Empagliflozin in adults with heart failure

Registration and administrative information (PROSPERO field set)

Extraction — every datum linked to its source

Every per-trial value this review pools, with a link to the record it came from. Derived by ssot/projectors_evidence.py for any topic whose rows carry an NCT, a PMID, an ISRCTN or a source URL.

2 of 2 rows are linked to a source; 0 carry no identifier and are shown as unlinked rather than omitted.

Outcome primary

Extracted values, and where each came from

One row per extracted value. Every row carries the value, the verbatim sentence it was read from, a resolvable link to the source, and whether the number was read or derived. Where any of those is absent the row says so rather than omitting the value.

Recompute envelope — the headline against the rows shown

Derived by ssot/recompute_envelope.py. The pooled number is recomputed from the per-trial rows this same page shows, so the arithmetic between the extraction table and the headline is checkable with no tool the reader does not already have.

Outcome primary

AGREES -- the stored point lies between the fixed-effect and DerSimonian-Laird estimates computed from the rows this page shows.

Scale used: log. Declared estimator: REML.

DerSimonian-Laird is biased at k below about ten and this project uses REML. DL is here only to WIDEN the envelope so a REML point falls inside it; it is never offered as the review's estimate.

Absolute effect at a baseline risk the reader chooses

Derived by ssot/absolute_effect.py for any topic with a pooled ratio measure AND a declared indirectness argument. Where either is missing it DECLINES with a reason rather than emitting a table the review has not licensed — a ratio becomes an absolute effect only against a baseline risk, and a baseline risk belongs to a population.

Risk of bias (RoB-2)

Variant:

Unit assessed: —

Assessor 1: (anthropic family). Assessor 2: (openai family).

Overall judgement per trial

Inter-assessor agreement

This assessment is DUAL — two assessors from different model families, the second asked blind. The agreement rate is withheld pending adjudication. Both readers were given this review’s decision rule; an earlier version of this sentence said the blinding had withheld it, and that was wrong. What the 10 domain comparison(s) show is a reading difference that runs in OPPOSITE directions by domain — on domains 1 to 3 the second assessor more often declines to judge at all, and on domains 4 and 5 it more often judges low. A single agreement rate averages those two behaviours into one number that describes neither. Both assessors’ per-result judgements are shown in the table above, unadjudicated, and neither is this review’s finding. No adjudication has been performed, so this review holds no final risk-of-bias judgement for these results.

References

Included studies

• EMPEROR-Preserved — https://clinicaltrials.gov/study/NCT03057951
• EMPEROR-Reduced — https://clinicaltrials.gov/study/NCT03057977

Regulatory documents

Methods and guidance

Sources

Visual abstract

⬇ SVG (vector) 2 KB ⬇ PNG 4500x2100 307 KB

All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: c7480d2868a1ef5a), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — visual-abstract.eps, 4 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — visual-abstract.tiff, 27,685 KB.

Projected from the canonical object, so it carries the same k, the same pooled estimate and the same interval as the paper and cannot drift from them. The interval is drawn to scale against the no-difference line, which it EXCLUDES: 0.7 to 0.849, with no difference at 1.

Risk of bias, both assessors

⬇ SVG (vector) 8 KB

Only the vector format is offered for this figure, by choice: it is line art — discrete marks, glyphs and labels — which SVG reproduces exactly at any size, so a raster would add weight without adding fidelity. The build was able to rasterise; it was asked not to.

Every cell carries BOTH independent cross-family assessments and they are not reconciled: showing one column would be a reconciliation presented as an observation. Glyph as well as colour, so the panel survives greyscale printing and colour-blind reading. A trial with no judgement is shown as a row of not-assessed markers rather than omitted, so a gap in the assessment cannot be mistaken for a clean assessment. Agreement as measured: {'per domain agreed': 8, 'per domain total': 10, 'per domain rate pct': 80.0, 'overall agreed': 0, 'overall total': 2, 'overall is derived': True, 'recomputed from the stored judgements': True, 'why recomputed': 'The stored disagreement tallies were frozen as text and 12 of 22 no longer match the judgements in the object -- a later guidance pass moved 51 the randomisation process judgements and the tallies were never recomputed. This is derived from what the object holds now.'}.

GOSH

⬇ SVG (vector) 1 KB ⬇ PNG 3500x540 81 KB

All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 9091822e99aa8781), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — gosh.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — gosh.tiff, 5,537 KB.

Deliberately not drawn. Every subset meta-analysis of 2 trials is 3 points; a cloud that small cannot show the multimodality GOSH exists to reveal, and a reader would take the picture as evidence of its absence.

Trial-sequential analysis

⬇ SVG (vector) 1 KB ⬇ PNG 3500x650 87 KB

All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 25ed9800fdf56614), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — tsa.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — tsa.tiff, 6,665 KB.

TSA boundaries depend entirely on a target information size that must be pre-specified. This review's protocol registers none, so any boundary drawn here would be a parameter chosen after seeing the data -- which is the practice TSA exists to protect against.

Meta-regression

⬇ SVG (vector) 1 KB ⬇ PNG 3500x540 87 KB

All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: e35ec93bbc9a1c10), at 600 dpi for a 6-inch print width, on a white ground.

Submission formats written to the figures directory, not embedded here because an uncompressed 600 dpi TIFF is tens of megabytes: EPS (vector, journal's first choice for line art) — bubble.eps, 2 KB; TIFF (uncompressed, 600 dpi -- journal fallback) — bubble.tiff, 5,537 KB.

The protocol pre-specifies no moderator, and at k = 2 a meta-regression would be fitted on 2 points. Not drawn rather than drawn with a caveat: a bubble plot invites reading a slope, and there is no slope here that any reader should read.

Summary of findings

1. This certainty rating is PENDING, not rated. It rests on a risk-of-bias judgement that this review has not finalised: two assessors read every contributing result independently, they disagree, and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Cochrane rates certainty per outcome by aggregating the risk-of-bias judgements of the results contributing to it, so a certainty rating cannot be more final than the risk-of-bias assessment it reads. The rating this object currently records, and the steps behind it, are shown below as the work so far rather than as this review's answer. No level is published for this outcome -- not the recorded one, not a more cautious one, and not a midpoint -- because choosing one would be the judgement that has not been made.
2. Read this beside `whether the estimand was established`. That flag records that every contributing trial measures the same quantity. It records nothing about what that quantity was measured against -- whether the comparators are of one kind, whether each comparison was randomised, whether it was concurrent. The two questions were never separated. Named as P48 in PAGE-STANDARD.md v1.21.0 and swept by scripts/audit_mixed_contrast_pools.py.

Reproducibility artifact

This page CANNOT be rebuilt from what is recorded here: no canonical object is recorded and no registered commit is recorded. Each figure on the Analysis tab downloads as an SVG carrying exactly the values shown.

Other recorded qualifications

Statements this review records about the limits of what it establishes, which are not shown elsewhere on this page. They are reproduced from the object verbatim and are not summarised.

Judgement register — what a harness cannot derive

Judgements a harness cannot derive, per outcome, with the alternative and its consequence. DERIVED AT BUILD TIME by ssot/topic_judgements.py — this table is not written for this topic and the same code produces it for every topic.

Outcome primary — 0 of 8 declared, 8 of 8 undeclared

A topic costs 0 declared judgements on this outcome, not four hundred. That is a stronger claim than "automated", because a reader can check a declared judgement and cannot check an inferred one.

⚠️ It does not make the judgements right, and it does not prove the SLOT LIST is complete -- the list is bounded by what its author enumerated. The honest form is "8 slots checked", never "8 judgements exist".

Paper

Each statement below cites the record it came from; those sources are listed at the end of every section. Where the record holds nothing, the section says so by name rather than being left out, so a procedure that was not carried out can be told from one that simply was never mentioned.

Title

Empagliflozin in adults with heart failure¹

A claim on this object is withdrawn as false. It asserted that no published synthesis pools this review's two trials. Emperor-pooled is exactly that: a prospectively planned pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved, at individual-patient level, with multiple indexed publications. It is not an obscure record and it is not a near-match; it is a pooled analysis of precisely the two trials, designed as one before either reported. The claim is withdrawn and not deleted. What it said, that it was false, and what is true are all recorded here, because a claim that quietly disappears cannot be audited and a reader who acted on it has no way to learn that it was wrong. What this means for the comparison: the published-synthesis comparison on this object was drawn against a stated absence that does not exist. It should be re-run against EMPEROR-Pooled. That is work, not a correction, and it is not done here.²

Abstract

Question. In adults with heart failure, does empagliflozin compared with placebo reduce the first occurrence of adjudicated cardiovascular death or adjudicated hospitalisation for heart failure -- the outcome both trials register as their primary?¹

Methods. estimates were pooled under a random-effects model with the REML estimator; risk of bias was assessed with RoB 2 (Cochrane risk-of-bias tool for randomized trials), 22 August 2019 version as reproduced in the Cochrane Handbook; and certainty was rated with GRADE, following the Cochrane Handbook chapter 14. Randomised evidence starts HIGH and is rated down with reasons.²

Results. Multiple trial-declared outcomes: Time to the First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF) | Time to First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF): hazard ratio 0.771 (0.7 to 0.849) across 2 trials; and no statistical heterogeneity was detected (I-squared 0%), though heterogeneity cannot be reliably assessed with two trials.³

Introduction

¹Background. This review asks: In adults with heart failure, does empagliflozin compared with placebo reduce the first occurrence of adjudicated cardiovascular death or adjudicated hospitalisation for heart failure -- the outcome both trials register as their primary? It pools 2 randomised trials, against placebo. The outcome pooled is Multiple trial-declared outcomes: Time to the First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF) | Time to First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF).

Methods — search

Primary trials. No bibliographic search for primary trials was run. The 2 included trials were identified by reading named registrations on the dates recorded on each entry. The basis on which this object was verified is not recorded. What this object does not claim is not recorded. The bar this object had to clear is not recorded.¹

Methods — eligibility criteria

not recorded on the page this object was extracted from¹

Methods — synthesis

For multiple trial-declared outcomes: Time to the First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF) | Time to First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF), a random-effects model was fitted with the REML estimator.¹

Risk of bias was assessed with RoB 2 (Cochrane risk-of-bias tool for randomized trials), 22 August 2019 version as reproduced in the Cochrane Handbook (), following . 2 result-level assessments were made.²

A ceiling applies to every risk-of-bias judgement in this review; it is stated with the assessment itself rather than summarised here.³

Certainty of evidence was rated with GRADE, following the Cochrane Handbook chapter 14. Randomised evidence starts HIGH and is rated down with reasons., following . 1 pooled outcome(s) were rated. No domain is rated UP. Rating up for a large effect or a dose-response gradient applies to observational evidence that has not already been rated down, and neither condition holds here.⁴

Results

The pooled hazard ratio for multiple trial-declared outcomes: Time to the First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF) | Time to First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF) was 0.771 (0.7 to 0.849) across 2 trials, against placebo.¹

The trials' results were closely consistent with one another: I-squared, the share of the variation between them that is more than chance alone would produce, was 0%; the estimated variance of the true effects between trials (tau-squared) was 0, the heterogeneity test statistic Q was 0.278. Q = 0.368949 on 1 df, I-squared 0.0 per cent, tau-squared 0.0 under REML: the two trials agree closely. That agreement is not the main uncertainty here. Both trials registered this endpoint as time to first event and this pool combines odds ratios computed from cumulative arm counts, over trials that ran for different lengths of time. An odds ratio over unequal follow-up is not a hazard ratio and does not become one by being pooled: it depends on how long each trial ran, so the weights do not mean what a reader would assume. Both trials published a hazard ratio and those are the right inputs. Direction and rough magnitude are not in doubt -- both favour empagliflozin, both intervals exclude no effect -- but read the pooled number as an approximation to the quantity the trials estimated, not as that quantity. Two trials agreeing about an odds ratio over unequal follow-up agree about something neither of them set out to measure.²

The grounds for pooling are recorded as: The extractor recovered a pooled result from this page, so the page pooled these trials. Whether they should have been pooled is not established by conversion - several pages in this corpus pooled harm with efficacy, or distinct agents, and their estimates were withdrawn for that reason. Where a later pool on this page rests on the same grounds, they are not restated.³

The full model output for every pooled outcome -- the call, the estimator, the heterogeneity statistics and the back-transformed interval -- is stored verbatim on this review object at `results.by_outcome.<outcome>.r_output.verbatim`. It is not reproduced as an Extended data section in this article; an earlier version of this sentence said it was, and no such section exists.⁴

Risk of bias in the included results

Risk of bias was assessed with RoB 2 at the level of each reported result, by two assessors reading independently. Their judgements differ on 2 of the 2 results and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Assessor 1 recorded: 2 at some concerns. Assessor 2 recorded: 2 at no information. Both are shown in the risk-of-bias table; neither is the review's finding. The per-domain judgements behind them are recorded with the extracted data.¹

Certainty of the evidence

Certainty was rated with GRADE, following the Cochrane Handbook chapter 14. Randomised evidence starts HIGH and is rated down with reasons..¹

No domain is rated UP. Rating up for a large effect or a dose-response gradient applies to observational evidence that has not already been rated down, and neither condition holds here.²

This certainty rating is pending, not rated. It rests on a risk-of-bias judgement that this review has not finalised: two assessors read every contributing result independently, they disagree, and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Cochrane rates certainty per outcome by aggregating the risk-of-bias judgements of the results contributing to it, so a certainty rating cannot be more final than the risk-of-bias assessment it reads. The rating this object currently records, and the steps behind it, are shown below as the work so far rather than as this review's answer. No level is published for this outcome -- not the recorded one, not a more cautious one, and not a midpoint -- because choosing one would be the judgement that has not been made.³

Certainty LOW. The risk-of-bias domain reads the per-result RoB 2 assessments made 2026-08-20 and named above, not a topic-level summary; indirectness reads the estimand findings recorded on this pool.⁴

Comparison with published syntheses

Published syntheses were identified as follows. PubMed E-utilities; query, counts and a per-record decision in ssot/empagliflozin-hf-auto-full-review/appraisal/the screen of published syntheses.json. 130 records matched, 25 retrieved, 5 appraised, 125 not read. No included-study table was read for any of the five: their trial sets are inferred from abstract text, participant totals and search cut-off dates, and every check resting on an inferred set says so.¹

Limitations

What this review does not give a clinician: any absolute effect or number needed to treat and any measure of harm. A relative effect cannot be turned into the benefit or the risk facing one patient without them, so this review can support a judgement about what these trials found and not a judgement about what to do.¹

Note on registration

No PROSPERO registration or protocol record is held on this object. That is not the same as knowing this review was not registered, and neither claim is made. It is recorded here as an absence so that a reader does not have to infer it from silence.¹

References

Figures

Trial characteristics

Not reported in this record

The items below were not written because the record does not hold what they would be composed from. They are named here so that an absence is not mistaken for an omission.