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Cited by 3Fatty Acid Research and HealthLipoproteins and Cardiovascular HealthNutritional Studies and Diet

Effects of Eicosapentaenoic Acid vs Eicosapentaenoic/Docosahexaenoic Acids on Cardiovascular Mortality

Open access
Sheppard, John P., Palatnic, Leonard, Lakshmanan, Suvasini, Drago, Thomas, Bhogal, Jaspreet, Roy, Sion K., Bhatt, Deepak L., Budoff, Matthew J. +1 more·2025·JACC: Advances
DOI 10.1016/j.jacadv.2025.102149PMC PMC12791848
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Abstract

BACKGROUND: Purified eicosapentaenoic acid (EPA) and mixed eicosapentaenoic/docosahexaenoic acids (EPA/DHA) are omega-3 polyunsaturated fatty acids (n-3 PUFAs) of interest for preventing cardiovascular disease (CVD) as adjunct to statins. Randomized clinical trial (RCT) evidence continues to emerge, including data from the RESPECT-EPA (Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid) trial, but n-3 PUFAs' roles in prevention remains controversial. OBJECTIVES: The objective of the study was to assess the efficacy of EPA vs EPA/DHA compared to the standard preventive therapy across published RCTs investigating the use of n-3 PUFAs for primary or secondary prevention of CVD. METHODS: Following a prespecified protocol registered in the PROSPERO database (CRD42023390587), we identified RCTs reporting CVD-attributable mortality in patients randomized to EPA, EPA/DHA, or a standard preventive therapy for primary or secondary CVD prevention. We used random effects meta-analysis to estimate pooled HRs of CVD-attributable mortality achieved with EPA or EPA/DHA relative to the standard preventive therapy. RESULTS: Sixteen RCTs met the inclusion criteria, representing 127,771 patients in total (41% women, mean age 64 ± 5 years). Median follow-up was 3.7 years (IQR: 2.7-5.0 years). Compared to the standard preventive therapy, CVD-attributable mortality was significantly reduced with purified EPA (HR: 0.79 [95% CI: 0.67-0.94]; P = 0.006); this effect was less for EPA/DHA (HR: 0.92 [95% CI: 0.84-1.00]; P = 0.044). CONCLUSIONS: EPA lowered incident CVD-attributable mortality in RCTs investigating its use for primary or secondary CVD prevention. Relative to EPA, benefits reported with EPA/DHA were attenuated. Although more work is needed to understand these differences, EPA should preferentially be used in cardiovascular conditions for which it is indicated.

AI snapshot

Written from the paper’s full text.

TL;DR

In a PROSPERO-registered random-effects meta-analysis of 16 RCTs and 127,771 patients, purified EPA reduced CVD-attributable mortality versus standard preventive therapy (HR: 0.79), whereas mixed EPA/DHA showed only modest reduction (HR: 0.92). The authors conclude EPA should be used preferentially where indicated, though the direct pooled comparison between EPA and EPA/DHA was not statistically significant.

Key findings

  • Across 16 RCTs, 127,771 patients were included (41% women; mean age 64 ± 5 years; median follow-up 3.7 years, IQR: 2.7-5.0 years).
  • Purified EPA versus standard preventive therapy reduced CVD-attributable mortality: HR: 0.79 (95% CI: 0.67-0.94; P = 0.006); after omitting the Nosaka et al. outlier, HR: 0.80 (95% CI: 0.68-0.95; P = 0.012).
  • Mixed EPA/DHA versus standard therapy showed a modest reduction: HR: 0.92 (95% CI: 0.84-1.00; P = 0.044); among statin-treated cohorts (STRENGTH plus a VITAL subset), HR: 0.99 (95% CI: 0.81-1.22; P = 0.95).
  • The pooled treatment effects for purified EPA versus mixed EPA/DHA did not differ significantly (Q(1) = 2.3; P = 0.128), and primary/secondary prevention subgroup pooled HRs were not significant.

Methods

  • Systematic review and random-effects meta-analysis following PRISMA, with a prespecified protocol registered in PROSPERO (CRD42023390587). Eligible studies were English-language RCTs of purified EPA or mixed EPA/DHA versus placebo/standard preventive therapy for primary or secondary CVD prevention that reported CVD-attributable mortality.
  • From 5,971 potentially relevant publications, 16 RCTs met inclusion criteria. Trial-level HRs were estimated when not reported, and pooled HRs were obtained using restricted maximum likelihood estimators in R with the meta and metafor packages.
  • Additional analyses included leave-one-out sensitivity analyses, Cochrane Risk of Bias 2 assessment, funnel plot/Egger test, meta-regression, and subgroup analyses restricted to statin-treated cohorts and to primary or secondary prevention.

Limitations

  • The paper states that CVD-attributable mortality was a secondary rather than primary endpoint in all but one reviewed trial (ORIGIN), and that including trials with negative primary endpoints raises a theoretic risk of bias if CVD-attributable mortality was not prespecified.
  • The paper also states that EPA trial designs differed: REDUCE-IT was the only double-blinded international EPA trial, while JELIS, RESPECT-EPA, and Nosaka et al. were open-label Japanese trials without placebo; EPA doses differed (1.8 g/day in Japanese studies vs 4 g/day in REDUCE-IT), and primary/secondary prevention subgroup analyses were not significant.
  • Evident from the text: meta-regression showed a significant association between reported HRs and composite risk-of-bias scores for EPA/DHA studies (β = −0.16; P = 0.0064) but not for purified EPA studies (β = −0.15; P = 0.77); only 2 EPA/DHA cohorts on statin therapy were available; and the direct pooled EPA versus EPA/DHA treatment-effect comparison was not statistically significant.

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

Integrity signals

Registry

Crossref · 10.1016/j.jacadv.2025.102149

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

12 of 21 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured

  • Interpretationcitation

    A broad literature examining effects of EPA vs EPA/DHA at molecular, cellular, imaging, and clinical endpoint levels suggests more robust benefit with purified EPA rather than mixed EPA/DHA.

    “a broad literature examining effects of EPA vs EPA/DHA at the molecular and cellular levels,39, 40, 41, 42 their effects at the level of atherosclerotic plaque quantifiable with clinical imaging,8 and their effects at the clinical endpoint level evidenced in the RCT literature reviewed here, all suggest more robust benefit with purified EPA rather than mixed EPA/DHA.”
    Quote in the paperSubstantial claim5 of 5 sources checked
    • cites [39] Sherratt, 2021, Eicosapentaenoic acid and docosahexaenoic acid containing phospholipids have contrasting effects on membrane structure, J Lipid Res source
    • cites [40] Mason, 2016, Eicosapentaenoic acid inhibits oxidation of ApoB-containing lipoprotein particles of different size in vitro when administered alone or in combination with Atorvastatin active metabolite compared with other triglyceride-lowering agents, J Cardiovasc Pharmacol source

      The Results section (page unavailable) reports that EPA inhibited oxidation of human lipoprotein particles more consistently than DHA in vitro, supporting the molecular-level comparison. The study tested EPA and DHA separately, not purified EPA against a mixed EPA/DHA product; its imaging and clinical findings are discussed from other studies rather than tested here. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [41] Mason, 2020, Emerging mechanisms of cardiovascular protection for the Omega-3 fatty acid eicosapentaenoic acid, Arterioscler Thromb Vasc Biol source
    • cites [42] Mason, 2016, Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes, Biochim Biophys Acta source
    • cites [8] Sheppard, 2022, EPA versus mixed EPA/DHA plus statin for coronary atherosclerosis: meta-analysis of prospective imaging trials, JACC Cardiovasc Imaging source
  • Findingown data

    Among studies of purified EPA, the RCT by Nosaka et al was identified as a potential outlier.

    “Among studies of purified EPA, the RCT by Nosaka et al15 was identified as a potential outlier; this study reported an HR of only 0.22 with wide confidence bounds (95% CI: 0.02-0.99).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Nosaka, 2017, Early initiation of eicosapentaenoic acid and statin treatment is associated with better clinical outcomes than statin alone in patients with acute coronary syndromes: 1-year outcomes of a randomized controlled study, Int J Cardiol source

      The Results (§3.2) and Table 2 report an HR of 0.22 for cardiovascular death, but our copy gives its 95% CI as 0.47–0.99, not the cited 0.02–0.99. Calling the trial a potential outlier is the citing authors’ assessment, not a finding attributed to Nosaka et al. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Findingcitation

    The Nosaka et al RCT reported an HR of 0.22 (95% CI 0.02-0.99).

    “Among studies of purified EPA, the RCT by Nosaka et al15 was identified as a potential outlier; this study reported an HR of only 0.22 with wide confidence bounds (95% CI: 0.02-0.99).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Nosaka, 2017, Early initiation of eicosapentaenoic acid and statin treatment is associated with better clinical outcomes than statin alone in patients with acute coronary syndromes: 1-year outcomes of a randomized controlled study, Int J Cardiol source

      Section 3.2 and Table 2 report an HR of 0.22 for cardiovascular death, but our copy gives its 95% CI as 0.47–0.99, not 0.02–0.99. The reported HR for the primary composite outcome is 0.42, so the 0.22 estimate applies specifically to cardiovascular death. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Findingown data

    The only study falling outside these confidence bounds was GISSI-P, the first trial to study EPA/DHA.

    “The only study falling outside these confidence bounds was dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction, the first trial to study EPA/DHA.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The full random effects model found no difference in pooled treatment effects achieved with purified EPA vs mixed EPA/DHA as compared to standard preventive therapy (Q(1) = 2.3; P = 0.128).

    “Our full random effects model found no difference in pooled treatment effects (ie, pooled HR) achieved with purified EPA vs mixed EPA/DHA as compared to the standard preventive therapy (Q(1) = 2.3; P = 0.128).”
    Quote in the paperSubstantial claim
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Premisecitation

    A recent retrospective study of 987 randomly selected patients from the INSPIRE biobank registry suggested that higher DHA serum levels may blunt beneficial actions of EPA and are associated with higher incidence of adverse cardiovascular events when serum EPA levels are low.

    “a recent retrospective study of 987 randomly selected patients from the INSPIRE biobank registry suggested that higher DHA serum levels may blunt beneficial actions of EPA, and are associated with higher incidence of adverse cardiovascular events when serum EPA levels are low.38”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] Le, 2023, Higher docosahexaenoic acid levels lower the protective impact of eicosapentaenoic acid on long-term major cardiovascular events, Front Cardiovasc Med 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

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

    Premisecitation

    The questions of efficacy and whether differences in study populations, drug formulations, and placebo arms may explain discrepant results of high-profile trials have been debated.

    “The questions of efficacy and whether differences in study populations, drug formulations, and placebo arms may explain discrepant results of high-profile trials have been debated.7,8”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [7] Ridker, 2022, Circulation source

      The introduction (page unavailable) notes differing outcomes for REDUCE-IT and a trial of a different EPA-containing formulation. The Discussion (page unavailable) explicitly describes controversy over whether REDUCE-IT’s mineral-oil comparator affected its results. Our copy does not discuss differences in study populations as an explanation for the discrepant trial results. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [8] Sheppard, 2022, EPA versus mixed EPA/DHA plus statin for coronary atherosclerosis: meta-analysis of prospective imaging trials, JACC Cardiovasc Imaging source

  • May combine two claims.

    Interpretationcitation

    No RCT has ever demonstrated significant reduction in cardiovascular events with EPA/DHA as adjunct to a high-intensity statin therapy, unlike purified EPA.

    “Despite an extensive literature investigating EPA/DHA for cardiovascular risk reduction, unlike purified EPA no RCT has ever demonstrated significant reduction in cardiovascular events with EPA/DHA as adjunct to a high-intensity statin therapy.1”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Toth, 2022, Differentiating EPA from EPA/DHA in cardiovascular risk reduction, Am Heart J Plus source

      The Conclusions (page not provided) state that only EPA-alone formulations have demonstrated reductions in major cardiovascular events when added to contemporary medical therapy, including statins. The STRENGTH and REDUCE-IT sections likewise contrast a null EPA/DHA trial with a beneficial purified-EPA trial in statin-treated patients. The paper does not specify high-intensity statin therapy, so that qualifier is not supported. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Contemporary high-intensity statin formulations achieve greater low-density lipoprotein-lowering effects and cardiovascular endpoint reduction than were used during the first mixed EPA/DHA trials, such as GISSI-P.

    “contemporary high-intensity statin formulations achieve greater low-density lipoprotein–lowering effects and cardiovascular endpoint reduction than were used during the first mixed EPA/DHA trials, such as GISSI-P.17,27,44”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [17] Italiano, 1999, 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 source
    • cites [27] Marchioli, 2001, Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo studio della Sopravvivenza nell'Infarto Miocardico, Lipids source
    • cites [44] Marchioli, 2002, Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-prevenzione, Circulation source

      The Acknowledgements (page not available) identify GISSI-Prevenzione as a trial using mixed EPA/DHA capsules, and Table 1 (Statistical Methods; page not available) reports cholesterol-lowering drug use of 4.7% at baseline and 45.5% at 42 months. The paper does not compare those drugs with contemporary high-intensity statins or establish greater LDL lowering or cardiovascular endpoint reduction from such statins. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingnone given

    Japanese studies used 1.8 g/day of EPA, compared to 4 g/day in REDUCE-IT.

    “Japanese studies used 1.8 g/day of EPA, compared to 4 g/day in REDUCE-IT.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The GISSI-P endpoint study yielded an HR of 0.70, which was below the 95% confidence bound for all studies under the assumption of fixed treatment effects.

    “The GISSI-P endpoint study yielded an HR of 0.70,17 which was below the 95% confidence bound for all studies under the assumption of fixed treatment effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Italiano, 1999, 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 source
    • The authors state this as an assumption: For funnel plot analysis, trial-level HRs were assessed under an assumption of fixed treatment effects.

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

    Findingown data

    Mean age at enrollment across trials was 64 ± 5 years.

    “Sixteen RCTs met the inclusion criteria, representing 127,771 patients in total (41% women, mean age 64 ± 5 years).”
    • Also stated in: § Results · plain
      “Across trials, the mean age at enrollment was 64 ± 5 years, and the median follow-up time was 3.7 years (IQR: 2.7-5.0 years).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Three studies-JELIS, Nosaka et al and RESPECT-EPA-reported endpoint data on secondary prevention cohorts for purified EPA, and 5 studies reported endpoint data on secondary prevention cohorts for EPA/DHA.

    “Three studies—JELIS, Nosaka et al and RESPECT-EPA—reported endpoint data on secondary prevention cohorts for purified EPA, and 5 studies reported endpoint data on secondary prevention cohorts for EPA/DHA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    On composite scoring across 5 domains, 8 studies (50%) were assessed to have low risk of bias, 7 studies (44%) had moderate concern for risk of bias, and 1 study (6%) scored high for risk of bias.

    “Overall, on composite scoring across 5 domains, 8 studies (50%) were assessed to have low RoB, 7 studies (44%) had moderate concern for RoB, and 1 study (6%) scored high for RoB.”
    Quote in the paperSubstantial claim

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

    Findingown data

    41% of enrolled patients across included trials were women.

    “Sixteen RCTs met the inclusion criteria, representing 127,771 patients in total (41% women, mean age 64 ± 5 years).”
    • Also stated in: § Results · plain
      “Across all trials, 127,771 total patients were enrolled, 41% of whom were women.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In a pooled analysis excluding REDUCE-IT, purified EPA studies had a pooled HR of 0.74 (95% CI: 0.50-1.10) for cardiovascular mortality reduction, compared to an HR of 0.79 (95% CI: 0.67-0.94) with REDUCE-IT included.

    “we obtained comparable results with a pooled HR of 0.74 (95% CI: 0.50-1.10) for cardiovascular mortality reduction among purified EPA studies after excluding REDUCE-IT from analysis entirely, compared to an HR of 0.79 (95% CI: 0.67-0.94) with REDUCE-IT included.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of the 16 included RCTs, 2 enrolled patients for primary CVD prevention, 6 for secondary prevention, and 8 for either primary or secondary prevention.

    “Two RCTs randomized patients to adjunctive PUFA therapy for primary CVD prevention,12,25 6 RCTs randomized patients for secondary prevention,10,15, 16, 17, 18, 19, 20, 21, 22 and 8 RCTs enrolled patients for either primary or secondary CVD prevention.3,4,19, 20, 21,23,24,26”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The domains for which concerns were identified included "deviation from intended interventions" and "selection of reported results."

    “The domains for which concerns were identified included “deviation from intended interventions” and “selection of reported results.””
    Quote in the paperNot a substantial claim

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

    Findingown data

    Median follow-up across trials was 3.7 years (IQR 2.7-5.0 years).

    “Median follow-up was 3.7 years (IQR: 2.7-5.0 years).”
    • Also stated in: § Results · plain
      “Across trials, the mean age at enrollment was 64 ± 5 years, and the median follow-up time was 3.7 years (IQR: 2.7-5.0 years).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The purified EPA cohort encompassed 29,522 Japanese or international patients, all on statin therapy.

    “This smaller cohort encompassed 29,522 Japanese or international patients, all on statin therapy”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Four RCTs meeting inclusion criteria compared CVD-attributable mortality between purified EPA and standard therapy alone, and 12 RCTs reported CVD-attributable mortality with mixed EPA/DHA compared to standard therapy.

    “Four RCTs meeting our inclusion criteria compared CVD-attributable mortality between purified EPA and standard therapy alone, and 12 RCTs reported CVD-attributable mortality with mixed EPA/DHA compared to the standard therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Our random effects meta-analysis of published randomized controlled trials demonstrated robust reduction in cardiovascular mortality with purified EPA but only modest reduction in cardiovascular mortality with mixed EPA/DHA when compared to standard preventive therapy.

    “Our random effects meta-analysis of published randomized controlled trials demonstrated robust reduction in cardiovascular mortality with purified EPA but only modest reduction in cardiovascular mortality with mixed EPA/DHA when compared to standard preventive therapy.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    REDUCE-IT was the only double-blinded and international trial on EPA.

    “REDUCE-IT was the only double-blinded and international trial on EPA.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The authors followed PRISMA guidelines throughout the design and conduct of the analysis.

    “We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines throughout the design and conduct of our analysis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Given the lack of studies reporting CVD-attributable mortality as a primary endpoint, the only tractable approach was to consider all trials reporting CVD-attributable mortality regardless of whether reported as a primary or secondary endpoint, and regardless of whether the primary endpoint was significant.

    “given the lack of studies reporting CVD-attributable mortality as a primary endpoint, the only tractable approach was to consider all trials reporting CVD-attributable mortality regardless of whether reported as a primary or secondary endpoint, and regardless of whether the primary endpoint was significant.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The primary analysis combined patients receiving n-3 PUFA therapy for primary and secondary CVD prevention.

    “Our primary analysis combined patients receiving n-3 PUFA therapy for primary and secondary CVD prevention.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    To minimize reporting bias, the authors prospectively registered a comprehensive literature search and analysis protocol to PROSPERO (CRD42023390587).

    “To minimize reporting bias, we prospectively registered a comprehensive literature search and analysis protocol to the PROSPERO database (CRD42023390587).11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Sheppard, 2023, Effects of purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cardiovascular endpoints: the current view from randomized clinical trials [CRD42023390587], PROSPERO: International Prospective Register of Systematic Reviews source

  • May combine two claims.

    Study design and conductreasoning

    The use of open-label designs in these trials presents a risk of bias and could have influenced the meta-analysis results.

    “The use of open-label designs in these trials presents a RoB and could have influenced our results.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Confusion remains regarding the broader utility of n-3 PUFAs in primary or secondary prevention of CVD.

    “but n-3 PUFAs’ roles in prevention remains controversial.”
    • Also stated in: § Conclusions · plain
      “Despite the well-established benefits of n-3 PUFAs in hypertriglyceridemia, confusion remains regarding their broader utility in primary or secondary prevention of CVD.6”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Quispe, 2022, Controversies in the use of Omega-3 fatty acids to prevent atherosclerosis, Curr Atheroscler Rep source

  • May combine two claims.

    Study design and conductnone given

    JELIS, RESPECT-EPA, and the trial by Nosaka et al were open-label Japanese trials with no placebo comparator and with patients unblinded to therapy.

    “In contrast, JELIS, RESPECT-EPA, and the trial by Nosaka et al were open-label Japanese trials with no placebo comparator and with patients unblinded to therapy.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    GISSI-P began enrolling patients in 1993, before the availability of high-intensity statin therapy.

    “This trial began enrolling patients in 1993, before the availability of high-intensity statin therapy.17,27”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Italiano, 1999, 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 source
    • cites [27] Marchioli, 2001, Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo studio della Sopravvivenza nell'Infarto Miocardico, Lipids source

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

    Study design and conductcitation

    The meta-analysis used a prespecified and published protocol for study search and eligibility screening.

    “Using a prespecified and published protocol for study search and eligibility screening,11 we identified 16 RCTs reporting hard endpoint data on CVD-attributable mortality achieved with n-3 PUFA as compared to standard preventive therapy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Sheppard, 2023, Effects of purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cardiovascular endpoints: the current view from randomized clinical trials [CRD42023390587], PROSPERO: International Prospective Register of Systematic Reviews source

  • May combine two claims.

    Interpretationreasoning

    The fact that RCTs of mixed EPA/DHA formulations achieved underwhelming efficacy compared to purified EPA despite their lack of consistent statin use speaks even more strongly to the greater success observed with purified EPA in reducing adverse cardiovascular events and attributable mortality.

    “The fact that RCTs of mixed EPA/DHA formulations achieved underwhelming efficacy compared to purified EPA despite their lack of consistent statin use speaks even more strongly to the greater success observed with purified EPA in reducing adverse cardiovascular events and attributable mortality.”
    Quote in the paperSubstantial claim
28 of 28

  • The authors state this as an assumption.

    For funnel plot analysis, trial-level HRs were assessed under an assumption of fixed treatment effects.

    “The reported trial-level HRs for 15 of 16 RCTs fell within 95% confidence bounds obtained under an assumption of fixed treatment effects.”
    “assuming fixed treatment effects”

  • The paper relies on this without support.

    Japanese patients have higher dietary consumption of n-3 PUFAs compared to Western patients.

    “However, Japanese patients also have higher dietary consumption of n-3 PUFAs compared to Western patients.”

  • The paper relies on this without support.

    Multiple national regulatory agencies have examined the evidence and concluded that meaningful benefits exist for the population at risk and have approved icosapent ethyl (EPA) for their respective countries.

    “Overall, multiple national regulatory agencies (including, among others, the U.S. Food and Drug Administration, European Medicines Agency, and Health Canada) have examined the evidence surrounding this debate and have each come to their own conclusion that meaningful benefits exist for the population at risk, and have approved icosapent ethyl (ie, EPA) for their respective countries.”
3 of 3

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentQ(1) = 1.8reported p = .179 · recomputed p = .180

    “Q(1) = 1.8, p = .179”

1 of 1

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.

  • Three trials are assigned to both prevention categories

    Minor

    The text cites references 19, 20, and 21 among trials classified as secondary prevention and again among trials classified as either primary or secondary prevention. Those categories are presented as distinct groups of 6 and 8 trials.

  • Placebo-only eligibility conflicts with an included open-label trial

    Minor

    The eligibility criteria require a placebo comparison, but Table 1 lists GISSI-P as having no control treatment and being open-label.

  • Primary-prevention estimate changes after excluding a secondary-prevention trial

    Minor

    The paper identifies Nosaka et al as a secondary-prevention study and JELIS as the only purified-EPA study contributing primary-prevention data. Excluding Nosaka et al therefore cannot change the purified-EPA primary-prevention estimate from the previously reported 1.10 to 0.76.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Sheppard, 2023, Effects of purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cardiovascular endpoints: the current view from randomized clinical trials [CRD42023390587], PROSPERO: International Prospective Register of Systematic Reviews, 1, 1

Cited by

Sorted by citations

Authors
Sheppard, J. P., Palatnic, L., Lakshmanan, S., Drago, T., Bhogal, J., Roy, S. K., Bhatt, D. L., Budoff, M. J., & Nelson, J. R.
Affiliations
  • Cedars-Sinai Medical Center (US)
  • University at Buffalo, State University of New York (US)
  • University of California, Los Angeles (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
  • Palatnic, Leonard
  • Budoff, Matthew J.
ORCID
Venue
JACC: Advances
Publisher
Elsevier BV
Published
2025-10
Volume
4
Issue
10
Pages
102149
ISSN
2772-963X (ISSN-L)
DOI
10.1016/j.jacadv.2025.102149
PMC
PMC12791848
OpenAlex
W4414382135
Semantic Scholar
734bca39d69b250b686975330a158ff65df09c40
Cited by
3
References
41
Citations by year
2026: 3
FWCI
1.69
Type
journal article
Language
en
Open access
Licence
Locations
  • JACC Advances (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
Keywords
eicosapentaenoic acid, docosahexaenoic acid, omega-3 polyunsaturated fatty acids, cardiovascular mortality, cardiovascular disease prevention, secondary prevention, statin combination therapy

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 ›

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