Multiple trial-declared outcomes: Time to the First Occurrence of Any of the Following Adjudicated Components of the Primary Composite Endpoint (3-point M | Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), | Subjects Included in the Composite Endpoint of CV Death, MI or Ischemic Stroke | Time to First Occurrence of MACE (Composite Endpoint of Major Adverse Cardiovascular Events [Cardiovascular Death, Non-f

Registration and administrative information (PROSPERO field set)

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.

References

Included studies

• — https://clinicaltrials.gov/study/NCT01131676
• — https://clinicaltrials.gov/study/NCT01730534

Regulatory documents

Methods and guidance

Sources

Visual abstract

⬇ SVG (vector) 4 KB ⬇ PNG 4500x2100 519 KB

All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 0dc3a91cd49865f1), at 600 dpi for a 6-inch print width, on a white ground. They are not screenshots of the page and do not change with the theme you are reading in.

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, 6 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: 0.831 to 0.991, with no difference at 1.

Risk of bias

⬇ SVG (vector) 1 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.

Not drawn, because there is nothing to draw it from.

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. They are not screenshots of the page and do not change with the theme you are reading in.

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. They are not screenshots of the page and do not change with the theme you are reading in.

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. They are not screenshots of the page and do not change with the theme you are reading in.

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. No GRADE assessment or reconciliation record is held in this object, so the certainty of this evidence has not been rated. This is recorded as a declared departure under Cochrane Handbook §III.3.4.1: the review reports a pooled estimate for which no certainty assessment was made. Rating it here would require two assessors and an adjudicator, and a rating produced by neither is not a GRADE assessment whatever letter it carries.
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.

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

Multiple trial-declared outcomes: Time to the First Occurrence of Any of the Following Adjudicated Components of the Primary Composite Endpoint (3-point M | Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), | Subjects Included in the Composite Endpoint of CV Death, MI or Ischemic Stroke | Time to First Occurrence of MACE (Composite Endpoint of Major Adverse Cardiovascular Events [Cardiovascular Death, Non-f¹

Abstract

Question. In the four trial-declared outcomes named in the title, what do the contributing trials show?¹

Methods. estimates were pooled under a random-effects model with the REML estimator.²

Results. the four trial-declared outcomes named in the title: odds ratio 0.907 (0.831 to 0.991) across 2 trials; 1 of these pooled outcome(s) carries a stated qualification -- a referral or a recorded finding -- given in full in Results and not reproduced here; and no statistical heterogeneity was detected (I-squared 2.3%), though heterogeneity cannot be reliably assessed with two trials.³

Introduction

Background. This review asks: In the four trial-declared outcomes named in the title, what do the contributing trials show? It pools 2 randomised trials. The outcome pooled is the four trial-declared outcomes named in the title.¹

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. Published syntheses. PubMed E-utilities esearch + esummary, executed 2026-08-20. Query as executed: (("SGLT2"[tiab] OR "sodium-glucose"[tiab] OR empagliflozin[tiab] OR dapagliflozin[tiab]) and ("cardiovascular outcome"[tiab] or MACE[tiab] OR "major adverse cardiovascular"[tiab])) and (meta-analysis[pt] OR "systematic review"[pt] OR meta-analysis[tiab]). It matched ? record(s), of which ? were retrieved and ? read; 2 appraised.¹

Methods — eligibility criteria

not recorded on the page this object was extracted from¹

Methods — synthesis

For the four trial-declared outcomes named in the title, a random-effects model was fitted with the REML estimator.¹

Results

The pooled odds ratio for the four trial-declared outcomes named in the title was 0.907 (0.831 to 0.991) across 2 trials.¹

This pool is referred, not withdrawn. The stroke component is not the same component. EMPA-REG's 3-point MACE counts non-fatal stroke of any type; declare's counts ischemic stroke only. Haemorrhagic stroke is inside one composite and outside the other. Two different endpoints sharing a name. Declare registers two co-primaries and this review silently used one. The other -- CV death or hospitalisation for heart failure -- is at the same rank and is the endpoint on which declare was positive. An unrecorded selection among co-primaries is an unrecorded analytic decision. The obstacle is in the evidence. Withdrawing a published estimate is a published-number decision and belongs to Mahmood. The estimate is unchanged; the finding is complete and stated.²

Noted on this pool. A published synthesis of this question included 3 trials where this pool carries 2. Source: Kluger et al., Reviews in Cardiovascular Medicine 2018, PMID 31032602, 'Cardiorenal Outcomes in the canvas, declare-timi 58, and empa-reg outcome Trials'. The third trial is named: the canvas Program. It is in the title of the review and is not carried by this object. This is the only topic in the corpus where a trial we do not pool can be named. The estimate above is computed from the trials this object carries and is not withdrawn or altered by this note. What a reader is owed is the scope: a larger evidence base on this question exists in the literature, and whether this review's search should be widened is a decision that has not been made.³

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 2.27%; the estimated variance of the true effects between trials (tau-squared) was 0.000106, the heterogeneity test statistic Q was 1.02, on degrees of freedom 1.⁴

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.⁵

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.⁶

Comparison with published syntheses

Published syntheses were identified as follows. PubMed E-utilities, executed 2026-08-20. Query, counts and per-record disposition in ssot/sglt2-mace-cvot-review/appraisal/the screen of published syntheses.json. 313 records matched; Only 300 ids were returned because the request capped at 300, so 13 matched records were never listed and are not merely unread -- they were never seen. 300 summaries read, 4 flagged by title, 2 appraised against their abstracts, 296 not appraised.¹

Disagreements between sources

not recorded on the page this object was extracted from¹

not recorded on the page this object was extracted from²

Limitations

What this review does not give a clinician: the number of events in each arm and any absolute effect or number needed to treat. 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

Software availability

Analyses were computed under R 4.6.0 with metafor 5.0.1.¹

Reporting guidelines

This review reports against PRISMA 2020. A screening record is held on this object and the flow it supports is shown in the Methods. The completed PRISMA checklist and FLOW diagram are not held here: the venue requires them deposited in an approved repository with a DOI cited in the Data Availability Statement, and minting that DOI is an author action rather than a build step.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.