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Comparison of Bleeding Complications With Omega-3 Fatty
Acids ؉ Aspirin ؉ Clopidogrel—Versus—Aspirin ؉ Clopidogrel
in Patients With Cardiovascular Disease
Pauline D. Watson, DO, Parijat S. Joy, MD, Chileshe Nkonde, MD, MRCP, Scott E. Hessen, MD, Fish oil is used to lower triglycerides and for the secondary prevention of cardiovascular
events in patients with coronary artery disease. Many of these patients will also be taking
aspirin and clopidogrel. Any of these medications alone can increase the risk of bleeding;
however, the risk of bleeding in patients taking all 3 of these medications has not been
studied. We retrospectively reviewed the medical records for bleeding complications in 182
patients, most with coronary artery disease (mean age 61 ؎ 11 years, 82% men) and being
treated with high-dose fish oil (mean dose 3 ؎ 1.25 g), aspirin (mean dose 161 ؎ 115 mg),
and clopidogrel (mean dose 75 mg), and in 182 age- and gender-matched controls treated
with aspirin and clopidogrel alone. During a mean follow-up period of 33 months, 1 major
bleeding episode occurred in the treatment group and no major bleeding episodes occurred
in the control group (p ؍ 1.0). During follow-up, 4 minor bleeding episodes (2.2%) occurred
in the treatment group and 7 (3.9%) in the control group. More patients had minor bleeding
complications in the control group than in the treatment group; however, the difference was
not statistically significant (p ؍ 0.5). In conclusion, high-dose fish oil is safe in combination
with aspirin and clopidogrel and does not increase the risk of bleeding compared with that
seen with aspirin and clopidogrel alone.
2009 Elsevier Inc. All rights reserved. (Am J
Cardiol 2009;104:1052–1054)
Clopidogrel, in combination with aspirin, is commonly as aspirin and clopidogrel. The control group included an used in the treatment of patients with unstable angina pec- equal number of age- and gender-matched patients taking toris and non–ST-segment elevation myocardial infarction, aspirin and clopidogrel but not any omega-3 fatty acid as well as in patients undergoing percutaneous coronary supplements. Patients taking warfarin were excluded from Often, these patients are treated long term both groups. The university institutional review board ap- with both antiplatelet agents, especially those receiving a drug-eluting stent. Studies have demonstrated a small, but We retrospectively reviewed the electronic medical significant, excess risk of major and minor bleeding with the records for patient demographics, a clinical history of cor- combination of clopidogrel and aspirin compared to either onary artery disease, peripheral vascular or cerebrovascular clopidogrel or aspirin Omega-3 fatty acids, used to disease, the patient’s fish oil, aspirin, and clopidogrel doses, lower triglycerides and for the secondary prevention of and the occurrence of bleeding complications. A major bleeding episode was defined as one that had led to a In clinical practice, patients with coronary artery disease decrease in hemoglobin of Ͼ2 g, an intracerebral hemor- might be taking all 3 of these medications. However, the rhage, or any bleeding episode that required hospitalization.
risk of bleeding from the combination of all 3 drugs has A minor bleeding episode was defined as epistaxis, abnor- not been studied. The purpose of the present study was to mal bruising, or gastrointestinal bleeding that did not re- evaluate the risk of bleeding in patients taking high-dose quire hospitalization nor led to a decrease in the hemoglobin omega-3 fatty acids in combination with aspirin and level of Ͼ2 g. The data are presented as percentages and the mean values with standard deviations. Statistical signifi-cance was assessed using the 2-tailed Fisher exact test to compare proportions and the Student t test to compare themean values. A p value of Ͻ0.05 was used to define statis- Patients were identified from a large private practice cardiology group. The patient database was screened forthose who had been prescribed omega-3 fatty acids, as well We retrospectively identified 182 patients (mean age 61 Ϯ 11 years, 82% men) who were taking fish oil (mean dose Division of Cardiology, Drexel University College of Medicine, Phil- adelphia, Pennsylvania. Manuscript received March 21, 2009; revised Ϯ 1.25 g), aspirin (mean dose 161 Ϯ 115 mg), and clopidogrel (mean dose 75 mg). No difference was seen in manuscript received and accepted May 22, 2009.
*Corresponding author: Tel: (215) 564-3050; fax: (215) 564-3398.
the patient characteristics between the group taking om- E-mail address: (D.G. Karalis).
ega-3 fatty acids and the control group Of the 182 0002-9149/09/$ – see front matter 2009 Elsevier Inc. All rights reserved.
Coronary Artery Disease/Fish Oil and Bleeding epistaxis and ear bleeding; . More patients had a minor bleeding episode in the control group taking aspi- rin and clopidogrel alone than in the group taking all 3 medications (high-dose omega-3 fatty acid supplements, aspirin, and clopidogrel), but the difference was not sig- Discussion
In our study, the use of high-dose omega-3 fatty acids in patients already taking aspirin and clopidogrel was not as- sociated with an increased risk of excess bleeding. These findings are consistent with those of other studies evaluating the risk of bleeding when omega-3 fatty acids were pre- scribed in combination with either aspirin or warfarin. Erits- land et randomized 610 patients already taking either 300 mg of aspirin daily or warfarin after coronary artery bypass surgery to 4 g of prescription formulation omega-3 fatty acids or placebo. They reported no significant differ- ence in the number of bleeding episodes at 1 year in thosepatients taking high-dose fish oil compared to the placebo Data are reported as mean Ϯ SD or number of patients (percentages).
group. Leaf et randomized 551 patients taking 325 mgaspirin daily after percutaneous coronary intervention to aneven a higher dose of fish oil, 8 g of omega-3 fatty acids(providing a total of 6.9 g of eicosapentaenoic acid anddocosahexaenoic acid daily) or placebo. At 6 months offollow-up, the incidence of bleeding was low at 3%, and nodifference in bleeding episodes was detected between thegroups. In another small study, no difference was found inthe bleeding episodes in patients taking long-term warfarintherapy randomized to Յ6 g of fish oil Our studyhas provided longer follow-up than the previous studies,and our findings further support the safety of high-doseomega-3 fatty acids when used in combination with anti-platelet or antithrombotic therapy.
Fish oil contains the N-3 polyunsaturated fatty acid eicosapentaenoate. Fish oil supplementation markedly in-creases the eicosapentaenoate content of phospholipids Figure 1. Incidence of major and minor bleeding episodes was low in from red blood cells and platelets and alters their pattern of patients taking high-dose fish oil, aspirin, and clopidogrel (white bars). No thromboxane and prostacyclin synthesis. These effects are difference was found in bleeding episodes in patients taking all 3 drugs thought to be responsible for the antiplatelet and antithrom- (white bars) compared to control group taking aspirin and clopidogrelalone (black bars). botic properties of omega-3 fatty Although, omega-3fatty acids at higher doses modestly prolong the bleedinglittle evidence exists to suggest that omega-3 fatty patients taking omega-3 fatty acid supplements, 172 (95%) acids, even at high doses, cause clinically significant bleed- were using the prescription formulation Lovaza and 10 were ing. Aspirin inhibits platelet aggregation by inhibition of using an over-the-counter formulation. Most patients were cyclooxygenase, and clopidogrel reduces platelet activation taking high doses of fish oil, with 140 (77%) of the 182 by way of the adenosine diphosphate receptor-dependent pathways. These findings raised concern that high-dose fish During a mean follow-up of 33 months, only 1 patient oil could further increase the risk of bleeding in patients had a major bleeding episode in the group taking omega-3 already taking aspirin and clopidogrel; however, our results fatty acid supplements plus aspirin and clopidogrel (rectal do not support an increased risk of bleeding when high-dose bleeding requiring transfusion in 1 patient with rectal car- fish oil is prescribed in combination with aspirin and clo- cinoma). No patient in the control group had a major bleed- ing episode (p ϭ 1.0). During follow-up, 4 patients had a Our study had several limitations. First, the study was minor bleeding episode (2.2%) in the group taking high- retrospective. This could have led to either underestimating dose omega-3 fatty acids plus aspirin and clopidogrel (2 or overestimating the risk of bleeding in our study patients.
cases of epistaxis, 1 of bruising, and 1 of mild rectal bleed- However, the incidence of major and minor bleeding epi- ing) compared to 7 patients (3.9%) in the control group with sodes seen in our study was within the range of bleeding a minor bleeding episode (3 cases of bruising, 1 of hema- complications reported by other studies of patients taking turia, 1 of mild rectal bleeding, 1 of epistaxis, and 1 of The American Journal of Cardiology (www.AJConline.org) our patients were taking the prescription formulation of 5. Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam omega-3 fatty acids, and high-dose nonprescription formu- PM, Elwood PC, Deadman NM. Effects of changes in fat, fish, andfibre intakes on death and myocardial reinfarction: Diet and Reinfarc- lations might not provide the same safety as the prescription tion Trial (DART). Lancet 1989;2:757–761.
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