Empagliflozin vs placebo for cardiovascular death or heart-failure hospitalisation in HFpEF/HFmrEF

Overview

Empagliflozin vs placebo for cardiovascular death or heart-failure hospitalisation in HFpEF/HFmrEF

In adults with heart failure and preserved or mildly reduced ejection fraction, does empagliflozin reduce the composite of cardiovascular death or hospitalisation for heart failure versus placebo? (Double-blind placebo-controlled RCTs.)

Primary outcome

Transparency (independently checkable)

7 of 7 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.
• Comparator scope mismatch. comparator is a DRUG-CLASS meta-analysis while this topic is a single agent — a PICO scope mismatch (single-drug review vs class-level review); the k difference vs this comparator is a scope difference, not unretrieved evidence
• 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 - Empagliflozin for cardiovascular death or worsening heart failure in HFmrEF/HFpEF

**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 and mildly reduced or preserved ejection fraction
  (HFmrEF/HFpEF; operationally LVEF >40% or preserved-EF trial eligibility).
- **I** - Empagliflozin 10 mg daily, added to usual heart-failure therapy.
- **C** - placebo or matching placebo, added to usual heart-failure therapy.
- **O (primary)** - time to first composite cardiovascular death or worsening heart
  failure, where worsening heart failure includes hospitalization or urgent visit for
  heart failure as defined by the trial.
- **Estimand** - hazard ratio (HR) with 95% confidence interval.

## Eligibility - on P/I/C/DESIGN ONLY
Include a record iff all hold:
- **Population** - adult HFmrEF/HFpEF or preserved-EF heart-failure population,
  judged from the title, registry conditions, or trial acronym.
- **Intervention** - Empagliflozin is named in the title or registry condition/acronym.
- **Comparator** - placebo or matching placebo.
- **Design** - randomized, double-blind, placebo-controlled trial.

Exclude (reason must be true of the record):
- **X1** - not a randomized controlled trial.
- **X2** - wrong population, including HFrEF/LVEF <=40%, diabetes-only, CKD-only,
  myocardial-infarction, or other non-HFmrEF/HFpEF populations.
- **X3** - wrong intervention or comparator.
- **X-DESIGN** - not double-blind/placebo-controlled in the machine-readable record.

Eligibility is not decided by outcome reporting. An eligible Empagliflozin HFpEF trial
that reports symptoms, hemodynamics, or safety but not the target composite HR is kept
as target-result absent, not excluded.

## Outcomes
- **Primary efficacy outcome** - composite cardiovascular death or worsening heart
  failure; HR estimand; intention-to-treat/randomized population; longest
  trial-reported randomized follow-up.
- **Secondary outcomes** - none preregistered for this topic.
- **Harms** - none preregistered for this topic.

## Search
- PubMed: UID-anchored queries for EMPEROR-Preserved (PMID 34449189), PRESERVED-HF
  (PMID 34711976), and CAMEO-DAPA (PMID 37534453), plus configured comparator and
  negative-control PMIDs.
- ClinicalTrials.gov: condition "heart failure with preserved ejection fraction",
  intervention "Empagliflozin".
- Citation chasing: enabled and bounded; every reached record is still screened by
  the same P/I/C/design rules.

## Synthesis method
Random-effects inverse-variance on log(HR) using source-reported trial HRs and 95%
CIs only. 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). For k=1,
the result is reported as the single trial's own HR with no random-effects pooling.

## Comparator
Pal et al., *Indian Heart Journal* 2023, "SGLT2 inhibitors and cardiovascular outcomes
in heart failure with mildly reduced and preserved ejection fraction: A systematic
review and meta-analysis" (PMID 36914068, DOI 10.1016/j.ihj.2023.03.003; Unpaywall
is_oa=true). This comparator matches the HFmrEF/HFpEF population, placebo comparison,
composite cardiovascular-death/HF-worsening outcome, and HR estimand, but is class-level
SGLT2 inhibitor evidence rather than Empagliflozin-only evidence; the overlap tab must
therefore not claim an identical trial set.

## Controls
- **Positive** - EMPEROR-Preserved (PMID 34449189) must be recovered and included.
- **Negative** - DAPA-HF (PMID 31535829), a Empagliflozin/placebo trial with the same
  endpoint but HFrEF/LVEF <=40%, must be recovered and excluded as wrong population.

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 1/1 of this topic's known trials (enumerated 72; 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 72 registry records matching the query (broad — reach, not precision): 22 have a linked publication; 4 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 11 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

34449189[uid]

ClinicalTrials.gov

{"cond": "heart failure with preserved ejection fraction", "intr": "empagliflozin"}

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 100 records: agreement 99/100, disagreement 1.0% (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 1 trials pooled across all outcomes on this page is retracted (checked 2026-09-11T23:50:05Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

100 records screened; 4 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 ['34449189'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['32865377'] recovered by the search and correctly EXCLUDED ['32865377'] by rule (same drug/design, wrong topic).

Results

Composite cardiovascular death or worsening heart failure (primary)

k = 1: the 1 trial(s) named below were pooled; 3 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Comparator

Composite cardiovascular death or urgent visit/hospitalization for heart failure in HFmrEF/HFpEF: 0.74 (HR), 95% CI 0.67–0.82

Scope match (is this the same question?)

⚠ SCOPE MISMATCH. Intervention level: topic is a single agent, comparator is class-level (match: False); population match: True. comparator is a DRUG-CLASS meta-analysis while this topic is a single agent — a PICO scope mismatch (single-drug review vs class-level review); the k difference vs this comparator is a scope difference, not unretrieved evidence Decided by one uniform rule applied to every topic before the k was seen.

Comparator resolution. No same-scope (single-agent) published meta-analysis exists to serve as a like-for-like comparator: empagliflozin in HF with preserved ejection fraction rests on a single pivotal RCT (EMPEROR-Preserved, NCT03057951), so k=1 is the COMPLETE single-drug RCT evidence base for this question, not a search gap. The nearest published synthesis pools the SGLT2-inhibitor CLASS (a different, network-level PICO question); its larger k reflects that broader scope, not evidence this review failed to retrieve. A complete review with k=1 is not a weak review; it is a complete one.

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.

Trials the comparator pools that this review EXCLUDES on estimand grounds

A larger k bought by pooling a different outcome is not a larger evidence base — it is a different question. These trials were found; they are excluded deliberately because the outcome they report is not this review's estimand, not because the search missed them.

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 heart failure and preserved or mildly reduced ejection fraction, does empagliflozin reduce the composite of cardiovascular death or hospitalisation for heart failure versus placebo? (Double-blind placebo-controlled RCTs.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA c5dc828d141f); a registry-first search was screened by two independent rule screeners with adjudication (100 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: RR 0.81 (95% CI 0.72 to 0.91); with k=1 no between-trial heterogeneity or prediction interval is estimable. 3 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 c5dc828d141f) 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: RR 0.81 (95% CI 0.72 to 0.91); 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. 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). 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 c5dc828d141f) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py empagliflozin-hfpef-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

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 (1 identical, 0 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.