Herbal Remedy Interactions with Warfarin and Aspirin
Herbal Remedy Interactions with Warfarin and Aspirin
By Dónal P. O'Mathùna, PhD. Dr. O'Mathùna is Senior Lecturer in Ethics, Decision-Making & Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationship relevant to this field of study.
A popular impression that herbs are basically safe exists along with a growing realization that some herbs interact with certain medications. Among potential interactions, one of significant concern is that between herbal remedies and anticoagulant medicines. The concern is highlighted in a survey of atrial fibrillation patients who were stabilized on warfarin.1 Those who consumed herbs four or more times per week were more likely to have suboptimal anticoagulation control. Optimal control was defined as an international normalizing ratio (INR) of 2.0 to 3.0. Yet in a survey of English patients taking warfarin, almost 20% were taking herbal remedies concomitantly.2 More than 90% had not discussed this with their health care professionals.
At least 180 dietary supplements have been noted as having the potential to interact with warfarin, and 120 with aspirin, clopidogrel, or dipyridamole.3 However, such concerns usually are accompanied by an acknowledgment that little evidence is available on this topic beyond case reports. Yet case reports cannot substantiate claims of causation. Given that warfarin remains a very useful drug, and the frequency with which it is used along with herbal remedies, clinicians should be aware of the evidence available to advise patients taking anticoagulant drugs about their concomitant use of herbal remedies.
Pharmacology
Anticoagulant therapy generally involves warfarin, while aspirin and other pharmaceuticals are used for their antiplatelet effects. However, most of the reports on herbs and bleeding problems focus on warfarin. This may arise because clinicians pay more attention to warfarin than other medications, monitoring its dosing and relevant laboratory tests closely. Although warfarin has proved to be a very valuable medication, its pharmacology is complex and raises clinical challenges.4 Individuals vary widely in their response to the medication, and regular monitoring is needed to ensure coagulation status remains stable. The average dose required is 5 mg/day, but individual needs range from 0.5 mg/day to 50 mg/day.5 Warfarin has a narrow therapeutic index, where too little can result in thrombotic or embolic events, while too much can lead to bleeding or hemorrhage.4
Warfarin is metabolized by the cytochrome P450 system in the liver. The enzymes in this large and complex group are known individually as CYP enzymes. Factors that influence this enzyme system will impact warfarin's therapeutic effectiveness. Different herbs impact various CYP enzymes differently, making correlations between herbal remedies and warfarin even more challenging.6 A growing number of herbs are known to impact this system, most notably St. John's wort.6 Herbs, foods, and dietary supplements can affect warfarin in other ways. Some contain vitamin K, others interfere with warfarin absorption, and some have antiplatelet effects or can interfere with protein carriers used by warfarin.6
Clinical Studies
As mentioned above, dozens of different herbs have been linked with anticoagulant effects. A recent systematic review of all reported herb-drug interactions identified 128 published case reports, of which 108 were for St. John's wort.6 Warfarin and aspirin were also associated with interactions with gingko, ginseng, and garlic. Therefore, this article will examine the evidence relating to these four commonly used herbal remedies.
Gingko
Several case studies have been published suggesting connections between gingko (Gingko biloba) and warfarin metabolism. Some of gingko's constituents have antiplatelet activity and are platelet-activating factor receptor antagonists.6 These activities have been suspected of being linked to postoperative bleeding. Ginkgo contains several aglycones which have been shown to inhibit P450 enzymes in vitro.4 However, for this to be clinically relevant, sufficient concentrations would need to accumulate in the liver to inhibit the enzymes in vivo. It is unclear whether this happens regularly.
Case reports have suggested that gingko leads to bleeding episodes in patients taking warfarin or aspirin.6 However, a systematic review of such case reports failed to substantiate such concerns.7 The review found that many case reports omitted crucial details which made it difficult to evaluate the role of gingko in the adverse events reported. With this, along with gingko's widespread usage, and the absence of bleeding problems in clinical trials that have involved almost 10,000 subjects, the reviewers concluded that the evidence does not support a causal link between gingko and bleeding.
A small number of controlled trials have been conducted in this area. In one, 50 healthy men were randomly assigned to receive either aspirin followed by aspirin plus ginkgo or vice versa.8 Treatment lasted 7 days. No significant differences were found in bleeding times or platelet aggregation between the two treatment regimens. Another trial involved 55 older patients with peripheral artery disease who had been taking 325 mg aspirin daily.9 They were randomly assigned to take 300 mg/day gingko or placebo for 4 weeks. No significant differences were found between the groups in a platelet function assay (PFA) or platelet aggregation.
In a controlled study, gingko failed to demonstrate an impact on warfarin anticoagulation in 24 patients on long-term warfarin therapy.10 INR values did not change significantly between 4-week periods when patients were taking gingko, coenzyme Q10, or placebo. In another study, researchers gave a single dose of warfarin to 12 healthy men after 7 days pretreatment with ginkgo.11 The men continued to take the herb for 7 days after the warfarin dose. INR values, platelet aggregation, and warfarin pharmacokinetics were not significantly different compared to when the men were given warfarin without any herb.
Another study involved 10 healthy adults whose PFA was measured with a PFA-100 analyzer.12 Subjects were blinded to which one of five herbs they took for 2 weeks. Each herb was followed by a 2-week wash-out period and then another herb given for 2 weeks until all subjects had taken all five herbs. They also took 325 mg aspirin daily for 2 weeks. No significant changes were found in the PFA-100 results while taking gingko or any of the other herbs compared to baseline (P > 0.10). The results were significantly different after taking aspirin (P < 0.02). This study will be referred to below as the PFA-100 Study.
A systematic review of eight randomized controlled trials (RCTs) concluded that gingko does not cause significant changes in blood coagulation parameters in a clinically relevant manner.13
Ginseng
Extracts of Asian ginseng (Panax ginseng) have been shown to inhibit platelet aggregation in vitro.6 However, case studies have reported both interfering and potentiating effects of ginseng on warfarin. Controlled trials have not confirmed that Asian ginseng affects platelet function. The PFA-100 study found that ginseng did not interfere with platelet function.12 In another RCT, 25 patients newly diagnosed with ischemic stroke were assigned to either warfarin or warfarin with Asian ginseng.14 After 2 weeks, INR and prothrombin time (PT) areas under the curve were significantly increased compared to baseline, but not significantly different between the groups. In another study, researchers gave a single dose of warfarin to 12 healthy men after 7 days pretreatment with ginseng.15 The men continued to take the herb for 7 days after the warfarin dose. INR values, platelet aggregation, and warfarin pharmacokinetics were not significantly impacted by ginseng as compared to results obtained when warfarin was given when the men were taking no herbal remedies.
However, in one study, different results were found with American ginseng (Panax quinquefolius). Twenty healthy subjects were randomly assigned to either American ginseng or placebo for 2 weeks.16 The impact of warfarin on INR was tested before and after the intervention phase. The peak INR, INR area under the curve, and peak plasma warfarin level all were significantly reduced in the ginseng group (P = 0.0012, 0.025, 0.026, respectively). The researchers speculated that these effects might be due to ginsenosides inducing liver enzymes.
Garlic
Case reports have suggested that garlic supplements might carry a risk of bleeding by influencing platelet function and coagulation.6 Some indirect evidence based on ratios of drugs to their metabolites points to garlic having an impact on some CYP enzymes making up the P450 system. However, clinical trials have again failed to substantiate these interactions. A RCT enrolled 52 patients on warfarin therapy for a variety of vascular or cardiac conditions.17 They were randomized to receive either aged garlic extract or placebo for 12 weeks. No significant differences were found in the number of bleeding-related adverse events between the groups.
The PFA-100 study discussed earlier included giving garlic to 10 people and did not find that it interfered with platelet function.12 Another study gave a single dose of warfarin to 12 healthy men either alone or after 14 days pretreatment with garlic.18 INR values, platelet aggregation, and warfarin pharmacokinetics were not significantly impacted by garlic.
St John's Wort
St John's wort (Hypericum perforatum) is an established inducer of P450 enzymes and thus can be expected to reduce the effectiveness of warfarin.19 This effect appears to be related to hyperforin content, which is one of the constituents used to standardize some St. John's wort preparations. Extracts with low hyperforin content had a weak or no effect on P450 and other metabolic enzymes.20 Accordingly, several case reports have been published where warfarin's anticoagulant effect was reduced in people taking St. John's wort concomitantly.21 Such interactions have been confirmed in clinical trials that found reduced plasma concentrations of warfarin and phenprocoumon (an anticoagulant similar to warfarin) in those taking St. John's wort.6,22
In a clinical trial, a single dose of warfarin was given to 12 healthy men either alone or after 7 days pretreatment with St. John's wort.15 The men continued to take the herb for 7 days after the warfarin dose. INR values and platelet aggregation were not significantly impacted by St. John's wort. However, the clearance rate of warfarin was significantly increased by St. John's wort, leading to a significantly reduced anticoagulant effect. The PFA-100 study did not find that St. John's wort interfered with platelet function.12 This may reflect the lack of a direct effect on coagulation, while the other studies looked at St. John's wort's effect on warfarin's metabolism.
Conclusion
Given the widespread use of herbal remedies and anticoagulant therapy, little controlled research has been published on their interactions. Numerous case reports have been published suggesting correlations, but these reports suffer from many of the weaknesses of anecdotal reports. While gingko, Asian ginseng (Panax ginseng), and garlic have been associated with bleeding problems related to anticoagulant and/or antiplatelet therapy, the small number of clinical trials available have not substantiated these effects.
However, one controlled study has identified concerns with American ginseng (Panax quinquefolius). This found that American ginseng reduced warfarin's anticoagulant effect in young, healthy volunteers. Also, studies have confirmed that St. John's wort increases the metabolism of warfarin, thus reducing its anticoagulant effect.
Recommendations
Given the widespread use of herbal remedies, and warfarin's narrow therapeutic index, it is important that clinicians ask their patients about all herbal remedies they are taking. The results of controlled trials indicate that earlier concerns about gingko, Asian ginseng, and garlic interacting with anticoagulants may not be warranted. However, open and full discussion about herbal remedies between clinicians and patients should help to identify concerns or help when exploring adverse effects. At the same time, patients taking American ginseng or St. John's wort should be alerted to their interactions with warfarin.
The available research has important limitations that must be taken into account when discussing these issues with patients. In all areas, relatively few studies have been conducted involving small numbers of patients. Most were of short duration. In addition, each herb is available in numerous brands and used in varying doses. The results obtained in the studies reviewed here may or may not be applicable to the other available brands. Numerous other herbs and herbal mixtures whose interactions with anticoagulant therapy have not been researched are available. For such reasons, patients on anticoagulant therapies should be alerted to the potential for drug interactions and urged to have their bleeding times and/or INR/PT monitored carefully, especially when making changes to the herbs they consume. To facilitate collection of better data in this area, drug-herb interactions should be reported to the FDA MedWatch program (http://www.fda.gov/Safety/MedWatch).
References
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7. Ernst E, et al. Does Ginkgo biloba increase the risk of bleeding? A systematic review of case reports. Perfusion 2005;18:52-56.
8. Wolf HR. Does Ginkgo biloba special extract EGb 761 provide additional effects on coagulation and bleeding when added to acetylsalicylic acid 500 mg daily? Drugs Res Dev 2006;7:163-172.
9. Gardner CD, et al. Effect of Ginkgo biloba (EGb 761) and aspirin on platelet aggregation and platelet function analysis among older adults at risk of cardiovascular disease: A randomized clinical trial. Blood Coagul Fibrinolysis 2007;18:787-793.
10. Engelsen J, et al. Effect of coenzyme Q10 and Ginkgo biloba on warfarin dosage in stable, long-term warfarin treated outpatients: A randomised, double blind, placebo-crossover trial. Thromb Haemost 2002;87:1075-1076.
11. Jiang X, et al. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2005;59:425-432.
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14. Lee SH, et al. Interaction between warfarin and Panax ginseng in ischemic stroke patients. J Altern Complement Med 2008;14:715-721.
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16. Yuan CS, et al. American ginseng reduces warfarin's effect in healthy patients: A randomized, controlled trial. Ann Intern Med 2004;141:23-27.
17. Macan H, et al. Aged garlic extract may be safe for patients on warfarin therapy. J Nutr 2006;136:793S-795S.
18. Mohammed Abdul MI, et al. Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects. Br J Pharmacol 2008;154:1691-1700.
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20. Madabushi R, et al. Hyperforin in St. John's wort drug interactions. Eur J Clin Pharmacol 2006;62:225-233.
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