Sonolysis during carotid endarterectomy: randomised controlled trial.
Školoudík D, Hrbáč T, Kovář M, Beneš V 3rd, Fiedler J, Branca M, Rossel JB, Netuka D, SONOBIRDIE Trial Investigators
- DOI
- 10.1136/bmj-2024-082750
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-22
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/7947075a-80ff-4b41-9216-a9eb462035e9 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×3−1.5★
- ClaimsOverstated claim−0.5★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 6 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.
- 01Conclusion reaches beyond the evidence
Sonolysis should be used to reduce periprocedural cerebrovascular events during carotid endarterectomy.
“The results of the SONOBIRDIE trial suggest that sonolysis should be used to reduce the risk of periprocedural cerebrovascular events during carotid endarterectomy in all patients with sufficient temporal bone window for transcranial Doppler.”
DiscussionFind 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, rigorously reported phase 3 randomised sham-controlled trial. The paper demonstrates strong methodology across all eight dimensions, with clear reporting of design, ethics, data availability, and statistical methods. Minor reporting gaps (e.g., software version, explicit CONSORT statement) and a few copyedit issues do not undermine the overall integrity.
Both reviewers classified the study as interventional, and this was adopted. The evaluation covered all eight dimensions; non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification covered only a subset of tests (2 tests), so the overall statistical soundness is not fully confirmed. The claim audit flagged one claim as 'overstated'.
Numerical inconsistencies
1 finding · worst lowValues 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 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.
- CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2Primary endpoint comparison (sonolysis vs control) using chi-square test
“The primary composite outcome, including ischaemic stroke, transient ischaemic attack, and death, occurred significantly less often in the sonolysis group than in the control group (2.2% v 7.6%; P<0.001)”
Taken as given: The numbers 11 and 38 are the event counts in the sonolysis and control groups, respectively.; The group totals are 507 and 497, respectively.; The test used is a chi-square test without continuity correction.Method: Pearson's chi-square test on the 2x2 table (11, 496, 38, 459).How we recomputed it: pChi2x2(11, 496, 38, 459) - CONSISTENTreported p < .004 · recomputed p = .004Reviewers 1, 2MRI substudy new ischaemic lesion comparison using chi-square test
“New brain ischaemia was detected in 20 (8.5%) patients in the sonolysis group, with five of them having a volume of ≥5 mL, and in 39 (17.4%) patients in the control group, with 13 of them having a volume of ≥5 mL.”
Taken as given: The numbers 20 and 39 are the event counts in the sonolysis and control groups, respectively.; The denominators are 236 and 224, respectively.; The test used is a chi-square test without continuity correction.Method: Pearson's chi-square test on the 2x2 table (20, 216, 39, 185).How we recomputed it: pChi2x2(20, 216, 39, 185)
- lowinternal contradictionThe paper states that 1004 patients were enrolled, but the interim analysis was performed on the first 1000 enrolled patients. This is a minor discrepancy but explained by the interim analysis timing.
“A total of 1004 patients from 16 centres in three European countries (Czech Republic, Slovakia, and Austria) were enrolled between 20 August 2015 and 14 October 2020 until interim analysis in the randomised phase of the trial.”
ResultsFind in source - lowinternal contradictionThe abstract reports 312 (31%) female, while Table 1 reports 149 (29%) in sonolysis and 163 (33%) in control, which sums to 312 (31% of 1004). This is consistent.
“312 (31%) female”
Table 1Find in source
Overstated conclusions
1 finding · worst mediumConclusions 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.
- Conclusions overstated beyond the evidenceAssessed
5 major claims checked against the paper's own evidence: 1 not fully backed by the presented evidence (unsupported or overstated).
- overstatedReviewer 2Sonolysis should be used to reduce periprocedural cerebrovascular events during carotid endarterectomy.The trial shows efficacy, but the recommendation for routine use may be premature given the single trial and the need for replication.Evidence: Primary endpoint result and discussion of clinical implications.
“The results of the SONOBIRDIE trial suggest that sonolysis should be used to reduce the risk of periprocedural cerebrovascular events during carotid endarterectomy in all patients with sufficient temporal bone window for transcranial Doppler.”
DiscussionFind in source - supportedReviewers 1, 2Sonolysis significantly reduces the composite incidence of ischaemic stroke, TIA, and death within 30 days.The primary endpoint result (11/507 vs 38/497, P<0.001) directly supports this claim.Evidence: Primary endpoint result in Table 2.
“Sonolysis was safe for patients undergoing carotid endarterectomy and resulted in a significant reduction in the composite incidence of ischaemic stroke, transient ischaemic attack, and death within 30 days.”
AbstractFind in source - supportedReviewers 1, 2Sonolysis reduces new ischaemic lesions on MRI.The substudy result (20/236 vs 39/224, P=0.004) supports this claim.Evidence: MRI substudy result in Table 4.
“as well as in the substudy for magnetic resonance imaging detected new ischaemic lesions (20/236 (8.5%) v 39/224 (17.4%); risk difference −8.9%, −15% to −2.8%; P=0.004)”
AbstractFind in source - supportedReviewers 1, 2Sonolysis is safe.No significant increase in adverse events or bleeding was observed, supporting safety.Evidence: Safety endpoints reported in Results.
“Sonolysis was found to be safe, and 94.4% of patients in the sonolysis group were free from serious adverse events 30 days after the procedure.”
AbstractFind in source - supportedReviewer 1Female sex is an independent risk factor for the primary outcome.The multivariable model identified female sex with OR 2.0, supporting this claim.Evidence: Multivariable logistic regression results.
“the multivariable model for the primary outcome identified only female sex as an independent risk factor that increased the risk of the primary composite endpoint, with an odds ratio of 2.0”
ResultsFind in source
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- ADEQUATESurrogate endpointThe primary endpoint is a composite of hard clinical outcomes (ischaemic stroke, transient ischaemic attack, and death within 30 days). The MRI substudy endpoint (new ischaemic lesions) is a surrogate, but the primary claim is based on the clinical composite. The surrogate is used as a secondary endpoint and is supported by the primary clinical outcome.
“The primary endpoint was the composite incidence of ischaemic stroke, transient ischaemic attack, and death within 30 days.”
- ADEQUATEEffect sizeThe primary endpoint showed a risk difference of -5.5% (95% CI -8.3% to -2.8%) with a risk ratio of 0.28, which is a substantial relative reduction. The absolute risk reduction is clinically meaningful given the baseline risk of 7.6% in the control group. The effect is statistically significant and anchored to clinical outcomes.
“The results favoured the sonolysis group for the primary endpoint (11 (2.2%) v 38 (7.6%); risk difference −5.5%, 95% confidence interval (CI) −8.3% to −2.8%; P<0.001)”
Data authenticity concerns
1 finding · worst lowAn 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.
- Other integrity concernAssessed
3 integrity concerns flagged (0 high).
- lowotherThe trial was stopped early for efficacy after 1000 patients, but the sample size calculation required 1342. This is a potential concern but is a common practice and was recommended by the DSMB.
“Members of the Data and Safety Monitoring Board evaluated the interim analysis results for the first 1000 enrolled patients and unanimously recommended stopping the SONOBIRDIE trial early owing to clear evidence of efficacy.”
ResultsFind in source
Reporting gaps
None foundRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
Checked — nothing surfaced.
The introduction cites in vitro, animal, and pilot studies supporting the potential of sonolysis, and acknowledges the unclear mechanism. The hypothesis follows logically from the cited evidence. Limitations of prior research are implicitly addressed by the design of a large RCT.
“Since the 1970s, in vitro and animal model studies have shown acceleration of thrombus dissolution by use of an ultrasound beam.”
“Therefore, we hypothesised that activation of the fibrinolytic system and a direct mechanical effect on flowing thrombi in intracranial arteries by use of sonolysis during carotid endarterectomy could reduce the risk of cerebrovascular events, such as ischaemic stroke, transient ischaemic attack, and silent brain infarction.”
“The exact mechanism of the therapeutic effect of sonolysis—that is, continuous pulsed wave Doppler insonation of an artery for prevention and treatment of brain ischaemia—remains unclear, although it has been studied for more than 50 years.”
“Since the 1970s, in vitro and animal model studies have shown acceleration of thrombus dissolution by use of an ultrasound beam.”
Randomisation was computer-generated with 1:1 allocation via an independent online system. Blinding was double-blind, with only the sonographer unblinded. A priori power analysis was performed for both the main trial and substudy. Inclusion/exclusion criteria were pre-specified. The analysis population (ITT and per-protocol) was defined, and missing data handling was described. The sham procedure served as a control.
“Consecutive patients were assigned to the sonolysis group or the control group by computer generated one-to-one randomisation using an independent online randomisation system.”
“Only the sonographer was not blinded to the application of sonolysis or sham procedure.”
“A χ 2 test indicated that 1342 patients (671 per group) were needed to detect such a difference with a two sided α level of 0.05 and a power of 80%.”
“Consecutive patients were assigned to the sonolysis group or the control group by computer generated one-to-one randomisation using an independent online randomisation system.”
“Only the sonographer was not blinded to the application of sonolysis or sham procedure.”
“A χ 2 test indicated that 1342 patients (671 per group) were needed to detect such a difference with a two sided α level of 0.05 and a power of 80%.”
The paper reports sex (31% female), age (mean 67.9 years), and health status (comorbidities, medication use). Demographics are detailed in Table 1. Since both sexes are enrolled, sex justification is not applicable. Species/strain and housing conditions are not applicable for a human trial.
“1004 patients (mean age 68 years; 312 (31%) female) were enrolled”
“1004 patients (mean age 68 years; 312 (31%) female) were enrolled”
“Arterial hypertension | 432 (85) | 448 (90)”
The protocol was approved by a named ethics committee (multicentre ethics committee of Vítkovice Hospital) and local IRBs. Written informed consent was obtained from all patients. Regulatory compliance is implied by adherence to standard trial conduct.
“The protocol was approved by the multicentre ethics committee of Vítkovice Hospital (2 June 2015) and local institutional review boards of the participating centres.”
“All patients provided written informed consent.”
“The protocol was approved by the multicentre ethics committee of Vítkovice Hospital (2 June 2015) and local institutional review boards of the participating centres.”
“All patients provided written informed consent.”
The investigational device is described in detail (2 MHz transcranial Doppler probe, ultrasound machines listed in supplementary table B). Statistical software (R, version not specified) is mentioned in the methods. No antibodies, cell lines, or other biological reagents are used.
“Sonolysis in the SONOBIRDIE trial was performed using a standard ultrasound machine and 2 MHz transcranial Doppler probe.”
“Sonolysis in the SONOBIRDIE trial was performed using a standard ultrasound machine and 2 MHz transcranial Doppler probe.”
“The code used to analyse the data in the paper can be found in the supplemental files.”
All statistical tests are named (χ², log-rank, cumulative incidence, etc.). Exact p-values are reported (e.g., P<0.001, P=0.004). Effect sizes with 95% CIs are provided. Statistical software (R) is identified. Data presentation includes Kaplan-Meier curves and tables with per-group n. Mathematical plausibility checks were not performed due to lack of raw data, but no obvious inconsistencies were found.
“risk difference −5.5%, 95% confidence interval (CI) −8.3% to −2.8%”
“We used a χ 2 test to compare the groups.”
“risk difference −5.5%, 95% confidence interval (CI) −8.3% to −2.8%”
The data availability statement provides a direct link to a public repository (Mendeley Data) with a DOI. The code is stated to be in supplemental files. This meets the criteria for adequate data and code sharing.
“The data underlying the findings in this paper are openly and publicly available and can be found here: https://data.mendeley.com/datasets/gkzrhyc6tj/1”
“The code used to analyse the data in the paper can be found in the supplemental files.”
“The data underlying the findings in this paper are openly and publicly available and can be found here: https://data.mendeley.com/datasets/gkzrhyc6tj/1”
“The code used to analyse the data in the paper can be found in the supplemental files.”
The trial is registered at ClinicalTrials.gov (NCT02398734). The paper follows CONSORT guidelines (flowchart provided). All outcomes are reported, including negative results. Limitations are discussed in the Discussion. Conclusions are proportional to the evidence. Funding sources and competing interests are declared.
“Trial registration Clinicaltrials.gov NCT02398734”
“One limitation of the study was that no study specific ultrasound device was used and only standard ultrasound (transcranial Doppler) machines were used, which did not allow blinding for the sonographer.”
“The study was partially founded by the Czech Health Research Council, grants No 16-29148A, NV19-04-00270, and NU22-04-00389.”
“Trial registration Clinicaltrials.gov NCT02398734”
“One limitation of the study was that no study specific ultrasound device was used and only standard ultrasound (transcranial Doppler) machines were used, which did not allow blinding for the sonographer.”
“The study was partially founded by the Czech Health Research Council, grants No 16-29148A, NV19-04-00270, and NU22-04-00389.”
Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None foundReferences 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 33 references by DOI: 31 verified — 2 no DOI (shown, not verified).
- NO DOICarotid endarterectomy for symptomatic carotid stenosisNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOISonothrombolysis for acute ischaemic strokeNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- dataMendeley DataLIVEHTTP 200https://data.mendeley.com/datasets/gkzrhyc6tj/1Resolves to Mendeley Data (data repository).
Copyediting
6 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 6 minor suggestions below.
6 copyedit issues flagged: mostly typo, consistency, grammar.
- MINORtypoAbstract“founded”→ fundedTypo in funding statement.
- MINORconsistencyTable 1“Calcificated”→ CalcifiedInconsistent terminology for plaque type.
- MINORgrammarDiscussion“the risk of the composite primary endpoint, including ischaemic stroke, transient ischaemic attack, and death, was statistically significantly lower by 5.5%”→ the risk of the composite primary endpoint (ischaemic stroke, transient ischaemic attack, or death) was statistically significantly lower by 5.5 percentage pointsClarify that the reduction is in percentage points, not relative percent.
- MINORtypoAbstract, Results“The results favoured the sonolysis group for the primary endpoint (11 (2.2%) v 38 (7.6%); risk difference −5.5%, 95% confidence interval (CI) −8.3% to −2.8%; P<0.001)”→ Consider using 'vs.' instead of 'v' for consistency.Minor style issue.
- MINORconsistencyTable 1, Type of plaque“Unclassified | 209 | 229”→ Ensure that the 'Unclassified' row is clearly defined and consistent with the total n.The unclassified counts are not percentages, which may be confusing.
- MINORgrammarDiscussion, Comparison with existing evidence“The exact mechanism of the therapeutic effect of sonolysis—that is, continuous pulsed wave Doppler insonation of an artery for prevention and treatment of brain ischaemia—remains unclear, although it has been studied for more than 50 years.”→ Consider rephrasing for clarity: 'The exact mechanism... remains unclear, despite being studied for more than 50 years.'Minor grammatical improvement.
The published work is robust and well-reported. An informed reader should weigh the minor reporting gaps (e.g., unspecified software version, lack of explicit CONSORT statement) and the single-trial basis for the efficacy claim. No erratum is warranted for the identified issues, but the authors could consider a correction to clarify the percentage-point reduction and fix the 'founded' typo.
- 1.HIGHreportingIn the Discussion, temper the claim that sonolysis 'should be used' to reduce periprocedural cerebrovascular events, as this is based on a single trial and may be premature; recommend replication before routine use.The claim audit rated this claim as 'overstated' because the evidence supports efficacy but not necessarily a recommendation for routine use.
- 2.HIGHreportingIn the Methods, explicitly state the version of R and any packages used for statistical analysis.Both reviewers noted that the software version is not specified, which hampers reproducibility.
- 3.HIGHreportingIn the Methods or Discussion, explicitly state adherence to the CONSORT reporting guideline.Reviewer 2 noted that a reporting guideline is not explicitly mentioned, though the paper follows CONSORT-like structure.
- 4.MEDIUMreportingIn the Methods, add a brief statement on how outliers or protocol deviations were handled in the analysis.Reviewer 2 flagged outlier handling as 'reported_but_inadequate'.
- 5.MEDIUMethicsIn the Ethics section, explicitly mention compliance with the Declaration of Helsinki or ICH-GCP guidelines.Reviewer 2 noted that regulatory compliance is not explicitly named.
- 6.MEDIUMdata codeIn the Data Availability Statement, provide a specific version or DOI for the code repository to enhance code sharing.Reviewer 2 suggested providing a version or DOI for the code to improve reproducibility.
- 7.MEDIUMcopyeditIn the Abstract, change 'founded' to 'funded' in the funding statement.Copyedit flagged a typo in the funding statement.
- 8.MEDIUMcopyeditIn the Discussion, clarify that the risk reduction is in percentage points, not relative percent, by rephrasing 'lower by 5.5%' to 'lower by 5.5 percentage points'.Copyedit flagged this as potentially misleading.
- 9.LOWcopyeditIn Table 1, change 'Calcificated' to 'Calcified' for consistency.Copyedit flagged inconsistent terminology for plaque type.
- 10.LOWcopyeditIn the Abstract, consider using 'vs.' instead of 'v' for consistency.Copyedit flagged a minor style issue.
- 11.LOWcopyeditIn Table 1, ensure the 'Unclassified' row is clearly defined and consistent with the total n.Copyedit noted that the unclassified counts are not percentages, which may be confusing.
- 12.LOWcopyeditIn the Discussion, consider rephrasing the sentence about the mechanism of sonolysis for clarity.Copyedit suggested a minor grammatical improvement.
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.