The traditional Chinese medicine Qiliqiangxin in heart failure with reduced ejection fraction: a randomized, double-blind, placebo-controlled trial.
Cheang I, Yao W, Zhou Y, Zhu X, Ni G, Lu X, Liao S, Gao R, Zhou F, Shen J, Leung AYL, Jiang M, Kong H, Bai L, Mahemuti A, Yuan H, Dong YG, Wong CK, Xu Q, Zhang G, Wu J, Lu Q, Zhang J, Cha C, Ren Q, Fu L, Wang B, Xu Y, Hu H, Dong J, Shang Z, Yu C, Li S, Yao C, Gao L, Zhang H, Rosenzweig A, Jia Z, Li X, QUEST Trial Committees and Investigators
- DOI
- 10.1038/s41591-024-03169-2
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-20
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/4f3656e9-b268-4799-b3b0-463fc4fa3e89 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- ReportingData & code availability partially met−0.25★
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 with rigorous design, clear ethics approval, and transparent reporting. The main weakness is the vague data availability statement, and there are minor internal inconsistencies in reported percentages that should be corrected.
Both reviewers classified the study as interventional, which is consistent with the randomized controlled trial design. The evaluation covered the full text, including methods, results, and discussion. Non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification recomputed only a subset of tests; the rest remain unverified.
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 4 tests: 4 consistent, 0 inconsistent; 4 via agent-written checks.
- CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2Primary composite outcome HR p-value
“hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.68−0.90; P < 0.001”
Taken as given: The HR is a ratio estimate with a 95% CI.; The CI is two-sided at 95%.Method: Two-tailed p-value derived from the HR and 95% CI using the normal approximation.How we recomputed it: pCI(0.78, 0.68, 0.90, 1) - CONSISTENTreported p = .045 · recomputed p = .056Reviewers 1, 2Cardiovascular death HR p-value
“cardiovascular death (13.31% versus 15.95%; HR, 0.83; 95% CI, 0.68−0.996; P = 0.045)”
Taken as given: The HR is a ratio estimate with a 95% CI.; The CI is two-sided at 95%.Method: Two-tailed p-value derived from the HR and 95% CI using the normal approximation.How we recomputed it: pCI(0.83, 0.68, 0.996, 1) - CONSISTENTreported p = .002 · recomputed p = .002Reviewers 1, 2Hospitalization for heart failure HR p-value
“hospitalization for heart failure (15.63% versus 19.16%; HR, 0.76; 95% CI, 0.64−0.90; P = 0.002)”
Taken as given: The HR is a ratio estimate with a 95% CI.; The CI is two-sided at 95%.Method: Two-tailed p-value derived from the HR and 95% CI using the normal approximation.How we recomputed it: pCI(0.76, 0.64, 0.90, 1) - CONSISTENTreported p = .058 · recomputed p = .062Reviewers 1, 2All-cause mortality HR p-value
“All-cause mortality did not differ significantly between the two groups (HR, 0.84; 95% CI, 0.70−1.01; P = 0.058)”
Taken as given: The HR is a ratio estimate with a 95% CI.; The CI is two-sided at 95%.Method: Two-tailed p-value derived from the HR and 95% CI using the normal approximation.How we recomputed it: pCI(0.84, 0.70, 1.01, 1)
- lowinternal contradictionThe percentage of patients stopping treatment for reasons other than death is reported as 1.3% versus 0.58%, but 16/1555 = 1.03% and 9/1555 = 0.58%.
“QLQX treatments was stopped in 16 patients and placebo was stopped in 9 patients for reasons other than death (1.3% versus 0.58%; P = 0.228)”
ResultsFind in source - lowinternal contradictionThe percentage for cardiovascular death in the placebo group is reported as 15.59% in the text but 15.95% in Table 2.
“A total of 207 deaths (13.31%) in the QLQX group and 248 deaths (15.59%) in the placebo group were due to cardiovascular causes”
ResultsFind 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.
5 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2QLQX reduces the composite of cardiovascular death and hospitalization for heart failure in HFrEF patients.The primary outcome result (HR 0.78, 95% CI 0.68-0.90, P<0.001) directly supports this claim.Evidence: Primary composite outcome occurred in 389 (25.02%) vs 467 (30.03%) patients, HR 0.78 (0.68-0.90), P<0.001.
“the primary outcome occurred in 389 patients (25.02%) in the QLQX group and 467 patients (30.03%) in the placebo group (hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.68−0.90; P < 0.001)”
AbstractFind in source - supportedReviewers 1, 2QLQX reduces hospitalization for heart failure.Secondary outcome analysis shows a significant reduction in HHF (HR 0.76, 95% CI 0.64-0.90, P=0.002).Evidence: HHF occurred in 243 (15.63%) vs 298 (19.16%), HR 0.76 (0.64-0.90), P=0.002.
“the QLQX group showed reductions in both hospitalization for heart failure (15.63% versus 19.16%; HR, 0.76; 95% CI, 0.64−0.90; P = 0.002)”
AbstractFind in source - supportedReviewers 1, 2QLQX reduces cardiovascular death.Cardiovascular death was significantly reduced (HR 0.83, 95% CI 0.68-0.996, P=0.045), though the upper CI is close to 1.0.Evidence: CV death occurred in 207 (13.31%) vs 248 (15.95%), HR 0.83 (0.68-0.996), P=0.045.
“cardiovascular death (13.31% versus 15.95%; HR, 0.83; 95% CI, 0.68−0.996; P = 0.045)”
AbstractFind in source - supportedReviewers 1, 2QLQX is safe and well tolerated.Adverse events were comparable between groups, with no significant differences in serious adverse events.Evidence: Adverse events related to study drug occurred in 21 (1.35%) vs 14 (0.9%), P=0.308; no notable excess except insomnia.
“Adverse events related to the study drug occurred in 21 patients (1.35%) in the QLQX group and 14 patients (0.9%) in the placebo group ( P = 0.308)”
ResultsFind in source - supportedReviewers 1, 2QLQX may improve clinical outcomes in HFrEF when added to conventional therapy.The primary and secondary outcomes support this claim, though the mechanism remains uncertain.Evidence: Primary composite outcome HR 0.78 (0.68-0.90), P<0.001; secondary outcomes generally favor QLQX.
“The results of this trial indicate that QLQX may improve clinical outcomes in patients with HFrEF when added to conventional therapy.”
AbstractFind in source
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- ADEQUATESurrogate endpointThe primary endpoint is a composite of hospitalization for heart failure and cardiovascular death, which are hard clinical outcomes. The secondary endpoint includes NT-proBNP, a surrogate, but the primary claim is based on clinical outcomes.
“The trial met its primary outcome, which was a composite of hospitalization for heart failure and cardiovascular death: over a median follow-up of 18.3 months, the primary outcome occurred in 389 patients (25.02%) in the QLQX group and 467 patients (30.03%) in the placebo group (hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.68−0.90; P < 0.001).”
- ADEQUATEEffect sizeThe primary outcome showed a 22% relative risk reduction (HR 0.78) with absolute event rates of 25.02% vs 30.03%, which is clinically meaningful in heart failure. The effect is statistically significant and anchored to hard outcomes.
“the primary outcome occurred in 389 patients (25.02%) in the QLQX group and 467 patients (30.03%) in the placebo group (hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.68−0.90; P < 0.001).”
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 a pilot study (ChiCTR1900021929) showing promising effects of QLQX on NT-proBNP, symptoms, and quality of life, and acknowledges its small sample size. It also cites preclinical studies on myocardial metabolism, fibrosis, and remodeling. The rationale links the unmet need in HFrEF treatment to the potential of TCM, and the hypothesis follows logically. Limitations of prior research (small sample, high risk of bias in meta-analyses) are acknowledged in the Discussion.
“In our pilot study, Qiliqiangxin (QLQX) capsules, a TCM formula, demonstrated promising results when added to established heart failure treatment for patients with HFrEF”
“To address this question, the Qiliqiangxin in Heart Failure: Assessment of Reduction in Mortality (QUEST) study was developed”
“In previous meta-analyses of studies , , it was shown that the combination of QLQX capsules with standard heart failure treatment can lead to improvement in clinical symptoms and a better quality of life for patients with chronic heart failure. However, it is important to note that these studies had a high risk of bias”
“In our pilot study, Qiliqiangxin (QLQX) capsules, a TCM formula, demonstrated promising results when added to established heart failure treatment for patients with HFrEF”
“However, randomized controlled trials and rigorous scientific evidence have yet to demonstrate the ability of TCM to improve clinical outcomes in patients with heart failure beyond established therapies.”
“Although the QLQX group experienced lower rates of mortality and readmission than the placebo group, the sample size was too small to draw definitive conclusions.”
Randomization used a block method via an RTSM system with allocation generated by an independent statistician. Blinding was double-blind with matched placebo and independent third-party coding. A priori sample size calculation was provided with assumptions (25% vs 20% annual event rates, α=0.05, β=0.20, 620 events). Inclusion/exclusion criteria are detailed. Outlier handling is addressed through pre-specified analysis populations (FAS, PPS, SS) and missing data assumptions. Controls are inherent in the placebo comparator. Independent replication is not applicable for a single pivotal trial.
“This study adopted a block randomization method, and the participants were randomly grouped and managed through the randomization and trial supply management (RTSM) system.”
“An independent third party conducted blind coding of the experimental drug and placebo, rendering them virtually indistinguishable to participants and investigators.”
“We estimated that the annual rate of the composite endpoint would be 25% in patients receiving placebo and 20% in the QLQX group within the 12−36 months of follow-up.”
“This study adopted a block randomization method, and the participants were randomly grouped and managed through the randomization and trial supply management (RTSM) system.”
“The matching placebo capsules had identical color, weight, size, smell, specification, property of contents, labels and packaging as the QLQX capsules to ensure blinding during the study.”
“On the basis of these calculations, it was estimated that approximately 3,080 patients would need to be included to provide the required number of 620 expected composite primary end point events”
The paper reports sex (72% male), age (mean 63 years), and detailed baseline characteristics including NYHA class, ejection fraction, NT-proBNP, and comorbidities. Since both sexes are enrolled, sex_justified is not applicable. Species/strain and housing conditions are not applicable for a human trial. Demographics are adequately reported.
“The mean age of the enrolled patients was 63 years and 72% were male.”
“Age (years) | 62.56 ± 12.18 | 62.52 ± 12.54”
“The mean age of the enrolled patients was 63 years and 72% were male.”
“Age (years) | 62.56 ± 12.18 | 62.52 ± 12.54”
The protocol was approved by the independent ethics committee of the First Affiliated Hospital of Nanjing Medical University (approval no. 2018-SR-275) and the ethics committee of each participating center. Written informed consent is mentioned in the inclusion criteria and study procedures. Regulatory compliance is implied by adherence to CONSORT and Chinese guidelines, though not explicitly naming a framework like the Declaration of Helsinki.
“The protocol was reviewed and approved by the independent ethics committee of the First Affiliated Hospital of Nanjing Medical University (approved no. of ethics committee: 2018-SR-275)”
“Inclusion criteria: (1) signed informed consent;”
“The protocol was reviewed and approved by the independent ethics committee of the First Affiliated Hospital of Nanjing Medical University (approved no. of ethics committee: 2018-SR-275)”
“All patients provided written informed consent and entered a 14-day screening period”
The QLQX capsules are described with their 11 components and proportions, and the placebo is described. The manufacturer (Shijiazhuang Yiling Pharmaceutical) is named. Batch consistency is demonstrated via UPLC fingerprint analysis. Software tools (SAS v.9.4, Epidata v.3.1) are identified. Antibodies, cell lines, and mycoplasma testing are not applicable.
“Statistical analyses were conducted using SAS v.9.4 software.”
“Statistical analyses were conducted using SAS v.9.4 software.”
Tests are named (Cox proportional-hazards, log-rank, chi-square, t-test, Wilcoxon). Assumptions are handled by design (Cox model with site as random effect, competing risk models). Exact p-values are reported for most outcomes, though some are reported as thresholds (e.g., P < 0.001). Effect sizes with 95% CIs are provided for primary and secondary outcomes. Software is identified. Data presentation includes Kaplan-Meier curves and per-group n. Mathematical plausibility checks were not performed due to large N and continuous outcomes.
“Time-to-event data were evaluated using Kaplan–Meier estimates and Cox proportional-hazards models”
“hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.68−0.90; P < 0.001”
“Time-to-event data were evaluated using Kaplan–Meier estimates and Cox proportional-hazards models”
“Cardiovascular death or hospitalization due to heart failure | 389 (25.02) | 467 (30.03) | 0.78 (0.68–0.90) | <0.001”
The data availability statement says data are available upon reasonable request via email to corresponding authors, with a one-month response timeframe and a signed agreement required. This is more concrete than a bare 'on request' but does not name a managed-access platform or data-access committee. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not applicable as no bespoke code is mentioned.
“The data that support the findings of this study are not publicly available due to restrictions on patient privacy, but are available upon reasonable request for access to the patient-level data from this study.”
“The data that support the findings of this study are not publicly available due to restrictions on patient privacy, but are available upon reasonable request for access to the patient-level data from this study.”
The trial is registered (ChiCTR1900021929). The paper adheres to CONSORT guidelines. All pre-specified outcomes are reported, including non-significant ones (all-cause mortality). Limitations are discussed in detail. Conclusions are proportional to the evidence. Funding sources and conflicts of interest are disclosed.
“ChiCTR registration: ChiCTR1900021929”
“The study adhered to the CONSORT guidelines.”
“Several limitations of this study are worth noting.”
“ChiCTR registration: ChiCTR1900021929”
“The study adhered to the CONSORT guidelines.”
“Several limitations of this study are worth noting.”
Registered (1 ID: Chinese Clinical Trial Registry). 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 33 references by DOI: 31 verified — 2 no DOI (shown, not verified).
- NO DOIQiliqiangxin prevents right ventricular remodeling by inhibiting apoptosis and improving metabolism reprogramming with pulmonary arterial hypertensionNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIChinese guidelines for diagnosis and treatment of heart failure in ChinaNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- datahttps://www.chictr.org.cn/showprojEN.html?proj=36805LIVEHTTP 200Resolves, but the content could not be matched to the paper.
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.
- MINORtypoAbstract“Qiliqiangxin”→ Ensure consistent spelling of Qiliqiangxin throughout.Spelling is consistent in the abstract.
- MINORconsistencyResults, Primary outcomes“248 deaths (15.59%)”→ Check if the percentage should be 15.95% to match Table 2.Table 2 reports 15.95% for cardiovascular death in placebo group.
- MINORtypoMethods, Participants“QXQL”→ Change to QLQX.Typographical error in the text.
- MINORconsistencyResults, Safety outcome“1.3% versus 0.58%”→ Verify the percentages match the counts (16/1555 and 9/1555).16/1555 = 1.03%, not 1.3%.
- MINORtypoAbstract, Results“0.68−0.90”→ Use consistent minus sign (hyphen) throughout.Inconsistent use of en-dash vs hyphen in ranges.
- MINORconsistencyResults, Primary outcomes“248 deaths (15.59%)”→ Check if this should be 15.95% as in Table 2.Potential inconsistency in percentage for cardiovascular death in placebo group.
The published work is robust and generally trustworthy, but readers should weigh the minor internal inconsistencies in reported percentages and the vague data availability statement. These issues do not undermine the main conclusions but warrant correction or clarification, possibly through an erratum or correspondence.
- 1.HIGHreportingCorrect the percentage for cardiovascular death in the placebo group in the Results text (15.59%) to match Table 2 (15.95%).Internal inconsistency between text and table undermines data integrity and could confuse readers.
- 2.HIGHreportingCorrect the percentage of patients stopping treatment for reasons other than death in the Results (1.3% versus 0.58%) to match the counts (16/1555 = 1.03% and 9/1555 = 0.58%).The reported percentage does not match the numerator/denominator, which is a demonstrable arithmetic error.
- 3.MEDIUMdata codeEnhance the data availability statement to name a managed-access platform or data-access committee (e.g., YODA, Vivli) with specific conditions and timeframe, rather than just email requests to corresponding authors.A concrete access mechanism improves transparency and reproducibility, addressing the only 'warn' dimension.
- 4.MEDIUMstatisticsProvide exact p-values for all outcomes where currently reported as thresholds (e.g., P < 0.001) to improve precision.Threshold-only p-values are less informative and were flagged as inadequate by one reviewer.
- 5.MEDIUMdata codeConsider depositing de-identified aggregate data or statistical analysis code in a public repository to increase transparency.Repository deposit would strengthen reproducibility and align with best practices for clinical trials.
- 6.MEDIUMethicsExplicitly state adherence to the Declaration of Helsinki or ICH-GCP in the ethics section.While ethics approval is documented, explicit mention of the framework would strengthen regulatory compliance reporting.
- 7.MEDIUMstatisticsClarify the handling of missing data in the statistical analysis section, specifying imputation methods if used.Missing data handling is not fully described, which is important for assessing the robustness of the analysis.
- 8.MEDIUMreportingReport the number of patients with missing data for each outcome in the results tables.Transparency about missing data is essential for readers to evaluate potential bias.
- 9.MEDIUMreportingInclude a statement on whether the trial was overseen by a data safety monitoring board and its role.DSMB oversight is a key element of trial governance and is not mentioned.
- 10.MEDIUMreportingProvide the full statistical analysis plan as a supplementary file for independent verification.A detailed SAP would allow readers to verify the pre-specified analyses and reduce the risk of selective reporting.
- 11.LOWcopyeditFix the typographical error 'QXQL' in the Methods, Participants section to 'QLQX'.Correcting the typo ensures consistency and professionalism.
- 12.LOWcopyeditStandardize the use of minus signs in ranges (e.g., '0.68−0.90' vs '0.68-0.90') throughout the manuscript.Consistent formatting improves readability and avoids confusion.
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.