The National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the Office of Dietary Supplements (ODS) and other Institutes and Centers of the National Institutes of Health (NIH), convened a national workshop on January 13-14, 2005, in Bethesda, MD. The goal of the two-day meeting was to gain greater understanding of the complex issues of dietary supplement use by patients receiving antithrombotic therapies. The Chairperson for the conference was Victor Marder, MD, Professor of Medicine & Neurosurgery and Director of the Vascular Medicine Program at Los Angeles Orthopaedic Hospital, UCLA. Invited faculty included individuals with scientific and medical expertise along with interested parties from academia, industry, patient-advocacy groups, and representative government agencies.
Participants were charged with reviewing the available evidence concerning the effects of dietary supplements on hemostasis (blood coagulation) and antithrombotic therapies (medications used to prevent or treat thrombi or blood clots formed within the blood vessel). Furthermore, they were to identify and discuss public health concerns about the use of these supplements and conceptualize a framework for developing clinical guidelines concerning the use of dietary supplements in patients who are either taking antithrombotic medications or who may be at risk for increased bleeding due to other medical factors.
Introduction to the Problem
To manage or treat their disease condition, an estimated 4 million patients are receiving long-term antithrombotic therapies (anticoagulants, drugs that prevent the coagulation of procoagulant plasma proteins in the blood and/or anti-platelet agents, drugs that alter a number of biochemical pathways to prevent platelets from aggregating and initiating the process of hemostasis). Some surveys suggest that dietary supplements are used by approximately 52% of the general population1 and consumed concurrently with prescription drugs by approximately 16% of the population.2 Many supplements have been reported to interact with antithrombotic therapies, although relatively little data are available concerning the scope of the problem. Many misconceptions exist in the literature concerning the presumed anticoagulant effects of "coumarins" present in botanical dietary supplements.3
Current Antithrombotic Therapies and Hemostasis
The conference began with an overview of normal hemostasis and current antithrombotic therapies, followed by a review of the available evidence on interactions between selected dietary supplements and antithrombotic therapy. Most of the evidence consists of individual case reports or small case series, with inconsistent and frequently incomplete data reported. In addition, many supplements are not available in standardized preparations. These factors make it difficult to compare the results from one report to another. The need for a more systematic approach to documenting and reporting the impact of dietary supplements on antithrombotic therapy was advocated.
The impact of dietary supplements on normal hemostasis and antithrombotic therapy was also considered. Supplements that have been reported to affect normal coagulation and platelet activity and/or have been reported to possibly interact with coumarin anticoagulants include danshen (Salvia miltiorrhiza Bunge, Lamiaceae), garlic (Allium sativum L., Lilliaceae), ginkgo (Ginkgo biloba L., Ginkgoaceae), American ginseng (Panax quinquefolius L., Araliaceae), Asian ginseng (P.ginseng C.A. Meyer), and St. John's wort (Hypericum perforatum L., Clusiaceae). However, most of these reports are either theoretical or consist of individual cases. In addition to supplement heterogeneity, individual patient responses also reflect specific genetic polymorphisms in the cytochrome P450 enzyme system and other metabolic pathways that can alter metabolism of warfarin (a synthetic dicoumarol, often sold under the trade name Coumadin®) and/or dietary supplements. Given the variety of dietary supplements available, an important aspect in the management of patients on oral anticoagulant therapy remains a regular assessment of supplement use and making sure that patients are aware of the potential risks and benefits of taking supplements in conjunction with their prescribed medications.
Research for the Future
Several new research tools and analytic strategies were also reviewed. For example, the pregnane X receptor (PXR), a member of the nuclear receptor family of ligand-activated transcription factors, mediates the interaction between St. John's wort and various prescription drugs, including warfarin. This observation has stimulated additional research to evaluate interactions of other prescription drugs, herbal supplements, and xenobiotics (a foreign substance introduced to the body that has pharmacologic or toxicologic effects) on the PXR receptor. Translating herb-drug interactions identified in the in vitro setting to clinical practice would still require well-designed, prospective clinical trials, of which few have been conducted in this area. Capturing dietary supplement interactions in free-living individuals would require a very well-defined and active surveillance system.
Conference participants identified a series of potential research topics and strategies to address these issues, including the need for in vitro studies to evaluate mechanism of action/interaction, in vivo studies to investigate interaction synergy and/or antagonism, the use of whole animal models for interaction testing, the use of national registries and epidemiologic studies, and the development of educational programs for patients and providers. Also highlighted was the need to encourage botanists, plant physiologists, and pharmacognosists to contribute to this research on herb-drug interactions. Following this panel discussion, a series of presentations provided an assessment of public health concerns from the perspectives of academia, the Food and Drug Administration, and industry. The conference also included a panel session featuring spokespeople from various patient advocacy groups, patient care organizations, and representatives from the American Herbal Products Association. More information about the conference is available at www.nhlbi.nih.gov/meetings/coagulation/index.htm. A Conference Bibliography has been prepared and is available in electronic format at: http://ods.od.nih.gov. The proceedings will be published in Thrombosis Research.
1. Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary Supplement Use by US Adults: Data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epi. 2004;160:339-349.
2. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone Survey. JAMA. 2002;287:337-344.
3. Booth NL, Nikolic D, van Breemen RB, et al. Confusion regarding anticoagulant coumarins in dietary supplements. Clin Pharmacol Ther. 2004;76:511-516.