Positive Health Online

Natural health products ranks number one among the ten most common complementary health approaches used by American adults.[1] These dietary supplements include for example fish oil, herbs or botanicals, vitamins, minerals, probiotics and amino acids. Close to one-third of all American adults use complementary, alternative or integrative approaches to healthcare.

Photo Credit: © Bob Stockfield. Courtesy: National Center for Complementary and Integrative Health.

Complementary health approaches refer to the use of natural products and/or mind and body practices (e.g. yoga) together with conventional (i.e. mainstream) medicine. Alternative health approaches refer to the use of natural products and/or mind and body practice alone, without the use of conventional medicine. Integrative medicine refers to bringing together complementary and conventional approaches in an organized fashion for the betterment of patient’s health (e.g. for pain/symptom management for cancer patients). This latter approach has grown in popularity.

The National Center for Complementary and Integrative Health is the lead department in the US for investigating complementary and alternative medicine. It reports science-based research for health professionals and for the general public. This institute is one of twenty-seven separate centres which make up the National Institutes of Health in the US[2] Conventional medicine is medical interventions practised by medical doctors, doctors of osteopathy and other allied health professionals for diagnosing and treating disorders/disease, using for example medication, surgery or radiation.[3]

Use of Natural Health Products Together with Medications

More than one-half of people with cancer or chronic disease use natural health products.[4] Up to two-thirds of these may not disclose this fact to their doctor.[5] Even with disclosure, doctors may lack adequate resources which provide science-based evidence regarding possible interactions between using natural products together with medications.[6]

A systematic review[6] has evaluated interactions which are potentially harmful, between using natural products together with medications. It appears that this concomitant use affecting the central nervous or cardiovascular system requires extra caution because a high number of interactions, often moderate in severity, have been documented. There are more interactions with the combination of using herbs with medication as opposed to using dietary supplements with medication. Evidence shows that warfarin tops the list of medications most often involved in interactions with natural products, with more than one hundred reports documented.[6] Warfarin has a narrow therapeutic range[7] and therefore, international normalized ratio (INR) blood levels are frequently monitored especially if it is taken together with natural products, some of which have anticoagulant and anti-platelet properties.[6]

INR Blood Levels

The INR blood test is a standard method used to measure the level of anticoagulation for patients using warfarin or another vitamin K antagonist. INR status is useful to clinicians in their decision making to follow guidelines for prescribing warfarin, to stabilize coagulation action, to stop or lessen bleeding and to make warfarin dose adjustments. When taking warfarin some individuals wear a Medic Alert ID bracelet listing all their medications and dosages, to prevent delay should the visit to the emergency department be required.[8] Having firsthand knowledge regarding current natural products being used is also beneficial.

Dietary Supplements: Anticoagulant Activity

Science-based research continues in regard to the effect of dietary supplements on blood flow in humans. Research shows that these supplements do have an effect on blood flow in non-human studies. Some dietary supplements which affect blood coagulation or platelet activity may be helpful in people with cardiovascular disease, even providing some protection against the disease. Other supplements affecting blood coagulation may be anti-inflammatory in action and therefore, may provide some relief of discomfort for people with arthritis. Extra caution is taken when individuals, who take dietary supplements, add on prescribed anticoagulant medication (e.g. warfarin, aspirin) because this combination may increase the risk of bleeding.[9]

A nutritional review[9] reports findings on six more popular dietary supplements that may alter blood flow in humans.  Garlic, used either raw or as an extract, may have antibacterial and cholesterol-lowering effects. Taking recommended doses of garlic, without using anticoagulant medication, should not pose an increased risk of bleeding. Ginkgo biloba has been given some credit for preventing Alzheimer’s disease and dementia. Other potential benefits include improving mental concentration and improving blood flow by restricting some action of clotting agents in blood. Some brands of energy drinks may contain high doses of ginkgo and therefore, consumption of these could pose an increased risk of bleeding.[9]

Panax ginseng has been credited for increasing physical stamina and improving alertness and sexual function. Some evidence shows that it may cause a drug interaction if a person is also taking warfarin.[10] Ginseng may also be found in certain energy drinks and may contain an active ingredient which affects the immune system by possibly reducing the number of platelets in blood. In this regard, ginseng used alone, without anticoagulant medication, appears to be safe. Ginger is known for reducing nausea. It contains the active ingredient gingerol which, in non-human studies, affects the action of platelets in the blood. Anticoagulant properties for ginger are still being investigated.  Fish oil has long been studied for its affect on red and white blood cells, platelets and plasma. Research shows that fish oil has an anti-platelet effect and therefore inhibits thrombus formation. Fish oil, taken alone, has an insignificant effect on coagulation but when taken with anticoagulant medication, bleeding time may increase.[9] Diets containing fish and fish oils may significantly reduce high triglyceride blood levels.[11]  Vitamin E is a fat-soluble vitamin which has shown to be an antioxidant. There is a wide range of doses (i.e. 200 IU to 1000 IU) of the supplement available in retail stores. Doses higher than 400 IU may have anticoagulant and anti-platelet properties.[9]

Warfarin is an anticoagulant agent for treating venous thromboembolism (i.e. deep vein thrombosis, pulmonary embolism) and preventing new blood clot formation, thus reducing the risk of stroke or myocardial infarction (MI). Warfarin is used for treating heart irregularities (e.g. atrial fibrillation), cardiac valve replacement, recent MI and certain post-surgeries (e.g. knee and hip surgery and extensive gynecologic surgery).[12] For more than fifty years, warfarin, a vitamin K antagonist, has been the most commonly prescribed oral anticoagulant. It carries an increased risk of bleeding which can be very serious.[8]

Vitamin K is a reversal agent for warfarin. This product is prescribed when INR levels move beyond the therapeutic range which increases the risk of bleeding.[14] The National Academy of Science recommends an adequate intake of vitamin K of 90 µg/day and 120 µg/day for women and men, respectively. Vegetables contain most of the Vitamin K in our diet. Some vegetables containing very high amounts of vitamin K are cooked kale, cooked spinach and cooked collards. Others (i.e. either raw or cooked) containing high amounts of vitamin K are swiss chard, mustard greens, turnip greens, parsley, broccoli and brussel sprouts. [13] Soybean, canola and olive oil which is stored in gold/orange colored bottles, are also a significant source of vitamin K.[7]

Hospitalizations due to Drug/Drug or Drug/Dietary Interactions

Researchers used the U.S. National Electronic Injury Surveillance System - Cooperative Adverse Drug Event Surveillance project (2007 - 2009) to estimate how many emergency hospitalizations occurred for older adults (i.e. > 65 years of age) because of significant side effects of medication. Two-thirds of nearly 100,000 hospitalizations were due to unintentional overdoses of medication. Four medications were implicated alone or in combination with other medications or natural products. Warfarin rates the highest of the four, causing over 33,000, out of 100,000 patients being hospitalized. Warfarin or other hematologic agents caused acute hemorrhages such as intracranial or gastrointestinal hemorrhage or hemoptysis. These results underscore the importance of the research community continually making improvements in the management of oral anticoagulant therapy.[15]

Newer Oral anticoagulants

During recent years, newer oral anticoagulants have become available in clinical practice. However, they are used only for specific cases.[8] A two year Canadian research study[16] ending in September 2012 shows that prescriptions for newer anticoagulants increased more than 20-fold in the study period. This was mainly due to the use of dabigatran, the first newer oral anticoagulant approved in 2010 for atrial fibrillation. In this study, by September 2012, dabigatran represented 17.2% of all oral anticoagulation medications prescribed. Other newer oral anticoagulants were less often prescribed. The highest increase in prescription rates for dabigatran was for patients age 85 years and older, with the second highest rates being for patients age 65 to 84 years.  Due to safety concern, there was a tendency for the oldest age group to be prescribed a lower dose of dabigatran (i.e. 110 mg/day), compared to the dosage prescribed for younger age groups. During the study period prescriptions for warfarin for atrial fibrillation decreased significantly. [16] Therapeutic blood levels and reversal agents for newer anticoagulants have yet to be established. “Knowledge on drug interactions with the novel oral anticoagulants is still in its infancy.” [14, p.327]

Warfarin/Medication and Warfarin/Dietary Interactions

During the early years of the twenty-first century, higher quality research was becoming available regarding warfarin/medication and warfarin/dietary interactions. The list for both types of interactions was growing.[17] In 2005, a systematic overview[17] analyzed literature on this subject. Findings show that many herbal remedies, vitamin K rich foods (e.g. leafy greens) and many anti-infective drugs decrease the effect of warfarin. There continues to be concern when individuals taking warfarin also introduce new medication, new foods, new dietary supplements[17] or new herbal products, for which information regarding quality control on their contents is lacking.[18] In these situations, INR blood levels are monitored often so that medication adjustments could be made to possibly prevent an episode of bleeding or prevent harm related to blood clot formation. In an organized fashion, the systematic overview lists drugs or groups of drugs found to interact with warfarin. Some of these drugs have a potentiating effect on warfarin and some have an inhibiting effect.[17]

Some dietary supplements such as alfalfa, dong quai and chamomile contain varying amounts of warfarin chemical compounds. Others may affect warfarin metabolism by either being an enzyme inducer, as in the case of St John’s wort and ginseng or being an enzyme inhibitor, as in the case of garlic and kava. Some dietary supplements affect platelet function, as in the case of garlic and fish oil. Others have anticoagulant effect, as in the case of melatonin and glucosamine. [7] 

Conclusion

This article is intended to raise awareness regarding blood flow and coagulation effect of using certain natural health products either alone or in combination with prescribed oral anticoagulant or other medication, to ultimately ensure patient safety.

References

1.         Clarke TC et al. Trends in the use of complementary health approaches among adults: United States, 2002-2012. Natl Health Stat Report 79: 1-16. 2015.

2.         U.S. Department of Health and Human Services: National Institutes of Health: National Center for Complementary and Integrative Health (NCCIH). Complementary, Alternative, or Integrative Health: What’s In a Name? 2015. https://nccih.nih.gov/health/integrative-health

3.         MedicineNet Inc. Definition of conventional medicine. www.medicinenet.com/script/main/art.asp?articlekey=33527

4.         Miller MF et al. Dietary supplement use in individuals living with cancer and other chronic conditions: a population-based study. J Am Diet Assoc 108: 483-494. 2008.

5.         Mehta DH et al. Herbal and dietary supplement disclosure to health care providers by individuals with chronic conditions. J Altern Complement Med 14: 1263-1269. 2008.

6.         Tsai HH et al. Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: a systematic literature review. Int J Clin Pract 66: 1056-1078. 2012.

7.         Nutescu EA et al. Warfarin and its interactions with foods, herbs and other dietary supplements. Expert Opin Drug Saf 5: 433-451. 2006.  

8.         Pollack Jr., CV. Coagulation assessment with the new generation of oral anticoagulants. Emerg Med J. 2015 May 18. pii: emermed-2015-204891. [Epub ahead of print]

9.         Stanger MJ et al. Anticoagulant activity of select dietary supplements. Nutr Rev 70: 107-117. 2012.           

10.       Coon JT and Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf 25: 323-344. 2002.

11.       Phillipson BE et al. Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia. N Engl J Med 312(19): 1210-1216. 1985.

12.       Schneider DM. The Coumadin (warfarin) help book: a guide to anticoagulation therapy to prevent and manage strokes, heart attacks, and other vascular disorders. DiaMedica Publications. New York. 2008.

13.       U.S. Department of Agriculture (USDA), Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 23. Important drug and food information: What foods are rich in vitamin K? 2010. www.cc.nih.gov/ccc/patient_education/drug_nutrient/coumadin1.pdf

14.       Nutescu E et al. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Throb Thrombolysis 31: 326-343. 2011.

15.       Budnitz DS et al. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 365: 2002-2012. 2011.     

16.       Xu Y et al. Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a population-based descriptive analysis. CMAJ Open 1(3); E115-119. 2013, Oct 16.

17.       Holbrook AM et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 165: 1095-1106. 2005.

18.       Joshi BS and Kaul PN. Alternative medicine: herbal drugs and their critical appraisal-Part 1. Prog Drug Res 56: 1-76. 2001.         

Acknowledgement

“The author acknowledges the Positive Health Online editor, whose comments and encouragement led to improvements in the article.”