Colchicine vs placebo for secondary prevention of cardiovascular events

Overview

Colchicine vs placebo for secondary prevention of cardiovascular events

In adults with coronary disease or recent myocardial infarction, does low-dose colchicine reduce major adverse cardiovascular events versus placebo? (Double-blind placebo-controlled RCTs.)

Primary outcome

Transparency (independently checkable)

89 of 89 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 3 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 - colchicine for secondary cardiovascular prevention

**Registration.** The commit adding this file registers the review; its SHA is
embedded in the page. Committed before the synthesis runs. This topic uses the
same fixed harness and declared method as the existing colchicine topics.

## PICO
- **P** - adults with coronary disease or recent myocardial infarction.
- **I** - low-dose colchicine added to guideline-based medical therapy.
- **C** - placebo added to guideline-based medical therapy.
- **O (primary)** - major adverse cardiovascular events (MACE) composite.
- **O (harms)** - gastrointestinal adverse effects; non-cardiovascular death.

## Estimand / population / timepoint
- **Estimand** - hazard ratio or other ratio effect as reported by each trial,
  pooled on the ratio scale by the fixed harness.
- **Population** - intention-to-treat as randomised.
- **Timepoint** - trial end / longest planned follow-up for the primary MACE
  composite.

## Eligibility - on P/I/C/DESIGN only
Include a record iff **all** hold:
- **I1** - randomised controlled trial;
- **I2** - population is coronary disease or recent myocardial infarction;
- **I3** - low-dose colchicine versus placebo;
- **design** - double-blind, placebo-controlled.

Exclude (reason must be true of the record):
- **X1** - not an RCT (review, guideline, observational, protocol-only);
- **X2** - wrong population (e.g. pericarditis, postoperative atrial fibrillation,
  primary stroke-only populations, hypertension, COVID-19, osteoarthritis);
- **X3** - wrong intervention/comparison (no colchicine-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 an included trial reports MACE
in its abstract, gives 2x2 data, gives only an effect plus confidence interval,
or reports neither extractable form is extraction status only, never a screening
exclusion.

## Search
- PubMed: exact landmark-trial title queries for COLCOT and LoDoCo2, plus a
  colchicine x coronary disease x placebo x randomised/double-blind sweep.
- ClinicalTrials.gov: condition "coronary artery disease", intervention
  "colchicine".

## Synthesis method (DECLARED = served)
Random-effects inverse-variance on log ratio effects; Paule-Mandel tau^2; HKSJ
95% CI on t_{k-1} (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)
Frontiers in Cardiovascular Medicine 2022, "Colchicine and coronary heart
disease risks: A meta-analysis of randomized controlled clinical trials" (PMID
36176989, PMC9512890, DOI 10.3389/fcvm.2022.947959; Unpaywall is_oa=true).
It reports colchicine reduced MACE (RR 0.65, 95% CI 0.38-0.77) in coronary
atherosclerotic heart disease trials, and reports gastrointestinal and mortality
safety outcomes.

## Controls
- **Positive** - the search must recover and include COLCOT (PMID 31733140) and
  LoDoCo2 (PMID 32865380).
- **Negative** - CORP recurrent pericarditis (PMID 21873705), a double-blind
  placebo colchicine trial from another topic/disease, must be recovered and
  excluded as the 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 2/3 of this topic's known trials (enumerated 59; status RAN_OK). 1 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: 34876021. 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 59 registry records matching the query (broad — reach, not precision): 27 have a linked publication; 0 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 6 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

"Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction"

"Colchicine in Patients with Chronic Coronary Disease"

colchicine coronary disease placebo randomized double-blind

ClinicalTrials.gov

{"cond": "coronary artery disease", "intr": "colchicine"}

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 120 records: agreement 103/120, disagreement 14.2% (17 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 17 content-bearing disagreements; it agrees with the served rule screener on 12/17. 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: 32407460 (served include, model exclude: This is an economic analysis of COLCOT rather than an eligible randomized trial record.); 34446156 (served include, model exclude: This is a duplicate secondary analysis of LoDoCo2 rather than an independent eligible trial report.); 34420373 (served exclude, model include: This is a randomized placebo-controlled colchicine trial in acute myocardial infarction.); 25784519 (served include, model exclude: This perioperative cardiac-surgery study is excluded by the wrong population.); 23500260 (served exclude, model include: This is a randomized placebo-controlled colchicine trial in a coronary PCI population.)

Trial integrity: none of the 3 trials pooled across all outcomes on this page is retracted (checked 2026-09-11T23:50:02Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

120 records screened; 28 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 ['31733140', '32865380'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['21873705'] recovered by the search and correctly EXCLUDED ['21873705'] by rule (same drug/design, wrong topic).

Results

Major adverse cardiovascular events (primary)

k = 2: the 2 trial(s) named below were pooled; 26 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Gastrointestinal adverse effects

k = 1: the 1 trial(s) named below were pooled; 27 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Non-cardiovascular death

k = 1: the 1 trial(s) named below were pooled; 27 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Comparator

Major adverse cardiovascular events: 0.65 (RR), 95% CI 0.38–0.77

Gastrointestinal adverse effects: 2.07 (RR), 95% CI 1.45–2.95

Non-cardiovascular death: 1.07 (RR), 95% CI 0.85–1.36

Scope match (is this the same question?)

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

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

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

Risk of bias

Coverage: 1 of 2 primary-outcome pooled trials have a registry (AACT) match and are assessed below; the other 1 are pooled but have no registry match (32865380) and are shown as not assessed with the reason — never guessed. RoB2 is scoped to the primary outcome; 1 trial(s) pooled only in secondary outcomes (34876021) are outside this assessment.

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 coronary disease or recent myocardial infarction, does low-dose colchicine 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 9355c4b9d848); a registry-first search was screened by two independent rule screeners with adjudication (120 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. Pooling 2 trials gave mixed (HR/RR) 0.73 (95% CI 0.29 to 1.82), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.29 to 1.82. 26 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 9355c4b9d848) 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 mixed (HR/RR) 0.73 (95% CI 0.29 to 1.82), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.29 to 1.82.

Risk-of-bias sensitivity. 1 of 2 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 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 9355c4b9d848) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py colchicine-secondary-cv-prevention

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

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 (1 identical, 1 same-result-different-statistic, 0 conflict; 2 not stated in the abstract). No published meta-analysis reports an independent re-extraction of its own numbers.

Verified but not pooled (refusals, with reasons)

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