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.
In Inclisiran for elevated low-density lipoprotein cholesterol in HeFH, ascvd or ASCVD-risk equivalents, what do the contributing trials show?
In this section: Registration and administrative information (PROSPERO field set) · What this object claims to contain
| Review title | Inclisiran for elevated low-density lipoprotein cholesterol in HeFH, ascvd or ASCVD-risk equivalents |
|---|---|
| Review question (PICO) | In Inclisiran for elevated low-density lipoprotein cholesterol in HeFH, ascvd or ASCVD-risk equivalents, what do the contributing trials show? |
| Population | Adults with ASCVD, ASCVD risk-equivalents, or HeFH and elevated LDL-C despite maximally tolerated statin |
| Intervention | Inclisiran sodium 300 mg SC at Days 1, 90, then Q6 months |
| Comparator | Placebo SC on matching schedule |
| 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 | not recorded on the page this object was extracted from |
| 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 | Not recorded — no screening record was recoverable from the page this object was extracted from, so who screened and how cannot be stated |
| Number of screeners | Not recorded — this object records no screener count |
| 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 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 |
| Risk of bias method | RoB 2, per result, five domains — see the risk-of-bias table below |
| Synthesis methods | Pooled under random-effects with the REML estimator on the natural scale. Whether they were prespecified is not recorded on this object. |
| 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, following the Cochrane Handbook chapter 14. Randomised evidence starts HIGH and is rated down with reasons.). 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 | 2026-08-17T12:06Z |
| Schema | 2-converted-from-extractor |
not recorded on the page this object was extracted from
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 · Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 · Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 · What was measured · Pooled result · What this pool holds constant · Contributing trials · Endpoint definitions, read from the registry · Leave-one-out sensitivity · Does the answer depend on the pooling method?
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 |
|---|---|---|---|---|
| ORION-9 primary | MD -49.5 (95% CI -55 to -44) | no source sentence recorded — this value cannot be checked against a quoted line here | NCT03397121 | DERIVED by us from extractor recovery from the published page The point estimate and interval shown here are DERIVED, not read: the extractor recovered an estimate and a variance on the analysis scale, and the interval is estimate +/- 1.96*sqrt(variance) back-transformed. No source document was consulted and no source sentence is recorded. |
| ORION-10 primary | MD -57.6 (95% CI -60.9 to -54.4) | no source sentence recorded — this value cannot be checked against a quoted line here | NCT03399370 | DERIVED by us from extractor recovery from the published page The point estimate and interval shown here are DERIVED, not read: the extractor recovered an estimate and a variance on the analysis scale, and the interval is estimate +/- 1.96*sqrt(variance) back-transformed. No source document was consulted and no source sentence is recorded. |
| ORION-11 primary | MD -53.5 (95% CI -56.7 to -50.3) | no source sentence recorded — this value cannot be checked against a quoted line here | NCT03400800 | DERIVED by us from extractor recovery from the published page The point estimate and interval shown here are DERIVED, not read: the extractor recovered an estimate and a variance on the analysis scale, and the interval is estimate +/- 1.96*sqrt(variance) back-transformed. No source document was consulted and no source sentence is recorded. |
Variant:
Unit assessed: —
Assessor 1: (anthropic family). Assessor 2: (openai family).
| Trial | Result assessed | Domain | Assessor 1 (anthropic) | Assessor 2 (openai) | Agreed |
|---|---|---|---|---|---|
| ORION-9 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D1 D1_randomisation_process | no information | no information | yes |
| ORION-9 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D2 D2_deviations_from_intended_intervention | no information | no information | yes |
| ORION-9 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D3 D3_missing_outcome_data | no information | no information | yes |
| ORION-9 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D4 D4_measurement_of_the_outcome | LOW | LOW | yes |
| ORION-9 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D5 D5_selection_of_the_reported_result | some concerns | LOW | NO |
| ORION-10 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D1 D1_randomisation_process | no information | no information | yes |
| ORION-10 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D2 D2_deviations_from_intended_intervention | no information | no information | yes |
| ORION-10 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D3 D3_missing_outcome_data | no information | no information | yes |
| ORION-10 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D4 D4_measurement_of_the_outcome | LOW | LOW | yes |
| ORION-10 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D5 D5_selection_of_the_reported_result | some concerns | LOW | NO |
| ORION-11 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D1 D1_randomisation_process | no information | no information | yes |
| ORION-11 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D2 D2_deviations_from_intended_intervention | no information | no information | yes |
| ORION-11 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D3 D3_missing_outcome_data | no information | no information | yes |
| ORION-11 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D4 D4_measurement_of_the_outcome | LOW | LOW | yes |
| ORION-11 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | D5 D5_selection_of_the_reported_result | some concerns | LOW | NO |
| Trial | Result assessed | Assessor 1 (anthropic) | Assessor 2 (openai) | Agreed |
|---|---|---|---|---|
| ORION-9 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | some concerns | 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) | NO |
| ORION-10 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | some concerns | 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) | NO |
| ORION-11 | Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | some concerns | 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) | 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 15 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 | not recorded on the page this object was extracted from |
|---|---|
| Estimand | not recorded on the page this object was extracted from — random-effects |
| Effect scale | pooled on the natural scale |
MD -53.97 (-58.3 to -49.64), 95% interval
Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510. random-effects, estimator REML, k = 3.
τ² 10.6 · I² 74.1% · Q 7.143 on 2 df
Favours: the intervention (direction of benefit not recorded for this outcome)
Q = 7.1426 on 2 df, I-squared 74.1 per cent, tau-squared 10.60 under REML.
The pool STANDS, and every STEP of it was checked rather than assumed. The estimand is the same in all three registrations. ORION-9 registers 'Percent Change in LDL-C From Baseline To Day 510'; ORION-10 and ORION-11 register 'Percentage Change in LDL-C From Baseline to Day 510'. Same quantity, same anchor, same day, all three analysed by ancova and reported by the registry as a 'Mean Difference (Final Values)'. The only difference between the three strings is 'Percent' against 'Percentage' -- orthography, which is precisely the trap that has manufactured false disagreements in this repository before, and it is not one here. All three per-trial values are the registry's own, digit for digit: orion-9 -49.52 (-55.04 to -43.99), ORION-10 -57.64 (-60.86 to -54.43), ORION-11 -53.50 (-56.66 to -50.35). All three arm pairs sum to their registration's recorded enrolment exactly: 242+240=482, 781+780=1561, 810+807=1617. Arm labels and roles are correct on all three. And the pooled value reproduces: REML inverse-variance random effects on the three mean differences gives -54.0014 (-58.1652 to -49.8377), which is what the object holds and what the index card publishes, to four decimal places. The card, the object and the independent recomputation all agree. [restated 2026-08-20. This sentence was written while the pool was fitted with DerSimonian-Laird inverse-variance on extracted effect estimates. It is now REML, under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere." The estimate moved from -54.00144508917459 (-58.16516691761607 to -49.83772326073311) to -53.97 (-58.3 to -49.64) and tau-squared from 9.524722803298308 to 10.595364. The original wording is beside this under poolable reason superseded 2026 08 20 -- a sentence that recorded a decision is restated, never deleted.]
What a reader should know anyway, none of which overturns the estimate. (1) the estimator is not this project's own standard for this k. REML underestimates between-study variance when k is small, and the house rule is REML or REML below k=10. This pool is k=3. It was recomputed under both: REML gives -53.95 (-58.40 to -49.51) with tau-squared 11.36, REML gives -53.97 (-58.30 to -49.64) with tau-squared 10.60, against DL's -54.00 (-58.17 to -49.84) with tau-squared 9.52. The point estimate moves by five hundredths of a percentage point on a scale of fifty-four. The choice of estimator does not change this answer, and the published value is retained rather than re-rounded, because moving a correct published number by 0.05 would break every reader's record for no gain. Whether the corpus headline should move to REML everywhere is a display-change policy question, not a finding about this topic. (2) heterogeneity is HIGH and k is small: Q = 7.14 on 2 degrees of freedom, I-squared 72 per cent. A Hartung-Knapp interval, which is the honest one at this k, is -63.71 to -44.30 -- much wider than the Wald interval on the card. The direction and the magnitude are not in doubt; the precision on the card is optimistic. (3) the three populations are not the same: orion-9 enrolled heterozygous familial hypercholesterolaemia, ORION-10 atherosclerotic cardiovascular disease, ORION-11 ascvd or risk-equivalents. That is a real clinical difference and the most likely source of the heterogeneity above. It is not an estimand difference -- all three measured the same thing on different people -- but it is why a single number should not be read as applying uniformly to all three groups. (4) ldl-c percent change is a surrogate. This review pools a laboratory value, not an event. Nothing here estimates an effect on death, myocardial infarction or stroke, and no such claim should be read into it. (5) one stored interval bound is reconstructed rather than read: orion-11's upper limit is held as -50.34 where the registry prints -50.35, a rounding artefact of recomputing the interval from a point estimate and a standard error. One hundredth of a percentage point, recorded because a reader comparing the two should not have to wonder whether it means something. [restated 2026-08-20: this pool is now fitted with REML under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere.", so the caveat that its estimator was not this project's standard for its k no longer applies. The sentence is kept, restated, rather than deleted, because a reader who saw the old one should be able to see what became of it.]
All three trials register two co-primary outcomes: percentage change in LDL-C from baseline to DAY 510, and the TIME-ADJUSTED percentage change after day 90 up to day 540. This pool uses the first. The selection is recorded nowhere. The two answer different questions about a drug given twice a year -- a single timepoint against an average across the dosing interval -- and a review that selects among registered options without recording the selection has made an analytic decision that cannot be audited from its own output. The estimate is not changed here: choosing the other co-primary is a content decision.
Read this beside the estimate. All three trials registered two co-primary outcomes: the percent change in LDL-C at Day 510, which this pool uses, and the TIME-ADJUSTED percent change from baseline after day 90 and up to day 540, which it does not. Pooling the other one by the same method gives -49.30 (-54.52 to -44.07) against this pool's -53.97 (-58.30 to -49.64). The choice of co-primary moves the headline by 4.7 percentage points, and until now this object said nowhere that a second one existed. Both are stored; neither is withdrawn; which one answers a given question is not a choice this page can make for a reader.
A cross-lane check reported this pool's point as wrong for its own estimand -- -53.97 against roughly -50.6 -- and its heterogeneity as largely an extraction artefact. Both were checked against the posted results on 2026-08-21 and neither holds. Every per-trial value here reproduces its registration's own Day-510 mean-difference analysis exactly: -49.52 (-55.04 to -43.99), -57.64 (-60.86 to -54.43), -53.50 (-56.66 to -50.35). The ~-50.6 is the other co-primary, recorded above. The reported defect was a comparison against a different estimand, and it is written here rather than dropped because a check that was run and did not hold is evidence too.
I-squared is 74.1% with tau-squared 10.60 on this pool. On the other co-primary it is 87.9% with tau-squared 18.89. The spread is not an artefact of how these numbers were read; it is larger on the estimand that was said to be cleaner.
| Dimension | Across the pooled cohorts | If it differs, why it is crossed anyway |
|---|---|---|
| effect measure | ESTABLISHED | all three are ancova mean differences in percent change in LDL-C, read from each trial's own registry results record |
| estimand | ESTABLISHED | all three registrations name percent change in LDL-C from baseline to Day 510 as their first primary outcome; the wording differs only between 'Percent' and 'Percentage' |
| Trial | Analysed treatment / control |
MD (95% CI), or events | Source of this cell |
|---|---|---|---|
| ORION-9 NCT03397121 | 242 / 240 | -49.52 (-55.05 to -44) | : |
| ORION-10 NCT03399370 | 781 / 780 | -57.64 (-60.86 to -54.42) | : |
| ORION-11 NCT03400800 | 810 / 807 | -53.5 (-56.66 to -50.34) | : |
This outcome's name is a concatenation of the trial-declared outcome titles the converter found. Here the concatenation is reassuring rather than alarming: it contains only two distinct strings for three trials, 'Percent Change in LDL-C From Baseline To Day 510' and 'Percentage Change in LDL-C From Baseline to Day 510', which differ by one word and denote the same quantity. Each trial's own registered definition is recorded beneath, and is rendered on this page under 'Endpoint definitions, read from the registry'.
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 |
|---|---|---|---|---|
| ORION-9 NCT03397121 | PRIMARY -- the FIRST of two registered co-primary outcomes. All three trials also register a TIME-ADJUSTED percent change from baseline after Day 90 and up to Day 540, which this review does NOT use. It is not used on any of the three, so the omission is uniform and does not mix estimands. | Percent Change in LDL-C From Baseline To Day 510 | The registry record carries no description for this outcome. The measure line above is the whole of what is registered. Nothing further was registered -- a different fact from nothing further having been read. | Least-squares mean from ancova; the registry reports the contrast as 'Mean Difference (Final Values)'. Population: heterozygous familial hypercholesterolaemia (HeFH). Randomised 242 inclisiran against 240 placebo/saline, which sums to this registration's own recorded enrolment exactly. |
| ORION-10 NCT03399370 | PRIMARY -- the FIRST of two registered co-primary outcomes. All three trials also register a TIME-ADJUSTED percent change from baseline after Day 90 and up to Day 540, which this review does NOT use. It is not used on any of the three, so the omission is uniform and does not mix estimands. | Percentage Change in LDL-C From Baseline to Day 510 | The registry record carries no description for this outcome. The measure line above is the whole of what is registered. Nothing further was registered -- a different fact from nothing further having been read. | Least-squares mean from ancova; the registry reports the contrast as 'Mean Difference (Final Values)'. Population: atherosclerotic cardiovascular disease (ascvd). Randomised 781 inclisiran against 780 placebo/saline, which sums to this registration's own recorded enrolment exactly. |
| ORION-11 NCT03400800 | PRIMARY -- the FIRST of two registered co-primary outcomes. All three trials also register a TIME-ADJUSTED percent change from baseline after Day 90 and up to Day 540, which this review does NOT use. It is not used on any of the three, so the omission is uniform and does not mix estimands. | Percentage Change in LDL-C From Baseline to Day 510 | The registry record carries no description for this outcome. The measure line above is the whole of what is registered. Nothing further was registered -- a different fact from nothing further having been read. | Least-squares mean from ancova; the registry reports the contrast as 'Mean Difference (Final Values)'. Population: Ascvd or ascvd risk-equivalents. Randomised 810 inclisiran against 807 placebo/saline, which sums to this registration's own recorded enrolment exactly. |
Two decisions. First, whether the pooled reduction depends on any single trial. Second, whether it depends on the between-study variance estimator and interval method -- which at k=3, with the house rule against REML below k=10, is not a formality but the reason this table exists. [restated 2026-08-20. This sentence was written while the pool was fitted with DerSimonian-Laird inverse-variance on extracted effect estimates. It is now REML, under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere." The estimate moved from -54.00144508917459 (-58.16516691761607 to -49.83772326073311) to -53.97 (-58.3 to -49.64) and tau-squared from 9.524722803298308 to 10.595364. The original wording is beside this under decision under test superseded 2026 08 20 -- a sentence that recorded a decision is restated, never deleted.]
| Cohort omitted | k | MD (95% CI) |
|---|---|---|
| orion-9 | 2 | -55.56 (-59.62 to -51.5) |
| orion-10 | 2 | -52.18 (-55.85 to -48.51) |
| orion-11 | 2 | -53.9 (-61.84 to -45.97) |
No single trial carries this result. Omitting each in turn gives -55.56 (-59.62 to -51.50), -52.18 (-55.85 to -48.51) and -53.90 (-61.84 to -45.97). All three exclude no effect and the pooled point moves by at most 1.8 percentage points on a scale of 54.
Cochrane Handbook version 6.5.1, section 10.10.4.4: methods other than DerSimonian and Laird estimate the between-study variance better, and restricted maximum likelihood is the RevMan default. Section 10.14 governs the leave-one-out half. Cited to 10.10.4.4 rather than 10.10.4.5 because 10.10.4.5 is about interpretation with few studies and the method it compares is the confidence interval, not the variance estimator -- a miscitation this repository has already made once and corrected.
Three between-study-variance estimators, each with Wald and Hartung-Knapp intervals. This pool is published under REML at k=3, and this project's own rule is REML or REML below k=10, so the first question a reader should be able to answer is whether that choice made the answer. [restated 2026-08-20. This sentence was written while the pool was fitted with DerSimonian-Laird inverse-variance on extracted effect estimates. It is now REML, under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere." The estimate moved from -54.00144508917459 (-58.16516691761607 to -49.83772326073311) to -53.97 (-58.3 to -49.64) and tau-squared from 9.524722803298308 to 10.595364. The original wording is beside this under why superseded 2026 08 20 -- a sentence that recorded a decision is restated, never deleted.]
| Between-study variance | Interval | Summary (95% CI) | τ² |
|---|---|---|---|
| DerSimonian-Laird (DL) | ordinary (Wald) | -54 (-58.17 to -49.84) | 9.525 |
| DerSimonian-Laird (DL) | Hartung-Knapp-Sidik-Jonkman (HKSJ) | -54 (-63.71 to -44.3) | 9.525 |
| Paule-Mandel (PM) | ordinary (Wald) | -53.95 (-58.4 to -49.51) | 11.36 |
| Paule-Mandel (PM) | Hartung-Knapp-Sidik-Jonkman (HKSJ) | -53.95 (-63.71 to -44.2) | 11.36 |
| restricted maximum likelihood (REML) | ordinary (Wald) | -53.97 (-58.3 to -49.64) | 10.6 |
| restricted maximum likelihood (REML) | Hartung-Knapp-Sidik-Jonkman (HKSJ) | -53.97 (-63.71 to -44.24) | 10.6 |
It did not. The point estimate spans -53.95 to -53.97 across all six combinations -- a range of five hundredths on a scale of fifty-four -- and every one of the six intervals excludes no effect, the widest by more than forty percentage points. The interval, not the point, is what the method changes: Wald gives about -58 to -50 and Hartung-Knapp about -64 to -44, roughly twice the width. At k=3 with I-squared of 72 per cent, hartung-knapp is the honest one, and the precision shown on the index card is optimistic even though its direction and magnitude are not in doubt. [restated 2026-08-20: this sentence carried the pooled estimate as it stood under DerSimonian-Laird inverse-variance on extracted effect estimates. The pool was refitted with REML under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere." and the estimate is now -53.97 (-58.3 to -49.64); the numbers in this sentence are updated and the original is beside it under verdict superseded 2026 08 20. Found by a number guard, not by the estimator guard -- a sentence can carry a superseded estimate without naming an estimator, and two such sentences survived this whole pass in the published comparison before one was noticed on the rendered page.
The published REML value is retained as the headline. It reproduces exactly, and moving a correct published number by five hundredths of a percentage point would break every reader's record for no gain. Whether the corpus headline should move to REML everywhere is a display-change policy question for the whole corpus, not a finding about this topic, and it is parked as such. [restated 2026-08-20. This sentence was written while the pool was fitted with DerSimonian-Laird inverse-variance on extracted effect estimates. It is now REML, under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere." The estimate moved from -54.00144508917459 (-58.16516691761607 to -49.83772326073311) to -53.97 (-58.3 to -49.64) and tau-squared from 9.524722803298308 to 10.595364. The original wording is beside this under estimator kept superseded 2026 08 20 -- a sentence that recorded a decision is restated, never deleted.]
In this section: Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 · 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
⬇ SVG (vector) 1 KB ⬇ PNG 4500x1090 117 KB
All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 94d7133203954930), 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, 4 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — forest_fit.tiff, 14,370 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. Ranges not offered because they would crop the data: 0.5 to 2, 0.25 to 4, 0.7 to 1.3.
⬇ SVG (vector) 2 KB ⬇ PNG 4500x2100 304 KB
All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 3f09ab5e1ee47485), 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: -58.3 to -49.64, with no difference at 0.
⬇ SVG (vector) 11 KB
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': 12, 'per domain total': 15, 'per domain rate pct': 80.0, 'overall agreed': 0, 'overall total': 3, '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.'}.
⬇ SVG (vector) 1 KB ⬇ PNG 3500x540 80 KB
All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: dd33d4f986f7c7c5), 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 3 trials is 7 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.
⬇ SVG (vector) 1 KB ⬇ PNG 3500x650 87 KB
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.
⬇ SVG (vector) 1 KB ⬇ PNG 3500x540 87 KB
All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 2316b730fa24744e), 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 = 3 a meta-regression would be fitted on 3 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 · Comparison with published syntheses · The syntheses reconciled against · Where the numbers differ, and why
| Outcome | k | Pooled effect | Certainty |
|---|---|---|---|
| Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | 3 | MD -54 (-58.3 to -49.6) | Pending12 |
| Canonical object | — |
|---|---|
| Registered at | — — |
| Schema | 2-converted-from-extractor |
| Object last updated | 2026-08-17T12:06Z |
| Source object SHA-256, first 16 hex characters | 62acb2b4ca79937c |
| Page generated | 2026-08-28 19:53 UTC |
| Generator build | a441e4187. The standard this page was built to is NOT ESTABLISHED: this object carries no build_stamp, so the version above is the standard that exists now, not the one this page was built against. |
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.
| Components as the registry states them | percent change in LDL-C from baseline to DAY 510. One continuous quantity, one anchor, one time point. No composite and no components. |
|---|---|
| Analysis set as the registry states it | Least-squares mean from ancova; the registry reports the contrast as 'Mean Difference (Final Values)'. Population: heterozygous familial hypercholesterolaemia (HeFH). Randomised 242 inclisiran against 240 placebo/saline, which sums to this registration's own recorded enrolment exactly. |
| Analysis set as the registry states it | Least-squares mean from ancova; the registry reports the contrast as 'Mean Difference (Final Values)'. Population: atherosclerotic cardiovascular disease (ascvd). Randomised 781 inclisiran against 780 placebo/saline, which sums to this registration's own recorded enrolment exactly. |
| Analysis set as the registry states it | Least-squares mean from ancova; the registry reports the contrast as 'Mean Difference (Final Values)'. Population: Ascvd or ascvd risk-equivalents. Randomised 810 inclisiran against 807 placebo/saline, which sums to this registration's own recorded enrolment exactly. |
| Estimator kept superseded | The published DerSimonian-Laird value is retained as the headline. It reproduces exactly, and moving a correct published number by five hundredths of a percentage point would break every reader's record for no gain. Whether the corpus headline should move to REML everywhere is a display-change policy question for the whole corpus, not a finding about this topic, and it is parked as such. |
| Decision under test superseded | Two decisions. First, whether the pooled reduction depends on any single trial. Second, whether it depends on the between-study variance estimator and interval method -- which at k=3, with the house rule against DerSimonian-Laird below k=10, is not a formality but the reason this table exists. |
| Caveats | What a reader should know anyway, none of which overturns the estimate. (1) the estimator is not this project's own standard for this k. REML underestimates between-study variance when k is small, and the house rule is REML or REML below k=10. This pool is k=3. It was recomputed under both: REML gives -53.95 (-58.40 to -49.51) with tau-squared 11.36, REML gives -53.97 (-58.30 to -49.64) with tau-squared 10.60, against DL's -54.00 (-58.17 to -49.84) with tau-squared 9.52. The point estimate moves by five hundredths of a percentage point on a scale of fifty-four. The choice of estimator does not change this answer, and the published value is retained rather than re-rounded, because moving a correct published number by 0.05 would break every reader's record for no gain. Whether the corpus headline should move to REML everywhere is a display-change policy question, not a finding about this topic. (2) heterogeneity is HIGH and k is small: Q = 7.14 on 2 degrees of freedom, I-squared 72 per cent. A Hartung-Knapp interval, which is the honest one at this k, is -63.71 to -44.30 -- much wider than the Wald interval on the card. The direction and the magnitude are not in doubt; the precision on the card is optimistic. (3) the three populations are not the same: orion-9 enrolled heterozygous familial hypercholesterolaemia, ORION-10 atherosclerotic cardiovascular disease, ORION-11 ascvd or risk-equivalents. That is a real clinical difference and the most likely source of the heterogeneity above. It is not an estimand difference -- all three measured the same thing on different people -- but it is why a single number should not be read as applying uniformly to all three groups. (4) ldl-c percent change is a surrogate. This review pools a laboratory value, not an event. Nothing here estimates an effect on death, myocardial infarction or stroke, and no such claim should be read into it. (5) one stored interval bound is reconstructed rather than read: orion-11's upper limit is held as -50.34 where the registry prints -50.35, a rounding artefact of recomputing the interval from a point estimate and a standard error. One hundredth of a percentage point, recorded because a reader comparing the two should not have to wonder whether it means something. [restated 2026-08-20: this pool is now fitted with REML under DECISIONS-COCHRANE-2026-08-18.md section 1, on Cochrane Handbook 6.5 section 10.10.4.4: "Decision: REML, everywhere.", so the caveat that its estimator was not this project's standard for its k no longer applies. The sentence is kept, restated, rather than deleted, because a reader who saw the old one should be able to see what became of it.] |
| Caveats superseded | What a reader should know anyway, none of which overturns the estimate. (1) the estimator is not this project's own standard for this k. DerSimonian-Laird underestimates between-study variance when k is small, and the house rule is REML or Paule-Mandel below k=10. This pool is k=3. It was recomputed under both: Paule-Mandel gives -53.95 (-58.40 to -49.51) with tau-squared 11.36, REML gives -53.97 (-58.30 to -49.64) with tau-squared 10.60, against DL's -54.00 (-58.17 to -49.84) with tau-squared 9.52. The point estimate moves by five hundredths of a percentage point on a scale of fifty-four. The choice of estimator does not change this answer, and the published value is retained rather than re-rounded, because moving a correct published number by 0.05 would break every reader's record for no gain. Whether the corpus headline should move to REML everywhere is a display-change policy question, not a finding about this topic. (2) heterogeneity is HIGH and k is small: Q = 7.14 on 2 degrees of freedom, I-squared 72 per cent. A Hartung-Knapp interval, which is the honest one at this k, is -63.71 to -44.30 -- much wider than the Wald interval on the card. The direction and the magnitude are not in doubt; the precision on the card is optimistic. (3) the three populations are not the same: orion-9 enrolled heterozygous familial hypercholesterolaemia, ORION-10 atherosclerotic cardiovascular disease, ORION-11 ascvd or risk-equivalents. That is a real clinical difference and the most likely source of the heterogeneity above. It is not an estimand difference -- all three measured the same thing on different people -- but it is why a single number should not be read as applying uniformly to all three groups. (4) ldl-c percent change is a surrogate. This review pools a laboratory value, not an event. Nothing here estimates an effect on death, myocardial infarction or stroke, and no such claim should be read into it. (5) one stored interval bound is reconstructed rather than read: orion-11's upper limit is held as -50.34 where the registry prints -50.35, a rounding artefact of recomputing the interval from a point estimate and a standard error. One hundredth of a percentage point, recorded because a reader comparing the two should not have to wonder whether it means something. |
| Stands because superseded | The pool STANDS, and every STEP of it was checked rather than assumed. The estimand is the same in all three registrations. ORION-9 registers 'Percent Change in LDL-C From Baseline To Day 510'; ORION-10 and ORION-11 register 'Percentage Change in LDL-C From Baseline to Day 510'. Same quantity, same anchor, same day, all three analysed by ancova and reported by the registry as a 'Mean Difference (Final Values)'. The only difference between the three strings is 'Percent' against 'Percentage' -- orthography, which is precisely the trap that has manufactured false disagreements in this repository before, and it is not one here. All three per-trial values are the registry's own, digit for digit: orion-9 -49.52 (-55.04 to -43.99), ORION-10 -57.64 (-60.86 to -54.43), ORION-11 -53.50 (-56.66 to -50.35). All three arm pairs sum to their registration's recorded enrolment exactly: 242+240=482, 781+780=1561, 810+807=1617. Arm labels and roles are correct on all three. And the pooled value reproduces: DerSimonian-Laird inverse-variance random effects on the three mean differences gives -54.0014 (-58.1652 to -49.8377), which is what the object holds and what the index card publishes, to four decimal places. The card, the object and the independent recomputation all agree. |
| Heterogeneity status superseded | Q = 7.1426 on 2 df, I-squared 72.0 per cent, tau-squared 9.52 under DerSimonian-Laird and 10.60 under REML. HIGH, and on only three studies. The Hartung-Knapp interval is -63.71 to -44.30. |
| Poolable reason superseded | The pool STANDS, and every STEP of it was checked rather than assumed. The estimand is the same in all three registrations. ORION-9 registers 'Percent Change in LDL-C From Baseline To Day 510'; ORION-10 and ORION-11 register 'Percentage Change in LDL-C From Baseline to Day 510'. Same quantity, same anchor, same day, all three analysed by ancova and reported by the registry as a 'Mean Difference (Final Values)'. The only difference between the three strings is 'Percent' against 'Percentage' -- orthography, which is precisely the trap that has manufactured false disagreements in this repository before, and it is not one here. All three per-trial values are the registry's own, digit for digit: orion-9 -49.52 (-55.04 to -43.99), ORION-10 -57.64 (-60.86 to -54.43), ORION-11 -53.50 (-56.66 to -50.35). All three arm pairs sum to their registration's recorded enrolment exactly: 242+240=482, 781+780=1561, 810+807=1617. Arm labels and roles are correct on all three. And the pooled value reproduces: DerSimonian-Laird inverse-variance random effects on the three mean differences gives -54.0014 (-58.1652 to -49.8377), which is what the object holds and what the index card publishes, to four decimal places. The card, the object and the independent recomputation all agree. |
| A two co primaries were registered and one is pooled | All three trials register two co-primary outcomes: percentage change in LDL-C from baseline to DAY 510, and the TIME-ADJUSTED percentage change after day 90 up to day 540. This pool uses the first. The selection is recorded nowhere. The two answer different questions about a drug given twice a year -- a single timepoint against an average across the dosing interval -- and a review that selects among registered options without recording the selection has made an analytic decision that cannot be audited from its own output. The estimate is not changed here: choosing the other co-primary is a content decision. |
| A each trial registered two co primaries and this pools one | Read this beside the estimate. All three trials registered two co-primary outcomes: the percent change in LDL-C at Day 510, which this pool uses, and the TIME-ADJUSTED percent change from baseline after day 90 and up to day 540, which it does not. Pooling the other one by the same method gives -49.30 (-54.52 to -44.07) against this pool's -53.97 (-58.30 to -49.64). The choice of co-primary moves the headline by 4.7 percentage points, and until now this object said nowhere that a second one existed. Both are stored; neither is withdrawn; which one answers a given question is not a choice this page can make for a reader. |
| B the extraction was checked against the registrations and is exact | A cross-lane check reported this pool's point as wrong for its own estimand -- -53.97 against roughly -50.6 -- and its heterogeneity as largely an extraction artefact. Both were checked against the posted results on 2026-08-21 and neither holds. Every per-trial value here reproduces its registration's own Day-510 mean-difference analysis exactly: -49.52 (-55.04 to -43.99), -57.64 (-60.86 to -54.43), -53.50 (-56.66 to -50.35). The ~-50.6 is the other co-primary, recorded above. The reported defect was a comparison against a different estimand, and it is written here rather than dropped because a check that was run and did not hold is evidence too. |
| C the heterogeneity is real and the alternative is worse | I-squared is 74.1% with tau-squared 10.60 on this pool. On the other co-primary it is 87.9% with tau-squared 18.89. The spread is not an artefact of how these numbers were read; it is larger on the estimand that was said to be cleaner. |
| Scope | inclisiran 284 mg, reported separately from the PCSK9 antibodies |
| Scope | network meta-analysis placing inclisiran against evolocumab, alirocumab, bempedoic acid and ezetimibe |
| What this denominator does not cover | The 51 records the screen retrieved and did not read. The check count is honest about the checks; the screen is separately honest about its own size in the appraisal file, and neither number should be read as the other. |
| What is not established | The concealment mechanism is not on the registry, and the published reports were not read. LOW is scored on the recorded allocation, not on a mechanism nobody here has seen. |
| Why this is not an adjudicated dispute | A blind second assessor from a different model family disagreed with this domain on 89% of judgements across 22 topics. That would ordinarily be a dispute to adjudicate. It is not one: the tool's own text names this exact evidential situation -- a bare statement that a study was randomised -- and prescribes the answer. The second assessor is not being deferred ; the guidance is being applied. |
| What the registry gives and does not | A ClinicalTrials.gov design module records `allocation: Randomized`. It carries no sequence-generation method and no allocation-concealment mechanism. The original judgement's own note said so before scoring LOW. |
| How this maps to the tool s algorithm | The tool maps 'No information' on 1.1 and 1.2 with no baseline concern to a domain judgement of some concerns. This project writes no information on the domain when it could not be judged from the sources read, and caps the overall at some concerns. Same place, and it keeps 'we could not judge this' distinguishable from 'we judged it and had concerns'. |
| What does not change | No overall rating and no GRADE CERTAINTY moves. All 51 judgements were already capped at some concerns or HIGH by another no information domain. |
| 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. |
| Why this profile differs from its siblings | Against empagliflozin: that result is an adjudicated time-to-event composite, so missing outcome data is LOW because censoring absorbs withdrawal and measurement of the outcome is LOW because a blinded committee adjudicates. Against icosapent: the same fixed-timepoint laboratory shape, but at DAY 510 rather than week 12, so the missing outcome data threat is materially larger for the same reasoning. selection of the reported result is some concerns here for a different reason than icosapent's -- there a dose arm was selected from three, here a co-primary was selected from two. |
| And it bounds a finding of ours | Class 94 records assessor 2 saying no information on the randomisation process/deviations from the intended intervention/missing outcome data `100 of 100`. Measured across all 23 topics now stored that is 239 of 243, and all four exceptions are the randomisation process=some concerns on `agyw-hiv-prep-review` and `cab-prep-hiv-review` -- two of the three topics asked under the earlier prompt build, the one whose reply ids are bare NCTs. Under that build it is 4 of 6; under the later build 0 of 75. The 100% was measured on the later build's topics. The two-defaults mechanism stands; its universality does not, and what varies with it is the prompt. |
| The rate is still conditional on the same allow list | Both numbers are conditional on the fact list in THE_ALLOW_LIST_THE_RATE_IS_CONDITIONAL_ON above. Neither is a rate of agreement between assessors in general. |
| Scope corrected | This topic is named `inclisiran-lipid-kidney` and it analyses no kidney outcome. Every result on this object is LDL-C percent change. No renal endpoint -- eGFR, albuminuria, kidney failure, dialysis -- is extracted, pooled, assessed for risk of bias or rated for certainty anywhere here. The slug is retained because it is the key a reader's URL resolves through and changing it would break a page a reader may already hold; the scope is corrected here instead. What this review covers: the effect of inclisiran on LDL-C. What it does not cover, despite its name: anything renal. |
| Which risk of bias domains drove the rating | Where a result is rated worse than LOW overall, the domain carrying that judgement is: selection of the reported result on 3 result(s). The overall rating is the worst domain, so these are the domains that determine it. |
Three trials, one drug, one endpoint, and every per-trial value posted by the registry -- so the trial-by-trial half of this comparison is complete in a way it cannot be where trials post no results. The error found is ours and it is in the table below with the same weight as anything found in the literature.
9 checks were applied and 6 came back clean, 1 found an error, 1 found something absent and 1 could not be settled at the layer available. The denominator is stated because a list of only the failures is not a finding, it is a selection.
Confirmations are listed in the same table, in the same detail, as errors. The one error found is ours -- an unrecorded selection between two registered co-primary endpoints -- and the published literature is implicated in none of the rows. That is the same result every cardiology topic reconciled in this corpus has produced, and a comparison with room only for their errors could not have found it out.
| Check | Verdict | What was found |
|---|---|---|
| ORION-9 (NCT03397121), this review's stored mean difference against the registry's own posted arm values per-trial-vs-registry-orion-9 | CONFIRMED checked and clean | The registry posts -41.15% in the inclisiran arm and 8.37% in the control arm for 'Percent Change in LDL-C From Baseline To Day 510'. Their difference is -49.52. This object stores -49.52. Identical, and the arithmetic is shown rather than asserted so a reader can repeat it. Quoted: “Percent Change in LDL-C From Baseline To Day 510: -41.15 vs 8.37” — https://clinicaltrials.gov/study/NCT03397121, results section |
| ORION-10 (NCT03399370), this review's stored mean difference against the registry's own posted arm values per-trial-vs-registry-orion-10 | CONFIRMED checked and clean | The registry posts -56.34% in the inclisiran arm and 1.3% in the control arm for 'Percentage Change in LDL-C From Baseline to Day 510'. Their difference is -57.64. This object stores -57.64. Identical, and the arithmetic is shown rather than asserted so a reader can repeat it. Quoted: “Percentage Change in LDL-C From Baseline to Day 510: -56.34 vs 1.3” — https://clinicaltrials.gov/study/NCT03399370, results section |
| ORION-11 (NCT03400800), this review's stored mean difference against the registry's own posted arm values per-trial-vs-registry-orion-11 | CONFIRMED checked and clean | The registry posts -49.3% in the inclisiran arm and 4.2% in the control arm for 'Percentage Change in LDL-C From Baseline to Day 510'. Their difference is -53.50. This object stores -53.50. Identical, and the arithmetic is shown rather than asserted so a reader can repeat it. Quoted: “Percentage Change in LDL-C From Baseline to Day 510: -49.3 vs 4.2” — https://clinicaltrials.gov/study/NCT03400800, results section |
| Arm participant counts summed per trial arm-totals | CONFIRMED checked and clean | ORION-9 482; ORION-10 1561; ORION-11 1617. Their total is 3660, which is the n reported by the 2020 meta-analysis below over 3 randomised trials -- the arithmetic that identifies its trial set as this review's. inputs.trials[].arms |
| 'Percent Change' on ORION-9 against 'Percentage Change' on ORION-10 and -11 estimand-orthography | CONFIRMED checked and clean | The three registered titles differ by one word and denote the same quantity at the same anchor and the same day, all three analysed by ancova and posted by the registry as a mean difference. This object already establishes it. It is listed here because orthographic difference is what has manufactured false disagreements in this repository before, and a check that finds nothing is still a check. Quoted: “Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510” — inputs.trials[].registration_primary_counts.title |
| Which of each trial's two registered co-primary LDL endpoints this review used co-primary-selected-without-record | ERROR a defect, in the source named | All three ORION trials register two primary outcomes, read from `registration other outcome counts` on this object: percent change in LDL-C from baseline to day 510, and time-adjusted percent change from baseline after day 90 and up to day 540. This review uses the day-510 endpoint on all three. The consistency is the good news -- the pool is not mixing endpoints, which is what would make it unpoolable. The defect is that the selection is nowhere recorded. Choosing between two registered co-primaries is an analytic decision, and this one is invisible from the object because the object simply holds one of the two. A reader cannot tell that a choice was made, let alone which. This is recorded as OUR error, not the literature's. Quoted: “Time-adjusted Percent Change in LDL-C From Baseline After Day 90 and up to Day 540” — inputs.trials[].registration_other_outcome_counts[type=primary] |
| This review's pooled value against a 2020 meta-analysis of what the arithmetic says are the same three trials ours-vs-khan-2020-same-trials | UNRESOLVED could not be settled at the layer available | Khan et al. 2020 report LDL-C lowered by 51% (48 to 53) over 3 RCTs with 3,660 patients. This review's three trials sum to 3,660 participants, and the trials were published five months before that paper, so its trial set is almost certainly this one -- but that is arithmetic and timing, not a read trial list, and it is recorded as such. This review reports -53.97% (-58.30 to -49.64). The intervals overlap and neither result changes the reading, but the point estimates differ by about three percentage points. The leading candidate is the co-primary endpoint above: their value may be the time-adjusted day 90 to 540 endpoint where ours is day 510. That cannot be decided from an abstract, so it is left unresolved rather than explained. Quoted: “inclisiran decreased LDL cholesterol levels by 51% (95% Confidence Interval, 48 to 53%; p < 0.001) compared with placebo” — PMID 32892993, doi 10.1016/j.amjcard.2020.08.018 |
| This review's pooled value against a 2023 meta-analysis reporting inclisiran 284 mg separately ours-vs-imran-2023 | CONFIRMED checked and clean | Imran et al. 2023 report inclisiran 284 mg reducing LDL-C by -54.83% (-59.04 to -50.62) over 4 studies with 9,522 participants. This review reports -53.97% (-58.30 to -49.64) over 3. A broader trial set including ORION-1 and a larger population, landing within one percentage point of this review's point estimate with heavily overlapping intervals. Quoted: “Inclisiran 284mg reduced LDL-c by -54.83% (95% CI: -59.04, -50.62)” — PMID 38055686, doi 10.1371/journal.pone.0295359 |
| This review's pooled value against pooled real-world observational data ours-vs-real-world | ABSENT the thing checked for is not there | Alaiz et al. 2025 pool 7 real-world studies with 1,454 patients and report a 42.77%% reduction (37.42 to 48.12), and attribute the gap against trial estimates to baseline LDL-C differences and real-world adherence. This is not a check on either number: a randomised placebo-corrected percent change and a single-arm observational change are different quantities, and neither can confirm the other. It is listed because a reader asking 'does this hold in practice' is asking a question this review does not answer, and the honest response is to name the study that does and say why it is not comparable. Quoted: “an average c-LDL reduction of 42.77% (95% CI: 37.42-48.12%)” — PMID 40565909, doi 10.3390/jcm14124163 |
| 32892993 | Khan SA, Naz A, Qamar Masood M, Shah R. Meta-Analysis of Inclisiran for the Treatment of Hypercholesterolemia. Am J Cardiol 2020;134:69-73. doi 10.1016/j.amjcard.2020.08.018 By arithmetic and timing it pools this review's own three trials -- its n of 3,660 is exactly their summed arm counts, and it was published five months after they reported. Its -51% (48 to 53) against this review's -53.97% is therefore a difference in extraction OR endpoint rather than in trial set, which is what makes it the most informative row here. |
|---|---|
| 38055686 | Imran TF, et al. PCSK9 inhibitors and small interfering RNA therapy for cardiovascular risk reduction: a systematic review and meta-analysis. PLoS One 2023;18(12):e0295359. doi 10.1371/journal.pone.0295359 Four inclisiran studies rather than three, across a broader population. Lands within one percentage point of this review. |
| 40565909 | Alaiz AR, et al. Inclisiran: Efficacy in Real World -- Systematic Review and Meta-Analysis. J Clin Med 2025;14(12):4163. doi 10.3390/jcm14124163 A different design, not a different trial set: single-arm observational change against a randomised placebo-corrected difference. It cannot confirm or contradict this review and is listed so the reader knows the question was asked. |
| 35262430 | Burnett H, et al. Comparative efficacy of non-statin lipid-lowering therapies in patients with hypercholesterolemia at increased cardiovascular risk: a network meta-analysis. Curr Med Res Opin 2022;38(5):777-784. doi 10.1080/03007995.2022.2049164 A different question -- relative efficacy between active agents, not the size of the effect against placebo. Its own reported heterogeneity is 'roughly equivalent to variation of 5-10% change in LDL-C', which is larger than the gap between this review and Khan 2020. |
| This review | Mean difference -53.97% (-58.30 to -49.64) in LDL-C percent change from baseline to day 510, k=3, random effects, REML. |
|---|---|
| The published synthesis | -51% (48 to 53) over what is by arithmetic the same three trials; -54.83% (-59.04 to -50.62) over four; -42.77% (37.42 to 48.12) over seven real-world cohorts; and a network analysis reporting relative rather than absolute effect. |
| Why they differ | Not by trial set, which is the unusual and useful thing about this comparison. The closest synthesis pools the same three trials and differs by about three percentage points, so the difference is in extraction or in which registered co-primary was taken -- day 510, or time-adjusted day 90 to 540. This review's own selection between those two is consistent across all three trials and was never recorded, which is the error listed above. The broader syntheses agree with this review closely; the real-world pooling does not, and its own authors attribute that to baseline LDL-C and adherence rather than to either estimate being wrong. |
How they were identified: PubMed E-utilities; query, counts and a per-record decision in ssot/inclisiran-lipid-kidney-auto-full-review/appraisal/the screen of published syntheses.json. 61 records matched, 30 retrieved, 10 appraised. The remaining 51 were not read and that is stated in the screen file rather than left to be inferred from the number.
In this section: Paper · Title · Abstract · Introduction · Methods — search · Methods — eligibility criteria · Methods — synthesis · Results · Risk of bias in the included results · Certainty of the evidence · Comparison with published syntheses · Limitations · Software availability · Note on registration · References · Figures · Trial characteristics · Not reported in this record
Each statement below cites the record it came from; those sources are listed at the end of every section. Where the record holds nothing, the section says so by name rather than being left out, so a procedure that was not carried out can be told from one that simply was never mentioned.
Inclisiran for elevated low-density lipoprotein cholesterol in HeFH, ascvd or ASCVD-risk equivalents1
This topic is named `inclisiran-lipid-kidney` and it analyses no kidney outcome. Every result on this object is LDL-C percent change. No renal endpoint -- eGFR, albuminuria, kidney failure, dialysis -- is extracted, pooled, assessed for risk of bias or rated for certainty anywhere here. The slug is retained because it is the key a reader's URL resolves through and changing it would break a page a reader may already hold; the scope is corrected here instead. What this review covers: the effect of inclisiran on LDL-C. What it does not cover, despite its name: anything renal.2
titleSCOPE_CORRECTED_2026_08_21Question. In Inclisiran for elevated low-density lipoprotein cholesterol in HeFH, ascvd or ASCVD-risk equivalents, what do the contributing trials show?1
Methods. estimates were pooled under a random-effects model with the REML estimator; risk of bias was assessed with RoB 2 (Cochrane risk-of-bias tool for randomized trials); and certainty was rated with GRADE, following the Cochrane Handbook chapter 14. Randomised evidence starts HIGH and is rated down with reasons.2
Results. Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510: mean difference -54 (-58.3 to -49.6) across 3 trials; 1 of these pooled outcome(s) carries a stated qualification -- a referral or a recorded finding -- given in full in Results and not reproduced here; and no statistical heterogeneity was detected (I-squared 74.1%).3
questionresults.by_outcome, risk_of_bias.by_outcome, grade.by_outcomeresults.by_outcomeBackground. This review asks: In Inclisiran for elevated low-density lipoprotein cholesterol in HeFH, ascvd or ASCVD-risk equivalents, what do the contributing trials show? It pools 3 randomised trials. The outcome pooled is Multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510.1
manuscript.introductionPrimary trials. No bibliographic search for primary trials was run. The 3 included trials were identified by reading named registrations on the dates recorded on each entry. The basis on which this object was verified is not recorded. What this object does not claim is not recorded. The bar this object had to clear is not recorded.1
bookkeeping_2026_08_21.the_search_its_date_and_its_databasesnot recorded on the page this object was extracted from1
screening.eligibilityFor multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510, a random-effects model was fitted with the REML estimator.1
Risk of bias was assessed with RoB 2 (Cochrane risk-of-bias tool for randomized trials) , following . 3 result-level assessments were made.2
A ceiling applies to every risk-of-bias judgement in this review; it is stated with the assessment itself rather than summarised here.3
Certainty of evidence was rated with GRADE, following the Cochrane Handbook chapter 14. Randomised evidence starts HIGH and is rated down with reasons., following . 1 pooled outcome(s) were rated. No domain is rated UP. Rating up for a large effect or a dose-response gradient applies to observational evidence that has not already been rated down, and neither condition holds here.4
results.by_outcome.primary.model, results.by_outcome.primary.estimator_usedrisk_of_bias.tool, risk_of_bias.by_outcomerisk_of_bias.ceilinggrade.approach, grade.by_outcomeThe pooled mean difference for multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 was -54 (-58.3 to -49.6) across 3 trials.1
Noted on this pool. All three trials register two co-primary outcomes: percentage change in LDL-C from baseline to DAY 510, and the TIME-ADJUSTED percentage change after day 90 up to day 540. This pool uses the first. The selection is recorded nowhere. The two answer different questions about a drug given twice a year -- a single timepoint against an average across the dosing interval -- and a review that selects among registered options without recording the selection has made an analytic decision that cannot be audited from its own output. The estimate is not changed here: choosing the other co-primary is a content decision. Read this beside the estimate. All three trials registered two co-primary outcomes: the percent change in LDL-C at Day 510, which this pool uses, and the TIME-ADJUSTED percent change from baseline after day 90 and up to day 540, which it does not. Pooling the other one by the same method gives -49.30 (-54.52 to -44.07) against this pool's -53.97 (-58.30 to -49.64). The choice of co-primary moves the headline by 4.7 percentage points, and until now this object said nowhere that a second one existed. Both are stored; neither is withdrawn; which one answers a given question is not a choice this page can make for a reader. A cross-lane check reported this pool's point as wrong for its own estimand -- -53.97 against roughly -50.6 -- and its heterogeneity as largely an extraction artefact. Both were checked against the posted results on 2026-08-21 and neither holds. Every per-trial value here reproduces its registration's own Day-510 mean-difference analysis exactly: -49.52 (-55.04 to -43.99), -57.64 (-60.86 to -54.43), -53.50 (-56.66 to -50.35). The ~-50.6 is the other co-primary, recorded above. The reported defect was a comparison against a different estimand, and it is written here rather than dropped because a check that was run and did not hold is evidence too. I-squared is 74.1% with tau-squared 10.60 on this pool. On the other co-primary it is 87.9% with tau-squared 18.89. The spread is not an artefact of how these numbers were read; it is larger on the estimand that was said to be cleaner.2
The trials' results were loosely consistent with one another: I-squared, the share of the variation between them that is more than chance alone would produce, was 74.1%; the estimated variance of the true effects between trials (tau-squared) was 10.6, the heterogeneity test statistic Q was 7.14, on degrees of freedom 2. Q = 7.1426 on 2 df, I-squared 74.1 per cent, tau-squared 10.60 under REML.3
The full model output for every pooled outcome -- the call, the estimator, the heterogeneity statistics and the back-transformed interval -- is stored verbatim on this review object at `results.by_outcome.<outcome>.r_output.verbatim`. It is not reproduced as an Extended data section in this article; an earlier version of this sentence said it was, and no such section exists.4
outcomes[id=primary].name, results.by_outcome.primary.pooledresults.by_outcome.primary.POOL_FINDINGS_2026_08_20, results.by_outcome.primary.POOL_FINDINGS_2026_08_21results.by_outcome.primary.heterogeneity.i2, results.by_outcome.primary.heterogeneity.tau2, results.by_outcome.primary.heterogeneity.q, results.by_outcome.primary.heterogeneity.df, results.by_outcome.primary.heterogeneity_statusresults.by_outcomeRisk of bias was assessed with RoB 2 at the level of each reported result, by two assessors reading independently. Their judgements differ on 3 of the 3 results and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Assessor 1 recorded: 3 at some concerns. Assessor 2 recorded: 3 at no information. Both are shown in the risk-of-bias table; neither is the review's finding. The per-domain judgements behind them are recorded with the extracted data.1
risk_of_bias.SECOND_ASSESSOR_2026_08_21.DISAGREEMENT_RATE, risk_of_bias.SECOND_ASSESSOR_2026_08_21.PER_DOMAIN, risk_of_bias.SECOND_ASSESSOR_2026_08_21.RECOUNTED_AFTER_THE_D1_RESOLUTION_2026_08_21, risk_of_bias.SECOND_ASSESSOR_2026_08_21.assessor_1, risk_of_bias.SECOND_ASSESSOR_2026_08_21.each_disagreement, risk_of_bias.SECOND_ASSESSOR_2026_08_21.how_it_was_asked, risk_of_bias.ceiling.statement, risk_of_bias.toolCertainty was rated with GRADE, following the Cochrane Handbook chapter 14. Randomised evidence starts HIGH and is rated down with reasons..1
No domain is rated UP. Rating up for a large effect or a dose-response gradient applies to observational evidence that has not already been rated down, and neither condition holds here.2
This certainty rating is pending, not rated. It rests on a risk-of-bias judgement that this review has not finalised: two assessors read every contributing result independently, they disagree, and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Cochrane rates certainty per outcome by aggregating the risk-of-bias judgements of the results contributing to it, so a certainty rating cannot be more final than the risk-of-bias assessment it reads. The rating this object currently records, and the steps behind it, are shown below as the work so far rather than as this review's answer. No level is published for this outcome -- not the recorded one, not a more cautious one, and not a midpoint -- because choosing one would be the judgement that has not been made.3
Certainty VERY_LOW. The risk-of-bias domain reads the per-result RoB 2 assessments made 2026-08-20 and named above, not a topic-level summary; indirectness reads the estimand findings recorded on this pool.4
Where a result is rated worse than LOW overall, the domain carrying that judgement is: selection of the reported result on 3 result(s). The overall rating is the worst domain, so these are the domains that determine it.5
| Outcome | Certainty | k | Started at | Rating steps |
|---|---|---|---|---|
| multiple trial-declared outcomes: Percent Change in LDL-C From Baseline To Day 510 | Percentage Change in LDL-C From Baseline to Day 510 | Pending | 3 | HIGH | the steps taken so far, not a final rating: risk of bias: HIGH to MODERATE, down 1 level(s) -- all three results are some concerns on selection of the reported result: each trial registers two co-primaries -- percentage change in LDL-C at DAY 510 and the TIME-ADJUSTED change after day 90 to day 540 -- and this review pools the first with no record of the choice. missing outcome data is no information and the threat is larger than icosapent's for the same reason at a different scale: a fixed measurement at DAY 510 is roughly seventeen months of attrition risk against twelve weeks. (rating: serious); inconsistency: MODERATE to LOW, down 1 level(s) -- I-squared is 74.1% with tau-squared 10.6 over k=3. Handbook 10.10.2 warns against reading I-squared mechanically, and at this k the estimate is imprecise -- but the point estimates themselves differ materially and the direction of the finding does not rest on the statistic alone. (rating: serious); indirectness: LOW to VERY_LOW, down 1 level(s) -- the pooled co-primary is one of two and the selection is unrecorded. Each ORION trial registers percentage change in LDL-C at DAY 510 and, equally ranked, the TIME-ADJUSTED percentage change from day 90 to day 540. For an agent dosed twice yearly those are different questions: a single timepoint against an average across the dosing interval, and the time-adjusted measure is the one that reflects the between-dose trough. A reader given the day-510 value alone is given the more favourable of two registered framings with no indication that a second exists. (rating: serious); imprecision: not rated down -- k=3 with 482, 1561 and 1617 participants -- 3,660 in total -- and an interval of -58.3 to -49.64 that is narrow relative to the effect and far from the null. Optimal information size is met for a continuous lipid endpoint at this scale. Handbook 15.6.2. Not rated down, and this is the domain on which inclisiran differs from the other two. (rating: not serious); publication bias: not rated down -- not assessed rather than assessed as ABSENT. Funnel-plot asymmetry and its tests are uninformative below about ten studies -- Handbook 13.3.5.4 -- and these pools carry two or three. 'Undetected' here means nobody looked with an instrument that could see, not that publication bias is unlikely. Not rated down, because rating down on an unmeasurable domain would invent a defect. (rating: undetected) |
grade.approachgrade.not_rated_uprisk_of_bias.by_outcomegrade.by_outcome.primary.summarybookkeeping_2026_08_21.which_risk_of_bias_domains_drove_the_ratinggrade.by_outcome.primaryPublished syntheses were identified as follows. PubMed E-utilities; query, counts and a per-record decision in ssot/inclisiran-lipid-kidney-auto-full-review/appraisal/the screen of published syntheses.json. 61 records matched, 30 retrieved, 10 appraised. The remaining 51 were not read and that is stated in the screen file rather than left to be inferred from the number.1
published_comparison._how_identifiedWhat this review does not give a clinician: any measure of harm. A relative effect cannot be turned into the benefit or the risk facing one patient without them, so this review can support a judgement about what these trials found and not a judgement about what to do.1
results.by_outcomeAnalyses were computed under R 4.6.0 with metafor 5.0.1.1
results.by_outcomeNo PROSPERO registration or protocol record is held on this object. That is not the same as knowing this review was not registered, and neither claim is made. It is recorded here as an absence so that a reader does not have to infer it from silence.1
bookkeeping_2026_08_21.whether_this_review_was_prospectively_registered| Trial | Registration | Registry | Read |
|---|---|---|---|
| NCT03397121 | ClinicalTrials.gov | ||
| NCT03399370 | ClinicalTrials.gov | ||
| NCT03400800 | ClinicalTrials.gov |
| Cited for | Reference |
|---|---|
| risk of bias in the included results | Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898 |
| certainty of the evidence | Schunemann HJ, Higgins JPT, Vist GE, et al. Chapter 14: Completing 'Summary of findings' tables and grading the certainty of the evidence. In: Cochrane Handbook for Systematic Reviews of Interventions version 6.5. Cochrane; 2024. |
| the model fitted, as R 4.6.0 with metafor 5.0.1 | Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36(3):1-48. doi:10.18637/jss.v036.i03 |
| the reporting guideline this manuscript is written against | Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71 |
manuscript.referencesmanuscript.referencesresults.by_outcome.primary.per_trial, results.by_outcome.primary.pooledresults.by_outcome.primary.per_trial, results.by_outcome.primary.pooled| Registration | Trial | Participants | Randomised | Primary outcome measured over | Design |
|---|---|---|---|---|---|
| NCT03397121 | ORION-9 | not recorded on the page this object was extracted from | 482 | Baseline, Day 510; Baseline, Day 90 | Inclisiran (treatment, n=242) vs Placebo (control, n=240) [+2 further fields recorded on the object] |
| NCT03399370 | ORION-10 | not recorded on the page this object was extracted from | 1561 | Baseline, Day 510; Baseline, Day 90 to Day 540 | Inclisiran (treatment, n=781) vs Saline Solution (control, n=780) [+2 further fields recorded on the object] |
| NCT03400800 | ORION-11 | not recorded on the page this object was extracted from | 1617 | Baseline, Day 510; Baseline, Day 90 to Day 540 | Inclisiran (treatment, n=810) vs Saline Solution (control, n=807) [+2 further fields recorded on the object] |
inputs.trialsThe items below were not written because the record does not hold what they would be composed from. They are named here so that an absence is not mistaken for an omission.
| Article area | Item not reported | Reason |
|---|---|---|
| Abstract | The Background sentence of the abstract | Background is argument -- why this question matters -- and no arrangement of the quantities this object holds yields it. It is emitted only from an authored field and there is no composition path for it here |
| Abstract | The Conclusions sentence of the abstract | A conclusion is argument -- what a reader should now believe -- and it is emitted only from an authored field. Composing one from the estimate would be this renderer telling the reader what to conclude, which no field supports |
| Methods — search | A database search for primary trials, which was not carried out for this review; the included trials were identified from named registrations | No further reason is recorded. |
| Methods — how many studies at each stage | The k cascade | No further reason is recorded. |
| Methods — outcomes sought at every registered rank | The statement that outcomes were sought below the primary | No further reason is recorded. |
| Methods — synthesis | The claim that records were screened in duplicate by two independent reviewers | No further reason is recorded. |
| Methods — synthesis | The claim that the review methods were prespecified before data collection | No further reason is recorded. |
| Funding and conflicts of interest | The funding and conflict-of-interest statement -- a content gap | A submission requires it and this object does not carry it; it is not inferable from anything held here |
| Note on registration | The registration note | No further reason is recorded. |
UNSTAMPED — unknown-version. This page carries no build_stamp, so the standard it was built to cannot be established. That is a statement about the record, not a claim that the page is below standard.
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.