Increased bruising with the combination of long-chain omega-3 fatty acids, flaxseed oil and clopidogrel

A recent national survey shows that 73% of Canadians are taking at least one natural health product (NHP), while more than one-third report taking 3 or more NHPs simultaneously. Of particular concern, patients with chronic medical conditions are more likely to take NHPs. These patients are also most likely to be prescribed conventional medications, and therefore the risk of interactions and patient harm is even greater. For example, 58% of patients taking narrow therapeutic index cardiovascular medications reported concurrent NHP use.  The Study Of Natural Health Product Adverse Reactions (SONAR) is a multicentre study assessing a community pharmacy‒based active surveillance system to identify adverse events following NHP use, with a particular focus on NHP–prescription drug interactions. The study was developed in partnership with Health Canada to train participating pharmacists to ask individuals collecting prescription medications about ) concurrent NHP/drug use in the previous month ) experiences of adverse events. If an adverse event was identified and if the patient provided written consent, a research pharmacist (CN) followed up with a detailed phone interview. This study was approved by the Human Research Ethics Board at the University of Alberta.  A patient identified in our study presented with increased bruising following the concurrent intake of clopidogrel, flaxseed oil and an additional long-chain omega-3 fatty acid supplement. (Authors abstract)

A 68-year-old woman presented to her community pharmacy on February 1, 2011, with concerns of increased spontaneous bruising on multiple areas of her body since 2007, increasingly since she was started on clopidogrel in June 2009. She reported the bruises as varying in size, with some appearing as large as a baseball, and no recollection of injury or direct causes for the bruising. Her medical conditions included hypertension, hypercholesterolemia, placement of a coronary stent in 2000, glucose intolerance, metabolic syndrome, fatty liver, decreased kidney function, hypothyroidism and vitamin D deficiency. Her medications included amlodipine (5 mg), bisoprolol (10 mg), ezetimibe (10 mg), levothyroxine (50 mcg), ramipril (20 mg) and rosuvastatin (10 mg), all of which were taken for 9 years prior to the addition of clopidogrel (75 mg). In addition to these medications, the patient reported taking numerous NHPs, including omega-3 fatty acids (500 mg, providing 200 mg of docosahexaenoic acid [DHA] and 300 mg of eicosapentaenoic acid [EPA]), flaxseed oil (1000 mg), vitamin B6 (100 mg), vitamin D3 (2000 IU) and calcium (666 mg)/magnesium (334 mg)/zinc (40 mg). After an extensive medication history, taken as part of the SONAR study protocol, the patient revealed that she had noticed an increase in bruising after initiating the omega-3 fatty acids and flaxseed oil in 2006; however, it was not until the addition of clopidogrel that the symptoms became enough of a concern to seek advice. Prior to seeking help from a health professional, the patient tried discontinuing the flaxseed oil for a 2-week period in December 2010. She reported a decrease, but not a disappearance, in spontaneous bruising, and the bruising appeared again after rechallenge. On February 14, 2011, she discontinued both the omega-3 supplement and the flaxseed oil and noticed considerable improvement in the frequency and quantity of bruising.
This particular case describes a potential clinically relevant interaction between clopidogrel and 2 natural health products containing omega 3 fatty acids. The omega 3 fatty acids product contains the long-chain polyunsaturated fatty acids, EPA and DHA, whereas the flaxseed oil product is a rich source of alpha-linolenic acid (ALA), a plant source of omega 3 fatty acids.  Flaxseed has been found to exhibit some inhibition of platelet aggregation.  It can be reasonably hypothesized that its effects on platelet aggregation would be similar to the omega 3 fatty acids reported.   Although several mechanisms explaining how omega-3 fatty acids can alter platelet aggregation and clot properties have been proposed, few published case reports demonstrate clinical adverse events associated with this effect.  In fact, some studies even conclude a lack of risk.  The present case demonstrates that clinically significant increased bleeding may occur with concurrent use of these natural health products. Caution is warranted when patients are taking flaxseed and other omega 3 fatty acids alone and especially in combination with other antiplatelet drugs such as clopidogrel. It is not uncommon for patients to omit discussion about NHP use with their physician or pharmacist.   Proactive screening and discussions around concurrent NHP-drug use are imperative to avoid preventable adverse events. (Editors comments)