Comparison of dual therapies for hypertension treatment in India: a randomized clinical trial.
Prabhakaran D, Roy A, Chandrasekaran AM, Kondal D, Mukherjee S, Kiru G, Singh K, Salwa H, Sobitharaj EC, Lobo AS, Mahajan G, Mohan B, Khanna A, Malviya A, Patil SG, Abichandani VK, Singh B, Gupta BK, Yellapantula B, Dandge S, Sengupta S, Kumar S, Bardoloi N, Senguttuvan NB, Sahay RK, Patil S, Deora S, Prahalad R, Sarvepalli VP, Gnanaraj JP, Khanna M, Mishra A, Aithal K, Chavda V, Cornelius VR, TOPSPIN Clinical Consortia, Poulter NR
- DOI
- 10.1038/s41591-025-03854-w
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-21
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/4c021528-f10d-437c-abd4-af9a8706673f is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×4−2★
- StatisticsStatistic did not reproduce−0.5★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- StatisticsPrinted percentage does not match its own count (capped)−0.25★
- ReportingData & code availability partially met−0.25★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 30 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.
- 01Printed percentage does not match its own count
44.2% does not match the reported count 260/658
“260 (44.2)”
Table 1 - 02Efficacy rests on an unvalidated surrogate endpoint
The primary outcome is the change in 24-hour ambulatory systolic blood pressure, which is a surrogate endpoint for cardiovascular outcomes. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD data) nor cite validated evidence linking this surrogate to clinical outcomes. The claim of efficacy is based on blood pressure reduction, which is a surrogate for hard outcomes like mortality or cardiovascular events.
“The primary outcome was the mean change in 24-hour ambulatory SBP at 6 months.”
- 03Printed percentage does not match its own count
29.2% does not match the reported count 193/658
“193 (29.2)”
Table 1 - 04Other integrity concern
Trial NCT05683301 was first submitted to ClinicalTrials.gov on 2022-12-10, after the registered study start date of 2022-08-30. 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.
NCT05683301
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, well-reported randomized clinical trial with a clear scientific premise, rigorous design, and transparent reporting. The main weaknesses are a vague data availability statement and an ethics statement that lacks specific committee names and protocol numbers, plus a few minor copyediting issues.
Both reviewers classified the study as interventional and agreed on all dimensions except the ethics statement's adequacy, which I resolved conservatively to warn. The statistics verification covered only a subset of reported tests; the 2 'inconsistent' entries were not machine-verifiable (likely threshold-only p-values) and do not indicate errors. Citation check found no retracted or missing references.
Numerical inconsistencies
3 findings · worst highValues 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 3 tests: 3 consistent, 0 inconsistent; 3 via agent-written checks. 1 reported summary statistic mathematically impossible for the stated N (PERCENT). 1 printed percentage that does not match its own count.
- PERCENT44.2% does not match the reported count 260/658
“260 (44.2)”
Table 1 - PERCENT29.2% does not match the reported count 193/658
“193 (29.2)”
Table 1
- CONSISTENTreported p = .270 · recomputed p = .276Reviewer 2Primary outcome comparison: amlodipine–perindopril vs perindopril–indapamide, Model 1
“24-hour systolic | −0.81 (−2.28 to 0.65) | 0.27”
Taken as given: The reported mean difference is -0.81 mmHg.; The 95% CI is -2.28 to 0.65.; The p-value is two-tailed.; The degrees of freedom approximate the total sample size minus number of parameters (approx 1978).Method: Recomputed p-value from the reported mean difference and 95% CI using the t-distribution approximation.How we recomputed it: pT(-1.09, 1978) - CONSISTENTreported p = .650 · recomputed p = .653Reviewer 2Primary outcome comparison: amlodipine–perindopril vs amlodipine–indapamide, Model 1
“−0.33 (−1.77 to 1.12) | 0.65”
Taken as given: The reported mean difference is -0.33 mmHg.; The 95% CI is -1.77 to 1.12.; The p-value is two-tailed.; The degrees of freedom approximate the total sample size minus number of parameters (approx 1978).Method: Recomputed p-value from the reported mean difference and 95% CI using the t-distribution approximation.How we recomputed it: pT(-0.45, 1978) - CONSISTENTreported p = .540 · recomputed p = .542Reviewer 2Primary outcome comparison: perindopril–indapamide vs amlodipine–indapamide, Model 1
“0.49 (−0.96 to 1.94) | 0.54”
Taken as given: The reported mean difference is 0.49 mmHg.; The 95% CI is -0.96 to 1.94.; The p-value is two-tailed.; The degrees of freedom approximate the total sample size minus number of parameters (approx 1978).Method: Recomputed p-value from the reported mean difference and 95% CI using the t-distribution approximation.How we recomputed it: pT(0.61, 1978)
- lowinternal contradictionThe abstract states 1,637 completed ABPM, while the results section states 1,637 (82.6%) had ABPM, which is consistent. However, the text says '1,663 (84.0%) participants completed follow-up' and '1,637 (82.6%)' had ABPM, which is plausible.
Of the 1,981 participants (42% females) enrolled in the trial, 1,637 completed a 24-hour ambulatory BP measurement. ... At 6 months, 1,663 (84.0%) participants completed follow-up, with a 24-hour ambulatory blood pressure monitoring (ABPM) in 1,637 (82.6%).
Abstractreviewer’s wording - lowinternal contradictionIn Table 1, the percentage of females in the amlodipine–indapamide group is reported as 44.2%, but 260/658 is 39.5%. This appears to be a typographical error.
260 (44.2)
Table 1reviewer’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.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- 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 results are generalizable to a broad spectrum of Indian patients with hypertension.The trial recruited from 32 sites across India with a wide age range and both sexes, but the exclusion of patients with cardiovascular disease and other conditions limits generalizability.Evidence: The trial population and recruitment section describes eligibility criteria, and the discussion notes the broad recruitment.
“The results of this trial may reasonably be extrapolated to a broad spectrum of Indian patients with hypertension because trial participants were recruited from 32 sites across the country with a wide age range (30–79 years); both men and women were well represented; and the trial included a mixture of treated and untreated patients.”
Discussion ¶5Find in source - supportedReviewers 1, 2All three dual combinations produced similar large reductions in ambulatory and office BP.The primary outcome showed no significant differences among groups, and the reductions were large and similar.Evidence: Table 2 shows adjusted mean differences with CIs crossing zero and p-values >0.05; Figure 2 shows similar reductions.
“All three drug combinations produced similar large reductions in the primary outcome, namely ambulatory (~14/8 mmHg) and office (~30/14 mmHg) BPs after 6 months”
AbstractFind in source - supportedReviewers 1, 2The three combinations were equally well tolerated.Adverse event rates were low and similar across groups, with no serious events attributed to study drugs.Evidence: Safety outcomes section reports 51 withdrawals due to adverse events, with 14, 19, and 18 in each group, and 21 serious adverse events none related to drugs.
“A total of 51 participants experienced adverse events causing withdrawal of the study drug. Of these, 14 were in the amlodipine–perindopril group, 19 were in the perindopril–indapamide group and 18 were in the amlodipine–indapamide group.”
ResultsFind in source - supportedReviewer 1The findings are compatible with current guidelines recommending any dual combination from among a RAS blocker, CCB, and diuretic.The equivalence of the three combinations supports the guideline recommendation.Evidence: The primary outcome showed no significant differences, and the discussion cites guidelines.
“However, in the South Asian context, the findings were compatible with several current guidelines that recommend using any dual combination from among a renin-angiotensin system blocker, a calcium channel blocker and a diuretic”
Discussion ¶1Find in source - supportedReviewer 2Hypertension control rates were achieved in approximately 70% of participants in all three groups.Table 4 shows control rates at 6 months of 71.1%, 73.4%, and 69.0% for the three groups, consistent with the claim.Evidence: Table 4 reports control rates (<140/90 mmHg) at 6 months.
“hypertension control rates (sitting BP < 140/90 mmHg) were achieved in approximately 70% of participants in all three groups”
AbstractFind in source - supportedReviewer 2No significant differences in secondary outcomes were observed among the study groups.Secondary outcomes including day/night ambulatory BP, office BP, and control rates showed no significant differences, except for a transient office DBP difference at 2 months.Evidence: Tables 2 and 3 show no significant differences for most secondary outcomes; Table 3 shows one significant difference at month 2 for DBP.
“Furthermore, no significant differences in secondary outcomes, such as mean day and night ambulatory and office BPs and hypertension control rates, were observed among the study groups.”
AbstractFind in source
Premise concern: surrogate not validated for clinical benefit.
- INADEQUATESurrogate endpointThe primary outcome is the change in 24-hour ambulatory systolic blood pressure, which is a surrogate endpoint for cardiovascular outcomes. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD data) nor cite validated evidence linking this surrogate to clinical outcomes. The claim of efficacy is based on blood pressure reduction, which is a surrogate for hard outcomes like mortality or cardiovascular events.
“The primary outcome was the mean change in 24-hour ambulatory SBP at 6 months.”
- ADEQUATEEffect sizeThe effect size is large and clinically meaningful: reductions of ~14/8 mmHg in ambulatory BP and ~30/14 mmHg in office BP, with control rates of ~70% for <140/90 mmHg. These are substantial and anchored to clinical targets.
“All three drug combinations produced similar large reductions in the primary outcome, namely ambulatory (~14/8 mmHg) and office (~30/14 mmHg) BPs after 6 months, such that hypertension control rates (sitting BP < 140/90 mmHg) were achieved in approximately 70% of participants in all three groups.”
Data authenticity concerns
2 findings · 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
- Data look implausibly cleanAssessed
4 integrity concerns flagged (0 high).
- mediumotherTrial NCT05683301 was first submitted to ClinicalTrials.gov on 2022-12-10, after the registered study start date of 2022-08-30. 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.
NCT05683301
reviewer’s wording - lowdata too cleanBaseline characteristics across the three groups are very similar, which is expected in a large randomized trial, but the near-identical means and SDs might be scrutinized.
Age | Mean (years) | 52.2±11.1 | 52.2±11.2 | 51.8±11.4
Table 1reviewer’s wording
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 global hypertension burden, the rationale for dual combinations, and ethnic differences in BP-lowering efficacy, including the CREOLE trial. It explicitly states the evidence gap for South Asian patients and the rationale for the TOPSPIN trial. Limitations of prior research are addressed by noting the lack of robust data for South Asians and the need for a dedicated trial.
“Hypertension affects over 1.3 billion adults worldwide . Elevated BP is the single largest contributor to the global burden of disease and mortality, annually causing 7.8% of the disability-adjusted life years lost and one in six deaths (10.9 million) .”
“Nevertheless, no robust data are available to inform optimal dual combinations for the treatment of hypertension in patients of South Asian origin, who constitute a quarter of the world’s population.”
“However, the BP-lowering efficacy of the major drug classes appears to differ among ethnic groups – , and the CREOLE trial identified significant differences in BP lowering caused by three dual combinations of agents taken by Black patients with hypertension in sub-Saharan Africa.”
“However, the BP-lowering efficacy of the major drug classes appears to differ among ethnic groups – , and the CREOLE trial identified significant differences in BP lowering caused by three dual combinations of agents taken by Black patients with hypertension in sub-Saharan Africa.”
“Nevertheless, no robust data are available to inform optimal dual combinations for the treatment of hypertension in patients of South Asian origin, who constitute a quarter of the world’s population.”
“We, therefore, conducted the Treatment Optimisation of blood Pressure with Single-Pill combinations in INdia (TOPSPIN) trial to compare the efficacy of amlodipine plus perindopril, amlodipine plus indapamide and perindopril plus indapamide in reducing the BP of Indian patients aged 30–79 years with hypertension.”
Randomization used variable permuted block electronic randomization stratified by age and center. The trial was single-blind (investigators unaware of assignments), with a rationale for not using identical pills (cost/logistics) and mitigation via opaque packs. A priori power analysis is reported (85% power to detect 3 mmHg difference). Inclusion/exclusion criteria are described, and the analysis population (ITT with multiple imputation) is defined. Outlier handling is addressed through multiple imputation for missing data and complete-case sensitivity analyses. Controls are inherent in the three-arm design. Independent replication is not applicable for a single pivotal trial.
“Eligible participants were randomly allocated to one of the three study arms in a 1:1:1 ratio using variable permuted block electronic randomization. The randomization was stratified by age (<55 years or ≥55 years) and recruiting center.”
“The investigators were unaware of the trial group assignments (single-blind randomization). The pills provided to the patients were not identical because of cost and logistical reasons; however, repackaging them in opaque packs minimized potential bias.”
“With a planned sample size of 1,968 participants, the TOPSPIN trial had 85% power to detect a clinically meaningful difference of 3 mmHg in the 24-hour ambulatory SBP among the three groups.”
“Eligible participants were randomly allocated to one of the three study arms in a 1:1:1 ratio using variable permuted block electronic randomization.”
“The investigators were unaware of the trial group assignments (single-blind randomization). The pills provided to the patients were not identical because of cost and logistical reasons; however, repackaging them in opaque packs minimized potential bias.”
“With a planned sample size of 1,968 participants, the TOPSPIN trial had 85% power to detect a clinically meaningful difference of 3 mmHg in the 24-hour ambulatory SBP among the three groups.”
The paper reports sex (42.1% women), age (mean 52.1±11.1 years), BMI, diabetes, dyslipidemia, and prior hypertension. Since both sexes are enrolled, sex_justified is not applicable. Age, weight (BMI), and health status are reported. Demographics are adequate for a human trial. Species/strain and housing are not applicable.
“Overall, the participants had a mean age of 52.1±11.1 years; 42.1% were women; 18.6% had self-reported diabetes; and 58.1% had previously diagnosed hypertension.”
“Females – no. (%) | 278 (42.1) | 265(40.0) | 260 (44.2)”
“Overall, the participants had a mean age of 52.1±11.1 years; 42.1% were women; 18.6% had self-reported diabetes; and 58.1% had previously diagnosed hypertension.”
“Table 1 Characteristics of the study participants at baseline”
The paper states the protocol was approved by ethics committees of participating centers and the coordinating center, and by the national regulatory authority. It does not name a specific IRB or provide protocol numbers, which is slightly inadequate. Informed consent is explicitly stated. Regulatory compliance is implied by national regulatory approval. Since this is human research, iacuc_statement is not applicable.
“The study protocol was approved by the ethics committees of the participating centers and the coordinating center and was approved by the national regulatory authority.”
“All participants provided written informed consent.”
“The study protocol was approved by the ethics committees of the participating centers and the coordinating center and was approved by the national regulatory authority.”
“All participants provided written informed consent.”
The trial uses three SPCs: amlodipine–perindopril, perindopril–indapamide, and amlodipine–indapamide, with doses and titration schedules described. The BP devices (Omron HEM-7201, A&D TM-2440) are named. Statistical software (Stata 16.0) and data collection software (Clinion 3.0) are identified. Antibodies, cell lines, mycoplasma, and organisms are not applicable.
“After randomization, the patients discontinued their previous antihypertensive medications without a washout period and received one of the following once-daily SPCs: amlodipine 5 mg plus perindopril 4 mg or perindopril 4 mg plus indapamide 1.25 mg or amlodipine 5 mg plus indapamide SR 1.5 mg.”
“Data from clinical sites were collected using Clinion software version 3.0, and statistical analyses were conducted at the research coordinating center using Stata version 16.0.”
“After randomization, the patients discontinued their previous antihypertensive medications without a washout period and received one of the following once-daily SPCs: amlodipine 5 mg plus perindopril 4 mg or perindopril 4 mg plus indapamide 1.25 mg or amlodipine 5 mg plus indapamide SR 1.5 mg.”
“Data from clinical sites were collected using Clinion software version 3.0, and statistical analyses were conducted at the research coordinating center using Stata version 16.0.”
The primary analysis uses multiple linear regression with multiple imputation, and secondary analyses use linear mixed models and logistic regression. Tests are named (chi-square, Fisher's exact, Wilcoxon rank-sum, t-test). Effect sizes are reported with 95% CIs. Exact p-values are given for primary comparisons (e.g., 0.27, 0.65, 0.54). Software is identified. Data presentation includes bar graphs with error bars and per-group n. Mathematical plausibility is not applicable for large-N continuous outcomes.
“The primary outcome analysis was performed using a multiple linear regression model adjusted for the ambulatory SBP at baseline, age strata (<55 years and ≥55 years), recruiting center and sex according to the intention-to-treat principle.”
“At 6 months, the unadjusted reduction in the primary outcome of 24-hour ambulatory SBP was 14.5 mmHg (95% confidence interval (CI): −16.0 to −13.2 mmHg) for amlodipine–perindopril; 13.3 mmHg (95% CI: −14.7 to −11.9 mmHg) for perindopril–indapamide; and 13.9 mmHg (95% CI: −15.3 to −12.4 mmHg) for amlodipine–indapamide”
“24-hour systolic | −0.81 (−2.28 to 0.65) | 0.27 | −0.33 (−1.77 to 1.12) | 0.65 | 0.49 (−0.96 to 1.94) | 0.54”
“Baseline characteristics and key safety outcomes were compared between the study groups using the chi-square test, Fisher’s exact test, Wilcoxon rank-sum test and the two-sample t -test.”
“24-hour systolic | −0.81 (−2.28 to 0.65) | 0.27 | −0.33 (−1.77 to 1.12) | 0.65 | 0.49 (−0.96 to 1.94) | 0.54”
“At 6 months, the unadjusted reduction in the primary outcome of 24-hour ambulatory SBP was 14.5 mmHg (95% confidence interval (CI): −16.0 to −13.2 mmHg) for amlodipine–perindopril; 13.3 mmHg (95% CI: −14.7 to −11.9 mmHg) for perindopril–indapamide; and 13.9 mmHg (95% CI: −15.3 to −12.4 mmHg) for amlodipine–indapamide”
The data availability statement says raw data cannot be publicly shared due to Indian government regulations, and anonymized data will be made available to bona fide researchers on request. This is reported_but_inadequate because it lacks a concrete platform or access committee. No code is shared, and no repository deposit or accession numbers are provided. Since the trial involves patient data, repository_deposit and accession_numbers are not applicable.
“Anonymized and tabulated or curated data will be made available to bona fide researchers for the purpose of meta-analysis and similar research interests with necessary approvals. Requests may be made to D.P. (dprabhakaran@ccdcindia.org). All such requests will be responded to within a 2-week timeframe.”
“Raw data cannot be publicly shared as per the Health Ministry Screening Committee of the Indian Government (National Regulatory Authority for human research with contributions from other countries), which mandates that no data can be shared beyond the borders without necessary approvals. Anonymized and tabulated or curated data will be made available to bona fide researchers for the purpose of meta-analysis and similar research interests with necessary approvals. Requests may be made to D.P. (dprabhakaran@ccdcindia.org). All such requests will be responded to within a 2-week timeframe.”
The trial is registered (NCT05683301). Methods are detailed enough for replication. Limitations are discussed (missing ABPM, dosing asymmetry, generalizability). Conclusions are proportional, noting equivalence and the need for outcome trials. Funding and COI are disclosed. Reporting guideline is not explicitly mentioned, but the paper includes a CONSORT flow diagram and a reporting summary.
“ClinicalTrials.gov registration: NCT05683301 (https://clinicaltrials.gov/study/NCT05683301)”
“Limitations of this trial include that 17.4% of participants did not provide 24-hour ambulatory recording at 6 months.”
“The trial was supported by Imperial College London, the Centre for Chronic Disease Control, New Delhi and Servier International, France (unrestricted educational grant and in-kind logistical support).”
“ClinicalTrials.gov registration: NCT05683301”
“Limitations of this trial include that 17.4% of participants did not provide 24-hour ambulatory recording at 6 months.”
“The trial was supported by Imperial College London, the Centre for Chronic Disease Control, New Delhi and Servier International, France (unrestricted educational grant and in-kind logistical support).”
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 28 references by DOI: 26 verified — 2 no DOI (shown, not verified).
- NO DOIGlobal report on hypertension: the race against a silent killerNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOITherapeutic benefit of a low dose of indapamide: results of a double-blind against placebo European controlled studyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- datahttps://clinicaltrials.gov/study/NCT05683301LIVEHTTP 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, clarity.
- MINORtypoTable 1, Sex row“265(40.0)”→ Add a space: '265 (40.0)'Inconsistent spacing in table.
- MINORconsistencyResults, Study participants“1,663 (84.0%) participants completed follow-up, with a 24-hour ambulatory blood pressure monitoring (ABPM) in 1,637 (82.6%)”→ Consider rephrasing for clarity: '...completed follow-up, and 1,637 (82.6%) had a 24-hour ABPM.'Slightly awkward phrasing.
- MINORclarityDiscussion, paragraph 3“The differential effects of the three drug combinations on serum potassium highlights that routine monitoring of electrolytes should be carried out particularly among those taking a diuretic.”→ Change 'highlights' to 'highlight' for subject-verb agreement.Grammar issue.
- MINORconsistencyTable 1, Sex row“260 (44.2)”→ Check if the percentage for amlodipine–indapamide females should be 39.5% (260/658) rather than 44.2%.Potential arithmetic inconsistency in the percentage.
- MINORtypoResults, Treatment combinations and office BP“perindopril–-indapamide”→ Remove the extra hyphen: 'perindopril–indapamide'.Typographical error.
- MINORclarityMethods, Statistical analysis“We did not plan for multiple comparison adjustments for secondary outcomes.”→ Clarify whether this was pre-specified in the protocol or a post-hoc decision.Could be clearer about pre-specification.
The published work is methodologically robust and its conclusions are supported by the reported data. An informed reader should weigh the retrospective registration (submitted after the study start date) and the vague data-sharing mechanism as minor transparency concerns; the Table 1 percentage error warrants a correction.
- 1.HIGHrigorCorrect the percentage for females in the amlodipine–indapamide group in Table 1: 260/658 is 39.5%, not 44.2%.This is an internal contradiction that could undermine trust in the data; it warrants an erratum.
- 2.HIGHethicsIn the Methods (Trial design and oversight), name the specific ethics committees and provide protocol approval numbers.A named committee and protocol number are standard for verifying ethical approval and strengthen the ethics statement.
- 3.HIGHdata codeIn the Data availability section, specify a concrete data access mechanism (e.g., a named data access committee or a platform like Vivli) and the conditions for access.The current 'on request' statement is vague and does not meet common data-sharing expectations.
- 4.HIGHreportingIn the Reporting summary, explicitly state adherence to CONSORT and reference the completed checklist.Explicitly referencing the reporting guideline improves transparency and reproducibility.
- 5.MEDIUMdata codeConsider sharing the statistical analysis code in a public repository (e.g., GitHub) to enhance reproducibility.Sharing code allows independent verification of the analyses.
- 6.MEDIUMdata codeIn the Data availability section, clarify whether any aggregate or de-identified datasets can be deposited in a public repository.Even if raw data cannot be shared, aggregate data may be shareable and would improve transparency.
- 7.MEDIUMstatisticsIn the Methods, provide more detail on the multiple imputation model (e.g., variables included, number of imputations) to aid replication.Detailed imputation methods are essential for reproducibility.
- 8.MEDIUMstatisticsIn the Methods, clarify whether the decision not to adjust for multiple comparisons in secondary outcomes was pre-specified in the protocol.Clarifying pre-specification avoids concerns about post-hoc decisions.
- 9.MEDIUMreportingIn the Discussion, explicitly address the potential impact of the single-blind design and the lack of identical pills on the results.Addressing blinding limitations directly strengthens the interpretation.
- 10.LOWcopyeditFix the typo in the Results section: 'perindopril–-indapamide' should be 'perindopril–indapamide'.Typographical errors detract from professionalism.
- 11.LOWcopyeditFix the spacing inconsistency in Table 1: '265(40.0)' should be '265 (40.0)'.Consistent formatting improves readability.
- 12.LOWcopyeditRephrase the sentence in Results, Study participants for clarity: '...completed follow-up, and 1,637 (82.6%) had a 24-hour ABPM.'The current phrasing is slightly awkward.
- 13.LOWcopyeditFix the subject-verb agreement in Discussion, paragraph 3: change 'highlights' to 'highlight'.Grammar errors are easily corrected.
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.
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