Intravenous iron vs placebo or standard care for heart-failure hospitalization in HFrEF with iron deficiency

Overview

Intravenous iron vs placebo or standard care for heart-failure hospitalization in HFrEF with iron deficiency

In adults with heart failure with reduced ejection fraction and iron deficiency, does intravenous iron reduce heart-failure hospitalization versus placebo or standard care?

Primary outcome

Transparency (independently checkable)

27 of 27 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 2 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 - intravenous iron for heart-failure hospitalization in HFrEF with iron deficiency

**Registration.** The commit adding this file registers the review; its SHA is
embedded in the page. The protocol is committed before the synthesis is run.

## PICO
- **P** - adults with heart failure with reduced or mildly reduced ejection fraction and iron deficiency.
- **I** - intravenous iron, including ferric carboxymaltose, ferric derisomaltose, or iron sucrose.
- **C** - placebo, usual care, standard care, or no-treatment control.
- **O (primary)** - heart-failure hospitalization at trial end / longest reported follow-up.
- **O (harms)** - injection-site/administration-site reactions; hypersensitivity reactions.

## Estimand / population / timepoint
- **Estimand** - risk ratio (RR), intravenous iron vs placebo/standard care.
- **Population** - intention-to-treat as randomized.
- **Timepoint** - trial end / longest reported follow-up.

## Eligibility - on P/I/C/DESIGN ONLY
Include a record iff **all** hold:
- **I1** - randomized controlled trial;
- **I2** - population is heart failure with reduced or mildly reduced ejection fraction and iron deficiency;
- **I3** - intravenous iron vs placebo, usual care, standard care, or no-treatment control;
- **design** - placebo-controlled or standard-care-controlled RCT; double blinding is not required.

Exclude (reason must be true of the record):
- **X1** - not an RCT (review, guideline, observational, protocol-only);
- **X2** - wrong population (for example HFpEF, COPD, pulmonary hypertension, dialysis, pregnancy/postpartum, inflammatory bowel disease, or restless legs);
- **X3** - wrong intervention/comparison (no intravenous iron vs eligible control contrast);
- **X5** - off-topic: a primary trial of another disease area in this set (negative control).

> Eligibility is NOT on the outcome axis. Whether a trial reports heart-failure
> hospitalization, 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. Composite cardiovascular-death/heart-failure-hospitalization effects
> are not treated as standalone heart-failure hospitalization for the primary outcome.

## Search (fetch-once; raw results committed under cache/iv-iron-hfref-hosp/records.json; screening replays offline)
- PubMed: targeted primary-report searches for FAIR-HF2, AFFIRM-AHF, and IRONMAN.
- PubMed comparator-reference seeding: trials cited by the resolved comparator are fetched and screened by the same rules.
- ClinicalTrials.gov: condition "heart failure reduced ejection fraction iron deficiency", intervention "intravenous iron".

## 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)
Parmananda et al., *Diseases* 2024, "The Efficacy and Safety of Ferric
Carboxymaltose in Heart Failure with Reduced Ejection Fraction and Iron Deficiency:
An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials"
(PMID 39727669, PMC11727542, DOI 10.3390/diseases12120339; Unpaywall is_oa=true).
It reports total HF hospitalizations OR 0.59 (95% CI 0.40 to 0.88) over six RCTs,
plus serious adverse events and qualitative angioedema/hypersensitivity detail.

## Controls
- **Positive** - the search must recover FAIR-HF2 (PMID 40159390), AFFIRM-AHF
  (PMID 33197395), and IRONMAN (PMID 36347265).
- **Negative** - the COPD intravenous-iron RCT (PMID 32565444) 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): NOT_RUN — RAN_OK = ran and returned records; RAN_ZERO = ran, none matched; RAN_ERROR = attempted but failed; NOT_RUN = not attempted for this topic.

PubMed

FAIR-HF2 JAMA 2025 randomized clinical trial ferric carboxymaltose

AFFIRM-AHF ferric carboxymaltose acute heart failure Lancet 2020

10.1016/S0140-6736(22)02083-9

ClinicalTrials.gov

{"cond": "heart failure reduced ejection fraction iron deficiency", "intr": "intravenous iron"}

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 39 records: agreement 37/39, disagreement 5.1% (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.

Trial integrity: none of the 2 trials pooled across all outcomes on this page is retracted (checked 2026-09-11T23:50:08Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

39 records screened; 8 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 ['40159390', '33197395', '36347265'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['32565444'] recovered by the search and correctly EXCLUDED ['32565444'] by rule (same drug/design, wrong topic).

Results

Heart-failure hospitalization (primary)

k = 2: the 2 trial(s) named below were pooled; 6 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Injection-site reactions

Hypersensitivity reactions

Comparator

Total HF hospitalizations: 0.59 (OR), 95% CI 0.4–0.88

Serious adverse events: 0.73 (OR), 95% CI 0.49–1.1

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 (25176939) 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 and iron deficiency, does intravenous iron reduce heart-failure hospitalization versus placebo or standard care?

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA a56039f46158); a registry-first search was screened by two independent rule screeners with adjudication (39 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. Pooling 2 trials gave mixed (HR/IRR) 0.61 (95% CI 0.01 to 51.59), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0 to 640.63. 6 eligible trial(s) were declared absent for this outcome (reported reason on each).

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 a56039f46158) 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/IRR) 0.61 (95% CI 0.01 to 51.59), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0 to 640.63.

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); between-trial heterogeneity was detected (inconsistency); 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 a56039f46158) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py iv-iron-hfref-hosp

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 = 3 — NEAR. 2/3. Gap = HEART-FID + AFFIRM-AHF, refused on estimand: CT.gov labels HEART-FID heart-failure hospitalizations as COUNT_OF_PARTICIPANTS (297/1532 vs 332/1533) but the publication says "297 hospitalizations" = RECURRENT EVENTS, not patients — pooling the CT.gov count as a binary would produce a wrong number, so the recurrent-event guard refuses it. FAIR-HF = no extractable data; EFFECT-HF = open-label (design-excluded). CONFIRM-HF recovered.

Independent second extraction (blind)

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