It is estimated that about one-third of adults in the United States use herbal supplements.1 These supplements are widely used, especially by patients with chronic conditions. Despite the lack of sufficient data to prove the safety and efficacy of these supplements, their use has increased greatly in elderly patients. Often, patients do not inform their providers about the use of herbal products; this can significantly hinder patient care and adverse event reporting. Many patients do not consider herbal products to be medications.

The use of herbal supplements is becoming a major safety concern because drug–herbal interactions can cause serious adverse events. These events are due to a lack of patient education and information about drug interactions involving alternative medicines. This is especially problematic in the use of medications with narrow therapeutic indices, such as warfarin.

Mechanism of Coumadin–Herbal Interactions
Warfarin–herbal interactions can be classified based on pharmacokinetics and pharmacodynamics.2 Pharmacokinetic interactions involve the processes by which warfarin is absorbed, distributed, metabolized, and excreted.2 Warfarin is metabolized by cytochrome P450 isoenzymes (CYPs), with CYP2C9 being responsible for the majority of the metabolism of the S-enantiomer of warfarin, which is more potent than the R-enantiomer.2 Herbal supplements that have an effect on CYP3A4 or CYP2C19 are also expected to affect the plasma concentration of warfarin.2 These supplements alter warfarin plasma concentration through the inhibition or induction of warfarin protein binding.

The other mechanism by which warfarin and herbs interact is called pharmacodynamics. In pharmacodynamic interactions, the presence of an herbal product affects warfarin mechanism through interference with the coagulation cascade, platelet function, or the vitamin K cycle.

It has been shown that some herbs decrease platelet aggregation by “inhibiting the binding of platelet activation factor to their receptors on platelet membrane".2 The coagulation cascade, which is composed of the extrinsic pathway, intrinsic pathway, and the common pathway, involves several coagulation factors (ie, factors I through XIII; protein C; and thrombomodulin).2 Any herbal product that affects the expression of these factors will interact with warfarin. Some herbs also interact with warfarin by reducing vitamin K synthesis by gut flora or by affecting enzymes involved in the vitamin K cycle; thus, pharmacodynamics play a major role in herbal and warfarin interaction mechanisms.

In a review article published in March 2014, 38 herbs were reviewed and were found to clinically interact with warfarin. The clinical effects of the herbs on warfarin were categorized as potentiation or inhibition. Herbs that may potentiate the effect of warfarin, increasing the risk for bleeding, are listed in Online Table 1.1-3 The potentiation was classified as major, moderate, minor, or non-clinical.2 Major potentiation was defined as death, major bleeding, or the need to interrupt warfarin therapy due to serious bleeding.2 Moderate potentiation was defined as an international normalized ratio (INR) that requires a dosage adjustment. Minor potentiation was defined as an INR that does not require a dosage adjustment.

Online Table 2 lists herbs that may inhibit the mechanism of warfarin.1,2 Nonclinical interactions for both potentiation and inhibition were defined as no change in INR. These herbs cause thrombosis, and their inhibitory effect on warfarin was classified as major, moderate, or minor. Major inhibition was defined by the signs of thrombosis, while moderate inhibition was defined by INRs that required a warfarin dosage adjustment. Minor inhibition was defined by INRs that did not require dosage changes.

Although several herbs have been proven to alter the mechanism of warfarin, there are not enough clinical trial data to prove the significance of those effects. The potential interactions are based on animal studies and individual case reports.1 To prevent unnecessary adverse drug interactions, health care professionals need to be proactive in caring for their patients. Further clinical trials are needed to prove the overall clinical effect of interactions between warfarin and herbal supplements.

TABLE 1: HERBS THAT MAY POTENTIATE THE EFFECT OF WARFARIN
Angelica
Anise
Arnica
Asafoetida
Bogbean
Borage seed
Bromelain
Cannabis
Capsicum
Celery
Chamomile
Clove
Corydalis yanhusuo
Cranberry
Devil’s claw
Fenugreek
Feverfew
Garlic
Geum japonicum
Ginger
Ginkgo biloba
Horse chestnut
Licorice root
Lovage root
Meadowsweet
Onion
Parsley
Passionflower herb
Poplar
Quassia
Red clover
Rue
Saw palmetto
Sweet clover
Turmeric
Willow bark

Adapted from references 1-3.
 
TABLE 2: HERBS THAT MAY INHIBIT THE EFFECT OF WARFARIN
Coenzyme Q10
Danshen
Dong quai
Green tea
Papain
Mistletoe
Agrimony
Dandelion
St. John’s wort
Vitamin E
yarrow

Adapted from references 1 and 2.


Dr. Dube is an advanced practice clinical pharmacist at the Anticoagulation Management Service at Brigham and Women's Hospital. She also serves as a preceptor to pharmacy students at the hospital.

References
  1. Heck AM, Dewitt BA, Lukes AL. Potential interactions between alternatives therapies and warfarin. Am J Health Syst Pharm. 2000;57(13): 1-11.
  2. Ge B, Zhang Z, Zuo Z. Updates on the clinical evidenced herb-warfarin interactions. Evid Based Complement Alternat Med. 2014:957362.
  3. Samuels N. Herbal remedies and anticoagulant therapy. Thromb Haemost. 2005;93:3-7.