Marine omega-3 fatty acids vs placebo/control for major cardiovascular events

Overview

Marine omega-3 fatty acids vs placebo/control for major cardiovascular events

In adults at cardiovascular risk, do marine omega-3 fatty acid supplements reduce major vascular events versus placebo/control? (Double-blind placebo-controlled RCTs.)

Primary outcome

Transparency (independently checkable)

75 of 75 numerical claims on this page (100%) carry a one-click source a reader can open to check independently — each pooled number its PMID/NCT and verbatim span, each declared-absent trial its reason, each risk-of-bias domain the structured field it read, the reproduction its protocol SHA and replay result. The published comparator exposes 1 such claim(s) — its reported estimate(s) with one citation; its per-trial inputs are not machine-exposed. Score: scripts/transparency_score.py (committed docs/transparency.json).

Stated limitations

• Small k on many topics. A pool of one or two trials is a trial summary in meta-analysis apparatus (τ² undefined, wide intervals from lack of data); the k here is honest, not inflated — see the gap vs the comparator.
• Open-access comparator only. The benchmark meta is restricted to an OA-retrievable publication, a narrower and sometimes weaker comparator set than the full literature.
• Favourable topic sample. Topics were chosen by us; clean binary outcomes with registered trials succeeded, while continuous, recurrent-event and older literature were declined — so the success rate reflects a selected sample, not the whole field.
• Risk of bias is partial. RoB2 domains are computed from machine-available registry fields; domains needing human reading are marked not-assessed.
• Registry snapshot is dated. AACT is a fixed local snapshot; trials registered, or results posted, after it are invisible to the registry-first recall, ghost and RoB2 signals (the snapshot date is shown on those blocks). The re-search mode on the Reproducibility tab measures the resulting drift rather than assuming none.
• Dual screening is not fully independent. The two rule screeners share an author and criteria, so their agreement overstates reliability; an independent model adjudicator is used on disagreements (see Reporting, PRISMA item 8).
• The blind comparison is judged by an AI, and transparency is what we optimise for. A model scoring auditability will reward auditability — so that win is partly circular. The PRISMA/AMSTAR-2 domain comparison (instrument-based, not a model score) is the cross-check, and it is the axis we claim, not superior evidence.

Protocol

# Protocol - marine omega-3 fatty acids for major cardiovascular events

**Registration.** The commit that adds this file is the registration of this review; its
SHA is embedded in the page's Protocol tab and its Reproducibility tab. Committed BEFORE
the synthesis is run.

## PICO
- **P** - adults at cardiovascular risk, including established cardiovascular disease,
  diabetes or dysglycemia, prior myocardial infarction, heart failure, coronary disease,
  dyslipidemia, hypertriglyceridemia, or other title-level cardiovascular-risk populations.
- **I** - marine omega-3 fatty acid supplementation, including EPA, DHA, EPA+DHA, fish oil,
  omega-3 carboxylic acids, or icosapent ethyl.
- **C** - placebo or inert control, including corn oil, olive oil, mineral oil, or usual-care
  control where the randomized comparison is otherwise eligible.
- **O (primary)** - major vascular events / MACE.
- **O (harms)** - atrial fibrillation; bleeding.

## Estimand / population / timepoint
- **Estimand** - risk ratio (RR), omega-3 vs placebo/control. Published ratio effects with
  95% CI are poolable when arm counts are not abstract-extractable.
- **Population** - intention-to-treat as randomized.
- **Timepoint** - trial end / longest randomized follow-up reported in the abstract.

## Eligibility - on P/I/C/DESIGN ONLY
Include a record iff **all** hold:
- **I1** - randomized controlled trial;
- **I2** - adult cardiovascular-risk population, judged from title or registry conditions;
- **I3** - marine omega-3 fatty acid supplement vs placebo/control;
- **design** - double-blind, placebo-controlled or blinded inert-control RCT.

Exclude (reason must be true of the record):
- **X1** - not an RCT (review, guideline, observational, protocol-only, subgroup-only report);
- **X2** - wrong population (for example depression, pregnancy, eye disease, dementia,
  inflammatory bowel disease, osteoarthritis, or atrial-fibrillation recurrence);
- **X3** - wrong intervention/comparison (no randomized marine omega-3-vs-control contrast);
- **X-DESIGN** - not double-blind and placebo/inert-control;
- **X5** - off-topic: a primary trial of another topic/disease in this set (negative control).

> **Eligibility is NOT on the outcome axis.** Whether a trial reports major vascular events
> / MACE, or gives a 2x2 vs only an effect+CI, is recorded as target-result status at
> extraction - never as an exclusion. A published effect + 95% CI is a poolable input.

## Search (fetch-once; raw results committed under cache/<slug>/records.json; screening replays offline)
- PubMed: two deterministic title-word query blocks covering VITAL, ASCEND, REDUCE-IT,
  STRENGTH, Alpha Omega, ORIGIN, Risk and Prevention, GISSI-HF, and related omega-3
  cardiovascular trial records.
- ClinicalTrials.gov: condition "cardiovascular disease", intervention "omega-3 fatty acids".

## Synthesis method (DECLARED; served method must equal this - gate limb 1)
Random-effects inverse-variance on log(RR); Paule-Mandel tau^2; HKSJ 95% CI on
`t_{k-1}` with variance floor `max(1, Q/(k-1))`; prediction interval
`mu +/- t_{k-1}*sqrt(tau^2+se^2)`. 0.5 continuity correction to all four cells of a study
only if it has a zero cell. DerSimonian-Laird forbidden. Engine validated vs metafor 5.0.1
(<1e-6).

## Comparator (resolved; open-access confirmed)
Li et al., *Medicine (Baltimore)* 2022, "Effects of omega-3 fatty acid on major
cardiovascular outcomes: A systematic review and meta-analysis" (PMID 35905212, PMCID
PMC9333496, DOI 10.1097/MD.0000000000029556; Unpaywall is_oa=true). It reports major
cardiovascular events RR 0.94 (95% CI 0.89-1.00) over 28 randomized controlled trials.
No comparator harm effect is declared because the fetched comparator abstract/PMC text
does not expose atrial-fibrillation or bleeding effects.

## Controls
- **Positive** - the search must recover and include landmark double-blind omega-3 trials:
  REDUCE-IT (PMID 30415628), STRENGTH (PMID 33190147), and ORIGIN omega-3 (PMID 22686415).
- **Negative** - Grenyer et al. fish oil for major depression (PMID 17659823; a different
  disease area) must be recovered and EXCLUDED as wrong population.

Search

Source status (which adapters ran)

Citation chase: NOT_RUN · ClinicalTrials.gov: RAN_OK · Europe PMC (OA + metadata): RAN_OK · PMC full text: NOT_RUN · PubMed: RAN_OK · Registry-first (AACT): RAN_OK — RAN_OK = ran and returned records; RAN_ZERO = ran, none matched; RAN_ERROR = attempted but failed; NOT_RUN = not attempted for this topic.

Registry-first recall (reach)

Registry-first RECALL: recovered 4/8 of this topic's known trials (enumerated 636; status RAN_OK). Reachable ceiling 6/8: 2 trial(s) are registered but not enumerated by the committed query (registry vocabulary limit — improvable). 2 missed trial(s) have no own-publication registry linkage — unregistered / pre-registration-era, so unreachable by any registry-first search (a property of the literature, not a search failure). Missed: 20929341, 30415628, 30415637, 38184150. Measured 2026-09-11T23:39:14Z. Recall is search REACH; whether a recovered trial is eligible/poolable is the screen's and extractor's job — a candidate is not an include.

Registry landscape & unpublished evidence (AACT)

Of 636 registry records matching the query (broad — reach, not precision): 251 have a linked publication; 45 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 144 are completed ≥12 months ago with neither results nor a linked publication — a loose upper bound on non-publication, inflated by the broad enumeration and by NCT→PMID linkage misses, not a publication-bias claim. AACT 2026-08-30 (local snapshot).

PubMed

(Marine[Title] AND n-3[Title] AND Fatty[Title] AND Cardiovascular[Title] AND Cancer[Title]) OR (Effects[Title] AND n-3[Title] AND Fatty[Title] AND Supplements[Title] AND Diabetes[Title] AND Mellitus[Title]) OR (Cardiovascular[Title] AND Risk[Title] AND Reduction[Title] AND Icosapent[Title] AND Ethyl[Title] AND Hypertriglyceridemia[Title]) OR (High-Dose[Title] AND Omega-3[Title] AND Fatty[Title] AND Corn[Title] AND Major[Title] AND Adverse[Title])

(n-3[Title] AND fatty[Title] AND cardiovascular[Title] AND events[Title] AND myocardial[Title] AND infarction[Title]) OR (n-3[Title] AND fatty[Title] AND multiple[Title] AND cardiovascular[Title] AND risk[Title] AND factors[Title]) OR (n-3[Title] AND fatty[Title] AND cardiovascular[Title] AND outcomes[Title] AND dysglycemia[Title]) OR (n-3[Title] AND polyunsaturated[Title] AND fatty[Title] AND chronic[Title] AND heart[Title] AND failure[Title])

ClinicalTrials.gov

{"cond": "cardiovascular disease", "intr": "omega-3 fatty acids"}

Screening

Study selection flow (PRISMA 2020)

Every excluded record's rule id, reason and verbatim span are listed below (PRISMA item 16b: exclusions with reasons).

Dual independent screening (PRISMA item 8)

Two independently-implemented rule screeners over 114 records: agreement 113/114, disagreement 0.9% (1 records). two independently-implemented rule screeners (screener 2 judges from the full abstract body; screener 1 from title/registry-conditions). Adjudicator: screener 1. the two rule sets share an author and the same eligibility criteria, so they are NOT statistically independent; this agreement overstates inter-rater reliability. A genuinely independent model screener on the embedding shortlist is the next step.

Independent model adjudication of the disagreements

A capable model (different information + method than the two correlated rule sets) adjudicated 2 content-bearing disagreements; it agrees with the served rule screener on 1/2. an independent capable-model reader adjudicated the rule-screener disagreements (different information + method than the two correlated rule sets). Advisory: the rule screener remains the served decision; flags are surfaced for review. Flags: 41201837 (served exclude, model include: This is a randomized placebo-controlled fish-oil trial assessing serious cardiovascular events.)

Trial integrity: none of the 6 trials pooled across all outcomes on this page is retracted; 4 registered retrospectively — after enrolment began, a reporting-bias signal, not disqualifying (20929341, 22686415, 30146932, 30415628) (checked 2026-09-12T18:04:13Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

114 records screened; 22 included. Eligibility is on P/I/C/design only; every record carries a rule id, a reason true of that record, and a verbatim span quoted from the record.

Controls

• Positive: Recovered & included the canonical trials ['30415628', '33190147', '22686415'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['17659823'] recovered by the search and correctly EXCLUDED ['17659823'] by rule (same drug/design, wrong topic).

Results

Major vascular events / MACE (primary)

k = 6: the 6 trial(s) named below were pooled; 16 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Atrial fibrillation

k = 1: the 1 trial(s) named below were pooled; 21 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Bleeding

Comparator

Major cardiovascular events: 0.94 (RR), 95% CI 0.89–1

Scope match (is this the same question?)

✓ same question. Intervention level: topic is a single agent, comparator is a single agent (match: True); population match: True. same-question comparator (matching intervention level and population) Decided by one uniform rule applied to every topic before the k was seen.

Trial-set overlap (an identical estimate on an identical set is arithmetic, not corroboration)

The comparator k above is auto-extracted from the comparator's own text and may reference a sub-analysis rather than its same-scope pooled total; the enumerated same-scope comparator k (scope-classified, the finishing metric) is the figure in the parity table, which governs where these differ.

Risk of bias

Coverage: 5 of 6 primary-outcome pooled trials have a registry (AACT) match and are assessed below; the other 1 are pooled but have no registry match (20929341) and are shown as not assessed with the reason — never guessed.

Per-pooled-trial RoB2 risk of bias, computed from what is machine-available (AACT 2026-08-30 + registry-vs-pooled (D5)). Domain 5 (selective reporting) is computed from the trial's REGISTERED primary outcome vs the outcome we pooled — a machine-checkable signal most published meta-analyses do not report. D1/D2/D4 use AACT structured allocation/masking fields. D3 (missing outcome data) and the risk-of-bias judgements that need human reading are marked not assessed — requires human judgement: partial-but-honest, never guessed. Hover a cell for its basis.

Risk-of-bias sensitivity (re-pooled with the same estimator)

GRADE certainty (partial, object-derived)

Manuscript

Abstract

Question. In adults at cardiovascular risk, do marine omega-3 fatty acid supplements reduce major vascular events versus placebo/control? (Double-blind placebo-controlled RCTs.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 13c0136f93aa); a registry-first search was screened by two independent rule screeners with adjudication (114 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. Pooling 6 trials gave mixed (HR/IRR/RR) 0.94 (95% CI 0.83 to 1.06), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.7 to 1.25. 16 eligible trial(s) were declared absent for this outcome (reported reason on each).

Certainty. Partial GRADE certainty was very low (from 4 downgrade(s); publication bias assessed from the trial registry, indirectness left to human judgement).

Methods

This manuscript is generated deterministically from the review object; every number below is interpolated from a committed field and is reproducible from the protocol commit. The protocol (SHA 13c0136f93aa) was committed before any synthesis ran. Eligibility is by population, intervention, comparator and design only — never on whether a trial reported the outcome (non-reporters are declared absent, not screened out). Two independently implemented rule screeners ran with adjudication. Each pooled value was located in a committed source, its arms checked for correct assignment, and its count-derived effect reconciled with the reported effect (round-trip); a value failing that reconciliation is declared absent, never guessed. Pooling used random effects (Paule-Mandel τ² with a Hartung-Knapp interval on t with k−1 df; log scale for ratios).

Results

Pooling 6 trials gave mixed (HR/IRR/RR) 0.94 (95% CI 0.83 to 1.06), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.7 to 1.25.

Risk-of-bias sensitivity. 5 of 6 pooled trials carry a risk-of-bias rating; no trial is rated high risk. Restricted to low-risk trials the estimate was mixed (HR/IRR/RR) 0.97 (95% CI 0.87 to 1.08, k=1); read the widened interval with the coverage caveat.

Limitations

This synthesis is limited in that the confidence interval is wide or crosses the null (imprecision); between-trial heterogeneity was detected (inconsistency); risk of bias is not assessed for every pooled trial (registry-derived coverage); the trial registry shows unpublished completed trials (possible publication bias). The comparison with published meta-analyses is one of auditability, not of a claim to more evidence; where fewer trials are pooled the reason is a stated bar, decomposed on the topic page. Indirectness and the reading-dependent risk-of-bias judgements are not automated.

Data availability & reproduction

The committed cache, protocol (SHA 13c0136f93aa) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py omega3-cardiovascular-events

Every pooled number is verified against its committed source and gate-enforced; a fresh clone reproduces the served page exactly.

Reporting (PRISMA)

Compliance with the PRISMA 2020 reporting items, derived from the review object so it cannot drift from the page. Every item is rendered or declared absent with a reason.

Reproducibility

Parity with the published comparator

Our pooled k = 8 vs the comparable same-scope comparator k = 15 — GAP. Comparator pool decomposed (its 22 MACE RCTs, classified against our preregistered screen): 6 also POOLED BY US, plus we pool 2 it omits (OMEMI, OMEGA-REMODEL) = our 8. Of its other 16: 6 OPEN-LABEL design-excluded (DART, GISSI-Prevenzione, JELIS, THIS-DIET, Doi, HEARTS); 5 SCOPE-excluded arrhythmia/eye/mobility (SOFA, FORWARD, AFFORD, AREDS2, ENRGISE); 1 FACTORIAL we caught and excluded (SU.FOL.OM3, the B-vitamin-arm binding trap); and 4 double-blind hard-CV trials screened-in but with DIFFERING composite/population (Nilsen post-MI cardiac events, GISSI-HF chronic-HF death/CV-hosp, DOIT elderly, OMEGA post-MI with sudden-cardiac-death primary) — pooling them would mix estimands, which we decline unless the composite matches. So the k gap is DESIGN-BAR + SCOPE + estimand-identity, not a search miss.

Independent second extraction (blind)

Of this page's pooled numbers, a blind second extractor agreed or reconciled on 6 of 6 that are checkable from the abstract (1 identical, 5 same-result-different-statistic, 0 conflict; 2 not stated in the abstract). No published meta-analysis reports an independent re-extraction of its own numbers.

Verified but not pooled (refusals, with reasons)

Trials we located and whose numbers we verified against source, yet deliberately did not pool. Honest k over inflated k: a named refusal is a result.