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. 2024 May 14;13(10):e032390. doi: 10.1161/JAHA.123.032390

Bleeding Risk in Patients Receiving Omega‐3 Polyunsaturated Fatty Acids: A Systematic Review and Meta‐Analysis of Randomized Clinical Trials

Mustafa Javaid 1, Kadhim Kadhim 1, Bilal Bawamia 1, Timothy Cartlidge 1, Mohamed Farag 1, Mohammad Alkhalil 1,2,✉
PMCID: PMC11179820  PMID: 38742535

Abstract

Background

There is a potential concern about increased bleeding risk in patients receiving omega‐3 polyunsaturated fatty acids (PUFAs). The aims of this study‐level meta‐analysis were to determine the risk of bleeding and to assess whether this relationship is linked to the received dose of omega‐3 PUFAs or the background use of antiplatelet treatment.

Methods and Results

Electronic databases were searched through May 2023 to identify randomized clinical trials of patients receiving omega‐3 PUFAs. Overall bleeding events, including fatal and central nervous system events, were identified and compared with those of a control group. A total of 120 643 patients from 11 randomized clinical trials were included. There was no difference in the pooled meta‐analytic events of bleeding among patients receiving omega‐3 PUFAs and those in the control group (rate ratio [RR], 1.09 [95% CI, 0.91–1.31]; P=0.34). Likewise, the incidence of hemorrhagic stroke, intracranial bleeding, and gastrointestinal bleeding were similar. A prespecified analysis was performed in patients receiving high‐dose purified eicosapentaenoic acid (EPA), which demonstrated a 50% increase in the relative risk of bleeding but only a modest increase in the absolute risk of bleeding (0.6%) when compared with placebo. Bleeding risk was associated with the dose of EPA (risk difference, 0.24 [95% CI, 0.05–0.43]; P=0.02) but not the background use of antiplatelet therapy (risk difference, −0.01 [95% CI, −0.02 to 0]; P=0.056).

Conclusions

Omega‐3 PUFAs were not associated with increased bleeding risk. Patients receiving high‐dose purified EPA may incur additional bleeding risk, although its clinical significance is very modest.

Keywords: antiplatelet, bleeding, meta‐analysis, polyunsaturated fatty acids

Subject Categories: Lipids and Cholesterol

Nonstandard Abbreviations and Acronyms

DHA

docosahexaenoic acid

EPA

eicosapentaenoic acid

REDUCE‐IT

Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

RR

rate ratio

Clinical Perspective.

What Is New?

  • Omega‐3 polyunsaturated fatty acids were not associated with increased bleeding risk, including fatal and central nervous system events, when compared with control.

What Are the Clinical Implications?

  • Bleeding risk appeared to be more closely associated with the dose of eicosapentaenoic acid than the background use of antiplatelet therapy.

The prognostic role of remnant cholesterol, including triglyceride‐rich very low‐density lipoprotein, in predicting cardiovascular outcomes has been highlighted in recent studies. 1 , 2 Omega‐3 polyunsaturated fatty acids (PUFAs) have triglyceride and very low‐density lipoprotein cholesterol–lowering effect, and early studies illustrate an association between omega‐3 PUFAs and cardiovascular risk reduction. 3 , 4 Nonetheless, clinical outcome data in favor of omega‐3 PUFAs are not consistent in demonstrating cardiovascular risk reduction. 5 , 6 The dose and purity of omega‐3 PUFAs such as eicosapentaenoic acid (EPA) has been proposed as a potential explanation for the discordance in results of large randomized clinical trials. 7

Nevertheless, the large reported absolute risk reduction in the REDUCE‐IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention) Trial appears to exceed the projected benefit of the lipid‐lowering effects of the omega‐3 PUFAs studied. 5 , 7 Therefore, other pleotropic effects, including anti‐inflammatory and antithrombotic mechanisms, have been proposed. 7 , 8 Omega‐3 PUFAs are an integral component of platelet hemostasis that regulate platelet aggregation and lower risk of thrombosis. 9 These effects were evident in some clinical outcome studies, including the REDUCE‐IT Trial, which reported numerically higher incidence of serious bleeding events when compared with placebo. 5

Therefore, the aims of this study‐level systematic review were to determine the risk of bleeding in patients receiving omega‐3 PUFAs, including the risk of intracranial bleeding, and to assess whether there is a relationship with the received dose of EPA or the background use of antiplatelet treatment.

METHODS

The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. 10 Data in this systematic review are available on reasonable request from the corresponding author. Institutional Review Board approval and consent form were waived (study‐level meta‐analysis). The MEDLINE, including PubMed, and the Cochrane Central Register of Controlled Trials databases were searched from inception until May 2023 using the following keywords: atherosclerosis, cardiovascular disease, lipid, triglycerides, omega‐3, polyunsaturated fatty acids, EPA, docosahexaenoic acid (DHA), very low‐density lipoprotein, chylomicrons, remnant cholesterol, antiplatelet, antithrombotic, and bleeding.

Studies were included if they were randomized trials that compared PUFAs, omega‐3 fatty acids, or its downstream products, DHA or EPA, to placebo or standard treatment in patients with established cardiovascular disease or at high risk of developing cardiovascular disease. Clinical studies that assessed the role of triglyceride‐lowering effect using non‐omega‐3 PUFAs such as niacin or fibrates were excluded. Only studies reporting the incidence of bleeding events were included. Nonrandomized clinical trials, observational studies, conference abstracts, and studies published in languages other than English were not considered. Likewise, studies that included <1000 patients were excluded to minimize the risk of type 1 statistical error.

All screened articles had initial assessment using the above prespecified inclusion criteria by 2 authors (MA and MJ), neither of whom was an investigator in any of the screened studies. Any case of disagreement was resolved by consensus. All identified citations were initially screened at title or abstract level to assess their relevance to the current analysis. Subsequently, full reports were retrieved and included if they met the inclusion criteria. The references of the eligible studies were also searched for any additional relevant trials. The search results were cross‐checked by reviewing systematic reviews and meta‐analyses on triglyceride‐lowering treatment.

Data on study characteristics and outcomes of interest were extracted independently by 2 authors. Baseline clinical characteristics including use of antiplatelet treatment were recorded. Bleeding risk, including any bleeding, fatal, central nervous system or gastrointestinal bleeding were collated and recorded according to the definition within each study. The experimental arm was defined as the group that received omega‐3 PUFAs, whereas the control arm was assigned to the group who received placebo (or standard treatment in studies that did not use placebo).

Statistical Analysis

Categorical variables are presented as percentages, while continuous data are presented as mean±SD or as a median (interquartile range) as reported in the original studies. To account for potential differences in study follow‐up, treatment effect of omega‐3 PUFAs was reported using rate ratio (RR) and 95% CI, adjusted by patient‐years. The summary RR was averaged across all included studies using random‐effect model and based on the inverse variance method, as previously described. 11 , 12 Funnel plot methodology was used to assess publication bias. The presence of heterogeneity across the included studies was assessed using the Cochrane Q (or χ 2) test and quantified using the Higgins I 2 test, as previously described. 12 , 13 Publication bias was evaluated using funnel plot methodology. All statistical analyses were performed using RevMan software version 5.4 (Cochrane Collaboration), and P<0.05 was considered statistically significant. Meta‐regression was performed using SPSS 28.0 (SPSS, Inc, Chicago, IL) to assess the relationship between the difference in bleeding events in the group receiving omega‐3 PUFAs compared with control against the proportion of patients receiving antiplatelet therapy or the dose of EPA.

RESULTS

The prespecified search strategy yielded 28 004 records (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses flow diagram; Figure 1). Fifteen randomized clinical trials met inclusion criteria and were included in the current meta‐analysis. The total number of patients was 120 643, of whom 60 360 (50.0%) received omega‐3 PUFAs. Except for 2 studies, 5 , 14 all included studies used a combination of EPA and DHA in their assessment of omega‐3 PUFAs.

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram of the selected studies.

Figure 1

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The mean age in all the included studies was ≤75 years old, and patients were predominately male (Table). 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 There was a significant variation in the proportion of patients with a history of ischemic heart disease or receiving antiplatelet treatment across the studies.

Table .

Summary of Clinical Characteristics of the Included Studies

Study name (year) No. of patients Age, y, mean±SD or median (IQR) Male sex, n (%) Diabetes, n (%) Hypertension, n (%) AF, n (%) IHD, n (%) Antiplatelet, n (%) Reported bleeding
JELIS (2007) 14 18 645 61±9 5859 (31%) 3040 (16%) 6611 (35%) … 2903 (16%) 2600 (14%)

Any bleeding

Hemorrhagic stroke
GISSI‐HF (2008) 18 6975 67±11 5459 (78%) 1974 (28%) 3809 (55%) 1325 (19%) 2909 (42%) 3358 (48%)

Hemorrhagic stroke

Intracranial bleeding
ORIGIN (2012) 19 12 536 64±8 8150 (65%) … 9962 (79%) … 7377 (59%) 8665 (69%)

Any bleeding

Intracranial bleeding
R&P (2013) 22 12 505 64±10 7687 (61%) 7494 (60%) 10 577 (85%) … 1508 (12%) 5170 (41%) Any bleeding
AREDs (2014) 15 4203 75±11 1816 (43%) 546 (13%) … … 405 (10%) …

Hemorrhagic stroke

Intracranial bleeding
ASCEND (2018) 20 15 480 63±9 9684 (63%) 14 569 (94%) 9533 (62%) … … 5508 (36%)

Intracranial bleeding

GI bleeding
VITAL (2019) 16 25 871 67±7 12 786 (49%) 3549 (14%) 12 791 (49%) … … 11 570 (45%) GI bleeding
REDUCE‐IT (2019) 5 8179 64 (57–69) 5822 (71%) 4787 (59%) … 751 (9%) 3693 (45%) …

Any bleeding

Hemorrhagic stroke

Intracranial bleeding

GI bleeding
STRENGTH (2020) 6 13 078 63±9 8510 (65%) 9170 (70%) 11 420 (87%) … 6035 (46%) 9323 (71%) Any bleeding
OMEMI (2021) 21 1014 74 (72–78) 720 (71%) 210 (21%) 611 (60%) 154 (15%) 261 (26%) 954 (94%) Any bleeding
DO‐HEALTH (2020) 17 2157 75±5 826 (38%) … 844 (39%) … 0 … Any bleeding
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AF, indicates atrial fibrillation; AREDs, the Age‐Related Eye Disease Study 2; ASCEND, A Study of Cardiovascular Events in Diabetes; DO‐HEALTH, Vitamin D3 ‐ Omega‐3 ‐ Home Exercise ‐ Healthy Ageing and Longevity Trial; GI, gastrointestinal; GISSI‐HF, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico; IHD, ischemic heart disease; IQR, interquartile range; JELIS, The Japan EPA Lipid Intervention Study; OMEMI, Omega‐3 Fatty acids in Elderly with Myocardial Infarction; ORIGIN, Outcome Reduction with an Initial Glargine Intervention; R&P, The Risk and Prevention Study; REDUCE‐IT, Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial; STRENGTH, Long‐Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia; and VITAL, The Vitamin D and Omega‐3 Trial.

Visual inspection of the funnel plots was used to assess the risk of publication bias for studies reporting any bleeding event (Figure S1). There was moderate between‐trial heterogeneity (I 2=65%, P=0.008); nonetheless, all included studies were randomized clinical trials and their data were reported according to intention‐to‐treat analysis.

There was no difference in the incidence of any bleeding events among patients receiving omega‐3 PUFAs and those who did not (2.6% versus 2.4%; RR, 1.09 [95% CI, 0.91–1.31]; P=0.34; Figure 2). 5 , 6 , 14 , 17 , 19 , 21 , 22 Similarly, the absolute risk was not different between the 2 treatment strategies (absolute risk, 0.07% [95% CI, −1.4% to 1.6%]). When data were restricted to randomized trials of icosapent ethyl (EPA only), the administration of high‐dose purified EPA was associated with a 50% higher risk of any bleeding when compared with control (RR, 1.50 [95% CI, 1.13–1.99]; P=0.006). However, the absolute increase in any bleeding remained very modest (absolute risk, 0.6% [95% CI, 0.1%–1.0%]) and translated into a number needed to harm of 166.

Figure 2. Meta‐analysis of any bleeding events of included studies.

Figure 2

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Individual and pooled rate ratio and 95% CIs of patients receiving omega‐3 polyunsaturated fatty acids (PUFAs) vs control.

The risk of hemorrhagic stroke was comparable among patients who did or did not receive omega‐3 PUFAs (0.41% versus 0.32%; RR, 1.29 [95%, 0.92–1.81]; P=0.14). The risk of hemorrhagic stroke was also similar when data were restricted to randomized trials of icosapent ethyl (RR, 1.26 [95% CI, 0.87– 1.84]; P=0.22; Figure 3). 5 , 14 , 15 , 18 Additionally, there was no difference in the incidence of all intracranial bleeding events among patients in the 2 treatment groups (0.28% versus 0.31%; RR, 0.90 [95% CI, 0.64–1.26]; P=0.54). 5 , 15 , 18 , 19 , 20

Figure 3. Meta‐analysis of hemorrhagic stroke (top panel) and intracranial bleed (bottom panel) of the included studies.

Figure 3

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Individual and pooled rate ratio and 95% CIs of patients receiving omega‐3 polyunsaturated fatty acids (PUFAs) vs control.

Finally, omega‐3 PUFAs were not associated with increased risk of gastrointestinal bleeding (3.1% versus 2.9%; RR, 1.07 [95% CI, 0.95–1.21]; P=0.27). There were no reports of fatal bleeding events in all the included studies.

When the administered EPA dose was plotted against the difference in bleeding risk between omega‐3 PUFAs and control, there was a significant relationship between the increased bleeding risk in response to daily dose of EPA in grams (risk difference, 0.24 [95% CI, 0.05–0.43]; P=0.02; Figure 4). Such an association was not present between the proportion of patients receiving antiplatelet therapy and the difference in bleeding risk in patients receiving omega‐3 PUFAs compared with control (risk difference, −0.01 [95% CI, −0.02 to 0]; P=0.056; Figure 4).

Figure 4. Meta‐regression of difference in bleeding risk, eicosapentaenoic acid (EPA) dose, and background use of antiplatelet therapy.

Figure 4

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Left panel illustrates the significant relationship between the dose of EPA and increased bleeding risk among the included studies (the size of the bubble reflects the sample size of the study). The risk difference was calculated per 1‐gram increase in EPA dose. Right panel demonstrates the negative and nonsignificant association between the proportion of patients receiving antiplatelet treatment and the difference in bleeding in patients receiving omega‐3 PUFAs and control.

DISCUSSION

The main findings of this study could be summarized as follows: (1) the incidence of any or central nervous system bleeding events were relatively low (2.6% and <1%, respectively); (2) omega‐3 PUFAs were not associated with an increased risk of overall, hemorrhagic stroke, intracranial or gastrointestinal bleeding; (3) high‐dose purified EPA was associated with increased bleeding risk, although the clinical significance is debatable; and (4) bleeding risk was associated with the dose of EPA rather than the background use of antiplatelet therapy.

Omega‐3 PUFAs were early recognized to be associated with favorable lipid profile and, subsequently, were linked to improved clinical outcomes. 7 However, randomized clinical trials did not consistently demonstrate incremental benefits when using omega‐3 PUFAs in reducing future cardiovascular risk. 6 , 16 , 20 , 23 The REDUCE‐IT trial reported a large absolute risk reduction from exposing patients with stable atherosclerotic disease to high‐dose purified EPA. 5 This reduction was not proportionate to the change in patients' lipid profile and suggested pleotropic effects of icosapent ethyl beyond its triglyceride‐lowering effects. The use of mineral oil as placebo in the REDUCE‐IT trial may have magnified its results; nonetheless, its unfavorable impact on lipid and inflammatory profile was modest and unlikely to explain the difference in clinical outcomes. 7 , 24 Anti‐inflammatory, cell membrane stabilization and antiplatelet effects were all proposed as plausible mechanisms that could explain the large reduction in future cardiovascular risks in patients who were exposed to icosapent ethyl. 7 , 25 , 26 , 27

The antiplatelet effect of omega‐3 PUFAs is well‐recognized and subsequent bleeding has been a potential concern for patients receiving this treatment. 28 In fact, bleeding time, as well as EPA and DHA levels in platelets, were higher among Inuit people with high consumption of omega‐3 PUFAs when compared with other groups. 29 This potential association has led to several recommendations advising patients to stop taking omega‐3 PUFAs before surgery or to delay elective procedures in patients consuming omega‐3 PUFAs. 30 , 31 Nonetheless, randomized clinical trials did not demonstrate an increase in periprocedural bleeding risk in patients receiving omega‐3 PUFAs. 30 , 31 , 32 Likewise, there was no evidence to support increased bleeding events in patients who are considered at high bleeding risk when receiving omega‐3 PUFA. 33 This includes patients with gastrointestinal cancer or patients on intensive care units. 33 Herein, we demonstrate that there is no increased risk of overall bleeding events in patients receiving omega‐3 PUFAs. Moreover, the incidence of serious bleeding, including hemorrhagic stroke and intracranial bleeding, was comparable between the 2 groups.

Mechanistically, omega‐3 and omega 6 PUFAs are regulated using similar cyclooxygenase enzymes and are in direct competitive process to utilize these enzymes. 7 , 34 , 35 Therefore, any excess in the bioavailability of one would lead to a significant reduction in the conversion of the other into its active metabolites. 7 , 34 , 35 Expectedly, the downstream metabolites of omega 6 PUFAs such as thromboxane and its precursor arachidonic acid are reduced in response to consumption of omega‐3 PUFAs with increased availability of their downstream metabolites such as EPA and prostacyclin. 36 , 37 Although thromboxane A2 is a platelet activator, prostacyclin has antiplatelet effect and can induce vasodilation and smooth‐muscle relaxation. 26

Notably, our meta‐analysis highlights an increase in bleeding risk only in patients receiving high‐dose purified EPA (icosapent ethyl). Moreover, we postulate a possible association between EPA dose and increased bleeding risk. An EPA dose‐dependent bleeding risk would be plausible, in line with the biochemical interactions between omega‐3 and omega 6 PUFAs. Nevertheless, it is important to highlight that icosapent ethyl has no DHA component as active product and the purity of icosapent ethyl may also enhance pleotropic effects on platelet activation. EPA can increase the release of nitric oxide, which is a potent inhibitor of platelet aggregation and could potentially exacerbate the bleeding risk when using icosapent ethyl. 38 Although DHA can also increase nitric oxide release, its effect on endothelial function was not similar to EPA. 38 Moreover, its ability to inhibit oxidation of Apo‐B‐containing particles was less sustained than that of EPA. 38

Overall, the increase in bleeding risk associated with high‐dose EPA was very modest. The absolute increase in the overall bleeding risk was 0.6% with no evidence to suggest an increase in serious bleeding such as intracranial or hemorrhagic stroke. Furthermore, there was no relationship between bleeding events and the background use of antiplatelet treatment in patients receiving omega‐3 PUFAs. In fact, the REDUCE‐IT PCI substudy reported similar total bleeding events, including gastrointestinal and central nervous system bleeding, in patients with a history of previous percutaneous coronary intervention who were randomly assigned to icosapent ethyl or placebo. 39 Moreover, early initiation of icosapent ethyl in patients with acute coronary syndrome not only showed no harm but demonstrated a significant reduction in major adverse vascular events, including cardiovascular mortality, when added to standard medical therapy post–percutaneous coronary intervention. 40 Similar results were reported from the REDUCE‐IT trial among patients with a recent acute coronary syndrome (<12 months). Importantly, bleeding rates did not differ between patients who were assigned to icosapent ethyl or placebo.

The current meta‐analysis has several limitations that need to be highlighted. It included trial‐level but not individual‐level data; therefore, assessment of bleeding risk according to race or sex was not possible. Although there was heterogeneity in the purity and dose of omega‐3 PUFAs across the included studies, we separately reported the bleeding outcomes in patients receiving high‐dose purified omega‐3 PUFAs (ie, icosapent ethyl). Bleeding events were defined according to the criteria used by each individual study and were not standardized when reporting patient outcomes.

In conclusion, omega‐3 PUFAs were not associated with increased bleeding risk. Patients receiving high‐dose purified EPA may incur additional bleeding risk, although its clinical significance is very modest and not evident when assessing serious bleeding.

Sources of Funding

This work was supported by an educational grant from Amarin.

Disclosures

None.

Supporting information

Figure S1

JAH3-13-e032390-s001.pdf (123.3KB, pdf)

This manuscript was sent to Monik C. Jiménez, SM, ScD, Associate Editor, for review by expert referees, editorial decision, and final disposition.

For Sources of Funding and Disclosures, see page 7.

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