Ticagrelor vs clopidogrel for major adverse cardiovascular events in acute coronary syndrome

Overview

Ticagrelor vs clopidogrel for major adverse cardiovascular events in acute coronary syndrome

In adults with acute coronary syndrome, does ticagrelor reduce major adverse cardiovascular events, defined as the composite of cardiovascular death, myocardial infarction, or stroke, compared with clopidogrel?

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 - ticagrelor vs clopidogrel for MACE in acute coronary syndrome

**Registration.** The commit that adds this file is the registration of this
review; its SHA is embedded in the page's Protocol tab and Reproducibility tab.
The integrator will commit this working-tree protocol on main.

## PICO
- **Population** - adults with acute coronary syndrome, including non-ST-elevation
  acute coronary syndrome and ST-elevation myocardial infarction.
- **Intervention** - ticagrelor, including the development name AZD6140.
- **Comparator** - clopidogrel.
- **Primary outcome** - major adverse cardiovascular events, defined as the composite
  of cardiovascular or vascular death, myocardial infarction, or stroke.
- **Secondary outcomes** - none prespecified for this micro-topic.
- **Harm outcomes** - major bleeding and dyspnea when extractable from the same source
  hierarchy.

## Eligibility - P/I/C/design only
Include a record iff all criteria hold:
- randomized controlled trial;
- adults with acute coronary syndrome, NSTE-ACS, or STEMI, judged from title,
  registry conditions, or acronym;
- ticagrelor/AZD6140 is the randomized intervention;
- clopidogrel is the randomized comparator;
- double-blind design.

Exclude records for wrong population, wrong intervention or comparator, non-randomized
design, non-double-blind design, reviews/meta-analyses, protocols without randomized
outcome results, or same-drug wrong-topic trials such as acute stroke/TIA. Prasugrel
comparisons are wrong-comparator trials for this PICO.

Eligibility is not based on whether the MACE outcome is reported. A screened-in trial
that does not report the exact primary outcome in its abstract with arm counts or an
effect plus 95% CI is declared target-result absent.

## Outcome Identity Discipline
The primary pooled value must be the trial result for MACE: cardiovascular or vascular
death, myocardial infarction, or stroke. Do not substitute a different primary endpoint,
platelet reactivity, myocardial infarction alone, bleeding, dyspnea, pharmacokinetics,
body weight, kidney outcomes, a subgroup result, or a design/rationale paper.

PLATO's outcomes paper is PMID 19717846. The PLATO rationale/design paper and early
pharmacodynamic or pharmacokinetic substudies are not outcome-result sources for this
review unless their abstracts state the exact MACE endpoint with a valid extractable
effect or count.

## Analysis Method
Random-effects inverse-variance synthesis on log ratio effects, using the harness
implementation declared in the served review: Paule-Mandel tau^2, HKSJ 95% CI on
`t_{k-1}` with variance floor `max(1,Q/(k-1))`, and prediction interval
`mu +/- t_{k-1}*sqrt(tau^2+se^2)`. A trial-level published HR plus 95% CI is the
preferred input for the primary outcome. If no HR is reported but percentage-
corroborated arm counts are available for the exact MACE outcome, those counts may be
used by the harness fallback; otherwise the trial is declared absent.

## Comparator
Comparator PMID 28545073 is Tan et al., *PLoS One* 2017, "The clinical efficacy and
safety evaluation of ticagrelor for acute coronary syndrome in general ACS patients and
diabetic patients: A systematic review and meta-analysis" (PMCID PMC5435320, DOI
10.1371/journal.pone.0177872). It is an open-access meta-analysis of ticagrelor versus
clopidogrel/prasugrel in ACS; the comparator extraction uses the ticagrelor-versus-
clopidogrel composite endpoint reported in the abstract.

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 1/1 of this topic's known trials (enumerated 126; 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 126 registry records matching the query (broad — reach, not precision): 64 have a linked publication; 10 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 25 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

19717846[uid]

17980250[uid]

ClinicalTrials.gov

{"cond": "STEMI fibrinolysis", "intr": "ticagrelor"}

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 31 records: agreement 29/31, disagreement 6.5% (2 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 2 content-bearing disagreements; it agrees with the served rule screener on 2/2. 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 2026-09-11T23:50:17Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

31 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 ['19717846'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['27160892'] recovered by the search and correctly EXCLUDED ['27160892'] by rule (same drug/design, wrong topic).

Results

Major adverse cardiovascular events: cardiovascular death, myocardial infarction, or stroke (primary)

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

Harms

Major bleeding

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

Dyspnea

Comparator

Composite endpoint of cardiovascular death, myocardial infarction, or stroke: 0.83 (OR), 95% CI 0.77–0.9

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 1 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 acute coronary syndrome, does ticagrelor reduce major adverse cardiovascular events, defined as the composite of cardiovascular death, myocardial infarction, or stroke, compared with clopidogrel?

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 3fb64a1e0143); a registry-first search was screened by two independent rule screeners with adjudication (31 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 0.84 (95% CI 0.77 to 0.92); with k=1 no between-trial heterogeneity or prediction interval is estimable. 1 eligible trial(s) were declared absent for this outcome (reported reason on each).

Certainty. Partial GRADE certainty was moderate (from 1 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 3fb64a1e0143) 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 0.84 (95% CI 0.77 to 0.92); with k=1 no between-trial heterogeneity or prediction interval is estimable.

Risk-of-bias sensitivity. 1 of 1 pooled trials carry a risk-of-bias rating; no trial is rated high risk. Restricted to low-risk trials the estimate was HR 0.84 (95% CI 0.77 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 3fb64a1e0143) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py ticagrelor-vs-clopidogrel-acs

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 = 1 — PARITY. comparator k=5 but 3 are a PLATO substudy(double-count)/observational/unindexed; 1 valid RCT (PLATO) = ours

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; 1 not stated in the abstract). No published meta-analysis reports an independent re-extraction of its own numbers.