Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

Name: Kaimen Rigor review — Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.
Item: Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.
Rating: 96
Author: Alpha1

Adeoye O, Broderick J, Derdeyn CP, Grotta JC, Barsan W, Bentho O, Berry S, Concha M, Davis I, Demel S, Elm J, Gentile N, Graves T, Hoffman M, Huang J, Ingles J, Janis S, Jasne AS, Khatri P, Levine SR, Majjhoo A, Panagos P, Pancioli A, Pizzella S, Ranasinghe T, Sabagha N, Sivakumar S, Streib C, Vagal A, Wilson A, Wintermark M, Yoo AJ, Barreto AD

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Kaimen Rigor review — 4.25★ (Strong), 0 critical, 2 high issues for “Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.”

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Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

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Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

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DOI

10.1056/NEJMoa2314779

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

Paper source

Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

Read full text (PMC)

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Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) covered 2 of 6 reported means. The other 4 do not state their group size where the value is printed, and these checks need the count the mean was averaged over, so they were not checked.

Findings by category

101ArithmeticNumerical inconsistencies 02OverreachNone found 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit3 minor suggestions

This Kaimen Rigor review uses Kaimen 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.

This is a well-conducted phase 3 randomized trial with rigorous design, clear ethical approvals, and appropriate statistical methods. The main weaknesses are minor reporting gaps: the data sharing statement is not detailed, statistical software is not named, and a few copyedit issues exist.

Both reviewers independently scored all eight dimensions and agreed on all statuses. The study type is interventional. Non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification checked only 1 test; other statistics were not machine-verified.

Numerical inconsistencies

1 finding · worst low

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Internal contradictions in the reported numbersAssessed

Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.

Overstated conclusions

None found

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Checked — nothing surfaced.

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

Data authenticity concerns

None found

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Checked — nothing surfaced.

Reporting gaps

1 finding · worst medium

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

The introduction cites prior trials with conflicting findings for argatroban and equivocal phase 2 results for eptifibatide, and explains the biological rationale for each drug. The premise logically leads to the trial objective of comparing these agents against placebo. Limitations of prior research are implicitly addressed by the design of a larger, phase 3 trial, though not explicitly framed as addressing prior limitations.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior trials and explaining the rationale for testing argatroban and eptifibatide as adjuncts to thrombolysis.

Evidence

“Two recent trials yielded conflicting findings regarding the benefit of argatroban in ischemic stroke.”

Introduction ¶2Find in source

“We previously conducted three phase 2 trials that showed equivocal effects of the combination of eptifibatide with thrombolysis.”

Introduction ¶3Find in source

“On the basis of these findings regarding argatroban and eptifibatide, we conducted the Multiarm Optimization of Stroke Thrombolysis (MOST) trial.”

Introduction ¶4Find in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise by citing prior trials and phase 2 studies, and provides a logical rationale for the trial.

Evidence

“Two recent trials yielded conflicting findings regarding the benefit of argatroban in ischemic stroke.”

Introduction ¶2Find in source

“On the basis of these findings regarding argatroban and eptifibatide, we conducted the Multiarm Optimization of Stroke Thrombolysis (MOST) trial.”

Introduction ¶3Find in source

absence[Introduction]

Limitations of prior work are not explicitly discussed.

The trial is described as randomized, single-blind, with response-adaptive randomization. The randomization method is described in terms of ratios and adaptation rules, but the specific algorithm (e.g., biased coin) is mentioned without full detail. Blinding is described: investigators were aware, but patients and outcome assessors were blinded. A power analysis is not explicitly stated, but the maximum planned sample size of 1200 is given, and the adaptive design includes futility and efficacy stopping rules. Inclusion/exclusion criteria are described. Outlier handling is not explicitly addressed, but missing data imputation is described. Controls are the placebo group. Independent replication is not applicable for a single pivotal trial.

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous with clear randomization, blinding, and pre-specified analysis methods, though some details like the randomization algorithm are not fully described.

Evidence

“The randomization algorithm controlled for imbalances in baseline NIHSS score and age with the use of a biased coin if the maximum tolerated imbalance was exceeded.”

MethodsFind in source

“Investigators were aware of the trial-group assignments, but patients and legally authorized representatives were unaware of the trial-group assignments throughout the trial.”

MethodsFind in source

“The maximum planned sample size was 1200.”

MethodsFind in source

PASSReviewer 2· 95% conf

The trial design is rigorous with clear randomization, blinding, and pre-specified analysis methods, though the single-blind design is a noted limitation.

Evidence

“The first 150 patients were randomly assigned in a 1:1:1 ratio to receive argatroban, eptifibatide, or placebo.”

MethodsFind in source

“Investigators were aware of the trial-group assignments, but patients and legally authorized representatives were unaware of the trial-group assignments throughout the trial.”

MethodsFind in source

“The maximum planned sample size was 1200.”

MethodsFind in source

The paper reports sex, age, race, ethnicity, and various comorbidities in Table 1. Since both sexes are enrolled, sex_justified is not applicable. Age and health status are reported. Demographics are adequately reported. Species/strain and housing conditions are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and clinical characteristics are well reported, including sex, age, race, and comorbidities.

Evidence

“Male sex — no. (%) | 118 (52) | 31 (53) | 109 (48)”

Table 1Find in source

“Median age (IQR) — yr | 66 (58–78) | 68 (60–79) | 68 (58–79)”

Table 1Find in source

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported, including sex, age, race, and comorbidities.

Evidence

“Male sex — no. (%) | 118 (52) | 31 (53) | 109 (48)”

Table 1Find in source

“Median age (IQR) — yr | 66 (58–78) | 68 (60–79) | 68 (58–79)”

Table 1Find in source

paraphrase[Table 1]

“Race — no. (%) | White | 170 (75) | 41 (69) | 156 (69)”

The trial was approved by the University of Cincinnati central institutional review board and the FDA, and written informed consent was obtained from all patients or their representatives. Regulatory compliance is implied through FDA oversight and the trial being conducted under an IND.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approval and informed consent are clearly documented.

Evidence

paraphrase[Methods, Trial Design and Oversight]

“The protocol ... was approved by the University of Cincinnati central institutional review board and the Food and Drug Administration (Investigational New Drug number, 63550).”

“All the patients or their legally authorized representatives provided written informed consent.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and consent are clearly documented, including IRB approval and written informed consent.

Evidence

paraphrase[Methods, Trial Design and Oversight]

“The protocol ... was approved by the University of Cincinnati central institutional review board and the Food and Drug Administration (Investigational New Drug number, 63550).”

“All the patients or their legally authorized representatives provided written informed consent.”

MethodsFind in source

The drugs are named with doses and regimens. The statistical software is not explicitly named, but the analysis methods are described. Since this is a drug trial, the investigational products are the key resources and are adequately identified. Antibodies, cell lines, mycoplasma, and organisms are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (argatroban, eptifibatide, alteplase, tenecteplase) are identified with dosing details, and statistical software is mentioned.

Evidence

“Patients in the argatroban group received a bolus (100 μ g per kilogram) followed by a 12-hour infusion (3 μ g per kilogram per minute).”

MethodsFind in source

absence[Methods, Statistical Analysis]

Statistical software is not explicitly named.

PASSReviewer 2· 90% conf

The investigational products (argatroban, eptifibatide, alteplase, tenecteplase) are identified with dosing regimens, and statistical software is implied.

Evidence

“Patients in the argatroban group received a bolus (100 μ g per kilogram) followed by a 12-hour infusion (3 μ g per kilogram per minute).”

MethodsFind in source

absence[Methods, Statistical Analysis]

Statistical software is not explicitly named.

The primary analysis uses a Bayesian normal dynamic linear model, and posterior probabilities are reported. Secondary outcomes use odds ratios with 95% CIs. The paper reports exact posterior probabilities (e.g., 0.002, 0.041) and CIs. Statistical software is not identified. Data presentation includes means, SDs, and percentages. Mathematical plausibility checks are not applicable due to continuous outcomes and large N.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well-described, with Bayesian analysis for the primary outcome and exact posterior probabilities reported.

Evidence

“The primary analysis compared each active-treatment group with the placebo group regarding 90-day utility-weighted modified Rankin scale scores, with adjustment for baseline NIHSS score in a Bayesian normal dynamic linear model.”

Statistical analysisFind in source

paraphrase[Results, Primary Efficacy Analysis]

“The posterior probability that argatroban was better than placebo was 0.002 ... and that eptifibatide was better than placebo was 0.041”

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with Bayesian analysis and sensitivity analyses; p-values are reported as posterior probabilities.

Evidence

Statistical analysisFind in source

paraphrase[Results, Primary Efficacy Analysis]

“The posterior probability that argatroban was better than placebo was 0.002 ... and that eptifibatide was better than placebo was 0.041.”

“90-Day modified Rankin scale score of 0 to 2 or return to prestroke score — no. (%) | 139 (61) | 26 (44) | 0.50 (0.28 to 0.90) | 126 (56) | 0.80 (0.55 to 1.16)”

Table 2Find in source

The paper mentions a data sharing statement is available with the full text, but the specific mechanism is not described in the text. No repository deposit or accession numbers are provided. Code sharing is not applicable as no custom code is mentioned.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data sharing statement is mentioned but not detailed, and no repository or accession numbers are provided.

Evidence

paraphrase[End of paper]

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

WARNReviewer 2· 80% conf

A data sharing statement is mentioned but not detailed in the text; no repository or accession numbers are provided.

Evidence

paraphrase[End of paper]

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

absence[End of paper]

No repository or accession numbers are provided.

The trial is registered (NCT03735979). Methods are detailed enough for replication. No reporting guideline is explicitly mentioned, but the paper follows CONSORT-like structure. All outcomes are reported, including negative results. Limitations are discussed. Funding and COI are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and conclusions are proportional.

Evidence

paraphrase[Abstract]

“MOST ClinicalTrials.gov number, NCT03735979”

“One limitation of the trial is the single-blind design.”

DiscussionFind in source

PASSReviewer 2· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and conclusions are proportional to the evidence.

Evidence

paraphrase[Abstract]

“MOST ClinicalTrials.gov number, NCT03735979”

“One limitation of the trial is the single-blind design.”

DiscussionFind in source

“Supported by a grant (1U01NS100699-01A1) from the National Institute of Neurological Disorders and Stroke.”

End of paperFind in source

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

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 31 references by DOI: 31 verified.

1 data/code link checked; 1 live.

Copyediting

3 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 3 minor suggestions below.

3 copyedit issues flagged: mostly consistency, typo.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and methodologically sound. An informed reader should weigh the minor reporting gaps (data sharing details, software identification) and the copyedit issues, but none undermine the validity of the findings. No erratum is warranted for the identified issues.

1.
HIGHdata code
In the Data Availability section, specify the data sharing mechanism (e.g., 'available on reasonable request to the corresponding author' with conditions) to meet the journal's data sharing policy.
The current statement is vague and does not provide readers with a clear path to access the data.
2.
HIGHreporting
In the Methods, name the statistical software (e.g., R version, SAS version) used for the Bayesian analysis and secondary analyses.
Identifying the software is essential for reproducibility and is a standard reporting requirement.
3.
MEDIUMreporting
In the Methods or Supplementary, reference the CONSORT reporting guideline to enhance transparency.
Explicitly stating adherence to CONSORT helps readers assess the completeness of reporting.
4.
MEDIUMreporting
In the Results, provide a CONSORT flow diagram to clearly show patient disposition and missing data.
A flow diagram improves transparency about patient flow and missing data handling.
5.
MEDIUMrigor
In the Discussion, explicitly address how the limitations of prior phase 2 trials (e.g., lack of thrombectomy) were mitigated in the current trial design.
Addressing prior limitations strengthens the scientific premise and contextualizes the trial's contribution.
6.
MEDIUMdata code
In the Data Availability, consider depositing de-identified aggregate data in a public repository (e.g., Dryad) if permitted by consent and privacy regulations.
Public data deposition maximizes transparency and allows independent verification.
7.
MEDIUMrigor
In the Methods, describe the randomization algorithm in more detail, including the specific biased coin procedure and how imbalances were controlled.
A fuller description of the randomization algorithm enhances reproducibility.
8.
MEDIUMrigor
In the Methods, include a formal power analysis or sample size justification, detailing the assumed effect size, alpha, and power.
A formal power analysis is expected for a phase 3 trial and helps readers assess the trial's ability to detect effects.
9.
LOWcopyedit
In Results, Secondary Efficacy Analyses, correct the typo 'odd ratio' to 'odds ratio'.
Fixing the typo improves clarity and professionalism.
10.
LOWcopyedit
In Table 3, ensure the safety population N is clearly labeled and consistent with the definition (e.g., 'Safety population' with N=483).
Clarifying the safety population N avoids confusion with the randomized N.
11.
LOWcopyedit
In the Abstract and Results, ensure consistent use of 'assigned' vs 'randomized' throughout.
Consistent terminology prevents ambiguity about the trial procedures.

Full text (32,312 chars)Analyzed: Aug 16, 2026

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Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

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DOI

10.1056/NEJMoa2314779

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Record fingerprint

d16e06dc529590e92d95a3ca8afbecae7d5c7e0f9c8919b7ce06565f578673a4

Verify via API

Issued Aug 16, 2026Engine 7.39.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

Kaimen Rigor review

Kaimen Rigor reviewed

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) covered 2 of 6 reported means. The other 4 do not state their group size where the value is printed, and these checks need the count the mean was averaged over, so they were not checked.

Findings by category

101ArithmeticNumerical inconsistencies 02OverreachNone found 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit3 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.

Overstated conclusions

None found

Checked — nothing surfaced.

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

Data authenticity concerns

None found

Checked — nothing surfaced.

Reporting gaps

1 finding · worst medium

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise by citing prior trials and explaining the rationale for testing argatroban and eptifibatide as adjuncts to thrombolysis.

Evidence

“Two recent trials yielded conflicting findings regarding the benefit of argatroban in ischemic stroke.”

Introduction ¶2Find in source

“We previously conducted three phase 2 trials that showed equivocal effects of the combination of eptifibatide with thrombolysis.”

Introduction ¶3Find in source

“On the basis of these findings regarding argatroban and eptifibatide, we conducted the Multiarm Optimization of Stroke Thrombolysis (MOST) trial.”

Introduction ¶4Find in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise by citing prior trials and phase 2 studies, and provides a logical rationale for the trial.

Evidence

“Two recent trials yielded conflicting findings regarding the benefit of argatroban in ischemic stroke.”

Introduction ¶2Find in source

“On the basis of these findings regarding argatroban and eptifibatide, we conducted the Multiarm Optimization of Stroke Thrombolysis (MOST) trial.”

Introduction ¶3Find in source

absence[Introduction]

Limitations of prior work are not explicitly discussed.

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous with clear randomization, blinding, and pre-specified analysis methods, though some details like the randomization algorithm are not fully described.

Evidence

“The randomization algorithm controlled for imbalances in baseline NIHSS score and age with the use of a biased coin if the maximum tolerated imbalance was exceeded.”

MethodsFind in source

“Investigators were aware of the trial-group assignments, but patients and legally authorized representatives were unaware of the trial-group assignments throughout the trial.”

MethodsFind in source

“The maximum planned sample size was 1200.”

MethodsFind in source

PASSReviewer 2· 95% conf

The trial design is rigorous with clear randomization, blinding, and pre-specified analysis methods, though the single-blind design is a noted limitation.

Evidence

“The first 150 patients were randomly assigned in a 1:1:1 ratio to receive argatroban, eptifibatide, or placebo.”

MethodsFind in source

“Investigators were aware of the trial-group assignments, but patients and legally authorized representatives were unaware of the trial-group assignments throughout the trial.”

MethodsFind in source

“The maximum planned sample size was 1200.”

MethodsFind in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and clinical characteristics are well reported, including sex, age, race, and comorbidities.

Evidence

“Male sex — no. (%) | 118 (52) | 31 (53) | 109 (48)”

Table 1Find in source

“Median age (IQR) — yr | 66 (58–78) | 68 (60–79) | 68 (58–79)”

Table 1Find in source

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported, including sex, age, race, and comorbidities.

Evidence

“Male sex — no. (%) | 118 (52) | 31 (53) | 109 (48)”

Table 1Find in source

“Median age (IQR) — yr | 66 (58–78) | 68 (60–79) | 68 (58–79)”

Table 1Find in source

paraphrase[Table 1]

“Race — no. (%) | White | 170 (75) | 41 (69) | 156 (69)”

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approval and informed consent are clearly documented.

Evidence

paraphrase[Methods, Trial Design and Oversight]

“The protocol ... was approved by the University of Cincinnati central institutional review board and the Food and Drug Administration (Investigational New Drug number, 63550).”

“All the patients or their legally authorized representatives provided written informed consent.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and consent are clearly documented, including IRB approval and written informed consent.

Evidence

paraphrase[Methods, Trial Design and Oversight]

“The protocol ... was approved by the University of Cincinnati central institutional review board and the Food and Drug Administration (Investigational New Drug number, 63550).”

“All the patients or their legally authorized representatives provided written informed consent.”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (argatroban, eptifibatide, alteplase, tenecteplase) are identified with dosing details, and statistical software is mentioned.

Evidence

“Patients in the argatroban group received a bolus (100 μ g per kilogram) followed by a 12-hour infusion (3 μ g per kilogram per minute).”

MethodsFind in source

absence[Methods, Statistical Analysis]

Statistical software is not explicitly named.

PASSReviewer 2· 90% conf

The investigational products (argatroban, eptifibatide, alteplase, tenecteplase) are identified with dosing regimens, and statistical software is implied.

Evidence

“Patients in the argatroban group received a bolus (100 μ g per kilogram) followed by a 12-hour infusion (3 μ g per kilogram per minute).”

MethodsFind in source

absence[Methods, Statistical Analysis]

Statistical software is not explicitly named.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well-described, with Bayesian analysis for the primary outcome and exact posterior probabilities reported.

Evidence

Statistical analysisFind in source

paraphrase[Results, Primary Efficacy Analysis]

“The posterior probability that argatroban was better than placebo was 0.002 ... and that eptifibatide was better than placebo was 0.041”

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with Bayesian analysis and sensitivity analyses; p-values are reported as posterior probabilities.

Evidence

Statistical analysisFind in source

paraphrase[Results, Primary Efficacy Analysis]

“The posterior probability that argatroban was better than placebo was 0.002 ... and that eptifibatide was better than placebo was 0.041.”

“90-Day modified Rankin scale score of 0 to 2 or return to prestroke score — no. (%) | 139 (61) | 26 (44) | 0.50 (0.28 to 0.90) | 126 (56) | 0.80 (0.55 to 1.16)”

Table 2Find in source

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data sharing statement is mentioned but not detailed, and no repository or accession numbers are provided.

Evidence

paraphrase[End of paper]

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

WARNReviewer 2· 80% conf

A data sharing statement is mentioned but not detailed in the text; no repository or accession numbers are provided.

Evidence

paraphrase[End of paper]

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

absence[End of paper]

No repository or accession numbers are provided.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and conclusions are proportional.

Evidence

paraphrase[Abstract]

“MOST ClinicalTrials.gov number, NCT03735979”

“One limitation of the trial is the single-blind design.”

DiscussionFind in source

PASSReviewer 2· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and conclusions are proportional to the evidence.

Evidence

paraphrase[Abstract]

“MOST ClinicalTrials.gov number, NCT03735979”

“One limitation of the trial is the single-blind design.”

DiscussionFind in source

“Supported by a grant (1U01NS100699-01A1) from the National Institute of Neurological Disorders and Stroke.”

End of paperFind in source

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

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 31 references by DOI: 31 verified.

1 data/code link checked; 1 live.

Copyediting

3 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 3 minor suggestions below.

3 copyedit issues flagged: mostly consistency, typo.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHdata code
In the Data Availability section, specify the data sharing mechanism (e.g., 'available on reasonable request to the corresponding author' with conditions) to meet the journal's data sharing policy.
The current statement is vague and does not provide readers with a clear path to access the data.
2.
HIGHreporting
In the Methods, name the statistical software (e.g., R version, SAS version) used for the Bayesian analysis and secondary analyses.
Identifying the software is essential for reproducibility and is a standard reporting requirement.
3.
MEDIUMreporting
In the Methods or Supplementary, reference the CONSORT reporting guideline to enhance transparency.
Explicitly stating adherence to CONSORT helps readers assess the completeness of reporting.
4.
MEDIUMreporting
In the Results, provide a CONSORT flow diagram to clearly show patient disposition and missing data.
A flow diagram improves transparency about patient flow and missing data handling.
5.
MEDIUMrigor
In the Discussion, explicitly address how the limitations of prior phase 2 trials (e.g., lack of thrombectomy) were mitigated in the current trial design.
Addressing prior limitations strengthens the scientific premise and contextualizes the trial's contribution.
6.
MEDIUMdata code
In the Data Availability, consider depositing de-identified aggregate data in a public repository (e.g., Dryad) if permitted by consent and privacy regulations.
Public data deposition maximizes transparency and allows independent verification.
7.
MEDIUMrigor
In the Methods, describe the randomization algorithm in more detail, including the specific biased coin procedure and how imbalances were controlled.
A fuller description of the randomization algorithm enhances reproducibility.
8.
MEDIUMrigor
In the Methods, include a formal power analysis or sample size justification, detailing the assumed effect size, alpha, and power.
A formal power analysis is expected for a phase 3 trial and helps readers assess the trial's ability to detect effects.
9.
LOWcopyedit
In Results, Secondary Efficacy Analyses, correct the typo 'odd ratio' to 'odds ratio'.
Fixing the typo improves clarity and professionalism.
10.
LOWcopyedit
In Table 3, ensure the safety population N is clearly labeled and consistent with the definition (e.g., 'Safety population' with N=483).
Clarifying the safety population N avoids confusion with the randomized N.
11.
LOWcopyedit
In the Abstract and Results, ensure consistent use of 'assigned' vs 'randomized' throughout.
Consistent terminology prevents ambiguity about the trial procedures.

Full text (32,312 chars)Analyzed: Aug 16, 2026