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Cited by 1Fatty Acid Research and HealthMeta-analysis and systematic reviewsLipoproteins and Cardiovascular Health

Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

Open access
Sattar, Yasar, Alraies, M. Chadi·2024·Annals of Medicine & Surgery
DOI 10.1097/ms9.0000000000002215PMC PMC11374301
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Abstract

We read the letter of concern by Sephy Philip, PharmD, published about our paper titled 'Cardiovascular outcomes of ethyl eicosapentaenoic acid in diabetes mellitus: a meta-analysis,' which was retracted on 11 November 2022, in the journal 'Annals of Medicine and Surgery' [1] .The letter published by Mr Phillip has raised a valid concern about Icosapent ethyl (IPE), an ester form of an ethyl eicosapentaenoic acid [2] .We highly appreciate the feedback provided by Mr Philip.Our meta-analysis had systematic search strategy errors, specifically using Boolean Operators, including "OR" and "AND" binders.We used the keywords "Vascepa" and "eicosapentaenoic acid (EPA)" as major items in our search strategy rather than the medical subject heading (MeSH).This can sometimes introduce a potential mistake as it includes synonyms with an entirely different class of action of medications.This was brought to our attention immediately after the paper was published in October 2022.A study published by Professor José Antonio Salvador-Oliván, MD, PhD, in April 2019 included 137 systematic reviews, and interestingly, up to 92.7% of studies had some systematic search strategy errors [3] .Furthermore, the study also reported that 78.1% of the errors were the effect of recalls, which constitutes the most common source of error.The most common search errors can be due to errors in natural language processing or can be related to MeSH terms.Also, to improve the quality of the manuscript, it is important to check the MeSH database in PubMed, see

AI snapshot

Written from the paper’s full text.

TL;DR

This letter reports a re-performed meta-analysis of three randomized trials showing that icosapent ethyl (IPE) added to statin therapy reduced a composite cardiovascular outcome versus statin alone or placebo, with benefit confined to secondary prevention. The authors also acknowledge the search-strategy errors that led to retraction of their original 2022 meta-analysis.

Key findings

  • The primary composite outcome (cardiovascular death, MI, stroke, hospitalization for unstable angina, coronary revascularization) favored IPE: RR 0.80 (95% CI 0.74–0.87; P<0.0001).
  • Benefit was seen in secondary prevention (RR 0.76; 95% CI 0.70–0.83; P<0.0001) but not primary prevention (RR 0.86; 95% CI 0.73–1.02; P=0.07).
  • Significant secondary outcomes: fatal/non-fatal MI (RR 0.72; 95% CI 0.62–0.82; P<0.0001), unstable angina requiring hospitalization (RR 0.73; 95% CI 0.62–0.85; P<0.0001), and coronary revascularization (RR 0.76; 95% CI 0.62–0.94; P=0.0117). Stroke (RR 0.87; P=0.415), all-cause mortality (RR 0.97; P=0.79), cardiovascular death (RR 0.83; P=0.05), and sudden cardiac death (RR 0.78; P=0.148) were not significant.
  • Bleeding risk was significantly higher with IPE (RR 1.50; 95% CI 1.13–1.99; P=0.005), while total adverse events (RR 1.08; P=0.296) and gastrointestinal adverse events (RR 1.45; P=0.396) did not differ significantly.

Methods

  • Systematic review and meta-analysis of RCTs in patients aged >18 years taking IPE plus a statin (experimental) versus statin alone or placebo (control); registered on PROSPERO (CRD42023443467) and reported per PRISMA and AMSTAR-2.
  • Search of PubMed and Embase using MeSH terms and keywords ("eicosapentaenoic acid ethyl ester," "ethyl-EPA," "ethyl eicosapentaenoic," "Icosapent-ethyl," "Epadel," "AMR-101," "Vascepa") combined with "OR"; 844 articles retrieved, 38 full-text screened, 3 studies included, comprising 29,284 IPE and 14,644 control patients (mean age 62.42±6.84 vs 62.43±7.59 years).
  • Pooled effect sizes calculated in CRAN-R using a meta-bin module with a Mantel–Haenszel random-effects model, reporting relative risk (P<0.05 significant), Higgins I² for heterogeneity, and Cochrane Risk of Bias assessment.

Limitations

  • Stated: moderate-to-severe heterogeneity was seen for all-cause mortality, coronary revascularization, stroke, total adverse events, and gastrointestinal events, which the authors attribute to sampling error; with fewer than 10 studies it is impossible to distinguish true heterogeneity from chance.
  • Evident from the text: only three trials met inclusion criteria, limiting power and generalizability; the cardiovascular death confidence interval is reported as "0.69– .00," an apparent typographical error; and this publication is a reply to a letter of concern about a previously retracted meta-analysis rather than a standalone primary report.

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

Integrity signals

Registry

Crossref · 10.1097/ms9.0000000000002215

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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

  • Premisecitation
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    The ACC Expert Consensus 2021 guideline states that IPE is indicated as an adjunct to statins for patients with triglycerides greater than 150 mg/dl with established coronary artery disease/ASCVD or diabetes mellitus with two ASCVD risk factors.

    “Our analysis included studies that lead to clinical guidelines of American College of Cardiology (ACC) Expert Consensus 2021 that stated indication of IPE as an adjunct to statins for patients with triglycerides greater than 150 mg/dl with established coronary artery disease/atherosclerotic cardiovascular disease (ASCVD) or diabetes mellitus with two ASCVD risk factors32.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [32] Virani SS Morris PB Agarwala A. 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients with Persistent Hypertriglyceridemia: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021; 78: 960– 993. 34332805 source
  • Findingreasoning
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    Moderate-to-severe heterogeneity was mostly seen in all-cause mortality outcomes, coronary revascularization, stroke, total adverse events, and gastrointestinal events.

    “Moderate-to-severe heterogeneity was mostly seen in all-cause mortality outcomes, coronary revascularization, stroke, total adverse events, and gastrointestinal events.”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    Sudden cardiac death did not show a statistically significant change (RR 0.78; 95% CI 0.55-1.10; P=0.148).

    “sudden cardiac death (RR: 0.78; 95% CI=0.55–1.10; P=0.148) did not show statistically significant changes.”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    The primary composite outcome showed a statistically significant difference in favor of the IPE group (RR 0.80; 95% CI 0.74-0.87; P<0.0001).

    “The primary outcome [composite of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, and coronary revascularization] showed a statistically significant difference in favor of the IPE group (RR: 0.80; 95% CI=0.74–0.87; P<0.0001; Fig. 1).”
    • Also stated in: § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials · plain
      “Our results show that IPE use was associated with lower odds of the primary composite outcome compared to a control group of patients.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    There was a statistically significant bleeding risk in patients taking IPE compared with control (RR 1.50; 95% CI 1.13-1.99; P=0.005).

    “Among safety outcomes, there was a statistically significant bleeding risk in patients taking IPE as compared to control (RR: 1.50; 95% CI=1.13–1.99; P=0.005).”
    Quote in the paperSubstantial claim
  • May combine two claims. 7
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Findingreasoning
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    The initial manuscript's results were skewed because its search strategy missed significant studies and included trials that mostly used EPA and DHA combinations rather than IPE.

    “Our initial manuscript included Trials such as ORIGIN8, ASCEND9, Alpha Omega10, and JELIS5; among these trials, only one trial had IPE, and the rest of the trials had a combination of EPA and DHA, so our results were skewed as search strategy missed significant studies.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [8] ORIGIN Trial Investigators. n–3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012; 367: 309– 318. 22686415 source
    • cites [9] ASCEND Study Collaborative Group. Effects of n−3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018; 379: 1540– 1550. 30146932 source
    • cites [10] Kromhout D Giltay EJ Geleijnse JM. n–3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010; 363: 2015– 2026. 20929341 source

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

    Study design and conductcitation
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    Quality assessment was done using the Cochrane Risk of Bias tool.

    “Quality assessment was done using the Cochrane Risk of Bias tool28.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Sterne JAC Savović J Page MJ. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898. 31462531 source

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

    Study design and conductcitation
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    The re-performed systematic search strategy was high-quality and based on the methodology of Bramer et al. and Atkinson et al.

    “We re-performed a high-quality systematic search strategy based on the methodology mentioned by Bramer et al.11 and Atkinson et al.12”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [11] Bramer WM de Jonge GB Rethlefsen ML. A systematic approach to searching: an efficient and complete method to develop literature searches. J Med Libr Assoc 2018; 106: 531– 541. 30271302 PMC6148622 source
    • cites [12] Atkinson LZ Cipriani A. How to carry out a literature search for a systematic review: a practical guide. BJPsych Advances 2018; 24: 74– 82.

      Not checked in the free run.

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

    Premisecitation
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    Icosapent ethyl is a highly purified prescribed ester form of EPA rather than EPA, and this terminology varies across major clinical trials.

    “We found that IPE is a highly purified prescribed ester form of EPA rather than EPA, and this terminology varies in different major clinical trials4–6.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [4] Bhatt DL Steg PG Miller M. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2018; 380: 11– 22. 30415628 source
    • cites [5] Yokoyama M Origasa H Matsuzaki M. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet ((2007; 369: 1090– 1098. 17398308 source
    • cites [6] Nishizaki Y Miyauchi K Iwata H. Study protocol and baseline characteristics of Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid: RESPECT-EPA, the combination of a randomized control trial and an observational biomarker study. Am Heart J 2023; 257: 1– 8. 36372250 source

      The Background identifies REDUCE-IT as the Icosapent Ethyl trial but describes its treatment as highly purified EPA; the Interventions section specifies that RESPECT-EPA used capsules containing more than 98% EPA ethyl ester. These passages support the formulation and show differing labels across trials, but the paper does not explicitly define icosapent ethyl as a prescribed product distinct from EPA. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Study design and conductcitation
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    The meta-analysis aligns with PRISMA and AMSTAR-2 guidelines.

    “Ours aligns with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and AMSTAR-2 (Assessing the methodological quality of Systematic Reviews-2) guidelines13,14.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [13] Page MJ McKenzie JE Bossuyt PM. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71. 33782057 PMC8005924 source
    • cites [14] Shea BJ Reeves BC Wells G. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017; 358: j4008. 28935701 PMC5833365 source

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

    Findingown data
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    The search yielded 844 articles, and after screening, three studies fulfilled the inclusion and exclusion criteria.

    “Our search yielded 844 articles. After removing duplicates and initial screening, 38 articles were left, which underwent full-length screening. Among them, three studies fulfilled our inclusion and exclusion criteria5,6,29,30”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [5] Yokoyama M Origasa H Matsuzaki M. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet ((2007; 369: 1090– 1098. 17398308 source
    • cites [6] Nishizaki Y Miyauchi K Iwata H. Study protocol and baseline characteristics of Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid: RESPECT-EPA, the combination of a randomized control trial and an observational biomarker study. Am Heart J 2023; 257: 1– 8. 36372250 source
    • cites [29] Late-Breaking Science Abstracts and Featured Science Abstracts From the American Heart Association’s Scientific Sessions 2022 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2022. Circulation 2022;146(25): e569–e611. 36848417 source

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

    Findingown data
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    The authors' previous meta-analysis had systematic search strategy errors, specifically in the use of Boolean operators and in using keywords rather than MeSH terms.

    “Our meta-analysis had systematic search strategy errors, specifically using Boolean Operators, including “OR” and “AND” binders. We used the keywords “Vascepa” and “eicosapentaenoic acid (EPA)” as major items in our search strategy rather than the medical subject heading (MeSH).”
    Quote in the paperNot a substantial claim

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

    Findingown data
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    The mean age of patients treated with IPE was 62.42±6.84 years, and the mean age of control patients was 62.43±7.59 years.

    “The mean age of patients included in the studies treated with IPE was 62.42±6.84 years, while the mean age of patients in the control group was 62.43±7.59 years”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    The analysis correlates with the guidelines after adding the RESPECT EPA trial, given that IPE is helpful in the secondary prevention of established cardiovascular disease with triglyceride greater than 150 mg/dl.

    “Our analysis correlates with the guidelines after adding the RESPECT EPA trial, given that IPE is helpful in the secondary prevention of established cardiovascular disease with triglyceride greater than 150 mg/dl.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data
    § Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials

    The meta-analysis was registered on PROSPERO (ID: CRD42023443467).

    “We registered our meta-analysis on PROSPERO (ID: CRD42023443467).”
    Quote in the paperNot a substantial claim
10 of 10

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.

  • Conclusion contradicts the reported cardiovascular-mortality result

    Major

    The results state that cardiovascular death did not change significantly, and the discussion says there was no difference in cardiovascular mortality. The conclusion instead says IPE is beneficial for cardiovascular mortality in secondary prevention.

1 of 1

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1016/j.amsu.2022.104846

    Major

    The cited work was retracted on 2022-11-17 (notice 10.1016/j.amsu.2022.104846), before this paper was published (2024-07-03). Its authors could have known.

    Cited work 10.1016/j.amsu.2022.104846 · retracted 2022-11-17 · notice 10.1016/j.amsu.2022.104846 · this paper published 2024-07-03

1 of 1

Cites

1 retracted

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Related

Authors
Sattar, Y., & Alraies, M. C.
Affiliations
  • West Virginia University (US)
  • Wayne State University (US)
Corresponding author
Alraies, M. Chadi
ORCID
Venue
Annals of Medicine & Surgery
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2024-07-03
Volume
86
Issue
9
Pages
4941-4943
ISSN
2049-0801 (ISSN-L)
DOI
10.1097/ms9.0000000000002215
PMC
PMC11374301
OpenAlex
W4400244037
Semantic Scholar
eb569e7e178fac52639421b3979529b6475d6325
Cited by
1
References
31
Citations by year
2025: 1
FWCI
0.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Medicine and Surgery (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
icosapent ethyl, eicosapentaenoic acid, Boolean operators, MeSH terms, cardiovascular outcomes, coronary heart disease prevention, diabetes mellitus

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