What You Should Know About Your Diet And Warfarin
What You Should Know About Your Diet and WarfarinWhat is warfarin?Warfarin is a medication that helps “thin” your blood to decrease your body’s chance of forming harmfulclots. Unwanted blood clots may cause strokes, heart attacks, or other potentially harmful events such asclots in the legs (deep vein thrombosis) or lungs (pulmonary embolism).How does warfarin work?There are proteins in your blood to help form clots. These proteins are made by your liver with the helpof vitamin K. Warfarin works by blocking the effects of vitamin K, making it harder for your body to formclots. In order to make sure the amount of warfarin you’re taking is right for you, your healthcareprofessional will test your blood periodically. The blood test checks your protime (PT) or internationalnormalized ratio (INR) to measure how long it takes for your blood to clot. If your PT/INR is outside yourtarget range, your warfarin dose will need to be adjusted.How does your diet affect warfarin?Since vitamin K and warfarin work against each other, the amount of vitamin K in your diet can changewarfarin’s effects. It is important to keep your dietary intake of vitamin K consistent. Foods such as greenleafy vegetables and certain oils have higher contents of vitamin K. (See the next page for a chart of vitaminK content in selected foods). If you DECREASE your intake of vitamin K (eat fewer foods containingvitamin K) your dose of warfarin may need to be lowered to prevent bleeding. If you INCREASE yourintake of vitamin K, your dose of warfarin may need to be increased to prevent blood clots. A MAJORchange in your vitamin K intake can affect your PT/INR, but normal daily variation in the foods you eat isokay. You DON’T have to avoid foods that are high in vitamin K, just keep your diet consistent. Youshould let your healthcare professional know if there is going to be a major change in your diet, so yourPT/INR can be closely monitored.Many people are on special diets, such as the Atkin’s or South Beach diets, to lose weight. These dietsare high protein diets and can also affect the way warfarin works in your body. Once you take a dose ofwarfarin, some of it binds to protein in your bloodstream. While warfarin is attached to this protein, it hasno effect on your body. It’s thought that high protein diets can increase the amount of proteins in your bodyand cause more warfarin to be bound to protein. This causes a DECREASE in warfarin available to preventclots, so your warfarin dose may need to be increased. Always check with your healthcare professionalbefore starting any special diets, so your PT/INR can be closely monitored.Certain foods can also affect how your liver clears warfarin from your body, causing warfarin levels toincrease or decrease. Examples include alcohol, cranberry products (e.g., juice, supplements), and possiblygrapefruit or grapefruit juice.Too much alcohol, cranberry products, or grapefruit products canINCREASE warfarin’s effect and increase your risk of bleeding. Avoid or limit your intake of alcohol,cranberry products, and grapefruit or grapefruit juice. Make sure your healthcare professional knows if yourdiet contains any of these products, so your PT/INR can be closely monitored.Other things to remember when taking warfarinIn addition to foods, many prescription and over-the-counter drugs, including vitamins and herbalsupplements, can affect your warfarin level. You should not start, stop, or change doses of any drugs orsupplements without first talking with your healthcare professional. Try to keep a healthy, well-balanceddiet and keep your vitamin K intake consistent. Take your warfarin dose around the same time each day. Ifyou miss a dose, take it as soon as you remember. If it is almost time for the next dose, skip the missed doseand continue your regular dosing schedule. Don’t double up doses without checking with your healthcareprofessional. Tell your healthcare professional immediately if you have unusual bleeding or bruising, blackor bloody stools, blood in the urine, or stomach pain. Prepared for the subscribers ofPharmacist’s Letter / Prescriber’s Letter to give to their patients.P.O. Box 8190, Stockton, CA 95208Phone: 209-472-2240 Fax: 209-472-2249www.pharmacistsletter.com www.prescribersletter.com
Vitamin K Content of Selected Foods*Note: This is NOT a list of foods to avoid. This list provides information on the vitamin Kcontent of certain foods.FoodsVegetablesLowVitamin K ContentModerateGreen beansCarrotsCauliflowerCeleryCornCucumber (peel removed)EggplantMushroomsOnionsGreen pepperPotatoPumpkinSauerkraut (canned)TomatoAsparagusAvocadoRed CabbageGreen peasPickle (dill)Lettuce (iceberg)HighBroccoliBrussels sproutsCabbageCollard greensEndive (raw)Kale (raw leaf)Lettuce (bib, red leaf)Mustard greens (raw)ParsleySpinachTurnip greens (raw)Watercress (raw)Swiss BeefChickenPorkTunaTurkeyFats and OilsCorn oilPeanut oilSafflower oilSesame oilSunflower oilMargarineOlive oilMayonnaiseCanola oilSoybean oilDairy ProductsButterCheese (cheddar)EggsSour creamYogurtBeveragesCoffeeColaFruit juicesMilkTea (black)Tea (green)*** Adapted with permission from Clotcare Online Resource at www.clotcare.com. (Accessed April 20, 2005).** There is some controversy as to whether brewing green tea alters the vitamin K content and/or whether green teamay alter the effect of warfarin by some other mechanism. Prepared for the subscribers ofPharmacist’s Letter / Prescriber’s Letter to give to their patients.P.O. Box 8190, Stockton, CA 95208Phone: 209-472-2240 Fax: 209-472-2249www.pharmacistsletter.com www.prescribersletter.com
(Page 3 of 8) Detail-Document #210507 This Detail-Document accompanies the related article published in PHARMACIST’S LETTER / PRESCRIBER’S LETTERMay 2005 Volume 21 Number 210507Warfarin-Food InteractionsLead author: Wan-Chih Tom, Pharm.D.BackgroundThe interaction between warfarin and vitaminK-containing foods is well documented. Patientson warfarin therapy are instructed to report anysignificant changes in their dietary vitamin Kintake in order to maintain a therapeuticinternational normalized ratio (INR). However,possible interactions between warfarin and highprotein diets, foods with antiplatelet effects, orfoods that affect the cytochrome P450 enzymesystem are not as well documented.Warfarin is a racemic mixture of R-warfarinand S-warfarin enantiomers.1 Warfarin ispredominately metabolized by the cytochromeP450 enzyme system.1The two warfarinenantiomers have different therapeutic potencyand are metabolized by different CYP450isoenzymes. S-warfarin is the most potent of thetwo enatiomers.1,2 S-warfarin is primarily asubstrate for CYP2C9 and secondarily CYP3A4.2R-warfarin is primarily a substrate for CYP1A2,secondarily CYP3A4, and slightly CYP2C19.2Foods that induce these isoenzymes can decreasewarfarin effect and foods that inhibit theseisoenzymes can potentiate warfarin effect.2 Thesignificance of the interaction will depend onwhich isoenzyme(s) the food affects and howmuch of the implicated food is consumed.Theoretically, foods such as cranberry juice,grapefruit juice, mango fruit, charbroiled foods,alcohol, and caffeine can affect warfarinmetabolism via the CYP450 enzyme system andpotentially alter warfarin effects.High Protein DietsIn the last few years, the popularity of highprotein, low carbohydrate diets, such as the Atkinsdiet and South Beach diet has soared in the U.S.Patients get on these diets in hopes of sheddingextra pounds. The diets instruct patients toincrease dietary intake of protein and decreaseintake of carbohydrate-containing foods. Bothdiets have an induction phase, where patients areto eliminate almost all carbohydrates from theirdiet for at least two weeks.3,4 Anticoagulationclinicians are seeing more INR fluctuations inpatients who are on high-protein, lowcarbohydrate diets. There are two case reports ofdecreased INR after initiation of high-protein,low-carbohydrate diets, requiring warfarin dosageto be increased by 20% to 30% to achievetherapeutic INR.5Warfarin is a medication that is highly proteinbound.1 The decreased INR in patients followinginitiation of a high-protein, low-carbohydrate dietmay be related to the effect of protein intake onalbumin level.5 An increase in albumin levelappears to occur within ten days of initiating ahigh-protein, low-carbohydrate diet.5 The increasein albumin level causes an increase in warfarinbinding to albumin, making less free warfarinavailable for anticoagulant effect.5 Some expertssuggest that a high-protein, low-carbohydrate dietmay also have an affect on warfarin’s metabolismvia the cytochrome P450 system.Because of the potentially significant decreasein INR level, patients are at high risk ofdeveloping thromboembolism shortly afterstarting the diet. Advise patients to consult theiranticoagulation clinician prior to starting a highprotein, low-carbohydrate diet in order to ensureclose monitoring of INR level [Evidence level D;Anecdotal evidence].5Cranberry JuiceIn 2003, the England-based Committee onSafety of Medicine (CSM) issued a warning aboutthe possible interaction between cranberry juiceand warfarin based on five case reports of suchinteractions.6 The potential interaction issuspected to be due to flavonoids found incranberry. It is theorized that the flavonoids incranberry might inhibit CYP2C9 metabolism ofwarfarin, and therefore, increase INR.7,8 AnotherMore. . .Copyright 2005 by Therapeutic Research CenterPharmacist’s Letter / Prescriber’s Letter P.O. Box 8190, Stockton, CA 95208 Phone: 209-472-2240 Fax: 209-472-2249www.pharmacistsletter.com www.prescribersletter.com
(Detail-Document #210507: Page 4 of 8)theoretical mechanism of interaction is theantiplatelet effect of the cranberry constituent,salicylic acid.8Cranberry juice containsapproximately 7 mg of salicylic acid per liter.Drinking three 250 mL servings of cranberry juicedaily for two weeks increases serum salicylatelevels.8Theoretically, the salicylic acid t effect.It is not known howdifferent cranberry products affect warfarinmetabolism or if this interaction can be avoidedby separating doses or limiting cranberry productconsumption. For now, advise warfarin patients toavoid or limit cranberry product consumption.Closely monitor warfarin patients who areconsuming cranberry products concurrently[Evidence level D; Anecdotal evidence].9Grapefruit JuiceGrapefruit juice contains flavonoids that caninhibit CYP3A4, CYP2C9, CYP2C19, andCYP1A2 isoenzymes.2,10 The effect of grapefruitjuice on drugs is difficult to predict because theamount of flavonoids may vary from product toproduct and the uptake of these flavonoids mayalso vary among individuals.10 Theoretically,grapefruit juice and the fruit itself might increasewarfarin effect by competing with both Rwarfarin and S-warfarin metabolism. There is onecase report of significantly increased INRassociated with consumption of 50 ounces ofgrapefruit juice daily.10 But a small clinical trialfound that consumption of 24 ounces of grapefruitjuice daily for one week had no effect on INR in agroup of men on warfarin therapy.10 Given theinconsistent findings and lack of clinical research,the best advice now is to advise warfarin patientsto avoid or limit grapefruit juice consumption to24 ounces or less a day [Evidence level D;Anecdotal evidence].10 Monitor INR closely if alarge amount of grapefruit juice or tly [Evidence level D; Anecdotalevidence].10AlcoholInteractions between alcohol and warfarin havebeen reported.There are two possiblemechanisms of interaction with alcohol: alterationof protein binding and inhibition or induction ofCYP2C9 isoenzyme.11 An increase in bloodalcohol levels competes for protein binding sites,making more active warfarin available for clinicalactivity.12Acute alcohol consumption candecrease warfarin metabolism and increasewarfarin effect, whereas chronic alcoholconsumption can induce warfarin metabolism anddecrease warfarin effect.12 Due to the increasedrisk of bleeding with acute alcohol consumption,patients should be advised to avoid or limitalcohol consumption while on warfarin [Evidencelevel D; Anecdotal evidence].12Mango FruitThere are at least thirteen cases of increasedINR associated with mango fruit consumptionreported.13 The subjects ingested anywhere fromone to six mangos daily for two days to a month.The average increase in INR was 38%. It istheorized that mango fruit inhibits CYP2C19;therefore, inhibit R-warfarin metabolism andincrease INR.13 Advise patients to limitconsumption of mangos while on warfarin therapy[Evidence level D; Anecdotal evidence].13Caffeine and Charbroiled FoodsCaffeine and charbroiled foods both have aneffect on the CYP450 enzyme system andtheoretically can affect warfarin metabolism;however, there are no case reports or evidence tosupport such interactions. Caffeine is a substratefor CYP1A2 and theoretically may compete withR-warfarin for metabolism.2 The hydrocarbons ofcharbroiled food can induce CYP1A2, thereforecan theoretically increase R-warfarin metabolismand decrease warfarin effect.2 Due to the lack ofevidence of these interactions, the best adviceright now is to tell warfarin patients to keep theircaffeine consumption consistent and limitconsumption of charbroiled foods [Evidence D,Anecdotal evidence].2GarlicGarlic can inhibit platelet aggregation andtheoretically can potentiate the effects ofwarfarin.14 There are case reports of excessivegarlic or garlic supplement consumptionassociated with altered platelet aggregation andprolonged bleeding.15 In addition, there are twoanecdotal reports of increased INR in patientspreviously stabilized on warfarin when they tookgarlic products.15 Patients taking warfarin shouldMore. . .Copyright 2005 by Therapeutic Research CenterPharmacist’s Letter / Prescriber’s Letter P.O. Box 8190, Stockton, CA 95208 Phone: 209-472-2240 Fax: 209-472-2249www.pharmacistsletter.com www.prescribersletter.com
(Detail-Document #210507: Page 5 of 8)be advised to avoid garlic supplements [Evidencelevel D; Anecdotal evidence].15 They should alsobe advised that regular consumption of foodscontaining small amounts of garlic is unlikely tohave an effect on warfarin efficacy [Evidencelevel D, Anecdotal evidence].15 Monitor INRclosely if excessive garlic consumption andwarfarin occurs concomitantly [Evidence level D,Anecdotal evidence].15GingerGinger is thought to inhibit thromboxanesynthetase and decrease platelet aggregation.16Theoretically, excessive consumption of gingermight increase the risk of bleeding. There is a casereport of increased INR when ginger supplementswere used concomitantly with phenprocoumon, acoumarin derivative.17 Regular consumption offood containing ginger is unlikely to pose aproblem in patients taking warfarin. However,ginger supplements contain much more gingerthan regularly found in food and might have thepotential of increasing bleeding risk in patientstaking warfarin. Patients taking warfarin andginger supplements concomitantly should beadvised to watch for symptoms of unusualbleeding or bruising and their INR should bemonitored closely [Evidence level D; Anecdotalevidence].15Green TeaThere are constituents in green tea that seem tohave antiplatelet effects and theoretically mightincrease the effect of warfarin.18 However, thereare no reports of green tea increasing the effect ofwarfarin in patients to date.Excessiveconsumption of green tea has been reported toantagonize the effects of warfarin in a patientpreviously stable on warfarin therapy.19 Theinteraction has been attributed to the vitamin K1content or possibly other constituents in greentea.18,19 The amount of vitamin K1 content or otherconstituents vary greatly among different greentea products depending on their sources andprocessing; therefore, it’s difficult to determinehow much green tea consumption would have aneffect on warfarin. Patients should be advised thatexcessive consumption of green tea mightdecrease the effectiveness of warfarin. Closemonitoring is warranted if concomitant use oflarge amounts of green tea and warfarin isexpected [Evidenceevidence].19levelD;AnecdotalSoySoybeans contain vitamin K and may alsoinhibit platelet aggregation.20 Different soypreparations have varying amounts of vitamin Kcontent. There is a case report where a patient’sINR decreased significantly after consuming soymilk daily for four weeks.20 However, the vitaminK content of soy milk is so low that there areprobably other mechanisms for the interactionbetween warfarin and soy milk.It’s beentheorized that soy can also decrease the absorptionof warfarin, but the exact mechanism ofinteraction is unknown.20,21Advise patients tolimit consumption of soy products and monitorINR closely if consumption of soy products andwarfarin occurs concurrently [Evidence level D;Anecdotal evidence].21ConclusionMost of the available information on thesepotential drug-food interactions is based on invitro data or case reports. Without well-designedclinical trials, it is difficult to prove a definitivecause and effect relationship between these foodsand warfarin.Drug-food interactions with warfarin canpotentiallyleadtohemorrhageorthromboembolism. Therefore, it is important thathealthcare professionals are aware of the potentialimplications of these drug-food interactions withwarfarin. Patients should be aware that changesin dietary habits can sometimes affect warfarinefficacy and should be advised to consult theirhealthcare professional prior to making majorchanges in their diet.In addition to foods, a number of dietarysupplements may also affect warfarin’s efficacy.(See the chart on the next page for a list ofselected dietary supplements that may increase ordecrease warfarin effectiveness). For more detailson interactions between warfarin and dietarysupplements, please refer to Natural MedicinesComprehensive Database at http://www.naturaldatabase.com. If you see a possible interactionbetween certain foods/supplements and cessdata.fda.gov/scripts/medwatch/to submit a report to the FDA.More. . .Copyright 2005 by Therapeutic Research CenterPharmacist’s Letter / Prescriber’s Letter P.O. Box 8190, Stockton, CA 95208 Phone: 209-472-2240 Fax: 209-472-2249www.pharmacistsletter.com www.prescribersletter.com
(Detail-Document #210507: Page 6 of 8)Potential Interactions of Dietary Supplements with WarfarinaPotential Increase in Risk of BleedingAcetyl-L-carnitineArnicaAlcohol, acute useBishop’s weedBlack teaBladderwrackBoldoBorage seed oilBurdockCaffeineChondroitin sulfateCod liver oilColtsfootCranberry, cranberry juiceDanshenDevil’s clawDong quaiEpimediumEucalyptus oilEvening primrose oilFenugreekFeverfewFish oilFlaxseed, Flaxseed oilFo-tiForskolinForsythiaGamma-linolenic acidGarlicGingerGinkgoGinseng, SiberianGlucosamineGrapefruit, Grapefruit juiceGuaranaGuggulHoly basilHoneysuckleHorse ateMelatoninMesoglycanMilk thistleN-acetyl glucosamineNattokinaseOolong teaPantethinePapayaPeppermint oilPropionyl-L-carnitineRed cloverReishi mushroomResveratrolSaw palmettoSea buckthornTiratricolTurmericVinpocetineVitamin AVitamin EWillow barkWintergreenPossible Decrease in Warfarin’s EffectsAcerolaAlcohol, chronic useAlfalfaCherokee rosehipChlorellaCoenzyme Q10Corn silkEDTAGinseng, AmericanGinseng, PanaxGreen teaLimoneneRose hipSmartweedSoySpinachSt. John’s wortStinging nettleVitamin CVitamin KWatercressaAdapted from Natural Medicines Comprehensive Database at www.naturaldatabase.com. (Accessed 4/21/05).More. . .Copyright 2005 by Therapeutic Research CenterPharmacist’s Letter / Prescriber’s Letter P.O. Box 8190, Stockton, CA 95208 Phone: 209-472-2240 Fax: 209-472-2249www.pharmacistsletter.com www.prescribersletter.com
protein, low carbohydrate diets, such as the Atkins diet and South Beach diet has soared in the U.S. Patients get on these diets in hopes of shedding extra pounds. The diets instruct patients to increase dietary intake of protein and decrease intake of carbohydrate-containing food
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