Phytotherapy review & commentary

Townsend Letter for Doctors and Patients,  April, 2004  by Kerry Bone

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Ginkgo and Bleeding Tendency: Guilt by Association?

Ginkgo biloba as the 50:1 standardized extract (EGb) has been used as an herbal treatment for "cerebral insufficiency" and intermittent claudication for almost 40 years.(1) It is often assumed that, given these vascular indications, Ginkgo has a clinical impact on bleeding parameters (in other words it is a "blood thinning" agent). This assumption is fuelled by the significant in vitro and in vivo activities of EGb and the isolated ginkgolides against PAF (platelet activating factor). (1) Platelet activating factor has several important biological properties, including the promotion of platelet aggregation under pathological conditions.

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Journals now abound with articles attributing antiplatelet or even anticoagulant properties to Ginkgo, warning against its concurrent use with aspirin or warfarin and advising that it should be discontinued prior to surgery. For a recent example, see the article published in The Journal of The Royal Society for the Promotion of Health. (2) Cases of spontaneous bleeding (3-8) and adverse interactions with warfarin (4) and aspirin (5) have been reported. The use of Ginkgo is most widespread in Germany, where it is commonly prescribed by medical doctors. Until recently, the German authorities were largely silent on the issue of increased bleeding tendency, suggesting they were not concerned. However, last year an "Important Notice" was released from the Pharmaceutical Commission of German Pharmacists. (6) This was in turn based on the publication of a summary of reports concerning Ginkgo from the German adverse reactions database. By 2002 there were 185 reports of adverse reactions to Ginkgo in Germany, (7) of which 20 reports were connected to coagulation disorders. The Commission warned that patients using Ginkgo extracts are in danger of suffering spontaneous bleeding or complications during surgery and there is an increased danger of bleeding with concomitant use of anticoagulant drugs.

But the case against Ginkgo is far from proven. The herb is one of the most popular in the Western world (for example more than five million units of Ginkgo products were sold in Germany alone in 1998) (8) and, because of its indications, Ginkgo is largely taken by older people. So the risk of spontaneous bleeding and the use of warfarin and aspirin are relatively high in the population taking Ginkgo. The possibility therefore exists that hemorrhagic episodes are inappropriately attributed to Ginkgo, when it is not the causative agent at all. In other words, a combination of Ginkgo's reputation, its popularity and the demographics of its use leads to a self-fulfilling prophecy: that the herb is a risk for bleeding tendency.

There are in fact, findings from several clinical studies which challenge the assumption that Ginkgo significantly alters bleeding parameters or interacts with antiplatelet or anticoagulant drugs. While a few early studies showed mild and probably insignificant effects, later studies failed to find any activity at all.

In studies with healthy volunteers, acute oral administration of standardized Ginkgo extract (15 mL probably corresponding to 600 mg dry extract) and a ginkgolide mixture (80 mg and 120 mg) inhibited PAF-induced platelet aggregation. (9), (10) The effect with the Ginkgo extract was only transient and there were no concomitant changes in coagulation, skin bleeding time, hematological and biochemical laboratory tests, blood pressure or pulse. (14) Longer-term oral administration with the standardized extract (120 mg/day for 3 months) resulted in inhibition of collagen-induced platelet aggregation, but failed to inhibit three other inducers, including PAF (1 [micro]mol/L), ex vivo. (11) Oral administration of standardized extract (112.5 mg) to healthy volunteers has been shown to reduce erythrocyte aggregation, but had no effect on plasma viscosity, platelet aggregation or blood pressure. (12) Another study reported a significant decrease in both diastolic and systolic blood pressure in healthy volunteers ingesting standardized extract (120 mg/day at bedtime) for 3 months. Bleeding times and fibrinogen levels showed no change. (13) Recently a double-blind, placebo-controlled study carried out in 32 healthy young male volunteers found that doses of EGb from 120 to 480 mg/day for 14 days had no effect on platelet function or coagulation parameters. (14)

Concomitant treatment with standardized Ginkgo extract (100 mg/day) for 4 weeks in patients who were stabilized on long-term warfarin therapy had no significant influence on their response to warfarin in a randomized, double blind, placebo-crossover trial (average age of patients was 64.5 years). The stability of international normalized ratio (INR) values was confirmed and major bleedings or thromboembolic events were not observed. (15) Administration of standardized Ginkgo extract (240 mg/day) for 7 days, alone or concomitantly with aspirin (500 mg/day), had no influence on bleeding parameters in a controlled trial involving 50 patients. (16)