Computed from this object's own state — a structural condition is unmet. This is not a fixed disclaimer: the conditions below are each testable, and a build in which they are met renders READY.
Does bempedoic acid reduce major cardiovascular events in statin-intolerant patients? One trial answers this; the other three registrations on this page measure something else, and one of them is not a bempedoic acid trial.
In this section: Registration and administrative information (PROSPERO field set) · What this object claims to contain
| Review title | Bempedoic acid and major cardiovascular events |
|---|---|
| Review question (PICO) | Does bempedoic acid reduce major cardiovascular events in statin-intolerant patients? One trial answers this; the other three registrations on this page measure something else, and one of them is not a bempedoic acid trial. |
| Population | Adults with ASCVD or high ASCVD risk with statin intolerance or inadequate LDL-C control |
| Intervention | Bempedoic acid 180 mg once daily |
| Comparator | Placebo |
| Background / rationale | Not recorded — this object holds no background field, and an introduction generated without one would be argument that no source in this review supports |
| Eligibility criteria | Eligible studies are those addressing the review's stated question: Does bempedoic acid reduce major cardiovascular events in statin-intolerant patients? One trial answers this; the other three registrations on this page measure something else, and one of them is not a bempedoic acid trial. Comparator: placebo. Outcome: Number of Participants With First Occurrence of Four Component Major Adverse Cardiovascular Events (MACE). Effect measure: HR. Design as recorded: 2 arms; declared contrast Bempedoic Acid 180 mg and Placebo Comparator. Derived post hoc on 2026-08-19 from this object's own recorded fields; Not pre-specified. See screening.eligibility_provenance for the per-element source paths. |
| Information sources | 0 source layers, listed on the Extraction tab |
| Search strategy | The executed strings, datetimes, filters and hit counts are on the Search tab |
| Study selection process | A second independent screen was NOT run. No second independent screen was run for this topic. This is recorded as owed rather than described: the remedy is to RUN one, and writing a duplicate-screening sentence without one would be the defect this whole exercise exists to prevent. |
| Number of screeners | One. No second independent screen was run. |
| Data extraction items | Extracted per trial on this object: registry id; primary publication; arms; per-arm counts and the published effect; the randomised total, separately from the analysed denominator. Fields not listed here were not extracted. |
| Outcomes and prioritisation | Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization |
| Risk of bias method | RoB 2, per result, five domains — see the risk-of-bias table below |
| Synthesis methods | Pooled under single study-effects with the none -- one trial, the registry's own Cox analysis estimator on the log scale. These methods were NOT prespecified before the search, and are not presented as though they were. |
| Subgroup analyses | Not recorded — this object records no subgroup-analysis field at all, so whether any were prespecified is UNKNOWN -- which is not the same as none having been |
| Meta-bias assessment | Not recorded — no funnel, Egger or Peters value is held on this object, so no meta-bias assessment is claimed |
| Certainty assessment | GRADE, recorded for 1 outcome(s) (GRADE). The ratings are on the Certainty tab. |
| Funding | Not recorded — no funding statement is recorded for this review |
| Competing interests | Not recorded — no declaration is recorded |
| Built | 2026-08-18T00:00Z |
| Schema | 2-authored-from-source |
not recorded on the page this object was built from
Query as executed:
condition="hypercholesterolemia OR dyslipidemia OR cardiovascular disease"; intervention="bempedoic acid"; study_type=INTERVENTIONAL; phase=[PHASE3,PHASE4]; count_total=true; page_size=60
Query as executed:
(bempedoic acid[tiab] OR ETC-1002[tiab] OR Nexletol[tiab] OR Nilemdo[tiab]) AND (cardiovascular[tiab] OR MACE[tiab] OR "major adverse cardiovascular events"[tiab]) AND (randomized controlled trial[pt] OR randomised[tiab] OR randomized[tiab])
In this section: Extracted values, and where each came from · Risk of bias (RoB-2) · Overall judgement per trial · Inter-assessor agreement · References · Included studies · Regulatory documents · Methods and guidance · Sources · Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization · Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization · What was measured · Pooled result · What this pool holds constant · Contributing trials · Endpoint definitions, read from the registry · Named on this review, contributing nothing to its pool
One row per extracted value. Every row carries the value, the verbatim sentence it was read from, a resolvable link to the source, and whether the number was read or derived. Where any of those is absent the row says so rather than omitting the value.
| Trial / outcome | Value as extracted | Verbatim source sentence | Source links | Read or derived |
|---|---|---|---|---|
| CLEAR Outcomes primary | HR 0.87 (95% CI 0.79 to 0.96) | no source sentence recorded — this value cannot be checked against a quoted line here | NCT02993406 · source | DERIVED by us from the trial's own ClinicalTrials.gov results record READ, not derived: this is the registry's own Cox analysis of the registered primary outcome. |
Variant:
Unit assessed: A result, not a study -- Handbook 8.2: 'risk of bias is assessed for a specific result'. Every judgement below names its outcome.
Assessor 1: (anthropic family). Assessor 2: (openai family).
| Trial | Result assessed | Domain | Assessor 1 (anthropic) | Assessor 2 (openai) | Agreed |
|---|---|---|---|---|---|
| CLEAR Outcomes | Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization | D1 D1_randomisation | no information | no information | yes |
| CLEAR Outcomes | Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization | D2 D2_deviations | no information | no information | yes |
| CLEAR Outcomes | Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization | D3 D3_missing_outcome_data | LOW | no information | NO |
| CLEAR Outcomes | Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization | D4 D4_measurement | some concerns | some concerns | yes |
| CLEAR Outcomes | Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization | D5 D5_selection_of_result | some concerns | LOW | NO |
| Trial | Result assessed | Assessor 1 (anthropic) | Assessor 2 (openai) | Agreed |
|---|---|---|---|---|
| CLEAR Outcomes | Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization | no overall judgement reached — this assessor answered “no information”, which RoB 2 defines as a response to a signalling question and not as one of the three overall categories (low, some concerns, high) | some concerns | NO |
This assessment is DUAL — two assessors from different model families, the second asked blind. The agreement rate is withheld pending adjudication. Both readers were given this review’s decision rule; an earlier version of this sentence said the blinding had withheld it, and that was wrong. What the 5 domain comparison(s) show is a reading difference that runs in OPPOSITE directions by domain — on domains 1 to 3 the second assessor more often declines to judge at all, and on domains 4 and 5 it more often judges low. A single agreement rate averages those two behaviours into one number that describes neither. Both assessors’ per-result judgements are shown in the table above, unadjudicated, and neither is this review’s finding. No adjudication has been performed, so this review holds no final risk-of-bias judgement for these results.
| Layer | Source | How it was obtained |
|---|
| Comparator | placebo |
|---|---|
| Estimand | time to first event — single study |
| Effect scale | reported on the log scale; nothing is pooled on this outcome |
HR 0.87 (0.79 to 0.96), 95% interval
Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. single study, estimator none, k = 1.
τ² not stated · I² not stated% · Q not stated on not stated df
Favours: the intervention (lower is better)
Not applicable: one trial, so there is no between-study variance to estimate.
Nothing is pooled: one trial. This is not a withheld estimate -- the value stands and is CLEAR Outcomes' own.
Three things a reader should know, none of which overturns the estimate. (1) one of the four included registrations is not a bempedoic acid trial at all. NCT02973841 is 'Sono-ease', a forty-patient device study of internal jugular vein cannulation whose registered primary outcome is 'complications rate'. It sits in this page's own include list. It carries no data record, so it touches no number here -- but it is the second wrong registration found in this corpus in one session, after NCT02583191 turned out to be a German treatment-satisfaction study on DOAC_CANCER_VTE. A registration that names an unrelated trial is invisible to every check that asks only whether an id is present and unique. (2) the published-comparison STEP compares this estimate against itself. The page's benchmark database holds exactly one entry for this outcome: 'CLEAR Outcomes bempedoic acid vs placebo', Nissen 2023, HR 0.87 (0.79 to 0.96), k=1, n=13,970. That IS the trial whose result is on the card. A comparison of a number with itself agrees perfectly and establishes nothing, and the agreement should not be read as external corroboration. The honest denominator here is zero: no independent synthesis of this estimand is recorded on this page. (3) a single trial is not a synthesis. Nothing here is pooled, there is no heterogeneity to report, and the interval is CLEAR Outcomes' own. The value of this page over reading the trial report is the provenance chain, not the statistics.
| Dimension | Across the pooled cohorts | If it differs, why it is crossed anyway |
|---|---|---|
| effect measure | NOT APPLICABLE | one trial |
| estimand | NOT APPLICABLE | one trial |
| Trial | Analysed treatment / control |
HR (95% CI), or events | Source of this cell |
|---|---|---|---|
| CLEAR Outcomes NCT02993406 | 6992 / 6978 | 0.87 (0.79 to 0.96) | : |
One trial, one registered primary outcome, quoted verbatim from its registry record. There is no concatenation here because there is nothing to concatenate.
What each trial COUNTED, in its own registry record's words, before anything here was pooled. A sentence saying what HAPPENED is not a sentence saying what was COUNTED, and only the second one licenses a pool. Read from the registry on 2026-08-18. Follow the registration link to disagree with any row.
| Trial | Rank in its own trial | Registered outcome measure | Description, verbatim | Analysis set / window |
|---|---|---|---|---|
| CLEAR Outcomes NCT02993406 | PRIMARY -- this registration's only primary outcome | Number of Participants With First Occurrence of Four Component Major Adverse Cardiovascular Events (MACE) | The primary efficacy end point was a four-component composite of adjudicated MACE, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, as assessed in a time-to first-event analysis. | Up to 68 months. Registry results: 819 of 6,992 on bempedoic acid against 927 of 6,978 on placebo; Cox hazard ratio 0.87 (0.79 to 0.96). the only included registration with a cardiovascular-event primary |
Three of the four registrations this page includes contribute nothing to its estimate, and nothing on the page said so. Two of them are excluded correctly -- their registered primary outcomes are not cardiovascular events -- and the third should never have been on the list at all: NCT02973841 is not a bempedoic acid trial. It is 'Sono-ease', a forty-patient device study of internal jugular vein cannulation.
| Trial | Why it contributes nothing | What the registry holds |
|---|---|---|
| Evaluation of Long-Term Safety and Toler NCT02666664 | its registered primaries are safety outcomes -- treatment-emergent adverse events and events of special interest -- not cardiovascular events. Correctly excluded from a MACE estimate. | treatment-emergent adverse events in 78.5% on bempedoic acid against 78.7% on placebo, and a set of adverse events of special interest |
| CLEAR Serenity NCT02988115 | its registered primary is percent change in ldl-c at week 12, a laboratory value. Correctly excluded from a MACE estimate. | LDL-C percent change -22.58 against -1.17, least-squares mean difference -21.41 (-25.13 to -17.70) |
| Sono-ease NCT02973841 | Wrong registration. This id belongs to 'Sono-ease', a 40-patient study of a device for internal jugular vein cannulation, whose registered primary outcome is 'complications rate'. It is not a bempedoic acid trial, it is not a cardiovascular outcomes trial, and it carries no data record on this page, so it touches no number here. | a 40-patient device trial with no relevance to this review |
In this section: Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization · Forest plot · Visual abstract · Risk of bias, both assessors · GOSH · Trial-sequential analysis · Meta-regression
Drawn from the same stored estimates the table above lists. Box area is proportional to inverse-variance weight.
x-axis range
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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 257d664df26f4f2d), at 600 dpi for a 6-inch print width, on a white ground. They are not screenshots of the page and do not change with the theme you are reading in.
Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — forest_fit.eps, 3 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — forest_fit.tiff, 9,887 KB.
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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 1e8d860df24d1774), at 600 dpi for a 6-inch print width, on a white ground. They are not screenshots of the page and do not change with the theme you are reading in.
Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — forest_w1.eps, 3 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — forest_w1.tiff, 9,887 KB.
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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 3c7e04042e7e9f65), at 600 dpi for a 6-inch print width, on a white ground. They are not screenshots of the page and do not change with the theme you are reading in.
Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — forest_w2.eps, 3 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — forest_w2.tiff, 9,887 KB.
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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 191fe6d6542ee7ee), at 600 dpi for a 6-inch print width, on a white ground. They are not screenshots of the page and do not change with the theme you are reading in.
Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — forest_w3.eps, 3 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — forest_w3.tiff, 9,887 KB.
Changing the range moves the axis window only. The guides stay labelled with the null and the extremes of the plotted intervals, so no plotted value and no printed number differs between these views — and that is checked at build time, not asserted.
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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: bb0911f0ec098c70), at 600 dpi for a 6-inch print width, on a white ground. They are not screenshots of the page and do not change with the theme you are reading in.
Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — visual-abstract.eps, 4 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — visual-abstract.tiff, 27,685 KB.
Projected from the canonical object, so it carries the same k, the same pooled estimate and the same interval as the paper and cannot drift from them. The interval is drawn to scale against the no-difference line, which it EXCLUDES: 0.79 to 0.96, with no difference at 1.
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Only the vector format is offered for this figure, by choice: it is line art — discrete marks, glyphs and labels — which SVG reproduces exactly at any size, so a raster would add weight without adding fidelity. The build was able to rasterise; it was asked not to.
Every cell carries BOTH independent cross-family assessments and they are not reconciled: showing one column would be a reconciliation presented as an observation. Glyph as well as colour, so the panel survives greyscale printing and colour-blind reading. A trial with no judgement is shown as a row of not-assessed markers rather than omitted, so a gap in the assessment cannot be mistaken for a clean assessment. Agreement as measured: {'per domain agreed': 3, 'per domain total': 5, 'per domain rate pct': 60.0, 'overall agreed': 0, 'overall total': 1, 'overall is derived': True, 'recomputed from the stored judgements': True, 'why recomputed': 'The stored disagreement tallies were frozen as text and 12 of 22 no longer match the judgements in the object -- a later guidance pass moved 51 the randomisation process judgements and the tallies were never recomputed. This is derived from what the object holds now.'}.
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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 5ec97d733b5a0686), at 600 dpi for a 6-inch print width, on a white ground. They are not screenshots of the page and do not change with the theme you are reading in.
Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — gosh.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — gosh.tiff, 5,537 KB.
Deliberately not drawn. Every subset meta-analysis of 1 trials is 1 points; a cloud that small cannot show the multimodality GOSH exists to reveal, and a reader would take the picture as evidence of its absence.
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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 25ed9800fdf56614), at 600 dpi for a 6-inch print width, on a white ground. They are not screenshots of the page and do not change with the theme you are reading in.
Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — tsa.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — tsa.tiff, 6,665 KB.
TSA boundaries depend entirely on a target information size that must be pre-specified. This review's protocol registers none, so any boundary drawn here would be a parameter chosen after seeing the data -- which is the practice TSA exists to protect against.
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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 655c850bcb4ad0dc), at 600 dpi for a 6-inch print width, on a white ground. They are not screenshots of the page and do not change with the theme you are reading in.
Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — bubble.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — bubble.tiff, 5,537 KB.
The protocol pre-specifies no moderator, and at k = 1 a meta-regression would be fitted on 1 points. Not drawn rather than drawn with a caveat: a bubble plot invites reading a slope, and there is no slope here that any reader should read.
In this section: Summary of findings · Reproducibility artifact · Other recorded qualifications
| Outcome | k | Pooled effect | Certainty |
|---|---|---|---|
| Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization | 1 | HR 0.87 (0.79 to 0.96) | Pending12 |
| Canonical object | — |
|---|---|
| Registered at | — — |
| Schema | 2-authored-from-source |
| Object last updated | 2026-08-18T00:00Z |
| Source object SHA-256, first 16 hex characters | 9902adc797347683 |
| Page generated | 2026-08-28 19:53 UTC |
| Generator build | a441e4187, built to STANDARD v1 |
This page CANNOT be rebuilt from what is recorded here: no canonical object is recorded and no registered commit is recorded. Each figure on the Analysis tab downloads as an SVG carrying exactly the values shown.
Statements this review records about the limits of what it establishes, which are not shown elsewhere on this page. They are reproduced from the object verbatim and are not summarised.
| Authority it does not satisfy | Mecir C5/C7 (Mandatory conduct standards) -- criteria defined in advance. A post hoc derivation cannot discharge pre-specification, and precondition `criteria predefined` therefore fails for this topic, permanently and correctly. |
|---|---|
| What the registry holds that the page does not | treatment-emergent adverse events in 78.5% on bempedoic acid against 78.7% on placebo, and a set of adverse events of special interest |
| The verdict still stands but on a different limb | Exclude is still correct. The failing limb is population, not outcome: this is CLEAR Harmony, in high-cardiovascular-risk patients on maximally tolerated statin therapy, whereas the review's population limb is statin-intolerant patients. |
| What the registry holds that the page does not | LDL-C percent change -22.58 against -1.17, least-squares mean difference -21.41 (-25.13 to -17.70) |
| Components as the registry states them | cardiovascular death; nonfatal myocardial infarction; nonfatal stroke; coronary revascularization. Four components, first occurrence, time-to-event. |
| Analysis set as the registry states it | Up to 68 months. Registry results: 819 of 6,992 on bempedoic acid against 927 of 6,978 on placebo; Cox hazard ratio 0.87 (0.79 to 0.96). the only included registration with a cardiovascular-event primary |
| Caveats | Three things a reader should know, none of which overturns the estimate. (1) one of the four included registrations is not a bempedoic acid trial at all. NCT02973841 is 'Sono-ease', a forty-patient device study of internal jugular vein cannulation whose registered primary outcome is 'complications rate'. It sits in this page's own include list. It carries no data record, so it touches no number here -- but it is the second wrong registration found in this corpus in one session, after NCT02583191 turned out to be a German treatment-satisfaction study on DOAC_CANCER_VTE. A registration that names an unrelated trial is invisible to every check that asks only whether an id is present and unique. (2) the published-comparison STEP compares this estimate against itself. The page's benchmark database holds exactly one entry for this outcome: 'CLEAR Outcomes bempedoic acid vs placebo', Nissen 2023, HR 0.87 (0.79 to 0.96), k=1, n=13,970. That IS the trial whose result is on the card. A comparison of a number with itself agrees perfectly and establishes nothing, and the agreement should not be read as external corroboration. The honest denominator here is zero: no independent synthesis of this estimand is recorded on this page. (3) a single trial is not a synthesis. Nothing here is pooled, there is no heterogeneity to report, and the interval is CLEAR Outcomes' own. The value of this page over reading the trial report is the provenance chain, not the statistics. |
| Why absent | k=1 and nothing was pooled, so there is NO model call to quote, NO pooled estimate, NO heterogeneity and NO package version. This is not a missing artefact; it is the correct state for a topic with no synthesis. |
| Refusal discharges P46 because | It names what exists (one trial's own Cox interval), why no quotable model output can exist (nothing was pooled), and what would change it. |
| Background is now zero and it is computed | 0 background is the result of classifying 21 records, not an unfilled field. P17: a field whose name implies a check carries a computed value. |
| Why this is a correction not a relaxation | It moved counts in both directions across the corpus: sglt2-hf +10, bempedoic-acid-review -1. A loosening only ever adds. Four regression guards pin the negative case, including apixaban vs rivaroxaban where both arms are active. |
| K unscreened remainder note | Was 1 after the placebo-discriminator restatement; NCT05263778 screened 2026-08-19 and excluded on intervention -- it randomises a bempedoic acid/ezetimibe fixed-dose combination against placebo, so two agents differ between arms and no estimate is attributable to bempedoic acid. Population (post-ACS, not statin-intolerant) and outcome (LDL-C, not MACE) also fail and are named rather than relied on. Disposition at screening of remainder.bempedoic_newly_unscreened_2026_08_19. |
| And k5 is now zero which is a claim | NO surfaced trial has bempedoic acid in every arm. That is a computed zero -- 21 records classified, 0 landing in background -- and not an empty field. It reads oddly for an add-on lipid agent and it is correct: the programme's non-experimental records are ACTIVE-COMPARATOR designs (bempedoic acid as the control against another agent), not background-therapy designs. |
| Refusal discharges P46 because | It names what was reached (one benchmark for this estimand), what was found insufficient (that benchmark IS the trial on the card, so the comparison would be the number against itself), and what would have to be obtained (an independent synthesis). The reason is a fact about the published evidence, not about our queue. |
| Why asked before deciding not to pool | Reading only registered primaries is how a poolable outcome one rank down goes unseen. Two of the three MACE-matching outcomes found here sit at secondary rank and a primaries-only screen would have missed both. |
| Three that are poolable but not eligible | Three trials report a MACE-matching outcome yet fail population or comparator. They could contribute a quantity but are out of scope, which is the opposite cell from the eleven eligible-but-not-poolable on sglt2-hf. Both cells are only visible under two axes. |
| Why this is stated rather than left implicit | A rating of some concerns with no explanation reads as a judgement against the trial. Omitting the reason would manufacture a criticism exactly as a low-by-default manufactures a reassurance -- the same defect pointed the other way. |
| This does not replace the stored judgement | This is the judgement the published algorithm proposes from the signalling responses named here. It does not replace the stored `judgement` beside it, and nothing reads it yet. The tool itself says its algorithms "provide proposed judgements, but users should verify these and change them if they feel this is appropriate" -- so this is an input to a person, not an output to a reader. |
| Registry facts backfilled | Read from ClinicalTrials.gov API v2 on 2026-08-21. The judgements above were not revisited -- this adds the registry evidence beside a verdict that was made from it and did not record it, so a blind second assessor can be shown the same facts. A second assessment built on fewer facts is not a comparable assessment. |
| The allow list the rate is conditional on | A disagreement rate is meaningless without the facts both assessors saw, so the list is stated here the way a denominator is stated. Fields emitted: trial, cohort, registered enrolment, registered masking, registered sites, registered comparator, number of registered arms, number of registered primary outcomes, registered primary outcome, registered analysis population, the rank the pooled result holds, the result being assessed, participants this review pools, registered enrolment minus participants pooled. Established by test, not argument: widening this list from 9 fields to 14 halved gepotidacin's disagreement -- its entire selection of the reported result divergence was a fact the second assessor had never been shown -- and left ceftaroline and tigecycline unmoved. |
| Which risk of bias domains drove the rating | Where a result is rated worse than LOW overall, the domain carrying that judgement is: the randomisation process on 1 result(s), deviations from the intended intervention on 1 result(s), selection of the reported result on 1 result(s). The overall rating is the worst domain, so these are the domains that determine it. |
In this section: Summary
Question. Does bempedoic acid reduce major cardiovascular events in statin-intolerant patients?
What was checked. ClinicalTrials.gov protocol and results records, read 2026-08-18
What was found. 1 registered trial:
| Registration | Trial |
|---|---|
| NCT02993406 | CLEAR Outcomes |
What the trials found. No estimate below is combined with any other; each is the result of a single trial, reported as that trial reported it.
| Trial | Outcome | Result |
|---|---|---|
| NCT02993406 | Four-component MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization | HR 0.87 (95% CI 0.79 to 0.96) |
Why no result is pooled. Nothing is pooled: one trial. This is not a withheld estimate -- the value stands and is clear Outcomes' own.
Whether these trials study this subject. Checked against each registration's arm structure on 2026-08-25. 1 of 1 trial was confirmed: the drug is part of the randomised comparison.
What would change this. A pooled result becomes possible when a second eligible trial reporting the same outcome is published.
No pooled estimate or certainty rating is published for this question, because there is no combined result for them to describe. A risk-of-bias assessment is published below and describes the trials, not a combined result.
Built 2026-08-19 by ssot/build_to_standard.py against PAGE-STANDARD.md. 10 held, 4 refusing. A refusal is a complete outcome; nothing is generated to fill a slot.
| property | state | reason |
|---|---|---|
| P1_executed_search | HELD | 2 database queries recorded verbatim with dates and counts; PRISMA arithmetic reconciles and the 0-trial unscreened remainder is stated as a number rather than omitted. |
| P2_k_cascade | HELD | k at every stage: surfaced 21, located 21, experimental 16, comparator 5, included 1, unscreened remainder 0. |
| P3_inclusion_criteria | HELD | Criteria provenance block present with predefined=False on its face (state 'DERIVED_FROM_THIS_OBJECT'). |
| P4_preconditions | HELD | All 8 recorded with verdict and cited authority: 1 FAIL, 1 NOT-ASSESSABLE. criteria_predefined is FAIL -- post hoc criteria, which R107 permits and C5/C7 does not satisfy. |
| P5_extraction_table | HELD | 9 cells: 8 READ with source path and verbatim text, 1 DERIVED with the method named. |
| P6_analysis_output | REFUSING | No quotable model output exists: k=1 and nothing was pooled. The absence is recorded as a finding with its cause and its trigger. |
| P7_published_comparison | REFUSING | No denominator yet. Blocked on external registration-id resolution; citation-string matching explicitly refused rather than substituted. |
| P8_registration_identity | HELD | 1 of 1 trial(s) verified live against the registry. |
| P18_restatement_is_reproducible | HELD | 2 restatement block(s), each naming a script that resolves on disk: restated_2026_08_19_placebo_discriminator -> scripts/regate_across_revisions.py, ssot/topic_identity.py; restated_2026_08_19_trailing_placebo -> scripts/regate_cascade_2026_08_19.py |
| P19_promotion_reaches_derived_blocks | HELD | inputs.trials, k_cascade.k_included_in_object and prisma_flow.included all say 1; no first-person field in published_comparison declares a k the pooled outcome(s) do not. |
| P20_cascade_reconciles | HELD | k2_role_located=21 == k3+k4+k5, and k0_surfaced=21 == k3+k4+k5+kNA. Both checked, and every failing limb would be reported rather than the first. |
| P21_ambiguous_question_split | REFUSING | This object records no split provenance. That is CORRECT for a topic whose question was never ambiguous and it is NOT a pass: this builder cannot tell the two apart, so the property is refused with the reason rather than held on an absence. What would settle it: a `split_provenance` block, or an explicit statement that the question admits one reading. |
| P22_sharing_recorded | HELD | No trial of this review appears in any other object's included set. COMPUTED over the corpus, not asserted: 1 trial(s) checked against every other topic object. |
| P23_recall_measured | REFUSING | 2 of 2 recorded quer(ies) do not state their recall against this review's own included set: ClinicalTrials.gov API v2 and PubMed (NCBI E-utilities esearch). A query whose recall was never measured may have lost an included trial, and A TRIAL THAT WAS NEVER SURFACED LEAVES NO TRACE IN ANY COUNT -- it cannot appear as an exclusion, a refusal or a remainder. |
| stage | k |
|---|---|
| k0_surfaced | 21 |
| k2_role_located | 21 |
| k3_experimental | 16 |
| k4_comparator | 5 |
| k5_background | 0 |
| kNA_not_assessable | 0 |
| k_included_in_object | 1 |
| k_unscreened_remainder | 0 |
| keyed_on | registration id |
| source | evidence/2026-08-19-batch1/cascade.json |
| k_unscreened_remainder_note | Was 16. All 16 were screened on 2026-08-19 against the derived criteria block; 0 met all four limbs. See screening_of_remainder. |
| restated_2026_08_19_placebo_discriminator | k3 was 17, k3 now 16, delta -1, why topic_identity.locate() read the registry's arm TYPES literally. Some registrations declare NO arm typed EXPERIMENTAL: AFFIRM-AHF and HEART-FID both type their active drug ACTIVE_COMPARATOR against a PLACEBO_COMPARATOR arm. The classifier called the intervention a comparator and silently shrank the evidence base. Rule adopted: PLACEBO IS NEVER THE INTERVENTION, so a drug compared against it is -- but where the other arm is an ACTIVE drug, the topic drug genuinely is one of two comparators and the rule must not fire., why this is a correction not a relaxation It moved counts in BOTH directions across the corpus: sglt2-hf +10, bempedoic-acid-review -1. A LOOSENING ONLY EVER ADDS. Four regression guards pin the negative case, including apixaban vs rivaroxaban where both arms are active., how it was found By CROSS-CHECKING TWO INSTRUMENTS. The executed search surfaced this object's OWN included trials, and the arm-role classifier then refused to recognise two of them as the intervention. Neither instrument found it alone. This is the first defect tonight found in the WITHHOLDING direction by an instrument rather than by a person noticing -- the class we had said has no guard., trials no longer experimental NCT06450366; NCT07614958, screening status after restatement 16 experimental, 1 included, 14 already screened, 1 NEWLY UNSCREENED. The screening of this topic was reported COMPLETE and is now INCOMPLETE again. That is the ratchet: no page is grandfathered, including one completed hours ago., newly unscreened ids NCT05263778, reproduced by scripts/regate_across_revisions.py <topic> -- re-executes this topic's own recorded query, loads EVERY revision of ssot/topic_identity.py from git, and reports at which of them the stored cascade reproduces. Added 2026-08-19 under PAGE-STANDARD P18, after sglt2-hf's cascade was found to reproduce at exactly one revision and no other while carrying a restatement note that made it look current., attribution corrected 2026 08 19 THIS BLOCK'S NUMBER IS RIGHT AND ITS ATTRIBUTION IS WRONG, and only a walk across revisions could show it. 17 -> 16 is not one move by the placebo-discriminator. It is 17 -> 15 at 92d84da72, where the BOTH-ARMS rule moved NCT06450366 and NCT07614958 experimental -> background, then 15 -> 16 at f2bf16022, where the placebo-discriminator moved NCT05263778 comparator -> EXPERIMENTAL. The stored sentence credits the placebo-discriminator with the entire delta and describes its single move in the opposite direction to the one it made. A CORRECT NUMBER REACHED BY A WRONG ACCOUNT passes every check that reads quantities. |
| k_unscreened_remainder_note_2026_08_19 | Was 1 after the placebo-discriminator restatement; NCT05263778 screened 2026-08-19 and EXCLUDED on INTERVENTION -- it randomises a bempedoic acid/ezetimibe FIXED-DOSE COMBINATION against placebo, so two agents differ between arms and no estimate is attributable to bempedoic acid. Population (post-ACS, not statin-intolerant) and outcome (LDL-C, not MACE) also fail and are named rather than relied on. Disposition at screening_of_remainder.bempedoic_newly_unscreened_2026_08_19. |
| restated_2026_08_19_trailing_placebo | k4 was 3, k4 now 5, k5 was 2, k5 now 0, k3 unchanged 16, why no trial needs rescreening k3 IS UNCHANGED, so the screened set is unchanged. The two movers (NCT06450366, NCT07614958) went background -> COMPARATOR, and both were already recorded on this object as trials the placebo-discriminator had moved OUT of the experimental set. They have now moved once more, within the non-experimental half, and the remainder is untouched., and k5 is now zero which is a claim NO surfaced trial has bempedoic acid in every arm. That is a COMPUTED zero -- 21 records classified, 0 landing in background -- and not an empty field. It reads oddly for an add-on lipid agent and it is correct: the programme's non-experimental records are ACTIVE-COMPARATOR designs (bempedoic acid as the control against another agent), not background-therapy designs., measured how Old classifier loaded from git at 7a08bcbe1; surfaced set re-executed and returned 21, identical to the stored k0. scripts/regate_cascade_2026_08_19.py., no included trial changed role This object includes one trial, NCT02993406, and it did not move. |
predefined: False | post_hoc: True — derived 2026-08-19
MECIR R107 'Changes from the protocol' (Mandatory): post hoc decisions about eligibility criteria are permitted where explained, justified, and keeping faith with the objectives of the review rather than being driven by the findings.
| limb | value | derived from |
|---|---|---|
| objective | Does bempedoic acid reduce major cardiovascular events in statin-intolerant patients? One trial answers this; the other three registrations on this page measure | question |
| comparator | placebo | outcomes[0].comparator |
| comparator_type | placebo | outcomes[0].comparator_type |
| outcome | Number of Participants With First Occurrence of Four Component Major Adverse Cardiovascular Events (MACE) | outcomes[0].definition |
| effect_measure | HR | outcomes[0].measure |
| effect_scale | log | outcomes[0].effect_scale |
| direction_of_benefit | lower is better | outcomes[0].direction_of_benefit |
| design | 2 arms; declared contrast ['Bempedoic Acid 180 mg', 'Placebo Comparator'] | inputs.trials[0].registration_arm_count + .registration_declared_contrasts |
screening.eligibility_provenance -- the DERIVED criteria block (predefined:false, post_hoc:true). This screen is the first test of whether a derived block can do the work criteria are for: admitting and excluding named trials with reasons. It could.
k after screening: 1. None of the 16 met all four limbs. k stays at 1, and P6 therefore continues to refuse a pooled model -- but it now refuses on a SCREENED basis rather than an unexamined one, which is a different and stronger statement.
| failing limb | n | registrations |
|---|---|---|
| COMPARATOR | 2 | NCT06381947, NCT07611747 |
| OUTCOME | 13 | NCT02988115, NCT02991118, NCT03001076, NCT03067441, NCT03337308, NCT06280976, NCT06450366, NCT06780410, NCT06925100, NCT07440381, NCT07474649, NCT07508254, NCT07614958 |
| POPULATION | 1 | NCT02666664 |
does this trial report, AT ANY RANK -- primary, secondary or other -- an outcome matching what the included trial reports as its primary?
Reading only registered PRIMARIES is how a poolable outcome one rank down goes unseen. Two of the three MACE-matching outcomes found here sit at SECONDARY rank and a primaries-only screen would have missed both.
| registration | rank | matching outcome |
|---|---|---|
| NCT02666664 | PRIMARY | Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event |
| NCT06381947 | SECONDARY | MACE at 12 and 28 weeks |
| NCT06381947 | SECONDARY | Rehospitalization at 12 and 28 weeks |
| NCT06381947 | SECONDARY | Death at 12 and 28 weeks |
| NCT07611747 | PRIMARY | Incidence of Major Adverse Cardiovascular Events (MACE) |
| registration | verdict | limb | reason |
|---|---|---|---|
NCT02666664 | EXCLUDE | POPULATION | reports a MACE-matching outcome against placebo, but its population is not stated as statin-intolerant. The review's population limb is statin-intolerant patients. |
NCT02988115 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 5 registered ranks (primary, secondary and other all searched). Its registered primary is 'Percent Change From Baseline (PCFB) in Low-density Lipoprotein Cholesterol (LDL-C) at Week'. Different quantity, not |
NCT02991118 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 20 registered ranks (primary, secondary and other all searched). Its registered primary is 'Percent Change From Baseline to Week 12 in Low-density Lipoprotein Cholesterol (LDL-C)'. Different quantity, not po |
NCT03001076 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 14 registered ranks (primary, secondary and other all searched). Its registered primary is 'Percent Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol (LDL-C)'. Different quantity, not po |
NCT03067441 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 17 registered ranks (primary, secondary and other all searched). Its registered primary is 'Number of Participants With Treatment-Emergent Adverse Events (TEAEs)'. Different quantity, not poolable with the r |
NCT03337308 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 7 registered ranks (primary, secondary and other all searched). Its registered primary is 'Percent Change From Baseline to Week 12 in Low-density Lipoprotein Cholesterol (LDL-C)'. Different quantity, not poo |
NCT06280976 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 20 registered ranks (primary, secondary and other all searched). Its registered primary is 'Plaque quantification'. Different quantity, not poolable with the review's estimand. |
NCT06381947 | EXCLUDE | COMPARATOR | reports a MACE-matching outcome but declares no placebo arm; arms are ['PCSK9 inhibitors plus ezetimibe and bempedoic acid', 'PCSK9 inhibitors plus ezetimibe']. The review's comparator is placebo. |
NCT06450366 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 8 registered ranks (primary, secondary and other all searched). Its registered primary is 'Mean Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Day 56'. Different quantity, not |
NCT06780410 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 3 registered ranks (primary, secondary and other all searched). Its registered primary is 'Percentage change from baseline in LDL-C levels at Week 12'. Different quantity, not poolable with the review's esti |
NCT06925100 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 7 registered ranks (primary, secondary and other all searched). Its registered primary is 'Percentage change from baseline in LDL-C level at Week 12'. Different quantity, not poolable with the review's estim |
NCT07440381 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 8 registered ranks (primary, secondary and other all searched). Its registered primary is 'Mean percent change in LDL-c levels'. Different quantity, not poolable with the review's estimand. |
NCT07474649 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 17 registered ranks (primary, secondary and other all searched). Its registered primary is 'Annualised change in percentage plaque burden (Δ%PB)'. Different quantity, not poolable with the review's estimand. |
NCT07508254 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 2 registered ranks (primary, secondary and other all searched). Its registered primary is 'Change in LDL cholesterol level'. Different quantity, not poolable with the review's estimand. |
NCT07611747 | EXCLUDE | COMPARATOR | reports a MACE-matching outcome but declares no placebo arm; arms are ['Experimental Group: Carotid Ultrasound', 'Control Group: Standard Care']. The review's comparator is placebo. |
NCT07614958 | EXCLUDE | OUTCOME | reports no four-component MACE outcome at ANY of its 7 registered ranks (primary, secondary and other all searched). Its registered primary is 'The primary efficacy endpoint is the percentage change from baseline to Day 84 in LDL-C in'. Different quantity, not |
The recorded reason reads: 'its registered primaries are SAFETY outcomes -- treatment-emergent adverse events and events of special interest -- not cardiovascular events.' That is FACTUALLY WRONG. NCT02666664 registers THIRTEEN primary outcomes and the SECOND is 'Percentage of Participants With Adjudicated Major Adverse Cardiovascular Event'. It has a MACE primary.
How it happened: The object stores `registered_primary_measure` as a SCALAR holding ONE of the trial's thirteen primaries -- the first, TEAEs -- and the exclusion reason was written by characterising all primaries from that single value. A scalar field standing for a list is how the other twelve became invisible.
Verdict: EXCLUDE is still correct. The failing limb is POPULATION, not OUTCOME: this is CLEAR Harmony, in high-cardiovascular-risk patients on maximally tolerated statin therapy, whereas the review's population limb is statin-intolerant patients.
Class: A correct verdict reached by broken reasoning. It passed every outcome-based check because the outcome -- exclusion -- was right. Only reading the REASON against the registry caught it, and only because the withholding question is asked at every rank rather than at the primary alone.
k=1 and nothing was pooled, so there is NO model call to quote, NO pooled estimate, NO heterogeneity and NO package version. This is not a missing artefact; it is the correct state for a topic with no synthesis.
What stands instead: HR 0.87 (95% CI 0.79 to 0.96)
Provenance: CLEAR Outcomes' OWN registry-posted analysis, NOT a synthesis result computed hereHazard Ratio (HR) 0.87, CI 0.79 - 0.96, statistical method Log Rank, p=0.004
Heterogeneity: Undefined: no between-study variance was estimated because no model was run.
What would change it: An estimand shared by two or more included trials. Where k is already above 1 and nothing pooled, the obstacle is the ESTIMAND rather than the evidence base, and this field must say which.
Denominator: —. The honest denominator here is ZERO, and that is a finding rather than a shortfall. The only benchmark this page holds for this estimand is CLEAR Outcomes itself -- the single trial whose result the card serves. A comparison of a number with itself agrees perfectly and establishes nothing, and that agreement must not be read as external corroboration. No INDEPENDENT synthesis of this estimand is recorded.
Explicitly not done: CITATION-STRING MATCHING. It would produce a comparison-shaped answer tonight and it is not identity: two syntheses citing the same trial under different labels would read as different, and the same label on different trials as the same. That is the substitution class this project audits for.
Blocked on: lane 2 registration-id resolution
Authority: Cochrane Handbook for Systematic Reviews of Interventions 6.5, 2024, verified 2026-08-19. Publishable: True.
| precondition | verdict | reason | authority |
|---|---|---|---|
| population_stated | PASS | present: question carries 223 characters | MECIR C62 'Ensuring meta-analyses are meaningful' (Mandatory, READ 2026-08-19): 'Undertake (or display) a meta-analysis only if participants, interventions, comparisons and outcomes are judged to be s |
| arm_role_resolved | PASS | inputs.trials: all 1 trial(s) carry arms with a readable role | MECIR C62 (Mandatory), 'interventions' limb -- this is a PRECONDITION FOR ASSESSING C62, not an enforcement of it: you cannot judge whether interventions are 'sufficiently similar' without knowing whi |
| comparators_identified | PASS | every outcome names a comparator type ['placebo']; none declares 'mixed'. Within-outcome consistency is visible only through the declared type, and cross-outcome differences are not judged. | MECIR C62 (Mandatory), 'comparisons' limb -- a synthesis pools one contrast. NOT cited to C7: C7 governs PREDEFINITION, and this check reads recorded comparator fields and tests them for consistency. |
| estimand_named | PASS | outcomes.estimand: all 1 outcome(s) name a quantity | MECIR C8 'Clarifying role of outcomes' (Mandatory, READ 2026-08-19); MECIR C62 (Mandatory), 'outcomes' limb |
| criteria_stated | PASS | present: screening.eligibility carries 704 characters | MECIR R29 'Eligibility criteria for types of participants', R30 '...types of interventions', R31 'Role of outcomes' -- ALL Mandatory REPORTING standards (READ 2026-08-19). Their verb is STATE. A block |
| criteria_predefined | FAIL | screening.eligibility_provenance.predefined is false: the criteria were DERIVED post hoc from this object's own question and recorded exclusions. That is auditable (R29/R30/R31) and is not pre-specification (C5/C7). This | MECIR C5 'Predefining unambiguous criteria for participants' AND C7 '...for interventions and comparators', BOTH Mandatory (READ 2026-08-19): 'Predefined, unambiguous eligibility criteria are a fundam |
| eligibility_met | NOT-ASSESSABLE | cannot assess: criteria are stated, but sources is an empty dict -- no full text was available this pass, and inclusion logic is conditional prose | MECIR C5/C7 (Mandatory) with C6 'Predefining a strategy for studies with a subset of eligible participants' (Highly desirable, READ 2026-08-19) -- eligibility is assessed against the full report |
| contributes_a_randomised_contrast | PASS | inputs.trials.arms: all 1 readable trial(s) contribute one topic-vs-control randomised contrast | Handbook 6.5 s23.3.4 'How to include multiple groups from one study' (READ 2026-08-19) and s23.3.6 'Factorial trials'; MECIR C7 'Predefining unambiguous criteria for interventions and comparators' (Ma |
This page is stamped to the standard version above. If the standard rises, this page is below it and knowably so. No page is grandfathered; arni-hfref is presently unstamped and is therefore unknown-version, not compliant.
Every number on this page is projected from a single canonical object, and each measured cell names the source analysis it was read from. That is what is machine-checked. It does not establish that the underlying sources are right, only that this page faithfully reports them.