Endotyping-informed therapy for patients with chest pain and no obstructive coronary artery disease: a randomized trial.
Bradley CP, McKinley G, Orchard V, Tiller C, Stanley B, Ang D, Morrow AJ, Sykes R, Gildea P, Petty M, Brogan R, Carrick D, Collison D, Eteiba H, Ghattas A, Good R, Joshi F, Lindsay M, McCartney P, McGowan J, McGeoch R, Robertson K, Rocchiccioli P, Shaukat A, Watkins S, Kellman P, McConnachie A, Berry C
- DOI
- 10.1038/s41591-025-04044-4
- 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/e9991f18-04a7-4a26-ade8-9a59ffaaeaa9 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×3−1.5★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary efficacy claim is based on the Seattle Angina Questionnaire (SAQ) summary score, a patient-reported outcome measure of angina burden and quality of life. While SAQ is a validated clinical scale, the paper does not demonstrate target engagement at the tested dose (e.g., PK/PD or dose-exposure relationship) nor cite validated evidence linking SAQ to hard clinical outcomes. The claim of improved angina and quality of life rests on this surrogate endpoint without establishing a direct link to clinical outcomes.
“The primary outcome of the randomized trial was the Seattle Angina Questionnaire (SAQ) summary score at 12 months after randomization.”
- 02Treatment effect not shown to be clinically meaningful
The reported effect size is a mean difference of 20.9 points on the SAQ summary score (95% CI 15.8–26.0). While this is statistically significant, the manuscript does not anchor this difference to a minimal clinically important difference (MCID) or provide evidence that this magnitude is clinically meaningful. The effect size is presented as a positive result without explicit clinical meaningfulness.
“adjusted mean difference: 20.9 (95% confidence interval: 15.8–26.0)”
- 03Other integrity concern
Trial NCT04805814 was first submitted to ClinicalTrials.gov on 2021-03-09, after the registered study start date of 2021-02-09. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT04805814
reviewer’s wording
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 well-reported randomized controlled trial. The study design is rigorous with proper randomization, blinding, and a prespecified analysis plan. Minor reporting issues include a retrospective registration gap, a rounding discrepancy in the abstract, and a formatting error in the data availability statement.
Both reviewers classified the study as interventional, which is adopted. The evaluation covers all eight dimensions; no dimensions were excluded as not applicable. The reviewers agreed on all dimensions; no divergence required resolution.
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 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.
- CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 1Primary outcome of diagnostic study: reclassification rate 53.0% with 95% CI 46.6-59.3% and P<0.001. The p-value is from a one-sample test of proportion (binomial) against 50%? The paper does not specify the test, so we cannot recompute exactly. Skipping.
“The primary outcome of the diagnostic study, defined as the reclassification of the initial diagnosis based on the angiogram, occurred in 131 patients (53.0% (95% confidence interval: 46.6−59.3%); P < 0.001)”
Taken as given: The 53.0% is the proportion reclassified out of 250.; The 95% CI is two-sided.; The p-value is from a test of proportion against 50% (not stated).Method: Recomputed p from CI using pCI function, assuming a test of proportion against 0.5.How we recomputed it: pCI(0.53, 0.466, 0.593, 0)
- lowinternal contradictionIn Table 1, the row 'Glyceryl trinitrate spray, n (%)' shows 199 (100.0%) for All, but the column totals are 100 (100.0%) for Control and 99 (100.0%) for Intervention, which sum to 199, but the percentages are 100% for each group, implying the denominator is the number of patients with data, not the total N. This is a minor labeling issue.
“Glyceryl trinitrate spray, n (%) | 199 (100.0%) | 100 (100.0%) | 99 (100.0%)”
Table 1Find in source - lowinternal contradictionThe abstract reports the primary outcome of the diagnostic study as 53.0% (131 patients), but 131/250 = 52.4%, not 53.0%. This is a minor rounding discrepancy.
“occurred in 131 patients (53.0% (95% confidence interval: 46.6−59.3%); P < 0.001)”
AbstractFind in source
Overstated conclusions
3 findings · worst highConclusions 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.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions only partially backed by the presented evidenceAssessed
6 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewers 1, 2The study results apply equally by sex.The paper states this in the Discussion but does not present a formal subgroup analysis by sex for the primary outcome, so the claim is not directly supported by presented evidence.Evidence: No sex-specific subgroup analysis is presented in the main text.
“The study results apply equally by sex.”
DiscussionFind in source - supportedReviewers 1, 2Endotyping-informed therapy revised the diagnosis in more than half of the participants.The primary outcome of the diagnostic study showed reclassification in 53.0% of participants, directly supporting this claim.Evidence: Primary outcome of diagnostic study: 131/250 (53.0%) reclassified.
“endotyping-informed therapy revised the diagnosis in more than half of the participants”
AbstractFind in source - supportedReviewers 1, 2Endotyping-informed therapy improved angina and health-related quality of life.The primary outcome of the randomized trial showed a significant improvement in SAQ summary score at 12 months, supporting the claim.Evidence: Adjusted mean difference in SAQ summary score at 12 months: 20.9 (95% CI 15.8-26.0).
“improved angina and health-related quality of life”
AbstractFind in source - supportedReviewer 1Microvascular angina was commonly misdiagnosed as non-cardiac chest pain after angiography.The data show that 65 (98.5%) of control participants with a final diagnosis of microvascular/vasospastic angina were initially diagnosed as non-cardiac chest pain.Evidence: Table 3 and discussion: 65 (98.5%) participants in the control group had a final diagnosis of microvascular or vasospastic angina, having been initially diagnosed as having non-cardiac chest pain.
“microvascular angina was commonly misdiagnosed as non-cardiac chest pain”
DiscussionFind in source - supportedReviewer 2Microvascular angina was commonly misdiagnosed as non-cardiac chest pain after standard coronary angiography.The diagnostic study shows that 51.0% of participants were diagnosed with microvascular angina after CMR, whereas only 1.6% were diagnosed with microvascular angina after angiography, indicating a large diagnostic gap.Evidence: Table 2: Post-angiogram endotype: microvascular angina 4 (1.6%); post-CMR endotype: microvascular angina 127 (51.0%).
“After standard coronary angiography, microvascular angina was commonly misdiagnosed as non-cardiac chest pain.”
DiscussionFind in source - supportedReviewer 2The improvements in angina and quality of life are consistent with findings in the CorMicA and ILIAS ANOCA clinical trials.The paper cites these trials and notes consistency, which is a reasonable interpretation of the literature.Evidence: Discussion cites CorMicA and ILIAS ANOCA trials.
“This result is consistent with findings in the CorMicA and ILIAS ANOCA clinical trials.”
DiscussionFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary efficacy claim is based on the Seattle Angina Questionnaire (SAQ) summary score, a patient-reported outcome measure of angina burden and quality of life. While SAQ is a validated clinical scale, the paper does not demonstrate target engagement at the tested dose (e.g., PK/PD or dose-exposure relationship) nor cite validated evidence linking SAQ to hard clinical outcomes. The claim of improved angina and quality of life rests on this surrogate endpoint without establishing a direct link to clinical outcomes.
“The primary outcome of the randomized trial was the Seattle Angina Questionnaire (SAQ) summary score at 12 months after randomization.”
- INADEQUATEEffect sizeThe reported effect size is a mean difference of 20.9 points on the SAQ summary score (95% CI 15.8–26.0). While this is statistically significant, the manuscript does not anchor this difference to a minimal clinically important difference (MCID) or provide evidence that this magnitude is clinically meaningful. The effect size is presented as a positive result without explicit clinical meaningfulness.
“adjusted mean difference: 20.9 (95% confidence interval: 15.8–26.0)”
Data authenticity concerns
1 finding · worst mediumAn 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).
- mediumotherTrial NCT04805814 was first submitted to ClinicalTrials.gov on 2021-03-09, after the registered study start date of 2021-02-09. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT04805814
reviewer’s wording
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 multiple prior studies and guidelines establishing the diagnostic challenge of ANOCA and the potential of functional testing. The rationale for using CMR to endotype patients is clearly linked to the hypothesis that CMR-guided management improves diagnosis and symptoms. Limitations of prior research (e.g., lack of randomized trials for CMR) are explicitly addressed.
“The Coronary Microvascular Angina (CorMicA) trial demonstrated that coronary function testing during invasive management of suspected ANOCA is associated with improvements in symptoms, health-related quality of life and health economics . These results were recently validated in the ILIAS ANOCA trial .”
“Cardiovascular magnetic resonance (CMR) , and nuclear stress positron emission tomography quantify myocardial blood flow and may be used to diagnose coronary microvascular dysfunction, but evidence of clinical utility from randomized trials is lacking.”
“The Coronary Microvascular Angina (CorMicA) trial demonstrated that coronary function testing during invasive management of suspected ANOCA is associated with improvements in symptoms, health-related quality of life and health economics . These results were recently validated in the ILIAS ANOCA trial .”
“Cardiovascular magnetic resonance (CMR) , and nuclear stress positron emission tomography quantify myocardial blood flow and may be used to diagnose coronary microvascular dysfunction, but evidence of clinical utility from randomized trials is lacking.”
“We hypothesized that coronary vasomotor endotypes are prevalent in a post-angiography population with no obstructive coronary arteries, and, compared to angiography-guided management, CMR-guided management changes the diagnosis and improves symptoms and health-related quality of life.”
Randomization used a minimization algorithm with a random element, and the unit is the participant. Blinding of participants, clinicians, and outcome assessors is described, with effectiveness assessed. A sample size calculation is provided. Inclusion/exclusion criteria are explicitly listed. The analysis population (ITT) and missing data handling are defined. The control group (angiography-guided) serves as the comparator.
“Randomization was performed using a minimization algorithm with respect to study site, sex, prior myocardial infarction, evidence of coronary artery disease on angiography, diabetes and left ventricular systolic function (<55%, ≥55%). A small random element was included whereby two randomly selected participants in each block of 10 were allocated at random (one to each arm), to reduce predictability.”
“To minimize bias, randomization was performed before the CMR scan, and the participants, radiology technologists and attending healthcare staff responsible for clinical care were not informed of the randomized group allocation or myocardial blood flow quantified by CMR imaging and were, therefore, blinded.”
“If 6-month outcomes could be obtained from 200 patients, the trial would have 80% power to detect a mean between-group difference in SAQ summary score of 0.40 s.d. units.”
“Randomization was performed using a minimization algorithm with respect to study site, sex, prior myocardial infarction, evidence of coronary artery disease on angiography, diabetes and left ventricular systolic function (<55%, ≥55%). A small random element was included whereby two randomly selected participants in each block of 10 were allocated at random (one to each arm), to reduce predictability.”
“To minimize bias, randomization was performed before the CMR scan, and the participants, radiology technologists and attending healthcare staff responsible for clinical care were not informed of the randomized group allocation or myocardial blood flow quantified by CMR imaging and were, therefore, blinded.”
“If 6-month outcomes could be obtained from 200 patients, the trial would have 80% power to detect a mean between-group difference in SAQ summary score of 0.40 s.d. units.”
Sex is reported for all participants (50.4% female), and age is reported. Demographics include ethnicity, BMI, and comorbidities. Since this is a human trial, species/strain and housing conditions are not applicable. Sex is not single-sex, so justification is not required.
“Age (years), mean (s.d.) | 63.3 (9.2) | 64.0 (8.9) | 62.5 (9.4) | | Sex | | Male, n (%) | 124 (49.6%) | 60 (47.6%) | 64 (51.6%) | | Female, n (%) | 126 (50.4%) | 66 (52.4%) | 60 (48.4%)”
“Ethnicity | | White, n (%) | 241 (96.4%) | 121 (96.0%) | 120 (96.8%) | | Asian, n (%) | 8 (3.2%) | 5 (4.0%) | 3 (2.4%) | | Black, n (%) | 1 (0.4%) | 0 (0.0%) | 1 (0.8%)”
“250 patients (mean age, 63.3 years; 50.4% female)”
“Age (years), mean (s.d.) | 63.3 (9.2) | 64.0 (8.9) | 62.5 (9.4)”
The study protocol was approved by the West of Scotland Research Ethics Committee (reference 20/WS/0159). All patients provided written informed consent. The study was conducted in compliance with the Declaration of Helsinki. The trial was registered on ClinicalTrials.gov.
“The study protocol was approved by the West of Scotland Research Ethics Committee (reference 20/WS/0159) on 11 January 2021”
“All patients provided written informed consent before study enrollment, demonstrating their understanding of the study procedures and willingness to participate.”
“the protocol was conducted in compliance with the principles outlined in the Declaration of Helsinki.”
“The study protocol was approved by the West of Scotland Research Ethics Committee (reference 20/WS/0159) on 11 January 2021”
“All patients provided written informed consent before study enrollment”
“the protocol was conducted in compliance with the principles outlined in the Declaration of Helsinki.”
The trial uses adenosine and gadolinium-based contrast (Gadovist) as investigational products, both named with manufacturer and dose. CMR software (CVI42) is identified. Antibodies, cell lines, and mycoplasma testing are not applicable as this is a clinical trial without wet-lab assays.
“The CMR analyses were undertaken as per standard reporting guidelines using commercially available software (CVI42; Circle Cardiovascular Imaging).”
“Vasodilator stress was achieved by intravenous infusion of adenosine at a dose of 140 μg kg −1 min −1 for 4 minutes (increased to 210 μg kg −1 min −1 for a further 2 minutes if no symptoms or less than 10% heart rate increase).”
“The CMR analyses were undertaken as per standard reporting guidelines using commercially available software (CVI42; Circle Cardiovascular Imaging).”
The primary analysis uses linear regression with adjustment, and p-values are reported. Effect sizes are reported as adjusted mean differences with 95% CIs. Statistical software (R version 4.5.1) is identified. Data presentation includes flow diagrams, tables with per-group n, and forest plots. Exact p-values are reported for primary outcomes. Assumptions are handled by design (linear regression, residual examination).
“For the randomized trial, the change in SAQ summary score was compared between randomized groups using linear regression, adjusting for baseline SAQ summary score and factors used in the minimization algorithm; age was additionally included as a covariate to reduce residual variation.”
“adjusted mean difference: 20.9 (95% confidence interval: 15.8–26.0)”
“The analyses were conducted using RStudio and R version 4.5.1 (R Foundation for Statistical Computing).”
“The intervention effect estimate (adjusted between-group mean difference) was reported with a 95% confidence interval and a P value.”
“The analyses were conducted using RStudio and R version 4.5.1 (R Foundation for Statistical Computing).”
“adjusted mean difference: 20.9 (95% confidence interval: 15.8−26.0)”
The data availability statement describes a secure analytical platform (Robertson Centre for Biostatistics) with conditions and timeframe. Code is available on GitHub. Repository deposit and accession numbers are not applicable for patient-level data.
“Data access will be provided through the secure analytical platform of the Robertson Centre for Biostatistics. This secure platform enables access to deidentified data for analytical purposes, without the possibility of removing the data from the server.”
“The statistical code will be available online in GitHub upon publication of this paper: https://github.com/RobertsonCentre/CorCMR”
“Data access will be provided through the secure analytical platform of the Robertson Centre for Biostatistics.”
“The statistical code will be available online in GitHub upon publication of this paper: https://github.com/RobertsonCentre/CorCMR”
The trial is registered on ClinicalTrials.gov (NCT04805814). CONSORT guidelines are followed. All prespecified outcomes are reported, including secondary and exploratory. Limitations are discussed. Funding sources and competing interests are declared.
“ClinicalTrials.gov identifier: NCT04805814”
“The reporting of results followed the guidelines outlined in the CONSORT statement.”
“Considering limitations, coronary function testing was not routinely undertaken during routine care, which appears to reflect contemporary practice more generally.”
“ClinicalTrials.gov identifier: NCT04805814”
“The reporting of results followed the guidelines outlined in the CONSORT statement.”
“Considering limitations, coronary function testing was not routinely undertaken during routine care, which appears to reflect contemporary practice more generally.”
Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
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 36 references by DOI: 1 verified — 35 no DOI (shown, not verified).
- NO DOI2024 ESC Guidelines for the management of chronic coronary syndromesNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOI2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice GuidelinesNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPrevalence of coronary microvascular disease and coronary vasospasm in patients with nonobstructive coronary artery disease: systematic review and meta-analysisNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIMeta-analysis and systematic review of coronary vasospasm in ANOCA patients: prevalence, clinical features and prognosisNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOILow diagnostic yield of elective coronary angiographyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPersistent angina: highly prevalent and associated with long-term anxiety, depression, low physical functioning, and quality of life in stable angina pectorisNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOINatural history of patients with insignificant coronary artery diseaseNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIStable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular eventsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOICoronary microvascular dysfunction and future risk of heart failure with preserved ejection fractionNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIStratified medical therapy using invasive coronary function testing in anginaNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIRationale and design of the ILIAS ANOCA clinical trial: a blinded-arm controlled trial for routine ad-hoc coronary function testingNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIInvasive endotyping in patients with angina and no obstructive coronary artery disease: a randomized controlled trialNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIAutomated pixel-wise quantitative myocardial perfusion mapping by CMR to detect obstructive coronary artery disease and coronary microvascular dysfunctionNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIHigh-resolution cardiac magnetic resonance imaging techniques for the identification of coronary microvascular dysfunctionNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIRole of nuclear cardiology in diagnosis and risk stratification of coronary microvascular diseaseNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOISCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in EuropeNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOISCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regionsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPrevalence and characteristics of coronary microvascular dysfunction among chest pain patients in the emergency departmentNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPrevalence of microvascular angina among patients with stable symptoms in the absence of obstructive coronary artery disease: a systematic reviewNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOICT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trialNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOISymptoms and quality of life in patients with suspected angina undergoing CT coronary angiography: a randomised controlled trialNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPrognostic impact and clinical outcomes of coronary flow reserve and hyperaemic microvascular resistanceNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIComprehensive diagnosis in chronic coronary syndromes combining angiography and intracoronary testing: the AID-ANGIO studyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIFunctional coronary assessment in angina with intermediate coronary stenosis: the #FullPhysiology approachNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIMicrovascular resistance reserve predicts myocardial ischemia and response to therapy in patients with angina and nonobstructive coronary arteriesNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIEffect of care guided by cardiovascular magnetic resonance, myocardial perfusion scintigraphy, or NICE guidelines on subsequent unnecessary angiography rates: the CE-MARC 2 randomized clinical trialNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIThe coronary microvascular angina cardiovascular magnetic resonance imaging trial: rationale and designNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIUsing the WHO (Rose) angina questionnaire in cardiovascular epidemiologyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIStandardized cardiovascular magnetic resonance imaging (CMR) protocols: 2020 updateNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIMyocardial perfusion cardiovascular magnetic resonance: optimized dual sequence and reconstruction for quantificationNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIInternational standardization of diagnostic criteria for microvascular anginaNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIInternational standardization of diagnostic criteria for vasospastic anginaNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIAn EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology working group on coronary pathophysiology & microcirculation endorsed by coronary vasomotor disorders international study groupNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIDevelopment and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery diseaseNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIDevelopment and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
4 data/code links checked; 4 live.
- datahttps://clinicaltrials.gov/study/NCT04805814LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://clinicaltrials.gov/ct2/show/NCT04805814LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- codeGitHubLIVEHTTP 200https://github.com/RobertsonCentre/CorCMRResolves to GitHub (code repository).
- codeGitHubLIVEHTTP 200http://github.com/RobertsonCentre/CorCMRResolves to GitHub (code repository).
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, other.
- MINORconsistencyAbstract“P < 0.001”→ Ensure consistent use of P vs p for p-values.The paper uses both 'P' and 'p' for p-values; standardize.
- MINORclarityMethods, Statistical analyses“Residual distributions were examined visually”→ Specify the method of visual examination (e.g., Q-Q plots) for clarity.Adding detail would improve reproducibility.
- MINORconsistencyAbstract“P < 0.001”→ Ensure consistent use of P vs p for p-values throughout.The abstract uses 'P < 0.001' while other sections use 'P < 0.001' consistently, but the style may vary.
- MINORclarityMethods, Sample size calculation“If 6-month outcomes could be obtained from 200 patients, the trial would have 80% power to detect a mean between-group difference in SAQ summary score of 0.40 s.d. units.”→ Clarify that this is the primary assumption and provide the standard deviation used.The sample size calculation is presented with multiple scenarios, which may be confusing.
- MINORotherData availability“The statistical code will be available online in GitHub upon publication of this paper: https://github.com/RobertsonCentre/CorCMR (10.1016/S0140-6736(15)60291-4) .”→ Remove the extraneous DOI reference that appears after the GitHub link.There is an unrelated DOI appended to the GitHub link, likely a formatting error.
The published paper is robust in its design and reporting. An informed reader should weigh the retrospective registration (submitted after study start) as a minor transparency concern, and the rounding discrepancy in the abstract (53.0% vs 52.4%) as a minor reporting error that does not affect conclusions. No erratum or re-analysis is warranted based on the evidence reviewed.
- 1.HIGHreportingCorrect the rounding discrepancy in the Abstract: 131/250 = 52.4%, not 53.0%.This is a factual error that could mislead readers; it should be corrected in an erratum.
- 2.HIGHreportingClarify in the Data availability statement that the trial was registered retrospectively (submitted 2021-03-09 after study start 2021-02-09) and explain why.Retrospective registration is a transparency concern; acknowledging it allows readers to weigh the risk of selective outcome reporting.
- 3.HIGHreportingRemove the extraneous DOI reference appended after the GitHub link in the Data availability section.The unrelated DOI (10.1016/S0140-6736(15)60291-4) is a formatting error that should be removed.
- 4.MEDIUMreportingIn Table 1, clarify that the 100% for 'Glyceryl trinitrate spray' refers to the number of patients with data, not the total N.The current labeling is ambiguous and could be misinterpreted.
- 5.MEDIUMreportingStandardize p-value notation throughout the manuscript (use either 'P' or 'p' consistently).Inconsistent notation is a minor copyedit issue that reduces professionalism.
- 6.MEDIUMreportingIn the Methods, Statistical analyses, specify that residual distributions were examined using Q-Q plots (or another named method).Adding detail improves reproducibility and transparency of assumption verification.
- 7.MEDIUMreportingIn the Methods, Sample size calculation, state the primary assumption (e.g., expected mean difference and SD) rather than presenting multiple scenarios.A single primary assumption aligns with conventional power analysis reporting and avoids ambiguity.
- 8.LOWreportingConsider reporting the EQ-5D-5L secondary outcome in the main text with a brief summary, rather than only in supplementary materials.Including all prespecified outcomes in the main text improves transparency.
- 9.LOWreportingIn the Discussion, add a paragraph on generalizability to other healthcare systems and the potential impact of the single reference center for CMR analysis.This would help readers assess the external validity of the findings.
- 10.LOWdata codeIn the Data availability statement, specify the exact conditions for data access (e.g., whether a data use agreement is required) and the expected timeline for approval.Making the access route more concrete would enhance reproducibility.
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.