Routine Spironolactone in Acute Myocardial Infarction.
Jolly SS, d'Entremont MA, Pitt B, Lee SF, Mian R, Tyrwhitt J, Kedev S, Montalescot G, Cornel JH, Stanković G, Moreno R, Storey RF, Henry TD, Mehta SR, Bossard M, Kala P, Bhindi R, Zafirovska B, Devereaux PJ, Eikelboom J, Cairns JA, Natarajan MK, Schwalm JD, Sharma SK, Tarhuni W, Conen D, Tawadros S, Lavi S, Asani V, Topic D, Cantor WJ, Bertrand OF, Pourdjabbar A, Yusuf S, CLEAR investigators, CLEAR Investigators
- DOI
- 10.1056/NEJMoa2405923
- Record issued
- 2026-08-16
- 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/c3941f5b-fb5a-4f7d-a792-bf11efb5ef6e is authoritative.
How this rating was calculated
- StatisticsImpossible or misreported statistic ×2−2★
- IntegrityIntegrity concern−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- StatisticsPrinted percentage does not match its own count (capped) ×2−0.25★
- ReportingData & code availability partially met−0.25★
A demonstrable critical failure caps the rating at the minimum, regardless of the deductions above.
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 4 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.
- 01Printed percentage does not match its own countdemonstrable
1.7% does not match the reported count 183/3537
“183 (1.7)”
Table 2 - 02Printed percentage does not match its own countdemonstrable
2.1% does not match the reported count 220/3525
“220 (2.1)”
Table 2 - 03Treatment effect not shown to be clinically meaningful
The trial reports no statistically significant benefit on either co-primary outcome. The hazard ratios are close to 1 (0.91 and 0.95) with confidence intervals crossing 1, and the authors acknowledge that a clinically important benefit cannot be excluded. The effect sizes are not anchored to a minimal clinically important difference, and the conclusion is that spironolactone did not reduce outcomes.
“Post myocardial infarction, spironolactone, did not reduce either co-primary outcomes.”
- 04Printed percentage does not match its own count
66.4% does not match the reported count 2349/3525
“2349 (66.4)”
Table 1 - 05Printed percentage does not match its own count
0.2% does not match the reported count 11/3537
“11 (0.2)”
Table 1
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 randomized controlled trial with rigorous design, clear reporting of ethics, and appropriate statistical methods. The main weaknesses are the lack of an explicit data availability statement and the failure to name the statistical software, both of which are minor reporting gaps. The copyedit issues are minor and do not affect the scientific integrity.
Both reviewers agreed on all dimensions; no divergence to reconcile. The statistics verification component checked only a subset of reported tests (those with test statistics + df or effect estimates + CI); 4 of 8 recomputed consistently, but the 4 inconsistent tests are not listed and no decision errors were found, so this does not constitute a demonstrable error. The citation check found no retracted or unresolvable references. The integrity check noted a low-severity internal consistency observation that is not a contradiction.
Numerical inconsistencies
3 findings · worst criticalValues 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.
- Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
- Printed percentage does not match its own countRecomputed
- Internal contradictions in the reported numbersAssessed
Recomputed 4 tests: 4 consistent, 0 inconsistent; 2 recomputed directly from the reported test statistics, 2 via agent-written checks. 2 reported summary statistics mathematically impossible for the stated N (PERCENT). 2 printed percentages that do not match their own count.
- PERCENT66.4% does not match the reported count 2349/3525
“2349 (66.4)”
Table 1 - PERCENT0.2% does not match the reported count 11/3537
“11 (0.2)”
Table 1 - PERCENT1.7% does not match the reported count 183/3537
“183 (1.7)”
Table 2 - PERCENT2.1% does not match the reported count 220/3525
“220 (2.1)”
Table 2
- CONSISTENTreported p = .510 · recomputed p = .510Recomputed hazard ratio 0.91 (95% CI 0.69–1.21), reported p=0.51
“hazard ratio 0.91; 95% confidence interval (CI) 0.69-1.21, p=0.51”
Taken as given: 0.69–1.21 is a two-sided 95% confidence interval for the hazard ratio of 0.91, not a range, an IQR, or a different interval level; the hazard ratio is a RATIO measure, so the interval is symmetric on the log scale; p=0.51 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(0.91, 0.69, 1.21, 1) - CONSISTENTreported p = .520 · recomputed p = .550Recomputed hazard ratio 0.95 (95% CI 0.80–1.12), reported p=0.52
“hazard ratio 0.95; 95% CI 0.80-1.12, p=0.52”
Taken as given: 0.80–1.12 is a two-sided 95% confidence interval for the hazard ratio of 0.95, not a range, an IQR, or a different interval level; the hazard ratio is a RATIO measure, so the interval is symmetric on the log scale; p=0.52 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(0.95, 0.8, 1.12, 1) - CONSISTENTreported p = .520 · recomputed p = .514Reviewers 1, 2Recompute p-value for co-primary outcome 2 using reported event counts and group totals.
“Co-primary outcome 2 occurred in 280 of 3537 patients (7.9%) in the spironolactone group and 294 of 3525 patients (8.3%) in the placebo group (hazard ratio 0.95; 95% CI 0.80-1.12, p=0.52).”
Taken as given: The 280 and 294 are the event counts in each group.; The 3537 and 3525 are the total patients in each group.; The p-value is from a chi-square test (or equivalent) for the 2x2 table.Method: Pearson chi-square test on the 2x2 table.How we recomputed it: pChi2x2(280, 3537-280, 294, 3525-294) - CONSISTENTreported p = .010 · recomputed p = .013Reviewer 2Recompute p-value for hyperkalemia leading to discontinuation using reported counts.
“Hyperkalemia (serum potassium >5.5 mmol/L), leading to discontinuation of the study drug, occurred in 39 (1.1%) of the spironolactone group and 20 (0.6%) of the placebo group (table 3).”
Taken as given: The event counts are 39 and 20 for spironolactone and placebo groups, respectively.; The group totals are 3537 and 3525 for spironolactone and placebo groups, respectively.; The p-value is from a chi-square test for the 2x2 table.Method: Pearson chi-square test on the 2x2 table.How we recomputed it: pChi2x2(39, 3537-39, 20, 3525-20)
- lowinternal contradictionThe abstract reports a competing risk hazard ratio of 0.91 for co-primary 1, while the results section reports a hazard ratio of 0.89 (without competing risks) and 0.91 (with competing risks). This is not a contradiction but a difference in analysis method.
competing risk hazard ratio 0.91; 95% confidence interval (CI) 0.69-1.21, p=0.51 (Abstract) vs hazard ratio [HR], 0.89; 95% CI 0.73-1.08; P=0.23 (Results)
Abstractreviewer’s wording
Overstated conclusions
2 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.
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions only partially backed by the presented evidenceAssessed
3 major claims checked against the paper's own evidence: 2 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewers 1, 2Spironolactone reduced new or worsening heart failure events.The reduction in heart failure events was nominally significant but not adjusted for multiplicity, and the competing risk analysis was not significant.Evidence: New or worsening heart failure occurred in 58 (1.6%) vs 84 (2.4%), HR 0.69 (95% CI 0.49-0.96); competing risk HR 0.77 (95% CI 0.51-1.16).
“New or worsening heart failure occurred in 58 (1.6%) in the spironolactone group, compared with 84 (2.4% in the placebo group (HR, 0.69; 95% CI 0.49-0.96, competing risk HR 0.77; 95% CI 0.51-1.16).”
ResultsFind in source - partialReviewers 1, 2The on-treatment analysis suggests a potential benefit with better compliance.The on-treatment analysis showed a trend toward benefit, but it is hypothesis-generating and not definitive.Evidence: On-treatment co-primary 1 HR 0.79 (95% CI 0.63-1.00); co-primary 2 HR 0.83 (95% CI 0.69-1.00).
“The on treatment analysis is hypothesis generating that with increased compliance and less discontinuation, a benefit may exist that should be tested in future trials.”
Discussion ¶2Find in source - supportedReviewers 1, 2Spironolactone did not reduce the co-primary outcomes in post-myocardial infarction patients.The primary outcomes were not statistically significant, supporting the claim of no benefit.Evidence: Co-primary 1 HR 0.91 (95% CI 0.69-1.21, p=0.51); co-primary 2 HR 0.95 (95% CI 0.80-1.12, p=0.52).
Post myocardial infarction, spironolactone, did not reduce either co-primary outcomes.
Conclusionreviewer’s wording
Premise concern: effect size not shown to be clinically meaningful.
- ADEQUATESurrogate endpointThe primary efficacy outcomes are hard clinical outcomes: cardiovascular death or new or worsening heart failure (co-primary 1) and a composite of cardiovascular death, myocardial infarction, stroke, or new or worsening heart failure (co-primary 2). These are clinical events, not surrogate biomarkers.
“The co-primary efficacy outcomes were total events of cardiovascular death or new or worsening heart failure (co-primary 1) and time-to-first occurrence of the composite of cardiovascular death, myocardial infarction, stroke or new or worsening heart failure (co-primary 2).”
- INADEQUATEEffect sizeThe trial reports no statistically significant benefit on either co-primary outcome. The hazard ratios are close to 1 (0.91 and 0.95) with confidence intervals crossing 1, and the authors acknowledge that a clinically important benefit cannot be excluded. The effect sizes are not anchored to a minimal clinically important difference, and the conclusion is that spironolactone did not reduce outcomes.
“Post myocardial infarction, spironolactone, did not reduce either co-primary outcomes.”
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 introduction cites prior trials (RALES, EPHESUS, ALBATROSS) and explains the uncertainty about routine spironolactone use post-MI. The rationale is logical: aldosterone antagonism reduces mortality in heart failure, but benefit in all post-MI patients is uncertain. Limitations of prior research (e.g., ALBATROSS not powered for mortality) are acknowledged, and the need for a large trial is identified.
“Aldosterone antagonism with spironolactone has been shown to reduce mortality in patients with chronic heart failure with reduced ejection fraction, and is a cornerstone of therapy.”
“We conducted the CLEAR trial to evaluate if routine spironolactone use is beneficial in patients post myocardial infarction.”
“A trial of routine aldosterone antagonism with spironolactone in addition to standard therapy in 1603 post-myocardial infarction patients without heart failure showed no improvement in outcomes.”
“We conducted the CLEAR trial to evaluate if routine spironolactone use is beneficial in patients post myocardial infarction.”
Randomization used permuted blocks within a 24-hour computerized central system, stratified by center and MI type. All participants, investigators, healthcare providers, data collectors, and outcome adjudicators were blinded. A priori sample size calculations were provided and updated based on blinded event rates. Inclusion/exclusion criteria were pre-specified and modified with a protocol amendment. The intention-to-treat principle was pre-specified. Outlier handling is not explicitly described, but missing data were rare and handled appropriately. Controls are inherent in the placebo group. Independent replication is not applicable for a single pivotal trial.
“Randomization was performed using permuted blocks within a 24-hour computerized central system at the Population Health Research Institute.”
“All participants, investigators, healthcare providers, data collectors and outcome adjudicators were blinded to treatment allocation.”
“Based on the above assumptions, it was estimated that 4,000 participants (an expected 512 events) were needed to detect a 25% relative risk reduction using a log-rank test.”
“Randomization was performed using permuted blocks within a 24-hour computerized central system at the Population Health Research Institute. Randomization was stratified by study center and whether the patient had a STEMI or NSTEMI.”
“All participants, investigators, healthcare providers, data collectors and outcome adjudicators were blinded to treatment allocation.”
“Based on the above assumptions, it was estimated that 4,000 participants (an expected 512 events) were needed to detect a 25% relative risk reduction using a log-rank test.”
The paper reports age (mean 61 years), sex (20.4% female), and various comorbidities (diabetes, hypertension, prior MI). Demographics are detailed in Table 1. Since both sexes are enrolled, sex_justified is not applicable. Species/strain and housing conditions are not applicable for a human trial.
“Baseline characteristics were well balanced between the groups, with mean age was 61 years and 20.4% of patients were female (Table 1).”
“Approximately 9% had prior myocardial infarction, 0.8% had a history of heart failure, and 19% had diabetes mellitus.”
“Baseline characteristics were well balanced between the groups, with mean age was 61 years and 20.4% of patients were female (Table 1).”
“Approximately 9% had prior myocardial infarction, 0.8% had a history of heart failure, and 19% had diabetes mellitus.”
The paper states that ethics committees of participating centers and national regulatory authorities approved the trial, and all patients provided written informed consent. This satisfies both irb_ethics_statement and informed_consent. Regulatory compliance is implied by the approval statement.
“Ethics committees of participating centers and national regulatory authorities approved the trial.”
“All patients provided written informed consent.”
“Ethics committees of participating centers and national regulatory authorities approved the trial.”
“All patients provided written informed consent.”
The study drug spironolactone is identified with manufacturer (Tiofarma, The Netherlands) and dose (25 mg). The statistical software is not explicitly named, but the analysis methods are described. Since this is a drug trial, bench resources like antibodies and cell lines are not applicable.
“Study drugs were spironolactone tablets of 25 mg and colchicine tablets of 0.5 mg with matching placebos for each.”
“Study drugs were spironolactone tablets of 25 mg and colchicine tablets of 0.5 mg with matching placebos for each. Tiofarma, The Netherlands, provided both study drugs with raw materials produced by Indena S.p.A., Milan, Italy.”
The paper names the statistical tests used (log-rank, Cox proportional hazards, Prentice-Williams-Peterson model, Fine-Gray). Assumptions are handled by design (e.g., stratified Cox model). Exact p-values are reported for primary outcomes. Effect sizes with 95% CIs are reported throughout. Statistical software is not explicitly identified, but this is a minor omission. Data presentation includes Kaplan-Meier curves and per-group n. Mathematical plausibility checks were not performed due to lack of raw data.
“Co-primary 2 (cardiovascular death, myocardial infarction, stroke or new or worsening heart failure) was analyzed as a time-to-first-event using the log-rank test for the P-value and a stratified (by allocation to colchicine and MI type) and Cox proportional hazards model for the effect size and 95% confidence intervals.”
“competing risk hazard ratio 0.91; 95% confidence interval (CI) 0.69-1.21, p=0.51”
“Co-primary outcome 2 occurred in 280 of 3537 patients (7.9%) in the spironolactone group compared with 294 of 3525 patients (8.3%) in the placebo group (hazard ratio [HR], 0.95; 95% CI 0.80-1.12; P=0.52”
“Co-primary 2 (cardiovascular death, myocardial infarction, stroke or new or worsening heart failure) was analyzed as a time-to-first-event using the log-rank test for the P-value and a stratified (by allocation to colchicine and MI type) and Cox proportional hazards model for the effect size and 95% confidence intervals.”
“competing risk hazard ratio 0.91; 95% confidence interval (CI) 0.69-1.21, p=0.51”
The paper does not include an explicit data availability statement in the provided text. The trial is registered, but no repository deposit or accession numbers are mentioned. Since this is a clinical trial with patient data, repository deposit and accession numbers are not applicable. Code sharing is not applicable as no bespoke code is mentioned.
The trial is registered (NCT03048825). Methods are detailed enough for replication. Limitations are explicitly discussed, including low event rates and underrepresentation of women. Conclusions are proportional to the results. Funding and COI are stated.
“ClinicalTrials.gov number NCT03048825”
“First, based on the 95% CI of the primary outcome results, we cannot exclude a beneficial relative risk reduction of 27% or smaller that could be clinically important.”
“The study was supported by Canadian Institutes of Health, Boston Scientific and Population Health Research Institute, Hamilton, Canada.”
“ClinicalTrials.gov number NCT03048825”
“First, based on the 95% CI of the primary outcome results, we cannot exclude a beneficial relative risk reduction of 27% or smaller that could be clinically important.”
Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None found · partly checkedReferences 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.
Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.
Checked 20 references by DOI: 18 verified — 2 no DOI (shown, not verified).
- NO DOIISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarctionNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIColchicine in Acute Myocardial Infarction- The CLEAR trialNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
Copyediting
4 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 4 minor suggestions below.
4 copyedit issues flagged: mostly consistency, typo, grammar.
- MINORtypoAbstract, Results“only 45 (0.6%) had an unknown vital status, .”→ Remove the extra comma and space before the period.Extra comma and space.
- MINORconsistencyResults, Efficacy“competing risks HR 0.96; 95% CI 0.81-1.13”→ Ensure consistent use of 'competing risk' vs 'competing risks'.Inconsistent terminology.
- MINORgrammarDiscussion, paragraph 1“We did not demonstrate a reduction in mortality with spironolactone.,Our results are consistent”→ Remove the stray comma and space before 'Our'.Stray punctuation.
- MINORconsistencyResults, Efficacy“hazard ratio [HR], 0.89; 95% CI 0.73-1.08; P=0.23,”→ Ensure consistent use of 'P' vs 'p' for p-values throughout.Inconsistent capitalization of p-value.
The published work is robust and well-reported; an informed reader should weigh the minor reporting gaps (no data availability statement, unnamed statistical software) and the fact that only a subset of statistics were machine-verified. No erratum or correction is warranted based on the identified issues, but the authors should consider adding a data availability statement and naming the software in any future version or correction.
- 1.CRITICALstatisticsCorrect or explain the statistically impossible value: PERCENT: 1.7% does not match the reported count 183/3537Demonstrable critical failure — blocks the verdict from passing.
- 2.CRITICALstatisticsCorrect or explain the statistically impossible value: PERCENT: 2.1% does not match the reported count 220/3525Demonstrable critical failure — blocks the verdict from passing.
- 3.HIGHdata codeAdd an explicit data availability statement in the Methods or a dedicated section, specifying how de-identified patient data can be accessed (e.g., via a data access committee or a repository like Vivli).The paper currently lacks any data availability statement, which is a transparency gap for a data-driven clinical trial.
- 4.HIGHstatisticsExplicitly name the statistical software (e.g., SAS version, R version) used for analyses in the Statistical Considerations section.The statistical software is not identified, which is a reproducibility gap.
- 5.MEDIUMreportingMention adherence to a reporting guideline (e.g., CONSORT) in the Methods or a footnote.The paper follows CONSORT-like structure but does not explicitly state adherence, which is a minor transparency improvement.
- 6.MEDIUMreportingProvide a link to the full trial protocol or statistical analysis plan in the supplementary materials.This would enhance transparency and allow readers to verify pre-specified analyses.
- 7.MEDIUMdata codeIf feasible, deposit aggregate data or summary statistics in a public repository to enhance transparency.This would partially address the lack of a data availability statement.
- 8.MEDIUMstatisticsClarify the handling of missing data for the 45 patients with unknown vital status in the statistical methods.The paper mentions these patients but does not describe how they were handled in the analysis.
- 9.LOWcopyeditIn the Abstract, Results, remove the extra comma and space before the period in 'only 45 (0.6%) had an unknown vital status, .'This is a typographical error that should be corrected.
- 10.LOWcopyeditIn the Results, Efficacy, ensure consistent use of 'competing risk' vs 'competing risks'.Inconsistent terminology may confuse readers.
- 11.LOWcopyeditIn the Discussion, paragraph 1, remove the stray comma and space before 'Our' in 'We did not demonstrate a reduction in mortality with spironolactone.,Our results are consistent'.This is a punctuation error that should be fixed.
- 12.LOWcopyeditIn the Results, Efficacy, ensure consistent capitalization of 'P' vs 'p' for p-values throughout.Inconsistent capitalization of p-values is a minor style issue.
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.