"I'm taking Coumadin may I eat vegetables? Is it OK to switch to nattokinase?"

Townsend Letter for Doctors and Patients, April, 2007 by Alan R. Gaby

Warfarin (Coumadin[R]) is a widely prescribed anticoagulant that is used to prevent and treat venous thrombosis and pulmonary embolism and to prevent complications after myocardial infarction. It is also frequently recommended for patients with chronic atrial fibrillation, a condition that increases the risk of thromboembolism.

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While warfarin has been shown to reduce the incidence of death and other adverse events in at-risk patients, the drug also increases the risk of bleeding, and in some cases, it causes severe hemorrhage. Patients taking warfarin must therefore be monitored frequently with a blood test, International Normalized Ratio (INR), that measures the clotting capacity of the blood. If the INR is too high, the warfarin dose is reduced in order to decrease the risk of bleeding. If the INR is too low, the dose is increased in order to assure that the drug will have a therapeutic effect. Some patients demonstrate wide fluctuations in their INR measurements, which may vary at different times from subtherapeutic to excessive. However, even patients whose INRs remain in the therapeutic range have a higher-than-normal risk of bleeding.

Warfarin works by inhibiting the vitamin K-dependent activation of coagulation factors II, VII, IX, and X. Because this inhibition is competitive in nature, the pharmacological effect of warfarin is influenced by dietary vitamin K intake. Greatly increasing vitamin K intake by eating more green leafy vegetables (and to a lesser extent certain oils such as soybean, canola, cottonseed, and olive oil) will inhibit the action of warfarin, whereas decreasing the intake of these foods will have the opposite effect. For this reason, people taking warfarin should maintain a consistent intake of foods that are high in vitamin K. (1)

Unfortunately, many physicians continue to advise their warfarin-treated patients to restrict their vitamin K intake, rather than to maintain a consistent intake of the vitamin. That recommendation is inappropriate for two reasons. First, restricting vitamin K intake requires the avoidance of green leafy vegetables and olive oil, both of which can play an important role in the prevention of cardiovascular disease. Most patients who are on warfarin have or are at high risk of developing cardiovascular disease, and these patients can benefit from eating a cardioprotective diet.

Second, keeping vitamin K intake relatively high may help prevent the potentially dangerous INR fluctuations that occur in some patients. That possibility was suggested by the results of a recent study. Eight patients receiving warfarin, whose INRs had been fluctuating for reasons that were not clear, were given 100 mcg per day of supplemental vitamin K1 for eight to 72 weeks (seven of the eight patients received vitamin K1 for at least 20 weeks). That dosage of vitamin K1 was chosen because it is similar to the amount found in a typical diet. After vitamin K1 supplementation, INR fluctuations decreased in nearly all patients, and more INRs (57% vs. 32% prior to supplementation) were within 0.2 units of the target range. (2) Thus, maintaining a consistent vitamin K intake of approximately twice the amount found in a typical diet appears to be beneficial for people taking warfarin.

Even when warfarin therapy is expertly managed (which all too often it is not, including at some specialty anticoagulation clinics), patients still must suffer from the inconvenience of frequent laboratory tests, the unsightly bruises that can occur after minimal trauma, and the fear that a major bleed will occur some day. Moreover, it cannot be encouraging to warfarin takers to learn that the drug was originally developed as a rat poison. For these reasons, many patients strongly dislike taking warfarin and would welcome any alternative therapy that has fewer adverse effects and offers a similar degree of protection.

Nattokinase, an enzyme obtained from natto (fermented soybeans), has become commercially available during the past several years. When administered orally, nattokinase has been shown to increase fibrinolytic activity in plasma and to promote the lysis of experimentally induced thrombi in dogs. (3) Based on these and other data, nattokinase has been promoted as a safe and effective alternative to warfarin. For example, one website claims, "No rat poison needed when taking nattokinase." (4)

However, no clinical trials have been done to determine whether nattokinase can prevent thromboembolism in humans. Nor is it clear from its known physiological effects whether one could expect nattokinase to be a reasonable alternative to warfarin. First, the fibrinolytic effect of nattokinase is relatively modest. Second, its "blood thinning" effect is mediated by a different mechanism of action than that of warfarin. Fibrinolytic agents promote the dissolution of clots once they have already formed, whereas warfarin prevents the formation of clots by inhibiting the activation of blood-clotting proteins. Because there are so many unknowns, it would be dangerous to assume that nattokinase is a clinically effective alternative to warfarin.