Statins vs placebo/control for primary prevention in older adults

Overview

Statins vs placebo/control for primary prevention in older adults

In older adults (>=70 years) without established cardiovascular disease, do statins versus placebo/control reduce major vascular events?

Primary outcome

Transparency (independently checkable)

14 of 14 numerical claims on this page (100%) carry a one-click source a reader can open to check independently — each pooled number its PMID/NCT and verbatim span, each declared-absent trial its reason, each risk-of-bias domain the structured field it read, the reproduction its protocol SHA and replay result. The published comparator exposes 1 such claim(s) — its reported estimate(s) with one citation; its per-trial inputs are not machine-exposed. Score: scripts/transparency_score.py (committed docs/transparency.json).

Stated limitations

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

Protocol

# Protocol - statins for primary prevention in older adults

**Registration.** The commit adding this file registers the review; its SHA is embedded
in the page's Protocol tab and Reproducibility tab. The protocol is committed before
the synthesis is run.

## PICO
- **P** - older adults (>=70 years) without established cardiovascular disease.
- **I** - statin therapy, including rosuvastatin, pravastatin, or atorvastatin.
- **C** - placebo, usual care, or no-statin control.
- **O (primary)** - major vascular events / major cardiovascular events.
- **O (harms)** - muscle symptoms/myopathy; new-onset diabetes.

## Estimand / population / timepoint
- **Estimand** - risk ratio (RR), statin vs placebo/control.
- **Population** - intention-to-treat as randomised.
- **Timepoint** - trial end.

## Eligibility - on P/I/C/DESIGN ONLY
Include a record iff all hold:
- **I1** - randomised controlled trial or randomised trial analysis;
- **I2** - title-level or registry-condition population is older/elderly adults;
- **I3** - title-level or registry intervention is a statin or statin name;
- **I4** - comparator is placebo, usual care, or control;
- **design** - randomised statin allocation; double-blinding is not required because
  usual-care trials are eligible.

Exclude (reason must be true of the record):
- **X1** - not an RCT (review, guideline, observational, protocol-only, or PubMed record
  not indexed as a randomized controlled trial by the fixed screen);
- **X2** - wrong population (e.g. heart failure, atrial fibrillation, prior stroke,
  acute coronary syndrome, coronary disease, perioperative/non-cardiovascular disease);
- **X3** - wrong intervention/comparison (no statin-vs-placebo/usual-care/control contrast);
- **X5** - off-topic: a primary trial of another disease/topic in this set (negative control).

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

## Search (fetch-once; raw results committed under cache/<slug>/records.json; screening replays offline)
- PubMed: focused statin-title searches for JUPITER older-person analyses, ALLHAT-LLT
  older-adult primary-prevention analyses, and STAREE older-adult atorvastatin reports.
- ClinicalTrials.gov: condition "Elderly", intervention "Atorvastatin".
- Comparator reference seeding is disabled for this topic because the resolved open-access
  comparator is an observational review; its reference list is not an RCT recall set for
  a randomized statin-vs-control harness.

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

## Comparator (resolved; open-access confirmed)
Huang, Zhu, and Ya, *Reviews in Cardiovascular Medicine* 2022, "Statin use in older
people primary prevention on cardiovascular disease: an updated systematic review and
meta-analysis" (PMID 39076238, PMCID PMC11273788, DOI 10.31083/j.rcm2304114; Unpaywall
is_oa=true). It reports total cardiovascular events HR 0.75 (95% CI 0.66-0.85) in older
primary-prevention statin users versus no-statin users. This is an external benchmark,
not an RCT-only comparator; exact RCT-only elderly primary-prevention meta-analyses
found during resolution were not open access.

## Controls
- **Positive** - the search must recover and include the JUPITER older-person rosuvastatin
  analysis (PMID 20404379) and ALLHAT-LLT older-adult pravastatin analyses (PMIDs
  28531241 and 30251369).
- **Negative** - CORONA (rosuvastatin in older patients with systolic heart failure,
  PMID 17984166 - different disease/topic) must be recovered and EXCLUDED as wrong
  population.

Search

Source status (which adapters ran)

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

Registry-first recall (reach)

Registry-first RECALL: recovered 1/3 of this topic's known trials (enumerated 129; status RAN_OK). 2 missed trial(s) have no own-publication registry linkage — unregistered / pre-registration-era, so unreachable by any registry-first search (a property of the literature, not a search failure). Missed: 20404379, 30251369. Measured 2026-09-11T23:39:14Z. Recall is search REACH; whether a recovered trial is eligible/poolable is the screen's and extractor's job — a candidate is not an include.

Registry landscape & unpublished evidence (AACT)

Of 129 registry records matching the query (broad — reach, not precision): 54 have a linked publication; 10 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 33 are completed ≥12 months ago with neither results nor a linked publication — a loose upper bound on non-publication, inflated by the broad enumeration and by NCT→PMID linkage misses, not a publication-bias claim. AACT 2026-08-30 (local snapshot).

PubMed

(rosuvastatin[Title] AND "primary prevention"[Title/Abstract] AND "older persons"[Title/Abstract])

(("Statin Treatment"[Title] AND "Usual Care"[Title] AND "Older Adults"[Title]) OR ("Pravastatin"[Title] AND "Primary Prevention"[Title] AND "Older Adults"[Title/Abstract]))

(atorvastatin[Title] AND "primary prevention"[Title/Abstract] AND "older adults"[Title/Abstract])

ClinicalTrials.gov

{"cond": "Elderly", "intr": "Atorvastatin"}

Screening

Study selection flow (PRISMA 2020)

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

Dual independent screening (PRISMA item 8)

Two independently-implemented rule screeners over 28 records: agreement 25/28, disagreement 10.7% (3 records). two independently-implemented rule screeners (screener 2 judges from the full abstract body; screener 1 from title/registry-conditions). Adjudicator: screener 1. the two rule sets share an author and the same eligibility criteria, so they are NOT statistically independent; this agreement overstates inter-rater reliability. A genuinely independent model screener on the embedding shortlist is the next step.

Independent model adjudication of the disagreements

A capable model (different information + method than the two correlated rule sets) adjudicated 3 content-bearing disagreements; it agrees with the served rule screener on 3/3. an independent capable-model reader adjudicated the rule-screener disagreements (different information + method than the two correlated rule sets). Advisory: the rule screener remains the served decision; flags are surfaced for review. Flags: none — the model agrees with the served rule screener on all of them

Trial integrity: none of the 1 trials pooled across all outcomes on this page is retracted (checked 2026-09-11T23:50:16Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

28 records screened; 4 included. Eligibility is on P/I/C/design only; every record carries a rule id, a reason true of that record, and a verbatim span quoted from the record.

Controls

• Positive: Recovered & included the canonical trials ['20404379', '28531241', '30251369'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['17984166'] recovered by the search and correctly EXCLUDED ['17984166'] by rule (same drug/design, wrong topic).

Results

Major vascular events (primary)

k = 1: the 1 trial(s) named below were pooled; 3 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Muscle symptoms/myopathy

New-onset diabetes

Comparator

Total cardiovascular events / major vascular events: 0.75 (HR), 95% CI 0.66–0.85

Scope match (is this the same question?)

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

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

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

Risk of bias

Coverage: 0 of 1 primary-outcome pooled trials have a registry (AACT) match and are assessed below; the other 1 are pooled but have no registry match (20404379) and are shown as not assessed with the reason — never guessed.

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

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

GRADE certainty (partial, object-derived)

Manuscript

Abstract

Question. In older adults (>=70 years) without established cardiovascular disease, do statins versus placebo/control reduce major vascular events?

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 036ee46c6c45); a registry-first search was screened by two independent rule screeners with adjudication (28 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. A single eligible trial contributed an extractable estimate: HR 0.61 (95% CI 0.46 to 0.81); with k=1 no between-trial heterogeneity or prediction interval is estimable. 3 eligible trial(s) were declared absent for this outcome (reported reason on each).

Certainty. Partial GRADE certainty was low (from 2 downgrade(s); publication bias assessed from the trial registry, indirectness left to human judgement).

Methods

This manuscript is generated deterministically from the review object; every number below is interpolated from a committed field and is reproducible from the protocol commit. The protocol (SHA 036ee46c6c45) was committed before any synthesis ran. Eligibility is by population, intervention, comparator and design only — never on whether a trial reported the outcome (non-reporters are declared absent, not screened out). Two independently implemented rule screeners ran with adjudication. Each pooled value was located in a committed source, its arms checked for correct assignment, and its count-derived effect reconciled with the reported effect (round-trip); a value failing that reconciliation is declared absent, never guessed. Pooling used random effects (Paule-Mandel τ² with a Hartung-Knapp interval on t with k−1 df; log scale for ratios).

Results

A single eligible trial contributed an extractable estimate: HR 0.61 (95% CI 0.46 to 0.81); with k=1 no between-trial heterogeneity or prediction interval is estimable.

Risk-of-bias sensitivity. 0 of 1 pooled trials carry a risk-of-bias rating; no trial is rated high risk. a low-risk-only subpool was not estimable.

Limitations

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

Data availability & reproduction

The committed cache, protocol (SHA 036ee46c6c45) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py statins-primary-prevention-elderly

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

Reporting (PRISMA)

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

Reproducibility

Parity with the published comparator

Our pooled k = 1 vs the comparable same-scope comparator k = 0 — COMPARATOR-INVALID. comparator pools 12 OBSERVATIONAL studies, 0 RCTs = not an RCT-meta comparator

Independent second extraction (blind)

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