Potential Interactions Between Alternative Therapies and Warfarin

Amy M. Heck, Beth A. Dewitt, and Anita L. Lukes

Disclosures

Am J Health Syst Pharm. 2000;57(13) 

In This Article

Documented Reports of Possible Herb-warfarin Interactions

Herbal products that have been associated with published case reports of possible interactions with warfarin include danshen, devil's claw, dong quai, green tea, ginseng, and papain. Dietary supplements such as Coenzyme Q 10 and vitamin E have also been reported to adversely affect warfarin therapy. It should be noted that the following information is derived primarily from individual case reports; further study is needed to identify the exact mechanism, time of onset, severity, and appropriate management of these potential interactions.

Coenzyme Q10

Coenzyme Q10 (also known as ubiquinone or ubidecarenone) is a provitamin found in the mitochondria of plant and animal cells. It is involved in electron transport and may act as a free-radical scavenger, an antioxidant, or a membrane stabilizer.[30] Coenzyme Q10 supplementation is primarily promoted to treat a variety of cardiovascular disorders, including heart failure, hypertension, stable angina, and ventricular arrhythmias.[30] Many patients with these conditions may also be prescribed warfarin.

Coenzyme Q10 is structurally related to menaquinone (vitamin K 2 ) and may have procoagulant effects.[31] The vitamin K-like effects of Coenzyme Q10 have been demonstrated in vitro and in four case reports describing possible warfarin and Coenzyme Q10 interactions. [32,33,34] In Denmark, a 72-year-old woman had a decreased response to warfarin while she was taking Coenzyme Q10. [33] Appropriate anticoagulation was achieved only when she stopped taking the product. A 68-year-old man who had a history of several episodes of pulmonary and cerebrovascular emboli and whose condition had been stabilized with warfarin (INR, 2-3) for six years had a reduction in his INR to 1.31 after consuming 30 mg of Coenzyme Q10 daily for two weeks.[34] The other case reports involved (1) a 72-year-old man with pulmonary embolism and repeated low INR measurements (1.46 and 1.27) while taking warfarin and undetermined doses of Coenzyme Q10 and (2) a 70-year-old woman with thromboemobolic disease stabilized on warfarin (INR, 2-3) for several months who had a reduction in her INR to 1.46 within two weeks of starting Coenzyme Q10. [34] In each of these patients the INR, which had been stable and therapeutic, fell below the therapeutic range during co-enzyme Q10 use and subsequently returned to the therapeutic range after the provitamin was discontinued.

Until more is known about the effect of the combination of Coenzyme Q10 and warfarin, patients should be advised to avoid the combination because of the possible risk of thrombotic complications. If warfarin and Coenzyme Q10 are used concomitantly, the patient's INR should be monitored periodically within the first two weeks.

Danshen

Although not commonly used in the United States, danshen (the root of Salvia miltiorrhiza), also known as tan seng, is a very popular herb recommended in the Chinese community for various cardiovascular diseases. The pharmacologic effects of danshen have been described primarily in vitro and in animals and include hypotensive effects, positive inotropic effects, coronary artery vasodilation, and inhibition of platelet aggregation.[35,36,37] Pharmacokinetic and pharmacodynamic studies in rats indicate that danshen root extracts increase the absorption rate, area under the plasma concentration-versus-time curve, and maximum concentration of warfarin, as well as reduce the elimination half-life.[38,39]

There have been several case reports of a warfarin-danshen interaction. [40,41,42,43] A 62-year-old man who had been receiving 5 mg of warfarin daily after a mitral valve replacement and who had had a stable INR for several weeks was admitted to a Hong Kong hospital with pleural and pericardial effusion; his hemoglobin concentration was 7.6 mg/dL and his INR was >8.4. [41] The man reported consuming a danshen extract daily for two weeks before his admission. The INR of a 48-year-old woman taking warfarin 4 mg/day increased to 5.6 after she consumed danshen every other day for about one month.[42] A 66-year-old man who had been receiving warfarin 2-2.5 mg/day for nearly a year and had an INR stabilized at 2.0 was hospitalized for bleeding from a gastric carcinoma; the associated INR was 5.5. [43] He reported consuming danshen three and five days before admission and using a Chinese medicated topical oil containing methyl salicylate. Both this man and the 48- year-old woman in the previous example achieved a therapeutic INR after discontinuing danshen.

The available evidence contraindicates concurrent use of danshen and warfarin.

Devil's Claw

Devil's claw (Harpagophytum procumbens) is an expensive herbal product that has been promoted for use as an analgesic in the treatment of arthritis, gout, and myalgia.[5,8] Although information about the pharmacologic effects of devil's claw is limited, one case of purpura was reported in a patient receiving warfarin and devil's claw.[44] This case was uncovered during a toxicology review conducted between 1991 and 1995 by the National Poisons Information Service, which provides emergency information for poisonings throughout the United Kingdom. However, key details of this case, including the patient's medical conditions, other medications, and the doses and duration of warfarin and devil's claw ingestion, were not reported. Until more is known about this possible interaction, patients taking warfarin should be advised to avoid devil's claw.

Dong quai

Dong quai (Angelica sinensis) is a Chinese herbal supplement promoted in the United States for use in the treatment of menopausal complaints and menstrual disorders. [6,45] Dong quai contains at least six coumarin derivatives; these substances are believed to promote vasodilation and uterine stimulation and to have anti-inflammatory, antipyretic, antispasmodic, immunosuppressant, and estrogen-like effects.[6,46] Dong quai may also exert an antithrombotic effect by inhibiting platelet activation and aggregation. [47] On the basis of the known pharmacologic effects of dong quai and a small pharmacokinetic study in rabbits that suggested the potential for increased prothrombin times when this herb is administered with warfarin, a potentially dangerous interaction was theorized.[7,48] A recent case report supports this idea. A 46-year-old woman who had been taking warfarin 5 mg/day for nearly two years and had an INR stabilized at 2-3 experienced a sudden increase in her INR to 4.9. [49] The patient denied any changes in her medication regimen, diet, alcohol consumption, or other lifestyle factors that may affect her INR except for the recent addition of dong quai 565 mg once or twice daily during the preceding four weeks for the management of menopausal symptoms (her herbalist had recommended this). The patient was instructed to discontinue dong quai, and within four weeks her INR declined to the therapeutic range. In view of this information, patients receiving warfarin should be advised to avoid dong quai.

Ginseng

Three ginseng species: American ginseng (Panax quinquefolius), Oriental ginseng (Panax ginseng), and Siberian ginseng (Eleutherococcus senticosus) have been promoted as enhancing energy, reducing the effects of stress, and improving mood, among several other claims.[7,14] The active components of ginseng are known as ginsenosides, more than 20 of which have been identified. The pharmacologic activity of each ginsenoside appears to vary depending on where the plant grew and the extraction techniques used.[50] Also, data suggest that the ginsenoside composition varies widely among commercially available ginseng products.[51] This variability makes it difficult to evaluate the safety and efficacy of ginseng products. Although the exact pharmacologic actions of ginsenosides in humans are not fully understood, studies in vitro and in animals suggest that these substances may increase adrenal hormone synthesis, decrease blood glucose concentrations, and promote immunomodulation.[52,53,54]

One published case report suggests that Oriental ginseng (Ginsana) may antagonize the anticoagulant effects of warfarin.[55] The INR of a 47- year-old man who had been receiving warfarin for nine months (7.5 mg every Tuesday and 5 mg on all other days) to prevent thrombotic complications associated with a mechanical heart valve was stabilized at 3.0-4.0. The patient began taking Oriental ginseng, and within two weeks his INR fell to 1.5. The patient denied any other changes in his medication regimen (including other nonprescription or herbal products), diet, alcohol consumption, or other lifestyle factors that may have affected his response to warfarin. The patient's INR returned to therapeutic level (3.3) two weeks after he stopped using ginseng.

The possible mechanism for this interaction has not been identified, and it is not known which ginsenoside or ginsenosides may be responsible. A 1999 pharmacokinetic study in rats did not reveal a significant interaction between warfarin and pure ginseng extract. [56] Nevertheless, because of the potential seriousness of thrombotic complications resulting from a subtherapeutic INR, patients receiving warfarin should avoid ginseng until more is known.

Green Tea

Green tea (Camellia sinensis), also known as Chinese tea, is a popular beverage purported to prevent various cancers, treat gastrointestinal disorders, and enhance cognition.[8,57] Although dried green tea leaves have been found to contain substantial amounts of vitamin K, brewed green tea is generally not considered a significant source of the vitamin. [58,59] However, large amounts of brewed green tea may potentially antagonize the effects of warfarin. The INR of a 44-year-old warfarin recipient with a mechanical heart valve decreased substantially when he started consuming large amounts of brewed green tea.[60] The patient reported to the outpatient clinic with an INR of 1.37; his INR 22 days prior to this visit had been 3.79. The patient was unable to be reached until his return visit to the clinic one month later, at which time his INR was 1.14. In an interview, the patient disclosed that he had begun drinking 0.5-1 gallon of brewed green tea daily approximately one week before the INR measurement of 1.37. There were no other identifiable causes of the dramatic decrease in the INR, including changes in the patient's medications, dietary intake, medication compliance, or medical conditions.

A significant drop in the INR would not generally be expected to result from usual consumption of moderate amounts of brewed green tea. It is probably not necessary to advise patients receiving warfarin therapy to avoid green tea. However, patients should be advised that large quantities of green tea might decrease the effectiveness of warfarin.

Papain

Papain is a mixture of proteolytic enzymes found in extract of papaya, the fruit of the papaya tree (Carica papaya).[8] It is taken orally in the belief that it reduces edema, inflammation, herpes zoster symptoms, diarrhea, and psoriasis symptoms.[8] The pharmacologic mechanisms by which papain may affect coagulation are not known. However, one case of an interaction between warfarin and papain was identified in the 1991-95 toxicology review conducted throughout the United Kingdom by the National Poisons Information Service.[44] A patient who had maintained a therapeutic INR while receiving warfarin began taking papaya extract containing papain as a weight-loss aid. The patient was admitted for cardiac surgery with an INR of 7.4. After withdrawal of both papaya extract and warfarin, the patient's INR decreased to 2.0. The details of the case have not been published, however.

Patients receiving warfarin should be advised to avoid papain supplementation until further information about this potential interaction becomes available.

Vitamin E

Vitamin E has received much publicity as one of several antioxidants that may be useful in treating a variety of disorders, including cardiovascular diseases. Vitamin E may inhibit the oxidation of reduced vitamin K.[61] Vitamin K oxidation is necessary for carboxylation of vitamin K-dependent clotting factors, which must occur for these clotting factors to be fully functional. Conflicting information exists about the effect of vitamin E on prothrombin time.

A 55-year-old man taking warfarin and 1200 units of vitamin E daily developed ecchymoses and hematuria, and his prothrombin time increased. After a two-month period of stable clinical and hematologic status without concomitant vitamin E intake, the patient was rechallenged with vitamin E 800 units/day. Again, multiple ecchymoses appeared on his extremities. His prothrombin time began to increase at four weeks and continued to increase over the next two weeks. Within a week after the patient stopped taking vitamin E, his prothrombin time returned to the value reported before he had begun the vitamin. [62]

Studies in animals and humans consuming adequate vitamin K and not receiving warfarin have found no effect of vitamin E on coagulation. However, vitamin K-deficient animals have demonstrated bleeding diatheses associated with vitamin E.[63,64] A study in 12 patients undergoing warfarin treatment who received 100 or 400 units of vitamin E daily for one month found that neither dose induced a clinical bleeding state.[64] Kim and White [65] conducted a randomized, double-blind study in which four patients received 1200 units of vitamin E daily, three patients received 800 units/day, and four received placebo, all for four weeks.[65] During the study's second phase, which was single-blind and not randomized, six subjects were told they would receive placebo or vitamin E, but all were given vitamin E 1200 units/day for an additional four weeks. The INR did not increase to a level necessitating warfarin dosage adjustments in either treatment group. Although these studies indicated no interaction between vitamin E and warfarin, both were small and limited to only one month.

Vitamin E up to 400 units/day does not appear to affect prothrombin time in patients receiving warfarin. Although higher dosages appeared to be safe in the study by Kim and White,[65] some conflicting information suggests the potential for certain patients to be adversely affected by the combination of vitamin E and warfarin. The characteristics of those patients have not been determined. Therefore, patients receiving warfarin who are beginning vitamin E therapy, particularly dosages greater than 400 units/day, should have INR measurements conducted one to two weeks after starting vitamin E. This should be followed by INR monitoring every two to four weeks during the first two months of combination therapy. Increased prothrombin times induced by combined vitamin E and warfarin therapy may be managed by discontinuing vitamin E, and, if necessary, by administering vitamin K.

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