Herbal and Non-Herbal Supplement Use is Common in Warfarin-Treated Patients and the Majority of These Agents Impact Warfarin Safety and Efficacy

DOI: 10.19102/icrm.2012.030103

^1,2JENNIFER L. STROHECKER, PharmD, ¹DANIELLE M. CARBAJAL, PharmD, ¹BRIAN CRANDALL, MD, ¹JOHN DAY, MD, ¹DONALD LAPPE, MD, ³SRIJOY MAHAPATRA, MD, ¹KRYSTAL MOORMAN, PharmD, ¹JEFFREY OSBORN, MD, ⁴MEGAN SMITH, RD, ¹J. PETER WEISS, MD and ¹T. JARED BUNCH, MD

¹Department of Pharmacy/Utah Heart Rhythm Specialists at Intermountain Medical Center, Murray, UT
²University of Southern Nevada College of Pharmacy, South Jordan, UT
³University of Virginia, Charlottesville, VA
⁴Utah State University, Logan, UT

Download PDF

Follow Us >> Tweet

ABSTRACT. National surveys indicate that 20–50% of adult Americans use herbal and dietary supplements (HDSs), but the majority do not report their use. Significant patient harm may occur when HDSs are taken in conjunction with warfarin. One hundred warfarin-treated patients were surveyed regarding habits of and attitudes to HDS use, and communication about HDSs with their medical provider. Additionally, the top 40 HDSs were reviewed for their potential to interact with warfarin using three herbal supplement databases. Database search terms included common herbal names, warfarin, anticoagulants, and drug–drug interactions. Survey results of warfarin-treated patients found that 69% use at least one HDS, yet over half do not view HDSs as “drugs”. Additionally, patients reported that while physicians routinely inquire about drug use (89%), they frequently fail to ask specifically about HDS use (63%). HDS use was not documented in the medical chart for the majority of patients (73%). Of the top 10 most commonly used supplements, 90% have been reported to interact with warfarin. Overall, 27 of 40 have been associated with an HDS–warfarin interaction. A total of 17 of 27 were found to potentiate a bleeding risk, and 10 of 27 were found to decrease the effectiveness of warfarin. Patients are using HDSs frequently without physician knowledge or clinical evaluation. The majority of commonly used HDSs interact with warfarin to potentiate bleeding or thromboembolic complications. These data emphasize the significant risk that warfarin-treated patients are exposed to when self-medicating with HDSs.

KEYWORDS. anticoagulants, dietary supplements, herbal drug interactions, herbals.

The authors report no conflicts of interest for the published content.
Manuscript received October 18, 2011, final version accepted November 11, 2011.
Address correspondence to: T. Jared Bunch, MD, Intermountain Heart Rhythm Specialists, Intermountain Medical Center, Eccles Outpatient Care Center, 5169 Cottonwood St, Suite 510, Murray, Utah, 84107. E-mail: Thomas.bunch@imail.org

Introduction

For centuries, botanicals and their derivatives have been utilized for prevention and treatment of disease. Owing to increasing availability and widespread acceptance, herbal and dietary supplement (HDS) use has become commonplace. One out of five adult Americans reports using at least one HDS in the last 12 months,¹ and nearly 50% of Americans over the age of 55 years use HDSs.² HDSs are not classified as “drugs” by the Food and Drug Administration (FDA), and are therefore free from the safety and regulatory standards set in place by the FDA for other over-the-counter and prescription products.³

Patients who take HDSs are exposed to potential drug–drug interactions with their prescribed medications. Medications with narrow therapeutic indexes that are influenced by HDSs may increase patient morbidity and mortality. Warfarin issues account for more emergency room visits than any other drug.⁴ Since 2008, the Joint Commission has made the appropriate use of warfarin a National Patient Safety Goal.⁵ As part of this effort, it is crucial to understand the influence that HDS use may have on international normalized ratio (INR) variability when taken concomitantly with warfarin.

The purpose of this study is: 1) to identify significant HDS–warfarin interactions among the most commonly used HDSs; 2) to measure the frequency of HDS use among warfarin-treated patients; and 3) to evaluate whether there is a disparity between those who report HDS use and documentation in the medical chart, which correlates to a communication gap.

Methods

The study was approved by the institutional review board. The authors determined the top 40 herbal and non-herbal supplements used by Americans utilizing sales data from 2008, and each product was reviewed for its potential to interact with warfarin.⁶ Electronic searches were conducted using the Natural Medicines Comprehensive Database, AltMedDex (Micromedex), and Natural Standard databases. Search terms included common herbal names, “warfarin,” “anticoagulants,” and “drug–drug interactions.” Databases were reviewed for individual herb/supplement–drug interactions with warfarin, and relevant clinical trials, case reports, animal data, and in vitro studies that reported an interaction were categorized for analysis. Collected data were limited to English-language articles; there were no time limitations for designated search criteria. HDS data were ranked according to gross sales per product, listed by trade name. Most common indications for use, effect on INR, mechanism of interaction, and level of scientific evidence was researched and recorded (Table 1).

To understand the extent of HDS use in a contemporary patient population, 100 warfarin-treated patients were surveyed upon their introductory visit to a clinical pharmacist anticoagulation service to assess various patterns of HDS use, attitudes about HDS use, and various aspects of communication with their medical provider (Table 2). Survey responses were recorded in a spreadsheet, and HDS use, if noted, was compared against the prior medical record.

Results

Survey data

A total of 69 of 100 (69%) patients surveyed use HDSs concomitantly with warfarin (Figure 1). The five most commonly used HDSs were multivitamins or individual vitamins (92%), glucosamine, chondroitin, or the combination of glucosamine/chondroitin (28%), fish oil (26%), and coenzyme Q10 (6%). Overall, only one-third of the patients stated that their medical provider questioned them about HDS use. This was not due to an unwillingness to admit to HDS use, as the majority (92%) indicated that they would tell their provider about supplement use if asked. Overall, the majority of patients on warfarin therapy use HDSs (69%); most patients reported that their doctor failed to ask about HDS as part of the medication history (63%); and documented HDS use was absent from the medical record (73%) (Table 2).

HDS–warfarin interactions

Of the 40 most commonly used herbal and non-herbal supplements,⁶ approximately two-thirds (67.5%) demonstrate an indirect or direct drug interaction with warfarin therapy. The data were derived from eight clinical trials, 32 case reports, three animal studies and 11 in vitro studies (Table 1).

The top 10 most commonly used supplements include glucosamine, chondroitin, essential fatty acids, coenzyme Q10, multi-herbs, probiotics/acidophilus, antioxidants (vitamins A and C, green tea), melatonin, cranberry, and soy. Of these supplements, 90% have been reported to interact with warfarin therapy (Table 1). Overall, 27 of 40 interacted with warfarin to produce a clinically significant change in INR or antiplatelet effect. Specifically, 17 of 27 were found to potentiate a bleeding risk, and 10 of 27 were found to decrease the effectiveness of warfarin. Documented bleeding events have been linked to the use of products such as cranberry, garlic, ginkgo, and saw palmetto. Several of the most commonly used supplements, including glucosamine, chondroitin, essential fatty acids, multi-herb products, and evening primrose oil, have been associated with increases in prothrombin time. Coenzyme Q10, soy, melatonin, ginseng, and St. John’s wort have been associated with decreases in prothrombin time.

Discussion

In this study, we found that HDS use in warfarin-treated patients is common (69%) and that physicians frequently fail to ask about HDS use during medication history (63%). The use of HDS in the majority of patients is not noted in their medical chart (73%). Of these commonly used HDS, 67.5% interact with warfarin and expose patients to either hemorrhagic or thrombosis risk. These findings are derived from the most commonly used products in a rapidly expanding industry. The dynamic nature of the HDS industry requires that these studies be performed on a frequent nature to address the potential harm of HDS–drug interactions.

The HDS industry has experienced enormous growth with extensive consumer acceptance and trust. Because of this growth, more patients will present with prescribed medications and self-prescribed HDSs. This evolving paradox of self-treatment is clinically important as, in this study, we found that 47% of patients do not view HDSs as drugs and most (63%) do not consult with their pharmacist or physician before taking an HDS. This is similar to prior studies that showed similar failures in patient and care provider communication.^1,2 The reasons for the communication gap are many: patients believe that health-care professionals lack knowledge of or acceptance for HDSs, patients perceive HDSs as “natural” and do not relate their use to drug interaction, and medical providers may fail to ask about HDS use due to a lack of knowledge, confidence, or comfort with the subject matter.⁷ Addressing these issues will be paramount, as clinicians seek to bridge this gap in order to improve safety outcomes, particularly in high-risk patient groups. The frequency of HDS use in this warfarin-treated population (69%), which is notably higher than previous reports,¹ suggests increased penetrance of HDS use in the community and highlights the need for these studies.

A survey of the literature shows that anticoagulant and antiplatelet therapies are among the drug classes most likely to interact with HDSs.⁸ Of the 40 most commonly used HDSs, 65% demonstrated a clinically significant change in INR values and were associated with hemorrhagic or thromboembolic complications. While most of these reports are cited as individual case reports, the true risk of harm for warfarin-treated patients may actually be greater than documented. Pharmacokinetic properties and toxicity parameters of individual herbs are not well studied, and drug–drug/drug–disease interactions are largely unknown. Additionally, a vast number of supplements are not marketed as “single-entity” products, but rather a potpourri of dozens or hundreds of individual ingredients. For example, a patient may report that he is taking “green tea extract,” when in fact he is taking a combination herbal supplement that contains green tea. Without industry standardization and sufficient scientific research, herbal–warfarin interactions will remain poorly defined, difficult to predict, and variable in effect.

Under the Drug Supplement Health and Education Act of 1994, the supplement industry is free to introduce products to consumers without investment in well-designed clinical trials that evaluate products for safety, efficacy, or other pharmacokinetic and pharmacodynamic properties.³ Additionally, post-marketing reporting of adverse events or toxicity is voluntary and occurs infrequently.⁹ The evaluation and subsequent recall of ephedra by the FDA, which took more than 4 years, 100 reports of severe cardiovascular adverse events, and 38 deaths, highlights the safety issues that surround HDSs.⁴

Development, implementation, and adherence to a comprehensive management program that outlines standards of care have been shown to improve safety outcomes in anticoagulated patients.^10,11 Given that approximately 72% of the warfarin-treated patients surveyed use one or more HDS products, and the majority of the commonly used medications interact with warfarin, inquiry and recommendation about HDS use is an essential part of such a program. Important aspects to incorporate include the following: proactive inquiry about herbal or supplement use separately from prescription or over-the-counter drug use; documentation of use in the medical record; active education of known risks/interactions between the specified herbal product and warfarin; and more frequent INR monitoring if necessary. Other valuable education points for patients who use HDS may include: encouraging dialogue with their physician and pharmacist before use; taking the product consistently to achieve a more predictable effect on INR; purchasing the same brand of product to minimize constituent variability; following up with routine testing as instructed; bringing the HDSs with them to all scheduled appointments; reporting any adverse events to their medical provider immediately.

Likewise, clinicians must acknowledge a communication gap exists with their patients and make efforts to minimize this barrier. This gap is evident in our study in that the majority of patients do not report HDS use. Self-education is critical, so that a knowledgeable exchange about the supplement industry, including DSHEA and rationale for safety risks, can be undertaken with patients. Physicians must recognize that HDS use is common and underreported, and therefore must be proactive and specific in patient interviews. Simply discouraging use of herbal medications is ineffective and perpetuates the patient’s belief that mainstream providers are not knowledgeable about HDSs. It is essential to be forthright with regard to the risks and benefits of using supplements, so that patients can be guided to an informed and educated decision. Likewise, it is imperative that clinicians be familiar with online herbal databases, such as AltMedDex (Micromedex), and utilize them to search for herbal information, such as herbal–warfarin interactions.

Conclusion

As hospitals seek to achieve compliance with the Joint Commission’s 2009 National Patient Safety Goals of medication reconciliation and 2008 goals of appropriate anticoagulant management,⁵ an opportune time for HDS-focused education is created. Patients are using HDSs frequently without physician knowledge or clinical evaluation. The majority of commonly used HDSs interact with warfarin and may potentiate bleeding or thromboembolic complications. It is imperative that clinicians routinely ask about HDS use during patient medication history, investigate HDS–drug interactions, and advise the patient on safe drug therapy choices. Future research should be aimed at bridging the gap through the development and implementation of both physician-focused and patient-focused educational tools.

Acknowledgments

Wendy Athens, MS, for her critical review and thoughtful editorial assistance. Kim Manubay, PharmD, for her data collection and synthesis.

References

1. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. National health statistics reports; no 12. Hyattsville, MD: National Center for Health Statistics.2008; 1-24. [CrossRef] [PubMed]
2. Qato DM, Alexander GC, Conti RM, Johnson M, Schumm P, Lindau ST. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA 2008; 300:2867–2878. [CrossRef] [PubMed]
3. US Dietary Supplement Health and Education Act of 1994. http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/ucm148003.htm (accessed October 31 2011). [CrossRef]
4. Budnitz D, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Annals of Internal Medicine 2007; 147:755–765. [CrossRef] [PubMed]
5. Joint Commission National Patient Safety Goals. 2009. http://www.jointcommission.org/assets/1/18/SEA_41.PDF (accessed November 7, 2011).
6. NBJ’s Supplement Business Report. 2009. http://www.nutritionbusinessjournal.com (accessed October 31 2011).
7. Kemper KJ, Gardiner P, Gobble J, Woods C. Expertise about herbs and dietary supplements among diverse health professionals. BMC Complement Altern Med 2006; 6:15. [CrossRef] [PubMed]
8. Sood A, Sood R, Brinker FJ, Mann R, Loehrer LL, Wahner-Roedler DL. Potential for interactions between dietary supplements and prescription medications. Am J Med 2008; 121:207–211. [CrossRef] [PubMed]
9. Adverse event reporting for Dietary Supplements, An inadequate safety valve. Department of Health and Human Services. http://oig.hhs.gov/oei/reports/oei-01-00-00180.pdf (accessed October 31 2011).
10. Ansell J, Hollowell J, Pengo V, Martinez-Brotons F, Caro J, Drouet L. Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with chronic non-valvular atrial fibrillation: the international study of anticoagulation management. J Thromb Thrombolysis 2007; 23:83–91. [CrossRef] [PubMed]
11. Garcia DA, Witt DM, Hylek E, et al. Delivery of optimized anticoagulant therapy: consensus statement from anticoagulation forum. Ann Pharmacol 2008; 42:979–988. [CrossRef] [PubMed]
12. Knudsen JF, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and medwatch database. Pharmacotherapy 2008; 28:540–548. [CrossRef] [PubMed]
13. Rozenfeld V, Crain JL, Callahan KA. Possible augmentation of warfarin effect by glucosamine-chondroitin. Am J Health Syst Pharm 2004; 61:306–307. [CrossRef] [PubMed]
14. Yue QY, Strandell J, Myrberg O. Concomitant use of glucosamine potentiates the effect of warfarin. Drug Safety. 2006; 29(10): 934 (abstract). [CrossRef]
15. Yokoyama M, Origasa H, Matsuzaki M, et al. Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis. Lancet 2007; 369:1090–1098. [CrossRef] [PubMed]
16. Buckley MS. Fish oil interaction with warfarin. Ann Pharmacother 2004; 38:50–52. [CrossRef] [PubMed]
17. Connor WE. N-3 fatty acids from fish and fish oil: panacea or nostrum? Am J Clin Nutr 2001; 74:415–416. [CrossRef] [PubMed]
18. Calder PC. N-3 polyunsaturated fatty acids, inflammation and immunity: pouting oil on troubled water or another fishy tale? Nutr Res 2001; 21:309–341. [CrossRef]
19. Hansen JB, Olsen JO, Wilsgard L, Osterud B. Effects of dietary supplementation with cod liver oil on monocyte thromboplastin synthesis, coagulation and fibrinolysis. J Intern Med 1989; 225(Suppl):133–139. [CrossRef] [PubMed]
20. Terano T, Hirai A, Hamazaki T, et al. A. Effect of oral administration of highly purified eicosapentaenoic acid on platelet function, blood viscosity and red cell deformability in healthy human subjects. Atherosclerosis 1983; 46:321–331. [CrossRef] [PubMed]
21. Engelsen J, Nielsen JD, Winther K. Effect of coenzyme Q₁₀ and gingko biloba on warfarin dosage in stable, long-term warfarin treated outpatients. A randomised, double blind, placebo-crossover trial. Thromb Haemost 2002; 87:1075–1076. [CrossRef] [PubMed]
22. Spigset O. Reduced effect of warfarin caused by ubidecarenone. Lancet 1994; 334:1372–1373. [CrossRef] [PubMed]
23. Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 2000; 57:1221–1227. [CrossRef] [PubMed]
24. Hansten PD. Effects of vitamins on drug action. Drug Interactions Newsletter. San Francisco, CA: Applied Therapeutics, Inc, 1981; 1:35–38.
25. Chesney CM, Elam MB, Herd JA, et al. Effect of niacin, warfarin and antioxidant therapy on coagulation parameters in patients with peripheral arterial disease multiple intervention trial (ADMIT). Am Heart J 2000; 140:1156–1166. [CrossRef] [PubMed]
26. Kim JM, White RH. Effect of vitamin E on the anticoagulant response to warfarin. Am J Cardiol 1996; 77:545–546. [CrossRef] [PubMed]
27. Rosenthal G. Interaction of ascorbic acid and warfarin. JAMA 1971; 215:1671. [CrossRef] [PubMed]
28. Smith EC, Skalski RH, Johnson GC, Rossi GV. Interaction of ascorbic acid and warfarin. JAMA 1972; 221:1166. [CrossRef] [PubMed]
29. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD001520. [CrossRef] [PubMed]
30. Grant P. Warfarin and cranberry juice: an interaction? J Heart Valve Dis 2004; 13:25–6. [CrossRef] [PubMed]
31. Mohammed Abdul MI, Jiang X, et al. Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects. Br J Pharmacol 2008; 154:1691–1700. [CrossRef] [PubMed]
32. Pham DQ, Pham AQ. Interaction potential between cranberry juice and warfarin. Am J Health Syst Pharm 2007; 64:490–494. [CrossRef] [PubMed]
33. Rindone JP, Murphy TW. Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding. Am J Ther 2005; 13:283–284. [CrossRef] [PubMed]
34. Suvarna R, Pirmohamed M, Henderson L. Possible interaction between warfarin and cranberry juice. BMJ 2003; 327:1454. [CrossRef] [PubMed]
35. Mergenhagen KA, Sherman O. Elevated international normalized ratio after concurrent ingestion of cranberry sauce and warfarin. Am J Health Syst Pharm 2008; 65:2113–2116. [CrossRef] [PubMed]
36. Homma K, Wakana N, Suzuki Y, et al. Treatment of natto, a fermented soybean preparation, to prevent excessive plasma vitamin K concentrations in patients taking warfarin. J Nutr Sci Vitaminol 2006; 52:297–301. [CrossRef] [PubMed]
37. Cambria-Kiely JA. Effect of soymilk on warfarin efficacy. Ann Pharmacother 2002; 36:1893–1896. [CrossRef] [PubMed]
38. Sunter WH. Warfarin and garlic. Pharm J 1991; 246:722.
39. Macan H, Uykimpang R, Alconcel M, et al. Aged garlic extract may be safe for patients on warfarin therapy. J Nutr 2006; 136(3 Suppl):793S–795S. [CrossRef] [PubMed]
40. Cheema P, El-Mefty O, Jazieh AR. Intraoperative haemorrhage associated with the use of extract of saw palmetto her: a case report and review of literature. J Intern Med 2001; 250:167–169. [CrossRef] [PubMed]
41. Yue QY, Jansson K. Herbal drug curbicin and anticoagulant effect with and without warfarin: possibly related to the vitamin E component. J Am Geriatr Soc 2001; 49:838. [CrossRef] [PubMed]
42. Kudolo GB, Dorsey S, Blodgett J. Effect of the ingestion of gingko biloba extract on platelet aggregation and urinary prostanoid excretion in healthy and type 2 diabetic subjects. Thromb Res 2002; 108:151–160. [CrossRef] [PubMed]
43. Aruna D, Naidu MU. Pharmacodynamic interaction studies of gingko biloba with cilostazol and clopidogrel in healthy human subjects. Br J Clin Pharmacol 2007; 63:333–338. [CrossRef] [PubMed]
44. Benjamin J, Muir T, Briggs K, Pentland B. A case of cerebral haemorrhage – can gingko biloba be implicated? Postgrad Med J 2001; 77:112–113. [CrossRef] [PubMed]
45. Gorski JC, Huang SM, Pinto A, et al. The effect of Echinacea on cytochrome P450 activity in vivo. Clin Pharmacol Ther 2004; 75:89–100. [CrossRef] [PubMed]
46. Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P. St. John’s wort (hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 2002; 54:349–356. [CrossRef] [PubMed]
47. Markowitz JS, Donovan JL, DeVane CL, et al. Effect of St. John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA 2003; 290:1519–1520. [CrossRef] [PubMed]
48. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther 2002; 72:276–287. [CrossRef] [PubMed]
49. Foster BC, Vandenhoek S, Hana J, et al. In vitro inhibition of human cytochrome P450-mediated metabolism of marker substrates by natural products. Phytomedicine 2003; 10:334–342. [CrossRef] [PubMed]
50. Komoroski BJ, Zhang S, Cai H, et al. Induction and inhibition of cytochromes P450 by the St. John’s wort constituent hyperforin in human hepatocyte cultures. Drug Metab Dispos 2004; 32:512–518. [CrossRef] [PubMed]
51. Jiang X, Williams KM, Liauw WS, et al. Effect of St. John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2004; 57:592–599. [CrossRef] [PubMed]
52. Jiang X, Blair EY, McLachlan AJ. Investigation of the effects of herbal medicines on warfarin response in healthy subjects: a population pharmacokinetic-pharmacodynamic modeling approach. J Clin Pharmacol 2006; 46:1370–1378. [CrossRef] [PubMed]
53. Yuan CS, Wei G, Dey L, et al. American ginseng reduces warfarin’s effect in healthy patients: a randomized, controlled trial. Ann Intern Med 2004; 141:23–27. [CrossRef] [PubMed]
54. Park HJ, Lee JH, Song YB, Park KH. Effects of dietary supplementation of lipophilic fraction from panax ginseng on cGMP and camp in rat platelets and on blood coagulation. Biol Pharm Bull 1996; 19:1434–1439. [CrossRef] [PubMed]
55. Product Information: COUMADIN^® oral tablets, IV injection, warfarin sodium oral tablets, IV injection. Princeton, NJ: Bristol-Myers Squibb Company, 2007. [CrossRef]
56. Son DJ, Cho MR, Jin YR, et al. Antiplatelet effect of green tea catechins: a possible mechanism through arachidonic acid pathway. Prostaglandins Leukot Essent Fatty Acids 2004; 71:25–31. [CrossRef] [PubMed]
57. Guivernau M, Meza M, Barja P, Roman O. Clinical and experimental study on the long-term effect of dietary gamma-linolenic acid on plasma lipids, platelet aggregation, thromboxane formation, and prostacyclin production. Prostaglandin Leukot Essent Fatty Acids 1994; 51:311–316. [CrossRef] [PubMed]
58. Gleitz J, Beile A, Wilkens P, Ameri A, Peters T. Antithrombotic action of the kava pyrone (+)-kavain prepared from piper methysticum on human platelets. Plant Medica 1997; 63:27–30. [CrossRef] [PubMed]
59. Carr ME. Coumadin resistance and the vitamin supplement “noni”. Am J Hematol 2004; 77:103–10460. [CrossRef] [PubMed].
60. Cirigliano MD, Szapary PO. Horny goat weed for erectile dysfunction. Alt Med Alert 2001;4:19–22. [CrossRef]
61. Xiao Dong S, Zhi Ping Z, Zhong Xiao W, et al. Possible enhancement of the first-pass metabolism of phenacetin by ingestion of grape juice in Chinese subjects. Br J Clin Pharmacol 1999; 48:638–640. [CrossRef] [PubMed]
62. Norred CL, Finlayson CA. Hemorrhage after the preoperative use of complementary and alternative medicines. AANA J 2000; 68:217–220. [CrossRef] [PubMed]
63. Kruth P, Brosi E, Fux R, Mörike K, Gleiter CH. Ginger-associated over anticoagulation by phenprocoumon. Ann Pharmacother 2004; 38:257–260. [CrossRef] [PubMed]
64. Beatty SJ, Mehta BH, Rodis JL. Decreased warfarin effect after initiation of high-protein, low-carbohydrate diets. Ann Pharmacother 2005; 39:744–747. [CrossRef] [PubMed]
65. Carbajal D, Arruzazabala ML, Valdes S, Mas R. Effect of policosanol on platelet aggregation and serum levels of arachidonic acid metabolites in healthy volunteers. Prostaglandins Leukot Essent Fatty Acids 1998; 58:61–64. [CrossRef] [PubMed]