Answered on May 28, 2024
Fish oil supplements, which are rich in omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been extensively studied for their cardiovascular effects. The evidence on whether fish oil supplements increase the risk of stroke and heart problems is mixed and context-dependent.
A study by Chen et al. published in BMJ Medicine found that regular fish oil use may increase the risks of atrial fibrillation and stroke in healthy individuals, with hazard ratios of 1.13 and 1.05, respectively.[1] However, in individuals with pre-existing cardiovascular disease, fish oil supplements were associated with beneficial effects, such as reduced transition rates from atrial fibrillation to major adverse cardiovascular events and from heart failure to death.[1]
Conversely, a meta-analysis by Chen et al. in the Asia Pacific Journal of Clinical Nutrition indicated that higher fish consumption and long-chain omega-3 PUFA intake were associated with a lower risk of stroke, particularly ischemic stroke, suggesting a protective effect.[2] This aligns with the American Heart Association's (AHA) advisory, which supports the consumption of marine omega-3s to potentially reduce risks of congestive heart failure, coronary heart disease, ischemic stroke, and sudden cardiac death.[3]
However, a systematic review and meta-analysis by Rizos et al. in JAMA found no significant association between omega-3 supplementation and a lower risk of major cardiovascular events, including stroke.[4] This highlights the variability in outcomes based on study design, population, and dosage.
In summary, while fish oil supplements may increase the risk of atrial fibrillation and stroke in healthy individuals, they appear to offer cardiovascular benefits in those with pre-existing cardiovascular conditions. The American Heart Association recommends marine omega-3s for cardiovascular health, particularly in high-risk populations.[3]

1.
Study Links Fish Oil Use to an Increased Risk of Atrial Fibrillation and Stroke in Healthy Individuals, but Fish Oil Could Be Beneficial in Persons With Cardiovascular Disease.

OpenEvidence

TL;Dr. Summary of https://bmjmedicine.bmj.com/content/3/1/e000451

TL;Dr.: In a study published in BMJ Medicine, Chen and colleagues investigated the effects of fish oil supplements on cardiovascular disease progression. The prospective cohort study involved 415,737 participants aged 40 to 69 from the UK Biobank, and the median follow-up was 11.9 years. Results indicated that regular fish oil use may increase risks of atrial fibrillation and stroke in healthy individuals (hazard ratios, 1.13 and 1.05, respectively). However, in participants with a cardiovascular disease diagnosis, regular fish oil use was associated with a beneficial impact on the transition of atrial fibrillation to major adverse cardiovascular events (HR, 0.92) and myocardial infarction (HR, 0.85) and of heart failure to death (HR, 0.91). These findings suggest a dual role of fish oil in cardiovascular progression, highlighting the need for targeted guidance on its use. This study by Chen et al. challenges the generally accepted belief, bolstered by landmark trials like JELIS and several meta-analyses, that omega-3 supplementation yields positive impacts on cardiovascular health. This UK Biobank-based cohort study of 415,737 participants found that regular intake of fish oil supplements may increase the risk of atrial fibrillation and stroke in individuals without cardiovascular diseases. However, for patients with pre-existing cardiovascular disease, these supplements appeared advantageous in lowering the transition rates from atrial fibrillation to major adverse cardiovascular events and from heart failure to death. While the research introduces intriguing new perspectives, the observational nature limits the ability to ascertain causality. The study does not factor in doses of supplements, dietary habits or omega-3 blood levels.

2.
Fish Consumption, Long-Chain Omega-3 Fatty Acids Intake and Risk of Stroke: An Updated Systematic Review and Meta-Analysis.

Chen C, Huang H, Dai QQ, et al.

Asia Pacific Journal of Clinical Nutrition. 2021;30(1):140-152. doi:10.6133/apjcn.202103_30(1).0017.

Background And Objectives: Although fish consumption or omega-3 intake is associated with cardio- cerebrovascular disease including stroke, their correlation is still controversial. Therefore, this meta-analysis is to identify the relationship between the risk of stroke and fish consumption or omega-3 intake.

Methods And Study Design: We searched the PubMed, EMBASE and Cochrane Library databases as of May 2019. Multivariateadjusted risk ratios (RRs) with 95% confidence interval (CI) for stroke in different level intake of fish or Longchain omega-3 polyunsaturated fatty acids (LC ω3-PUFAs) were pooled using a random-effects meta-analysis. A dose-response analysis was conducted with the 2-stage generalized least-squares trend program.

Results: Our meta-analysis identified a total of 17 prospective cohort studies including 14986 strokes events in 672711 individuals. Meta-analysis revealed that the higher fish consumption was significantly associated with lower risk of stroke (RR=0.871, 95%

Ci: 0.779-0.975, p=0.016), especially with ischemic stroke (RR=0.808, 95%

Ci: 0.696- 0.937, p=0.005). Meantime, the combined RR of total stroke was 0.859 (95%

Ci: 0.769-0.959, p=0.007) for the highest versus lowest intake of LC ω3-PUFAs, and stratification analysis showed that higher LC ω3-PUFAs intake was associated with reduced stroke risk in women (RR=0.793, 95%

Ci: 0.706-0.891, p=0.000) but not in men. In addition, the dose-response analysis showed fish consumption with 1000g per month and LC ω3-PUFAs intake with 0.5g per month was associated with 17.3% (RR=0.927, 95%

Ci: 0.83-0.98) and 14% (RR=0.86, 95%

Ci: 0.78-0.95) lower risk of stroke, respectively.

Conclusions: Both fish consumption and LC ω3-PUFAs intake were negatively associated with the risk of stroke, especially in women, which suggest that increased intake of fishery products and LC ω3-PUFAs may benefit primary prevention of stroke.

3.
Seafood Long-Chain N-3 Polyunsaturated Fatty Acids and Cardiovascular Disease: A Science Advisory From the American Heart Association.

Rimm EB, Appel LJ, Chiuve SE, et al.

Circulation. 2018;138(1):e35-e47. doi:10.1161/CIR.0000000000000574.

Leading Journal

Although initial cohort studies focused on the associations between seafood intake and LC n-3 PUFA intake and total stroke,67,68 studies since the 2002 AHA statement on seafood intake and CVD have examined the associations with ischemic stroke and hemorrhagic stroke separately. Results from the Nurses’ Health Study and Health Professionals Follow-up Study indicate that intake of seafood was associated with a lower risk of thrombotic (ischemic) stroke but not with (either a lower or higher) risk of hemorrhagic stroke.69,70 In the Cardiovascular Health Study, consumption of tuna or other broiled and baked fish was associated with a 40% lower risk of ischemic stroke among older adults; however, intake of fried fish or fish sandwiches was associated with a higher risk of ischemic stroke.50 Whether the type of fish (lean fish low in n-3 PUFAs) or the method of preparation (frying in partially hydrogenated oils) accounted for this difference could not be determined. The association of seafood intake and stroke mortality was examined in a combined analysis of 2 large cohort studies of men and women of Chinese ancestry. In that analysis, the risk of mortality from ischemic stroke was lower among those who consumed saltwater fish and had a higher intake of LC n-3 PUFAs.71
This was further summarized in a recent meta-analysis of cohort studies that suggested that compared with no or infrequent consumption of seafood, consumption of 1 serving of seafood a week was associated with a 14% lower risk of ischemic stroke with little or no association with hemorrhagic stroke.72 Taken together, evidence from prospective studies supports the incorporation of regular seafood consumption to lower the risk of ischemic stroke.

4.
Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events: A Systematic Review and Meta-Analysis.

Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS.

Jama. 2012;308(10):1024-33. doi:10.1001/2012.jama.11374.

Leading Journal

Context: Considerable controversy exists regarding the association of omega-3 polyunsaturated fatty acids (PUFAs) and major cardiovascular end points.

Objective: To assess the role of omega-3 supplementation on major cardiovascular outcomes.

Data Sources: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through August 2012.

Study Selection: Randomized clinical trials evaluating the effect of omega-3 on all-cause mortality, cardiac death, sudden death, myocardial infarction, and stroke.

Data Extraction: Descriptive and quantitative information was extracted; absolute and relative risk (RR) estimates were synthesized under a random-effects model. Heterogeneity was assessed using the Q statistic and I2. Subgroup analyses were performed for the presence of blinding, the prevention settings, and patients with implantable cardioverter-defibrillators, and meta-regression analyses were performed for the omega-3 dose. A statistical significance threshold of .0063 was assumed after adjustment for multiple comparisons.

Data Synthesis: Of the 3635 citations retrieved, 20 studies of 68,680 patients were included, reporting 7044 deaths, 3993 cardiac deaths, 1150 sudden deaths, 1837 myocardial infarctions, and 1490 strokes. No statistically significant association was observed with all-cause mortality (RR, 0.96; 95% CI, 0.91 to 1.02; risk reduction [RD] -0.004, 95% CI, -0.01 to 0.02), cardiac death (RR, 0.91; 95% CI, 0.85 to 0.98; RD, -0.01; 95% CI, -0.02 to 0.00), sudden death (RR, 0.87; 95% CI, 0.75 to 1.01; RD, -0.003; 95% CI, -0.012 to 0.006), myocardial infarction (RR, 0.89; 95% CI, 0.76 to 1.04; RD, -0.002; 95% CI, -0.007 to 0.002), and stroke (RR, 1.05; 95% CI, 0.93 to 1.18; RD, 0.001; 95% CI, -0.002 to 0.004) when all supplement studies were considered.

Conclusion: Overall, omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association.

Expanded question: Are there specific populations at higher risk with fish oil, particularly considering the increased risks of atrial fibrillation and stroke in healthy individuals?

Answered on May 28, 2024
Certain populations are at higher risk when using fish oil supplements, particularly concerning the increased risks of atrial fibrillation (AF) and stroke in healthy individuals.
1. Healthy Individuals Without Cardiovascular Disease (CVD): Multiple studies have indicated that fish oil supplementation may increase the risk of atrial fibrillation in individuals without pre-existing cardiovascular conditions. For instance, a study by Chen et al. found that regular fish oil use increased the risks of atrial fibrillation and stroke in healthy individuals, with hazard ratios of 1.13 and 1.05, respectively. Similarly, Zhang et al. reported that fish oil users without baseline CVD had a higher rate of incident AF compared to non-users (5.3% vs. 4.1%, P < 0.0001).[1-2]
2. Individuals with Genetic Predisposition to AF: The same study by Zhang et al. demonstrated that the risk of incident AF was higher in fish oil users across all genetic risk groups for AF, including low, intermediate, and high genetic risk groups.[2]
3. Patients with Paroxysmal or Persistent AF: According to the FDA, omega-3-acid ethyl esters have been associated with a higher rate of recurrent AF or flutter in patients with symptomatic paroxysmal or persistent AF, particularly within the first few months of therapy.[3]
In contrast, individuals with pre-existing cardiovascular disease may benefit from fish oil supplementation, as it has been associated with a reduced risk of major adverse cardiovascular events and heart failure progression.[1]
In summary, healthy individuals, those with a genetic predisposition to AF, and patients with paroxysmal or persistent AF are at higher risk when using fish oil supplements. Clinicians should carefully evaluate the potential risks and benefits of fish oil supplementation in these populations.

1.
Study Links Fish Oil Use to an Increased Risk of Atrial Fibrillation and Stroke in Healthy Individuals, but Fish Oil Could Be Beneficial in Persons With Cardiovascular Disease.

OpenEvidence

TL;Dr. Summary of https://bmjmedicine.bmj.com/content/3/1/e000451

TL;Dr.: In a study published in BMJ Medicine, Chen and colleagues investigated the effects of fish oil supplements on cardiovascular disease progression. The prospective cohort study involved 415,737 participants aged 40 to 69 from the UK Biobank, and the median follow-up was 11.9 years. Results indicated that regular fish oil use may increase risks of atrial fibrillation and stroke in healthy individuals (hazard ratios, 1.13 and 1.05, respectively). However, in participants with a cardiovascular disease diagnosis, regular fish oil use was associated with a beneficial impact on the transition of atrial fibrillation to major adverse cardiovascular events (HR, 0.92) and myocardial infarction (HR, 0.85) and of heart failure to death (HR, 0.91). These findings suggest a dual role of fish oil in cardiovascular progression, highlighting the need for targeted guidance on its use. This study by Chen et al. challenges the generally accepted belief, bolstered by landmark trials like JELIS and several meta-analyses, that omega-3 supplementation yields positive impacts on cardiovascular health. This UK Biobank-based cohort study of 415,737 participants found that regular intake of fish oil supplements may increase the risk of atrial fibrillation and stroke in individuals without cardiovascular diseases. However, for patients with pre-existing cardiovascular disease, these supplements appeared advantageous in lowering the transition rates from atrial fibrillation to major adverse cardiovascular events and from heart failure to death. While the research introduces intriguing new perspectives, the observational nature limits the ability to ascertain causality. The study does not factor in doses of supplements, dietary habits or omega-3 blood levels.

2.
Habitual Fish Oil Supplementation and the Risk of Incident Atrial Fibrillation: Findings From a Large Prospective Longitudinal Cohort Study.

Zhang J, Cai A, Chen G, et al.

European Journal of Preventive Cardiology. 2022;29(14):1911-1920. doi:10.1093/eurjpc/zwac192.

Aims: Mixed effects of fish oil supplementation on the risks of atrial fibrillation (AF) were observed in several large-scale randomized controlled trials. Whether this relationship would be modified by genetic AF risk, baseline cardiovascular disease (CVD) status and background oily fish consumption are unknown.

Methods And Results: We included 468 665 participants without AF at baseline from the UK Biobank cohort. The association between fish oil supplementation and the AF risk was assessed in the study cohort and in several subgroups, including genetic AF predisposition, baseline CVD status, and background oily fish consumption. During a median follow-up of 11.1 years, fish oil users had a higher rate of incident AF (6.2% vs. 5.2%, adjusted hazard ratio of 1.10, and 95% confidence interval of 1.07, 1.13). Compared with non-users, fish oil users had a higher rate of incident AF in the low (3.7% vs. 3.0%, P= 0.02), intermediate (5.8% vs. 4.8%, P < 0.0001), and high (9.8% vs. 8.1%, P < 0.0001) genetic AF risk groups. In participants without CVD at baseline, fish oil users had a higher rate of incident AF (5.3% vs. 4.1%, P < 0.0001), which was not observed in participants with CVD at baseline (11.6% vs. 11.1%, P = 0.56), with significant interaction (P-interaction < 0.0001). The association between fish oil supplementation and the AF risk was not modified by background oily fish consumption (P-interaction = 0.62).

Conclusion: Habitual fish oil supplementation was associated with the risk of incident AF, regardless of genetic AF predisposition and background oily fish consumption. This association was observed only in individuals without CVD at baseline.

3.
Omega-3-Acid Ethyl Esters. FDA Drug Label.

Food and Drug Administration (DailyMed)

Updated date: 2024-02-14

FDA

Omega-3-acid ethyl esters should be used with caution in patients with known hypersensitivity to fish and/or shellfish. 5.3 Recurrent Atrial Fibrillation (AF) or Flutter In a double-blind, placebo-controlled trial of 663 subjects with symptomatic paroxysmal AF (n = 542) or persistent AF (n = 121), recurrent AF or flutter was observed in subjects randomized to omega-3-acid ethyl esters who received 8 grams per day for 7 days and 4 grams per day thereafter for 23 weeks at a higher rate relative to placebo. Subjects in this trial had median baseline triglycerides of 127 mg per dL, had no substantial structural heart disease, were taking no anti-arrhythmic therapy (rate control permitted), and were in normal sinus rhythm at baseline. At 24 weeks, in the paroxysmal AF stratum, there were 129 (47%) first recurrent symptomatic AF or flutter events on placebo and 141 (53%) on omega-3-acid ethyl esters [primary endpoint, HR 1.19; 95%

Ci: 0.93, 1.35]. In the persistent AF stratum, there were 19 (35%) events on placebo and 34 (52%) events on omega-3-acid ethyl esters [HR 1.63; 95%

Ci: 0.91, 2.18]. For both strata combined, the HR was 1.25; 95%

Ci: 1.00, 1.40. Although the clinical significance of these results is uncertain, there is a possible association between omega-3-acid ethyl esters and more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, particularly within the first 2 or 3 months of initiating therapy. Omega-3-acid ethyl esters are not indicated for the treatment of AF or flutter.