times more anticoagulant activity than the R-enantiomer, it was proposed that certain flavonoids in cranberry juice or cranberry products might inhibit cytochrome P450 (CYP) 2C9, the enzyme responsible for the hepatic elimination of S-warfarin. Study results have been consistent, showing no effect on CYP2C9, although some questionable effect on the less important enzyme, CYP3A4.[8,9,10,11,12,13]

One of the 3 randomized clinical trials that investigated the effects of cranberry juice on warfarin-stabilized patients was carried out by Dr. Ansell and colleagues at Boston University School of Medicine.[10] The study, which was supported by Ocean Spray Co. (Lakeville-Middleboro, Massachusetts), manufacturer of the juice used, and the US Department of Health and Human Services, found that in 30 patients receiving long-term warfarin, 2 weeks' consumption of cranberry (240 mL once daily) had no effect on plasma S- or R-warfarin plasma levels compared with placebo. Mean INR did not differ significantly between the 2 cranberry and placebo groups except at one time point (day 12; P <.02) but then returned to previous levels, which the investigators suggested was unlikely to be clinically important and might be a random change. This and other clinical evidence was reviewed by Dr. Ansell and colleagues at Lenox Hill Hospital in their recent paper.[14] They examined 6 published case reports and 7 clinical trials (3 that used warfarin and 4 surrogate drugs) identified from MEDLINE via PubMed and the Cochrane Library database, along with 9 unpublished case reports originally submitted to the UK CSM.[4] The authors concluded that given the "poor quality of the case reports and the almost uniform findings in randomized studies," the FDA and CSM advisories should be reconsidered. Like 2 previous reviews,[15,16] Dr. Ansell and co-authors concluded that that there is no evidence of a clinically relevant interaction when cranberry juice is consumed in moderation, although they did not rule out that consuming large quantities of cranberry juice might affect warfarin.

Dr. Ansell spoke with Linda Brookes, MSc, for Medscape, to discuss the evidence for and against a warfarin-cranberry juice interaction, as recently reviewed, and the way in which regulatory bodies assess data from clinical reports and studies before warnings are issued about potential interactions with drugs, such as warfarin.

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