RapidMeta Pulmonary | Chronic Thromboembolic PH NMA Ultra-Precision v12.0

Systematic Review Protocol

PROSPERO-style Registration — PRISMA 2020 & AMSTAR 2 Compliant

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

Review Title	Pharmacologic and Interventional Therapies for Chronic Thromboembolic Pulmonary Hypertension (Riociguat, Treprostinil, Macitentan, Balloon Pulmonary Angioplasty): A Living Network Meta-Analysis
Protocol Version	v1.0 (Living Protocol — auto-updating)
Date of First Registration	2026-03-03
Last Substantive Amendment	2026-03-03
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; HF hospitalization; urgent HF visits; renal composite where reported
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	Adults with HF	Healthy volunteers, paediatric, animal/in-vitro
Intervention	Riociguat CTEPH and related agents	SGLT2i as background only; open-label extensions without comparator
Comparator	Placebo, sham, or standard of care	Active comparator without placebo arm
Outcomes	≥1 heart-failure clinical endpoint with extractable 2×2 counts or published HR/RR with confidence interval	Biomarker-only, PK-only, no clinical 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.term=heart%20failure%20sglt2&pageSize=100&filter.overallStatus=COMPLETED`	Registry (API v2)
PubMed (Europe PMC)	`(Riociguat CTEPH OR Riociguat extension OR Treprostinil inhaled CTEPH OR Macitentan inoperable CTEPH OR Inhaled MK-5475 CTEPH ph2) AND "Chronic Thromboembolic PH" AND (randomized OR "randomized controlled trial")"heart failure" AND (TITLE:randomized OR PUB_TYPE:"Randomized Controlled Trial" OR PUB_TYPE:"Clinical Trial") AND SRC:MED`	Bibliographic (REST)
OpenAlex	`search=sglt2%20heart%20failure&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: Full Text	Verify eligibility criteria against full manuscript; extract 2×2 table. 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	Intervention dose/regimen, trial phase, treatment duration	Extraction → Data Entry
Outcome events	2×2 table: Events(Tx), N(Tx), Events(Ctrl), N(Ctrl); or published HR/RR with confidence interval for recurrent/time-to-event estimands	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 published manuscripts with page/table references	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	Odds Ratio (OR) computed on log scale; 0.5 continuity correction for zero cells	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 HF phenotype (HFrEF vs HFpEF/HFmrEF); 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)
HR Data Source	Published HRs cross-validated against ClinicalTrials.gov API v2 `resultsSection` structured data (Cox regression). All 5 trials have concordant HR values between NEJM publications and CT.gov registry. Renal composite HRs sourced exclusively from CT.gov.	Evidence → CT.gov API v2 Validation
HR Pooling (sensitivity)	Fixed-effect inverse-variance pooling of log(HR); SE derived from published 95% CI. Displayed in HR chip and HR/RR mode. Excludes recurrent-event estimands (SOLOIST-WHF) from HR pool.	Analysis → Stats

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

10b. Safety Profile (Adverse Events) [PRISMA #20d]

Component	Description	App Location
Data Source	ClinicalTrials.gov API v2 `resultsSection.adverseEventsModule` for all 5 included trials. Provides MedDRA preferred terms with event counts per arm.	Analysis → Chart 19
Reporting Threshold	CT.gov only reports events exceeding the trial's reporting threshold (typically ≥5 events per arm). Events below threshold are noted but excluded from pooled rate calculations.	Chart 19 footnote
Pooling Method	Crude pooled rates: sum of events across trials / sum of arm-level denominators. Risk ratio (RR) with Wald-type CI from log-RR ± z×SE. Not inverse-variance weighted (events too sparse for proper MA).	Chart 19 table
AE Categories	Total serious AEs (SAE), plus SGLT2i-specific signals: UTI, Fournier's gangrene, DKA, genital mycotic infections, hypotension, dehydration, diarrhoea (SGLT1-mediated for sotagliflozin).	Chart 19 rows
Limitations	CT.gov primarily reports SAEs above a reporting threshold (≥5 events), so non-serious but clinically important AEs (e.g., genital mycotic infections, the most established SGLT2i class effect) are systematically undercounted or absent. Not all trials report all AE terms — rates use only denominators from trials reporting each term. Volume depletion/hypovolemia data is incomplete across trials. Total SAE data available from only 1 of 5 trials (DAPA-HF). SOLOIST-WHF (100% T2DM, dual SGLT1/2i) may inflate GI and metabolic AE rates when pooled with mixed-diabetes trials. Pooled rates are unadjusted (no covariate or exposure correction). Concordance with published safety meta-analyses (Vaduganathan et al., Lancet 2022) should be verified for clinical interpretation.	Chart 19 description

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	Yes	This protocol tab (living 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 Odds Ratio (Random-Effects)

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:

Subgroup By:

Egger's: --

ROB-ME: --

Fragility: --

Trim-Fill: --

Selection Sensitivity: --

RIS: --

HR Sensitivity: --

Method Sensitivity: --

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. Selection Sensitivity (Copas-inspired heuristic)

14. Conditional Power Curve

15. Egger's Regression Plot

16. Risk of Bias Summary

17. Method Sensitivity

18. Network Meta-Analysis (Exploratory League Table)

19. Safety Profile (CT.gov Adverse Events)

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)

R Cross-Validation (metafor v4.8)

Click "Validate" after running the analysis to compare JS engine output against R (metafor).

Auto-Generated Manuscript Text

Click "Generate Output" to create manuscript text.

Scientific Synthesis

Generating Visual Abstract & PRISMA Diagram...

PRISMA 2020 Flow Diagram (SVG)

CTEPH Therapy

Multi-source meta-analysis of landmark RCTs

Patient Population

N = -- Patients

Acquisition Era

Post-2015 Enrollment

Primary HF Composite Result

Odds Ratio [95% CI]

Consistency (I²)

Scientific Verdict

Waiting Room Summary

--/100

NNT Pictogram

--%

Risk Change

Odds Ratio

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 CTEPH Evidence

A quantitative synthesis of landmark randomized trials.

Pooled OR

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 Riociguat CTEPH and related agents vs comparator for 6mwd change chest-1 16wk 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.

GRADE Evidence Profile (Summary of Findings)

Cumulative Meta-Analysis

Click "Run Cumulative" to generate a cumulative meta-analysis ordered by publication year.

Quality Assurance (18 Checks)

Click "Run QA" to execute 18 automated quality checks on the current analysis.

Version Timeline

Generate a report to create the first snapshot.

Data Seal: -- · --