CoChat
Sign Up
Cited by 150Fatty Acid Research and HealthAtrial Fibrillation Management and OutcomesCardiac Health and Mental Health

Effect of Long-Term Marine ɷ-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

Open access
Gencer, Baris, Djousse, Luc, Al-Ramady, Omar T., Cook, Nancy R., Manson, JoAnn E., Albert, Christine M.·2021·Circulation
DOI 10.1161/circulationaha.121.055654PMC PMC9109217
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: Some, but not all, large-scale randomized controlled trials (RCTs) investigating the effects of marine ɷ-3 fatty acids supplementation on cardiovascular outcomes have reported increased risks of atrial fibrillation (AF). The potential reasons for disparate findings may be dose-related. Methods: The MEDLINE and Embase databases were searched for articles and abstracts published between January 1, 2012, and December 31, 2020, in addition to a meta-analysis of large cardiovascular RCTs published in 2019. RCTs of cardiovascular outcomes of marine ɷ-3 fatty acids that reported results for AF, either as a prespecified outcome, an adverse event, or a cause for hospitalization, with a minimum sample size of 500 patients and a median follow-up of at least 1 year were included. RCTs specifically examining shorter-term effects of ɷ-3 fatty acids on recurrent AF in patients with established AF or postoperative AF were not included. The hazard ratio (HR) for the reported AF outcomes within each trial was meta-analyzed using random effects model with Knapp-Hartung adjustment and evaluated a dose-response relationship with a meta-regression model. Results: Of 4049 screened records, 7 studies were included in the meta-analysis. Of those, 5 were already detected in a previous meta-analysis of cardiovascular RCTs. Among the 81 210 patients from 7 trials, 58 939 (72.6%) were enrolled in trials testing ≤1 g/d and 22 271 (27.4%) in trials testing >1 g/d of ɷ-3 fatty acids. The mean age was 65 years, and 31 842 (39%) were female. The weighted average follow-up was 4.9 years. In meta-analysis, the use of marine ɷ-3 fatty acid supplements was associated with an increased risk of AF (n=2905; HR, 1.25 [95% CI, 1.07–1.46]; P =0.013). In analyses stratified by dose, the HR was greater in the trials testing >1 g/d (HR, 1.49 [95% CI, 1.04–2.15]; P =0.042) compared with those testing ≤1 g/d (HR, 1.12 [95% CI, 1.03–1.22]; P =0.024; P for interaction <0.001). In meta-regression, the HR for AF increased per 1 g higher dosage of ɷ-3 fatty acids dosage (HR, 1.11 [95% CI, 1.06–1.15]; P =0.001). Conclusions: In RCTs examining cardiovascular outcomes, marine ɷ-3 supplementation was associated with an increased risk of AF. The risk appeared to be greater in trials testing >1 g/d.

AI snapshot

Written from the paper’s full text.

TL;DR

In randomized cardiovascular outcome trials, marine omega-3 fatty acid supplementation was associated with increased atrial fibrillation (AF) risk. The risk was greater in trials testing >1 g/day and showed a dose-response relationship.

Key findings

  • Among 81,210 patients from 7 trials, 2,905 (3.6%) had an AF outcome; pooled HR for AF with marine omega-3 supplementation was 1.25 (95% CI 1.07–1.46, P=0.013).
  • Risk was higher in trials testing >1 g/day (HR 1.49, 95% CI 1.04–2.15, P=0.042) than in trials testing ≤1 g/day (HR 1.12, 95% CI 1.03–1.22, P=0.024; P for interaction <0.001).
  • Meta-regression showed an 11% higher relative risk of AF per 1 g increase in omega-3 dosage (HR 1.11, 95% CI 1.06–1.15, P=0.001).
  • Sensitivity analyses generally persisted, including after excluding REDUCE-IT (HR 1.23, 95% CI 1.02–1.49, P=0.038) and after trim-and-fill imputation (HR 1.23, 95% CI 1.10–1.39).

Methods

  • Systematic review and meta-analysis registered to PROSPERO; MEDLINE and Embase searched for records published January 1, 2012–December 31, 2020, plus trials from a previous meta-analysis of cardiovascular RCTs.
  • Included RCTs of cardiovascular outcomes with marine omega-3 fatty acids, minimum sample size 500, median follow-up at least 1 year, and reported AF as pre-specified outcome, adverse event, or hospitalization; trials of post-operative or recurrent AF in established AF were excluded.
  • Primary analysis used random-effects DerSimonian-Laird meta-analysis with Knapp-Hartung adjustment; dose-response was assessed by meta-regression, with sensitivity analyses stratified by dose and other trial features.

Limitations

  • The paper states differences in AF outcome assessment across trials, including that some trials did not systematically exclude preexisting AF; HRs were not directly available for REDUCE-IT and ASCEND, requiring use of RR or adverse-event rates; not every large omega-3 trial reported AF outcomes; limited dosage variability at the lower range constrained testing of linearity; and trial participants may not represent everyday practice.
  • The paper also states that it pooled aggregate-level trial data, not individual participant data, so subgroup analyses by age or other patient-level characteristics were not possible.
  • The text makes evident that no trial directly compared different dosages (e.g., high vs. low vs. placebo) on AF risk, so the dose-related findings are based on between-trial comparisons.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1161/circulationaha.121.055654

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

9 of 17 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The VITAL Rhythm Study did not find a significant increased risk of incident atrial fibrillation with 1 g/day marine omega-3 fatty acids (460 mg EPA and 380 mg DHA) compared with placebo (HR 1.09, 95%CI 0.96-1.24, P=0.19).

    “The study with the largest number of AF events, the VITAL Rhythm Study, did not find a significant increased risk of incident AF with 1gram per day of marine omega-3 fatty acids (460 mg of eicosapentaenoic acid [EPA] and 380 mg of docosahexaenoic acid [DHA]) compared with placebo (HR 1.09, 95%CI 0.96–1.24, P=0.19).8”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Albert CM, Cook NR, Pester J, Moorthy MV, Ridge C, Danik JS, Gencer B, Siddiqi HK, Ng C, Gibson H, Mora S, Buring JE and Manson JE. Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation: A Randomized Clinical Trial. JAMA. 2021; 325: 1061– 1073. 33724323 PMC7967086 source

      The Trial Design and Oversight section describes 840 mg/day of marine omega-3 fatty acids—460 mg EPA and 380 mg DHA—not 1 g/day of those fatty acids. The Omega-3 Fatty Acid Supplementation results report the claimed nonsignificant comparison with placebo (HR 1.09, 95% CI 0.96–1.24; P = .19). The Results section reports 900 confirmed AF events, consistent with the study's characterization as having the largest number of events among the trials discussed. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Some, but not all, large-scale randomized controlled trials of marine omega-3 fatty acid supplementation for cardiovascular outcomes have reported increased risks of atrial fibrillation.

    “Some, but not all, large-scale randomized controlled trials (RCTs) investigating the effects of marine omega-3 fatty acids supplementation on cardiovascular outcomes have reported increased risks of atrial fibrillation (AF).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [2] Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr., Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CMand Investigators R-I. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019; 380: 11– 22. 30415628 source
    • cites [6] Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, Mozaffarian D, Ridker PM, Ray KK, Katona BG, Himmelmann A, Loss LE, Rensfeldt M, Lundström T, Agrawal R, Menon V, Wolski K and Nissen SE. 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. 2020; 324: 2268– 2280. 33190147 PMC7667577 source

      The Clinical End Points section (p. 6) reports more new-onset atrial fibrillation with omega-3 fatty acids than with corn oil in STRENGTH. The adverse-events discussion (p. 12) says REDUCE-IT reported a similar finding. These passages support “some,” but our copy does not establish that other large cardiovascular-outcomes trials did not report an increased risk. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [7] Kalstad AA, Myhre PL, Laake K, Tveit SH, Schmidt EB, Smith P, Nilsen DWT, Tveit A, Fagerland MW, Solheim S, Seljeflot I, Arnesen H and investigators O. Effects of n-3 Fatty Acid Supplements in Elderly Patients after Myocardial Infarction: A Randomized Controlled Trial. Circulation. 2021 Feb 9; 143(6): 528– 539. 33191772 source

      The Discussion reports increased atrial fibrillation in REDUCE-IT and a numerical increase in OMEMI that was not statistically significant. It does not identify trials that reported no increase in atrial fibrillation, so the “but not all” part is not fully supported by this paper. (LLM, conf=0.80)

      Experimental — accuracy not yet measured
  • Premisecitation

    In STRENGTH, 4 g of marine omega-3 fatty acids was associated with an increased risk of atrial fibrillation events (2.2% vs 1.3%, HR 1.69, 95%CI 1.29-2.21, P<0.001).

    “In the STRENGTH trial, 4 gr of marine omega-3 fatty acids was associated with an increased risk of AF events (2.2% vs 1.3%, HR 1.69, 95%CI 1.29–2.21<P<0.001).6”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, Mozaffarian D, Ridker PM, Ray KK, Katona BG, Himmelmann A, Loss LE, Rensfeldt M, Lundström T, Agrawal R, Menon V, Wolski K and Nissen SE. 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. 2020; 324: 2268– 2280. 33190147 PMC7667577 source
  • Premisecitation

    In OMEMI, the absolute risk difference for developing atrial fibrillation (>3%) was highest among those 75 years or older.

    “In the OMEMI trial, the absolute risk difference for developing AF (>3%) was the highest among those 75 years or older.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Kalstad AA, Myhre PL, Laake K, Tveit SH, Schmidt EB, Smith P, Nilsen DWT, Tveit A, Fagerland MW, Solheim S, Seljeflot I, Arnesen H and investigators O. Effects of n-3 Fatty Acid Supplements in Elderly Patients after Myocardial Infarction: A Randomized Controlled Trial. Circulation. 2021 Feb 9; 143(6): 528– 539. 33191772 source

      The Discussion reports new-onset AF in 7.2% of the n-3 PUFA group and 4.0% of the placebo group, an overall absolute difference of 3.2 percentage points. Our copy does not establish that the difference was greatest among patients aged 75 or older; the Outcomes section says subgroup analysis was not performed for AF. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingown data

    The effect of marine omega-3 fatty acid supplements on atrial fibrillation after excluding REDUCE-IT remained significant (HR 1.23, 95%CI 1.02-1.49, P=0.038).

    “The effect of marine omega-3 fatty acid supplements on the risk of AF events after excluding REDUCE-IT (the only trial without DHA) remained significant (HR 1.23, 95%CI 1.02–1.49, P=0.038, Figure VII in the Supplement).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 10
  • May combine two claims. 19
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    Egger's test was not performed because testing for publication bias is not advised for fewer than 10 studies.

    “Because the test for a publication is not advised for fewer than 10 studies, Egger’s test was not performed.20”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [20] Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, Carpenter J, Rucker G, Harbord RM, Schmid CH, Tetzlaff J, Deeks JJ, Peters J, Macaskill P, Schwarzer G, Duval S, Altman DG, Moher D and Higgins JP. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011; 343:d4002. 21784880 source

  • May combine two claims.

    Premisecitation

    In VITAL, the largest atrial fibrillation primary prevention randomized trial testing 1 g of omega-3 fatty acids, findings were neutral (HR 1.09, 95%CI 0.96-1.24, P=0.19) and did not support supplemental use for primary prevention of atrial fibrillation.

    “In the VITAL trial, the largest AF primary prevention randomized trial that tested 1 gr of omega-fatty acids, the findings were neutral (HR 1.09, 95%CI 0.96–1.24, P=0.19) and did not support the use of supplemental for the primary prevention of AF.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Albert CM, Cook NR, Pester J, Moorthy MV, Ridge C, Danik JS, Gencer B, Siddiqi HK, Ng C, Gibson H, Mora S, Buring JE and Manson JE. Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation: A Randomized Clinical Trial. JAMA. 2021; 325: 1061– 1073. 33724323 PMC7967086 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Marine omega-3 fatty acid supplements may have a beneficial effect on the risk of atherosclerotic cardiovascular events.

    “Marine omega-3 fatty acids supplements may have a beneficial effect on the risk of atherosclerotic cardiovascular events 1–4”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [1] Hu Y, Hu FB and Manson JE. Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants. J Am Heart Assoc. 2019; 8:e013543. PMC6806028 31567003 source
    • cites [2] Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr., Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CMand Investigators R-I. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019; 380: 11– 22. 30415628 source
    • cites [3] Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999; 354: 447– 55. 10465168

  • May combine two claims.

    Premisecitation

    In OMEMI, older patients with recent myocardial infarction (≥75 years) randomized to 1.8 g supplements had a higher risk of atrial fibrillation events compared with placebo, but the result did not reach statistical significance (7.2% vs 4.0%, HR 1.94, 95%CI 0.98-3.45, P=0.06).

    “In the OMEMI trial, older patients with recent myocardial infarction (≥ 75 years) who were randomized to 1.8 gr supplements also had a higher risk of AF events detected clinically or by electrocardiographic monitoring when compared with placebo, although the result did not reach statistical significance (7.2% vs. 4.0%, HR 1.94, 95%CI 0.98–3.45, P=0.06).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Kalstad AA, Myhre PL, Laake K, Tveit SH, Schmidt EB, Smith P, Nilsen DWT, Tveit A, Fagerland MW, Solheim S, Seljeflot I, Arnesen H and investigators O. Effects of n-3 Fatty Acid Supplements in Elderly Patients after Myocardial Infarction: A Randomized Controlled Trial. Circulation. 2021 Feb 9; 143(6): 528– 539. 33191772 source

      The Abstract and Outcomes section support the higher, statistically nonsignificant rate of new-onset AF with 1.8 g n-3 PUFA (7.2% vs 4.0%; P=0.06). But they report an HR of 1.84, not 1.94, and the Patients section says participants were aged 70–82, not exclusively ≥75. Page numbers were unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Among 81,210 patients from seven trials, 58,939 (72.6%) were enrolled in trials testing ≤1 g/day and 22,271 (27.4%) in trials testing >1 g/day of omega-3 fatty acids.

    “Among the 81,210 patients from seven trials, 58,939 (72.6%) were enrolled in trials testing low dose marine omega 3-fatty acids (≤1 gr per day) and 22,271 (27.4%) in trials testing high dose of marine omega 3-fatty acids (>1 gr per day).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Findingown data

    After screening 4,059 records, seven articles were included in the systematic review and meta-analysis.

    “After screening 4,059 records (Figure I in the Supplement for the PRISMA flowchart), data from seven articles were included in the systematic review and meta-analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Sensitivity analysis excluding the RP trial yielded similar results (HR 1.26, 95%CI 1.04-1.52, P=0.028), with no significant interaction (P=0.85).

    “Additional sensitivity analysis excluding the RP trial, which only reported AF hospitalizations, yielded similar results (HR 1.26, 95%CI 1.04–1.52, P=0.028) with no significant interaction (P=0.85).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In meta-regression using post-hoc ASCEND data, the hazard ratio was 1.10 (95%CI 1.05-1.14, P=0.002) per 1 g increase of omega-3 fatty acid dosage.

    “In the meta-regression model for the association of omega-3 fatty acid dosage with the risk of AF events, the HR was 1.10 (95%CI 1.05–1.14, P=0.002, Figure IV in the Supplement) per 1 gr increase of omega-3 fatty acids dosage (residual heterogeneity I2=0.00%, P=0.46).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: In the meta-regression, as the omega-3 fatty acid dose goes to zero, the lipid effect goes to zero and the treatment effect goes to one (neutral effect), assuming linearity.

  • May combine two claims.

    Findingown data

    The pooled hazard ratio for atrial fibrillation versus placebo was higher in high-dose trials (HR 1.49, 95%CI 1.04-2.15, P=0.042) than in low-dose trials (HR 1.12, 95%CI 1.03-1.22, P=0.024), with P for interaction <0.001.

    “The pooled hazard ratio for AF events compared with placebo was higher in trials testing high-dose (HR 1.49, 95% 1.04–2.15, P=0.042) than in those testing low-dose of marine omega 3 fatty acids (HR 1.12, 95%CI 1.03–1.22, P=0.024, Figure 2; P for interaction <0.001) with Knapp-Hartung adjustment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The trim and fill method imputed one study on the left side of the funnel plot, and the effect size after imputation (HR 1.23, 95%CI 1.10-1.39) was similar to the observed effect size (HR 1.25, 95%CI 1.11-1.40) using the DerSimonian-Laird approach.

    “The ‘trim and fill’ method imputed one study on the left side of the funnel plot (Figure IX in the Supplement ) and the effect size after imputation (HR 1.23, 95%CI 1.10–1.39) was similar to the observed effect size (HR 1.25, 95%CI 1.11–1.40) using the DerSimonian-Laird approach.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Sensitivity analysis with studies that excluded baseline atrial fibrillation or qualified events as new-onset yielded similar results (HR 1.26, 95%CI 0.85-1.87) compared with studies that did not exclude baseline atrial fibrillation (HR 1.28, 95%CI 1.11-1.48), with no significant interaction (P=0.92).

    “Sensitivity analysis with studies that excluded baseline AF or qualified AF events as new-onset yielded similar results (HR 1.26, 95%CI 0.85–1.87) compared with studies that did not exclude baseline AF (HR 1.28, 95%CI 1.11–1.48) with no significant interaction (Figure VI in the Supplement, P=0.92).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of 81,210 participants, 2,905 (3.6%) had an atrial fibrillation outcome; 2,258 (77.8%) occurred in low-dose trials and 647 (22.2%) in high-dose trials.

    “Of the 81,210 participants included in this analysis, 2,905 (3.6%) patients had an AF outcome during the trial period, of which 2,258/2,905 (77.8%) occurred in trials testing low-dose of omega-3 fatty acids supplements and 647/2,905 (22.2%) occurred in trials testing high-dose of omega-3 fatty acids.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In sensitivity analysis using post-hoc ASCEND data, high-dose trials remained statistically significant (HR 1.49, 95%CI 1.04-2.15, P=0.042), but low-dose trials did not (HR 1.08, 95%CI 0.99-1.17, P=0.077).

    “The estimates remained statistically significant with Knapp-Hartung adjustment among trials testing high dose of omega-3 fatty acids (>1 gr per day) with an HR of 1.49 (95%CI 1.04–2.15, P=0.042), but not in trials testing low-dose (≤1 gr per day) with an HR of 1.08 (95%CI 0.99–1.17, P=0.077, Figure III in the Supplement).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The funding sources had no role in the design, conduct, collection, management, analysis, interpretation, preparation, review, approval, or decision to submit the manuscript.

    “The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    This meta-analysis was registered to PROSPERO (CRD42021234291).

    “This meta-analysis was registered to PROSPERO (CRD42021234291).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The PRISMA guidelines were followed for this systematic review and meta-analysis.

    “The PRISMA guidelines was followed for this systematic review and meta-analysis.9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Moher D, Liberati A, Tetzlaff J, Altman DG and Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009; 151: 264– 9, W64. 19622511 source

  • May combine two claims.

    Study design and conductown data

    Atrial fibrillation outcomes were pre-specified in the methods of the VITAL, OMEMI, and STRENGTH trials, but not in the remaining included trials.

    “The AF outcomes were pre-specified in the methods of the VITAL, OMEMI and STRENGTH trials. For the remaining trials, the assessment of AF events was not pre-specified in the methods of the original article.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    Publication bias was assessed with a funnel plot and the trim and fill method.

    “Publication bias was assessed with a funnel plot,18 as well as the trim and fill method.19”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Egger M, Davey Smith G, Schneider M and Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315: 629– 34. 9310563 PMC2127453 source
    • cites [19] Duval S and Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000; 56: 455– 63. 10877304 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Risk of bias was assessed according to the Cochrane tool for assessing risk of bias in randomized clinical trials.

    “The risk of bias was assessed according to the Cochrane tool for assessing risk of bias in randomized clinical trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    In ASCEND (main paper), REDUCE-IT, and RP, participants with preexisting atrial fibrillation were not systematically excluded from analysis, while in other trials the analysis reported new-onset atrial fibrillation events and/or excluded participants with preexisting atrial fibrillation.

    “In the ASCEND (main paper), REDUCE-IT and RP trials, participants with preexisting AF were not systematically excluded from the analysis, while in other trials, the analysis reported new-onset AF events and/or excluded participants with preexisting AF.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    Hazard ratios with 95% confidence intervals were provided in each trial except REDUCE-IT, where the risk ratio was calculated based on the number of patients with atrial fibrillation in each treatment arm.

    “Second, the HR with 95%CI were provided in each trial, except REDUCE-IT where the RR was calculated based on the number of patients with AF in each of the treatment arms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Extracted atrial fibrillation outcomes were centrally adjudicated in VITAL and OMEMI, but not in REDUCE-IT, ASCEND, STRENGTH, GISSI-HF, and RP.

    “The extracted AF outcomes were centrally adjudicated by a panel of clinicians in the VITAL and OMEMI trials, whereas in the REDUCE-IT, ASCEND, STENGTH, GISSI-HF and RP trials, the AF outcomes were not.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Participants included in clinical trials might not be representative of those seen in everyday practice.

    “Fifth, participants who are included in clinical trials might not be representative of those seen in everyday practice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In this meta-analysis incorporating data from seven large-scale randomized controlled trials, omega-3 fatty acid supplementation was associated with a risk of atrial fibrillation, especially in trials testing higher doses of omega-3 fatty acids.

    “In conclusion, in this meta-analysis incorporating data from 7 large scale RCTs, omega-3 fatty acid supplementation was associated with a risk of AF, especially in trials testing higher dose of omega-3 fatty acids.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These data do not exclude the possibility that specific omega-3 formulations used across trials may have differing impacts on atrial fibrillation risk.

    “However, these data do not exclude the possibility that specific omega-3 formulations used across trials may have differing impacts on AF risk.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    This meta-analysis of large cardiovascular trials with different doses and formulations, with over 2,900 atrial fibrillation events, provided adequate power to assess small-to-moderate risk of atrial fibrillation and to examine the dose-effect relationship at the study level.

    “This meta-analysis of large cardiovascular trials with different doses and formulations of omega-3 fatty acid supplementations (Icosapent Ethyl, carboxylic acid formulations, regular EPA/DHA combinations) with over 2900 AF events provided adequate power to assess small-to-moderate risk of AF and an examination of dose effect relationship at the study-level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Because the incidence rate of atrial fibrillation was quite uncommon, the use of risk ratio is an appropriate proxy of hazard ratio and this limitation should not affect the results.

    “Since the incidence rate of AF was quite uncommon, the use of RR is an appropriate proxy of HR and this limitation should not affect the results.”
    Quote in the paperSubstantial claim
27 of 27

  • The authors state this as an assumption.

    In the meta-regression, as the omega-3 fatty acid dose goes to zero, the lipid effect goes to zero and the treatment effect goes to one (neutral effect), assuming linearity.

    “where the intercept was set at zero to reflect the clinical assumption that as the dose goes to zero, the lipid effect goes to zero and the treatment effect goes to one (neutral effect) assuming linearity.21”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting numbers of screened records

    Minor

    The abstract reports 4,049 screened records, while the Results section reports 4,059.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Gencer, B., Djousse, L., Al-Ramady, O. T., Cook, N. R., Manson, J. E., & Albert, C. M.
Affiliations
  • Cardiology Division, Geneva University Hospitals, Switzerland (B.G.).
  • Department of Medicine, Brigham and Women’s Hospital, Boston, MA (L.D., O.T.A., N.R.C., J.E.M.).
  • Brigham and Women's Hospital (US)
  • Cedars-Sinai Medical Center (US)
Corresponding author
Albert, Christine M.
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2021-12-21
Volume
144
Issue
25
Pages
1981-1990
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.121.055654
PMC
PMC9109217
OpenAlex
W3203031064
Cited by
150
References
30
Citations by year
2026: 26 · 2025: 32 · 2024: 34 · 2023: 32 · 2022: 25 · 2021: 1
FWCI
4.44
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Circulation (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • BORIS (University Library Bern) (submittedVersion, other-oa)
  • IRIS (submittedVersion)
  • Open Access CRIS of the University of Bern
Funders
  • National Heart, Lung, and Blood Institute (R01 HL116690)
  • National Cancer Institute (U01CA138962, R01CA138962)
  • National Center for Complementary and Integrative Health (R01AT011729)
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 Health and Mental Health
Keywords
marine omega-3 fatty acids, omega-3 supplementation, atrial fibrillation, atrial fibrillation risk, dose-response relationship, cardiovascular outcomes, randomized controlled trials, cardiovascular disease prevention, omega-3 deficiency
MeSH terms
Aged, Animals, Atrial Fibrillation, Cardiovascular Diseases, Female, Fishes, Humans, Male, Risk Factors, Fatty Acids, Omega-3, Treatment Outcome, 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