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Warfarin

Also indexed as: Coumadin®

Warfarin is an anticoagulant (slows blood clotting) used to prevent and treat people with venous thrombosis (blood clots in the veins) and pulmonary embolism (blood clots in the lungs). Warfarin is also used to treat or prevent dangerous blood clotting in people with atrial fibrillation (an irregularity in heartbeat) and, in some cases, to prevent stroke.

Interactions with Dietary Supplements

Bromelain
In theory, bromelain might enhance the action of anticoagulants. This theoretical concern has not been substantiated by human research, however.1

Coenzyme Q10
Coenzyme Q10 (CoQ10) is structurally similar to vitamin K and may affect blood coagulation.2 Four case reports describe possible interference by CoQ10 with warfarin activity.3 4 5 It remains unknown how common or rare this interaction is. Those taking warfarin should only take CoQ10 with the guidance of their doctor.

Minerals
Iron, magnesium, and zinc may bind with warfarin, potentially decreasing their absorption and activity.6 People on warfarin therapy should take warfarin and iron/magnesium/zinc-containing products at least two hours apart.

Papain
Papain, an enzyme extract of papaya, was associated with increased warfarin activity in one patient.7 Persons taking warfarin should avoid papain supplements until further information about this potential interaction becomes available.

Vitamin C
Although case reports have suggested that vitamin C might increase the activity of anticoagulants in a potentially dangerous way, this interaction has not been confirmed in research studies.8 In fact, a possible interference by vitamin C with the effect of anticoagulants has also been reported.9 A 52-year-old woman maintained on 7.5 mg of warfarin per day had a shortening of the blood clotting time which was not corrected by increasing warfarin up to 20 mg per day. Further questioning revealed she had begun taking an unspecified amount of vitamin C each morning. After stopping vitamin C, the blood clotting time returned to desired levels. Based on this and other case reports, people taking warfarin should consult with their physician before taking vitamin C supplements.

Vitamin D
In 1975, a single letter to the Journal of the American Medical Association suggested that vitamin D increases the activity of anticoagulants and that this interaction could prove dangerous.10 However, there have been no other reports of such an interaction, even though tens of millions of people are taking multivitamins that contain vitamin D. Most doctors typically do not tell patients taking anticoagulant medications to avoid vitamin D.

Vitamin E
An isolated case was reported in 1974 of vitamin E (up to 1,200 IU per day) being associated with increased anticoagulation (blood thinning) in a patient treated with warfarin.11 A study of 12 people undergoing warfarin therapy found that additional vitamin E (100 IU or 400 IU per day) did not induce a clinical bleeding state.12 Moreover, a double-blind trial found that supplementation with vitamin E in amounts up to 1,200 IU per day had no effect on warfarin activity.13 It now appears safe for people taking warfarin to supplement vitamin E despite information to the contrary often provided by doctors about this purported interaction. These warnings are based on the isolated case report from 1974.

Vitamin K
Warfarin slows blood clotting by interfering with vitamin K activity. Since vitamin K reverses the anticoagulant effects of warfarin,14 people taking warfarin should avoid vitamin K–containing supplements unless specifically directed otherwise by their prescribing doctor. Some vegetables (broccoli, Brussels sprouts, kale, parsley, spinach, and others) are high in vitamin K. Eating large quantities15 or making sudden changes in the amounts eaten of these vegetables can interfere with the effectiveness and safety of warfarin therapy. The greener the plant, the higher the vitamin K content.16 Other significant dietary sources of vitamin K include soybean oil, olive oil, cottonseed oil, and canola oil.17

Vitamin K supplementation can be used, however, to counteract an overdose of warfarin.18 Such treatment requires the supervision of a doctor.

Interactions with Herbs

Asian ginseng  (Panax ginseng)
Asian ginseng was associated with a decrease in warfarin activity in a case report.19 Persons taking warfarin should consult with a physician knowledgeable about botanical medicines if they are considering taking Asian ginseng or eleuthero/Siberian ginseng (Eleutherococcus senticosus). A 1999 animal study did not reveal any significant interaction between warfarin and pure ginseng extract.20

Dan shen (Salvia miltiorrhiza)
Dan shen, a Chinese herb, was associated with increased warfarin activity in several cases.21 22 23 24 Dan shen should only be used under close medical supervision by people taking warfarin. Sage (Salvia officinalis), a plant relative of dan shen found in the West, is not associated with interactions involving warfarin.

Devil’s claw (Harpagophytum procumbens)
Devil’s claw was associated with purpura (bleeding under the skin) in a patient treated with warfarin.25 However, key details in this case—including other medications taken and the amounts and duration of warfarin and devil’s claw taken—were not reported, making it impossible to evaluate this reported interaction. Until more is known, people taking warfarin should avoid taking devil’s claw.

Dong quai (Angelica sinensis)
A 46-year-old woman taking warfarin experienced increased strength of the anticoagulant properties of the drug after starting to use dong quai for menopause.26 The daily amount of dong quai was 1,130–2,260 mg per day. Her bleeding tendency returned to normal after discontinuing the dong quai. While little is known about the potential interaction of dong quai and warfarin, women should discuss the use of the herb with a healthcare professional if they are taking an anticoagulant drug and wish to use dong quai.

Feverfew (Tanacetum parthenium)
Although there are no documented cases of feverfew interacting with warfarin in humans, feverfew has been shown to interfere with certain aspects of blood clotting in test tube studies.27 28 29

Garlic (Allium sativum)
Garlic has been shown to help prevent atherosclerosis (hardening of the arteries), perhaps by reducing the ability of platelets to stick together.30 This can result in an increase in the tendency toward bleeding.31 Standardized extracts have, on rare occasions, been associated with bleeding in people.32 Garlic extracts have also been associated with two human cases of increased warfarin activity.33 The extracts were not definitively shown to be the cause of the problem. People taking warfarin should consult with a doctor before taking products containing standardized extracts of garlic or eating more than one clove of garlic daily.

Ginger (Zingiber officinale)
Ginger has been shown to reduce platelet stickiness in test tubes. Although there are no reports of interactions with anticoagulant drugs, people should consult a healthcare professional if they are taking an anticoagulant and wish to use ginger.34

Ginkgo (Ginkgo biloba)
Ginkgo extracts may reduce the ability of platelets to stick together, possibly increasing the tendency toward bleeding.35 Standardized extracts of ginkgo have been associated with two cases of spontaneous bleeding, although the ginkgo extracts were not definitively shown to be the cause of the problem.36 37 There are two case reports of people taking warfarin in whom bleeding occurred after the addition of ginkgo.38 39 People taking warfarin should consult with a physician knowledgeable about botanical medicines if they are considering taking ginkgo.

Green tea (Camellia sinensis)
One man taking warfarin and one-half to one gallon of green tea per day developed signs based on laboratory testing suggesting his blood was too thick because the green tea was blocking the effect of warfarin.40 Removal of the green tea caused normalization of his blood tests. Those taking green tea and warfarin together should have their blood monitored regularly to avert any problems and should consult with a doctor, healthcare practitioner and/or pharmacist before taking any medication.

Herbs containing coumarin derivatives
Although there are no specific studies demonstrating interactions with anticoagulants, the following herbs contain coumarin-like substances that may interact with warfarin and may cause bleeding.41 These herbs include angelica root, arnica flower, anise, asafoetida, celery, chamomile, corn silk, fenugreek, horse chestnut, licorice root, lovage root, parsley, passion flower herb, quassia, red clover, rue, sweet clover, and sweet woodruff. Dong quai contains at least six coumarin derivatives, which may account for the interaction noted above. People should consult a healthcare professional if they’re taking an anticoagulant and wish to use one of these herbs.

Quinine (Cinchona species)
Quinine, a chemical found in cinchona bark and available as a drug product, has been reported to increase warfarin activity.42 People should read labels for quinine/cinchona content. People taking warfarin should avoid quinine-containing products.

Reishi (Ganoderma lucidum)
As it may increase bleeding time, reishi is not recommended for those taking anticoagulant (blood-thinning) medications.43

St. John’s wort (Hypericum perforatum)
According to a preliminary report, volunteers taking 900 mg per day of St. John’s wort were given a single dose of an anticoagulant similar in action to warfarin.44 There was a significant drop in the amount of the drug measured in the blood. Seven case studies reported to the Medical Products Agency in Sweden also found a decrease in the anticoagulant activity of warfarin when St. John’s wort was taken at the same time.45 This may have occurred because certain chemicals found in St. John’s wort activate liver enzymes that are involved in the elimination of some drugs.46 47 People taking warfarin should consult with their doctor before taking St. John’s wort.

Interactions with Foods and Other Compounds

Alcohol
Alcohol use, especially long-term heavy drinking, can decrease the effectiveness of warfarin.48 People taking warfarin are cautioned to avoid alcohol.

Food
Some vegetables (broccoli, Brussels sprouts, kale, parsley, spinach, and others) are high in vitamin K. Eating large quantities49 or making sudden changes in the amounts eaten of these vegetables, interferes with the effectiveness and safety of warfarin therapy. Eating charbroiled food may decrease warfarin activity,50 while eating soy meal foods and cooked onions may increase warfarin activity.51 The significance of these last two interactions remains unclear.

Olestra
The FDA-approved fat substitute, olestra, interferes with fat absorption, including the absorption of fat-soluble vitamins. Vitamin K, a fat-soluble vitamin, is added to olestra to offset this adverse effect.52 Since vitamin K interferes with the activity of warfarin, eating snacks containing olestra may also interfere with the drug’s activity. The impact of eating snacks containing olestra has not been evaluated in people taking warfarin. However, until more is known, it makes sense for people taking warfarin to avoid olestra-containing foods.53

Summary of Interactions for Warfarin

Depletion or interference None known
Adverse interaction Asian ginseng*
Dan shen
Devil’s claw*
Dong quai*
Fenugreek*
Garlic*
Ginger*
Ginkgo*
Horse chestnut*
Papain*
Quinine*
Red clover*
Reishi
Sweet clover*
Sweet woodruff*
Vitamin D*
Vitamin K
Side effect reduction/prevention None known
Supportive interaction None known
Reduced drug absorption/bioavailability Coenzyme Q10
Green tea*
Iron*
Magnesium*
St. John’s wort*
Vitamin C
Zinc*
Other (see text) Alcohol
Bromelain
Eleuthero
Olestra
Soy
Vitamin C
Vitamin E

For the convenience of the reader, the information in the summary is categorized as follows: “Depletion or interference” indicates the drug may deplete or interfere with the absorption or function of the supplement or herb. “Adverse interaction” indicates that the supplement or herb used together with the drug may result in undesirable effects. “Side effect reduction/prevention” indicates the supplement or herb may reduce the likelihood and/or severity of a potential side effect caused by the drug. “Supportive interaction” indicates the supplement or herb may support or aid the function of the drug. “Reduced drug absorption/bioavailability” indicates that the supplement or herb may decrease the absorption and/or activity of the drug in the body. An asterisk (*) next to an item in the summary indicates that the interaction is supported only by weak, fragmentary, and/or contradictory scientific evidence.

References:

1. Harris JE. Interaction of dietary factors with oral anticoagulants: Review and applications. J Am Diet Assoc 1995;95:580–4 [review].

2. Morton RA. Ubiquinones, plastoquinones and vitamins K. Biol Rev Camb Philos Soc 1971;46:47–96.

3. Spigset O. Reduced effect of warfarin caused by ubidecarenone. Lancet 1994;344:1372–3 [letter].

4. Combs AB, Porter TH, Folkers K. Anticoagulant activity of a naphthoquinone analog of vitamin K and an inhibitor of coenzyme Q10- enzyme systems. Res Commun Chem Pathol Pharmacol 1976;13:109–14.

5. Landbo C, Almdal TP. [Interaction between warfarin and coenzyme Q10]. Ugeskr Laeger 1998;160:3226–7 [in Danish].

6. Pinto JT. The pharmacokinetic and pharmacodynamic interactions of foods and drugs. Topics in Clinical Nutrition 1991;6:14–33.

7. Shaw D, Leon C, Kolev S, Murray V. Traditional remedies and food supplements: a 5-year toxicological study (1991–1995). Drug Saf 1997;17:342–56.

8. Harris JE. Interaction of dietary factors with oral anticoagulants: Review and applications. J Am Diet Assoc 1995;95:580–4 [review].

9. Rosenthal G. Interaction of ascorbic acid and warfarin. JAMA 1971;215:1671.

10. Schrogie JJ. Coagulopathy and fat soluble vitamins. JAMA 1975;232:19 [letter].

11. Corrigan J, Marcus FI. Coagulopathy associated with vitamin E ingestion. JAMA 1974;230:1300–1.

12. Corrigan JJ Jr, Ulfers LL. Effect of vitamin E on prothrombin levels in warfarin-induced vitamin K deficiency. Am J Clin Nutr 1981;34:1701–5.

13. Kim JM, White RH. Effect of vitamin E on the anticoagulant response to warfarin. Am J Cardiol 1996;77:545–6.

14. Taylor CT, Chester EA, Byrd DC, Stephens MA. Vitamin K to reverse excessive anticoagulation: A review of the literature. Pharmacotherapy 1999;19:1415–25 [Review].

15. Harris JE. Interaction of dietary factors with oral anticoagulants: Review and applications. J Am Diet Assoc 1995;95:580–4 [review].

16. Kodaka K, Ujiie T, Ueno T, Saito M. Contents of vitamin K1 and chlorophyll in green vegetables. J Jpn Soc Nutr Food Sci 1986;39:124–6.

17. Booth SL, Centurelli MA. Vitamin K: a practical guide to the dietary management of patients on warfarin. Nutr Rev 1999;57:288–96 [review].

18. Weibert RT, Le DT, Kayser SR, et al. Correction of excessive anticoagulation with low-dose oral vitamin K1. Ann Intern Med 1997;125:959–62.

19. Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Health Syst Pharm 1997;54:692–3.

20. Zhu M, Chan KW, Ng LS, et al. Possible influences of ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats. J Pharm Pharmacol 1999;51:175–80.

21. Yu CM, Chan JCN, Sanderson JE. Chinese herbs and warfarin potentiation by “danshen.”J Intern Med 1997;241:337–9.

22. Tam LS, Chan TYK, Leung WK, Critchley JAJH. Warfarin interactions with Chinese traditional medicines: Danshen and methyl salicylate medicated oil. Aust NZ J Med 1995;25:258.

23. Chan TY. Drug interactions as a cause of overanticoagulation and bleedings in Chinese patients receiving warfarin. Int J Clin Pharmacol Ther 1998;36:403–5.

24. Izzat MB, Yim AP, El-Zufari MH. A taste of Chinese medicine! Ann Thorac Surg 1998;66:941–2.

25. Shaw D, Leon C, Kolev S, Murray V. Traditional remedies and food supplements: a 5-year toxicological study (1991–1995). Drug Saf 1997;17:342–56.

26. Page RL, Lawrence JD. Potentiation of warfarin by dong quai. Phamacotherapy 1999;19:870–6.

27. Heptinstall S, Groenewegen WA, Spangenberg P, Loesche W. Extracts of feverfew may inhibit platelet behaviour via neutralization of sulphydryl groups. J Pharm Pharmacol 1987;39:459–65.

28. Heptinstall S, Groenewegen WA, Spangenberg P, Losche W. Inhibition of platelet behaviour by feverfew: a mechanism of action involving sulphydryl groups. Folia Haematol Int Mag Klin Morphol Blutforsch 1988;115:447–9.

29. Loesche W, Mazurov AV, Voyno-Yasenetskaya TA, et al. Feverfew—an antithrombotic drug? Folia Haematol Int Mag Klin Morphol Blutforsch 1988;115:181–4.

30. Rose KD, Croissant PD, Parliment CF, Levin MB. Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic ingestion: A case report. Neurosurgery 1990;26:880–2.

31. Gadkari JV, Joshi VD. Effect of ingestion of raw garlic on serum cholesterol level, clotting time and fibrinolytic activity in normal subjects. J Postgrad Med 1991;37:128–31.

32. Burnham BE. Garlic as a possible risk for postoperative bleeding. Plast Reconst Surg 1995;95:213.

33. Sunter WH. Warfarin and garlic. Pharm J 1991;246:722 [letter].

34. Newall CA, Anderson LA, Phillipson JD. Herbal Medicines: A Guide for Health-Care Professionals. London: The Pharmaceutical Press, 1996, 135–7.

35. Kleijnen J, Knipschild P. Ginkgo biloba.  Lancet 1992;340:1136–9.

36. Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. N Engl J Med 1997;336:1108.

37. Rowin J, Lewis SL. Spontaneous bilateral subdural hematoma with chronic Gingko biloba ingestion. Neurology 1996;46:1775–6.

38. Mathews MK. Association of Ginkgo biloba with intracerebral hemorrhage. Neurology 1998;50:1934.

39. Gilbert GJ. Ginkgo biloba. Lancet 1997;1137 [letter].

40. Taylor JR, Wilt VM. Probable antagonism of warfarin by green tea. Ann Pharmacother 1999;33:426–8.

41. Miller LG, Murray WJ, eds. Herbal Medicinals: A Clinician’s Guide. New York: Pharmaceutical Products Press, 1999, 313–5.

42. Tatro D, ed. Anticoagulants-quinine derivatives. In Drug Interaction Facts. St. Louis, MO: Facts and Comparisons, Jul 1993.

43. Brinker F. Herb Contraindications and Drug Interactions. Sandy, OR: Eclectic Medical Publications, 1998,166–9.

44. Mauer A, Johne A, Bauer S, et al. Interaction of St. John’s wort extract with phenprocoumon [abstract]. Eur J Clin Pharmacol 1999;55:A22.

45. Safety of St. John’s wort (Hypericum perforatum) [Letters to the Editor from various authors]. Lancet 2000;355:575–7.

46. Nebel A, Schneider BJ, Baker RK, Kroll DJ. Potential metabolic interaction between St. John’s wort and theophylline [letter]. Ann Pharmacother 1999;33:502.

47. Mai I, Schmider J, et al. Unpublished results, May 1999. Reported in: Johne A, Brockmöller, Bauer S, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St. John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999;66:338–45.

48. Holt GA. Food & Drug Interactions. Chicago: Precept Press, 1998, 282.

49. Harris JE. Interaction of dietary factors with oral anticoagulants: Review and application. J Am Diet Assoc 1995;95:580–4 [review].

50. Holt GA. Food & Drug Interactions. Chicago: Precept Press, 1998, 293.

51. Holt GA. Food & Drug Interactions. Chicago, Precept Press, 1998, 284–5.

52. Food additives for direct addition to food for human consumption; olestra; final rule. 21 Federal Register 1996:3118–73.

53. Harrell CC, Kline SS. Vitamin K-supplemented snacks containing olestra: implication for patients taking warfarin. JAMA 1999;282:1133–4.