Akintoye E, Sethi P, Harris WS, et al. Fish oil and perioperative bleeding: insights from the OPERA randomized trial. Circ Cardiovasc Qual Outcomes. 2018;11(11):e004584.
To evaluate the effect of fish oil on a range of standardized intraoperative and postoperative bleeding outcomes.
Randomized, double-blind, placebo-controlled, multinational clinical trial.
A total of 1,516 participants (mean age 64 years, 72% male) were recruited from 28 centers in the United States, Italy, and Argentina. Adult patients with sinus rhythm who were scheduled for cardiac surgery, which included any combination of coronary artery bypass graft (CABG), valve surgery, or other cardiac surgery opening the pericardium, were eligible. The main exclusion criteria were regular use (≥3 days/week) of fish oil or absence of sinus rhythm at enrollment.
Comorbid conditions among participants included diabetes (26%), hypertension (76%), dyslipidemia (62%), chronic renal failure (6.3%), chronic obstructive pulmonary disease (COPD; 11%), congestive heart failure (CHF; 27%), history of atrial fibrillation (7.5%), and prior percutaneous coronary intervention (PCI; 12%). Distribution of scheduled cardiac surgeries (patients could have >1 procedure) were CABG (52%), valvular (mainly aortic) surgery (50%), and other (18%).
Participants were randomized to receive capsules containing either 1 g of fish oil (n=758) or matching placebo (olive oil; n=758). Baseline characteristics between the 2 groups were comparable.
The fish oil used in the study was Lovaza by GalaxoSmithKline (GSK). According to the drug packet insert, Lovaza contains 465 mg of eicosapentaenoic acid (EPA) plus 375 mg of docosahexaenoic acid (DHA) as ethyl esters. It also contains 4 mg alpha-tocopherol (in a carrier of partially hydrogenated vegetable oils, including soybean oil), gelatin, glycerol, and purified water (components of the capsule shell).1
Depending on the time between enrollment and day of surgery, participants were given a total loading dose of 10 g of fish oil or placebo for 3 to 5 days (or 8 g for 2 days) prior to surgery, including 2 g on the morning of surgery. This 2 g daily dose was continued postoperatively until discharge or postoperative day 10, whichever came first.
Study Parameters Assessed
The following parameters were used to assess bleeding, including several standardized assessments: 1) Bleeding Academic Research Consortium (BARC) rating system; 2) Thrombolysis in Myocardial Infarction (TIMI) major and minor bleeding score; 3) International Society on Thrombosis and Hemostasis (ISTH) definitions for surgical bleeding; 4) chest tube output within 24 hours after cardiac surgery; and 5) total units of blood transfused.
Biomarkers associated with bleeding were also examined, including platelet counts, international normalized ratio (INR), plasminogen activator inhibitor-1 (PAI-1) levels, and 11-dehydro-thromboxane-B2 (11-dhTXB2) levels at postoperative day 2.
In a subset of 564 patients in the United States and Italy, plasma phospholipid EPA, docosapentaenoic acid (DPA), and DHA were measured as percentage of total fatty acids.
Primary Outcome Measures
All bleeding outcomes were prespecified safety end points of the OPERA (Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation) trial.
Primary outcome was the occurrence of a BARC type 4 or 5 event, which is defined as the composite of fatal bleeding; perioperative intracranial bleeding; reoperation after closure of the sternotomy for the purpose of controlling bleeding; transfusion of ≥5 red blood cell units or whole blood, excluding cell salvage, within 48 hours; or 24-hour chest tube output >2 L.
Secondary outcomes included the study parameters defined above, namely TIMI, ISTH, chest tube output within 24 hours of surgery, and total units of blood transfused.
There was no difference in any of the bleeding outcomes between fish oil and placebo groups. Patients randomized to the fish oil group received fewer units of blood transfusion (total, during, and after surgery). The results were consistent in subgroups divided by age, sex, preoperative antithrombotic therapy, or CABG use. No significant difference was found for biomarkers of bleeding.
Key bleeding results:
Fish oil vs placebo (olive oil) groups:
- BARC type 4 or 5 bleeding, n (%): 42 (5.5%) vs 50 (6.6%)
- TIMI major bleeding, n (%): 31 (4.1%) vs 42 (5.5%)
- TIMI minor bleeding, n (%): 54 (7.1%) vs 59 (7.8%)
- ISTH surgical bleeding, n (%): 45 (5.9%) vs 54 (7.1%)
- 24-hour chest tube output, median (interquartile range): 388 mL (330 mL) vs 370 mL (300 mL)
Units of blood transfusion in fish oil vs placebo (olive oil) groups:
- Total units of blood transfused, mean (standard deviation [SD]): 1.61 (2.62) vs 1.92 (3.33) (P<0.001; rate ratio [RR]: 0.83; 95% confidence interval [CI]: 0.77-0.90)
- Units during surgery, mean (SD): 0.80 (1.51) vs 1.00 (1.80) (P=0.002; RR: 0.84; 95% CI: 0.76-0.94)
- Units after surgery, mean (SD): 0.81 (1.82) vs 0.92 (2.13) (P=0.006; RR: 0.85; 95% CI: 0.76-0.95)
In addition, higher baseline plasma omega-3 fatty acid levels were associated with a nonsignificant trend toward lower bleeding risk (P for trend=0.05). On the morning of cardiac surgeries, higher levels of plasma omega-3 fatty acids were associated with lower bleeding risk, with 64% lower risk in the highest quartile compared with the lowest quartile (P for trend=0.01).
In practice, providers frequently recommend that patients stop fish oil supplementation days or weeks prior to elective surgeries because of theoretical concerns of bleeding from antiplatelet aggregation effects. This practice could even lead to delay in procedures for some, because the risk of increased bleeding from fish oil was has been assumed to be considerable. This common assumption, however, must be called into question in light of available evidence.
The OPERA study was initially designed to determine whether taking fish oil before and after cardiac surgery reduces atrial fibrillation/flutter, a common complication associated with the procedure.2 (The investigators concluded that fish oil did not change atrial fibrillation rates.) This current study used the OPERA data to present a detailed evaluation of several standardized bleeding outcomes from cardiac interventions. They found that short-term, high-dose fish oil supplementation (with an ethyl-ester form of EPA/DHA) does not lead to increased risk of bleeding in patients undergoing cardiac surgeries. Practitioners should be mindful of this study when discussing fish oil supplements for surgery with their patients.
The debate over whether fish oil has a “blood-thinning” effect probably dates back over 3 decades, when investigators observed prolonged bleeding times in Eskimos consuming diets high in marine fatty acids. Studies in the 1980s reported higher doses of fish oil (6 g of EPA or more) were needed to produce significant inhibitory effect on platelet aggregation, but even with this much EPA the effect was never closer to what acetylsalicylic acid (ie, aspirin) would produce.3-5 In 1990, Li and Steiner carried out an experiment in which healthy participants took fish oil equivalent to 6 g of EPA a day for 25 days. They observed a minor inhibition of platelet aggregation but a striking decrease in platelet adhesiveness.6
At the time, fish oil was known to have an antiplatelet effect and was a promising lipid-lowering agent. With this in mind, a randomized controlled trial examined the cholesterol-lowering effect of policosanol (a long-chain alcohol extracted from plant wax that also has an antiplatelet effect) plus fish oil (1 g/day) or placebo. The addition of fish oil to policosanol enhanced inhibition of platelet aggregation without significantly affecting bleeding time.7 So it was demonstrated that taking fish oil was safe, at least in people with atherosclerotic risk factors who were not taking another blood thinner. But what about the effects of fish oil in people who are taking other drugs that also affect bleeding?
In 2006, a systematic review of 9 studies involving 2,612 patients (some of these patients were taking aspirin or warfarin) reported either no bleeding or no consistent association between the dosage of omega-3 fatty acids and risk of bleeding.8
Growing evidence from randomized controlled studies has suggested the biochemical antiplatelet effect of fish oil does not translate into an increased bleeding risk during or after surgery.
The debate came up again around 2016, when Qato et al indicated potential interaction between warfarin and fish oil, based on case reports and information from drug compendia.9,10 This was challenged by Harris,11 who referred to a review he and colleagues conducted of randomized controlled trials and epidemiological studies. The review found consistent evidence that fish oil does not cause clinically significant bleeding, either alone or with blood thinners.12
Since then, growing evidence from randomized controlled studies has suggested the biochemical antiplatelet effect of fish oil does not translate into an increased bleeding risk during or after surgery.13 A randomized controlled study demonstrated that taking 2 g of fish oil a day for 3 months did not lead to changes in platelet aggregation, thrombin generation, fibrin clot properties, or inflammatory markers in patients with atherosclerosis and type 2 diabetes who are treated with optimal medical therapy, including aspirin and clopidogrel (commonly known as dual antiplatelet therapy), among other medications for blood pressure, cholesterol, and diabetes.14 Several enteral (oral or tube feeding) medical nutrition products containing omega-3 fatty acids were included in an analysis of 8 clinical studies involving patients with diverse diseases (eg, various cancers, HIV infection, Alzheimer’s disease, and critical illness requiring intensive care). The doses of omega-3 fatty acids in the products ranged from 1.5 to 10.2 g per day. No increase in bleeding-related, serious adverse events was reported, even in patients concomitantly using anticoagulant or antiplatelet drugs.15
A recent randomized controlled trial of 8-week home parenteral nutrition regimens with omega-3 oils containing lipid emulsion or control lipid emulsion demonstrated similar and stable coagulation parameters between the 2 groups, with no increased risk of bleeding.16
The risk of bleeding was also not found to be a concern in a recent Cochrane Review article on fish oil and cardiovascular disease prevention, which was featured in the Abstracts & Commentary section of Natural Medicine Journal.17 The report from the OPERA randomized trial further corroborates past studies showing fish oil does not increase one’s risk of bleeding.
For now, the US Food and Drug Administration product labeling for the fish oil used in the OPERA trial (Lovaza) states: “Some studies with omega-3 fatty acids demonstrated prolongation of bleeding times. The prolongation of bleeding time reported in these trials has not exceeded normal limits and did not produce clinically significant bleeding episodes… [P]atients receiving treatment with both Lovaza and an anticoagulant should be monitored periodically.”1 Considering the available safety data among healthy individuals and patients with diverse disease types who have been supplemented with omega-3 fatty acids, the long-standing myth that fish oil causes bleeding is being slowly dispelled.
The potential benefit of taking fish oil for surgery merits consideration. In the present study, the number of blood transfusions was reduced in the fish oil groups, and more importantly, lower risk of bleeding was associated with higher achieved plasma omega-3 levels.
Two other studies have provided insights into the therapeutic use of fish oil for patients undergoing surgery. In a randomized pilot study, patients with aneurysmal subarachnoid hemorrhage who were scheduled for aneurysm clipping procedures, oral or parenteral omega-3 fatty acids showed a trend towards improvement in a variety of post-surgical outcomes.18 Another study of high bleeding-risk patients whose hearts were implanted with a mechanical pump (left ventricular assist device) found that 4 g fish oil a day was associated with significantly lower blood product transfusion, shorter length of stay in the hospital, and reduced gastrointestinal bleeding in the 1-year follow-up period.19
The benefits of fish oil have recently been called into question, with 2 trials finding little to no benefit. One trial studied fish oil for primary prevention of cardiovascular disease and cancer in generally healthy middle-aged adults, and the other trial assessed the benefits of fish oil for asthma control among overweight/obese teens and young adults.20,21
While the health advantages of taking fish oil undergo further research, the results from the OPERA trial demonstrated some benefits that were not expected, namely that fish oil may reduce the number of blood transfusions needed after cardiac surgery.
Fish oil as a nutritional supplement comes in several forms. Some companies offer the ethyl ester form, used in the OPERA trial reviewed here, while others carry naturally occurring equivalents, such as phospholipid or triglyceride forms. There is an assumption that once ingested, all EPA/DHA capsules are going to have similar physiological effects. However, this needs to be demonstrated in larger studies in the future, particularly when fatal adverse events such as postsurgical bleeding are part of the risk/benefit equation.
The current study needs to be repeated, but for now it appears that fish oil supplementation does not increase risk of bleeding after surgery and it may even reduce the need for transfusions. More studies are needed to identify patients who would benefit the most, optimize forms and dosages of fish oils, and investigate possible benefits beyond reduction of blood transfusion.
When one door closes, another window opens.
- LOVAZA (omega-3-acid ethyl esters) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.
- Mozaffarian D, Marchioli R, Macchia A, et al. Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA. 2012;308(19):2001-2011.
- Dyerberg J, Bang HO. Haemostatic function and platelet polyunsaturated fatty acids in Eskimos. Lancet. 1979;2(8140):433-435.
- Siess W, Roth P, Scherer B, et al. Platelet-membrane fatty acids, platelet aggregation, and thromboxane formation during a mackerel diet. Lancet. 1980;1(8166):441-444.
- von Schacky C, Weber PC. Metabolism and effects on platelet function of the purified eicosapentaenoic and docosahexaenoic acids in humans. J Clin Invest. 1985;76(6):2446-2450.
- Li XL, Steiner M. Fish oil: a potent inhibitor of platelet adhesiveness. Blood. 1990;76(5):938-945.
- Castano G, Arruzazabala ML, Fernandez L, et al. Effects of combination treatment with policosanol and omega-3 fatty acids on platelet aggregation: a randomized, double-blind clinical study. Curr Ther Res Clin Exp. 2006;67(3):174-192.
- Wang C, Harris WS, Chung M, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr. 2006;84(1):5-17.
- Qato DM, Wilder J, Schumm LP, Gillet V, Alexander GC. Changes in prescription and over-the-counter medication and dietary supplement use among older adults in the United States, 2005 vs 2011. JAMA Intern Med. 2016;176(4):473-482.
- Qato DM, Alexander GC. Fish Oils and bleeding-where is the evidence?-Reply. JAMA Intern Med. 2016;176(9):1406-1407.
- Harris WS. Fish oils and bleeding-where is the evidence? JAMA Intern Med. 2016;176(9):1405-1406.
- Wachira JK, Larson MK, Harris WS. n-3 Fatty acids affect haemostasis but do not increase the risk of bleeding: clinical observations and mechanistic insights. Br J Nutr. 2014;111(9):1652-1662.
- Begtrup KM, Krag AE, Hvas AM. No impact of fish oil supplements on bleeding risk: a systematic review. Dan Med J. 2017;64(5): pii: A5366.
- Poreba M, Mostowik M, Siniarski A, et al. Treatment with high-dose n-3 PUFAs has no effect on platelet function, coagulation, metabolic status or inflammation in patients with atherosclerosis and type 2 diabetes. Cardiovasc Diabetol. 2017;16(1):50.
- Jeansen S, Witkamp RF, Garthoff JA, van Helvoort A, Calder PC. Fish oil LC-PUFAs do not affect blood coagulation parameters and bleeding manifestations: analysis of 8 clinical studies with selected patient groups on omega-3-enriched medical nutrition. Clin Nutr. 2018;37(3):948-957.
- Bohnert H, Maurer M, Calder PC, et al. Efficacy of a long-term home parenteral nutrition regimen containing fish oil-derived n-3 polyunsaturated fatty acids: a single-centre, randomized, double blind study. Nutr J. 2018;17(1):113.
- Goldenberg JZ, Day A. Fish oil for cardiovascular disease prevention. Natural Medicine Journal. 2018;10(12).
- Saito G, Zapata R, Rivera R, et al. Long-chain omega-3 fatty acids in aneurysmal subarachnoid hemorrhage: a randomized pilot trial of pharmaconutrition. Surg Neurol Int. 2017;8:304.
- Imamura T, Nguyen A, Rodgers D, et al. Omega-3 therapy is associated with reduced gastrointestinal bleeding in patients with continuous-flow left ventricular assist device. Circ Heart Fail. 2018;11(10):e005082.
- Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380(1):23-32.
- Lang JE, Mougey EB, Hossain MJ, et al. Fish oil supplementation in overweight/obese patients with uncontrolled asthma: a randomized trial [published online ahead of print January 25, 2019]. Ann Am Thorac Soc.