Warfarin Institute of America

DEDICATED TO YOUR HEALTH SINCE 2000

EDITOR'S NOTE

During October 2006 the US Food and Drug Administration mandated a new Medication Guide for warfarin.  It includes the following statement, "Avoid drinking cranberry juice or eating cranberry products."  By its nature the FDA is conservative but this looks like another one of those government "feel-good" projects that is in reality useless. They even extended the warning to cranberry products even though no cranberry product other than juice has ever been implicated or studied.  As you will see by reading the report below, there is practically no science to justify this conclusion. 

CRANBERRY JUICE INTERACTION WITH WARFARIN (Coumadin, Jantoven)

 by

Jo Yacko, RPh, Pharm D. Candidate

University of Colorado School of Pharmacy

 

            Many foods, drugs, and herbal supplements can interfere with the effects of warfarin.  Some products interfere with the metabolism of warfarin, the way the body clears warfarin.  Other products/foods contain vitamin K.  Vitamin K is what warfarin works against to prevent clots. There has been some recent controversy over the effects of cranberry juice on warfarin.

            In September 2003, the United Kingdom’s Committee on Safety of Medicines and Healthcare Products Regulatory Agency ( UK CSM) advised patients taking warfarin to limit or avoid drinking cranberry juice1.  This advice was based on five case reports.  In October of 2004, the UK CSM revised their warning to say: Patients taking warfarin should avoid taking cranberry juice or cranberry products unless the health benefits are considered to outweigh the risks2. They now had twelve case reports. The CSM reported that eight cases had an increase in INR (international normalization ratio), three cases had an unstable INR, and one case had a decrease in INR.  This wasn’t consistent.  Dr. David Greenblatt reports in the Anticoagulation Forum Newsletter3, that his research group at Tufts University looked at these case reports very carefully.  They could not find that cranberry juice had caused the loss of warfarin control in any of these cases.  Nor could they find a good reason for the action taken by the UK CSM.

            If cranberries and or cranberry juice interact with warfarin, what is the mechanism for that interaction?  Cranberries are not a good source of vitamin K, so it was thought that they might interfere with the metabolism of warfarin.  The researchers at Tufts University developed a plan to study the possible interaction between cranberry juice and warfarin4.  Because of safety concerns, it was decided to use a substitute for warfarin.  They used a drug called flurbiprofen.  It is a drug that is metabolized by the same enzyme system as warfarin.  Healthy volunteers were given an oral dose of flurbiprofen and then drank cranberry juice.  Blood samples were taken multiple times after the drink and used to determine blood levels of flurbiprofen.  The same volunteers, on a different day, repeated the process but with a drink that looked and tasted like cranberry juice, but wasn’t (“placebo”).  The researchers found that cranberry juice had no different effect on the blood concentrations of flurbiprofen than did the placebo.  This would lead us to believe that cranberry juice has no effect on warfarin levels or INR.

            The researchers at Tufts University are now studying real patients on warfarin.  The patients are randomly assigned to drink cranberry juice or “placebo” for two weeks.  The INR values are being followed during the study.  Results are not available yet.

            In the spring 2005 newsletter of the Cranberry Institute, they report a study out of UCLA, Center for Human Nutrition.  This study measured the effect of cranberry juice vs. placebo on the INR of patients taking warfarin for atrial fibrillation.  The results showed no significant interaction between cranberry juice and warfarin.  This article has been accepted for future publication in the Journal of the American Dietetic Association.

            These studies lead us to believe that there is no interaction between cranberry juice and warfarin.  Recently a clinic patient that we saw, who had been stable on a warfarin dose of 13 mg/wk for the past 9 months (INR values ranged from 2.5 to 3.9), had an INR of 6.5.  The only thing that had changed was his diet.  He had started drinking a gallon of cranberry juice every day.  He was asked to cut back on his cranberry juice consumption and continue the same warfarin dose (13 mg/wk).  When he returned to clinic 2 weeks later, he was drinking ½ gallon of cranberry juice every day and his INR had decreased to 4.3.  His warfarin dose was reduced to 12 mg/wk and his INR will be closely monitored.

            Now, a case report has been published of a patient with a stable warfarin dose (18mg/wk) and a stable INR (between 2 and 3)5.  He was admitted to the hospital for shortness of breath and bleeding.  His INR was >18.  He was given fresh-frozen plasma, vitamin K and packed red blood cells.  Prior to admission there had been no changes to his medications or health status.  He had started drinking 24 ounces of cranberry juice every day.  The patient resumed warfarin after discharge, but not the cranberry juice.  He is stable again on the same dose he was on prior to admission.

            Perhaps there is no significant interaction between cranberry juice and warfarin at moderate doses.  But what is a moderate dose? The flurbiprofen study used 8 ounces of cranberry juice the night before and the morning of the tests.  That is total of 16 ounces.  How much is being used in the warfarin study from Tuft’s University?  How much was used in the UCLA study?  We won’t know until those studies are published. But it appears that extreme amounts, 24 ounces to a gallon every day, do have an effect on warfarin metabolism and the INR.  Moderation and monitoring is still the best advice.

UPDATE:

A study by Lilija et al found that cranberry juice had no effect on the enzymes responsible for the metabolism of warfarin, therefore it is very unlikely that any interaction occurs.  Drinking cranberry juice daily caused no effect on the action of warfarin.

References

  1. Committee on Safety of Medicines. Possible interaction between warfarin and cranberry juice.  Current Problems in Pharmacovigilance 2003;29(Sept)8.
  2. Committee on Safety of Medicines. Interaction between warfarin and cranberry juice:  new advice.  Current Problems in Pharmacovigilance 2004:30(Oct)10.
  3. Greenblatt D. Cranberry juice and warfarin:  Is there an interaction?  Anticoagulation Forum 2006;10(Spring)1-4.
  4. Greenblatt D, vonMoltke L, Perloff E, Luo Y, Harmatz J, and Zinny M.  Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: in vitro and clinical studies.  Clinical Pharmacology and Therapeutics 2006;79;125-133.
  5. Rindone J and Murphy T.  Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding.  American Journal of Therapeutics 2006 May-Jun;13(3):283-284.
  6. Lilija JJ et al. Effects of Daily Ingestion of Cranberry Juice on the Pharmacokinetics of Warfarin, Tizanidine, and Midazolam-Probes of CYP2C9, CYP1A2, and CYP3A4. Clin Pharmacol Ther. 2007 Mar 28; Epub ahead of print.

©2006 Jo Yacko

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Last modified April 8, 2007