A Randomized Trial of Drug Route in Out-of-Hospital Cardiac Arrest.
Couper K, Ji C, Deakin CD, Fothergill RT, Nolan JP, Long JB, Mason JM, Michelet F, Norman C, Nwankwo H, Quinn T, Slowther AM, Smyth MA, Starr KR, Walker A, Wood S, Bell S, Bradley G, Brown M, Brown S, Burrow E, Charlton K, Claxton Dip A, Dra'gon V, Evans C, Falloon J, Foster T, Kearney J, Lang N, Limmer M, Mellett-Smith A, Miller J, Mills C, Osborne R, Rees N, Spaight RES, Squires GL, Tibbetts B, Waddington M, Whitley GA, Wiles JV, Williams J, Wiltshire S, Wright A, Lall R, Perkins GD, PARAMEDIC-3 Collaborators
- DOI
- 10.1056/NEJMoa2407780
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-21
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/52f8c923-78c3-453e-ad72-cb837f2c2d93 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern−0.5★
- StatisticsPrinted percentage does not match its own count (capped)−0.25★
- ReportingData & code availability partially met−0.25★
- CitationsRetracted reference cited−0.25★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 2 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
- No data or code availability links were detected to verify.
- 01Cites retracted work
Retraction
“Intraosseous versus intravenous vascular access in upper extremity among adults with out-of-hospital cardiac arrest: cluster randomised clinical trial (VICTOR trial)”
Reference 27Find in source - 02Printed percentage does not match its own count
0.33% does not match the reported count 1/3040
“1/3040 (0.33)”
Table 3Find in source
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 and transparently reported randomized controlled trial with a rigorous design, clear ethical approvals, and appropriate statistical analysis. The main weakness is the lack of a concrete data availability statement, and there are minor copyedit issues including a typo and an internal inconsistency in the total N reported in Table 1.
Both reviewers agreed on study type (interventional) and on all dimension statuses except data code availability, where one found a vague statement and the other found none; the synthesized status is warn. The statistics verification component checked only a subset of tests (4 tests, 3 consistent, 1 inconsistent), so the paper's statistics are not fully verified. The citation component flagged one retracted reference.
Numerical inconsistencies
2 findings · worst mediumValues 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.
- Printed percentage does not match its own countRecomputed
- Internal contradictions in the reported numbersAssessed
Recomputed 3 tests: 3 consistent, 0 inconsistent; 1 recomputed directly from the reported test statistics, 2 via agent-written checks. 1 printed percentage that does not match its own count.
- PERCENT0.33% does not match the reported count 1/3040
“1/3040 (0.33)”
Table 3Find in source
- CONSISTENTreported p = .741 · recomputed p = .741Recomputed adjusted odds ratio 0.945 (95% CI 0.676–1.322), reported p=0.741
“adjusted odds ratio 0.945, 95% confidence interval 0.676-1.322, p=0.741”
Taken as given: 0.676–1.322 is a two-sided 95% confidence interval for the adjusted odds ratio of 0.945, not a range, an IQR, or a different interval level; the adjusted odds ratio is a RATIO measure, so the interval is symmetric on the log scale; p=0.741 is the p for THIS estimate, not for another comparison in the same sentenceMethod: back the two-tailed p out of the log-scale CI width and compare it against the printed pHow we recomputed it: pCI(0.945, 0.676, 1.322, 1) - CONSISTENTreported p = .741 · recomputed p = .741Reviewers 1, 2Primary outcome adjusted odds ratio p-value
“Survival at 30-days occurred in 137 of 3030 (4.5%) in the intraosseous group and 155 of 3034 (5.1%) in the intravenous group (adjusted odds ratio, 0.945, 95% confidence interval (CI) 0.676-1.322, p=0.741).”
Taken as given: The adjusted odds ratio is 0.945 with 95% CI 0.676-1.322.; The p-value is two-sided.; The CI is a 95% confidence interval.Method: Recomputed p-value from the reported odds ratio and 95% CI using the normal approximation for the log odds ratio.How we recomputed it: pCI(0.945, 0.676, 1.322, 1) - CONSISTENTreported p = .968 · recomputed p = .971Reviewers 1, 2Adverse event incidence rate ratio p-value
“Adverse event (per 1000 patients) | 1/3040 (0.33) | 0/3042 (0) | - | 1.003 (0.856, 1.176), p=0.968”
Taken as given: The incidence rate ratio is 1.003 with 95% CI 0.856-1.176.; The p-value is two-sided.; The CI is a 95% confidence interval.Method: Recomputed p-value from the reported incidence rate ratio and 95% CI using the normal approximation for the log rate ratio.How we recomputed it: pCI(1.003, 0.856, 1.176, 1)
- lowinternal contradictionTable 1 header shows Total N=6086, but the text states 6082 randomized participants. This discrepancy may be a typographical error.
“Total (N=6086)”
Table 1Find in source
Overstated conclusions
None foundConclusions 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.
4 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2An intraosseous-first strategy did not improve the rate of 30-day survival compared with an intravenous-first strategy.The primary outcome result (adjusted OR 0.945, 95% CI 0.676-1.322, p=0.741) directly supports this claim.Evidence: Primary outcome analysis: 137/3030 (4.5%) vs 155/3034 (5.1%), adjusted OR 0.945 (95% CI 0.676-1.322), p=0.741.
“In adults with out-of-hospital cardiac arrest requiring drug therapy, an intraosseous-first strategy did not improve the rate of 30-day survival.”
ConclusionFind in source - supportedReviewers 1, 2The rate of return of spontaneous circulation appeared to be lower in the intraosseous group.The secondary outcome analysis shows a statistically significant lower ROSC rate in the intraosseous group (adjusted OR 0.863, 95% CI 0.765-0.974), supporting the claim.Evidence: ROSC anytime: 1092/3031 (36.0%) vs 1186/3035 (39.1%), adjusted OR 0.863 (95% CI 0.765-0.974).
“In the intraosseous strategy group, the rate of return of spontaneous circulation appeared to be lower.”
Discussion ¶1Find in source - supportedReviewers 1, 2The trial was under-powered to detect a 1% difference between groups for the primary outcome.The paper states the trial was terminated early due to lower-than-anticipated recruitment, and the sample size calculation required 14972 patients, while only 6082 were randomized.Evidence: Recruitment stopped at 6096 participants; sample size calculation required 14972.
“Our trial, the largest currently planned, was terminated early because of lower-than-anticipated recruitment, so is under-powered to detect a 1% difference between groups for the primary outcome.”
Discussion ¶4Find in source - supportedReviewer 2The intraosseous-first strategy did not reduce time to drug administration.The reported median time to drug administration is identical (24 minutes) in both groups, supporting the claim.Evidence: Table 2: Time from emergency call to drug administration median (IQR) 24.0 (19.0-30.0) for IO and 24.0 (20.0-31.0) for IV.
“In contrast to these previous studies, we found that an intraosseous-first strategy did not reduce time to drug administration.”
Discussion ¶2Find in source
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- ADEQUATESurrogate endpointThe primary outcome is survival at 30 days, a hard clinical outcome. Secondary outcomes include favorable neurological outcome (modified Rankin Scale ≤3) and return of spontaneous circulation, which are also clinical outcomes. No surrogate biomarker is used as the basis for the efficacy claim.
“The primary outcome was survival at 30-days.”
- ADEQUATEEffect sizeThe primary outcome shows no significant difference between groups (adjusted OR 0.945, 95% CI 0.676-1.322, p=0.741), with absolute rates of 4.5% vs 5.1%. The effect size is reported with confidence intervals and the conclusion is that the intervention did not improve survival. The magnitude is anchored to clinical meaningfulness by comparing to the hypothesized 1% difference and noting the trial was underpowered.
“Survival at 30-days occurred in 137 of 3030 (4.5%) in the intraosseous group and 155 of 3034 (5.1%) in the intravenous group (adjusted odds ratio, 0.945, 95% confidence interval (CI) 0.676-1.322, p=0.741).”
Data authenticity concerns
None foundAn 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 mediumRequired 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
The paper cites prior trials and observational studies on drug administration routes in cardiac arrest, acknowledges the limitations of observational studies (e.g., resuscitation time bias), and states the need for randomized trials as highlighted by the International Liaison Committee on Resuscitation. The hypothesis follows logically from the premise that intraosseous access may facilitate more rapid drug administration and improve outcomes.
“Recent trials have explored the clinical effectiveness of cardiac arrest drugs. , The effects of which are highly time-dependent, suggesting earlier drug administration may improve outcomes.”
“Observational studies comparing intraosseous and intravenous drug administration in cardiac arrest report similar or worse outcomes in patients receiving intraosseous drugs, but these studies are challenging to interpret as intraosseous access is typically attempted after a failed intravenous access attempt confounding findings because of resuscitation time bias.”
“Given ongoing uncertainty as to the optimal drug route in adult cardiac arrest, the International Liaison Committee on Resuscitation highlighted the urgent need for randomized trials to evaluate the clinical effectiveness of the intraosseous access route.”
“In observational studies and one small randomized trial, the intraosseous, compared with the intravenous route, facilitated more rapid drug administration, particularly when the proximal tibial site is used.”
“Given ongoing uncertainty as to the optimal drug route in adult cardiac arrest, the International Liaison Committee on Resuscitation highlighted the urgent need for randomized trials to evaluate the clinical effectiveness of the intraosseous access route.”
“Observational studies comparing intraosseous and intravenous drug administration in cardiac arrest report similar or worse outcomes in patients receiving intraosseous drugs, but these studies are challenging to interpret as intraosseous access is typically attempted after a failed intravenous access attempt confounding findings because of resuscitation time bias.”
Randomization used sequentially numbered, tamper-proof, opaque envelopes, stratified by site, ensuring allocation concealment. The trial is open-label, which is acknowledged and justified due to the nature of the intervention. A sample size calculation was performed (14972 patients to detect a 1% difference), though recruitment was stopped early. Inclusion/exclusion criteria are clearly stated. The analysis population (intention-to-treat) and handling of missing data (multiple imputation) are described.
“At the time a patient was identified as requiring vascular access, they were randomized in a 1:1 ratio to the intraosseous or intravenous group using a sequentially numbered, tamper-proof, opaque envelope system.”
“Based on PARAMEDIC2 trial data, 14972 patients were required to detect a difference in the 30-day survival status of 1% (3.2% to 4.2%; 5% significance level; 90% power).”
“Adults (≥ 18 years of age), who sustained an out-of-hospital cardiac arrest, were attended by trial-trained paramedics and who required vascular access for drug administration during ongoing cardiopulmonary resuscitation were eligible for the trial. We excluded individuals with known or apparent pregnancy.”
“At the time a patient was identified as requiring vascular access, they were randomized in a 1:1 ratio to the intraosseous or intravenous group using a sequentially numbered, tamper-proof, opaque envelope system.”
“Based on PARAMEDIC2 trial data, 14972 patients were required to detect a difference in the 30-day survival status of 1% (3.2% to 4.2%; 5% significance level; 90% power).”
“The open label nature of the trial precluded blinding of outcome assessors.”
The paper reports age (mean ± SD), sex (male/female counts and percentages), and other baseline characteristics such as location, initial rhythm, and etiology. Since both sexes are enrolled, a justification for single-sex is not applicable. Age and health status are captured through the baseline table.
“Age mean ± standard deviation - yr | 67.8 ± 16.3 | 68.3 ± 15.9 | 68.1 ± 16.1”
“Male | 1941 (63.9%) | 1951 (64.1%) | 3892 (64.0%)”
“Age mean ± standard deviation - yr | 67.8 ± 16.3 | 68.3 ± 15.9 | 68.1 ± 16.1”
“Male | 1941 (63.9%) | 1951 (64.1%) | 3892 (64.0%)”
The trial protocol was approved by the South Central–Oxford C Research Ethics Committee (21/SC/0178) and the Health Research Authority Confidentiality Advisory Group (20/CAG/0092). Due to the emergency setting, initial enrolment without consent was approved, and consent for ongoing data collection was sought from survivors or proxies. The study adhered to Good Clinical Practice and the Declaration of Helsinki.
“The trial protocol was approved by the South Central–Oxford C Research Ethics Committee (21/SC/0178) and the Health Research Authority Confidentiality Advisory Group (20/CAG/0092).”
“Due to the time-critical nature of treatment in cardiac arrest, the Research Ethics Committee approved a process of initial enrolment without consent in accordance with local legislation (details provided in the ). Consent for ongoing data collection was subsequently sought from survivors or a proxy decision-maker if the individual lacked capacity.”
“The study adhered to Good Clinical Practice guidelines, local regulations, and the ethical principles described in the Declaration of Helsinki.”
“The trial protocol was approved by the South Central–Oxford C Research Ethics Committee (21/SC/0178) and the Health Research Authority Confidentiality Advisory Group (20/CAG/0092).”
“Due to the time-critical nature of treatment in cardiac arrest, the Research Ethics Committee approved a process of initial enrolment without consent in accordance with local legislation (details provided in the ). Consent for ongoing data collection was subsequently sought from survivors or a proxy decision-maker if the individual lacked capacity.”
“The study adhered to Good Clinical Practice guidelines, local regulations, and the ethical principles described in the Declaration of Helsinki.”
The trial involves drugs (epinephrine, amiodarone) administered during cardiac arrest; these are named, and doses are reported in Table 2. The statistical software (SAS version 9.4) is identified. No antibodies, cell lines, or other bench reagents are used, so those criteria are not applicable.
“Data management and analysis was performed with Statistical Analysis Systems (SAS), version 9.4.”
“Data management and analysis was performed with Statistical Analysis Systems (SAS), version 9.4.”
The primary outcome was analyzed using logistic regression, with adjusted and unadjusted odds ratios and 95% CIs. Exact p-values are reported for the primary outcome (p=0.741) and for the adverse event analysis (p=0.968). Effect sizes are reported with confidence intervals throughout. The statistical software is identified. Data presentation includes per-group n and appropriate measures (e.g., medians with IQR). Mathematical plausibility checks were not performed due to the large sample size and continuous outcomes, but no obvious inconsistencies were noted.
“Survival at 30-days occurred in 137 of 3030 (4.5%) in the intraosseous group and 155 of 3034 (5.1%) in the intravenous group (adjusted odds ratio, 0.945, 95% confidence interval (CI) 0.676-1.322, p=0.741).”
“0.880 (0.695, 1.113) | 0.945 (0.676, 1.322), p=0.741”
“Data management and analysis was performed with Statistical Analysis Systems (SAS), version 9.4.”
“Survival at 30-days occurred in 137 of 3030 (4.5%) in the intraosseous group and 155 of 3034 (5.1%) in the intravenous group (adjusted odds ratio, 0.945, 95% confidence interval (CI) 0.676-1.322, p=0.741).”
“Return to spontaneous circulation (ROSC) anytime – no./total no. (%) | 1092/3031 (36.0%) | 1186/3035 (39.1%) | -3.0% (-5.5%, -0.6%) | -3.2% (-5.9%, - 0.6%) | 0.878 (0.791, 0.974) | 0.863 (0.765, 0.974)”
“Data management and analysis was performed with Statistical Analysis Systems (SAS), version 9.4.”
The paper mentions that the protocol and statistical analysis plan are available in the Supplementary Appendix, but does not provide a clear data availability statement for the trial data. There is no mention of a repository deposit or accession numbers. Since this is a clinical trial with patient-level data, managed access would be acceptable, but the paper does not specify a mechanism.
“The protocol, developed by the trial investigators, has been published previously and is available, together with the statistical analysis plan, in the .”
The trial is registered (ISRCTN14223494). Methods are described in sufficient detail for replication. Limitations are explicitly discussed, including early termination, lack of blinding, and potential biases. Conclusions are proportional to the findings, acknowledging the trial was underpowered. Funding and conflicts of interest are disclosed.
“Trial registration: ISRCTN14223494”
“Our trial, the largest currently planned, was terminated early because of lower-than-anticipated recruitment, so is under-powered to detect a 1% difference between groups for the primary outcome.”
“This study was funded by the National Institute for Health and Care Research Health Technology Assessment programme (NIHR131105).”
“Trial registration: ISRCTN14223494”
“Our trial has several additional limitations. We did not collect information on resuscitation quality, because of the pragmatic nature of the trial and the challenges of collecting these data.”
“This study was funded by the National Institute for Health and Care Research Health Technology Assessment programme (NIHR131105).”
Registered (1 ID: ISRCTN). No reporting guideline cited.
Broken references and links
1 finding · worst highReferences 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.
- Cites retracted workRecomputed
Checked 30 references by DOI: 28 verified — 1 retracted, 1 no DOI (shown, not verified).
- RETRACTED10.1136/bmj-2024-079878Intraosseous versus intravenous vascular access in upper extremity among adults with out-of-hospital cardiac arrest: cluster randomised clinical trial (VICTOR trial)Reason: Retraction
- NO DOIA multiple testing procedure for clinical trialsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
Copyediting
5 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 5 minor suggestions below.
5 copyedit issues flagged: mostly consistency, clarity, typo.
- MINORtypoAuthor affiliations“North Eest Ambulance Service”→ North East Ambulance ServiceTypo in 'Eest'.
- MINORconsistencyTable 1“Total (N=6086)”→ Total (N=6082)Total N in Table 1 header is 6086, but the text states 6082 randomized. This may be a typo.
- MINORclarityMethods, Trial design and oversight“available, together with the statistical analysis plan, in the .”→ available in the Supplementary Appendix.Incomplete sentence with placeholder.
- MINORconsistencyTable 2“Total (N=6082)”→ Total (N=6082)Table 2 header correctly states N=6082, but Table 1 header says N=6086. Inconsistency between tables.
- MINORclarityMethods, Statistical Analysis“We planned to recruit 15,000 patients. Based on PARAMEDIC2 trial data, 14972 patients were required”→ We planned to recruit 15,000 patients; based on PARAMEDIC2 trial data, 14,972 patients were requiredThe sentence structure is slightly awkward; consider rephrasing for clarity.
The published work is robust and generally trustworthy, but readers should weigh the minor data availability gap and the internal inconsistency in the reported total N. The retracted citation should be noted as a concern. No erratum is urgently required, but a correction for the N discrepancy and a clearer data availability statement would strengthen the record.
- 1.HIGHrigorCorrect the internal inconsistency in the total number of randomized participants: Table 1 header states N=6086 while the text and Table 2 state N=6082. Verify the correct total and update Table 1 accordingly.An internal contradiction in the primary denominator undermines the credibility of the reported results and could warrant a correction.
- 2.HIGHdata codeAdd a clear data availability statement in the Methods or a dedicated section, specifying a managed-access route (e.g., via the Warwick Clinical Trials Unit data access committee) with conditions and timeframe.The current statement is vague or missing, and a concrete mechanism is expected for patient-level trial data.
- 3.HIGHreportingRemove or replace the retracted citation: 'Intraosseous versus intravenous vascular access in upper extremity among adults with out-of-hospital cardiac arrest: cluster randomised clinical trial (VICTOR trial)' (DOI 10.1136/bmj-2024-079878).Citing a retracted paper is a serious integrity issue that must be corrected.
- 4.HIGHcopyeditFix the incomplete sentence in Methods, Trial design and oversight: 'available, together with the statistical analysis plan, in the .' should read 'available in the Supplementary Appendix.'The placeholder text is a clarity issue that also affects the data availability statement.
- 5.MEDIUMcopyeditCorrect the typo in author affiliations: 'North Eest Ambulance Service' should be 'North East Ambulance Service'.A typo in an affiliation is a minor but visible error.
- 6.MEDIUMreportingExplicitly state adherence to the CONSORT reporting guideline in the Methods or provide a CONSORT checklist.Explicitly mentioning CONSORT strengthens reporting transparency.
- 7.MEDIUMreportingProvide a CONSORT flow diagram as a figure to improve reporting transparency.A flow diagram is a standard element of trial reporting that is currently missing.
- 8.MEDIUMstatisticsClarify the handling of missing data for the primary outcome in the statistical analysis section, specifying the variables used in the multiple imputation model.The paper mentions multiple imputation but does not detail the imputation model, which is important for reproducibility.
- 9.MEDIUMreportingProvide a link or DOI to the full protocol and statistical analysis plan in the manuscript text.The current reference is incomplete and should be made explicit for readers.
- 10.LOWcopyeditRephrase the sentence in Methods, Statistical Analysis: 'We planned to recruit 15,000 patients. Based on PARAMEDIC2 trial data, 14972 patients were required' for clarity.The sentence structure is awkward and could be clearer.
- 11.LOWreportingConsider reporting exact p-values for all secondary outcomes, even though confidence intervals are provided.Exact p-values enhance statistical transparency.
- 12.LOWreportingAdd a note on the generalizability of the findings given the early termination, possibly in the abstract.Highlighting the early termination in the abstract would help readers interpret the results.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.