RapidMeta Cardiology | Non-Statin LDL-Lowering CVOT NMA for MACE v1.0

Systematic Review Protocol

Retrospective Public Protocol Pack (OSF-ready) — PRISMA 2020 & AMSTAR 2 aligned

1. Registration & Administrative Information [PRISMA #24, AMSTAR #2]

Review Title	Network Meta-Analysis of Non-Statin Lipid-Lowering Therapies (Ezetimibe, Evolocumab, Alirocumab, Bempedoic Acid) Added to Statin Background vs Placebo for Major Adverse Cardiovascular Events: Phase 3/4 Cardiovascular Outcome Trial Network
Protocol Version	v15.0 (Living Protocol — auto-updating)
Protocol Freeze Date	2026-03-10
Protocol Registration	Immutable timestamp via GitHub commit history at `github.com/mahmood726-cyber/rapidmeta-finerenone`. Each protocol amendment is a separate commit; the freeze date above corresponds to the most recent protocol-affecting commit. For external registration (PROSPERO / OSF) on submission-bound topics, see the per-topic Submission Cockpit. Per ICMJE 2023, GitHub commit hash + timestamp constitutes a verifiable pre-registration record equivalent to PROSPERO for tracking outcome / eligibility / analysis-plan changes.
Last Substantive Amendment	2026-03-10
Planned Update Frequency	Continuous (living review); formal snapshot at each new trial publication
Funding Source	No external funding (independent academic review)
Conflicts of Interest	None declared
Contributor Roles (CRediT)	MA — Conceptualization, Methodology, Data Curation, Writing (Original Draft & Review & Editing), Supervision. Per ICMJE 2023: human author takes full responsibility for accuracy and integrity of the work, including all AI-assisted components.
AI Assistance Disclosure	AI tools (Claude / Anthropic) provided: (a) automated audit tooling implementation (internal-consistency, fragility-index, PI-gap, GRIM/Benford, AACT cross-check, PMID DataBankList verification), (b) statistical module implementation (REML+HKSJ primary with DerSimonian-Laird sensitivity pooling, node-splitting, Doi/LFK, comparison-adjusted funnel, CINeMA-lite, POTH, Q-decomposition, contribution matrix), (c) initial drafts of summary text subject to human verification. AI is NOT listed as an author per ICMJE 2023; AI cannot take responsibility for a manuscript. All AI-generated content was reviewed and verified by the human author. The audit/extraction infrastructure is open-source at the GitHub repository for independent verification.

2. Review Question — PICO Framework [PRISMA #3, AMSTAR #1]

Population
Intervention
Comparator
Primary Outcome
Secondary Outcomes	All-cause mortality; renal composite (eGFR decline, ESKD, renal death); individual MACE components; hyperkalemia
Subgroup Plan

3. Eligibility Criteria [PRISMA #5–6, AMSTAR #3]

Criterion	Inclusion	Exclusion
Study Design	Randomized controlled trials (RCTs), parallel or crossover	Non-randomized, observational, single-arm, case series
Phase	Phase III or IV	Phase I/II (including IIa/IIb), PK/PD, dose-finding, bioequivalence, first-in-human
Participants	ASCVD or very high CV risk	Healthy volunteers, paediatric, animal/in-vitro
Intervention	PCSK9i as primary experimental drug	PCSK9i as background only; open-label extensions without comparator
Comparator	Placebo, sham, or standard of care	Active comparator without placebo arm
Outcomes	≥1 clinical cardiovascular or renal endpoint with extractable 2×2 data	Biomarker-only, PK-only, no event data
Publication	Published or registered; any language	Pre-2015; duplicate cohorts; editorials, letters, reviews
Follow-up	≥12 weeks (primary outcome assessment)	<12 weeks or acute/single-dose studies

4. Information Sources & Search Strategy [PRISMA #7–8, AMSTAR #4–5]

Database	Search String / API Query	Type
ClinicalTrials.gov	`https://clinicaltrials.gov/api/v2/studies?query.intr=empagliflozin+OR+dapagliflozin+OR+sacubitril+AND+heart+failure+reduced&pageSize=100&filter.overallStatus=COMPLETED`	Registry (API v2)
PubMed (Europe PMC)	`hfref quadruple therapy AND (TITLE:randomized OR PUB_TYPE:"Randomized Controlled Trial" OR PUB_TYPE:"Clinical Trial") AND SRC:MED`	Bibliographic (REST)
OpenAlex	`search=hfref quadruple therapy&filter=concepts.id:C71924100&per_page=50`	Bibliographic (REST)
Reference Check	Backward citation search: built-in landmark database cross-checked against API returns	Manual supplement

Deduplication [PRISMA #16a]

NCT-ID exact match → PubMed dbCrossReferenceList linkage → NCT pattern extraction from abstract → fuzzy title dedup (normalized alphanumeric). Enrichment: abstracts, authors, journal metadata merged from PubMed into registry stubs. All 3 fetches run in parallel via Promise.allSettled.

5. Study Selection Process [PRISMA #16, AMSTAR #5–7]

Stage 1: Auto-Screening	RCT relevance classifier (keyword + publication type scoring, 0–100). Auto-exclude <25. App location: Screening tab
Stage 2: Title/Abstract	Two-reviewer adjudication workflow with rationale note and second-review confirmation (I = propose include, E = propose exclude, C = second confirmation, N/P = navigate). App location: Screening tab
Stage 3: Source Verification	Verify eligibility and endpoint fit against CT.gov records plus PubMed/OpenAlex abstracts; no full-text extraction in the locked constrained-source workflow. App location: Extraction tab
Conflict Resolution	Re-review with exclusion reason recorded in audit log. PRISMA flow auto-generated.
PRISMA Flow Diagram	Auto-computed from search/screening counts. App location: Report tab → PRISMA section

6. Data Collection & Extraction [PRISMA #10, AMSTAR #6]

Data Item	Details	App Location
Study identifiers	NCT ID, PMID, DOI, first author, year	Extraction → Data Entry
Participants	N randomized per arm, age, sex distribution, indication, baseline eGFR	Extraction → Demographics
Intervention details	PCSK9i dose/regimen, trial phase, treatment duration	Extraction → Data Entry
Outcome events	2×2 table: Events(Tx), N(Tx), Events(Ctrl), N(Ctrl); continuity correction 0.5 for zero cells	Extraction → Data Entry
Risk of Bias	RoB 2 domains D1–D5, each rated Low/Some/High	Extraction → Risk of Bias
Source evidence	Verbatim extracts from ClinicalTrials.gov records and PubMed/OpenAlex abstracts with source citations	Extraction → Evidence panels

7. Risk of Bias Assessment [PRISMA #11–12, AMSTAR #9]

Domain	Signalling Questions (RoB 2)	App Location
D1: Randomization	Sequence generation, allocation concealment	Extraction → RoB (click to cycle)
D2: Deviations	Blinding, ITT adherence, co-interventions	Extraction → RoB (click to cycle)
D3: Missing Data	Completeness, attrition handling, sensitivity for missing	Extraction → RoB (click to cycle)
D4: Measurement	Outcome assessment blinding, adjudication committees	Extraction → RoB (click to cycle)
D5: Selective Reporting	Pre-registered endpoints, protocol deviations	Extraction → RoB (click to cycle)
Presentation	Traffic-light summary table (per-study) + stacked horizontal bar chart (per-domain)	Analysis → Charts #16, Extraction → RoB

8. Synthesis & Statistical Methods [PRISMA #13, AMSTAR #11–12]

Method	Specification	App Location
Effect Measure	Primary analysis uses published hazard ratios when available; otherwise risk ratios from 2x2 counts. Odds ratios are retained for sensitivity analysis.	Analysis → Stats
Pooling Model	REML random-effects, HKSJ-adjusted (inverse-variance weighting)	Analysis → Forest (#1)
CI Adjustment	Hartung-Knapp-Sidik-Jonkman (HKSJ); t-distribution with df = k−1	Analysis → Stats
Prediction Interval	t-distribution, df = k−1 (Cochrane Handbook v6.5)	Analysis → Stats
Heterogeneity	Cochran Q (p-value), I² (%), τ² (DL estimator)	Analysis → Stats
Subgroup Analysis	By pre-specified subgroup; Q-between test for interaction	Analysis → Subgroup (#2)
Cumulative MA	Sequential addition by year; monitoring evidence accrual	Analysis → Cumulative (#3)
Leave-One-Out	Influence analysis: remove each study, re-pool	Analysis → LOO (#5)
Bayesian RE	Grid approximation (200 τ × 300 μ); half-normal prior on τ; posterior OR + CrI + P(OR<1)	Analysis → Posterior (#11)
Meta-Regression	WLS on log-OR; covariates: Year, Phase, Indication; Knapp-Hartung SE; permutation p (1000x)	Analysis → Meta-Reg (#12)
Fragility Index	Walsh method: sequential single-arm event modification until significance flips	Analysis → Stats
NNT / Clinical Utility	NNT = 1 / ARR; curve across baseline risk range	Analysis → NNT (#8)

9. Publication Bias Assessment [PRISMA #14–15, AMSTAR #15]

Method	Specification	App Location
Visual	Contour-enhanced funnel plot with significance regions (p < 0.01/0.05/0.10)	Analysis → Funnel (#9)
Statistical	Egger's weighted regression test: intercept ≠ 0 (k ≥ 3 required)	Analysis → Egger (#15)
Correction	Duval-Tweedie trim-and-fill (L0 estimator); imputed studies shown as open circles on funnel	Analysis → Stats chip
Sensitivity	Copas-style sensitivity (heuristic rank-reweighting, not Copas-Shi MLE): ρ sweep −0.99 to 0 (34 steps); classify Robust/Sensitive	Analysis → Copas (#13)
Power	RIS formula with D² diversity; conditional power curve (next-study N 100–2000)	Analysis → Power (#14)

10. Certainty of Evidence [PRISMA #22, AMSTAR #14]

GRADE Domain	Criteria for Downgrading	App Location
Risk of Bias	≥50% studies rated Some Concerns or High on any domain	Report → GRADE
Inconsistency	I² ≥ 50% or prediction interval crosses null	Report → GRADE
Indirectness	Population, intervention, or outcome mismatch with review question	Report → GRADE
Imprecision	CI crosses MID (OR = 0.80 or 1.25) or optimal information size not met	Report → GRADE
Publication Bias	Egger p < 0.10, asymmetric funnel, Copas sensitivity, trim-fill k0 > 0	Report → GRADE
Supplementary	Bayesian P(OR < 1), Information Fraction (RIS), Summary of Findings table	Report → SoF table

11. AMSTAR 2 Critical Domains Compliance

#	AMSTAR 2 Item	Critical?	How Addressed
1	PICO components for research question	No	Section 2 above
2	Protocol registered before commencement	No	Retrospective public protocol pack prepared on March 10, 2026; this tab is the living internal protocol
4	Comprehensive literature search strategy	Yes	Section 4: 3 databases + reference check; search strings visible
7	List of excluded studies with justifications	Yes	Screening tab: excluded with auto/manual reason
9	Satisfactory RoB assessment technique	Yes	Section 7: Cochrane RoB 2, 5 domains
11	Appropriate meta-analytical methods	Yes	Section 8: DL RE + HKSJ, R/Python cross-validated
13	RoB impact on results considered	Yes	GRADE domain 1, Extraction → RoB tab
15	Publication bias assessment	Yes	Section 9: Funnel + Egger + Trim-Fill + Copas

12. Reporting & Dissemination [PRISMA #23–27, AMSTAR #16]

Reporting Guideline	PRISMA 2020 (27-item checklist auto-generated as CSV)
Export Formats	CSV (study data), JSON (full state), R validation script, Python validation script, PRISMA checklist CSV, HTML standalone report
Data Integrity	SHA-256 data seal (cryptographic fingerprint) on every report; version timeline with delta alerts
Cross-Validation	R (`metafor`) and Python (`scipy`) scripts included for independent replication of pooled OR, CI, τ²
Patient Mode	Plain-language summary with traffic-light visual; hides technical statistics for lay audiences

Search History Log [PRISMA #8]

No searches recorded yet. Run an acquisition from the Search tab to log results here.

Evidence Acquisition

Multi-Source: ClinicalTrials.gov + PubMed + OpenAlex

Saved Search Log

No searches recorded yet.

PRISMA-NMA Flow Diagram

Pooled Primary Effect (HR/RR)

Precision (95% CI)

Heterogeneity (I²)

HKSJ-Adjusted CI

Prediction Interval

Q-test (Cochran)

τ² (95% CI)

Bayesian CrI

P(OR < 1)

Information Fraction

Bayesian Prior:

Meta-Regression:

Egger's: --

ROB-ME: --

Fragility: --

Trim-Fill: --

Copas: --

RIS: --

HR Sensitivity: --

REML: --

TSA: --

Study Characteristics

Trial	Year	Phase	Indication	N (Tx)	N (Ctrl)	ER Tx%	ER Ctrl%	RoB

ER = Event Rate. Values extracted from registry records — verify against published manuscripts before finalizing.

Precision Analytics Suite

1. Forest Plot (Fixed/Random Effects)

2. Subgroup Synthesis

3. Cumulative Meta-Analysis

4. Cumulative Z-Curve Analysis

5. Leave-One-Out Sensitivity

6. L'Abbe Plot (Event Incidence)

7. Galbraith Plot (Heterogeneity Check)

8. Clinical Utility (NNT Curve)

9. Funnel Plot (Publication Bias)

10. Baujat Plot (Influence x Heterogeneity)

11. Bayesian Posterior Density

12. Meta-Regression

13. Copas Sensitivity Curve

14. Conditional Power Curve

15. Egger's Regression Plot

16. Risk of Bias Summary

17. Sensitivity Analysis Panel

18. Influence & Outlier Diagnostics

What does this mean for you?

This is a summary for general understanding. Always discuss with your healthcare provider.

9. Quality Appraisal (RoB 2.0)

WebR: Validate with R in Your Browser

Not loaded

Runs metafor::rma() directly in your browser via WebAssembly. No server needed. First load installs R + metafor (~20-40s).

10. Evidence Summary (GRADE)

TruthCert R-Metafor Script (DL Model)

Reference Cross-Validation

Click "Validate" after running the analysis to compare the current result against the stored harmonized reference baseline.

Scientific Synthesis

Generating Visual Abstract & PRISMA Diagram...

HFrEF Drug Comparison NMA

Multi-source meta-analysis of landmark RCTs

Patient Population

N = -- Patients

Acquisition Era

Post-2015 Enrollment

Primary MACE Result

Primary Effect [95% CI]

Consistency (I²)

Scientific Verdict

Auto-Generated Manuscript Text

Click "Generate Output" to create manuscript text.

Waiting Room Summary

--/100

NNT Pictogram

--%

Risk Change

Primary Effect

For general understanding only. Discuss treatment decisions with your healthcare provider.

PRISMA 2020 Flow Diagram

Databases & Registers

Records from ClinicalTrials.gov
(n = --)

Records removed before screening
Duplicates / Ineligible
(n = --)

Records screened
(n = --)

Records excluded
(n = --)

Other Sources

Records from PubMed
(n = --)

Records from OpenAlex
(n = --)

Reference-checked trials
(n = --)

Reports assessed for eligibility
(n = --)

Reports excluded
(n = --)

Included in synthesis
(n = --)

The hfref quadruple therapy Evidence

A quantitative synthesis of landmark randomized trials.

Pooled Effect

NNT

I² Heterogeneity

Trials Included

Confidence Interval Comparison

Visual comparison of estimation methods on the odds ratio scale. The pooled point estimate is identical; interval widths differ by method.

Fig. — DerSimonian-Laird (standard), Hartung-Knapp-Sidik-Jonkman (adjusted), and Prediction Interval estimates

Publication-Quality Forest Plot

Annotated forest plot with trial-level statistics and weight contributions. Suitable for manuscript figures.

Fig. — Forest plot of hfref quadruple therapy vs placebo for MACE composite (random-effects, DL estimator)

Summary of Findings

Outcome	No. Trials	Total N	Effect (OR)	95% CI	I²	GRADE

SoF table follows GRADE Working Group recommendations. Verify values against R validation script output.

Evidence Guardian

Release-style validation for a constrained-source pairwise review: search coverage, dual-review status, endpoint harmonization, and sparse-evidence risks.

Awaiting report generation

Health

Integrity

Evidence

Risk

Validation Checks

Constraint Ledger

Recommendations

Reviewer Concordance

Generate a report to summarize documented dual-review coverage, reviewer-pair activity, and adjudication load.

No concordance snapshot yet

Screen Dual Coverage

Extraction Dual Coverage

Reviewers Logged

Active Reviewer Pairs

Capture Note

Screening & Extraction

Reviewer Pair Activity

Pair	Screen	Extract	Total
No concordance pairs rendered yet.

Recommendations

CT.gov Evidence Delta

Generate a report to audit CT.gov results coverage, protocol/SAP attachment coverage, endpoint bridging against registered primaries, and publication-without-results watchlist signals.

No registry delta snapshot yet

Results Posted

Protocol / SAP

Ghost / Lag Signals

Bridge / Drift

Capture Note

Registry Checks

Recommendations

Trial	Scope	Registered Primary	Current Endpoint	CT.gov / Docs	Publication	Delta Signal
No CT.gov evidence delta rendered yet.

Published Meta Benchmark

Generate a report to compare the current pooled estimate against published hfref quadruple therapy pooled analyses.

No benchmark yet

Comparator	Year	Trials	N	Measure	Estimate	95% CI	Alignment
No benchmark rendered yet.

Benchmarks use a locked local comparator database of published hfref quadruple therapy pooled analyses.

PRISMA 2020 Flow Diagram (SVG)

Auto-Generated Manuscript Draft

Click "Generate Draft" to create a manuscript methods + results section from the current analysis.

GRADE Evidence Profile (Summary of Findings)

Cumulative Evidence Over Time

Shows pooled effect estimate as each trial is added chronologically. Narrowing CI indicates evidence stabilization.

Quality Assurance (18 Automated Checks)

Click "Run QA" to check data integrity across all included trials.

Living Update Log

Run analysis and click "Snapshot Version" to create the first entry.

Reproducibility Artifact

Frozen analysis fingerprint linking search scope, included trials, pooled result, threat ledger, and data seal.

Fingerprint

Analysis Scope

Search Coverage

Included Trials

Threat Ledger

Audit Tail

Data Seal: -- · --

Network Meta-Analysis

Indirect comparisons via connected treatment network

Treatment Network

Nodes = treatments (sized by total N). Edges = direct trial comparisons. Dashed = indirect only.

League Table (All Pairwise Comparisons)

Upper triangle: effect estimates with 95% CI. Green = significantly favors row. Red = favors column. Gray = non-significant.

Live Re-pool from Raw 2×2 (verifier)

Re-pools the trial-level raw event counts in realData using REML random-effects + HKSJ + Cochrane v6.5 prediction interval (t_k-1). Compare the pooled estimate (cyan diamond) vs the published headline (gold dashed). Per-trial rows show the back-transformed RR with 95% CI and RE weight.

Treatment Rankings (P-Score)

SUCRA/P-score measures ranking probability, NOT effect magnitude. Always interpret alongside the league table effect estimates.

Consistency Assessment (Node-Splitting)

Network Consistency (NMA Pro Transplant)

NMA-Pro-style direct/indirect node-splitting with Fisher-combined global inconsistency test (Dias et al. 2010 back-calculation). Star networks (every comparison via a common reference) trigger an explicit transitivity-only disclosure since no closed loops exist to test consistency by node-splitting.

ROB-NMA + Transitivity (Cochrane 2025)

Lunny 2025 BMJ ROB-NMA tool (17 items, 3 domains) with auto-prefill from existing modules + transitivity effect-modifier balance per Brignardello-Petersen 2023 GRADE-NMA Article 5 / Lasch 2025 Res Synth Methods.

Bias & Certainty (Tier 2 Transplants)

Small-study-effects (Doi plot + LFK index, Furuya-Kanamori 2018), comparison-adjusted funnel (Chaimani & Salanti 2012), and per-pairwise certainty (CINeMA, Nikolakopoulou 2020). Tools chosen for k<10 networks where Egger's test is underpowered.

Compares direct vs indirect evidence for each comparison. P < 0.10 suggests inconsistency.

NMA Scientific Output

Click “Run NMA” to generate the forest plot of all pairwise comparisons.

Auto-Generated NMA Manuscript Text

Click "Run NMA" to generate Methods + Results text describing this network.

PRISMA-NMA Checklist Items

Network geometry: Star topology — all treatments connected via common comparator

Transitivity assumption: Similar patient populations across trials (all obesity/overweight adults)

Consistency: Run NMA to assess

Ranking: P-scores with uncertainty (SUCRA interpretation caveat displayed)

Systematic Review Protocol

1. Registration & Administrative Information [PRISMA #24, AMSTAR #2]

2. Review Question — PICO Framework [PRISMA #3, AMSTAR #1]

3. Eligibility Criteria [PRISMA #5–6, AMSTAR #3]

4. Information Sources & Search Strategy [PRISMA #7–8, AMSTAR #4–5]

5. Study Selection Process [PRISMA #16, AMSTAR #5–7]

6. Data Collection & Extraction [PRISMA #10, AMSTAR #6]

7. Risk of Bias Assessment [PRISMA #11–12, AMSTAR #9]

8. Synthesis & Statistical Methods [PRISMA #13, AMSTAR #11–12]

9. Publication Bias Assessment [PRISMA #14–15, AMSTAR #15]

10. Certainty of Evidence [PRISMA #22, AMSTAR #14]

11. AMSTAR 2 Critical Domains Compliance

12. Reporting & Dissemination [PRISMA #23–27, AMSTAR #16]

Search History Log [PRISMA #8]

Evidence Acquisition

Search Strings Used

Saved Search Log

PRISMA-NMA Flow Diagram

Extraction & Source Verification

Outcome-Switching Audit (registry vs paper)

Cochrane RoB-2 (per-domain traffic light)

Study Characteristics

Precision Analytics Suite

1. Forest Plot (Fixed/Random Effects)

2. Subgroup Synthesis

3. Cumulative Meta-Analysis

4. Cumulative Z-Curve Analysis

5. Leave-One-Out Sensitivity

6. L'Abbe Plot (Event Incidence)

7. Galbraith Plot (Heterogeneity Check)

8. Clinical Utility (NNT Curve)

9. Funnel Plot (Publication Bias)

10. Baujat Plot (Influence x Heterogeneity)

11. Bayesian Posterior Density

12. Meta-Regression

13. Copas Sensitivity Curve

14. Conditional Power Curve

15. Egger's Regression Plot

16. Risk of Bias Summary

17. Sensitivity Analysis Panel

18. Influence & Outlier Diagnostics

What does this mean for you?

9. Quality Appraisal (RoB 2.0)

WebR: Validate with R in Your Browser

10. Evidence Summary (GRADE)

TruthCert R-Metafor Script (DL Model)

Reference Cross-Validation

Scientific Synthesis

HFrEF Drug Comparison NMA

Auto-Generated Manuscript Text

Waiting Room Summary

PRISMA 2020 Flow Diagram

The hfref quadruple therapy Evidence

Confidence Interval Comparison

Publication-Quality Forest Plot

Summary of Findings

Evidence Guardian

Validation Checks

Constraint Ledger

Recommendations

Reviewer Concordance

Screening & Extraction

Reviewer Pair Activity

Recommendations

CT.gov Evidence Delta

Registry Checks

Recommendations

Published Meta Benchmark

PRISMA 2020 Flow Diagram (SVG)

Auto-Generated Manuscript Draft

GRADE Evidence Profile (Summary of Findings)

Cumulative Evidence Over Time

Quality Assurance (18 Automated Checks)

Living Update Log

Reproducibility Artifact

Network Meta-Analysis

Treatment Network

League Table (All Pairwise Comparisons)

Live Re-pool from Raw 2×2 (verifier)

Treatment Rankings (P-Score)