Oral extended-release nicotinic acid added to atorvastatin × Improvement in brachial FMD in adults with coronary artery disease

Required evidence, verification status and materials actually read
Item	AVerification status	BReading scope	CReview item	DCurrent findings	EWhy unverified	FRequired materials and conditions	GFurther research
1	Met	Full text not readStored summary read	N01 · Separate questionWhich FMD comparison is being tabulated?Required	The original /ko/effect is improvement in brachial FMD in adults with coronary artery disease. The identity of the adjudicated question fixes the comparison as ER nicotinic acid versus placebo on common atorvastatin treatment, with each period lasting 3 months. The subclaims key is absent, and there is a single table for the original main question. S01	The target of the judgment and the identity of the narrowly defined actual comparison were verified. This item does not declare that the evidence for FMD efficacy is sufficient.	The identity of the current claim and adjudicated question, descriptive attributes (facets), canonical URL, and actual list of keys in the retained summary.	Cross-check included reports by population, intervention, comparator, endpoint and time point, keeping other questions separate in the scope-boundary table.
2	Partly verified	Full text not readStored summary read	N02 · Molecule and release formulationHave the molecule, release formulation, salt and brand of the actual nicotinic acid product been verified?Required	The main trial evaluated oral ER nicotinic acid as add-on therapy. The exact salt, manufacturing origin, brand/manufacturer and excipients are unverified. The original classification, kind M, denotes drug add-on therapy; do not reclassify it as a supplement solely because of the NUT module. S01 S12	The molecule, ER formulation and route have been linked, but the detailed identity of the actual batch and formulation is unavailable.	Trial product label, batch certification, basis for specifying the salt/active amount, manufacturing/quality information, and release-formulation information.	Cross-check the trial batch against product documents, and code information on other release formulations, molecules and combination products separately.
3	Partly verified	Full text not readStored summary read	N03 · Add-on therapy and comparatorCan background treatment in both periods be distinguished from the placebo comparison?Required	The common atorvastatin dose is 80 mg/day, and the comparison is with the placebo crossover period on the same background treatment. The main trial's placebo ingredients, other common treatments and changes by period are unverified. S01	The background to the add-on comparison was verified, but not all concomitant-treatment/placebo conditions could be cross-checked.	Records of common treatment, concomitant medication, rescue treatment, placebo composition, changes and adherence by arm/period.	Cross-check treatment changes by period against the effect of interest, and do not attribute the effect of the common statin treatment to added nicotinic acid.
4	Partly verified	Full text not readStored summary read	N04 · Dose and adherenceCan the nominal dose of 1500 mg/day be distinguished from actual exposure?Required	The original target dose is 1500 mg/day. Titration has no recorded value and is unverified; actual adherence, doses taken and discontinuation data by period were also not verified within the retained scope reviewed here. S01	The nominal dose is clear, but data needed to verify actual exposure remain outstanding.	Titration schedule, actual intake/adherence by period, washout/discontinuation, and the basis for specifying the active amount.	Extract nominal dose and actual exposure separately by period, and do not convert or fill in unverified doses taken.
5	Unverified	Full text not readStored summary read	N05 · Duration and carryoverHave the 3 months per period and the crossover sequence, washout and handling of carryover been verified?Required	Each treatment period lasted 3 months, with measurements at baseline and at the end of each period. The detailed washout, period sequence and handling of period/carryover effects in the crossover model are unverified. S01	The period length is known, but data needed to complete the review of crossover-specific time/carryover effects are unavailable.	Complete visit schedule, sequence allocation, washout, and analysis plans and results for period/sequence/carryover.	Cross-check the crossover schedule and analysis equation, and do not add the individual 3-month periods together to create an arbitrary overall follow-up duration or a single treatment period.
6	Partly verified	Full text not readStored summary read	N06 · CAD eligibilityAre the CAD population, screening for endothelial dysfunction and baseline characteristics known?Required	The participants are adults with coronary artery disease receiving common atorvastatin treatment. The eligibility threshold for endothelial dysfunction has no recorded value. Do not fill in the full baseline/eligibility profile beyond the scope of the abstract accessed in the original review. S01	The disease scope has been linked, but screening thresholds and detailed data on representativeness are unavailable.	CAD diagnosis, age/sex, baseline FMD, inclusion/exclusion criteria, and distributions of disease/nutritional status.	Create an inclusion table by diagnosis and baseline status, and treat application beyond the verified population as a separate question.
7	Partly verified	Full text not readStored summary read	N07 · FMD measurementHave the measurement, blinding and unit conditions for brachial FMD been verified?Required	The brachial FMD endpoint and comparisons at the end of each period were verified. The device method, cuff protocol, post-deflation imaging time and details of image analysis are unverified. S01 S09	The endpoint name/time point was verified, but data needed to assess measurement limitations and differences in detection by arm remain outstanding.	The main trial's FMD SOP, device/analysis method, cuff/imaging timing, baseline diameter and assessment-blinding records.	Cross-check units/directions in the main trial's SOP and results tables, and do not substitute MRI or the protocol of an adjacent trial.
8	Partly verified	Full text not readStored summary read	N08 · Randomization and allocation concealmentHave the actual randomization, allocation concealment and baseline balance in the crossover trial been verified?Required	S01 is reported as a randomized crossover trial. Details of sequence generation/concealment and sequence-specific baseline balance are unverified within the abstract information retained and reused here. S01	The design type was verified, but detailed cross-checking of the allocation process remains outstanding.	The randomized sequence, allocation concealment, baseline table and recruitment flow in the main trial's full text.	Cross-check the actual allocation section and baseline table, distinguishing an RCT label from sections that have been verified.
9	Unverified	Full text not readStored summary read	N09 · Blinding and placeboDid the placebo and assessment blinding address differences caused by flushing?Required	The main trial's placebo ingredients and active masking information have no recorded value. The FDA label warns about flushing but does not provide S01's blinding assessment results. S01 S12	The direct source section needed to verify the measurement/sensory differences of interest has not been obtained.	The main trial's blinding section, placebo composition, flushing management/assessment of treatment guesses, and blinded interpretation.	Compare the placebo/blinding sections, and do not use the existence of a flushing risk as confirmation that blinding failed in the main trial.
10	Unverified	Full text not readStored summary read	N10 · Crossover effect of interestCan the paired data, analysis population and effect of interest in the reported test be identified?Required	The original report gives a between-treatment P=0.48 for FMD at the end of each period. The paired-model coefficient, ITT/PP, adjustment/analysis population and paired-data correlation are unverified. The +0.5%p figure is the existing simple descriptive difference. S01	The comparison direction has been linked, but the actual model used for the test and details of the estimand are unavailable.	The main trial's statistical methods section, paired/crossover model, analysis population, covariates and test results table.	Cross-check the comparison of interest against the actual model, and do not fill in an independent-groups analysis or an assumed ITT analysis.
11	Unverified	Full text not readStored summary read	N11 · Denominators and missing dataCan the study total of 66 participants be distinguished from the denominators for the actual FMD analysis and missing data?Required	The original study total is 66 participants; the FMD analysis denominator fields, evidence_core.analysis_n and endpoint_analysis_n, have no recorded value (null). Actual completion counts by period, paired-analysis n and handling of missing data are also unverified. S01	The existence of a sample was verified, but data needed to verify the analysis denominator/losses for the selected outcome are unavailable.	The main trial's flow diagram, analysis n by period, reasons for missing data/discontinuation, and their handling in the analysis.	Cross-check denominators in the flow diagram and results tables, and do not substitute the study total of 66 participants for the paired-analysis n.
12	Met	Full text not readStored summary read	N12 · Original FMD values and testHave the period-end FMD values been distinguished from the scope of the failure to demonstrate improvement?Required	Period-end FMD was 6.6 ± 4.8% with nicotinic acid and 6.1 ± 4.9% with placebo, P=0.48. The +0.5%p figure is simple subtraction in the original calculation history, not a verified crossover-model effect or a between-treatment difference in changes from baseline. Failure to demonstrate improvement does not mean an effect of exactly 0 or equivalence. S01	The retained original values/analysis boundaries and the interpretation of nonsignificance were linked. Adequacy of precision remains an unverified condition in a later item.	Results in the original research abstract, original results tables, crossover-model estimates and baseline-change data.	Cross-check values, units and comparison direction in the abstract/results tables, and preserve the old simple difference as a separate descriptive historical record.
13	Unverified	Full text not readStored summary read	N13 · ± and paired varianceHave the type of ± statistic and the paired variance for FMD been verified?Required	The original ± figures are 4.8 for nicotinic acid and 4.9 for placebo, but the dispersion type field (dispersion_type) has no recorded value. Paired variance/correlation and analysis n were also not verified. S01	The displayed period-end values are known, but data needed to verify the actual definition of dispersion are unavailable.	SD/SE definitions in the original table, paired-data variance/correlation, test model and analysis n.	Even after cross-checking dispersion definitions in the table notes and statistical methods section, do not newly calculate an unreported CI.
14	Unverified	Full text not readStored summary read	N14 · CI and important differenceIs there a paired between-group CI and an applicable important FMD difference?Required	The reported paired-contrast CI (reported_paired_contrast_CI) and the difference in changes from baseline (baseline_change_difference) are blank (null). An applicable between-group MCID is also unverified, and the original CX indicates the current limits of access/verification. It does not assert that reconstruction is permanently impossible. S01 S13	Without the interval and a threshold for an important difference, it is not possible to assess which magnitudes of effect are excluded.	Between-group CI from the crossover model, paired variance/denominator, and evidence for an important difference in the same population/measure.	Compare the reported CI with a justified threshold for an important difference, and leave unverified thresholds and CIs unverified.
15	Unverified	Full text not readStored summary read	N15 · Registration and plansDo the planned status, analysis, and timing of FMD agree with what was reported?Required	S01 is linked to NCT00150722, but the historical access level for S13 was registry_shell_only: only the basic registry display was available. FMD is the page's priority endpoint; its registered primary/co-primary status and the registry text on analyses and sponsorship are unverified. S01 S13	The registration number is linked, but the structured registry text needed to compare the plans with the actual report could not be read.	Version-specific registry text, protocol, SAP, and the history of changes to endpoints/analyses.	Compare the original versions of the registration/plans with the original study report, and indicate only the status/discrepancies that have been verified.
16	Met	Full text not readStored summary read	N16 · Direct trial familyHave the original study report and registration been linked to the same direct trial family?Required	S01 Philpott/PMID23174368/DOI10.1016/j.atherosclerosis.2012.10.067 and S13 NCT00150722 belong to one direct trial family, PHILPOTT-NCT00150722. Do not count the current 15 bibliographic records as 15 independent trials. S01 S13	The identity of the direct trial and its registration link are confirmed in the original manuscript; no total of unique trials/participants was newly produced.	Identifiers and registry links for each report, and a family table of populations/doses/durations/outcomes.	Compare the identifiers and actual comparisons, and do not double-count related reports or registrations as new independent trials.
17	Partly verified	Full text not readStored summary read	N17 · INEF post-hoc subgroupHave the analysis denominators for each arm, prespecified plans, and interaction testing been verified for the INEF whole-cohort and post-hoc low-HDL results?Supplementary; required for an extension to that stratum	INEF randomized 107 participants and lasted 12 weeks, and did not establish a whole-cohort FMD benefit. Changes in the post-hoc low-HDL subgroup were 3.25 versus 1.03%p, P=0.047, and n for each arm is unverified. The original descriptive difference of 2.22%p belongs to the post-hoc context and is not direct replication. S02	The directions of the whole-cohort/post-hoc results were verified, but stratum-specific denominators and planning/interaction information remain unverified.	INEF whole-cohort/subgroup results tables, n for each arm, prespecified subgroup plans/SAP, and interaction testing.	Compare the whole-cohort/post-hoc results with the plans, and do not elevate a positive subgroup result to a whole-cohort result or to the current fixed comparison.
18	Partly verified	Full text not readStored summary read	N18 · Metabolic-syndrome study familyHave the actual study linkage for Thoenes/Vaccari and the between-group FMD estimate and CI been verified?Supplementary	The original record treats Thoenes/Vaccari as a possible single metabolic-syndrome family. The randomized study had 50 participants and lasted 52 weeks, with a within-nicotinic-acid-group 22% improvement/P<0.001. The between-group FMD difference and CI are unverified. S03 S04	The within-group result and the boundary around possible overlap have been linked, but the family identity and between-group contrast have not been fully compared.	Study identities, populations/durations/registrations, between-group results/CIs, and links to the original participants for the two reports.	Compare report identities and results tables, and do not add the 50 participants twice across reports that may describe the same study.
19	Partly verified	Full text not readStored summary read	N19 · Differences between HIV analysesHave the analysis denominators, adjustment models, between-group CIs, and plans been verified for Chow's two analyses?Supplementary	The Chow HIV trial had 10 participants receiving nicotinic acid and 9 receiving placebo, lasted 12 weeks, and used a maximum dose of 1500 mg/day. The between-group P value for unadjusted change was P=0.67; the end-of-period comparison adjusted for baseline FMD/HDL-C gave P=0.048, and the adjusted-contrast CI is unverified. S05	The original differences between analyses were preserved, but information needed to verify the adjusted-contrast interval/plans remains outstanding.	Chow results tables, adjustment models, between-group CIs, baseline/completion/analysis denominators, and SAP.	Compare unadjusted/adjusted estimands, covariates, and plans, and do not turn the two P values into a conflict within the same analysis.
20	Partly verified	Full text not readStored summary read	N20 · A different comparator in HIVHave Dubé's actual analysis denominators, handling of missing data, and between-group FMD effect and CI been verified?Supplementary	Dubé is a 24-week trial in HIV comparing ER nicotinic acid+aspirin with fenofibrate. There were 99 randomized participants/74 with complete scans (35/39); within-group median changes were 0.6%p/P=0.28 versus 0.5%p/P=0.19, and the between-group contrast CI is unverified. S06	The exposure, participant flow, and within-group results have been linked, but the between-group contrast of interest and its CI are unavailable.	Dubé's flow diagram, analysis denominators for each arm, co-intervention/active comparator, and between-group results/CI.	Extract the within-group tests separately from the actual comparator/co-intervention, and assign 99/74/35/39 only to their respective stages in that study's participant flow.
21	Met	Full text not readStored summary read	N21 · Mechanistic evidenceHave HDL, eNOS, and cellular responses been kept from being used as direct effects on brachial FMD?Supplementary	S07 concerns mechanisms involving HDL, vasorelaxation/eNOS, while S11 concerns a diabetes/healthy comparison and endothelial assays of isolated HDL. The current bibliographic records and source locations (citation/locator) do not provide direct clinical results for brachial FMD in the CAD crossover comparison. S07 S11	The outcome levels in the original material were distinguished. This does not newly certify the clinical validity of the mechanisms as a whole.	The actual experimental systems, populations, assays, and links to clinical FMD outcomes in mechanistic studies.	Map the evidence by outcome level/experimental system, and do not substitute changes in cells or isolated HDL for comparative clinical effects.
22	Partly verified	Full text not readStored summary read	N22 · No-flush boundaryHave the actual molecule and composition of the S08 no-flush product and its direct applicability to the same comparison been verified?Supplementary	The source-location description (locator) for S08 concerns no-flush niacin and participants with isolated low HDL/no other CAD risk. Do not automatically combine it with the main question's ER nicotinic acid/CAD/common high-dose statin comparison. S08	The differences in formulation and population have been linked, but the exact product identity and direct applicability to the same comparison are unverified.	The original text on the actual molecule/composition, release formulation, population, comparator/outcomes for the S08 product.	Use a product/population eligibility table to identify differences, and do not claim equivalence with ER nicotinic acid based solely on the no-flush name.
23	Unverified	Full text not readStored summary read	N23 · MRI results unverifiedHave the original FMD results of the MRI modified-release study been verified?Supplementary	S09 is an MRI-based modified-release study. Its historical access level was publisher_metadata_indexed_fulltext_inaccessible: indexed publisher metadata with inaccessible full text, and no original FMD results were extracted. In this review, only the retained bibliographic record was read; the external full text was not opened. S09	The bibliographic identity is available, but the actual original results and the material needed to assess direct applicability have not been obtained.	The FMD tables, measurement methods, analysis/population, and formulation information in the original full text of S09.	If obtained, compare the actual original results/measurement methods; do not infer the direction or magnitude of an effect from search/index titles.
24	Met	Full text not readStored summary read	N24 · Combination with laropiprantHave the positive combination result and the termination/nonposting of results been kept from being used as effects of nicotinic acid alone?Supplementary	S10 is a positive FMD report on an ER nicotinic acid/laropiprant combination after myocardial infarction. The separate S14 NCT01052311 had an actual enrollment of 8 participants, no results posted, and was terminated following the decision to withdraw the study drug from the market. Do not count either as a direct effect of nicotinic acid alone. S10 S14	The actual distinctions among positive findings, termination, and nonposting were preserved. Ingredient-specific causal contributions are not verified.	The compositions, trial/registration identities, results tables, reasons for termination, and posting histories of the two studies.	Compare reports, registrations, and products, and do not invent ingredient-specific contributions to combination results or unposted FMD values.
25	Met	Full text not readStored summary read	N25 · Other vascular endpointsHave carotid IMT and lipids been kept from substituting for success on brachial FMD?Supplementary	S16 is a 2-year carotid IMT study in participants who had reached their LDL target and had high Lp(a); the original HTML was used for screening at the time. It is not a main FMD result. The manuscript likewise does not use lipid improvement as this page's criterion for FMD success. S16 S01	The boundaries between related outcomes and direct FMD evidence were distinguished. No new efficacy judgment is made for other endpoints.	Material directly linking the endpoints/timing/population of S16 to clinical FMD outcomes.	Map the material by endpoint, and do not transfer improvements in IMT or LDL/HDL into effects on brachial FMD.
26	Unverified	Full text not readStored summary read	N26 · Funding and independenceHave funding, drug supply, and COI for the main trial been verified?Supplementary; required for claims of independence	Funding, drug supply, and author conflicts of interest for S01 are unverified. The original I1 applies the rule for unverified information in precedent 29 and does not mean that mixed funding was actually verified. The check of the Chow acknowledgements belongs to the history of an adjacent study. S01 S05 S13	The disclosure/funding sections needed to support the main trial's independence have not been obtained.	Original records for S01 funding/acknowledgements, product supply, author COI, and the registry sponsor.	Compare disclosures in the original study report/registration with related reports, and do not turn unverified information into confirmation of independent/mixed funding.
27	Met	Full text not readStored summary read	N27 · Reading status and reference datesHave the reading of summaries in this review, historical external access, and document dates been distinguished?Required	The complete retained KO/EN, structural, evidence, and bibliographic summaries were read. The original evidence cutoff/verification date (verified_date) is 2026-09-15. Individual access dates for each bibliographic record (citation) are absent and remain blank; historical access levels/locations and the overall review date are preserved separately. Access to all 15 external materials was not attempted, and none were obtained or read in this review. S01 S02 S03 S04 S05 S06 S07 S08 S09 S10 S11 S12 S13 S14 S16	The scope of current actions and of the original history/dates was separated for each material. This does not imply completeness of the latest literature as a whole.	The bytes/SHA of the current input; original bibliographic source locations and access levels (citation locator/access_level); the original evidence cutoff and verification date (evidence_cutoff/verified_date); and historical search/selection records.	Compare access/obtaining/reading events for each material together with their dates, and distinguish external URLs from the current reader displaying the summaries actually read.
28	Met	Full text not readStored summary read	N28 · Preservation of the original assessmentHave the meanings of the original D28, axes, and uncertainties been retained unchanged?Required	The original grade D, score of 28, and B/S/R1/I1/E0/B1/CX are retained. E0 means failure to demonstrate improvement; I1 denotes how unverified funding was handled; CX means precision remains unverified within the scope of access. Because direct human data exist, the original indicator for absence of human studies remains no_human_study=false. S01	Accurate preservation of the original assessment and its interpretation was checked. This is not a new efficacy judgment or clinical certification.	The original grade, score, and axes (grade/score/axes), rationales for each axis, and metadata on the original calculation/document review in the assessment record (assessment).	Check that the original values and their display match, and do not generate new scores, criterion-fulfillment rates, or a judgment of effect 0.
29	Unverified	Full text not readStored summary read	N29 · Harms in the main trialAre harm-collection data, person/event counts, and discontinuation denominators available for the same main trial?Supplementary; essential for safety under the same exposure	The numbers of people with adverse events or discontinuations in the main FMD trial and its long-term safety could not be verified. The original Caution status is retained, without inventing person counts, event counts, severity, systematic collection, or denominators. S01	No material is available for reviewing a harm tally in the same population under the same exposure.	S01 harm/discontinuation tables, collection plan, exposure by group/period, person/event counts, severity, and missing-data records.	Compare the harm tables with the flow diagram; do not fill unreported data with 0 or rates from a label used as adjacent evidence.
30	Met	Full text not readStored summary read	N30 · Boundaries of FDA risk informationHave warnings in the FDA label been distinguished from the main trial's product and events?Supplementary	S12 is the 2020 NIASPAN FDA label. Retain its information on flushing, liver injury, increased blood glucose/uric acid, the risk of myopathy/rhabdomyolysis with statin co-treatment, and contraindications including active liver disease. The brand in S01 is unverified, and the label is not a harm tally from the main FMD trial itself. S12 S01	The official document's risk information was linked with the limits on attribution to a product/trial. This does not certify individual safety.	The product/release formulation, contraindications/warnings, and evidence scope of the original FDA label, together with the identity of the S01 trial batch.	Compare the product/safety sections of the label with the main trial's product and co-treatment conditions; do not count the regulatory document as an additional independent trial or event.
31	Partly verified	Full text not readStored summary read	N31 · Pooled discontinuations and denominatorsHave group-specific exposure denominators, discontinuation definitions, and the composition of the trials pooled in the NIASPAN data been verified?Supplementary	The FDA label's evidence comprises 402 pooled participants and a median treatment duration of 16 weeks; AE-related discontinuations were 16% with nicotinic acid versus 4% with placebo. These are not period-specific event rates or discontinuation counts for S01, and no individual-group denominators are newly filled in. S12	The original pooled comparison and duration were verified, but details of the corresponding group-specific denominators and composition are absent from the retained summary.	Group-specific/exposure denominators, discontinuation definitions/reasons, the composition of the original trials, and collection data for the label's pooled analysis.	Compare the label's pooling definitions/denominators; do not transfer its rates to S01, with a total of 66 participants and periods of 3 months each, or newly back-calculate person counts.
32	Unverified	Full text not readStored summary read	N32 · Long-term safety and vulnerable groupsHas long-term safety or safety in vulnerable groups beyond the current observations been directly verified?Supplementary; essential for that extension	Long-term safety in the main trial is unverified. The label's contraindications, metabolic/muscle risks, and pooled data with a median of 16 weeks are not used to verify safety in all vulnerable groups or during long-term exposure. S01 S12	The follow-up information by time period and population directly needed for the extended safety question is unavailable.	Data on long-term exposure, rare/serious events, and follow-up by underlying-disease/co-treatment strata for the same formulation/population.	Review exposure, timing, and vulnerable-group data separately for each question and, where needed, address rare events with an appropriate long-term observational or pharmacovigilance design.
33	Not applicable	Full text not readStored summary read	N33 · Event-outcome extension not applicableAre trials of myocardial infarction, stroke, or mortality a mandatory condition for this FMD question?Supplementary; the obligation to extend the question does not currently apply	The original endpoint is the surrogate brachial FMD. Prevention of myocardial infarction, stroke, or death is a separate question and is not imposed as a mandatory event-trial condition in this table. No event benefit is estimated. S01	The obligation to extend the narrow numerical question to event outcomes was treated as inapplicable. This does not mean that event evidence exists.	If an extension to event outcomes is requested: direct event trials in the same population with the same intervention, event definitions, durations, and denominators.	If an event-outcome question is added, review its separate, independent boundaries and extract the FMD and event estimates separately.
34	Not applicable	Full text not readStored summary read	N34 · Optimal-dose extension not applicableDoes the current question also address the optimal dose, persistence of effects, and effects in specific strata?Supplementary; the obligation to extend the question does not currently apply	The current table concerns the fixed add-on comparison of 1500 mg over periods of 3 months each. It does not require every study of the optimal dose, persistence after discontinuation, or effects by deficiency status, sex, or low-HDL stratum. This does not mean that direct evidence for these extensions has been acquired. S01 S02	The obligation to extend the assessment to optimal dose, persistence, or strata outside its target was treated as inapplicable. Unverified actual exposure remains recorded in N04/N05.	If an extension is requested: direct dose comparisons, discontinuation/long-term follow-up, and prespecified plans/interactions by stratum.	Set a separate question for each extension and link only data from direct dose, persistence, or stratum-specific designs to the corresponding estimate.
35	Not applicable	Full text not readStored summary read	N35 · Plant-part condition not applicableIs plant-part information needed for a drug question?Not applicable: plant-part condition for a non-botanical drug	The original plant-part information (plant_part) is marked not_applicable, while manufacturing origin (source_origin) has no value (null) and remains unverified. The plant-part condition does not apply to the nicotinic acid drug, and its manufacturing origin is not assigned arbitrarily. S01	The applicability exception for a non-botanical intervention was verified. This does not verify formulation quality or origin.	Manufacturing-origin/quality data for the actual trial batch; separate identity information if a botanical ingredient is claimed.	Compare formulation-identity data; do not interpret the non-applicability of plant-part information as verification of a synthetic or fermentation origin.

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35 itemsWhat the statuses mean

Assessment scope

Stored-material review date: 2026-10-05
Original evidence date: 2026-09-15
Scope actually checked: Retained Korean and English manuscripts and case-specific criteria and application records. Full papers, supplements, registrations, plans and original data were not read.
What the dates mean: This is the date on which the retained materials were checked, not the date of a search for the latest clinical literature.
Population: Adults with coronary artery disease receiving common background treatment with atorvastatin 80 mg/day
Ingredient, formulation and route: Extended-release (ER); exact salt, brand and manufacturer unverified
Dose: 1500 mg/day
Comparator: Placebo period on the same atorvastatin treatment; placebo ingredients unverified
Measured outcome: Page-priority endpoint: between-treatment comparison of brachial FMD at the end of each period; registered primary-endpoint status unverified
Duration: Each treatment period lasts 3 months; titration and washout unverified
Questions outside this scope: nicotinamide; nicotinamide riboside; nicotinamide mononucleotide; IR or SR formulations; no-flush formulations of unverified molecular identity; niacin/laropiprant combinations; niacin without statins; healthy adults; all metabolic or HIV populations; MRI and ultrasound FMD assumed interchangeable; cardiovascular event prevention

Evidence and sources

The links below lead to the sources. A link alone does not mean the original source was read or its latest publication status verified.

S01 · Philpott AC et al. Niacin improves lipid profile but not endothelial function in patients with coronary artery disease on high dose statin therapy. Atherosclerosis. 2013;226(2):453–458.

Official source

Material type: Direct randomized crossover trial
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: Total of 66 participants; analysis n unverified. Periods of 3 months each, with ER nicotinic acid 1500 mg/day and common atorvastatin 80 mg/day. Period-end values: 6.6 ± 4.8% versus 6.1 ± 4.9%, P=0.48. The type of ± and the paired CI are unverified; +0.5%p is the original descriptive arithmetic.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed article abstract and bibliographic page	No lookup in this review	Not attempted in this review	Unread	Decisive direct FMD result; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S02 · Warnholtz A et al. Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: results of the randomized, double-blind, placebo-controlled INEF study. Atherosclerosis. 2009;204(1):216–221.

Official source

Material type: Adjacent randomized trial
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: 107 participants/12 weeks. An FMD benefit in the overall cohort was not demonstrated; post hoc low-HDL changes were 3.25 versus 1.03%p/P=0.047. Group-specific n is unverified; the original 2.22%p arithmetic belongs to the post hoc context and is not direct replication.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed article abstract and bibliographic page	No lookup in this review	Not attempted in this review	Unread	Overall-cohort/post hoc context under different conditions; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S03 · Thoenes M et al. The effects of extended-release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome. Int J Clin Pract. 2007;61(11):1942–1948.

Official source

Material type: Report possibly from the same study family
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: S03/S04 are treated as possibly belonging to the same metabolic-syndrome study family. 50 participants/52 weeks; a 22% within-nicotinic-acid-group improvement/P<0.001. The between-group FMD contrast and CI are unverified; this finding is not used as a direct effect for the main comparison.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed article abstract and bibliographic page	No lookup in this review	Not attempted in this review	Unread	Within-group change in a different population over a different duration; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S04 · Vaccari CS et al. Efficacy of controlled-release niacin in treatment of metabolic syndrome: Correlation to surrogate markers of atherosclerosis, vascular reactivity, and inflammation. J Clin Lipidol. 2007;1:605–613.

Official source

Material type: Report possibly from the same study family
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: This report may overlap with S03: its authors, population, dose, and 52-week design match. The family's within-group 22% is not re-extracted as a new independent between-group effect for this report, and the 50 participants are not counted again.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed article abstract and bibliographic page	No lookup in this review	Not attempted in this review	Unread	Possible overlap and comparison boundaries; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S05 · Chow DC et al. Short-term effects of extended-release niacin on endothelial function in HIV-infected patients on stable antiretroviral therapy. AIDS. 2010;24(7):1019–1023.

Official source

Material type: Adjacent placebo-controlled HIV trial
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: Nicotinic acid: 10 participants/placebo: 9 participants; 12 weeks/maximum 1500 mg/day. Unadjusted change P=0.67; period-end comparison adjusted for baseline FMD/HDL-C P=0.048, with the adjusted CI unverified. This is contrasting context from a different population/analysis.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Online full text of the article (author manuscript HTML)	No lookup in this review	Not attempted in this review	Unread	Different analyses before/after adjustment; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S06 · Dubé MP et al. Extended-Release Niacin Versus Fenofibrate in HIV-Infected Participants With Low High-Density Lipoprotein Cholesterol: Effects on Endothelial Function, Lipoproteins, and Inflammation.

Official source

Material type: Adjacent trial with an active comparator/co-intervention
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: ER nicotinic acid+aspirin versus fenofibrate; 24 weeks. 99 randomized/74 complete scans (35/39). Within-group median changes: 0.6%p/P=0.28 versus 0.5%p/P=0.19; the between-group CI is unverified.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed article abstract and bibliographic page	No lookup in this review	Not attempted in this review	Unread	Different exposure/denominator and within-group analysis; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S07 · Kuvin JT et al. A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric oxide synthase expression. Am Heart J. 2002;144(1):165–172.

Official source

Material type: Mechanistic study report
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: Mechanistic data on HDL, vasorelaxation, and eNOS. The currently retained bibliography/source locator is not promoted to numerical evidence of a direct FMD effect in a CAD crossover trial or of clinical-event prevention.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed article abstract and bibliographic page	No lookup in this review	Not attempted in this review	Unread	Not used as a direct FMD result; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S08 · Benjó AM et al. Accumulation of chylomicron remnants and impaired vascular reactivity occur in subjects with isolated low HDL cholesterol: effects of niacin treatment. Atherosclerosis. 2006;187:116–122.

Official source

Material type: Adjacent evidence with a different formulation/population
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: The original source locator concerns a no-flush product and a population with isolated low HDL and no other CAD risk. Equivalence of the exact molecule/product to ER is not assumed, and the report is not combined with the main CAD add-on comparison.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed article abstract and bibliographic page	No lookup in this review	Not attempted in this review	Unread	Direct relevance of the molecule, formulation, and population is unverified; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S09 · Lee JMS et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function. A randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol. 2009;54:1787–1794.

Official source

Material type: Report with unverified original results
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: At the time, only the publisher metadata/indexed identity was verified; the full text was inaccessible, and the original FMD result could not be extracted. The MRI method or title is not copied as the S01 result.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Publisher's article webpage (link target for the full text; not acquired at the time)	No lookup in this review	Not attempted in this review	Unread	Full text, measurements, and direct relevance are unverified; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S10 · Bregar U et al. Extended-release niacin/laropiprant improves endothelial function in patients after myocardial infarction.

Official source

Material type: Adjacent combination-treatment article
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: A report of a positive FMD finding for an ER nicotinic acid/laropiprant combination after myocardial infarction. No new values absent from the retained bibliography/manuscript are invented, and the finding is not attributed to a main effect of nicotinic acid alone.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed article abstract and bibliographic page	No lookup in this review	Not attempted in this review	Unread	Boundaries of the positive combination-treatment finding; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S11 · Sorrentino SA et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy.

Official source

Material type: Mechanistic/adjacent-population report
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: A diabetes/healthy-population comparison and endothelial assays using isolated HDL are retained. These are not counted as direct results or independent replication of brachial FMD in the main CAD crossover trial.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
PubMed article abstract and bibliographic page	No lookup in this review	Not attempted in this review	Unread	Outcome distinct from direct FMD; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S12 · NIASPAN (niacin extended-release tablets), FDA prescribing information revised 09/2020.

Official source

Material type: Regulatory product safety document
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: Flushing, liver injury, increased blood glucose/uric acid, muscle risks with statin co-treatment, and contraindications. Pooled data: 402 participants/median 16 weeks, with AE-related discontinuations of 16% versus 4%; these are not event rates from the main FMD trial. The main trial's product brand is unverified.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full PDF of the official FDA product prescribing information	No lookup in this review	Not attempted in this review	Unread	Safety context separate from efficacy; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S13 · ClinicalTrials.gov NCT00150722, linked by Philpott 2013.

Official source

Material type: Link to the direct trial's registration
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: The NCT00150722 link was verified in S01, but only the registry shell was acquired at the time. The structured registration content on endpoint status, analysis, and sponsorship could not be read. External access was not attempted in this review either.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
ClinicalTrials.gov registration webpage (only the shell was acquired at the time)	No lookup in this review	Not attempted in this review	Unread	Registration content/SAP unverified; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S14 · ClinicalTrials.gov NCT01052311 — The Impact of Tredaptive on Flow-Mediated Dilation in Cardiac Patients.

Official source

Material type: Registration for a different combination treatment
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: Actual enrollment: 8 participants; no results posted; terminated following the decision to withdraw the study drug from the market. No FMD values are filled in, and the record is not automatically merged into the same study family as S10.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Official ClinicalTrials.gov registration web document	No lookup in this review	Not attempted in this review	Unread	Context of unposted results/termination; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

S16 · Song S et al. Effect of Niacin on Carotid Atherosclerosis in Patients at Low-Density Lipoprotein-Cholesterol Goal but High Lipoprotein (a) Level: a 2-Year Follow-Up Study. J Lipid Atheroscler. 2019;8(1):58–66.

Official source

Material type: Adjacent article with a different endpoint
Materials actually read: Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.
Findings recorded in the stored summary: A 2-year carotid IMT study in people who had reached their LDL target but had high Lp(a); the HTML was used for eligibility screening at the time. It does not substitute for the same FMD effect or for clinical-event outcomes.
Record level: Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.
Study overlap and independent replication: The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Article webpage (link target for the full text)	No lookup in this review	Not attempted in this review	Unread	Not used as direct FMD evidence; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.

Report counts versus independent study counts

Retains the original R1 single direct study family and the contexts of possible overlap/adjacent evidence; the total number of reports is not newly totaled as unique trials or participants.

Review criteria

Version NGM-v3091-ER-NICOTINIC-ACID-CAD-ATORVASTATIN-CROSSOVER-FMD-1.2 · Criteria record date 2026-10-05. These are Chamgap's own application conditions, informed by the referenced methods. They do not constitute official assessment-tool certification or a new efficacy score.

N01 · Which FMD comparison is being tabulated?

Required materials and conditions: The identity of the current claim and adjudicated question, descriptive attributes (facets), canonical URL, and actual list of keys in the retained summary.
Conditions for verification: Link the single question covering adults with CAD, common atorvastatin 80 mg/day, oral ER nicotinic acid 1500 mg/day, each 3-month period, and period-end brachial FMD in the placebo crossover comparison.
Requirement and applicability: Required
Application exceptions: Do not fill the absent subclaims key with a null value or an empty array. This is a development question narrowed after the results were known, not a preregistration.
Why this condition is needed: Needed to avoid combining the ingredient as a whole, lipid endpoints and clinical-event endpoints into a single effect.
Referenced methods: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed — a specific adaptation for the separate question. Not official methodological certification.

N02 · Have the molecule, release formulation, salt and brand of the actual nicotinic acid product been verified?

Required materials and conditions: Trial product label, batch certification, basis for specifying the salt/active amount, manufacturing/quality information, and release-formulation information.
Conditions for verification: Specify clinical nicotinic acid and ER, and distinguish the unverified exact salt, purity, origin, brand, manufacturer and excipients.
Requirement and applicability: Required
Application exceptions: Do not automatically combine this with nicotinamide, NR, NMN, IR/SR, no-flush preparations or laropiprant combinations. Do not infer that NIASPAN was the main trial's brand.
Why this condition is needed: Needed to avoid treating similarities in release formulation or vitamin names as product equivalence.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — a specific adaptation for molecule and release formulation. Not official methodological certification.

N03 · Can background treatment in both periods be distinguished from the placebo comparison?

Required materials and conditions: Records of common treatment, concomitant medication, rescue treatment, placebo composition, changes and adherence by arm/period.
Conditions for verification: Compare the ER nicotinic acid add-on period with the placebo period on common atorvastatin 80 mg/day, retaining the unverified status of other concomitant treatments/placebo ingredients.
Requirement and applicability: Required
Application exceptions: Do not copy the low-dose nicotinic acid placebo composition from AIM-HIGH into this trial. This is not a question about nicotinic acid monotherapy.
Why this condition is needed: It is necessary to assess whether differences in other medications are mixed with the effect of add-on therapy.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — a specific adaptation for add-on therapy and comparator. Not official methodological certification.

N04 · Can the nominal dose of 1500 mg/day be distinguished from actual exposure?

Required materials and conditions: Titration schedule, actual intake/adherence by period, washout/discontinuation, and the basis for specifying the active amount.
Conditions for verification: Cross-check the reported target dose of 1500 mg/day against actual doses taken, titration, discontinuation, adherence and the basis for specifying the active amount.
Requirement and applicability: Required
Application exceptions: Do not substitute 1000/2000 mg or concomitant aspirin from another study for exposure in the main trial.
Why this condition is needed: Needed to avoid turning a stated target dose into identical exposure for every participant.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — a specific adaptation for dose and adherence. Not official methodological certification.

N05 · Have the 3 months per period and the crossover sequence, washout and handling of carryover been verified?

Required materials and conditions: Complete visit schedule, sequence allocation, washout, and analysis plans and results for period/sequence/carryover.
Conditions for verification: Link each 3-month treatment period to baseline/period-end measurements, and verify sequence, washout, period effects and handling of carryover.
Requirement and applicability: Required
Application exceptions: Do not remove washout/carryover considerations in a crossover design by marking them NA, or count unverified details as additional confirmed design defects.
Why this condition is needed: Because exposure in the preceding period and time effects may become mixed with the period-end FMD comparison.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.1–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application — a specific adaptation for duration and carryover. Not official methodological certification.

N06 · Are the CAD population, screening for endothelial dysfunction and baseline characteristics known?

Required materials and conditions: CAD diagnosis, age/sex, baseline FMD, inclusion/exclusion criteria, and distributions of disease/nutritional status.
Conditions for verification: Verify adult CAD and common high-dose statin treatment, along with the FMD screening cut-off, diagnosis/inclusion/exclusion criteria and baseline distributions.
Requirement and applicability: Required
Application exceptions: Do not invent an FMD cut-off or state that all participants had endothelial dysfunction defined by a threshold.
Why this condition is needed: Because similarly named cardiovascular-risk groups cannot be assumed to be the same selected population.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed — a specific adaptation for CAD eligibility. Not official methodological certification.

N07 · Have the measurement, blinding and unit conditions for brachial FMD been verified?

Required materials and conditions: The main trial's FMD SOP, device/analysis method, cuff/imaging timing, baseline diameter and assessment-blinding records.
Conditions for verification: Link period-end brachial FMD to the unit %, and verify the device, cuff site/pressure/duration, imaging/interpretation, baseline diameter and assessment blinding.
Requirement and applicability: Required
Application exceptions: Do not conclude that blinding/standardization was completed solely because the measure is described as objective.
Why this condition is needed: Needed to avoid confusing differences in measurement conditions with actual changes in endothelial function.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application — a specific adaptation for FMD measurement. Not official methodological certification.

N08 · Have the actual randomization, allocation concealment and baseline balance in the crossover trial been verified?

Required materials and conditions: The randomized sequence, allocation concealment, baseline table and recruitment flow in the main trial's full text.
Conditions for verification: Link the randomized crossover design to the verified scope of sequence generation, allocation concealment and baseline balance by period.
Requirement and applicability: Required
Application exceptions: Do not turn unverified sections into confirmed defects or a nonrandomized design.
Why this condition is needed: Because the label 'randomized' alone cannot establish that all allocation issues were resolved.
Referenced methods: M08 §8.1–8.2.3; internal application — a specific adaptation for randomization and allocation concealment. Not official methodological certification.

N09 · Did the placebo and assessment blinding address differences caused by flushing?

Required materials and conditions: The main trial's blinding section, placebo composition, flushing management/assessment of treatment guesses, and blinded interpretation.
Conditions for verification: Verify the main trial's placebo ingredients, participant/assessor blinding, and information on handling flushing and sensory differences.
Requirement and applicability: Required
Application exceptions: The label's flushing risk is separate from the success/failure of blinding in an individual trial.
Why this condition is needed: Needed to examine how sensory differences in exposure affected outcome assessment.
Referenced methods: M08 Table 8.2.a, M03 §3.2.4; internal application; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — a specific adaptation for blinding and placebo. Not official methodological certification.

N10 · Can the paired data, analysis population and effect of interest in the reported test be identified?

Required materials and conditions: The main trial's statistical methods section, paired/crossover model, analysis population, covariates and test results table.
Conditions for verification: Cross-check the period-end between-treatment test against the paired-data model, ITT/PP, adjustment, period effects and analysis population.
Requirement and applicability: Required
Application exceptions: Do not reconstruct an independent-groups Cohen d or a paired CI from ± and P alone.
Why this condition is needed: Needed to avoid treating within-group changes or a simple difference in means as a verified crossover-model effect.
Referenced methods: M08 §8.2.2, M15 §15.3.1; internal application; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed — a specific adaptation for the crossover effect of interest. Not official methodological certification.

N11 · Can the study total of 66 participants be distinguished from the denominators for the actual FMD analysis and missing data?

Required materials and conditions: The main trial's flow diagram, analysis n by period, reasons for missing data/discontinuation, and their handling in the analysis.
Conditions for verification: Link the denominators for recruitment, allocation, completion, measurement by period and paired analysis, along with the reasons for missing data/discontinuation and how they were handled.
Requirement and applicability: Required
Application exceptions: Do not describe unverified missing-data information as 0 dropouts or complete data for all 66 participants.
Why this condition is needed: Needed to avoid converting the retained sample size into the actual analysis denominator.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application — a specific adaptation for denominators and missing data. Not official methodological certification.

N12 · Have the period-end FMD values been distinguished from the scope of the failure to demonstrate improvement?

Required materials and conditions: Results in the original research abstract, original results tables, crossover-model estimates and baseline-change data.
Conditions for verification: Attribute 6.6 ± 4.8% versus 6.1 ± 4.9%, P=0.48, and the existing +0.5%p only to the corresponding period-end/descriptive contrast.
Requirement and applicability: Required
Application exceptions: The formal between-group CI/difference in changes from baseline has no recorded value; do not perform new arithmetic or back-calculation.
Why this condition is needed: Needed to avoid turning nonsignificance into an effect of 0, equivalence or exclusion of a meaningful benefit.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is internally designed; M08 §8.2.2, M15 §15.3.1; internal application — a specific adaptation for original FMD values and the test. Not official methodological certification.

N13 · Have the type of ± statistic and the paired variance for FMD been verified?

Required materials and conditions: SD/SE definitions in the original table, paired-data variance/correlation, test model and analysis n.
Conditions for verification: Verify the dispersion types for 4.8/4.9, paired variance, between-period correlation and analysis n, and retain the unverified status of the original source information.
Requirement and applicability: Required
Application exceptions: Do not apply independent-groups formulas to values from the same participant in two periods.
Why this condition is needed: Because arbitrarily assigning an unknown ± statistic to SD/SE would change the interpretation of effect and precision.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M15 §15.3.1–15.3.3; internal application — a specific adaptation for ± and paired variance. Not official methodological certification.

N14 · Is there a paired between-group CI and an applicable important FMD difference?

Required materials and conditions: Between-group CI from the crossover model, paired variance/denominator, and evidence for an important difference in the same population/measure.
Conditions for verification: Compare the crossover-contrast CI with a justified threshold for an important difference in the same analysis, and explain the range of effects compatible with the findings.
Requirement and applicability: Required
Application exceptions: Do not arbitrarily adopt a universal FMD MCID or a minimum sample size/duration.
Why this condition is needed: A P value alone cannot exclude a meaningful benefit or establish sufficient precision.
Referenced methods: M15 §15.3.1–15.3.3; internal application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for specific designs were developed internally — an individual adaptation for CIs and important differences. This is not official methodological certification.

N15 · Do the planned status, analysis, and timing of FMD agree with what was reported?

Required materials and conditions: Version-specific registry text, protocol, SAP, and the history of changes to endpoints/analyses.
Conditions for verification: Compare the original NCT00150722 registration/protocol/SAP with the reported endpoints/crossover analysis and the reasons for changes.
Requirement and applicability: Required
Application exceptions: Do not turn the historical record of obtaining only the basic registry display into confirmation that the study was unregistered or selectively reported.
Why this condition is needed: This is needed to avoid elevating the page's priority endpoint to the status of a registered primary endpoint.
Referenced methods: M08 Table 8.2.a, M04 §4.6.3; internal application — an individual adaptation for registration and plans. This is not official methodological certification.

N16 · Have the original study report and registration been linked to the same direct trial family?

Required materials and conditions: Identifiers and registry links for each report, and a family table of populations/doses/durations/outcomes.
Conditions for verification: Place the Philpott original study report/PMID/DOI/NCT in the same direct trial family, and distinguish the number of reports from the number of independent replications.
Requirement and applicability: Required
Application exceptions: The original designation of 1 direct trial, R1, does not certify confirmatory preregistration or the number of independent study families across the entire literature.
Why this condition is needed: This is needed to avoid counting the existence of a paper and a registration as two independent replications.
Referenced methods: The distinction between studies and reports in M04 §4.6.1–4.6.2; internal application to cohort/outcome linkage; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the direct trial family. This is not official methodological certification.

N17 · Have the analysis denominators for each arm, prespecified plans, and interaction testing been verified for the INEF whole-cohort and post-hoc low-HDL results?

Required materials and conditions: INEF whole-cohort/subgroup results tables, n for each arm, prespecified subgroup plans/SAP, and interaction testing.
Conditions for verification: Separate the whole-cohort and post-hoc subgroup results, and verify the analysis denominator for each arm, whether the subgroup plan was prespecified, interaction testing, and eligibility as a direct comparison.
Requirement and applicability: Supplementary; required for an extension to that stratum
Application exceptions: The original post-hoc difference of 2.22%p is existing descriptive arithmetic. Do not produce new totals or recalculate it.
Why this condition is needed: This is needed to preserve both the unfavorable whole-cohort result and the favorable post-hoc result.
Referenced methods: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M03 §3.2.1–3.2.4; details of dose, persistence, and effect modification were developed internally — an individual adaptation for the INEF post-hoc subgroup. This is not official methodological certification.

N18 · Have the actual study linkage for Thoenes/Vaccari and the between-group FMD estimate and CI been verified?

Required materials and conditions: Study identities, populations/durations/registrations, between-group results/CIs, and links to the original participants for the two reports.
Conditions for verification: Link S03/S04 as a possible single family, while verifying whether the actual participants and study identities match and checking the between-group FMD estimate and CI; separately preserve the 52 weeks, 50 participants, and within-group 22% improvement.
Requirement and applicability: Supplementary
Application exceptions: A possible family relationship does not establish a confirmed number of independent trials. 22% is neither 22%p nor a between-group difference.
Why this condition is needed: This is needed to prevent a positive within-group result and potentially overlapping reports from being turned into direct replication.
Referenced methods: The distinction between studies and reports in M04 §4.6.1–4.6.2; internal application to cohort/outcome linkage; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the metabolic-syndrome study family. This is not official methodological certification.

N19 · Have the analysis denominators, adjustment models, between-group CIs, and plans been verified for Chow's two analyses?

Required materials and conditions: Chow results tables, adjustment models, between-group CIs, baseline/completion/analysis denominators, and SAP.
Conditions for verification: Separate the unadjusted change comparison in the HIV context of 10/9 participants and 12 weeks from the end-of-period test adjusted for baseline FMD/HDL-C, then link the extent of verification for each analysis population, adjustment model, between-group CI, and prespecified plan.
Requirement and applicability: Supplementary
Application exceptions: Because the population and analyses differ, do not count these results as independent replication of the current CAD add-on treatment.
Why this condition is needed: This is needed to avoid selecting a single value from favorable/unfavorable results obtained from different analyses.
Referenced methods: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for differences between HIV analyses. This is not official methodological certification.

N20 · Have Dubé's actual analysis denominators, handling of missing data, and between-group FMD effect and CI been verified?

Required materials and conditions: Dubé's flow diagram, analysis denominators for each arm, co-intervention/active comparator, and between-group results/CI.
Conditions for verification: Link ER nicotinic acid+aspirin versus fenofibrate, HIV, and 24 weeks with 99 participants assigned/74 with complete scans (35/39), and distinguish the extent of verification of actual analysis denominators for each arm, handling of missing data, between-group estimates, and CIs.
Requirement and applicability: Supplementary
Application exceptions: Do not copy the aspirin co-intervention or the fenofibrate effect into the placebo composition/background treatment of the main trial.
Why this condition is needed: This is needed to avoid turning an active comparison, co-intervention, and medians into the main trial's contrast for adding the single agent.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations were developed internally; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for specific designs were developed internally; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for a different comparator in HIV. This is not official methodological certification.

N21 · Have HDL, eNOS, and cellular responses been kept from being used as direct effects on brachial FMD?

Required materials and conditions: The actual experimental systems, populations, assays, and links to clinical FMD outcomes in mechanistic studies.
Conditions for verification: Distinguish the level of outcomes in the mechanistic evidence and isolated-HDL/endothelial assays in S07/S11 from brachial FMD in the main trial.
Requirement and applicability: Supplementary
Application exceptions: Do not use mechanistic plausibility as evidence of effect magnitude or prevention of clinical events.
Why this condition is needed: This is needed to prevent related biological explanations from being elevated to replication of a direct clinical endpoint.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to the specific question were developed internally; M03 §3.2.4; internally defined extension boundaries — an individual adaptation for mechanistic evidence. This is not official methodological certification.

N22 · Have the actual molecule and composition of the S08 no-flush product and its direct applicability to the same comparison been verified?

Required materials and conditions: The original text on the actual molecule/composition, release formulation, population, comparator/outcomes for the S08 product.
Conditions for verification: Verify the actual molecule, composition, release formulation, population, comparator, and outcomes of S08 to assess eligibility for the original ER-drug/CAD add-on comparison; separately preserve the currently known differences involving no-flush and a population with isolated low HDL/no other CAD risk.
Requirement and applicability: Supplementary
Application exceptions: Do not infer the molecular identity of no-flush products.
Why this condition is needed: This is needed to prevent results from different molecules/formulations and selected populations from being mixed in as direct replication.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations were developed internally; M03 §3.2.1; detailed population criteria were developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the No-flush boundary. This is not official methodological certification.

N23 · Have the original FMD results of the MRI modified-release study been verified?

Required materials and conditions: The FMD tables, measurement methods, analysis/population, and formulation information in the original full text of S09.
Conditions for verification: Separate the S09 bibliographic record/metadata from the historical inability to access the full text, and do not fill in unverified FMD results.
Requirement and applicability: Supplementary
Application exceptions: Access has not been attempted in this review. Do not recast the historical record of inaccessible material as an access failure in this review.
Why this condition is needed: This is needed to avoid using the existence of a link as verification of original results or replication of the main measurement.
Referenced methods: The data-collection/selection principles in M04 §4.5–4.6; the distinction between access and reading, and the hyperlink conventions, were developed internally; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to the specific question were developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for unverified MRI results. This is not official methodological certification.

N24 · Have the positive combination result and the termination/nonposting of results been kept from being used as effects of nicotinic acid alone?

Required materials and conditions: The compositions, trial/registration identities, results tables, reasons for termination, and posting histories of the two studies.
Conditions for verification: Separate the positive combination report S10 from the separate terminated registration S14, its actual enrollment of 8 participants, and its unposted results.
Requirement and applicability: Supplementary
Application exceptions: Do not merge S10 and S14 as the same trial without comparing their identifiers.
Why this condition is needed: This is needed to prevent the contributions of combined active ingredients and unreported results from being attributed to the main add-on treatment.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations were developed internally; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the combination with laropiprant. This is not official methodological certification.

N25 · Have carotid IMT and lipids been kept from substituting for success on brachial FMD?

Required materials and conditions: Material directly linking the endpoints/timing/population of S16 to clinical FMD outcomes.
Conditions for verification: Separate the priority IMT endpoint and lipid values in S16 from the FMD and cardiovascular-event questions.
Requirement and applicability: Supplementary
Application exceptions: Retain positive results on other endpoints, but do not use them as the direct success criterion.
Why this condition is needed: Calling outcomes vascular or lipid-related does not make them the same outcome.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to the specific question were developed internally; M03 §3.2.4; internally defined extension boundaries — an individual adaptation for other vascular endpoints. This is not official methodological certification.

N26 · Have funding, drug supply, and COI for the main trial been verified?

Required materials and conditions: Original records for S01 funding/acknowledgements, product supply, author COI, and the registry sponsor.
Conditions for verification: Link the main trial's funding, product supply, and authors' employment/patents/COI to the actual sections in the report.
Requirement and applicability: Supplementary; required for claims of independence
Application exceptions: Do not automatically attribute sponsorship described in the Chow acknowledgements or the FDA document to S01.
Why this condition is needed: This is needed to prevent unverified conflicts of interest from becoming evidence of independent replication.
Referenced methods: Chamgap's own criteria for independence and attribution. The official methodology sections used in this pilot do not warrant all of these detailed items — an individual adaptation for funding and independence. This is not official methodological certification.

N27 · Have the reading of summaries in this review, historical external access, and document dates been distinguished?

Required materials and conditions: The bytes/SHA of the current input; original bibliographic source locations and access levels (citation locator/access_level); the original evidence cutoff and verification date (evidence_cutoff/verified_date); and historical search/selection records.
Conditions for verification: Separately preserve the 2026-09-15 evidence/review date, the reading of the retained summaries on 2026-10-05, and each report's access level and absence of access dates.
Requirement and applicability: Required
Application exceptions: The 15 bibliographic records (citation) have no individual access-date keys (accessed). Do not fill individual access dates with the overall verification date (verified_date). The original ZIP/search files were not opened in this review.
Why this condition is needed: This is needed to avoid overstating the reading of retained summaries as new full-text verification or a current comprehensive search.
Referenced methods: The data-collection/selection principles in M04 §4.5–4.6; the distinction between access and reading, and the hyperlink conventions, were developed internally; M04 §4.5, §4.6.3; the limits of the current data conversion follow the user-defined scope and internal design — an individual adaptation for reading status and reference dates. This is not official methodological certification.

N28 · Have the meanings of the original D28, axes, and uncertainties been retained unchanged?

Required materials and conditions: The original grade, score, and axes (grade/score/axes), rationales for each axis, and metadata on the original calculation/document review in the assessment record (assessment).
Conditions for verification: Preserve the original D28/B/S/R1/I1/E0/B1/CX and the indicator for absence of human studies, no_human_study=false, solely as historical assessments.
Requirement and applicability: Required
Application exceptions: Apart from the small sample size underlying the original B1, do not count unverified design items as new defects.
Why this condition is needed: This is needed to avoid confusing the table's verification statuses with the existing efficacy grade.
Referenced methods: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M04 §4.5, §4.6.3; the limits of the current data conversion follow the user-defined scope and internal design — an individual adaptation for preservation of the original assessment. This is not official methodological certification.

N29 · Are harm-collection data, person/event counts, and discontinuation denominators available for the same main trial?

Required materials and conditions: S01 harm/discontinuation tables, collection plan, exposure by group/period, person/event counts, severity, and missing-data records.
Conditions for verification: Link the S01 definitions of adverse events, systematic collection, severity, person/event counts, discontinuations, and exposure/follow-up denominators.
Requirement and applicability: Supplementary; essential for safety under the same exposure
Application exceptions: The original FMD result is not deleted or regraded because harms are unverified.
Why this condition is needed: Needed to avoid treating the existence of an efficacy summary as evidence of safety or a complete event tally.
Referenced methods: M19 §19.1.2–19.2.4; own application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; own application — individually adapted to harms in the main trial. This is not official methodological certification.

N30 · Have warnings in the FDA label been distinguished from the main trial's product and events?

Required materials and conditions: The product/release formulation, contraindications/warnings, and evidence scope of the original FDA label, together with the identity of the S01 trial batch.
Conditions for verification: Distinguish the contraindications, warnings, and interactions in the 2020 NIASPAN product document from the unverified brand in S01.
Requirement and applicability: Supplementary
Application exceptions: A historical label is not treated as verification of current approval status or individual safety.
Why this condition is needed: Needed because the existence of official warnings differs from verification of safety in the particular trial under consideration.
Referenced methods: M19 §19.1.2–19.2.4; own application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding is internally designed; M04 §4.6.1–4.6.2; adaptation for harm data is internally designed; Chamgap's own interpretive boundaries. The M19 principles are referenced; no official causality tool was applied — individually adapted to the boundaries of FDA risk information. This is not official methodological certification.

N31 · Have group-specific exposure denominators, discontinuation definitions, and the composition of the trials pooled in the NIASPAN data been verified?

Required materials and conditions: Group-specific/exposure denominators, discontinuation definitions/reasons, the composition of the original trials, and collection data for the label's pooled analysis.
Conditions for verification: Link the pooled NIASPAN data—402 participants, a median of 16 weeks, and AE-related discontinuations of 16% versus 4%—to the product document, then distinguish what has been verified about group-specific exposure denominators, discontinuation collection/definitions, and the composition of the pooled trials.
Requirement and applicability: Supplementary
Application exceptions: Do not substitute the total of 402 for each group's n. The median of 16 weeks and the periods of 3 months each belong to different sources.
Why this condition is needed: Needed to avoid using pooled discontinuations from a different data source as an event rate for a particular FMD trial.
Referenced methods: M19 §19.2.2–19.2.4, M03 §3.2.3; own application; M19 §19.1.2–19.2.4; own application; M19 §19.1.2–19.2.4, M04 §4.6.3; own application — individually adapted to pooled discontinuations and denominators. This is not official methodological certification.

N32 · Has long-term safety or safety in vulnerable groups beyond the current observations been directly verified?

Required materials and conditions: Data on long-term exposure, rare/serious events, and follow-up by underlying-disease/co-treatment strata for the same formulation/population.
Conditions for verification: Distinguish the FMD observations over periods of 3 months each from the median of 16 weeks in the prescribing document when considering long-term/rare harms, liver disease/metabolic risks, and interactions.
Requirement and applicability: Supplementary; essential for that extension
Application exceptions: This narrow FMD question does not require every study of rare harms, and contraindications/risks are not interpreted as permission for self-medication.
Why this condition is needed: Needed to avoid extending results from a short observation period and a restricted population to overall long-term safety.
Referenced methods: Design-specific harm questions in M19 §19.2; details of temporal relationships are internally designed; M19 §19.1.2–19.2.4; own application; M03 §3.2.1–3.2.4; details of dose, persistence, and effect modification are internally designed — individually adapted to long-term safety and vulnerable groups. This is not official methodological certification.

N33 · Are trials of myocardial infarction, stroke, or mortality a mandatory condition for this FMD question?

Required materials and conditions: If an extension to event outcomes is requested: direct event trials in the same population with the same intervention, event definitions, durations, and denominators.
Conditions for verification: Separate the current question about FMD values from the distinct question of clinical-event prevention or mortality.
Requirement and applicability: Supplementary; the obligation to extend the question does not currently apply
Application exceptions: The selected question concerns FMD itself. Absence of an event trial does not justify deleting the FMD observation or treating Not applicable as evidence that material was acquired.
Why this condition is needed: Needed to avoid automatically extending a surrogate difference to a clinical-event benefit.
Referenced methods: M03 §3.2.4; own boundaries for extensions; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptation of outcomes to each question is internally designed — individually adapted to the non-applicability of the event-outcome extension. This is not official methodological certification.

N34 · Does the current question also address the optimal dose, persistence of effects, and effects in specific strata?

Required materials and conditions: If an extension is requested: direct dose comparisons, discontinuation/long-term follow-up, and prespecified plans/interactions by stratum.
Conditions for verification: Distinguish the fixed comparison of 1500 mg over periods of 3 months each from extensions to dose response, persistence after discontinuation, and prespecified interactions by stratum.
Requirement and applicability: Supplementary; the obligation to extend the question does not currently apply
Application exceptions: The positive post hoc low-HDL finding in INEF is not used to establish an optimal dose or stratum-specific effects across CAD populations.
Why this condition is needed: Needed to avoid determining the optimal dose, persistence of effects, or effects in all subgroups from a single main effect.
Referenced methods: M03 §3.2.1–3.2.4; details of dose, persistence, and effect modification are internally designed — individually adapted to the non-applicability of the optimal-dose extension. This is not official methodological certification.

N35 · Is plant-part information needed for a drug question?

Required materials and conditions: Manufacturing-origin/quality data for the actual trial batch; separate identity information if a botanical ingredient is claimed.
Conditions for verification: Distinguish the unverified manufacturing origin of the nicotinic acid drug from the non-applicability of plant-part information.
Requirement and applicability: Not applicable: plant-part condition for a non-botanical drug
Application exceptions: Manufacturing origin (source_origin) remains unverified and is distinguished from the not_applicable designation for plant-part information (plant_part).
Why this condition is needed: Needed to avoid imposing an unsupported plant-part axis on a question about a drug molecule.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — individually adapted to the non-applicability of the plant-part condition. This is not official methodological certification.

Referenced methods and the sections actually reviewed

M03 · Cochrane Handbook 6.5 (2024), chapter updated 2023-08

Official methodology · §3.1, §3.2.1–3.2.3, MECIR C5/C7/C13

Referenced principle: Clearly record the question, eligibility criteria, and reasons for changes, and distinguish variations in the intervention.
Extent of review: Reuses the existing methods copy for 1585 and historical principles. This is not a new full-text methods review, application of an official tool, or certification.

M04 · Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03

Official methodology · §4.5, §4.6.1–4.6.3, MECIR C42

Referenced principle: Distinguish studies from reports and link them; do not omit a study solely because results were not reported.
Extent of review: Reuses the existing methods copy for 1585 and historical principles. This is not a new full-text methods review, application of an official tool, or certification.

M08 · Cochrane Handbook 6.5 (2024), chapter updated 2019-10

Official methodology · §8.1–8.2.3, Table 8.2.a

Referenced principle: Fix the outcome and effect of interest when reviewing randomization, deviations, missing data, measurement, and selective reporting.
Extent of review: Reuses the existing methods copy for 1585 and historical principles. This is not a new full-text methods review, application of an official tool, or certification.

M15 · Cochrane Handbook 6.5 (2024), chapter updated 2023-08

Official methodology · §15.2.4, §15.3.1–15.3.3

Referenced principle: Distinguish effect estimates, intervals, importance, and application. Sample size alone does not determine precision.
Extent of review: Reuses the existing methods copy for 1585 and historical principles. This is not a new full-text methods review, application of an official tool, or certification.

M19 · Cochrane Handbook 6.5 (2024), chapter updated 2019-10

Official methodology · §19.1.2, §19.2.1–19.2.4

Referenced principle: Questions about harms may require designs, populations, and follow-up different from those for efficacy. Case reports do not establish incidence.
Extent of review: Reuses the existing methods copy for 1585 and historical principles. This is not a new full-text methods review, application of an official tool, or certification.

What the statuses mean

Met: The identity, original values, and attribution/interpretation boundaries for this condition were verified within the retained material. This is separate from sufficient evidence of efficacy or certification.
Partly verified: Some information has been linked, but actual material, comparisons, or details remain to be verified.
Unverified: The required analyses, values, or material remain unverified within the retained material that was read. This is distinct from 0 events, no effect, or incomplete preparation of the table.
Conflicting data: Preserves an actual discrepancy in the original data for the same item. This is distinct from differences between analyses.
Not applicable: A condition or an obligation to extend the inquiry outside the narrow assessment target does not apply. This is distinct from insufficient data.
Not applicable (spaced label): Gray-display alias for Not applicable.
Unread: The external material was not read directly in this review. This is distinct from actually reading the retained summary.
Review incomplete: Individual review work for preparing the table remains unfinished. This is distinct from unverified data.

Change history

2026-11-01 · Public page/material version 1.0

The public view and materials were prepared from the existing 35 items. No new clinical search, change in verification status, or scoring was performed.

The stored-material review date (2026-10-05) and original evidence cut-off (2026-09-15) were retained unchanged.

Researcher downloads

These materials provide the same evidence, scope and verification status as this page.

View all item details

N01 · Which FMD comparison is being tabulated?

Current findings: The original /ko/effect is improvement in brachial FMD in adults with coronary artery disease. The identity of the adjudicated question fixes the comparison as ER nicotinic acid versus placebo on common atorvastatin treatment, with each period lasting 3 months. The subclaims key is absent, and there is a single table for the original main question.
Verification status: Met
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The target of the judgment and the identity of the narrowly defined actual comparison were verified. This item does not declare that the evidence for FMD efficacy is sufficient.
Reason for missing information: Unverified information about the product, measurement and denominator remains in later items.
Required materials and conditions: The identity of the current claim and adjudicated question, descriptive attributes (facets), canonical URL, and actual list of keys in the retained summary.
Materials to obtain first: The identity of the current claim and adjudicated question, descriptive attributes (facets), canonical URL, and actual list of keys in the retained summary.
Further research: Cross-check included reports by population, intervention, comparator, endpoint and time point, keeping other questions separate in the scope-boundary table.
Remaining uncertainty: Retrospective definition of the scope and freezing of the criteria are separate events.
Conditions for verification: Link the single question covering adults with CAD, common atorvastatin 80 mg/day, oral ER nicotinic acid 1500 mg/day, each 3-month period, and period-end brachial FMD in the placebo crossover comparison.
Why this condition is needed: Needed to avoid combining the ingredient as a whole, lipid endpoints and clinical-event endpoints into a single effect.
Application exceptions: Do not fill the absent subclaims key with a null value or an empty array. This is a development question narrowed after the results were known, not a preregistration.
Referenced methods: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed — a specific adaptation for the separate question. Not official methodological certification.

Related sources S01

N02 · Have the molecule, release formulation, salt and brand of the actual nicotinic acid product been verified?

Current findings: The main trial evaluated oral ER nicotinic acid as add-on therapy. The exact salt, manufacturing origin, brand/manufacturer and excipients are unverified. The original classification, kind M, denotes drug add-on therapy; do not reclassify it as a supplement solely because of the NUT module.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The molecule, ER formulation and route have been linked, but the detailed identity of the actual batch and formulation is unavailable.
Reason for missing information: Information on the salt, purity, batch, brand, origin and excipients remains to be verified.
Required materials and conditions: Trial product label, batch certification, basis for specifying the salt/active amount, manufacturing/quality information, and release-formulation information.
Materials to obtain first: Trial product label, batch certification, basis for specifying the salt/active amount, manufacturing/quality information, and release-formulation information.
Further research: Cross-check the trial batch against product documents, and code information on other release formulations, molecules and combination products separately.
Remaining uncertainty: Safety information in the label of another ER product cannot serve as verification of the actual product used in the main trial.
Conditions for verification: Specify clinical nicotinic acid and ER, and distinguish the unverified exact salt, purity, origin, brand, manufacturer and excipients.
Why this condition is needed: Needed to avoid treating similarities in release formulation or vitamin names as product equivalence.
Application exceptions: Do not automatically combine this with nicotinamide, NR, NMN, IR/SR, no-flush preparations or laropiprant combinations. Do not infer that NIASPAN was the main trial's brand.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — a specific adaptation for molecule and release formulation. Not official methodological certification.

Related sources S01 S12

N03 · Can background treatment in both periods be distinguished from the placebo comparison?

Current findings: The common atorvastatin dose is 80 mg/day, and the comparison is with the placebo crossover period on the same background treatment. The main trial's placebo ingredients, other common treatments and changes by period are unverified.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The background to the add-on comparison was verified, but not all concomitant-treatment/placebo conditions could be cross-checked.
Reason for missing information: Data on placebo composition, other treatments by period and handling of adherence are unavailable.
Required materials and conditions: Records of common treatment, concomitant medication, rescue treatment, placebo composition, changes and adherence by arm/period.
Materials to obtain first: Records of common treatment, concomitant medication, rescue treatment, placebo composition, changes and adherence by arm/period.
Further research: Cross-check treatment changes by period against the effect of interest, and do not attribute the effect of the common statin treatment to added nicotinic acid.
Remaining uncertainty: A stated background treatment does not mean that all concurrent treatments were balanced.
Conditions for verification: Compare the ER nicotinic acid add-on period with the placebo period on common atorvastatin 80 mg/day, retaining the unverified status of other concomitant treatments/placebo ingredients.
Why this condition is needed: It is necessary to assess whether differences in other medications are mixed with the effect of add-on therapy.
Application exceptions: Do not copy the low-dose nicotinic acid placebo composition from AIM-HIGH into this trial. This is not a question about nicotinic acid monotherapy.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — a specific adaptation for add-on therapy and comparator. Not official methodological certification.

Related sources S01

N04 · Can the nominal dose of 1500 mg/day be distinguished from actual exposure?

Current findings: The original target dose is 1500 mg/day. Titration has no recorded value and is unverified; actual adherence, doses taken and discontinuation data by period were also not verified within the retained scope reviewed here.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The nominal dose is clear, but data needed to verify actual exposure remain outstanding.
Reason for missing information: Data on titration, adherence, individual exposure and the basis for the stated dose are unavailable.
Required materials and conditions: Titration schedule, actual intake/adherence by period, washout/discontinuation, and the basis for specifying the active amount.
Materials to obtain first: Titration schedule, actual intake/adherence by period, washout/discontinuation, and the basis for specifying the active amount.
Further research: Extract nominal dose and actual exposure separately by period, and do not convert or fill in unverified doses taken.
Remaining uncertainty: Do not determine dose response or an effect of treatment adherence from the nominal target dose alone.
Conditions for verification: Cross-check the reported target dose of 1500 mg/day against actual doses taken, titration, discontinuation, adherence and the basis for specifying the active amount.
Why this condition is needed: Needed to avoid turning a stated target dose into identical exposure for every participant.
Application exceptions: Do not substitute 1000/2000 mg or concomitant aspirin from another study for exposure in the main trial.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — a specific adaptation for dose and adherence. Not official methodological certification.

Related sources S01

N05 · Have the 3 months per period and the crossover sequence, washout and handling of carryover been verified?

Current findings: Each treatment period lasted 3 months, with measurements at baseline and at the end of each period. The detailed washout, period sequence and handling of period/carryover effects in the crossover model are unverified.
Verification status: Unverified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The period length is known, but data needed to complete the review of crossover-specific time/carryover effects are unavailable.
Reason for missing information: Washout, sequence and period/carryover models remain to be verified.
Required materials and conditions: Complete visit schedule, sequence allocation, washout, and analysis plans and results for period/sequence/carryover.
Materials to obtain first: Complete visit schedule, sequence allocation, washout, and analysis plans and results for period/sequence/carryover.
Further research: Cross-check the crossover schedule and analysis equation, and do not add the individual 3-month periods together to create an arbitrary overall follow-up duration or a single treatment period.
Remaining uncertainty: The same 3-month duration label does not imply the same estimand as 12 weeks in a parallel-group trial.
Conditions for verification: Link each 3-month treatment period to baseline/period-end measurements, and verify sequence, washout, period effects and handling of carryover.
Why this condition is needed: Because exposure in the preceding period and time effects may become mixed with the period-end FMD comparison.
Application exceptions: Do not remove washout/carryover considerations in a crossover design by marking them NA, or count unverified details as additional confirmed design defects.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.1–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application — a specific adaptation for duration and carryover. Not official methodological certification.

Related sources S01

N06 · Are the CAD population, screening for endothelial dysfunction and baseline characteristics known?

Current findings: The participants are adults with coronary artery disease receiving common atorvastatin treatment. The eligibility threshold for endothelial dysfunction has no recorded value. Do not fill in the full baseline/eligibility profile beyond the scope of the abstract accessed in the original review.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The disease scope has been linked, but screening thresholds and detailed data on representativeness are unavailable.
Reason for missing information: Detailed diagnosis/eligibility criteria, baseline FMD and sex/deficiency strata remain to be verified.
Required materials and conditions: CAD diagnosis, age/sex, baseline FMD, inclusion/exclusion criteria, and distributions of disease/nutritional status.
Materials to obtain first: CAD diagnosis, age/sex, baseline FMD, inclusion/exclusion criteria, and distributions of disease/nutritional status.
Further research: Create an inclusion table by diagnosis and baseline status, and treat application beyond the verified population as a separate question.
Remaining uncertainty: Do not combine results from HIV, metabolic-syndrome, healthy or low-HDL populations as direct replication in this population.
Conditions for verification: Verify adult CAD and common high-dose statin treatment, along with the FMD screening cut-off, diagnosis/inclusion/exclusion criteria and baseline distributions.
Why this condition is needed: Because similarly named cardiovascular-risk groups cannot be assumed to be the same selected population.
Application exceptions: Do not invent an FMD cut-off or state that all participants had endothelial dysfunction defined by a threshold.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed — a specific adaptation for CAD eligibility. Not official methodological certification.

Related sources S01

N07 · Have the measurement, blinding and unit conditions for brachial FMD been verified?

Current findings: The brachial FMD endpoint and comparisons at the end of each period were verified. The device method, cuff protocol, post-deflation imaging time and details of image analysis are unverified.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The endpoint name/time point was verified, but data needed to assess measurement limitations and differences in detection by arm remain outstanding.
Reason for missing information: Data on the device, cuff, imaging/interpretation, blinding and reproducibility are unavailable.
Required materials and conditions: The main trial's FMD SOP, device/analysis method, cuff/imaging timing, baseline diameter and assessment-blinding records.
Materials to obtain first: The main trial's FMD SOP, device/analysis method, cuff/imaging timing, baseline diameter and assessment-blinding records.
Further research: Cross-check units/directions in the main trial's SOP and results tables, and do not substitute MRI or the protocol of an adjacent trial.
Remaining uncertainty: Do not copy the MRI measurement in S09 into S01 as its verified device.
Conditions for verification: Link period-end brachial FMD to the unit %, and verify the device, cuff site/pressure/duration, imaging/interpretation, baseline diameter and assessment blinding.
Why this condition is needed: Needed to avoid confusing differences in measurement conditions with actual changes in endothelial function.
Application exceptions: Do not conclude that blinding/standardization was completed solely because the measure is described as objective.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application — a specific adaptation for FMD measurement. Not official methodological certification.

Related sources S01 S09

N08 · Have the actual randomization, allocation concealment and baseline balance in the crossover trial been verified?

Current findings: S01 is reported as a randomized crossover trial. Details of sequence generation/concealment and sequence-specific baseline balance are unverified within the abstract information retained and reused here.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The design type was verified, but detailed cross-checking of the allocation process remains outstanding.
Reason for missing information: Information on sequence generation and allocation concealment, and sequence-specific baseline tables, is unavailable.
Required materials and conditions: The randomized sequence, allocation concealment, baseline table and recruitment flow in the main trial's full text.
Materials to obtain first: The randomized sequence, allocation concealment, baseline table and recruitment flow in the main trial's full text.
Further research: Cross-check the actual allocation section and baseline table, distinguishing an RCT label from sections that have been verified.
Remaining uncertainty: Do not create new bias counts or scores beyond the small-sample defect in the original B1.
Conditions for verification: Link the randomized crossover design to the verified scope of sequence generation, allocation concealment and baseline balance by period.
Why this condition is needed: Because the label 'randomized' alone cannot establish that all allocation issues were resolved.
Application exceptions: Do not turn unverified sections into confirmed defects or a nonrandomized design.
Referenced methods: M08 §8.1–8.2.3; internal application — a specific adaptation for randomization and allocation concealment. Not official methodological certification.

Related sources S01

N09 · Did the placebo and assessment blinding address differences caused by flushing?

Current findings: The main trial's placebo ingredients and active masking information have no recorded value. The FDA label warns about flushing but does not provide S01's blinding assessment results.
Verification status: Unverified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The direct source section needed to verify the measurement/sensory differences of interest has not been obtained.
Reason for missing information: Information on placebo composition, blinded interpretation, and flushing management/assessment of treatment guesses remains to be verified.
Required materials and conditions: The main trial's blinding section, placebo composition, flushing management/assessment of treatment guesses, and blinded interpretation.
Materials to obtain first: The main trial's blinding section, placebo composition, flushing management/assessment of treatment guesses, and blinded interpretation.
Further research: Compare the placebo/blinding sections, and do not use the existence of a flushing risk as confirmation that blinding failed in the main trial.
Remaining uncertainty: Do not turn a known potential risk into confirmed measurement bias in the actual trial.
Conditions for verification: Verify the main trial's placebo ingredients, participant/assessor blinding, and information on handling flushing and sensory differences.
Why this condition is needed: Needed to examine how sensory differences in exposure affected outcome assessment.
Application exceptions: The label's flushing risk is separate from the success/failure of blinding in an individual trial.
Referenced methods: M08 Table 8.2.a, M03 §3.2.4; internal application; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — a specific adaptation for blinding and placebo. Not official methodological certification.

Related sources S01 S12

N10 · Can the paired data, analysis population and effect of interest in the reported test be identified?

Current findings: The original report gives a between-treatment P=0.48 for FMD at the end of each period. The paired-model coefficient, ITT/PP, adjustment/analysis population and paired-data correlation are unverified. The +0.5%p figure is the existing simple descriptive difference.
Verification status: Unverified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The comparison direction has been linked, but the actual model used for the test and details of the estimand are unavailable.
Reason for missing information: The crossover-model equation, analysis population, paired correlation/variance and adjustment information remain to be verified.
Required materials and conditions: The main trial's statistical methods section, paired/crossover model, analysis population, covariates and test results table.
Materials to obtain first: The main trial's statistical methods section, paired/crossover model, analysis population, covariates and test results table.
Further research: Cross-check the comparison of interest against the actual model, and do not fill in an independent-groups analysis or an assumed ITT analysis.
Remaining uncertainty: Do not treat a difference in changes from baseline as the same as a period-end contrast.
Conditions for verification: Cross-check the period-end between-treatment test against the paired-data model, ITT/PP, adjustment, period effects and analysis population.
Why this condition is needed: Needed to avoid treating within-group changes or a simple difference in means as a verified crossover-model effect.
Application exceptions: Do not reconstruct an independent-groups Cohen d or a paired CI from ± and P alone.
Referenced methods: M08 §8.2.2, M15 §15.3.1; internal application; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed — a specific adaptation for the crossover effect of interest. Not official methodological certification.

Related sources S01

N11 · Can the study total of 66 participants be distinguished from the denominators for the actual FMD analysis and missing data?

Current findings: The original study total is 66 participants; the FMD analysis denominator fields, evidence_core.analysis_n and endpoint_analysis_n, have no recorded value (null). Actual completion counts by period, paired-analysis n and handling of missing data are also unverified.
Verification status: Unverified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The existence of a sample was verified, but data needed to verify the analysis denominator/losses for the selected outcome are unavailable.
Reason for missing information: Analysis n, losses by period, reasons, handling and follow-up remain to be verified.
Required materials and conditions: The main trial's flow diagram, analysis n by period, reasons for missing data/discontinuation, and their handling in the analysis.
Materials to obtain first: The main trial's flow diagram, analysis n by period, reasons for missing data/discontinuation, and their handling in the analysis.
Further research: Cross-check denominators in the flow diagram and results tables, and do not substitute the study total of 66 participants for the paired-analysis n.
Remaining uncertainty: Do not calculate new precision estimates or harm frequencies from the 66 participants.
Conditions for verification: Link the denominators for recruitment, allocation, completion, measurement by period and paired analysis, along with the reasons for missing data/discontinuation and how they were handled.
Why this condition is needed: Needed to avoid converting the retained sample size into the actual analysis denominator.
Application exceptions: Do not describe unverified missing-data information as 0 dropouts or complete data for all 66 participants.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application — a specific adaptation for denominators and missing data. Not official methodological certification.

Related sources S01

N12 · Have the period-end FMD values been distinguished from the scope of the failure to demonstrate improvement?

Current findings: Period-end FMD was 6.6 ± 4.8% with nicotinic acid and 6.1 ± 4.9% with placebo, P=0.48. The +0.5%p figure is simple subtraction in the original calculation history, not a verified crossover-model effect or a between-treatment difference in changes from baseline. Failure to demonstrate improvement does not mean an effect of exactly 0 or equivalence.
Verification status: Met
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The retained original values/analysis boundaries and the interpretation of nonsignificance were linked. Adequacy of precision remains an unverified condition in a later item.
Reason for missing information: The model contrast, changes from baseline and CI are still unavailable.
Required materials and conditions: Results in the original research abstract, original results tables, crossover-model estimates and baseline-change data.
Materials to obtain first: Results in the original research abstract, original results tables, crossover-model estimates and baseline-change data.
Further research: Cross-check values, units and comparison direction in the abstract/results tables, and preserve the old simple difference as a separate descriptive historical record.
Remaining uncertainty: Do not present a small favorable descriptive difference as a confirmed estimate of clinical benefit.
Conditions for verification: Attribute 6.6 ± 4.8% versus 6.1 ± 4.9%, P=0.48, and the existing +0.5%p only to the corresponding period-end/descriptive contrast.
Why this condition is needed: Needed to avoid turning nonsignificance into an effect of 0, equivalence or exclusion of a meaningful benefit.
Application exceptions: The formal between-group CI/difference in changes from baseline has no recorded value; do not perform new arithmetic or back-calculation.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is internally designed; M08 §8.2.2, M15 §15.3.1; internal application — a specific adaptation for original FMD values and the test. Not official methodological certification.

Related sources S01

N13 · Have the type of ± statistic and the paired variance for FMD been verified?

Current findings: The original ± figures are 4.8 for nicotinic acid and 4.9 for placebo, but the dispersion type field (dispersion_type) has no recorded value. Paired variance/correlation and analysis n were also not verified.
Verification status: Unverified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The displayed period-end values are known, but data needed to verify the actual definition of dispersion are unavailable.
Reason for missing information: The SD/SE type, paired variance/correlation and denominator are unavailable.
Required materials and conditions: SD/SE definitions in the original table, paired-data variance/correlation, test model and analysis n.
Materials to obtain first: SD/SE definitions in the original table, paired-data variance/correlation, test model and analysis n.
Further research: Even after cross-checking dispersion definitions in the table notes and statistical methods section, do not newly calculate an unreported CI.
Remaining uncertainty: The presence of ± is different from having obtained a formal effect CI.
Conditions for verification: Verify the dispersion types for 4.8/4.9, paired variance, between-period correlation and analysis n, and retain the unverified status of the original source information.
Why this condition is needed: Because arbitrarily assigning an unknown ± statistic to SD/SE would change the interpretation of effect and precision.
Application exceptions: Do not apply independent-groups formulas to values from the same participant in two periods.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M15 §15.3.1–15.3.3; internal application — a specific adaptation for ± and paired variance. Not official methodological certification.

Related sources S01

N14 · Is there a paired between-group CI and an applicable important FMD difference?

Current findings: The reported paired-contrast CI (reported_paired_contrast_CI) and the difference in changes from baseline (baseline_change_difference) are blank (null). An applicable between-group MCID is also unverified, and the original CX indicates the current limits of access/verification. It does not assert that reconstruction is permanently impossible.
Verification status: Unverified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: Without the interval and a threshold for an important difference, it is not possible to assess which magnitudes of effect are excluded.
Reason for missing information: The paired CI, paired variance, analysis n, and a justified important difference remain unverified.
Required materials and conditions: Between-group CI from the crossover model, paired variance/denominator, and evidence for an important difference in the same population/measure.
Materials to obtain first: Between-group CI from the crossover model, paired variance/denominator, and evidence for an important difference in the same population/measure.
Further research: Compare the reported CI with a justified threshold for an important difference, and leave unverified thresholds and CIs unverified.
Remaining uncertainty: The nonsignificant P=0.48 is not evidence for C1 or equivalence.
Conditions for verification: Compare the crossover-contrast CI with a justified threshold for an important difference in the same analysis, and explain the range of effects compatible with the findings.
Why this condition is needed: A P value alone cannot exclude a meaningful benefit or establish sufficient precision.
Application exceptions: Do not arbitrarily adopt a universal FMD MCID or a minimum sample size/duration.
Referenced methods: M15 §15.3.1–15.3.3; internal application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for specific designs were developed internally — an individual adaptation for CIs and important differences. This is not official methodological certification.

Related sources S01 S13

N15 · Do the planned status, analysis, and timing of FMD agree with what was reported?

Current findings: S01 is linked to NCT00150722, but the historical access level for S13 was registry_shell_only: only the basic registry display was available. FMD is the page's priority endpoint; its registered primary/co-primary status and the registry text on analyses and sponsorship are unverified.
Verification status: Unverified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The registration number is linked, but the structured registry text needed to compare the plans with the actual report could not be read.
Reason for missing information: The registration/SAP/protocol, version history, and reasons for departures from the plans remain unverified.
Required materials and conditions: Version-specific registry text, protocol, SAP, and the history of changes to endpoints/analyses.
Materials to obtain first: Version-specific registry text, protocol, SAP, and the history of changes to endpoints/analyses.
Further research: Compare the original versions of the registration/plans with the original study report, and indicate only the status/discrepancies that have been verified.
Remaining uncertainty: Do not represent the historical access to the basic registry display as a registry lookup or successful reading of the registry text in this review.
Conditions for verification: Compare the original NCT00150722 registration/protocol/SAP with the reported endpoints/crossover analysis and the reasons for changes.
Why this condition is needed: This is needed to avoid elevating the page's priority endpoint to the status of a registered primary endpoint.
Application exceptions: Do not turn the historical record of obtaining only the basic registry display into confirmation that the study was unregistered or selectively reported.
Referenced methods: M08 Table 8.2.a, M04 §4.6.3; internal application — an individual adaptation for registration and plans. This is not official methodological certification.

Related sources S01 S13

N16 · Have the original study report and registration been linked to the same direct trial family?

Current findings: S01 Philpott/PMID23174368/DOI10.1016/j.atherosclerosis.2012.10.067 and S13 NCT00150722 belong to one direct trial family, PHILPOTT-NCT00150722. Do not count the current 15 bibliographic records as 15 independent trials.
Verification status: Met
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The identity of the direct trial and its registration link are confirmed in the original manuscript; no total of unique trials/participants was newly produced.
Reason for missing information: Registry details and the complete relationships among adjacent reports remain limited.
Required materials and conditions: Identifiers and registry links for each report, and a family table of populations/doses/durations/outcomes.
Materials to obtain first: Identifiers and registry links for each report, and a family table of populations/doses/durations/outcomes.
Further research: Compare the identifiers and actual comparisons, and do not double-count related reports or registrations as new independent trials.
Remaining uncertainty: Do not extend the meaning of the original R1 to a factual claim of repeated confirmation or independent funding.
Conditions for verification: Place the Philpott original study report/PMID/DOI/NCT in the same direct trial family, and distinguish the number of reports from the number of independent replications.
Why this condition is needed: This is needed to avoid counting the existence of a paper and a registration as two independent replications.
Application exceptions: The original designation of 1 direct trial, R1, does not certify confirmatory preregistration or the number of independent study families across the entire literature.
Referenced methods: The distinction between studies and reports in M04 §4.6.1–4.6.2; internal application to cohort/outcome linkage; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the direct trial family. This is not official methodological certification.

Related sources S01 S13

N17 · Have the analysis denominators for each arm, prespecified plans, and interaction testing been verified for the INEF whole-cohort and post-hoc low-HDL results?

Current findings: INEF randomized 107 participants and lasted 12 weeks, and did not establish a whole-cohort FMD benefit. Changes in the post-hoc low-HDL subgroup were 3.25 versus 1.03%p, P=0.047, and n for each arm is unverified. The original descriptive difference of 2.22%p belongs to the post-hoc context and is not direct replication.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The directions of the whole-cohort/post-hoc results were verified, but stratum-specific denominators and planning/interaction information remain unverified.
Reason for missing information: Subgroup n, prespecification, interaction testing, and evidence of direct applicability to the same fixed comparison are unavailable.
Required materials and conditions: INEF whole-cohort/subgroup results tables, n for each arm, prespecified subgroup plans/SAP, and interaction testing.
Materials to obtain first: INEF whole-cohort/subgroup results tables, n for each arm, prespecified subgroup plans/SAP, and interaction testing.
Further research: Compare the whole-cohort/post-hoc results with the plans, and do not elevate a positive subgroup result to a whole-cohort result or to the current fixed comparison.
Remaining uncertainty: Do not label subgroup significance and whole-cohort nonsignificance as an actual conflict within the same analysis.
Conditions for verification: Separate the whole-cohort and post-hoc subgroup results, and verify the analysis denominator for each arm, whether the subgroup plan was prespecified, interaction testing, and eligibility as a direct comparison.
Why this condition is needed: This is needed to preserve both the unfavorable whole-cohort result and the favorable post-hoc result.
Application exceptions: The original post-hoc difference of 2.22%p is existing descriptive arithmetic. Do not produce new totals or recalculate it.
Referenced methods: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M03 §3.2.1–3.2.4; details of dose, persistence, and effect modification were developed internally — an individual adaptation for the INEF post-hoc subgroup. This is not official methodological certification.

Related sources S02

N18 · Have the actual study linkage for Thoenes/Vaccari and the between-group FMD estimate and CI been verified?

Current findings: The original record treats Thoenes/Vaccari as a possible single metabolic-syndrome family. The randomized study had 50 participants and lasted 52 weeks, with a within-nicotinic-acid-group 22% improvement/P<0.001. The between-group FMD difference and CI are unverified.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The within-group result and the boundary around possible overlap have been linked, but the family identity and between-group contrast have not been fully compared.
Reason for missing information: Report relationships, the between-group estimate/CI, and direct applicability to the same population/dose remain unverified.
Required materials and conditions: Study identities, populations/durations/registrations, between-group results/CIs, and links to the original participants for the two reports.
Materials to obtain first: Study identities, populations/durations/registrations, between-group results/CIs, and links to the original participants for the two reports.
Further research: Compare report identities and results tables, and do not add the 50 participants twice across reports that may describe the same study.
Remaining uncertainty: Do not combine the improvement-rate unit and within-group analysis with the main trial's end-of-period % as if they were the same effect.
Conditions for verification: Link S03/S04 as a possible single family, while verifying whether the actual participants and study identities match and checking the between-group FMD estimate and CI; separately preserve the 52 weeks, 50 participants, and within-group 22% improvement.
Why this condition is needed: This is needed to prevent a positive within-group result and potentially overlapping reports from being turned into direct replication.
Application exceptions: A possible family relationship does not establish a confirmed number of independent trials. 22% is neither 22%p nor a between-group difference.
Referenced methods: The distinction between studies and reports in M04 §4.6.1–4.6.2; internal application to cohort/outcome linkage; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the metabolic-syndrome study family. This is not official methodological certification.

Related sources S03 S04

N19 · Have the analysis denominators, adjustment models, between-group CIs, and plans been verified for Chow's two analyses?

Current findings: The Chow HIV trial had 10 participants receiving nicotinic acid and 9 receiving placebo, lasted 12 weeks, and used a maximum dose of 1500 mg/day. The between-group P value for unadjusted change was P=0.67; the end-of-period comparison adjusted for baseline FMD/HDL-C gave P=0.048, and the adjusted-contrast CI is unverified.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The original differences between analyses were preserved, but information needed to verify the adjusted-contrast interval/plans remains outstanding.
Reason for missing information: The adjusted coefficient/CI, analysis population, and prespecified analysis plan are unavailable.
Required materials and conditions: Chow results tables, adjustment models, between-group CIs, baseline/completion/analysis denominators, and SAP.
Materials to obtain first: Chow results tables, adjustment models, between-group CIs, baseline/completion/analysis denominators, and SAP.
Further research: Compare unadjusted/adjusted estimands, covariates, and plans, and do not turn the two P values into a conflict within the same analysis.
Remaining uncertainty: The different conclusions of the two tests do not imply a numerical error for the same question/analysis.
Conditions for verification: Separate the unadjusted change comparison in the HIV context of 10/9 participants and 12 weeks from the end-of-period test adjusted for baseline FMD/HDL-C, then link the extent of verification for each analysis population, adjustment model, between-group CI, and prespecified plan.
Why this condition is needed: This is needed to avoid selecting a single value from favorable/unfavorable results obtained from different analyses.
Application exceptions: Because the population and analyses differ, do not count these results as independent replication of the current CAD add-on treatment.
Referenced methods: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for differences between HIV analyses. This is not official methodological certification.

Related sources S05

N20 · Have Dubé's actual analysis denominators, handling of missing data, and between-group FMD effect and CI been verified?

Current findings: Dubé is a 24-week trial in HIV comparing ER nicotinic acid+aspirin with fenofibrate. There were 99 randomized participants/74 with complete scans (35/39); within-group median changes were 0.6%p/P=0.28 versus 0.5%p/P=0.19, and the between-group contrast CI is unverified.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The exposure, participant flow, and within-group results have been linked, but the between-group contrast of interest and its CI are unavailable.
Reason for missing information: The between-group effect/CI, analysis/handling of missing data, and direct applicability to CAD remain unverified.
Required materials and conditions: Dubé's flow diagram, analysis denominators for each arm, co-intervention/active comparator, and between-group results/CI.
Materials to obtain first: Dubé's flow diagram, analysis denominators for each arm, co-intervention/active comparator, and between-group results/CI.
Further research: Extract the within-group tests separately from the actual comparator/co-intervention, and assign 99/74/35/39 only to their respective stages in that study's participant flow.
Remaining uncertainty: Do not turn simple subtraction of the two within-group values or substitution of the total count into a new between-group effect.
Conditions for verification: Link ER nicotinic acid+aspirin versus fenofibrate, HIV, and 24 weeks with 99 participants assigned/74 with complete scans (35/39), and distinguish the extent of verification of actual analysis denominators for each arm, handling of missing data, between-group estimates, and CIs.
Why this condition is needed: This is needed to avoid turning an active comparison, co-intervention, and medians into the main trial's contrast for adding the single agent.
Application exceptions: Do not copy the aspirin co-intervention or the fenofibrate effect into the placebo composition/background treatment of the main trial.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations were developed internally; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for specific designs were developed internally; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for a different comparator in HIV. This is not official methodological certification.

Related sources S06

N21 · Have HDL, eNOS, and cellular responses been kept from being used as direct effects on brachial FMD?

Current findings: S07 concerns mechanisms involving HDL, vasorelaxation/eNOS, while S11 concerns a diabetes/healthy comparison and endothelial assays of isolated HDL. The current bibliographic records and source locations (citation/locator) do not provide direct clinical results for brachial FMD in the CAD crossover comparison.
Verification status: Met
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The outcome levels in the original material were distinguished. This does not newly certify the clinical validity of the mechanisms as a whole.
Reason for missing information: Within this scope, there is no material linking the mechanisms to the same direct comparison.
Required materials and conditions: The actual experimental systems, populations, assays, and links to clinical FMD outcomes in mechanistic studies.
Materials to obtain first: The actual experimental systems, populations, assays, and links to clinical FMD outcomes in mechanistic studies.
Further research: Map the evidence by outcome level/experimental system, and do not substitute changes in cells or isolated HDL for comparative clinical effects.
Remaining uncertainty: Do not fill in an FMD benefit for the main trial based solely on improvement language in a bibliographic title.
Conditions for verification: Distinguish the level of outcomes in the mechanistic evidence and isolated-HDL/endothelial assays in S07/S11 from brachial FMD in the main trial.
Why this condition is needed: This is needed to prevent related biological explanations from being elevated to replication of a direct clinical endpoint.
Application exceptions: Do not use mechanistic plausibility as evidence of effect magnitude or prevention of clinical events.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to the specific question were developed internally; M03 §3.2.4; internally defined extension boundaries — an individual adaptation for mechanistic evidence. This is not official methodological certification.

Related sources S07 S11

N22 · Have the actual molecule and composition of the S08 no-flush product and its direct applicability to the same comparison been verified?

Current findings: The source-location description (locator) for S08 concerns no-flush niacin and participants with isolated low HDL/no other CAD risk. Do not automatically combine it with the main question's ER nicotinic acid/CAD/common high-dose statin comparison.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The differences in formulation and population have been linked, but the exact product identity and direct applicability to the same comparison are unverified.
Reason for missing information: The exact molecule/composition, comparator/estimand, and eligibility for the main comparison remain unverified.
Required materials and conditions: The original text on the actual molecule/composition, release formulation, population, comparator/outcomes for the S08 product.
Materials to obtain first: The original text on the actual molecule/composition, release formulation, population, comparator/outcomes for the S08 product.
Further research: Use a product/population eligibility table to identify differences, and do not claim equivalence with ER nicotinic acid based solely on the no-flush name.
Remaining uncertainty: The historical access record for the original title/abstract is not current inspection of the physical product.
Conditions for verification: Verify the actual molecule, composition, release formulation, population, comparator, and outcomes of S08 to assess eligibility for the original ER-drug/CAD add-on comparison; separately preserve the currently known differences involving no-flush and a population with isolated low HDL/no other CAD risk.
Why this condition is needed: This is needed to prevent results from different molecules/formulations and selected populations from being mixed in as direct replication.
Application exceptions: Do not infer the molecular identity of no-flush products.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations were developed internally; M03 §3.2.1; detailed population criteria were developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the No-flush boundary. This is not official methodological certification.

Related sources S08

N23 · Have the original FMD results of the MRI modified-release study been verified?

Current findings: S09 is an MRI-based modified-release study. Its historical access level was publisher_metadata_indexed_fulltext_inaccessible: indexed publisher metadata with inaccessible full text, and no original FMD results were extracted. In this review, only the retained bibliographic record was read; the external full text was not opened.
Verification status: Unverified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The bibliographic identity is available, but the actual original results and the material needed to assess direct applicability have not been obtained.
Reason for missing information: The original FMD results, measurement methods, analysis, and detailed formulation information are unavailable.
Required materials and conditions: The FMD tables, measurement methods, analysis/population, and formulation information in the original full text of S09.
Materials to obtain first: The FMD tables, measurement methods, analysis/population, and formulation information in the original full text of S09.
Further research: If obtained, compare the actual original results/measurement methods; do not infer the direction or magnitude of an effect from search/index titles.
Remaining uncertainty: An unverified effect does not mean a negative result or 0 studies.
Conditions for verification: Separate the S09 bibliographic record/metadata from the historical inability to access the full text, and do not fill in unverified FMD results.
Why this condition is needed: This is needed to avoid using the existence of a link as verification of original results or replication of the main measurement.
Application exceptions: Access has not been attempted in this review. Do not recast the historical record of inaccessible material as an access failure in this review.
Referenced methods: The data-collection/selection principles in M04 §4.5–4.6; the distinction between access and reading, and the hyperlink conventions, were developed internally; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to the specific question were developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for unverified MRI results. This is not official methodological certification.

Related sources S09

N24 · Have the positive combination result and the termination/nonposting of results been kept from being used as effects of nicotinic acid alone?

Current findings: S10 is a positive FMD report on an ER nicotinic acid/laropiprant combination after myocardial infarction. The separate S14 NCT01052311 had an actual enrollment of 8 participants, no results posted, and was terminated following the decision to withdraw the study drug from the market. Do not count either as a direct effect of nicotinic acid alone.
Verification status: Met
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The actual distinctions among positive findings, termination, and nonposting were preserved. Ingredient-specific causal contributions are not verified.
Reason for missing information: The contribution of the combination's ingredients and a direct estimate for the current fixed comparison are unavailable.
Required materials and conditions: The compositions, trial/registration identities, results tables, reasons for termination, and posting histories of the two studies.
Materials to obtain first: The compositions, trial/registration identities, results tables, reasons for termination, and posting histories of the two studies.
Further research: Compare reports, registrations, and products, and do not invent ingredient-specific contributions to combination results or unposted FMD values.
Remaining uncertainty: Do not replace unposted results with negative FMD values.
Conditions for verification: Separate the positive combination report S10 from the separate terminated registration S14, its actual enrollment of 8 participants, and its unposted results.
Why this condition is needed: This is needed to prevent the contributions of combined active ingredients and unreported results from being attributed to the main add-on treatment.
Application exceptions: Do not merge S10 and S14 as the same trial without comparing their identifiers.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations were developed internally; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the combination with laropiprant. This is not official methodological certification.

Related sources S10 S14

N25 · Have carotid IMT and lipids been kept from substituting for success on brachial FMD?

Current findings: S16 is a 2-year carotid IMT study in participants who had reached their LDL target and had high Lp(a); the original HTML was used for screening at the time. It is not a main FMD result. The manuscript likewise does not use lipid improvement as this page's criterion for FMD success.
Verification status: Met
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The boundaries between related outcomes and direct FMD evidence were distinguished. No new efficacy judgment is made for other endpoints.
Reason for missing information: The current manuscript contains no estimate for the same direct FMD comparison.
Required materials and conditions: Material directly linking the endpoints/timing/population of S16 to clinical FMD outcomes.
Materials to obtain first: Material directly linking the endpoints/timing/population of S16 to clinical FMD outcomes.
Further research: Map the material by endpoint, and do not transfer improvements in IMT or LDL/HDL into effects on brachial FMD.
Remaining uncertainty: The biological relevance of IMT and lipids does not permit endpoint substitution.
Conditions for verification: Separate the priority IMT endpoint and lipid values in S16 from the FMD and cardiovascular-event questions.
Why this condition is needed: Calling outcomes vascular or lipid-related does not make them the same outcome.
Application exceptions: Retain positive results on other endpoints, but do not use them as the direct success criterion.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to the specific question were developed internally; M03 §3.2.4; internally defined extension boundaries — an individual adaptation for other vascular endpoints. This is not official methodological certification.

Related sources S16 S01

N26 · Have funding, drug supply, and COI for the main trial been verified?

Current findings: Funding, drug supply, and author conflicts of interest for S01 are unverified. The original I1 applies the rule for unverified information in precedent 29 and does not mean that mixed funding was actually verified. The check of the Chow acknowledgements belongs to the history of an adjacent study.
Verification status: Unverified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The disclosure/funding sections needed to support the main trial's independence have not been obtained.
Reason for missing information: Funding, product supply, COI, and sponsor details remain unverified.
Required materials and conditions: Original records for S01 funding/acknowledgements, product supply, author COI, and the registry sponsor.
Materials to obtain first: Original records for S01 funding/acknowledgements, product supply, author COI, and the registry sponsor.
Further research: Compare disclosures in the original study report/registration with related reports, and do not turn unverified information into confirmation of independent/mixed funding.
Remaining uncertainty: The presence or absence of a disclosure also does not automatically establish the magnitude of bias or invalidate a study.
Conditions for verification: Link the main trial's funding, product supply, and authors' employment/patents/COI to the actual sections in the report.
Why this condition is needed: This is needed to prevent unverified conflicts of interest from becoming evidence of independent replication.
Application exceptions: Do not automatically attribute sponsorship described in the Chow acknowledgements or the FDA document to S01.
Referenced methods: Chamgap's own criteria for independence and attribution. The official methodology sections used in this pilot do not warrant all of these detailed items — an individual adaptation for funding and independence. This is not official methodological certification.

Related sources S01 S05 S13

N27 · Have the reading of summaries in this review, historical external access, and document dates been distinguished?

Current findings: The complete retained KO/EN, structural, evidence, and bibliographic summaries were read. The original evidence cutoff/verification date (verified_date) is 2026-09-15. Individual access dates for each bibliographic record (citation) are absent and remain blank; historical access levels/locations and the overall review date are preserved separately. Access to all 15 external materials was not attempted, and none were obtained or read in this review.
Verification status: Met
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The scope of current actions and of the original history/dates was separated for each material. This does not imply completeness of the latest literature as a whole.
Reason for missing information: The original search/selection/full-text files were not compared in this review.
Required materials and conditions: The bytes/SHA of the current input; original bibliographic source locations and access levels (citation locator/access_level); the original evidence cutoff and verification date (evidence_cutoff/verified_date); and historical search/selection records.
Materials to obtain first: The bytes/SHA of the current input; original bibliographic source locations and access levels (citation locator/access_level); the original evidence cutoff and verification date (evidence_cutoff/verified_date); and historical search/selection records.
Further research: Compare access/obtaining/reading events for each material together with their dates, and distinguish external URLs from the current reader displaying the summaries actually read.
Remaining uncertainty: The historical first-publication date (first_published_at) and the blank deployment timestamp (deployed_at, null) do not record a current deployment event.
Conditions for verification: Separately preserve the 2026-09-15 evidence/review date, the reading of the retained summaries on 2026-10-05, and each report's access level and absence of access dates.
Why this condition is needed: This is needed to avoid overstating the reading of retained summaries as new full-text verification or a current comprehensive search.
Application exceptions: The 15 bibliographic records (citation) have no individual access-date keys (accessed). Do not fill individual access dates with the overall verification date (verified_date). The original ZIP/search files were not opened in this review.
Referenced methods: The data-collection/selection principles in M04 §4.5–4.6; the distinction between access and reading, and the hyperlink conventions, were developed internally; M04 §4.5, §4.6.3; the limits of the current data conversion follow the user-defined scope and internal design — an individual adaptation for reading status and reference dates. This is not official methodological certification.

Related sources S01 S02 S03 S04 S05 S06 S07 S08 S09 S10 S11 S12 S13 S14 S16

N28 · Have the meanings of the original D28, axes, and uncertainties been retained unchanged?

Current findings: The original grade D, score of 28, and B/S/R1/I1/E0/B1/CX are retained. E0 means failure to demonstrate improvement; I1 denotes how unverified funding was handled; CX means precision remains unverified within the scope of access. Because direct human data exist, the original indicator for absence of human studies remains no_human_study=false.
Verification status: Met
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: Accurate preservation of the original assessment and its interpretation was checked. This is not a new efficacy judgment or clinical certification.
Reason for missing information: Precision, replication, funding, and detailed information on bias each remain unverified.
Required materials and conditions: The original grade, score, and axes (grade/score/axes), rationales for each axis, and metadata on the original calculation/document review in the assessment record (assessment).
Materials to obtain first: The original grade, score, and axes (grade/score/axes), rationales for each axis, and metadata on the original calculation/document review in the assessment record (assessment).
Further research: Check that the original values and their display match, and do not generate new scores, criterion-fulfillment rates, or a judgment of effect 0.
Remaining uncertainty: The document's self-review grade B does not replace efficacy grade D or an independent clinical review.
Conditions for verification: Preserve the original D28/B/S/R1/I1/E0/B1/CX and the indicator for absence of human studies, no_human_study=false, solely as historical assessments.
Why this condition is needed: This is needed to avoid confusing the table's verification statuses with the existing efficacy grade.
Application exceptions: Apart from the small sample size underlying the original B1, do not count unverified design items as new defects.
Referenced methods: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M04 §4.5, §4.6.3; the limits of the current data conversion follow the user-defined scope and internal design — an individual adaptation for preservation of the original assessment. This is not official methodological certification.

Related sources S01

N29 · Are harm-collection data, person/event counts, and discontinuation denominators available for the same main trial?

Current findings: The numbers of people with adverse events or discontinuations in the main FMD trial and its long-term safety could not be verified. The original Caution status is retained, without inventing person counts, event counts, severity, systematic collection, or denominators.
Verification status: Unverified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: No material is available for reviewing a harm tally in the same population under the same exposure.
Reason for missing information: Trial-specific adverse-event (AE) and discontinuation data, person/event counts, exposure denominators, and collection methods remain to be verified.
Required materials and conditions: S01 harm/discontinuation tables, collection plan, exposure by group/period, person/event counts, severity, and missing-data records.
Materials to obtain first: S01 harm/discontinuation tables, collection plan, exposure by group/period, person/event counts, severity, and missing-data records.
Further research: Compare the harm tables with the flow diagram; do not fill unreported data with 0 or rates from a label used as adjacent evidence.
Remaining uncertainty: Nonreporting establishes neither absence of events nor selective reporting.
Conditions for verification: Link the S01 definitions of adverse events, systematic collection, severity, person/event counts, discontinuations, and exposure/follow-up denominators.
Why this condition is needed: Needed to avoid treating the existence of an efficacy summary as evidence of safety or a complete event tally.
Application exceptions: The original FMD result is not deleted or regraded because harms are unverified.
Referenced methods: M19 §19.1.2–19.2.4; own application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; own application — individually adapted to harms in the main trial. This is not official methodological certification.

Related sources S01

N30 · Have warnings in the FDA label been distinguished from the main trial's product and events?

Current findings: S12 is the 2020 NIASPAN FDA label. Retain its information on flushing, liver injury, increased blood glucose/uric acid, the risk of myopathy/rhabdomyolysis with statin co-treatment, and contraindications including active liver disease. The brand in S01 is unverified, and the label is not a harm tally from the main FMD trial itself.
Verification status: Met
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The official document's risk information was linked with the limits on attribution to a product/trial. This does not certify individual safety.
Reason for missing information: Correspondence with the main trial batch, events/causality in the same population, and current approval status remain unverified.
Required materials and conditions: The product/release formulation, contraindications/warnings, and evidence scope of the original FDA label, together with the identity of the S01 trial batch.
Materials to obtain first: The product/release formulation, contraindications/warnings, and evidence scope of the original FDA label, together with the identity of the S01 trial batch.
Further research: Compare the product/safety sections of the label with the main trial's product and co-treatment conditions; do not count the regulatory document as an additional independent trial or event.
Remaining uncertainty: Although the common statin dose of 80 mg is known, individual contraindications or alternative causes cannot be determined automatically.
Conditions for verification: Distinguish the contraindications, warnings, and interactions in the 2020 NIASPAN product document from the unverified brand in S01.
Why this condition is needed: Needed because the existence of official warnings differs from verification of safety in the particular trial under consideration.
Application exceptions: A historical label is not treated as verification of current approval status or individual safety.
Referenced methods: M19 §19.1.2–19.2.4; own application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding is internally designed; M04 §4.6.1–4.6.2; adaptation for harm data is internally designed; Chamgap's own interpretive boundaries. The M19 principles are referenced; no official causality tool was applied — individually adapted to the boundaries of FDA risk information. This is not official methodological certification.

Related sources S12 S01

N31 · Have group-specific exposure denominators, discontinuation definitions, and the composition of the trials pooled in the NIASPAN data been verified?

Current findings: The FDA label's evidence comprises 402 pooled participants and a median treatment duration of 16 weeks; AE-related discontinuations were 16% with nicotinic acid versus 4% with placebo. These are not period-specific event rates or discontinuation counts for S01, and no individual-group denominators are newly filled in.
Verification status: Partly verified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The original pooled comparison and duration were verified, but details of the corresponding group-specific denominators and composition are absent from the retained summary.
Reason for missing information: Group-specific exposure denominators, the composition of the pooled trials, and discontinuation collection/definitions remain to be verified.
Required materials and conditions: Group-specific/exposure denominators, discontinuation definitions/reasons, the composition of the original trials, and collection data for the label's pooled analysis.
Materials to obtain first: Group-specific/exposure denominators, discontinuation definitions/reasons, the composition of the original trials, and collection data for the label's pooled analysis.
Further research: Compare the label's pooling definitions/denominators; do not transfer its rates to S01, with a total of 66 participants and periods of 3 months each, or newly back-calculate person counts.
Remaining uncertainty: Do not newly calculate the numbers of people with events from rates and the overall n.
Conditions for verification: Link the pooled NIASPAN data—402 participants, a median of 16 weeks, and AE-related discontinuations of 16% versus 4%—to the product document, then distinguish what has been verified about group-specific exposure denominators, discontinuation collection/definitions, and the composition of the pooled trials.
Why this condition is needed: Needed to avoid using pooled discontinuations from a different data source as an event rate for a particular FMD trial.
Application exceptions: Do not substitute the total of 402 for each group's n. The median of 16 weeks and the periods of 3 months each belong to different sources.
Referenced methods: M19 §19.2.2–19.2.4, M03 §3.2.3; own application; M19 §19.1.2–19.2.4; own application; M19 §19.1.2–19.2.4, M04 §4.6.3; own application — individually adapted to pooled discontinuations and denominators. This is not official methodological certification.

Related sources S12

N32 · Has long-term safety or safety in vulnerable groups beyond the current observations been directly verified?

Current findings: Long-term safety in the main trial is unverified. The label's contraindications, metabolic/muscle risks, and pooled data with a median of 16 weeks are not used to verify safety in all vulnerable groups or during long-term exposure.
Verification status: Unverified
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The follow-up information by time period and population directly needed for the extended safety question is unavailable.
Reason for missing information: Data on long-term/rare events, disease/co-treatment strata, and time to onset/recovery remain to be verified.
Required materials and conditions: Data on long-term exposure, rare/serious events, and follow-up by underlying-disease/co-treatment strata for the same formulation/population.
Materials to obtain first: Data on long-term exposure, rare/serious events, and follow-up by underlying-disease/co-treatment strata for the same formulation/population.
Further research: Review exposure, timing, and vulnerable-group data separately for each question and, where needed, address rare events with an appropriate long-term observational or pharmacovigilance design.
Remaining uncertainty: Temporal ordering or a single label warning does not establish trial-specific rates of causally related events or individual safety.
Conditions for verification: Distinguish the FMD observations over periods of 3 months each from the median of 16 weeks in the prescribing document when considering long-term/rare harms, liver disease/metabolic risks, and interactions.
Why this condition is needed: Needed to avoid extending results from a short observation period and a restricted population to overall long-term safety.
Application exceptions: This narrow FMD question does not require every study of rare harms, and contraindications/risks are not interpreted as permission for self-medication.
Referenced methods: Design-specific harm questions in M19 §19.2; details of temporal relationships are internally designed; M19 §19.1.2–19.2.4; own application; M03 §3.2.1–3.2.4; details of dose, persistence, and effect modification are internally designed — individually adapted to long-term safety and vulnerable groups. This is not official methodological certification.

Related sources S01 S12

N33 · Are trials of myocardial infarction, stroke, or mortality a mandatory condition for this FMD question?

Current findings: The original endpoint is the surrogate brachial FMD. Prevention of myocardial infarction, stroke, or death is a separate question and is not imposed as a mandatory event-trial condition in this table. No event benefit is estimated.
Verification status: Not applicable (spaced label)
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The obligation to extend the narrow numerical question to event outcomes was treated as inapplicable. This does not mean that event evidence exists.
Reason for missing information: The current table does not review direct evidence of event prevention.
Required materials and conditions: If an extension to event outcomes is requested: direct event trials in the same population with the same intervention, event definitions, durations, and denominators.
Materials to obtain first: If an extension to event outcomes is requested: direct event trials in the same population with the same intervention, event definitions, durations, and denominators.
Further research: If an event-outcome question is added, review its separate, independent boundaries and extract the FMD and event estimates separately.
Remaining uncertainty: Improvement in FMD or lipids does not automatically answer the question of effects on clinical events.
Conditions for verification: Separate the current question about FMD values from the distinct question of clinical-event prevention or mortality.
Why this condition is needed: Needed to avoid automatically extending a surrogate difference to a clinical-event benefit.
Application exceptions: The selected question concerns FMD itself. Absence of an event trial does not justify deleting the FMD observation or treating Not applicable as evidence that material was acquired.
Referenced methods: M03 §3.2.4; own boundaries for extensions; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptation of outcomes to each question is internally designed — individually adapted to the non-applicability of the event-outcome extension. This is not official methodological certification.

Related sources S01

N34 · Does the current question also address the optimal dose, persistence of effects, and effects in specific strata?

Current findings: The current table concerns the fixed add-on comparison of 1500 mg over periods of 3 months each. It does not require every study of the optimal dose, persistence after discontinuation, or effects by deficiency status, sex, or low-HDL stratum. This does not mean that direct evidence for these extensions has been acquired.
Verification status: Not applicable (spaced label)
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The obligation to extend the assessment to optimal dose, persistence, or strata outside its target was treated as inapplicable. Unverified actual exposure remains recorded in N04/N05.
Reason for missing information: Direct dose comparisons and persistence/stratum-specific effects remain unverified within the present scope.
Required materials and conditions: If an extension is requested: direct dose comparisons, discontinuation/long-term follow-up, and prespecified plans/interactions by stratum.
Materials to obtain first: If an extension is requested: direct dose comparisons, discontinuation/long-term follow-up, and prespecified plans/interactions by stratum.
Further research: Set a separate question for each extension and link only data from direct dose, persistence, or stratum-specific designs to the corresponding estimate.
Remaining uncertainty: The existence of a fixed target dose does not verify the optimal dose.
Conditions for verification: Distinguish the fixed comparison of 1500 mg over periods of 3 months each from extensions to dose response, persistence after discontinuation, and prespecified interactions by stratum.
Why this condition is needed: Needed to avoid determining the optimal dose, persistence of effects, or effects in all subgroups from a single main effect.
Application exceptions: The positive post hoc low-HDL finding in INEF is not used to establish an optimal dose or stratum-specific effects across CAD populations.
Referenced methods: M03 §3.2.1–3.2.4; details of dose, persistence, and effect modification are internally designed — individually adapted to the non-applicability of the optimal-dose extension. This is not official methodological certification.

Related sources S01 S02

N35 · Is plant-part information needed for a drug question?

Current findings: The original plant-part information (plant_part) is marked not_applicable, while manufacturing origin (source_origin) has no value (null) and remains unverified. The plant-part condition does not apply to the nicotinic acid drug, and its manufacturing origin is not assigned arbitrarily.
Verification status: Not applicable (spaced label)
Materials actually read: Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.
Why unverified: The applicability exception for a non-botanical intervention was verified. This does not verify formulation quality or origin.
Reason for missing information: Manufacturing origin remains unverified under N02.
Required materials and conditions: Manufacturing-origin/quality data for the actual trial batch; separate identity information if a botanical ingredient is claimed.
Materials to obtain first: Manufacturing-origin/quality data for the actual trial batch; separate identity information if a botanical ingredient is claimed.
Further research: Compare formulation-identity data; do not interpret the non-applicability of plant-part information as verification of a synthetic or fermentation origin.
Remaining uncertainty: NA for plant-part information and unverified manufacturing origin are different statuses.
Conditions for verification: Distinguish the unverified manufacturing origin of the nicotinic acid drug from the non-applicability of plant-part information.
Why this condition is needed: Needed to avoid imposing an unsupported plant-part axis on a question about a drug molecule.
Application exceptions: Manufacturing origin (source_origin) remains unverified and is distinguished from the not_applicable designation for plant-part information (plant_part).
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — individually adapted to the non-applicability of the plant-part condition. This is not official methodological certification.

Related sources S01