Sacubitril/valsartan vs ACE inhibitor or ARB for cardiovascular death or heart-failure hospitalization in HFrEF

Overview

Sacubitril/valsartan vs ACE inhibitor or ARB for cardiovascular death or heart-failure hospitalization in HFrEF

In adults with heart failure with reduced ejection fraction, does sacubitril/valsartan reduce the composite of cardiovascular death or heart-failure hospitalization versus an ACE inhibitor or ARB? (Double-blind active-controlled RCTs.)

Primary outcome

Transparency (independently checkable)

9 of 9 numerical claims on this page (100%) carry a one-click source a reader can open to check independently — each pooled number its PMID/NCT and verbatim span, each declared-absent trial its reason, each risk-of-bias domain the structured field it read, the reproduction its protocol SHA and replay result. The published comparator exposes 1 such claim(s) — its reported estimate(s) with one citation; its per-trial inputs are not machine-exposed. Score: scripts/transparency_score.py (committed docs/transparency.json).

Stated limitations

• Small k on many topics. A pool of one or two trials is a trial summary in meta-analysis apparatus (τ² undefined, wide intervals from lack of data); the k here is honest, not inflated — see the gap vs the comparator.
• Open-access comparator only. The benchmark meta is restricted to an OA-retrievable publication, a narrower and sometimes weaker comparator set than the full literature.
• Comparator scope mismatch. comparator is a DRUG-CLASS meta-analysis while this topic is a single agent — a PICO scope mismatch (single-drug review vs class-level review); the k difference vs this comparator is a scope difference, not unretrieved evidence
• Favourable topic sample. Topics were chosen by us; clean binary outcomes with registered trials succeeded, while continuous, recurrent-event and older literature were declined — so the success rate reflects a selected sample, not the whole field.
• Risk of bias is partial. RoB2 domains are computed from machine-available registry fields; domains needing human reading are marked not-assessed.
• Registry snapshot is dated. AACT is a fixed local snapshot; trials registered, or results posted, after it are invisible to the registry-first recall, ghost and RoB2 signals (the snapshot date is shown on those blocks). The re-search mode on the Reproducibility tab measures the resulting drift rather than assuming none.
• Dual screening is not fully independent. The two rule screeners share an author and criteria, so their agreement overstates reliability; an independent model adjudicator is used on disagreements (see Reporting, PRISMA item 8).
• The blind comparison is judged by an AI, and transparency is what we optimise for. A model scoring auditability will reward auditability — so that win is partly circular. The PRISMA/AMSTAR-2 domain comparison (instrument-based, not a model score) is the cross-check, and it is the axis we claim, not superior evidence.

Protocol

# Protocol - sacubitril/valsartan for cardiovascular death or heart-failure hospitalization in HFrEF

**Registration.** The commit that adds/updates this file is the registration of this
review; its SHA is embedded in the page's Protocol tab and its Reproducibility tab.
Committed BEFORE the synthesis is run.

## PICO
- **P** - adults with heart failure with reduced ejection fraction (HFrEF).
- **I** - sacubitril/valsartan, also reported as sacubitril, LCZ696, or ARNI.
- **C** - an ACE inhibitor or ARB active comparator, usually enalapril; ramipril is also eligible where used as the active renin-angiotensin-system comparator.
- **O (primary)** - composite cardiovascular death or heart-failure hospitalization.
- **O (secondary)** - cardiovascular death; heart-failure hospitalization.
- **O (harms)** - hypotension; hyperkalemia.

## Eligibility - on P/I/C/DESIGN ONLY
Include a record iff **all** hold:
- **P** - adult HFrEF / reduced-ejection-fraction heart-failure population, judged from title or registry conditions.
- **I** - sacubitril/valsartan, sacubitril, LCZ696, ARNI, or a title-level angiotensin-neprilysin-inhibition phrase.
- **C** - enalapril, ACE inhibitor, ARB, ramipril, or another explicit RAS-inhibitor active comparator. Standalone valsartan text inside sacubitril/valsartan does not satisfy this criterion.
- **Design** - randomized, double-blind active-controlled trial.

Eligibility is not on the outcome axis. Whether an included trial reports the primary
composite, or gives a 2x2 table versus only an effect plus CI, is recorded as target-result
status at extraction and is never an exclusion.

## Outcomes
- **Primary** - composite cardiovascular death or heart-failure hospitalization, estimand HR, intention-to-treat population, trial end / longest randomized follow-up.
- **Secondary** - cardiovascular death; heart-failure hospitalization, estimand HR where reported.
- **Harms** - hypotension; hyperkalemia, estimand RR when arm-level counts are extractable.

## Analysis Method
Random-effects inverse-variance on the configured log ratio scale; for the primary outcome
this is log(HR) when an abstract-reported HR with 95% CI is machine-extractable. Paule-Mandel
tau^2; HKSJ 95% CI on `t_{k-1}` with variance floor `max(1, Q/(k-1))`; prediction interval
`mu +/- t_{k-1}*sqrt(tau^2+se^2)`. If only one trial reports the outcome, the estimate is
reported as that trial's own effect, with no tau^2, HKSJ interval, or prediction interval.

## Comparator
Ji et al., *ESC Heart Failure* 2023, "The cardiovascular effects of SGLT2 inhibitors,
RAS inhibitors, and ARN inhibitors in heart failure" (PMID 36722326, DOI
10.1002/ehf2.14298; open access with PMC10053170 available). The comparator is a published
network meta-analysis of randomized trials and reports the assigned HFrEF composite endpoint
for ARNI versus RAS inhibitors as RR 0.83 (95% CI 0.77-0.89).

Search

Source status (which adapters ran)

Citation chase: NOT_RUN · ClinicalTrials.gov: RAN_OK · Europe PMC (OA + metadata): RAN_OK · PMC full text: NOT_RUN · PubMed: RAN_OK · Registry-first (AACT): NOT_RUN — RAN_OK = ran and returned records; RAN_ZERO = ran, none matched; RAN_ERROR = attempted but failed; NOT_RUN = not attempted for this topic.

PubMed

25176015[uid]

"Angiotensin-neprilysin inhibition versus enalapril in heart failure"[Title]

"PARADIGM-HF"[Title/Abstract] LCZ696 enalapril

ClinicalTrials.gov

{"cond": "Heart Failure With Reduced Ejection Fraction", "intr": "LCZ696"}

Screening

Study selection flow (PRISMA 2020)

Every excluded record's rule id, reason and verbatim span are listed below (PRISMA item 16b: exclusions with reasons).

Dual independent screening (PRISMA item 8)

Two independently-implemented rule screeners over 81 records: agreement 80/81, disagreement 1.2% (1 records). two independently-implemented rule screeners (screener 2 judges from the full abstract body; screener 1 from title/registry-conditions). Adjudicator: screener 1. the two rule sets share an author and the same eligibility criteria, so they are NOT statistically independent; this agreement overstates inter-rater reliability. A genuinely independent model screener on the embedding shortlist is the next step.

Trial integrity: none of the 1 trials pooled across all outcomes on this page is retracted (checked 2026-09-11T23:50:13Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

81 records screened; 7 included. Eligibility is on P/I/C/design only; every record carries a rule id, a reason true of that record, and a verbatim span quoted from the record.

Controls

• Positive: Recovered & included the canonical trials ['25176015'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['31475794'] recovered by the search and correctly EXCLUDED ['31475794'] by rule (same drug/design, wrong topic).

Results

Composite cardiovascular death or heart-failure hospitalization (primary)

k = 1: the 1 trial(s) named below were pooled; 6 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Comparator

Composite cardiovascular death or heart-failure hospitalization versus RAS inhibitors in HFrEF: 0.83 (RR), 95% CI 0.77–0.89

Scope match (is this the same question?)

⚠ SCOPE MISMATCH. Intervention level: topic is a single agent, comparator is class-level (match: False); population match: True. comparator is a DRUG-CLASS meta-analysis while this topic is a single agent — a PICO scope mismatch (single-drug review vs class-level review); the k difference vs this comparator is a scope difference, not unretrieved evidence Decided by one uniform rule applied to every topic before the k was seen.

Comparator resolution. Single-drug review vs a multi-class comparator (SCOPE MISMATCH, stated): the only available open-access comparator (PMID 36722326) is a network meta-analysis across SGLT2 inhibitors, RAS inhibitors and ARNIs, not a sacubitril-specific pairwise meta. No same-scope sacubitril-vs-ACEi/ARB meta exists because PARADIGM-HF is the single pivotal HFrEF RCT, so k=1 (PARADIGM-HF) is the COMPLETE single-drug HFrEF evidence, not a gap. Component/harm secondaries were dropped rather than shipped ambiguous (see refusals).

Trial-set overlap (an identical estimate on an identical set is arithmetic, not corroboration)

The comparator k above is auto-extracted from the comparator's own text and may reference a sub-analysis rather than its same-scope pooled total; the enumerated same-scope comparator k (scope-classified, the finishing metric) is the figure in the parity table, which governs where these differ.

Risk of bias

Coverage: 0 of 1 primary-outcome pooled trials have a registry (AACT) match and are assessed below; the other 1 are pooled but have no registry match (25176015) and are shown as not assessed with the reason — never guessed.

Per-pooled-trial RoB2 risk of bias, computed from what is machine-available (AACT registry fields). Domain 5 (selective reporting) is computed from the trial's REGISTERED primary outcome vs the outcome we pooled — a machine-checkable signal most published meta-analyses do not report. D1/D2/D4 use AACT structured allocation/masking fields. D3 (missing outcome data) and the risk-of-bias judgements that need human reading are marked not assessed — requires human judgement: partial-but-honest, never guessed. Hover a cell for its basis.

Risk-of-bias sensitivity (re-pooled with the same estimator)

GRADE certainty (partial, object-derived)

Manuscript

Abstract

Question. In adults with heart failure with reduced ejection fraction, does sacubitril/valsartan reduce the composite of cardiovascular death or heart-failure hospitalization versus an ACE inhibitor or ARB? (Double-blind active-controlled RCTs.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 3fb64a1e0143); a registry-first search was screened by two independent rule screeners with adjudication (81 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. A single eligible trial contributed an extractable estimate: HR 0.8 (95% CI 0.73 to 0.87); with k=1 no between-trial heterogeneity or prediction interval is estimable. 6 eligible trial(s) were declared absent for this outcome (reported reason on each).

Certainty. Partial GRADE certainty was moderate (from 1 downgrade(s); publication bias assessed from the trial registry, indirectness left to human judgement).

Methods

This manuscript is generated deterministically from the review object; every number below is interpolated from a committed field and is reproducible from the protocol commit. The protocol (SHA 3fb64a1e0143) was committed before any synthesis ran. Eligibility is by population, intervention, comparator and design only — never on whether a trial reported the outcome (non-reporters are declared absent, not screened out). Two independently implemented rule screeners ran with adjudication. Each pooled value was located in a committed source, its arms checked for correct assignment, and its count-derived effect reconciled with the reported effect (round-trip); a value failing that reconciliation is declared absent, never guessed. Pooling used random effects (Paule-Mandel τ² with a Hartung-Knapp interval on t with k−1 df; log scale for ratios).

Results

A single eligible trial contributed an extractable estimate: HR 0.8 (95% CI 0.73 to 0.87); with k=1 no between-trial heterogeneity or prediction interval is estimable.

Risk-of-bias sensitivity. 0 of 1 pooled trials carry a risk-of-bias rating; no trial is rated high risk. a low-risk-only subpool was not estimable.

Limitations

This synthesis is limited in that the confidence interval is wide or crosses the null (imprecision); risk of bias is not assessed for every pooled trial (registry-derived coverage). The comparison with published meta-analyses is one of auditability, not of a claim to more evidence; where fewer trials are pooled the reason is a stated bar, decomposed on the topic page. Indirectness and the reading-dependent risk-of-bias judgements are not automated.

Data availability & reproduction

The committed cache, protocol (SHA 3fb64a1e0143) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py sacubitril-valsartan-hfref

Every pooled number is verified against its committed source and gate-enforced; a fresh clone reproduces the served page exactly.

Reporting (PRISMA)

Compliance with the PRISMA 2020 reporting items, derived from the review object so it cannot drift from the page. Every item is rendered or declared absent with a reason.

Reproducibility

Verified but not pooled (refusals, with reasons)

Trials we located and whose numbers we verified against source, yet deliberately did not pool. Honest k over inflated k: a named refusal is a result.