Associate Professor Lesley Braun PhD, BPharm, DipAppscinat, gradDipPhyto, research pharmacist, The Alfred Hospital; senior research fellow, Department of Medicine, Monash University; National Institute of Complementary Medicine, University of Western Sydney
Fish oil supplements provide a rich source of omega-3 essential fatty acids. But do they pose a clinically significant bleeding risk?
Fish oils supplements are consistently reported as among the most popular complementary medicine (CM) supplements used by Australians.1 They are chiefly used to provide a rich source of omega-3 essential fatty acids (n-3 EFAs). More than 4500 studies have been published which explore the potential benefits of n-3 EFAs on human metabolism and health.2
While much research has focused on the role of n-3 EFAs in cardiovascular disease as a means of reducing all-cause mortality, sudden death and coronary heart disease death,3 research is accumulating to suggest roles in other diseases such as Alzheimer’s dementia, mood disorders, ADHD, depression and various autoimmune diseases.4-8 As a result, the use of fish oil supplements is likely to continue unabated in Australia’s ageing society.
It is generally recognised that fish oil supplements are well-tolerated with few side effects, however the question as to whether they pose a clinically significant bleeding risk has been under debate for some time.
The suggestion fish oil consumption could affect bleeding was first made when it was reported that Greenland Eskimos who consumed a diet rich in fish and marine mammal oils had marked increases in bleeding time and decreased platelet aggregation. The plasma and platelets of these Eskimos contained high concentrations of eicosapentaenoic (EPA) and docosahcxaenoic acids (DHA), and very low concentrations of arachidonic acid (AA), a fatty acid normally derived from linoleic acid ingested through dietary sources such as meat, eggs and dairy products.9 In contrast, a study of Alaskan Eskimos found that although they had a high dietary fish intake, platelet counts were within or above the normal range. When the whole sample
was evaluated, no statistical correlation was found between bleeding time and n-3 EFAs, EPA, AA or the ratio of EPA to AA. Only three people out of 80 in the sample were found to have increased bleeding times, a finding that did not correlate with high total n-3 EFAs levels. To provide some context, the concentration of n-3 EFAs in the Alaskan Eskimos ranged from 6.8 to 13 times the concentration of a non-native control group.10 A closer look at the results indicates that the Greenland Eskimos at the time (1975) had very low levels of AA, lower than the Alaskan Eskimos (1985) and a suggestion has been made that bleeding risk may relate to the ratio of EPA:AA.
A search through Medline reveals several case reports where bleeding episodes are attributed to fish oil ingestion.11-13 In each case, the person affected was elderly and also taking warfarin. There is also preclinical research with animal models suggesting an increase in bleeding times.14 However the real question remains, is it clinically significant and, if so, for whom?
IN SURGICAL PATIENTS
One method of determining whether ingestion of n-3 EFAs supplements increases bleeding risk in a clinically significant manner is to study surgical patients. As a matter of routine, data is collected on patient’s blood loss and transfusion requirements during major surgery making them ideal study candidates. Some other hospital inpatients are also good to study if bleeding events and medication histories are routinely recorded.
In 2007, a review was published by Harris which examined the results of 19 clinical studies involving 4387 surgical patients who were taking fish oil supplements in doses ranging from 1gm/day to 21gm/day.15 Two studies involved patients undergoing coronary artery bypass graft surgery, two studies were in carotid endarterectomy, and 15 studies involved patients undergoing femoral artery catheterisation. In 16 out of 19 studies, patients were also taking aspirin and in three studies, patients were taking heparin. The review concluded that the risk for bleeding was virtually non-existent. Frequent comments accompanying the studies were ‘no difference in clinically significant bleeding noted’ or ‘no patient suffered from bleeding complications’. The same conclusion was reached in a 2008 review, which stated no published studies have reported clinically significant bleeding episodes among patients treated with antiplatelet drugs and fish oils (3–7g/day).3
At The Alfred Hospital, we conducted an audit of elective cardiothoracic surgical patients enrolled in the Integrative Cardiac Wellness Program to see whether the use of fish oils supplements (900mg EPA; 600mg DHA daily) taken for at least two weeks before surgery increased the risk of bleeding when compared to a historical cohort of similar patients. We analysed data from 922 patients and found no significant differences between the groups for incidence of serious bleeding events defined as increased blood transfusion requirements or return to theatre due to haemorrhage. (The full paper will be available in the journal Advances in Integrative Medicine before the end of the year).
A smaller study of 95 spinal surgery patients in the United States compared those taking fish oil supplements within 14 days of surgery to non-users and found no increase in intra- operative blood loss or postoperative bleeding complications for fish oils consumption.16 In fact there were two complications related to bleeding in the control group compared to the fish oil group, although the difference wasn’t statistically significant.
Also recently, a large study of 1523 patients who were treated for acute myocardial infarction at one of 24 US centres found no correlation between mild, moderate or serious bleeding and omega-3 levels. The researchers assessed patient’s n-3 EFA levels at the time of acute myocardial infarction and looked for associations between the n-3 index (a reflection of long-term use) and Thrombolysis in Myocardial Infarction [TIMI]. They concluded that concerns about bleeding should not preclude the use of n-3 EFAs or increased fish intake when clinically indicated.17
Similarly, a retrospective study of 182 patients with coronary artery disease being treated with fish oils (mean dose 3 +/– 1.25g), aspirin (mean dose 161 +/– 115mg), and clopidogrel (mean dose 75mg) compared to 182 age- and gender-matched controls treated with aspirin and clopidogrel alone found more people had minor bleeding complications in the control group than in the treatment group; although the difference was not statistically significant.18 In other words, fish oil use did not increase the risk of bleeding complications when added to antiplatelet medication.
Several intervention studies also suggest that the effect of fish oils on platelet aggregation and bleeding risk is relatively minor, and of questionable clinical significance. For example, one randomised study of fish oils (2.7gm/ daily) taken from week 20 onwards by a high-risk population of 968 pregnant women found no increase in blood loss during delivery for the fish oil group.19 Numerous smaller studies have also been conducted with different populations using different fish oil products (MaxEPA and Omacor) or investigating the effects of ingesting a high fish diet and found only modest effects.20,21,22
Most recently, an Australian study found that four weeks of n-3 EFA supplementation (640mg of n-3 EFA giving EPA 120mg; DHA 520mg daily) taken by 40 healthy subjects reduced some parameters of platelet aggregation and platelet activation but induced fewer changes in a cohort of 16 patients with stable cardiovascular disease.23 Interestingly, the people with CVD were also taking aspirin and statin therapy at the same time and the authors suggested that based on these results, and other studies, the combined use of antiplatelet agents might reduce the effects of n-3 EFAs on platelet aggregation and activation. Whether this is the case, requires further testing.
It is apparent that while some in vitro studies and those with animal models have shown significant effects on platelets for n-3 EFAs, randomised trials and observational studies conducted in hospitals with inpatients have largely failed to find evidence of clinically significant bleeding at standard doses. This conclusion is supported by a 2013 systematic review of 10 randomised trials involving 994 older adults (older than 60) which reported no difference in total adverse event rates between placebo and fish oil groups.24 Daily fish oil doses ranged from 0.03g to 1.86g EPA and/or DHA with study durations ranging from 6 to 52 weeks.
Finally, the relative lack of serious adverse event reports to fish oils, despite their extensive use by the Australian population, often as a result of self-selection and not by professional recommendation, provides a further level of surety that serious bleeding events are rare.
In practice, the potential benefits of n-3 EFAs outweigh possible bleeding risks for the vast majority of people, when used as clinically indicated. As with all people taking warfarin, INR should continue to be monitored and medication dosage adjusted if there’s a significant change. Additionally, people with bleeding disorders or listed for neurosurgery need special supervision.
Published in the Australian Journal of Pharmacy Volume 94 August 2013; p82-83.
1. Braun LA, Tiralongo E, Wilkinson JM, et al. Perceptions, use and attitudes of pharmacy customers on complementary medicines and pharmacy practice. BMC Complement Altern Med 2010;10:38.
2. O’Keefe JH, Harris WS. Omega-3 fatty acids: time for clinical implementation? Am J Cardiol 2000 May 15;85(10):1239-41. 3. Harris WS, Miller M, Tighe AP, et al. Omega- 3 fatty acids and coronary heart disease
risk: clinical and mechanistic perspectives. Atherosclerosis 2008 Mar;197(1):12-24. 4. Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 2002 Dec;21(6):495-505.
5. Tanskanen A, Hibbeln JR, Tuomilehto J, et al. Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv 2001 Apr;52(4):529-31. 6. Maidment ID. Are fish oils an effective therapy in mental illness—an analysis of the data. Acta Psychiatr Scand 2000 Jul;102(1):3-11. 7. Morris MC, Evans DA, Bienias JL, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol 2003 Jul;60(7):940-6. 8. Sinn N, Bryan J. Effect of supplementation with polyunsaturated fatty acids and micronutrients on learning and behavior problems associated with child ADHD. J Dev Behav Pediatr 2007 Apr;28(2):82-91. 9. Dyerberg J, Bang HO. Haemostatic function and
platelet polyunsaturated fatty acids in Eskimos. Lancet 1979 Sep 1;2(8140):433-5. 10. Parkinson AJ, Cruz AL, Heyward WL, et al. Elevated concentrations of plasma omega-3 polyunsaturated fatty acids among Alaskan Eskimos. Am J Clin Nutr 1994 Feb;59(2):384-8. 11. McClaskey EM, Michalets EL. Subdural hematoma after a fall in an elderly patient taking high-dose omega-3 fatty acids with warfarin and aspirin: case report and review of the literature. Pharmacotherapy 2007 Jan;27(1):152-60.
12. Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother 2004 Jan;38(1):50-2. 13. Jalili M, Dehpour AR. Extremely prolonged INR associated with warfarin in combination with both trazodone and omega-3 fatty acids. Arch Med Res 2007 Nov;38(8):901-4.
14. Braun L, Cohen M. Herbs and natural supplements: an evidence based guide, 3rd ed. Sydney: Elsevier; 2010. 15. Harris WS. Expert opinion: omega-3 fatty acids and bleeding-cause for concern? Am J Cardiol 2007 Mar 19;99(6A):44C-6C.
16. Kepler CK, Huang RC, Meredith D, et al. Omega-3 and fish oil supplements do not cause increased bleeding during spinal decompression surgery. J Spinal Disord Tech 2012 May;25(3):129-32.
17. Salisbury AC, Harris WS, Amin AP, et al. Relation between red blood cell omega-3 fatty acid index and bleeding during acute myocardial infarction. Am J Cardiol 2012 Jan 1;109(1):13-8.
18. Watson PD, Joy PS, Nkonde C, et al. Comparison of bleeding complications with omega-3 fatty acids + aspirin + clopidogrel versus aspirin + clopidogrel in patients with cardiovascular disease. Am J Cardiol 2009 Oct 15;104(8):1052-4.
19. Olsen SF, Osterdal ML, Salvig JD, et al. Duration of pregnancy in relation to fish oil supplementation and habitual fish intake: a randomised clinical trial with fish oil. Eur J Clin Nutr 2007 Aug;61(8):976-85. 20. Zucker ML, Bilyeu DS, Helmkamp GM, et al. Effects of dietary fish oil on platelet function and plasma lipids in hyperlipoproteinemic and normal subjects. Atherosclerosis 1988 Sep;73(1):13-22. 21. Serebruany VL, Miller M, Pokov AN, et al. Early impact of prescription Omega-3 fatty acids on platelet biomarkers in patients with coronary artery disease and hypertriglyceridemia. Cardiology 2011;118(3):187-94.
22. Harris WS, Connor WE, Goodnight J. Dietary fish oils, plasma lipids and platelets in man. Progress in Lipid Research 1981;20(0):75-9. 23. McEwen BJ, Morel-Kopp MC, Chen W, et al. Effects of omega-3 polyunsaturated fatty acids on platelet function in healthy subjects and subjects with cardiovascular disease. Semin Thromb Hemost 2013 Feb;39(1):25-32.
24. Villani AM, Crotty M, Cleland LG, et al. Fish oil administration in older adults: is there potential for adverse events? A systematic review of the literature. BMC Geriatr 2013 May 1;13(1):41.