Risk of Hemorrhage Associated with Co-Prescriptions for Ginkgo biloba and Antiplatelet or Anticoagulant Drugs

Introduction

G inkgo biloba extract (GBE) is one of the most popular herbal products and has been used in traditional medicine for several hundred years. ^1,2 Its active constituents were terpene trilactones such as bilobalide, ginkgolide A, ginkgolide B, ginkgolide C, and flavonoids. The beneficial effects of G. biloba extract described by numerous studies included improvement of memory, cognitive functions associated with aging and senility, all types of dementias, ^3,4 peripheral vascular diseases (intermittent claudication), ^5,6 and neurosensory problems (tinnitus). ^7,8 In addition, it is believed to possess radical scavenging, blood flow improvement, vasoprotection, and anti-platelet activating factor activity. ^9,10 GBE is known to inhibit adenosine diphosphate (ADP) and collagen-induced platelet aggregation in vitro and in vivo through cyclic adenosine monophosphate (cAMP) increase and inhibition of thromboxane A2 synthesis. ^{11 –13} Recently, ginkgolides C from G. biloba were reported to have inhibitory effects on platelet aggregation through the increase of intracellular cAMP and cyclic guanine monophosphate production and matrix metalloproteinase-9 activation. ^14,15

Several recent review articles have indicated that ginkgo may increase the risk of bleeding. ^{16 –20} On the contrary, several randomized clinical trials suggested that no significant current evidence is available to support that GBE is associated with an inhibition of blood coagulation or platelet aggregation. ^{21 –24}

There is an increasing trend to use herbal medicine in recent years. It is categorized as an alternative/complementary medicine and sold as over-the-counter products in various forms of preparations and dose in Europe, the United States, and Asian countries. ^25,26 More than 60% of patients do not disclose their use of herbal medicine on their own when physicians take a medical history, and many physicians are unaware of the potential herb–drug interactions which might possibly cause severe adverse drug reactions. ^27,28 Whether GBE alone or co-prescription with antiplatelet or anticoagulant drugs is associated with hemorrhage is still an argument. To explore this possibility, prescribing data were retrieved from a large population-based health care dataset to explore the risk of hemorrhage in patients taking GBE concomitant with antiplatelet or anticoagulant agents.

Methods

Results

The trends of prescribing G. biloba in combination with one of the following drugs: clopidogrel, cilostazol, ticlopidine, and warfarin, by age and gender from 2000 to 2008 are shown in Table 1. The total number of sampling prescriptions increased dramatically during the study period, from 1,916,652 in 2000 to 2,023,164 in 2008. Of the total prescriptions each year, the prescription of G. biloba alone and in combination with one of the following—clopidogrel, cilostazol, ticlopidine, and warfarin—increased gradually from 1547 (0.08%) and 3575 (0.19%) in 2000 to 4676 (0.23%) and 15,297 (0.79%) in 2008, respectively. There was an upward trend in G. biloba alone for patients ages 20–39, 40–49, 50–59, in particular for the age of ≥60, with the proportion of 0.51% (792/1547) in 2000 to 0.7% (3087/4676) in 2008.

Table 2 shows the univariate and multivariate analyses for the risk of hemorrhage associated with co-prescription, patient age, and gender. The results of univariate analyses indicated that co-prescription of GBE with any one of the antiplatelet or anticoagulant drugs was associated with the risk of hemorrhage insignificantly (OR: 2.0; 95% CI: 0.6–6.5, p = 0.479). However, for patients age ≥65 years old (OR: 3.86; 95% CI: 2.8–5.3, p < 0.0001) and male patients (OR:1.5; 95% CI: 1.1–2.0, p = 0.0157), the univariate estimate of relative risk for hemorrhage was significant. Multivariate analyses adjusted for patients' age, gender, and co-prescriptions revealed the same results as univariate analyses (Table 2).

Discussion

This study showed that the prescription of G. biloba alone or in combination with antiplatelet (anticoagulant) drugs is increasing in the 9-year study period. The result is likely supported by the real-world situation that the use of herbal supplements in recent years worldwide exhibits an upward trend. ^25,26,30,31 The increased consumption of G. biloba reported in this study is likely because it is usually prescribed by primary physicians in the private or district clinic as an all-round circulation booster. Aspirin was not included in this study because aspirin was rarely prescribed in combination with G. biloba in a medical center in Taiwan; furthermore, some studies concluded that the co-administration of ginkgo with aspirin does not constitute a safety risk. ^21,32

The results of this study revealed that the relative risk of hemorrhage associated with the combined use of GBE with antiplatelet (anticoagulant) drugs is not significant (OR: 2.0; 95% CI: 0.6–6.5, p = 0.479). This finding is deemed to be consistent with the current clinical studies, which suggested that there was no significant correlation between hemorrhage and co-prescription of GBE and antiplatelet or anticoagulant drugs. ^{21 –23}

The bleeding events associated with GBE alone or in combination with antiplatelet or anticoagulants have been reported previously, but the causal relationship was not established conclusively.^33-48 The current finding showed that the risk of hemorrhage is associated with elderly patients (aged ≥65) identified in the GBE intake population (OR: 3.86; 95% CI: 2.8–5.3; p < 0.0001). This may lead to the conclusion that age was the most common risk factor. ^{33 –48} Therefore, it is suggested that elderly patients and health care providers should be concerned about the risk of hemorrhage associated with GBE.

G. biloba is a common herbal product available in the United States and Europe used as a dietary supplement to improve cognitive function. ^30,31,48 Additionally, it is reimbursed as a prescription drug by BNHI in Taiwan. The provision of information with the clinical practitioner on the potential risk of hemorrhage associated with co-prescription of GBE and the antiplatelet or anticoagulant drugs is necessary. This is the first study using large population-based data to explore whether use of GBE alone or in combination with antiplatelet or anticoagulant drugs is associated with hemorrhage. These findings deserve to be of concern by the general public.

The limitation of this study is similar to other that of studies using administrative databases and needs to be illustrated. First, the claim database was developed for administrative purposes; the conversion of claims into a research database requires substantial efforts to retrieve data. Second, the database can only provide information on the frequency and classes of medical resources prescribed; it cannot provide any clinical laboratory data or clinical information and possibility of product variation and dosage variation to evaluate the response of patients on drug therapy. Third, the true prevalence of co-prescriptions may be underestimated because the claim data did not included over-the-counter or self-administered alternative medications. However, claim databases are a rich and relatively inexpensive source of research information for studies of prescription patterns or health care utilization and medical expenditures; furthermore, they may have a high congruence with medical records data compared to patient surveys, both telephone and mail; therefore, they may avoid recall bias in research of patient surveys.

Conclusions

In conclusion, the combination of G. biloba extract with antiplatelet or anticoagulant drugs correlated with the risk of hemorrhage is not statistically significant. However, patients using ginkgo, particularly those with known bleeding risks and those who are elderly, should be particularly cautious about the possibility of increasing risk of bleeding. Additionally, G. biloba is being increasingly prescribed in hospitals, and it is also widely used as a health care supplement in the market. How to extend the drug-safety net to patients in the community who want to self-administer over-the-counter/alternative medications may be a major concern in the field of pharmacy.