Rigor Reviewed

Rigor-Reviewed Manuscript

Anticoagulation to prevent ischemic stroke and neurocognitive impairment in atrial fibrillation: the BRAIN-AF randomized clinical trial.

Name: Adcurare Rigor Record — Anticoagulation to prevent ischemic stroke and neurocognitive impairment in atrial fibrillation: the BRAIN-AF randomized clinical trial.
Item: Anticoagulation to prevent ischemic stroke and neurocognitive impairment in atrial fibrillation: the BRAIN-AF randomized clinical trial.
Rating: 96
Author: Adcurare

Rivard L, Khairy P, Talajic M, Tardif JC, Healey JS, Black SE, Andrade JG, Field TS, Nault I, Bherer L, Massoud F, Nattel S, Lanthier S, Racine N, Roux JF, Greiss I, Macle L, Guerra PG, Tadros R, Mayrand H, Gosselin G, Conen D, Bocti C, Chayer C, Deschaintre Y, Sandhu RK, Manlucu J, Khaykin Y, Verma A, Mondésert B, Dyrda K, Cadrin-Tourigny J, Thibault B, Raymond-Paquin A, Aguilar M, Brouillette J, Roussin A, Robillard A, Tremblay-Gravel M, David LP, Cossette M, Parkash R, Guertin MC, Roy D, BRAIN-AF investigators

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Adcurare Rigor Review — 3.75★ (Adequate), 0 critical, 3 high issues for “Anticoagulation to prevent ischemic stroke and neurocognitive impairment in atrial fibrillation: the BRAIN-AF randomized clinical trial.”

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Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 7, 2026

Adcurare Rigor Review

Rigor Reviewed

3.75 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.6.0Source: full text

Problems surfaced2 types

Data/code availability incomplete
Internal contradictions in the reported numbers

This Adcurare Rigor Review uses AI Rigor Reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

The BRAIN-AF trial manuscript is methodologically strong: a rigorous double-blind placebo-controlled RCT with clear rationale, appropriate design, detailed reporting of biological variables, ethical approvals, and transparent reporting. Minor gaps exist in data/code sharing (no analysis code shared), assumptions verification (proportional hazards not formally tested), and two small internal inconsistencies (denominator discrepancy, sample size typo).

Evaluated the full manuscript text. All eight dimensions were applicable. Two independent reviewers (R1 and R3) agreed on all dimensions; a third reviewer (R2) downgraded 'key resources' to warn based on lot-number absence, but the synthesis adopted the majority pass after weighing field norms. The statistics verification covered 2 tests (both consistent); untested assertions (e.g., untestable p-values) were not independently verified. Citations check: no retracted or unfound references — no citation actions needed. The internal contradictions flagged by the integrity check (denominators 610/623 vs 611/624; sample size 1424 vs 1428) are tracked as action items.

12 major claims checked against the paper's own evidence: all adequately supported.

Recomputed 2 tests: 2 consistent, 0 inconsistent, 2 via agent-written checks.

2 integrity concerns flagged (0 high).

Reporting

Eight Dimensions7 pass · 1 warn

Prior work is cited establishing AF as a risk factor for cognitive decline and dementia, with proposed mechanisms. The manuscript clearly acknowledges the uncertainty regarding cognitive benefit in low-stroke-risk patients, providing a logical rationale for the trial. Gaps in prior research (e.g., lack of randomized data in this population) are explicitly addressed by the design.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The scientific premise is well-established with clear citations, a logical rationale linking AF to cognitive decline, and acknowledgment of limitations in prior work.

Evidence

direct quote[Introduction, paragraph 1]

“Observational studies have also established a link between AF and cognitive decline and dementia”

direct quote[Introduction, paragraph 2]

“Observational studies and real-world healthcare data further suggest that anticoagulation may reduce cognitive decline and dementia risk in AF patients at high stroke risk”

direct quote[Introduction, paragraph 2]

“We, therefore, conducted the BRAIN-AF trial to determine whether a low dose of rivaroxaban reduces a composite endpoint of cognitive decline, stroke or transient ischemic attack compared to placebo in participants with AF who have no established indication for thromboprophylaxis”

PASSReviewer 2· 95% conf

The scientific premise is well-established with clear rationale linking AF to cognitive decline via subclinical cerebral emboli, and prior observational studies are cited showing anticoagulation may reduce cognitive decline in high-risk patients. The gap regarding low-risk patients is clearly identified.

Evidence

paraphrase[Introduction, paragraph 1]

“The authors state: 'More recently, observational studies have also established a link between AF and cognitive decline and dementia.'”

direct quote[Introduction, last paragraph]

“We, therefore, conducted the BRAIN-AF trial to determine whether a low dose of rivaroxaban (15 mg once daily) reduces a composite endpoint of cognitive decline, stroke or transient ischemic attack (TIA) compared to placebo in participants with AF who have no established indication for thromboprophylaxis.”

paraphrase[Discussion, paragraph 1 and 3]

“The authors note that previous evidence came from observational studies and that the benefit of anticoagulation in low-risk patients was uncertain, justifying the placebo-controlled design.”

PASSReviewer 3· 95% conf

The paper clearly establishes the scientific foundation by citing prior research on AF, cognitive decline, and anticoagulation, and provides a logical rationale for the trial.

Evidence

direct quote[Introduction, paragraph 2]

“Observational studies and real-world healthcare data further suggest that anticoagulation may reduce cognitive decline and dementia risk in AF patients at high stroke risk”

direct quote[Introduction, last paragraph]

direct quote[Introduction, paragraph 2]

“Observational studies and real-world healthcare data further suggest that anticoagulation may reduce cognitive decline and dementia risk in AF patients at high stroke risk”

All six applicable sub-criteria (randomization_method, randomization_unit, blinding_levels, power_analysis, inclusion_exclusion, outlier_handling in the form of analysis population definitions) are reported and adequate. Randomization used a permuted block method via IWRS, blinding was double-blind, sample size was justified, and missing data were handled by ITT, censored, and on-treatment analyses.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous: multicenter, double-blind, placebo-controlled with appropriate randomization, prespecified endpoints, and a comprehensive statistical analysis plan.

Evidence

direct quote[Methods, Trial procedures / Interventions]

“randomized in a 1:1 ratio to receive either rivaroxaban 15 mg once daily orally or a matching placebo through an interactive web response system (IWRS) using a permuted block randomization method”

direct quote[Methods, Statistical analysis]

“a sample size of 1,424 patients was required to detect a relative risk reduction of 30% with a power of 85% and a two-sided significance level of 0.05”

direct quote[Methods, Interventions]

“Patients and investigators remained blinded to treatment assignments until data analysis”

PASSReviewer 2· 95% conf

The study uses a rigorous double-blind, placebo-controlled randomized design with a pre-specified protocol, clear eligibility criteria, and appropriate statistical methods including a futility stopping rule. Applicable sub-criteria are adequately reported.

Evidence

direct quote[Methods, Interventions]

“Patients with an MMSE score ≥25 were then randomized in a 1:1 ratio to receive either rivaroxaban 15 mg once daily orally or a matching placebo through an interactive web response system (IWRS) using a permuted block randomization method.”

direct quote[Methods, Interventions]

“Patients and investigators remained blinded to treatment assignments until data analysis.”

direct quote[Methods, Statistical analysis]

“Based on these assumptions, a sample size of 1,424 patients was required to detect a relative risk reduction of 30% with a power of 85% and a two-sided significance level of 0.05. This sample size corresponded to an expected 410 patients with a primary efficacy outcome event.”

PASSReviewer 3· 98% conf

The study design is rigorous: double-blind, placebo-controlled, with permuted block randomization, a priori power analysis, detailed inclusion/exclusion criteria, and appropriate analysis populations.

Evidence

direct quote[Methods, Trial procedures]

direct quote[Methods, Statistical analysis]

“Based on these assumptions, a sample size of 1,424 patients was required to detect a relative risk reduction of 30% with a power of 85% and a two-sided significance level of 0.05.”

direct quote[Methods, Inclusion criteria and Exclusion criteria]

“Inclusion criteria: Age at consent ≥30 to ≤62 years; Non-valvular AF ... documented within the past 2 years ... Low risk of stroke as defined by the absence of all of the following: (i) Prior stroke or TIA; (ii) Hypertension; (iii) Diabetes mellitus; (iv) Congestive heart failure.”

The paper reports age, sex, race, education, depression, alcohol use, CHA2DS2-VA score, and other baseline characteristics in Table 1. Sex and age are reported and balanced. For a human clinical trial, species/strain/housing are not applicable. Demographics are comprehensively reported.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Key biological variables (age, sex, health status, demographics) are well-reported and balanced between groups.

Evidence

direct quote[Table 1]

“Age—years 53.4 ± 7.3; Female sex—no. (%) 316 (25.6)”

paraphrase[Table 1]

“Table 1 shows balance across age, sex, race, education, tobacco use, alcohol, and other clinical variables.”

PASSReviewer 2· 95% conf

Biological variables are well-reported: sex, age, weight, comorbidities, and baseline cognitive scores are provided in Table 1. Species/strain and housing are not applicable as this is a human trial.

Evidence

direct quote[Results, Table 1]

“Table 1 Characteristics of patients at baseline... Female sex—no. (%) 316 (25.6)... Age—years 53.4 ± 7.3”

direct quote[Table 1]

“Race or ethnic group—no. (%)... Caucasian 1,181 (95.6)... Level of education—years of schooling 15.2 ± 3.3”

PASSReviewer 3· 95% conf

Subject characteristics are well-reported: sex, age, race/ethnicity, and other demographics are provided in a baseline table.

Evidence

direct quote[Results, Table 1]

“Female sex—no. (%) | 316 (25.6) | 163 (26.7) | 153 (24.5)”

direct quote[Results, Table 1]

“Race or ethnic group—no. (%) ... Caucasian | 1,181 (95.6) | 588 (96.2) | 593 (95.0)”

direct quote[Results, Table 1]

“Body mass index—m kg −2 | 29.3 ± 5.4 | 29.3 ± 5.4 | 29.3 ± 5.5”

The paper names the IRB of the Montreal Heart Institute (protocol number MP-33-2014-1559) and states that it was authorized by Health Canada and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants. All three applicable sub-criteria are reported_and_adequate.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approval from a named IRB, informed consent, and regulatory compliance are clearly documented.

Evidence

direct quote[Methods, Trial design and ethical approval]

“institutional review boards of the Montreal Heart Institute (MP-33-2014-1559)”

direct quote[Methods, Study participants]

“All patients provided written informed consent to participate”

direct quote[Methods, Trial design and ethical approval]

“conducted in accordance with the principles of the Declaration of Helsinki”

PASSReviewer 2· 95% conf

Ethical approvals are clearly documented: the study was approved by the Montreal Heart Institute IRB (named protocol number) and each participating center, and written informed consent was obtained. Compliance with the Declaration of Helsinki is stated. Human-subject research requirements are fully met.

Evidence

direct quote[Methods, Trial design and ethical approval]

“The study was authorized by Health Canada and the institutional review boards of the Montreal Heart Institute (MP-33-2014-1559) and each participating center and was conducted in accordance with the principles of the Declaration of Helsinki.”

direct quote[Methods, Study participants]

“All patients provided written informed consent to participate.”

PASSReviewer 3· 98% conf

Ethical approval, informed consent, and regulatory compliance are all explicitly and adequately documented.

Evidence

direct quote[Methods, Trial design and ethical approval]

“The study was authorized by Health Canada and the institutional review boards of the Montreal Heart Institute (MP-33-2014-1559) and each participating center”

direct quote[Methods, Trial procedures]

“All patients provided written informed consent before any trial activities.”

direct quote[Methods, Trial design and ethical approval]

“conducted in accordance with the principles of the Declaration of Helsinki.”

This is a drug trial; the key resource is the investigational product. Rivaroxaban 15 mg and matching placebo are named, and Bayer Inc. is the supplier (an in-kind contribution). The dose and regimen are clear. For a human drug trial, antibodies, cell lines, mycoplasma, and organisms are not applicable. Statistical software (SAS version 9.4) is identified. This meets criteria.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (rivaroxaban and matching placebo) is identified with manufacturer and dose. Statistical software is identified. Other biological resources are not applicable.

Evidence

paraphrase[Methods, Interventions / Discussion]

“Rivaroxaban 15 mg once daily and a matching placebo were used, provided by Bayer Inc.”

direct quote[Methods, Statistical analysis]

“All statistical analyses were conducted using SAS software version 9.4”

WARNReviewer 2· 90% conf

The investigational product (rivaroxaban 15 mg) and placebo are identified, and the manufacturer (Bayer Inc.) is named. However, the dose, formulation, and regimen are reported but not with a catalog/lot number. Software (SAS 9.4) is adequately identified. Antibodies, cell lines, and organisms are not applicable for this clinical trial. The reagent identification is borderline adequate.

Evidence

direct quote[Methods, Interventions]

“Patients... randomized in a 1:1 ratio to receive either rivaroxaban 15 mg once daily orally or a matching placebo”

direct quote[Methods, Statistical analysis]

“All statistical analyses were conducted using SAS software version 9.4.”

direct quote[Methods, Trial design and ethical approval]

“Funding was provided by... Bayer Inc., including an in-kind contribution of study drugs.”

PASSReviewer 3· 90% conf

The investigational drug (rivaroxaban) and statistical software (SAS) are identified with sufficient detail; other resource types are not applicable.

Evidence

direct quote[Methods, Interventions; Acknowledgments]

“rivaroxaban 15 mg once daily orally or a matching placebo”

direct quote[Methods, Statistical analysis]

“All statistical analyses were conducted using SAS software version 9.4.”

The primary test is the generalized log-rank test for interval-censored data. The hazard ratio (1.10) and 95% CI (0.86–1.40) are reported, with exact p-value (0.46). Sensitivity analyses (censored, on-treatment) use the same method. The MMSE change is analyzed via ordinal logistic regression. Data presentation includes Kaplan-Meier-like curves with numbers at risk, and a forest plot for subgroups. Mathematical plausibility is high: e.g., percentages from Table 1 sum correctly (e.g., 95.6+0.5+0.1+2.4+0.7+0.6=99.9% for race, consistent with rounding). The reported mean age 53.4 with SD 7.3 and N 1235 is plausible. The MoCA baseline mean 27.5 with SD 2.0 is typical. The reported p-value for the primary outcome is exactly computed via the described method; I cannot recompute it exactly without the interval-censored data, but there is no reason to suspect error.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical methods are appropriate and well-described: named tests, handling of interval-censored data, prespecified analyses, and exact p-values reported.

Evidence

direct quote[Methods, Statistical analysis]

“analyzed using a generalized log-rank test for interval-censored data, stratified for the study phase. The primary efficacy outcome was also analyzed using a proportional hazards regression model fitted to handle interval-censored data and stratified for study phase”

direct quote[Results, Efficacy outcomes; Safety outcomes]

“hazard ratio of 1.10 (95% CI 0.86–1.40); P = 0.46 by generalized log-rank test”

direct quote[Methods, Statistical analysis]

“All statistical analyses were conducted using SAS software version 9.4”

PASSReviewer 2· 95% conf

Statistical methods are appropriate and well-described: tests are named (generalized log-rank, proportional hazards, ordinal logistic regression), exact p-values are reported (e.g., P=0.46), software is identified (SAS 9.4), and data presentation includes survival curves, effect sizes with 95% CIs, and per-group n. The primary analysis accounts for interval-censoring. Internal consistency checks show no arithmetic issues.

Evidence

direct quote[Methods, Statistical analysis]

“The primary efficacy outcome included an interval-censored component... analyzed using a generalized log-rank test for interval-censored data”

direct quote[Abstract and Results]

“P = 0.46”

direct quote[Results, Efficacy outcomes]

“hazard ratio of 1.10 (95% confidence interval 0.86–1.40); P = 0.46”

PASSReviewer 3· 92% conf

Statistical methods are well-described, tests are named, effect sizes with CIs are reported, and software is identified. Assumptions are handled through standard models for clinical trials.

Evidence

direct quote[Methods, Statistical analysis]

“The primary efficacy outcome included an interval-censored component (that is, cognitive decline) such that it was analyzed using a generalized log-rank test for interval-censored data, stratified for the study phase.”

direct quote[Results, Table 2]

“Hazard ratio (95% CI) | 1.10 (0.86, 1.40) | P = 0.46”

direct quote[Methods, Statistical analysis]

“All statistical analyses were conducted using SAS software version 9.4.”

The data availability paragraph states that deidentified data are stored at SERIANT and that requests directed to the corresponding author will be reviewed by the steering committee and IRB within 3 months. This is a concrete route (controlled access) with stated conditions and timeframe, which for patient-level data in Quebec may be considered adequate. However, the statement in the paper is not fully transparent about the criteria for approval, and the requirement to contact the corresponding author rather than a formal data access committee is less robust. Code sharing is not addressed.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

A data availability statement is present but offers only managed access via a secure environment; this is acceptable for clinical trial data but may limit reproducibility. No code sharing is reported.

Evidence

direct quote[Data availability]

“Deidentified data underlying the results reported in this article are stored in a secure research environment at SERIANT ... Qualified academic investigators may request controlled on-site access to analyze these data”

absence[Data availability / Methods]

No mention of code sharing or repository for analysis scripts.

WARNReviewer 2· 90% conf

A data availability statement is present but provides controlled access only and does not meet the field norm for clinical trial data sharing (no platform or clear conditions beyond 'on request'). No code repository is mentioned. The paper does not make data openly available, but invests in managed access per Quebec privacy law. The statement is reported but inadequate because the route is vague (requests to the corresponding author, no stated platform).

Evidence

direct quote[Data availability section]

“Deidentified data underlying the results reported in this article are stored in a secure research environment at SERIANT... Qualified academic investigators may request controlled on-site access... Requests should be directed to the corresponding author.”

WARNReviewer 3· 85% conf

A data availability statement is present with a concrete access route, but custom code is not shared or mentioned, triggering a warn.

Evidence

direct quote[Data availability section]

“Deidentified data underlying the results reported in this article are stored in a secure research environment at SERIANT (formerly the Montreal Health Innovations Coordinating Centre). Qualified academic investigators may request controlled on-site access to analyze these data after completion of all prespecified primary and secondary analyses and beginning 12 months after publication, for a period of 36 months.”

absence[Data availability and Methods]

No mention of code sharing; only the protocol and SAP are available in supplementary materials.

Trial registration is provided. The protocol and statistical analysis plan are available in the supplementary material. Limitations are discussed extensively (MoCA sensitivity, dose selection, generalizability, etc.). Conclusions are appropriately cautious: 'stopped early for futility' and 'no benefit' are stated. Funding sources and conflicts of interest are fully disclosed. A reporting summary is available (Nature Portfolio).

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Reporting is transparent: methods are detailed, the trial is registered (NCT02387229), limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

direct quote[Abstract; Methods]

“ClinicalTrials.gov registration: NCT02387229”

direct quote[Discussion, paragraph 6]

“A few methodological aspects merit consideration. First, by design, the primary outcome was heavily driven by cognitive decline...”

direct quote[Acknowledgements; Competing interests]

“This trial was funded by the Canadian Institutes of Health Research ... Competing interests L.R. reports research grants...”

PASSReviewer 2· 95% conf

The manuscript is well-reported: it includes a trial registration number (NCT02387229), methods detailed enough to replicate (protocol and SAP available as supplementary), limitations discussed, funding/COI statements, and conclusions proportional. Reporting guideline adherence is acknowledged via a links to a Reporting Summary.

Evidence

direct quote[Abstract and Methods]

“ClinicalTrials.gov registration: NCT02387229”

paraphrase[Discussion, paragraph 5-8]

“The authors discuss the reliance on MoCA for cognitive decline, the chosen dose of rivaroxaban, and the limited generalizability to other populations.”

direct quote[Acknowledgements and Competing interests]

“Funding was provided by the Canadian Institutes of Health Research... L.R. reports research grants from... Competing interests...”

PASSReviewer 3· 95% conf

The manuscript is transparent: methods are detailed, trial is registered, reporting guidelines are followed, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

direct quote[Abstract and Methods]

“ClinicalTrials.gov registration: NCT02387229”

direct quote[Discussion, paragraph 5]

“A few methodological aspects merit consideration. First, by design, the primary outcome was heavily driven by cognitive decline... Another consideration is the choice of a 15-mg dose of rivaroxaban.”

direct quote[Acknowledgements and Competing interests]

“This trial was funded by the Canadian Institutes of Health Research (CIHR, grant no. PJT-175207, L.R.), Canadian Stroke Prevention Network (CSPIN, L.R.), Montreal Heart Institute Foundation (L.R.) and BAYER Inc”

6 copyedit issues flagged: mostly consistency, clarity, punctuation.

Checked 50 references: 49 verified — 1 not checked.

Reproducibility

2 data/code links checked; 2 live.

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

Adcurare Rigor Action ItemsFinal pass before journal submission

The manuscript is ready to submit after correcting two small internal inconsistencies (denominator discrepancy in Results vs Table 2; sample size typo 1,424 vs 1,428) and adding a code availability statement. These are minor fixes; no reformulation of the science is needed. The methodological rigor is strong and the transparency is high.

1.
HIGHreporting
In the Results section (Efficacy outcomes), reconcile the denominators: the text states 130/610 and 126/623 participants, but Table 2 shows total randomized n=611 and n=624. Explain why 1 participant per group is excluded from the denominator (e.g., missing primary outcome data, withdrawn consent) and add a footnote or sentence clarifying.
This internal contradiction between text and table undermines reader trust in the reported event rates and is the most likely reviewer catch.
2.
HIGHreporting
Correct the planned sample size inconsistency: the Methods state 1,424 patients; the Discussion states 1,428. Unify to the correct number (confirm from the protocol/statistical analysis plan) and ensure all instances match.
A simple typographical inconsistency in the same manuscript suggests carelessness and invites questions about whether other numbers have been proofread.
3.
HIGHdata code
Add a code availability statement in the Data availability section (or a separate 'Code availability' section) specifying that the analysis scripts (SAS code) are available upon request or deposited in a repository (e.g., Zenodo, GitHub) with a DOI or link.
No code sharing is currently mentioned; this is the primary deficiency in data_code_availability and an increasingly standard expectation for clinical trial reports.
4.
MEDIUMstatistics
In the Methods (Statistical analysis), add a brief statement verifying that the proportional hazards assumption for the interval-censored data model was assessed (e.g., by testing Schoenfeld residuals or a time-by-covariate interaction), even if the test was non-significant.
Assumptions verification is not reported; adding this strengthens the statistical transparency and preempts reviewer queries.
5.
MEDIUMreporting
In the Methods (Trial design), add a sentence stating that the DSMB and interim analysis were blinded, or if not, describe the unblinding procedure for the futility analysis.
One reviewer noted that DSMB blinding is implicit but not explicitly described; a single sentence adds clarity and addresses a potential concern.
6.
MEDIUMreporting
In the Methods or Discussion, provide a brief justification for the 2-point MoCA threshold for cognitive decline (e.g., citing the reliable change index or a prior validation study).
The Discussion mentions that a 2-point change is a limitation, but placing the justification or citation in the Methods strengthens the a priori definition.
7.
MEDIUMreporting
In the Methods (Statistical analysis), explicitly state that no outliers were excluded from the primary intention-to-treat analysis; if any sensitivity analyses excluded outliers, describe the criteria.
Outlier handling is currently not reported; even if no outliers were excluded, stating this explicitly closes a checklist gap.
8.
MEDIUMreporting
In the Abstract, rephrase 'patients with prior AF' to 'patients with AF' for clarity, since all enrolled participants had AF at baseline.
Minor wording issue flagged by copyedit; 'prior AF' could confuse readers into thinking the AF had resolved.
9.
MEDIUMcopyedit
In the Discussion (paragraph 5), correct the subject-verb agreement: change 'induces' to 'induce' to agree with the plural subject 'contractions' ('The irregular cardiac contractions characteristic of AF induce beat-to-beat variability').
Grammatical error flagged by copyedit; a minor but visible fix.
10.
MEDIUMreporting
In the Methods (Statistical analysis), rephrase the sentence about right-censored outcomes to explicitly state they were analyzed using log-rank tests and proportional hazards models stratified by study phase, to avoid ambiguity flagged by copyedit.
Minor clarity improvement to ensure the analysis for each outcome type is unambiguously described.
11.
LOWreporting
In Table 1 footnote, add a note that MoCA and MMSE scores are reported as means ± SD, in addition to the existing note for other continuous variables.
Minor consistency improvement flagged by copyedit; ensures all mean values in the table are clearly labeled.
12.
LOWreporting
If possible, deposit the deidentified aggregate data or summary statistics (e.g., baseline demographics by group, event counts per visit) in a public repository (e.g., Figshare, ClinicalTrials.gov results) to complement the controlled-access mechanism at SERIANT.
Although the controlled-access route is adequate, a public aggregate dataset would increase transparency and reduce barriers for meta-analyses.

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Anticoagulation to prevent ischemic stroke and neurocognitive impairment in atrial fibrillation: the BRAIN-AF randomized clinical trial.

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DOI

10.1038/s41591-025-04101-y

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