Omega-3 fatty acids supplementation and risk of atrial fibrillation: an updated meta-analysis of randomized controlled trials
Open accessAbstract
Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia worldwide1 and it is associated with high morbidity and mortality, ultimately making it a major public health burden. Omega-3 fatty acids (O3FA) supplementation are being utilized in clinical practice to reduce cardiovascular disease (CVD) risk in patients with elevated plasma triglycerides. Safety has been, however, questioned as several cardiovascular (CV) outcomes trials of O3FA supplementation showed a potential increase of AF, when compared with placebo.2 In this meta-analysis of randomized controlled trials (RCTs), we investigated whether O3FA supplementation is associated with an increased risk for AF compared to placebo. We conducted a systematic search of RCTs of O3FA supplementation on CV outcomes, which also included data on the incidence of AF up to November 2020. The main endpoint of the study was the onset of AF. For inferential purposes, a frequentist pairwise meta-analysis was conducted by using Poisson regression model with random study effects. Incidence rate ratio (IRR) and 95% confidence interval (CI) were chosen over relative risk as outcome measure because of the different follow-up of the selected studies. The pairwise meta-analysis was performed with the R statistical software (4.0.0 version) using R package ‘meta’. Heterogeneity across studies was assessed with Cochran’s Q method and I2 testing. A threshold of P < 0.10 was used to define the presence of heterogeneity for the Q test. I2 was considered substantial when it was >50%. The presence of publication bias for small study effect appraisal was assessed by visual examination of funnel plots and was quantified by Egger’s test and Begg’s test. Detailed characteristics of the five included studies are presented in Supplementary material online, Table S1.3–7 In the random effect model, O3FA supplementation was associated with an increased risk of incident AF as compared with placebo [IRR 1.37, 95% CI (1.22–1.54), P < 0.001] (Figure 1). There were no significant statistical heterogeneity between studies and no publication bias, even if the funnel plot suggested some asymmetry. As a sensitivity analysis, we included the VITAL rhythm trial. Results confirmed a higher risk of AF in the group receiving O3FA supplementation as compared with placebo [IRR 1.29, 95% CI (1.13–1.48), P = 0.0002] (Supplementary material online, Figure S1). Forest plot for atrial fibrillation events. IRR, incidence rate ratio. Forest plot for atrial fibrillation events. IRR, incidence rate ratio. The results of this meta-analysis show that individuals at high risk for, or with established CVD and elevated plasma triglycerides treated with O3FA supplementation have a significantly higher incidence of AF events, compared to placebo. We also found no heterogeneity and no small study publication bias. O3FA supplementation has been utilized to reduce CVD and CVD-related mortality in patients at high CV risk and elevated plasma triglycerides. The CV benefits, however, have been inconsistent; specifically, in the REDUCE-IT trial, a high dose of O3FA supplementation with highly purified icosapent ethyl was associated with a significantly lower risk for the primary composite CV endpoint3. Contrarily, the recent STRENGTH trial, which utilized the same dose of O3FA supplementation, but containing a formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), was neutral on the composite primary endpoint.6 Moreover, lower doses of O3FA supplementation have not improved CV outcomes.2 Although the positive effects of O3FA supplementation on the composite CV endpoints have been inconsistent, most trials have been associated with an increased risk for AF occurrence. Patients receiving icosapent ethyl in the REDUCE-IT3 trial presented a significantly greater risk for incidence AF or atrial flutter, which was further confirmed in STRENGTH. Even lower doses of O3FA supplementation has shown a potential signal for increased risk for AF,2,4,5 proposing that regardless of the dose of O3FA supplementation implemented in the trials and potential-related benefits on CV outcomes, O3FA supplementation may increase the risk for AF. The results of our meta-analysis confirmed this finding, which is concerning given the large proportion of patients eligible for treatment with O3FA supplementation. The conflicting results of the beneficial effects of O3FA supplementation on CV outcomes along with their potential risk for harm, highlight the need for future studies to ultimately confirm the potential beneficial effects of this class of drugs. Moreover, the mechanisms through which O3FA supplementation may increase the risk for AF remain largely unknown, clearly highlighting the need for more mechanistic clinical trials to investigate such effects. In fact, O3FA have been previously shown to stabilize the cardiac membrane resulting in protective effects against arrhythmias, including ventricular arrhythmias
AI snapshot
Written from the paper’s full text.
TL;DR
In this updated meta-analysis of five randomized controlled trials, omega-3 fatty acid supplementation was associated with a higher incidence of atrial fibrillation compared with placebo (IRR 1.37, 95% CI 1.22–1.54). A sensitivity analysis including the VITAL rhythm trial confirmed the association (IRR 1.29, 95% CI 1.13–1.48).
Key findings
- In the random-effects model, O3FA supplementation was associated with an increased risk of incident AF versus placebo: IRR 1.37, 95% CI 1.22–1.54, P < 0.001.
- In a sensitivity analysis including the VITAL rhythm trial, the higher AF risk persisted: IRR 1.29, 95% CI 1.13–1.48, P = 0.0002.
- There was no significant statistical heterogeneity between studies and no publication bias, although the funnel plot suggested some asymmetry.
- Five RCTs were included; the population was individuals at high risk for, or with established, cardiovascular disease and elevated plasma triglycerides.
Methods
- Systematic search of RCTs of O3FA supplementation on cardiovascular outcomes that also included data on AF incidence, up to November 2020; five studies were included.
- Main endpoint was onset of AF; a frequentist pairwise meta-analysis used a Poisson regression model with random study effects, reporting incidence rate ratio (IRR) and 95% CI because of differing follow-up across studies.
- Analysis was performed in R 4.0.0 using the “meta” package; heterogeneity was assessed with Cochran’s Q and I², and publication bias with funnel plots plus Egger’s and Begg’s tests.
Limitations
- Stated: lack of systematic haemorrhagic risk assessment, lack of a systematic search for AF events in the individual studies, and some studies did not include AF as a prespecified outcome, potentially under-reporting AF events.
- Stated: it was a study-level meta-analysis, so individual participant aspects were not accounted for; placebo arms were often different among trials; and the sensitivity analysis used only VITAL rhythm results presented at the American Heart Association 2020 because full data had not been disclosed.
- Evident from the text: this is a brief letter reporting five included studies, so detailed protocol and risk-of-bias assessment are not reported.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
4 of 14 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured
- Premisecitation§ 8 Mediterranea Cardiocentro, Napoli, Italy
The STRENGTH trial confirmed a greater risk for incident atrial fibrillation or atrial flutter with icosapent ethyl.
“Patients receiving icosapent ethyl in the REDUCE-IT3 trial presented a significantly greater risk for incidence AF or atrial flutter, which was further confirmed in STRENGTH.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Nicholls, 2020, Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial, JAMA source
The Clinical End Points section (p. 6) reports more new-onset atrial fibrillation in STRENGTH patients receiving omega-3 CA than corn oil (2.2% vs 1.3%). The discussion (p. 12) distinguishes that treatment from icosapent ethyl in REDUCE-IT. STRENGTH therefore supports a similar atrial-fibrillation finding, but it did not test icosapent ethyl or establish an increased risk of atrial flutter. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Interpretationreasoning§ 8 Mediterranea Cardiocentro, Napoli, Italy
Regardless of the dose of omega-3 fatty acid supplementation implemented in the trials and potential-related benefits on cardiovascular outcomes, omega-3 fatty acid supplementation may increase the risk for atrial fibrillation.
“proposing that regardless of the dose of O3FA supplementation implemented in the trials and potential-related benefits on CV outcomes, O3FA supplementation may increase the risk for AF.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [2] Lombardi, 2020, Impact of different doses of omega-3 fatty acids on cardiovascular outcomes: a pairwise and network meta-analysis, Curr Atheroscler Rep source
- cites [4] Kromhout, 2010, N-3 fatty acids and cardiovascular events after myocardial infarction, N Engl J Med source
Our copy discusses ventricular arrhythmias and cardiovascular outcomes (Abstract, End Points, and Subgroup Analyses), but the retrieved passages do not address atrial fibrillation risk. Searches for atrial fibrillation and adverse events found no passage supporting a dose-independent increase in that risk. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites [5] Roncaglioni, 2013, N-3 fatty acids in patients with multiple cardiovascular risk factors, N Engl J Med source
- Premisecitation§ 8 Mediterranea Cardiocentro, Napoli, Italy
Even lower doses of omega-3 fatty acid supplementation have shown a potential signal for increased risk for atrial fibrillation.
“Even lower doses of O3FA supplementation has shown a potential signal for increased risk for AF,2,4,5”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [2] Lombardi, 2020, Impact of different doses of omega-3 fatty acids on cardiovascular outcomes: a pairwise and network meta-analysis, Curr Atheroscler Rep source
- cites [4] Kromhout, 2010, N-3 fatty acids and cardiovascular events after myocardial infarction, N Engl J Med source
The Abstract describes a low-dose omega-3 trial, but it does not report atrial fibrillation risk. The End Points section and Subgroup Analyses report ventricular-arrhythmia-related events, which are distinct from atrial fibrillation; searches for atrial fibrillation and adverse-event incidence found no passage establishing the claimed signal. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites [5] Roncaglioni, 2013, N-3 fatty acids in patients with multiple cardiovascular risk factors, N Engl J Med source
- Premisecitation§ 8 Mediterranea Cardiocentro, Napoli, Italy
The STRENGTH trial, which utilized the same dose of omega-3 fatty acid supplementation but containing a formulation of eicosapentaenoic acid and docosahexaenoic acid, was neutral on the composite primary endpoint.
“Contrarily, the recent STRENGTH trial, which utilized the same dose of O3FA supplementation, but containing a formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), was neutral on the composite primary endpoint.6”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Nicholls, 2020, Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial, JAMA source
- Findingown data§ 8 Mediterranea Cardiocentro, Napoli, Italy
There was no significant statistical heterogeneity between the included studies.
“There were no significant statistical heterogeneity between studies and no publication bias, even if the funnel plot suggested some asymmetry.”
- Also stated in: § 8 Mediterranea Cardiocentro, Napoli, Italy · plain
“We also found no heterogeneity and no small study publication bias.”
- Also stated in: § 8 Mediterranea Cardiocentro, Napoli, Italy · plain
“Moreover, although placebo arms were often different among the trials, we did not find heterogeneity in the results.”
Quote in the paperNot a substantial claim - Also stated in: § 8 Mediterranea Cardiocentro, Napoli, Italy · plain
- Findingown data§ 8 Mediterranea Cardiocentro, Napoli, Italy
In a sensitivity analysis including the VITAL rhythm trial, omega-3 fatty acid supplementation was associated with a higher risk of atrial fibrillation compared with placebo (IRR 1.29, 95% CI 1.13-1.48, P = 0.0002).
“As a sensitivity analysis, we included the VITAL rhythm trial. Results confirmed a higher risk of AF in the group receiving O3FA supplementation as compared with placebo [IRR 1.29, 95% CI (1.13–1.48), P = 0.0002] (Supplementary material online, Figure S1).”
Quote in the paperSubstantial claim - Findingown data§ 8 Mediterranea Cardiocentro, Napoli, Italy
There was no small study publication bias.
“There were no significant statistical heterogeneity between studies and no publication bias, even if the funnel plot suggested some asymmetry.”
- Also stated in: § 8 Mediterranea Cardiocentro, Napoli, Italy · plain
“We also found no heterogeneity and no small study publication bias.”
Quote in the paperNot a substantial claim - Also stated in: § 8 Mediterranea Cardiocentro, Napoli, Italy · plain
- Findingown data§ 8 Mediterranea Cardiocentro, Napoli, Italy
Omega-3 fatty acid supplementation is associated with an increased risk of incident atrial fibrillation compared with placebo in patients at high cardiovascular risk or with established cardiovascular disease and elevated plasma triglycerides (IRR 1.37, 95% CI 1.22-1.54, P < 0.001).
“In the random effect model, O3FA supplementation was associated with an increased risk of incident AF as compared with placebo [IRR 1.37, 95% CI (1.22–1.54), P < 0.001] (Figure 1).”
- Also stated in: § 8 Mediterranea Cardiocentro, Napoli, Italy · boosted
“The results of this meta-analysis show that individuals at high risk for, or with established CVD and elevated plasma triglycerides treated with O3FA supplementation have a significantly higher incidence of AF events, compared to placebo.”
- Also stated in: § 8 Mediterranea Cardiocentro, Napoli, Italy · hedged
“In conclusion, our study suggests that O3FA supplementation is associated with an increased risk of AF in patients with elevated plasma triglyceride and at elevated CV risk.”
Quote in the paperSubstantial claim - Also stated in: § 8 Mediterranea Cardiocentro, Napoli, Italy · boosted
- Premisecitation§ 8 Mediterranea Cardiocentro, Napoli, Italy
Several cardiovascular outcomes trials of omega-3 fatty acid supplementation showed a potential increase in atrial fibrillation compared with placebo.
“Safety has been, however, questioned as several cardiovascular (CV) outcomes trials of O3FA supplementation showed a potential increase of AF, when compared with placebo.2”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Lombardi, 2020, Impact of different doses of omega-3 fatty acids on cardiovascular outcomes: a pairwise and network meta-analysis, Curr Atheroscler Rep source
- Premisecitation§ 8 Mediterranea Cardiocentro, Napoli, Italy
In the REDUCE-IT trial, a high dose of omega-3 fatty acid supplementation with highly purified icosapent ethyl was associated with a significantly lower risk for the primary composite cardiovascular endpoint.
“specifically, in the REDUCE-IT trial, a high dose of O3FA supplementation with highly purified icosapent ethyl was associated with a significantly lower risk for the primary composite CV endpoint3.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Bhatt, 2019, Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia, N Engl J Med source
- Premisecitation§ 8 Mediterranea Cardiocentro, Napoli, Italy
Lower doses of omega-3 fatty acid supplementation have not improved cardiovascular outcomes.
“Moreover, lower doses of O3FA supplementation have not improved CV outcomes.2”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] Lombardi, 2020, Impact of different doses of omega-3 fatty acids on cardiovascular outcomes: a pairwise and network meta-analysis, Curr Atheroscler Rep source
- Study design and conductnone given§ 8 Mediterranea Cardiocentro, Napoli, Italy
Some of the included studies did not include atrial fibrillation as a prespecified outcome.
“This study has some limitations such as the lack of systematic haemorrhagic risk of the patients, the lack of a systematic search for AF events in the individual studies, and the fact that some of the studies did not include AF as a prespecified outcome, potentially resulting in under-reporting of AF-related events.”
Quote in the paperNot a substantial claim - Premisecitation§ 8 Mediterranea Cardiocentro, Napoli, Italy
In the REDUCE-IT trial, patients receiving icosapent ethyl presented a significantly greater risk for incident atrial fibrillation or atrial flutter.
“Patients receiving icosapent ethyl in the REDUCE-IT3 trial presented a significantly greater risk for incidence AF or atrial flutter, which was further confirmed in STRENGTH.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Bhatt, 2019, Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia, N Engl J Med source
- Interpretationreasoning§ 8 Mediterranea Cardiocentro, Napoli, Italy
The lack of atrial fibrillation as a prespecified outcome in some studies may have resulted in under-reporting of atrial fibrillation-related events.
“This study has some limitations such as the lack of systematic haemorrhagic risk of the patients, the lack of a systematic search for AF events in the individual studies, and the fact that some of the studies did not include AF as a prespecified outcome, potentially resulting in under-reporting of AF-related events.”
Quote in the paperNot a substantial claim - Premisereasoning§ 8 Mediterranea Cardiocentro, Napoli, Italy
Most trials of omega-3 fatty acid supplementation have been associated with an increased risk for atrial fibrillation occurrence.
“Although the positive effects of O3FA supplementation on the composite CV endpoints have been inconsistent, most trials have been associated with an increased risk for AF occurrence.”
Quote in the paperSubstantial claim - Study design and conductnone given§ 8 Mediterranea Cardiocentro, Napoli, Italy
The study lacked a systematic search for atrial fibrillation events in the individual studies.
“This study has some limitations such as the lack of systematic haemorrhagic risk of the patients, the lack of a systematic search for AF events in the individual studies, and the fact that some of the studies did not include AF as a prespecified outcome, potentially resulting in under-reporting of AF-related events.”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 8
- May combine two claims. 2
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ 8 Mediterranea Cardiocentro, Napoli, ItalyThe funnel plot suggested some asymmetry.
“There were no significant statistical heterogeneity between studies and no publication bias, even if the funnel plot suggested some asymmetry.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone given§ 8 Mediterranea Cardiocentro, Napoli, ItalyPublication bias for small study effect was assessed by visual examination of funnel plots and quantified by Egger's test and Begg's test.
“The presence of publication bias for small study effect appraisal was assessed by visual examination of funnel plots and was quantified by Egger’s test and Begg’s test.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown data§ 8 Mediterranea Cardiocentro, Napoli, ItalyThe study conducted a systematic search of randomized controlled trials of omega-3 fatty acid supplementation on cardiovascular outcomes, including data on the incidence of atrial fibrillation up to November 2020.
“We conducted a systematic search of RCTs of O3FA supplementation on CV outcomes, which also included data on the incidence of AF up to November 2020.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data§ 8 Mediterranea Cardiocentro, Napoli, ItalyThe study lacked a systematic assessment of the haemorrhagic risk of the patients.
“This study has some limitations such as the lack of systematic haemorrhagic risk of the patients, the lack of a systematic search for AF events in the individual studies, and the fact that some of the studies did not include AF as a prespecified outcome, potentially resulting in under-reporting of AF-related events.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone given§ 8 Mediterranea Cardiocentro, Napoli, ItalyThe study conducted a study-level meta-analysis, with individual aspects of the participants not being accounted for.
“We conducted a study-level meta-analysis, with individual aspects of the participants not being accounted for.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data§ 8 Mediterranea Cardiocentro, Napoli, ItalyThe sensitivity analysis on the VITAL rhythm trial was limited to results presented at the American Heart Association 2020 because the full data had not been disclosed.
“Finally, we only included a sensitivity analysis on the VITAL rhythm results presented at the American Heart Association 2020, as the fully data have not been disclosed yet.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data§ 8 Mediterranea Cardiocentro, Napoli, ItalyHeterogeneity across studies was assessed with Cochran's Q method and I2 testing.
“Heterogeneity across studies was assessed with Cochran’s Q method and I2 testing.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ 8 Mediterranea Cardiocentro, Napoli, ItalyOmega-3 fatty acids have been previously shown to stabilize the cardiac membrane resulting in protective effects against arrhythmias, including ventricular arrhythmias.
“In fact, O3FA have been previously shown to stabilize the cardiac membrane resulting in protective effects against arrhythmias, including ventricular arrhythmias.2,8”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] Lombardi, 2020, Impact of different doses of omega-3 fatty acids on cardiovascular outcomes: a pairwise and network meta-analysis, Curr Atheroscler Rep source
- cites [8] 1999, Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial, Lancet source
The paper relies on this without support.
Omega-3 fatty acid supplementation is used in clinical practice to reduce cardiovascular disease risk in patients with elevated plasma triglycerides.
“Omega-3 fatty acids (O3FA) supplementation are being utilized in clinical practice to reduce cardiovascular disease (CVD) risk in patients with elevated plasma triglycerides.”
“O3FA supplementation has been utilized to reduce CVD and CVD-related mortality in patients at high CV risk and elevated plasma triglycerides.”
Cites
Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia
Bhatt, D. L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Doyle, R. T., Juliano, R. A., Jiao, L., Granowitz, C., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1812792 · Cited by 3,317 · see citing works
(1999) · PubMed · Cited by 2,062 · see citing works
Nicholls, S. J., Lincoff, A. M., Garcia, M., Bash, D., Ballantyne, C. M., Barter, P. J., Davidson, M. H., Kastelein, J. J. P., Koenig, W., McGuire, D. K., et al. (2020) · JAMA · doi:10.1001/jama.2020.22258 · Cited by 1,028 · cited 1× · see citing works
“Contrarily, the recent STRENGTH trial, which utilized the same dose of O3FA supplementation, but containing a formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), was neutral on the composite primary endpoint.(6) Moreover, lower doses of O3FA supplementation have not improved CV outcomes.”
Methodn–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction
Kromhout, D., Giltay, E. J., & Geleijnse, J. M. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1003603 · Cited by 936 · see citing works
n–3 Fatty Acids in Patients with Multiple Cardiovascular Risk Factors
The Risk and Prevention Study Collaborative Group (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1205409 · Cited by 510 · see citing works
Patel, N., Deshmukh, A. J., Pant, S., Singh, V., Patel, N., Arora, S., Shah, N. N., Chothani, A., Savani, G. T., Mehta, K. D., et al. (2014) · Circulation · doi:10.1161/circulationaha.114.008201 · Cited by 429 · see citing works
Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction
Kalstad, A. A., Myhre, P. L., Laake, K., Tveit, S. H., Schmidt, E. B., Smith, P., Nilsen, D. W. T., Tveit, A., Fagerland, M. W., Solheim, S., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.052209 · Cited by 311 · see citing works
Lombardi, M., Chiabrando, J. G., Vescovo, G. M., Bressi, E., Del Buono, M. G., Carbone, S., Koenig, R. A., Van Tassell, B. W., Abbate, A., Biondi-Zoccai, G., et al. (2020) · Current Atherosclerosis Reports · doi:10.1007/s11883-020-00865-5 · Cited by 33 · see citing works
Self-citation
Flagged first, then by citations
1 of the 10 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Dobrev, D., Heijman, J., Hiram, R., Li, N., & Nattel, S. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-022-00759-w · Cited by 274 · see citing works
Impact of α-Linolenic Acid, the Vegetable ω-3 Fatty Acid, on Cardiovascular Disease and Cognition
Sala‐Vila, A., Fleming, J. A., Kris‐Etherton, P. M., & Ros, E. (2022) · Advances in Nutrition · doi:10.1093/advances/nmac016 · Cited by 158 · see citing works
Nutrition Assessment and Dietary Interventions in Heart Failure
Driggin, E., COHEN, L. P., Gallagher, D., Karmally, W., Maddox, T. M., Hummel, S. L., Carbone, S., & Maurer, M. S. (2022) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2022.02.025 · Cited by 134 · see citing works
Self-citationSystemic Aging Fuels Heart Failure: Molecular Mechanisms and Therapeutic Avenues
Fang, Z., Raza, U., Song, J., Lu, J., Yao, S., Liu, X., Zhang, W., & Li, S. (2024) · ESC Heart Failure · doi:10.1002/ehf2.14947 · Cited by 114 · see citing works
Pros and Cons of Long-Chain Omega-3 Polyunsaturated Fatty Acids in Cardiovascular Health
Djuricic, I. D., & Calder, P. C. (2023) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-051921-090208 · Cited by 101 · see citing works
Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19
Talasaz, A. H., Sadeghipour, P., Aghakouchakzadeh, M., Dreyfus, I., Kakavand, H., Ariannejad, H., Gupta, A., Madhavan, M. V., Tassell, B. W. V., Jiménez, D., et al. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.08.021 · Cited by 60 · see citing works
Self-citationDrenjančević, I., & Pitha, J. V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042104 · Cited by 41 · see citing works
Myhre, P. L., Kalstad, A. A., Tveit, S. H., Laake, K., Schmidt, E. B., Smith, P., Nilsen, D. W. T., Tveit, A., Solheim, S., Arnesen, H., et al. (2022) · Journal of Internal Medicine · doi:10.1111/joim.13442 · Cited by 36 · see citing works
Aldoori, J., Cockbain, A. J., Toogood, G. J., & Hull, M. A. (2022) · Gut · doi:10.1136/gutjnl-2021-326362 · Cited by 32 · see citing works
Omega‐3 fatty acids for the prevention of atherosclerotic cardiovascular disease
Barry, A. R., & Dixon, D. L. (2021) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.2615 · Cited by 30 · see citing works
Self-citationDiet and risk of atrial fibrillation: a systematic review
Gawalko, M. M., Middeldorp, M. E., Saljic, A., Penders, J., Jespersen, T., Albert, C. M., Marcus, G. M., Wong, C. X. J., Sanders, P., & Linz, D. (2024) · European Heart Journal · doi:10.1093/eurheartj/ehae551 · Cited by 22 · see citing works
Regulatory Compliance of Health Claims on Omega-3 Fatty Acid Food Supplements
Fuentes, J. B., Beara, I. N., & Torović, L. D. (2024) · Foods · doi:10.3390/foods14010067 · Cited by 20 · see citing works
“This is suggested by studies indicating a link between ω - 3-FA supplementation and an increased risk of atrial fibrillation and other cardiovascular events [58].”
Drug-induced atrial fibrillation. A narrative review of a forgotten adverse effect
Tamargo, J. L., Pérez‐Villacastín, J., Caballero, R., & Delpón, E. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107077 · Cited by 22 · see citing works
Myhre, P. L., Berge, T., Kalstad, A. A., Tveit, S. H., Laake, K., Schmidt, E. B., Solheim, S., Arnesen, H., Seljeflot, I., & Tveit, A. (2023) · Clinical Nutrition · doi:10.1016/j.clnu.2023.07.002 · Cited by 19 · see citing works
Dietary Interventions in Heart Failure With Preserved Ejection Fraction
Billingsley, H., Carbone, S., Driggin, E., Kitzman, D. W., & Hummel, S. L. (2024) · JACC Advances · doi:10.1016/j.jacadv.2024.101465 · Cited by 18 · see citing works
Self-citationOmega-3 fatty acids and atrial fibrillation
Huh, J. H., & Jo, S. (2022) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2022.266 · Cited by 21 · see citing works
Inflammation pathways as therapeutic targets in angiotensin II induced atrial fibrillation
Hou, A., Shi, D., Huang, H., Liu, Y., & Zhang, Y. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1515864 · Cited by 16 · see citing works
Omega-3 Fatty Acids and Muscle Strength—Current State of Knowledge and Future Perspectives
Tomczyk, M. (2024) · Nutrients · doi:10.3390/nu16234075 · Cited by 15 · see citing works
“The meta-analyses by Albert et al. and Lombardi et al. with a total of 12 RCTs showed that supplementation with n -3 PUFAs was associated with an increased risk of AF, particularly when high doses of n -3 PUFAs were applied [60,61].”
Li, L., Wang, C., Ye, Z., Spall, H. G. C. V., Zhang, J., Lip, G. Y. H., & Li, G. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.123.033840 · Cited by 13 · see citing works
“44 Our exploratory analysis showed participants in the highest quartile of LDL-C, triglycerides, and TC had a 10%, 16%, and 11% lower risk of incident AF than those in the lowest quartile, respectively (Table S6).”
Yokoyama, Y., Kuno, T., Morita, S. X., Slipczuk, L. N., Takagi, H., Briasoulis, Α., Latib, A., Bangalore, S., & Heffron, S. P. (2022) · Journal of Cardiology · doi:10.1016/j.jjcc.2022.07.008 · Cited by 11 · see citing works
Omega 3 Fatty Acids and Health: The Little We Know after All These Years
Visioli, F., & Agostoni, C. V. (2022) · Nutrients · doi:10.3390/nu14020239 · Cited by 9 · see citing works
Metabolic and Inflammatory Mechanisms Driving Atrial Fibrillation
Stoll, L., Ha, E. E., & Lo, J. C. (2025) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-062124-025403 · Cited by 8 · see citing works
Gao, G., Zhou, J., Wang, H., Ke, L., Zhou, J., Ding, Y., Ding, W., Zhang, S., & Rao, P. (2022) · Food Chemistry · doi:10.1016/j.foodchem.2022.135249 · Cited by 8 · see citing works
A stepwise approach to prescribing novel lipid-lowering medications
Kakavand, H., Aghakouchakzadeh, M., Shahi, A., Virani, S. S., Dixon, D. L., Tassell, B. W. V., & Talasaz, A. H. (2022) · Journal of clinical lipidology · doi:10.1016/j.jacl.2022.10.003 · Cited by 7 · see citing works
Self-citationGuan, M., Hu, H., Qi, D., Qin, X., & Wan, Q. (2024) · Scientific Reports · doi:10.1038/s41598-024-67100-y · Cited by 7 · see citing works
Cardioprotective Effects of Nutraceuticals: Focus on Omega-3 Polyunsaturated Fatty Acids
Sypniewska, G., & Kruszewski, S. (2021) · Nutrients · doi:10.3390/nu13093184 · Cited by 6 · see citing works
Lipid lowering therapy in 2022 and beyond - How far we have come
Saseen, J. J., & Virani, S. S. (2022) · Progress in Cardiovascular Diseases · doi:10.1016/j.pcad.2022.11.008 · Cited by 6 · see citing works
n-3 fatty acids and the risk of atrial fibrillation, review
Herrmann, W., & Herrmann, M. (2024) · Diagnosis · doi:10.1515/dx-2024-0077 · Cited by 7 · see citing works
Omega‐3 Fatty Acids and Heart Rhythm, Rate, and Variability in Atrial Fibrillation
Baumgartner, P., Reiner, M. F., Wiencierz, A., Coslovsky, M., Bonetti, N. R., Filipovic, M. G., Aeschbacher, S., Kühne, M., Zuern, C. S., Rodondi, N., et al. (2023) · Journal of the American Heart Association · doi:10.1161/jaha.122.027646 · Cited by 5 · see citing works
Rosmalina, R. T., Kosasih, W., & Priatni, S. (2021) · Jurnal Teknologi dan Industri Pangan · doi:10.6066/jtip.2021.32.1.16 · Cited by 5 · see citing works
Hamaya, R., Cook, N. R., Sesso, H. D., Buring, J. E., & Manson, J. E. (2025) · American Journal of Clinical Nutrition · doi:10.1016/j.ajcnut.2025.02.028 · Cited by 4 · see citing works
Liver X Receptor Agonist 4β‐Hydroxycholesterol as a Prognostic Factor in Coronary Artery Disease
Rahunen, R., Tulppo, M. P., Rinne, V. M., et al. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.123.031824 · Cited by 4 · see citing works
Fallahtafti, P., Nayebirad, S., Karimi, E., Hassanzadeh, A., Habibzadeh, A., Safaee, E., Ebrahimi, R., Tajdini, M., Najafi, K., Askari, M. K., et al. (2024) · Cardiology Plus · doi:10.1097/cp9.0000000000000102 · Cited by 4 · see citing works
“Notably, a recent meta-analysis of RCTs has shown that high doses of omega-3 fatty acids like EPA may increase the risk of AF, particularly in patients with high cardiovascular risk and elevated plasma TG levels [39] .”
Fatty Acids - From Biosynthesis to Human Health
Froyen, E. (2022) · Biochemistry · doi:10.5772/intechopen.100947 · Cited by 4 · see citing works
Mori, T., Murasaki, K., Hayashi, K., & Yokoyama, Y. (2022) · Journal of clinical lipidology · doi:10.1016/j.jacl.2022.06.007 · Cited by 3 · see citing works
Eicosapentaenoic Acid: between Cardiovascular Benefits and the Risk of Atrial Fibrillation
Egalini, F., Rossi, M., Massussi, M., Gaggero, G., Beccuti, G., Benso, A. S., Piepoli, M. F., & Broglio, F. (2023) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/0118715303280825231122153024 · Cited by 3 · see citing works
New data on NOVEL ORAL ANTICOAGULANT, SGLT2i, lipid treatment and genetics
Agewall, S. (2024) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvae005 · Cited by 3 · see citing works
Patil, T., Gregory, M., Savona, N., Jarmukli, N. F., & Leonard, C. E. (2025) · Clinical Drug Investigation · doi:10.1007/s40261-024-01417-4 · Cited by 3 · see citing works
“A recent meta-analysis of six randomized controlled trials showed that OM-3 increased the risk of incident AF compared with placebo (incidence rate ratio 1.29; 95% CI 1.13–1.48) [33].”
InfluentialSide effects of anti-lipid medications
Choi, S., Kulig, C. E., & Wilczynski, J. A. (2022) · Side effects of drugs annual · doi:10.1016/bs.seda.2022.08.010 · Cited by 2 · see citing works
Singh, N., Dove, E., & Bhatt, D. L. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-88286-6.00019-4 · Cited by 2 · see citing works
Ouagueni, A., Shi, Z., Shraim, M., Al‐Zoubi, R. M., Zarour, A. M., Al-Ansari, A. A., & Bawadi, H. A. (2024) · Nutrients · doi:10.3390/nu16193298 · Cited by 2 · see citing works
“The effect of omega-3 PUFA on post-operative atrial fibrillation has been studied extensively and many systematic reviews were conducted in the literature [30–33].”
BackgroundVelappan, M., & Munusamy, D. (2023) · Biochemistry · doi:10.5772/intechopen.110824 · Cited by 2 · see citing works
Current Evidence and Future Directions of Omega-3 Supplementation and Cardiovascular Disease Risk
Dwiputra, B., Santoso, A., Purwowiyoto, B. S., Radi, B., Pandhita, B. A. W., Fatrin, S., & Ambari, A. M. (2023) · International Journal of Angiology · doi:10.1055/s-0043-1777258 · Cited by 1 · see citing works
Screening metabolic features of stroke in atrial fibrillation
Zhang, H., Zhang, H., Zhai, S., et al. (2025) · Analytica Chimica Acta · doi:10.1016/j.aca.2025.344576 · Cited by 1 · see citing works
Bendadani, C., Bakhiya, N., Breitweg‐Lehmann, E., Ehlers, A., Hirsch‐Ernst, K. I., Liebscher, B., & Weißenborn, A. (2025) · Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz · doi:10.1007/s00103-025-04134-1 · Cited by 1 · see citing works
Assessing pharmacists’ knowledge and practices involving dietary supplement omega-3 fatty acids
Backes, J. M., Beavers, C. J., Dixon, D. L., et al. (2025) · Journal of clinical lipidology · doi:10.1016/j.jacl.2025.09.007 · Cited by 1 · see citing works
Self-citationOmega-3 fatty acids supplementation: increased risk of atrial fibrillation
(2021) · Reactions Weekly · doi:10.1007/s40278-021-96393-5
Omega-3-Fettsäuren: Widersprüchliche Studien
(2021) · DMW - Deutsche Medizinische Wochenschrift · doi:10.1055/a-1438-2608
Safety update: omega-3-acid ethyl esters and atrial fibrillation
BMJ Publishing Group Ltd (2024) · Drug and Therapeutics Bulletin · doi:10.1136/dtb.2024.000010
New Aspects of the Efficacy and Safety Profile of Medicines Containing Omega-3-Acids Ethyl Esters
Гринько, Д. В., Кучко, А. М., Ефремова, И. Н., et al. (2024) · Рецепт · doi:10.34883/pi.2024.27.1.012
When “old” lipid lowering therapies not should be discontinued
Sbrana, F., & Pino, B. D. (2024) · Clínica e Investigación en Arteriosclerosis · doi:10.1016/j.arteri.2024.08.002
Ros, E., Pérez‐Martínez, P., Estruch, R., López‐Miranda, J., Ferrer, C. S. I., Delgado‐Lista, J., Gómez-Delgado, F., Solà, R., & Pascual, V. (2024) · Clínica e Investigación en Arteriosclerosis · doi:10.1016/j.arteri.2024.10.001 · Cited by 2 · see citing works
Long-Chain Polysaturated Fatty Acid in Atrial Fibrillation–Associated Stroke: Lipidomic-GWAS Study
Jung, Y., Kim, B., Kim, C. K., Won, H., Chae, S.-H., Oh, K., Shin, M., Hwang, G., & Seo, W. (2024) · Thrombosis and Haemostasis · doi:10.1055/a-2504-0903
Ros, E., Pérez‐Martínez, P., Estruch, R., López‐Miranda, J., Ferrer, C. S. I., Delgado‐Lista, J., Gómez-Delgado, F., Solà, R., & Pascual, V. (2024) · Clínica e Investigación en Arteriosclerosis (English Edition) · doi:10.1016/j.artere.2024.100741
When “old” lipid lowering therapies not should be discontinued
Sbrana, F., & Pino, B. D. (2025) · Clínica e Investigación en Arteriosclerosis (English Edition) · doi:10.1016/j.artere.2025.100732
Aging-related comorbidities, life-style interventions and therapeutic strategies in heart failure
Phan, N. N., & Yunus, F.-U.-N. (2025) · doi:10.32948/ajsep.2025.03.20
Ernährungsmedizin in der augenärztlichen Praxis – Interesse und Motivation der Patienten
Arend, N. (2025) · Die Ophthalmologie · doi:10.1007/s00347-025-02251-5
Edel, A., & Scholtz, K. (2025) · Springer eBooks · doi:10.1007/978-3-032-00818-3_5
Hartl, W. H., Meybohm, P., Pirlich, M., Mayer, K., Elke, G., Stoppe, C., & von Loeffelholz, C. (2025) · Clinical Nutrition · doi:10.1016/j.clnu.2025.11.013 · Cited by 1 · see citing works
Saad, R. A., Hasan, R. A., Qutob, H. M., Ali, H. S., Elayate, W. M., & Saad, D. A. (2025) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s1234567825600191
Wang, Y., Long, M., Chen, F., Wu, D., Pei, Z., Wang, X., Zhao, W., Mori, T., & Zhao, S. (2025) · Journal of clinical lipidology · doi:10.1016/j.jacl.2025.12.007
OMEGA-3 FATTY ACIDS AND CARDIOVASCULAR DISEASE: A DECADE OF EVIDENCE
Janiszewska, M., Juchniewicz, A., Sapikowski, J., Kuba, I., Jagodzińska, J., Lubomska, A., Grześkowiak, M., & Idziński, J. (2025) · International Journal of Innovative Technologies in Social Science · doi:10.31435/ijitss.4(48).2025.4279
Liu, S., Yuan, H., Cao, J., et al. (2026) · Medicine · doi:10.1097/md.0000000000047645
“[29,30] Compared to CVD studies, research on PAH in relation to FAs is limited, with most studies focusing on surrogate end-points such as pulmonary vascular resistance or right ventricular (RV) function.”
Tao, G., Li, X., Wu, J., et al. (2026) · Cardiology · doi:10.1159/000550761
Yang, D. X., Thakur, S., Akunor, H., Stacey, R. B., & Upadhya, B. (2026) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd13070291 · Cited by 1 · see citing works
“Linked to AF [63] Oral supplementation needs further safety evaluation.”
Kolanowski, W., & Foligni, R. (2026) · Applied Sciences · doi:10.3390/app16147116
Egalini, F., Riccio, E., Grasso, M., Nelva, A., & Geronimo, V. D. (2026) · Nutrients · doi:10.3390/nu18152538
“Given that risk factors for AF, such as increasing age, hypertension and obesity, are very common in patients with hyper-triglyceridemia [143], some clinicians highlight the need for a careful prescription of ω -3 in susceptible individuals [144].”
Natural Fish Oil Versus Purified Fish Oil: Composition, Efficacy, and Applications
Nie, J., Fan, L., Du, J., 王伟华, Li, J., & Chen, L. (2026) · Journal of Nutrition and Metabolism · doi:10.1155/jnme/5029849
- Authors
- Lombardi, M., Carbone, S., Del Buono, M. G., Chiabrando, J. G., Vescovo, G. M., Camilli, M., Montone, R. A., Vergallo, R., Abbate, A., Biondi-Zoccai, G., Dixon, D. L., & Crea, F.
- Affiliations
- Università Cattolica del Sacro Cuore (IT)
- Virginia Commonwealth University (US)
- Department of Cardiovascular and Thoracic Sciences, Catholic University of the Sacred Heart , Rome,
- Universidad de Buenos Aires (AR)
- University of Padua (IT)
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome , Latina,
- Corresponding author
- Carbone, Salvatore
- ORCID
- Venue
- European Heart Journal - Cardiovascular Pharmacotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-04-28
- Volume
- 7
- Issue
- 4
- Pages
- e69-e70
- ISSN
- 2055-6837 (ISSN-L)
- 2055-6845
- PMC
- PMC8302253
- OpenAlex
- W3159099931
- Cited by
- 68
- References
- 10
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 19 · 2023: 7 · 2022: 15 · 2021: 6
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- European Heart Journal - Cardiovascular Pharmacotherapy (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Funders
- Career Development Award (19CDA34660318)
- American Heart Association
- Clinical and Translational Science Awards Program (UL1TR002649)
- National Institutes of Health
- Virginia Commonwealth University
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- omega-3 fatty acids, dietary supplementation, atrial fibrillation, incident atrial fibrillation risk, cardiovascular outcomes, VITAL trial, triglycerides, cardiac arrhythmias, publication bias, sensitivity analysis, omega-3 index, n-6/n-3 ratio
- MeSH terms
- Atrial Fibrillation, Humans, Fatty Acids, Omega-3, Randomized Controlled Trials as Topic, Dietary Supplements
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
