Mineralocorticoid receptor antagonists vs placebo for all-cause mortality in HFrEF

Overview

Mineralocorticoid receptor antagonists vs placebo for all-cause mortality in HFrEF

In adults with heart failure with reduced ejection fraction, do spironolactone or eplerenone reduce all-cause mortality 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 - mineralocorticoid receptor antagonists for all-cause mortality in HFrEF

**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 heart failure with reduced ejection fraction (HFrEF) / systolic heart failure.
- **I** - a steroidal mineralocorticoid receptor antagonist, specifically spironolactone or eplerenone, added to recommended therapy.
- **C** - placebo added to recommended therapy.
- **O (primary)** - all-cause mortality.
- **O (harms)** - hyperkalemia; gynecomastia or breast pain.

## Estimand / population / timepoint
- **Estimand** - published RR/HR with 95% CI when reported, or risk ratio (RR) when only percentage-corroborated arm counts are extractable.
- **Population** - intention-to-treat as randomised.
- **Timepoint** - trial end / longest randomised follow-up reported for all-cause mortality.

## Eligibility - on P/I/C/DESIGN ONLY
Include a record iff **all** hold:
- **I1** - randomised controlled trial;
- **I2** - adult HFrEF / systolic heart-failure population, judged from title or registry conditions;
- **I3** - spironolactone or eplerenone versus placebo;
- **design** - double-blind, placebo-controlled.

Exclude (reason must be true of the record):
- **X1** - not an RCT (review, guideline, observational, protocol-only, or post-hoc analysis not indexed as an RCT);
- **X2** - wrong population (e.g. HFpEF, mildly reduced EF, post-myocardial-infarction LV dysfunction, CKD, diabetes, dialysis, hypertension, cirrhosis, or other non-HFrEF population);
- **X3** - wrong intervention/comparison (no eligible spironolactone/eplerenone-vs-placebo contrast);
- **X-DESIGN** - not double-blind and placebo-controlled in the machine-readable record;
- **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 all-cause
> mortality, or gives a 2x2 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>/search.json; screening replays offline)
- PubMed: UID-anchored queries for RALES, EMPHASIS-HF, and the resolved open-access comparator.
- ClinicalTrials.gov: condition "HFrEF", intervention "mineralocorticoid receptor antagonist".
- Citation chasing: enabled from the comparator and positive-control trials; every retrieved record is still screened on P/I/C/design.

## Synthesis method (DECLARED; served method must equal this - gate limb 1)
Random-effects inverse-variance on the log ratio (RR/HR as configured for the outcome);
**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)
Zhang et al., *Frontiers in Cardiovascular Medicine* 2025, "Mineralocorticoid receptor
antagonists in heart failure: a systematic review and meta-analysis" (PMID 40959489,
DOI 10.3389/fcvm.2025.1667236; PubMed links PubMed Central/free full text). The
comparator reports the HFrEF subgroup for all-cause mortality.

## Controls
- **Positive** - the search must recover the canonical HFrEF MRA trials:
  RALES (spironolactone) and EMPHASIS-HF (eplerenone).
- **Negative** - EPHESUS (eplerenone after acute myocardial infarction complicated by
  LV dysfunction and heart failure) must be recovered and EXCLUDED as same-drug but wrong-topic.

Search

Source status (which adapters ran)

Citation chase: RAN_OK · 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 1/2 of this topic's known trials (enumerated 66; 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: 10471456. 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 66 registry records matching the query (broad — reach, not precision): 23 have a linked publication; 7 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 13 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

10471456[uid]

21073363[uid]

40959489[uid]

ClinicalTrials.gov

{"cond": "HFrEF", "intr": "mineralocorticoid receptor antagonist"}

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 225 records: agreement 224/225, disagreement 0.4% (1 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 2026-09-11T23:50:16Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

225 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 ['10471456', '21073363'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['12668699'] recovered by the search and correctly EXCLUDED ['12668699'] by rule (same drug/design, wrong topic).

Results

All-cause mortality (primary)

Harms

Hyperkalemia

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.

Gynecomastia or breast pain

Comparator

All-cause mortality in HFrEF patients: 0.78 (HR), 95% CI 0.72–0.85

Scope match (is this the same question?)

✓ same question. Intervention level: topic is class-level, comparator is class-level (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 (10471456) 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 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 heart failure with reduced ejection fraction, do spironolactone or eplerenone reduce all-cause mortality versus placebo? (Double-blind placebo-controlled RCTs.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 5d75f715df81); a registry-first search was screened by two independent rule screeners with adjudication (225 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) 0.72 (95% CI 0.32 to 1.61), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.32 to 1.61.

Certainty. Partial GRADE certainty was very low (from 3 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 5d75f715df81) 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) 0.72 (95% CI 0.32 to 1.61), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.32 to 1.61.

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 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 5d75f715df81) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py spironolactone-hfref-mortality

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 = 2 vs the comparable same-scope comparator k = 2 — PARITY. 2/2 within PREREGISTERED scope: comparator HFrEF-mortality pool is RALES/EPHESUS/EMPHASIS, but EPHESUS is acute-post-MI LV dysfunction, which our population_none preregisters as excluded (chronic HFrEF only). RALES + EMPHASIS = our pool. EPHESUS is a named, preregistered scope difference, not a miss.

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; 1 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.