Apixaban for the treatment of venous thromboembolism: eight trials report an outcome named for recurrent VTE, and three of them count the same thing

Registration and administrative information (PROSPERO field set)

ClinicalTrials.gov API v2

Query as executed:

Executed 2026-08-19 against ClinicalTrials.gov API v2, raw. query.cond="venous thromboembolism OR deep vein thrombosis OR pulmonary embolism"; query.intr="apixaban"; filter.advanced=AREA[StudyType]INTERVENTIONAL -- NO PHASE FILTER. 82 records, returned == totalCount, nextPageToken null.

ClinicalTrials.gov API v2 -- first query, recorded because it missed

Query as executed:

same terms with filter.advanced=... AND AREA[Phase](PHASE3 OR PHASE4)

PubMed (ncbi e-utilities esearch)

Query as executed:

apixaban AND venous thromboembolism

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.

Risk of bias (RoB-2)

Variant:

Unit assessed: A result, not a study -- Handbook 8.2. Every judgement below names the outcome it is about, and for two of the three that outcome is a secondary.

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 15 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

• — https://clinicaltrials.gov/study/NCT01780987
• — https://clinicaltrials.gov/study/NCT02829957
• — https://clinicaltrials.gov/study/NCT03045406
• — https://clinicaltrials.gov/study/NCT03266783

Regulatory documents

Methods and guidance

Sources

Visual abstract

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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 9f309bd655dc7b7c), 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, 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 CROSSING the no-difference line because it does: 0.344 to 1.753 spans 1. A graphical abstract travels without its caption, and one showing a favourable point estimate without showing that its interval includes no effect would overstate a null result.

Risk of bias, both assessors

⬇ SVG (vector) 13 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': 15, 'per domain total': 15, 'per domain rate pct': 100.0, 'overall agreed': 3, 'overall total': 3, '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 80 KB

All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: dd33d4f986f7c7c5), 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 3 trials is 7 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

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All raster formats were generated at build time from the same SVG as the graphic above (SHA-256, first 16 hex characters: 2316b730fa24744e), 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 = 3 a meta-regression would be fitted on 3 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.

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

Apixaban for the treatment of venous thromboembolism: eight trials report an outcome named for recurrent VTE, and three of them count the same thing¹

Abstract

Question. In adults with acute or recent venous thromboembolism, what is the effect of apixaban compared with conventional anticoagulation, another direct oral anticoagulant, or placebo on recurrent venous thromboembolism and on bleeding?¹

Methods. ClinicalTrials.gov API v2 and PubMed (ncbi e-utilities esearch) were searched; 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); and certainty was rated with GRADE.²

Results. Recurrent symptomatic venous thromboembolism -- nonfatal deep vein thrombosis or nonfatal pulmonary embolism -- with NO death term: risk ratio 0.776 (0.344 to 1.75) across 3 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 0%).³

Introduction

Background. This review asks: In adults with acute or recent venous thromboembolism, what is the effect of apixaban compared with conventional anticoagulation, another direct oral anticoagulant, or placebo on recurrent venous thromboembolism and on bleeding? It pools 3 randomised trials, against another anticoagulant. The outcome pooled is Recurrent symptomatic venous thromboembolism -- nonfatal deep vein thrombosis or nonfatal pulmonary embolism -- with NO death term.¹

Methods — search

Searches were executed in ClinicalTrials.gov API v2 on 2026-08-19 with the query, verbatim: Executed 2026-08-19 against ClinicalTrials.gov API v2, raw. query.cond="venous thromboembolism OR deep vein thrombosis OR pulmonary embolism"; query.intr="apixaban"; filter.advanced=area[StudyType]interventional -- no phase filter. 82 records, returned == totalCount, nextPageToken null.. It returned 82 record(s).¹

Searches were executed in ClinicalTrials.gov API v2 -- first query, recorded because it missed on 2026-08-19 with the query, verbatim: same terms with filter.advanced=... And area[Phase](PHASE3 OR PHASE4). It returned 49 record(s).²

Searches were executed in PubMed (ncbi e-utilities esearch) on 2026-08-19 with the query, verbatim: apixaban and venous thromboembolism. It returned 50 record(s).³

Primary trials. No bibliographic search for primary trials was run. The 4 included trials were identified by reading named registrations on the dates recorded on each entry.⁴

Methods — eligibility criteria

Population: adults with acute or recent venous thromboembolism being treated for it. Intervention: apixaban as the randomised intervention -- the drug itself, not a class of which it is one member. Comparator: conventional anticoagulation, another direct oral anticoagulant, or placebo. Estimand, which governs poolability and not eligibility: recurrent venous thromboembolism, or major bleeding, at any registered rank. And the boundary with the prophylaxis review: extended anticoagulation in patients who have already had a venous thromboembolism is treatment and belongs here; primary prophylaxis in patients who have not is prevention and belongs to the sibling. The discriminator is read from each trial's eligibility criteria, because the registry's coded `primaryPurpose` does not carry it and both conventions are used for both situations. Criteria are derived post hoc and say so.¹

Each criterion above is recorded with the source it was derived from in `screening.eligibility_provenance`; none is asserted here without one.²

Methods — how many studies at each stage

The PRISMA 2020 flow counts are held for this review and reconcile with the executed searches above; they are set out in the flow figure and its accompanying counts.¹

The unscreened remainder is 0.²

Methods — outcomes sought at every registered rank

Before deciding which outcomes could be combined, every trial was read at every registered rank -- primary, secondary and other -- asking: does each trial report a recurrent-VTE efficacy outcome at any registered rank -- primary, secondary or other -- before concluding which trials can be combined? Yes at every rank, and the answer does not settle poolability¹

Methods — synthesis

For recurrent symptomatic venous thromboembolism -- nonfatal deep vein thrombosis or nonfatal pulmonary embolism -- with NO death term, a random-effects model was fitted with the REML estimator.¹

Intervals are 95% confidence intervals.²

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 Higgins JPT, Savovic J, Page MJ, Elbers RG, Sterne JAC. Chapter 8: Assessing risk of bias in a randomized trial. In: Cochrane Handbook for Systematic Reviews of Interventions version 6.5.1. A result, not a study -- Handbook 8.2. Every judgement below names the outcome it is about, and for two of the three that outcome is a secondary. 3 result-level assessments were made. A domain that cannot be judged from the registration and the posted results is no information, never LOW. Low-by-default asserts a fact; high-by-default invents a defect.³

A ceiling applies to every risk-of-bias judgement in this review; it is stated with the assessment itself rather than summarised here.⁴

Certainty of evidence was rated with GRADE, following Cochrane Handbook for Systematic Reviews of Interventions version 6.5.1, Chapter 14. HIGH for a body of randomised evidence, then rated down. 1 pooled outcome(s) were rated. No domain is rated up.⁵

Results

The pooled risk ratio for recurrent symptomatic venous thromboembolism -- nonfatal deep vein thrombosis or nonfatal pulmonary embolism -- with NO death term was 0.776 (0.344 to 1.75, 95% interval) across 3 trials, against another anticoagulant.¹

Noted on this pool. Read this beside the estimate. Not one of the three contributing trials masks anybody: NCT03045406, NCT03266783 and NCT01780987 all register masking: none. The endpoint is adjudicated on all three, which is the standard mitigation for an open-label anticoagulation trial, but no registration states that the adjudicators were blinded. On NCT03266783 the registered primary is clinically relevant bleeding and recurrent VTE is the third of nine secondaries. On NCT01780987 the registered primary is major bleeding and recurrent VTE is the first of five. Only caravaggio contributes its own registered primary. Dalteparin, rivaroxaban, and unfractionated heparin followed by warfarin. The pooled quantity is therefore apixaban against whatever else was given, which is one step from any question a reader has. This object's GRADE rates indirectness down for it and the certainty here is very LOW.²

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 1.26, on degrees of freedom 2. computed; tau-squared is 0 and at k=3 that is an estimate from almost no information, which is why the interval is Knapp-Hartung on 2 degrees of freedom rather than a normal one³

The grounds for pooling are recorded as: Three trials randomise apixaban itself against another anticoagulant for the acute event and post an arm-level count of recurrent symptomatic VTE with no death term. Their definitions were read and compared, not their names. Where a later pool on this page rests on the same grounds, they are not restated.⁴

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.⁵

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 0 of the 3 results and no adjudication has been performed, so this review holds no final risk-of-bias judgement for these results. Assessor 1 recorded: 3 at some concerns. Assessor 2 recorded: 3 at some concerns. 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. HIGH for a body of randomised evidence, then rated down.¹

No domain is rated up.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

Where a result is rated worse than LOW overall, the domain carrying that judgement is: measurement of the outcome on 3 result(s), selection of the reported result on 2 result(s). The overall rating is the worst domain, so these are the domains that determine it.⁴

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

Data availability

Every trial in this review is keyed to a registration identifier, verified by live fetch of the raw ClinicalTrials.gov v2 record and comparison of the returned nctId against the id stored on this object on 2026-08-19.¹

Software availability

Analyses were computed under R 4.6.0 with metafor 5.0.1.¹

Intervals are reported at the 95% level.²

Note on registration

Protocol status. Prespecified: False. A protocol specified before data collection is a historical fact about the past and cannot be created retrospectively. Writing one now and calling it prespecified would invalidate every other refusal on this page, because a reader who caught it would be right to disbelieve all of them.¹

Eligibility criteria were derived post hoc when `apixaban-vte` was split in two on 2026-08-19, after the parent object's included set existed. The derivation is recorded element by element in `screening.eligibility`, and the criterion that separates this review from its sibling is stated in full at `screening.boundary_criterion`.²

Authority: Mecir R107 permits post-hoc eligibility criteria provided they are declared as such. They are declared, here and on the page.³

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.⁴

References

Figures

Trial characteristics

Submission conformance

This review was built to page standard 1.14.0-2026-08-19 (PAGE-STANDARD.md), by ssot/build_to_standard.py on 2026-08-19. A page built below the current standard is knowably below it rather than silently stale.¹

12 machine-checked properties were verified for this page before it was published; the checks and their names are recorded with the build rather than here.²

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.