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Interaction Between Warfarin and Cranberry Juice Jonathan L. Aston, B.S., Amy E. Lodolce, Pharm.D., and Nancy L. Shapiro, Pharm.D. Warfarin is extensively used for anticoagulation to a target international normalized ratio of 2.0–3.0 for most indications or 2.5–3.5 for high-risk indications; however, many drugs and dietary supplements induce fluctuations in the international normalized ratio. Such fluctuations may lead to therapeutic failure or bleeding complications. Cranberry juice is increasingly used for the prevention and adjunctive treatment of urinary tract infections. The United Kingdom’s Committee on Safety of Medicines has alerted clinicians to a potential interaction between warfarin and cranberry juice and has advised that patients avoid their concurrent use. Review and analysis of the literature revealed that ingestion of large volumes of cranberry juice destabilize warfarin therapy. Small amounts of juice are not expected to cause such an interaction. Clinicians should be aware of this potential interaction and monitor and counsel patients accordingly. Key Words: warfarin, drug-interaction, cranberry, cranberry juice, dietary supplements. (Pharmacotherapy 2006;26(9):1314–1319) OUTLINE Identification of Articles Literature Review Potential Mechanisms of the Interaction Since its discovery in the early 1940s, warfarin has become the most extensively used anticoagulant drug. 1 Warfarin is indicated for the treatment and prophylaxis of thromboembolic events associated with myocardial infarction, atrial fibrillation, prosthetic valve replacement, deep vein thrombosis, and pulmonary embolism. Its mechanism of action involves inhibiting the activation of vitamin K–dependent clotting factors II, VII, IX, and X. Anticoagulation with warfarin is often difficult to manage and stabilize because of interpatient variability, the high degree of protein binding, its narrow therapeutic index, and its penchant for drug and food interactions. 1, 2 The target international normalized ratio (INR) is 2.0–3.0 for most indications and 2.5–3.5 for high-risk indications. Many drugs induce fluctuations in the INR by inhibiting or inducing the metabolism of warfarin and by competing with albumin-binding sites. In addition, concomitant use of antithrombotic, antiplatelet, or nonsteroidal antiinflammatory drugs can potentiate the risk of bleeding in patients taking warfarin. Alterations in dietary intake of vitamin K and consumption of alcohol can elicit instability in anticoagulation management. 2 Such variations can lead to therapeutic failure, resulting in thrombo- embolism or bleeding complications. 1 Given the capricious nature of warfarin, extensive patient education, continuous monitoring, and identification of impending sources of variability are needed to achieve safe and effective anti- coagulation. Several case reports have implicated cranberry juice as another potential substance that interacts with warfarin. 3–7 The prescribing information for warfarin was updated in September 2005 to include cranberry products as a potential herb that may increase the effects of warfarin. 2 Cranberries, a fruit native to North America, are primarily cultivated for consumption as foods and beverages. 8 The juice and concentrated From the Department of Pharmacy Practice, College of Pharmacy (all authors); and the Antithrombosis Center (Dr. Shapiro), University of Illinois at Chicago, Chicago, Illinois. Address reprint requests to Nancy L. Shapiro, Pharm.D., Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, MC 886, Chicago, IL 60612; e-mail: nlasack @uic.edu.

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Page 1: Interaction Between Warfarin and Cranberry Juice

Interaction Between Warfarin and Cranberry Juice

Jonathan L. Aston, B.S., Amy E. Lodolce, Pharm.D., and Nancy L. Shapiro, Pharm.D.

Warfarin is extensively used for anticoagulation to a target internationalnormalized ratio of 2.0–3.0 for most indications or 2.5–3.5 for high-riskindications; however, many drugs and dietary supplements inducefluctuations in the international normalized ratio. Such fluctuations may leadto therapeutic failure or bleeding complications. Cranberry juice isincreasingly used for the prevention and adjunctive treatment of urinary tractinfections. The United Kingdom’s Committee on Safety of Medicines hasalerted clinicians to a potential interaction between warfarin and cranberryjuice and has advised that patients avoid their concurrent use. Review andanalysis of the literature revealed that ingestion of large volumes of cranberryjuice destabilize warfarin therapy. Small amounts of juice are not expected tocause such an interaction. Clinicians should be aware of this potentialinteraction and monitor and counsel patients accordingly.Key Words: warfarin, drug-interaction, cranberry, cranberry juice, dietarysupplements.(Pharmacotherapy 2006;26(9):1314–1319)

OUTLINE

Identification of ArticlesLiterature ReviewPotential Mechanisms of the Interaction

Since its discovery in the early 1940s, warfarinhas become the most extensively usedanticoagulant drug.1 Warfarin is indicated for thetreatment and prophylaxis of thromboembolicevents associated with myocardial infarction,atrial fibrillation, prosthetic valve replacement,deep vein thrombosis, and pulmonary embolism.Its mechanism of action involves inhibiting theactivation of vitamin K–dependent clottingfactors II, VII, IX, and X. Anticoagulation withwarfarin is often difficult to manage and stabilizebecause of interpatient variability, the high degreeof protein binding, its narrow therapeutic index,and its penchant for drug and food interactions.1,

2 The target international normalized ratio (INR)is 2.0–3.0 for most indications and 2.5–3.5 for

high-risk indications.Many drugs induce fluctuations in the INR by

inhibiting or inducing the metabolism of warfarinand by competing with albumin-binding sites. Inaddition, concomitant use of antithrombotic,antiplatelet, or nonsteroidal antiinflammatorydrugs can potentiate the risk of bleeding inpatients taking warfarin. Alterations in dietaryintake of vitamin K and consumption of alcoholcan elicit instability in anticoagulationmanagement.2 Such variations can lead totherapeutic failure, resulting in thrombo-embolism or bleeding complications.1 Given thecapricious nature of warfarin, extensive patienteducation, continuous monitoring, andidentification of impending sources of variabilityare needed to achieve safe and effective anti-coagulation. Several case reports have implicatedcranberry juice as another potential substancethat interacts with warfarin.3–7 The prescribinginformation for warfarin was updated inSeptember 2005 to include cranberry products asa potential herb that may increase the effects ofwarfarin.2

Cranberries, a fruit native to North America,are primarily cultivated for consumption as foodsand beverages.8 The juice and concentrated

From the Department of Pharmacy Practice, College ofPharmacy (all authors); and the Antithrombosis Center (Dr.Shapiro), University of Illinois at Chicago, Chicago, Illinois.

Address reprint requests to Nancy L. Shapiro, Pharm.D.,Department of Pharmacy Practice, College of Pharmacy,University of Illinois at Chicago, 833 South Wood Street,MC 886, Chicago, IL 60612; e-mail: nlasack @uic.edu.

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INTERACTION BETWEEN WARFARIN AND CRANBERRY JUICE Aston et al

extract from cranberries are increasingly used forthe prevention and adjunctive treatment ofurinary tract infections.8, 9 Cranberry fruit is alsoused in alternative medicine as an antipyretic anda urinary deodorizer in patients with incontinence.The bacteriostatic mechanism of cranberries wasinitially attributed to the acidification of urinedue to increased urinary concentration ofhippuric acid. However, data now suggest thatseveral high-molecular-weight components ofcranberry juice, including proanthocyanidin,decrease virulence by disrupting the adhesion ofbacterial fimbriae to glycolipids in theendothelial layer of the genitourinary tract.Cranberry juice seems to be most effective inpreventing the adhesion of Escherichia coli andEnterococcus faecalis, which are responsible formore than 85% of urinary tract infections.10

Identification of Articles

Articles about the potential interaction wereidentified by searching the MEDLINE database(from January 1966–June 2006) and theInternational Pharmaceutical Abstracts (fromJanuary 1970–June 2006) by using the termscranberry and warfarin together. A search of theMedWatch database of the United States Foodand Drug Administration (available fromhttp://www.fda.gov/medwatch/index.html) from1996–present revealed no safety reports specificto a warfarin-cranberry interaction. A search ofthe newsletter published by the UnitedKingdom’s Committee on Safety of Medicinesrevealed a summary of 12 case reports. Referencelists of identified articles were manually searchedfor additional relevant citations.

Literature Review

Several case reports prompted the speculationsurrounding the interaction between cranberryjuice and warfarin. Three were published in theliterature.3–5 The first involved a man in his 70swho had lethal gastrointestinal and pericardialhemorrhage after presenting to the hospital withan INR greater than 50.3 He had been drinkingcranberry juice for 6 weeks before the incident,and his condition had been stabilized with a drugregimen consisting of warfarin, phenytoin, anddigoxin. The man was adherent to treatment andwas not taking any over-the-counter or herbalproducts. For 2 weeks before his admission tothe hospital, the patient received cephalexin totreat a chest infection. During this time, hisappetite was severely reduced, and his diet

consisted primarily of cranberry juice. Nofurther details were provided. This was the firstpublished case to implicate cranberry juice indestabilizing warfarin therapy.

Several potential confounders should beconsidered in this case. The patient’s sparse dietcould have led to vitamin K deficiency, treatmentwith cephalexin might have disrupted thebiosynthesis of vitamin K by the gastrointestinalflora, and the patient’s infection, with or withoutfever, might have created a hypermetabolic statethat increased degradation of clotting factors.These factors could have contributed to thepatient’s elevated INR and lethal hemorrhage andmay undermine the validity of the interactiondescribed. This drug interaction was scored aspossible on the Naranjo adverse drug reactionprobability scale11 and on a modified Naranjoscale tailored for assessing anticoagulant druginteractions.12

Three opinions published in response to thiscase report questioned its validity and thesubsequent warnings issued in the UnitedKingdom to limit the consumption of cranberryjuice in patients receiving warfarin.13–15 Oneauthor questioned why any amount of cranberryjuice was considered safe, whereas the secondauthor commented that the patient’s poor dietaryintake (vitamin K deficiency) most likelycontributed to the supratherapeutic INR. Thethird author agreed that the patient’s dietaryintake likely influenced the outcome and statedthat warning patients to avoid cranberry juice isimpractical.

Notwithstanding the ambiguity surroundingthis case, another report of an interaction betweencranberry juice and warfarin was published.4 A69-year-old man was taking warfarin to treatatrial fibrillation and to prevent thromboemboliccomplications associated with mitral valvereplacement that occurred 26 years before hispresentation to the hospital. When the patientwas admitted to discontinue warfarin therapybefore elective bladder surgery, he had anunexpectedly elevated INR of 12. He was closelymonitored for several days after discontinuingthe warfarin, but his INR remained elevated at 10for 4 days. Vitamin K was eventually adminis-tered on day 4 (dose and route not reported), andhis INR was 2 several days later. During surgery,heparin was given intravenously, and theoperation progressed without complications.Several days after surgery, warfarin was restartedand resulted in an INR of 11 followed byepisodes of frank hematuria into his catheter and

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bleeding from the anastomosis site.Before his admission, the patient had never had

bleeding complications, and his INR had neverexceeded 4. His only other preadmission drugwas digoxin, and the only other postadmissiondrug was acetaminophen (paracetamol) withcodeine (amount taken not specified). The onlyapparent alteration in the patient’s dietary intakeor drug therapy leading up to the incident was anincrease in his consumption of cranberry juice.Two weeks before the planned surgery, thepatient began drinking nearly 2 L/day ofcranberry juice to prevent recurrent urinary tractinfections. Three days after ceasing his intake ofcranberry juice, his INR stabilized at 3, and hefully recovered.

Although controversy surrounds the existenceof a warfarin-acetaminophen drug interactionthat increases the INR, this patient did not takeacetaminophen until after surgery, which doesnot explain the initial increase in INR onadmission.16 Unlike the previous case, theabsence of any apparent confounding factors inthis report strengthens the evidence supportingan interaction. On both the Naranjo scale11 andthe Naranjo scale modified for anticoagulants,12

this interaction was rated as probable.Recently, a third case report was published

describing a 71-year-old man receiving warfarinfor stroke prophylaxis who had three previousstable INRs at a dosage of 18 mg/week.5 Duringthis time he had no changes in his drug therapy,diet, or overall health, and he denied alcohol use.He was admitted to the hospital for hemoptysis,hematochezia, and shortness of breath. Twoweeks before his admission, he had starteddrinking 24 ounces/day of cranberry juice as asource of vitamin C.

The patient’s laboratory values showed adecrease in hemoglobin level from 15.3 g/dl to8.8 g/dl, an INR above 18, and prothrombin timeabove 120 seconds. He was given 2 units ofpacked red blood cells, 1 unit of fresh frozenplasma, and vitamin K 5 mg subcutaneously. Healso was treated with gatifloxacin 200 mg/dayintravenously for presumed exacerbation ofchronic bronchitis. Over the next 24 hours, thebleeding subsided, and his INR was 7.0,necessitating an additional dose of vitamin K 2.5mg subcutaneously.

Five days after admission, the patient’shemoglobin level had increased to 11.5 g/dl andhis INR was 2.6. A colonoscopy performed 1year earlier showed arteriovenous malformationin the cecum and diverticulosis in the sigmoid

colon. On discharge, his warfarin was restartedat 14 mg/week; the dosage was escalated to 18mg/week, with resumption of INR control. Thepatient did not drink any more cranberry juiceafter discharge.

Again in this case, the presence of infectionwith or without fever presents as a possibleconfounder to the likelihood of cranberry juicecausing the bleeding and increase in INR. Detailsregarding the patient’s medical and drug therapyhistory were not provided and, therefore, cannotbe assessed. Using the Naranjo scale11 theinteraction was rated as possible, whereas usingthe Naranjo scale modified for anticoagulants12

this interaction was rated as probable.Including these cases, at least 12 interactions

between cranberry juice and warfarin werereported to the United Kingdom’s Committee onSafety of Medicines as of October 2004.6 Eightinvolved an increase in the INR with or withoutbleeding, three were characterized by an unstableINR, and one had a decreased INR. After review,the committee advised that patients takingwarfarin should avoid consuming cranberryjuice, capsules, and concentrates if possible. Ifpatients have a medical need for cranberry juice,they should be closely monitored duringconcurrent use.

We identified one other case report.7 Theapparent purpose of this brief report was toeducate clinicians that they should carefullyquestion patients when they suspect a potentialdrug-drug or drug-food interaction. The patientwas an elderly man with hypertension and atrialfibrillation whose INR fluctuated between 1 and10. The physician was unable to identify areason for the fluctuations and describedconsulting colleagues for input. A pharmacistmentioned the potential interaction withcranberry juice and, on further questioning,learned that the patient had been drinkingcranberry juice.

Patient education materials offered at manychain store pharmacies do not containinformation about a potential interactionbetween warfarin and cranberry juice. However,the interaction is listed in drug interactionresources. The Evaluation of Drug Interactions17

describes a moderate interaction on the basis ofthe first two case reports discussed earlier.3, 4 Itsrecommendation is to instruct patients receivingwarfarin to limit their consumption of cranberryjuice and to report changes in their consumptionto their health care provider. Drug InteractionsFacts18 suspect a major, delayed interaction based

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on documentation (first case report3), andpatients should limit or avoid concurrent use.Citing the first case report,3 Hansten and Horn’sDrug Interactions: Analysis and Management19

states that no action was needed, but cliniciansshould be alert to the possibility. Finally, Drug-Reax20 suggests a major, delayed interaction basedon good documentation (first case report3), andpatients receiving warfarin should avoidexcessive use of cranberry.

Potential Mechanisms of the Interaction

Several mechanisms of the interaction betweencranberry juice and warfarin have beenpostulated. One potential mechanism involvessalicylic acid, a constituent of many fruits andvegetables, including cranberries.8 Dietsconsisting of primarily vegetarian sourcessignificantly increased serum and urinaryconcentrations of salicylates, often overlapping(at the lower end of the confidence interval) withconcentrations measured in patients takingaspirin 75 mg/day.21 In addition, the amount ofsalicylic acid found in cranberry juice is 7 mg/L,and consuming 750 ml/day for 2 weeks cansignificantly increase the serum concentration toa mean of 0.34 µM/L.22 By comparison, theserum concentration of salicylic acid in patientstaking aspirin 75 mg/day can range from0.23–25.40 µM/L.21

Although this explanation is based on theargument that salicylic acid exerts an antiplateleteffect that can increase bleeding risk, it does notaccount for the increase in the INR becausealterations in platelet function do not affect theINR. The determination of INR is based on theprothrombin time, which reflects the activity offibrinogen and vitamin K–dependent clottingfactors II, VII, and X.1 The three published casereports3–5 described substantial fluctuations inINR in addition to bleeding. Furthermore, unlikeaspirin, which extensively inhibits plateletaggregation by means of irreversible acetylationof platelet cyclooxygenase-1 (COX-1), salicylicacid does not significantly reduce plateletfunction.22–24 Although salicylates may increasethe risk of gastrointestinal bleeding by reversiblyinhibiting COX-1 in the gastric mucosa, theycannot irreversibly acetylate COX-1 and,therefore, are unlikely to induce the systemicbleeding risk described in the three reports.

Another possible explanation for the increasedINR may stem from the increased salicylic acidconcentration, which is highly protein bound,

causing a displacement of warfarin fromalbumin-binding sites. Salicylic acid is usually50–80% bound to plasma proteins but mayexhibit high (90%) protein binding at low ortherapeutic serum concentrations. Toxic levelsare associated with 76% protein binding and highfree levels.25, 26 Therefore, the salicylic acidcontent in cranberry juice leads to low serumlevels of salicylic acid and a high percentage ofprotein binding.

Until recently, the most plausible explanationfor the increase in INR in patients who takewarfarin and drink cranberry juice involvedflavonoids in cranberry extract. Flavonoids arephytochemicals with diverse chemical structuresand a range of pharmacologic activities.27 Thesechemicals modify a variety of biochemicalpathways to exert antimicrobial, antioxidant,analgesic, antitumorigenic, and estrogenicproperties. In addition, certain flavonoidsmodulate the expression of specific cytochromeP450 (CYP) enzymes, inducing or inhibitingtheir activity.

Warfarin exists as a racemic mixture of the R-and S-enantiomers, with the S-enantiomer having2–5 times more anticoagulant activity than the R-enantiomer.2 Biotransformation of the S-enantiomer to an inactive metabolite occurspredominantly by means of hydroxylation byCYP2C9, whereas the R-enantiomer involvesCYP1A2 and CYP3A4.28 Inhibition of theCYP2C9 isoenzyme substantially increases theINR and potentiates the anticoagulant effect ofwarfarin. Several flavonoids, such as hyperforinand silibinin, inhibit the activity of CYP2C9.27

Such alterations in metabolic processes havebeen well publicized, prompted by evidence thatcertain flavonoids in grapefruit juice can inhibitthe activity of CYP3A4.27, 29 It had beenpostulated that flavonoids in cranberry juice mayfeasibly interfere with the enzymes responsiblefor metabolizing warfarin. However, a recentsingle-dose pharmacokinetic study in 12 healthyvolunteers who drank 240 ml of cranberry juicereconstituted from frozen concentrate with asingle 200-mg dose of cyclosporine failed toshow significant influences on the disposition ofcyclosporine, a CYP3A and P-glycoproteinsubstrate.30 In addition, a recent randomizedfive-way crossover study of healthy volunteersgiven single doses of flurbiprofen (as a surrogateindex of CYP2C9 activity) after receiving 8ounces of cranberry juice reconstituted fromconcentrate failed to show a significant reductionin flurbiprofen clearance or elimination half-life,

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suggesting that a pharmacokinetic interactionwith warfarin by this mechanism was unlikely.31

Whereas neither of these studies defend apharmacokinetic mechanism for this interaction,much smaller quantities of cranberry juice wereconsumed in these trials than what has beendocumented in the case reports and, therefore, donot rule out a dose-dependent alteration in thepharmacokinetics. A well-documented mechanismdescribing the interaction between warfarin andcranberry juice remains elusive.

Conclusion

Evidence supporting most drug interactions isoften derived from case reports, which haslimitations, including publication bias and aninability to prove causal relationships. However,they frequently help in identifying adverse eventsand drug interactions that may be otherwiseoverlooked.

Together, case reports substantiate thelikelihood that a clinically significant interactioncan occur when patients taking warfarin drinklarge amounts of cranberry juice. Long-termconsumption of large volumes of the juice canpotentially amplify destabilization of warfarintherapy. Therefore, patients receiving anticoag-ulation with warfarin should be informed toreduce or eliminate concomitant ingestion ofcranberry juice until additional data becomeavailable. Given that patients with recurrenturinary tract infections may tend to haveexcessive intake of cranberry juice, theyespecially should be cautioned about animpending interaction. In addition, careful andfrequent monitoring of the INR and of signs andsymptoms of bleeding is warranted whenconcurrent consumption does occur, and dosagesshould be adjusted accordingly.

Extensive patient education regarding theramifications of inconsistent dietary habits andfluctuations in drug use is imperative to achievestable and effective anticoagulation withwarfarin. In patients taking warfarin, aninteraction may occur if they increase theirintake of cranberry juice or occasionally ingest alarge volume; however, small amounts of thejuice are not expected to cause such aninteraction.

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