Systematic Review Protocol
Retrospective Public Protocol Pack (OSF-ready) — PRISMA 2020 & AMSTAR 2 aligned
1. Registration & Administrative Information [PRISMA #24, AMSTAR #2]
| Review Title | Sacubitril/Valsartan for Heart Failure: A Living Systematic Review and Meta-Analysis of Randomized Controlled Trials |
| Protocol Version | v12.0 (Living Protocol — auto-updating) |
| Protocol Freeze Date | 2026-03-10 |
| 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 |
2. Review Question — PICO Framework [PRISMA #3, AMSTAR #1]
| Population | |
| Intervention | |
| Comparator | |
| Primary Outcome | |
| Secondary Outcomes | All-cause mortality; CV death; HF hospitalization; renal composite; quality of life |
| 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 >=18 years with HFrEF, HFpEF, or recent MI with LV dysfunction | Healthy volunteers, paediatric, animal/in-vitro |
| Intervention | Sacubitril/Valsartan (any dose) as primary experimental drug | Sacubitril/valsartan 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 post-2015; 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=sacubitril AND valsartan&pageSize=100&filter.overallStatus=COMPLETED | Registry (API v2) |
| PubMed (Europe PMC) | sacubitril valsartan AND (TITLE:randomized OR PUB_TYPE:"Randomized Controlled Trial" OR PUB_TYPE:"Clinical Trial") AND SRC:MED | Bibliographic (REST) |
| OpenAlex | search=sacubitril valsartan&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 | Sacubitril/Valsartan 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 | DerSimonian-Laird random-effects (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−2 (Higgins 2009) | Analysis → Stats |
| Heterogeneity | Cochran Q (p-value), I² (%), τ² (DL estimator) | Analysis → Stats |
| Subgroup Analysis | By indication (HF vs CKD); 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
Polling sources...
ClinicalTrials.gov
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PubMed
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OpenAlex
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After Dedup
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Search Strings Used
ClinicalTrials.gov API v2
https://clinicaltrials.gov/api/v2/studies?query.intr=sacubitril AND valsartan&pageSize=100&filter.overallStatus=COMPLETED
Europe PMC (PubMed mirror)
sacubitril valsartan AND (TITLE:randomized OR PUB_TYPE:"Randomized Controlled Trial" OR PUB_TYPE:"Clinical Trial") AND SRC:MED
OpenAlex API
search=sacubitril valsartan&filter=concepts.id:C71924100&per_page=50
Saved Search Log
No searches recorded yet.
Review Queue: 0
N/P = nav | C = confirm
Extraction & Source Verification
Provisional RoB-2 and GRADE โ AI-drafted from the record excerpts; authors confirm each domain against those excerpts before submission (Protocol ยง7 and ยง9)
Interactive truth capture with highlighted registry denominators.
View:
Add Study Manually
Audit Log
0
No actions recorded yet.
RoB Legend (click to cycle):
Low
Some concerns
High
Pooled Primary Effect (HR/RR)
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Precision (95% CI)
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Heterogeneity (Iยฒ)
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HKSJ-Adjusted CI
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Prediction Interval
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Q-test (Cochran)
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ฯยฒ (95% CI)
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Bayesian CrI
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P(OR < 1)
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Information Fraction
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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 โ verify against published manuscripts before finalizing.
Precision Analytics Suite
1. Forest Plot (Fixed/Random Effects)
Transportability & External Validity
2. Subgroup Synthesis (HF vs CKD)
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 loadedRuns metafor::rma() directly in your browser via WebAssembly. No server needed. First load installs R + metafor (~20-40s).
◠
Initializing R...
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.
Auto-Generated Manuscript Text
Click "Generate Output" to create manuscript text.
Scientific Synthesis
Generating Visual Abstract & PRISMA Diagram...
Sacubitril/Valsartan in Heart Failure
Multi-source meta-analysis of landmark RCTs
Patient Population
N = -- Patients
Acquisition Era
Post-2015 Enrollment
Primary MACE Result
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Primary Effect [95% CI]
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Consistency (Iยฒ)
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Scientific Verdict
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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 = --)
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Records removed before screening
Duplicates / Ineligible
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Duplicates / Ineligible
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Records screened
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Records excluded
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Other Sources
Records from PubMed
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Records from OpenAlex
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Reference-checked trials
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Reports assessed for eligibility
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Reports excluded
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Included in synthesis
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The Sacubitril/Valsartan Evidence
A quantitative synthesis of landmark randomized trials.
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Pooled Effect
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NNT
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Iยฒ Heterogeneity
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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. โ 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 the registered primary continuous outcome (random-effects, DL estimator)
Summary of Findings
| Outcome | No. Trials | Total N | Effect (OR) | 95% CI | Iยฒ | 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
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Integrity
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Evidence
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Risk
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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
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Extraction Dual Coverage
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Reviewers Logged
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Active Reviewer Pairs
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Capture Note
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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
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Protocol / SAP
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Ghost / Lag Signals
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Bridge / Drift
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Capture Note
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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 sacubitril/valsartan 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 sacubitril/valsartan pooled analyses.
PRISMA 2020 Flow Diagram (SVG)
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.
Reproducibility Artifact
Frozen analysis fingerprint linking search scope, included trials, pooled result, threat ledger, and data seal.
Fingerprint
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Analysis Scope
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Search Coverage
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Included Trials
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Threat Ledger
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Audit Tail
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Data Seal: -- · --