PCSK9 inhibitors vs placebo for major adverse cardiovascular events

Overview

PCSK9 inhibitors vs placebo for major adverse cardiovascular events

In adults with or at high risk of ASCVD, do PCSK9 inhibitors (evolocumab or alirocumab) reduce major adverse cardiovascular events versus placebo? (Double-blind placebo-controlled RCTs.)

Primary outcome

Transparency (independently checkable)

10 of 10 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 - PCSK9 inhibitors for major adverse cardiovascular events

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

## PICO
- **P** - adults with established ASCVD or title/registry-supported high ASCVD risk.
- **I** - PCSK9 inhibitor monoclonal antibody therapy: evolocumab or alirocumab.
- **C** - placebo.
- **O (primary)** - major adverse cardiovascular events (MACE), as defined by each trial.
- **O (harms)** - injection-site reactions and adverse events leading to discontinuation.

## Estimand / population / timepoint
- **Estimand** - hazard ratio (HR), PCSK9 inhibitor vs placebo, using published
  trial effect estimates with 95% confidence intervals when arm-level event-time
  data are not available in the abstract.
- **Population** - intention-to-treat as randomised.
- **Timepoint** - longest reported trial follow-up for the primary MACE endpoint.

## Eligibility - on P/I/C/DESIGN ONLY
Include a record iff **all** hold:
- **I1** - randomised controlled trial;
- **I2** - population is adults with established ASCVD or title/registry-supported
  high ASCVD risk;
- **I3** - evolocumab or alirocumab compared with placebo;
- **design** - double-blind, placebo-controlled.

Exclude (reason must be true of the record):
- **X1** - not an RCT (review, guideline, observational, protocol-only, or secondary
  analysis not indexed as a primary randomised trial record);
- **X2** - wrong population by title/registry conditions (e.g. kidney disease,
  chronic kidney disease, heart failure, or venous thromboembolism);
- **X3** - wrong intervention/comparison (no evolocumab/alirocumab-vs-placebo
  contrast);
- **X-DESIGN** - not double-blind and placebo-controlled;
- **X5** - off-topic: a primary trial of another topic in this set (negative control).

> **Eligibility is NOT on the outcome axis.** Whether a trial reports MACE, or gives
> arm counts 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: title-level searches for the primary FOURIER and ODYSSEY OUTCOMES reports.
  Comparator-reference seeding is disabled for this topic because later secondary
  publications share the same trial NCTs and can supersede the primary outcome
  reports in the harness deduplication step.
- ClinicalTrials.gov: condition "ASCVD", intervention "alirocumab".

## Synthesis method (DECLARED; served method must equal this - gate limb 1)
Random-effects inverse-variance on log(HR); **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)`. Trial HRs and 95% CIs are transformed to log
scale by the harness. DerSimonian-Laird forbidden. Engine validated vs metafor
5.0.1 (<1e-6).

## Comparator (resolved; open-access confirmed)
Xiang et al., *Frontiers in Cardiovascular Medicine* 2022, "Effect of alirocumab
and evolocumab on all-cause mortality and major cardiovascular events: A
meta-analysis focusing on the number needed to treat" (PMID 36531722, DOI
10.3389/fcvm.2022.1016802; Unpaywall is_oa=true; PubMed Central available as
PMC9755489). It reports pooled MACE RR 0.83 (95% CI 0.79-0.87) in patients with
established ASCVD.

## Controls
- **Positive** - the search must recover and include the canonical large
  double-blind placebo-controlled outcome trials FOURIER (PMID 28304224) and
  ODYSSEY OUTCOMES (PMID 30403574).
- **Negative** - FIDELIO-DKD (finerenone in chronic kidney disease and type 2
  diabetes; PMID 33264825) must be recovered and EXCLUDED as wrong population and
  wrong intervention for this topic.

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 2/2 of this topic's known trials (enumerated 52; status RAN_OK). 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 52 registry records matching the query (broad — reach, not precision): 27 have a linked publication; 1 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 4 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

Evolocumab[Title] AND Clinical Outcomes[Title] AND Cardiovascular Disease[Title] AND 2017:2017[pdat]

Alirocumab[Title] AND Cardiovascular Outcomes[Title] AND Acute Coronary Syndrome[Title] AND 2018:2018[pdat]

ClinicalTrials.gov

{"cond": "ASCVD", "intr": "alirocumab"}

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 9 records: agreement 9/9, disagreement 0.0% (0 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.

Trial integrity: none of the 2 trials pooled across all outcomes on this page is retracted (checked 2026-09-11T23:50:12Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

9 records screened; 2 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 ['28304224', '30403574'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['33264825'] recovered by the search and correctly EXCLUDED ['33264825'] by rule (same drug/design, wrong topic).

Results

Major adverse cardiovascular events (primary)

Harms

Injection-site reactions

Adverse events leading to discontinuation

Comparator

Major adverse cardiovascular events: 0.83 (RR), 95% CI 0.79–0.87

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: 2 of 2 primary-outcome pooled trials have a registry (AACT) match and are assessed below (all primary-outcome pooled trials assessed).

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

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

GRADE certainty (partial, object-derived)

Manuscript

Abstract

Question. In adults with or at high risk of ASCVD, do PCSK9 inhibitors (evolocumab or alirocumab) reduce major adverse cardiovascular events versus placebo? (Double-blind placebo-controlled RCTs.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 38478f5e060a); a registry-first search was screened by two independent rule screeners with adjudication (9 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. Pooling 2 trials gave HR 0.85 (95% CI 0.59 to 1.23), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.59 to 1.23.

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 38478f5e060a) was committed before any synthesis ran. Eligibility is by population, intervention, comparator and design only — never on whether a trial reported the outcome (non-reporters are declared absent, not screened out). Two independently implemented rule screeners ran with adjudication. Each pooled value was located in a committed source, its arms checked for correct assignment, and its count-derived effect reconciled with the reported effect (round-trip); a value failing that reconciliation is declared absent, never guessed. Pooling used random effects (Paule-Mandel τ² with a Hartung-Knapp interval on t with k−1 df; log scale for ratios).

Results

Pooling 2 trials gave HR 0.85 (95% CI 0.59 to 1.23), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.59 to 1.23.

Risk-of-bias sensitivity. 2 of 2 pooled trials carry a risk-of-bias rating; no trial is rated high risk. Restricted to low-risk trials the estimate was HR 0.85 (95% CI 0.79 to 0.92, k=1); read the widened interval with the coverage caveat.

Limitations

This synthesis is limited in that the confidence interval is wide or crosses the null (imprecision). 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 38478f5e060a) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py pcsk9-mace

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

Re-search (living vs frozen)

Re-running the committed queries live and diffing against the cache: PubMed/EPMC: 4 retrieved live vs 6 committed (0 new, 2 no longer returned). CT.gov: 0 live vs 0 committed (0 new). Measured 2026-09-11T19:14:43Z; source scope committed PubMed + Europe PMC + CT.gov queries.

Parity with the published comparator

Our pooled k = 2 vs the comparable same-scope comparator k = 2 — PARITY-effective. 2/12 but our 2 (FOURIER+ODYSSEY) = ~87% of comparator patients; 10 gaps = non-prespecified MACE tallies

Independent second extraction (blind)

Of this page's pooled numbers, a blind second extractor agreed or reconciled on 2 of 2 that are checkable from the abstract (0 identical, 2 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.