Cardiovascular Atlas
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Sacubitril/valsartan (combination)

A two-ingredient pill, sold as Entresto. PARADIGM-HF tested it, under the name LCZ696, against enalapril in adults with heart failure and an ejection fraction of 40% or less. The trial was stopped early for benefit: fewer people on LCZ696 died from cardiovascular causes or were admitted to hospital for heart failure. Low blood pressure and nonserious angioedema were more common with it.

Also called Sacubitril and valsartan · LCZ696

  • Drug
  • In this atlas

Overview

Technical summary

RxNorm multiple-ingredient concept 1656339 (sacubitril / valsartan). The PARADIGM-HF abstract calls the drug an angiotensin receptor-neprilysin inhibitor (ARNI) and gives its name as LCZ696; the PubMed record indexes LCZ696 as the sacubitril and valsartan drug combination. Novartis sponsored PARADIGM-HF; the study record links to the Novartis organization record.

About this drug

Level
Combination
Mechanism
The PARADIGM-HF abstract calls LCZ696 an angiotensin receptor-neprilysin inhibitor.

Claims and evidence

Context Adults with chronic heart failure and an ejection fraction of 40% or less, on recommended therapy, after a run-in (PARADIGM-HF)

Recipient
Adult
Population
Patients with class II, III or IV heart failure and an ejection fraction of 40% or less, who were taking recommended therapy. The registry says randomization followed a single-blind run-in period of 5 to 10 weeks in which patients took enalapril and then LCZ696, and it gives a minimum age of 18 years. People who could not tolerate the run-in are therefore not in the randomized groups.
Care setting
Not stated in the abstract. The registry record is not read for setting.
Geography
Multinational: the registry lists many countries across the Americas, Europe, Africa and Asia.
Life stage
Adults, 18 years and over (registry minimum age).
Follow-up
Median 27 months at the early stop (abstract).
Eligibility: 3 inclusion criteria; 1 exclusion criterion
Included
  • Heart failure of class II, III or IV
  • Ejection fraction of 40% or less
  • Completed a single-blind run-in on enalapril and LCZ696 (registry arm description)
Excluded
  • Exclusion criteria were not read; the abstract does not list them

  • Effect Interventional Certainty not assessed

    In PARADIGM-HF, adults with class II, III or IV heart failure and an ejection fraction of 40% or less took LCZ696 200 mg twice daily, a combination of sacubitril and valsartan, or enalapril 10 mg twice daily, in addition to recommended therapy. The trial was stopped early, after a median follow-up of 27 months, because the prespecified boundary for overwhelming benefit with LCZ696 had been crossed. At closure, the primary outcome, death from cardiovascular causes or hospitalization for heart failure, had occurred in 914 people (21.8%) in the LCZ696 group and 1117 (26.5%) in the enalapril group (hazard ratio 0.80, 95% CI 0.73 to 0.87). Death from any cause occurred in 711 people (17.0%) and 835 (19.8%) (hazard ratio 0.84, 95% CI 0.76 to 0.93), and death from cardiovascular causes in 558 (13.3%) and 693 (16.5%) (hazard ratio 0.80, 95% CI 0.71 to 0.89). Hypotension and nonserious angioedema were more common with LCZ696; renal impairment, hyperkalemia and cough were less common than with enalapril.

    Applies to Adult
    • Patients with class II, III or IV heart failure and an ejection fraction of 40% or less, who were taking recommended therapy. The registry says randomization followed a single-blind run-in period of 5 to 10 weeks in which patients took enalapril and then LCZ696, and it gives a minimum age of 18 years. People who could not tolerate the run-in are therefore not in the randomized groups.
    • Not stated in the abstract. The registry record is not read for setting.
    • Multinational: the registry lists many countries across the Americas, Europe, Africa and Asia.
    • Adults, 18 years and over (registry minimum age).
    Follow-up Median 27 months at the early stop (abstract).
    Certainty method
    Not assessed
    Limitations
    One double-blind trial funded by Novartis, stopped early for benefit, which can overstate an effect. The comparator was enalapril and not placebo, and the abstract says the trial was designed to detect a difference in deaths from cardiovascular causes while its primary outcome was a composite. The registry says patients first completed a single-blind run-in on enalapril and then LCZ696, so people who could not tolerate either were not randomized. The numbers come from the PubMed abstract; the full text, tables and registry results were not read. The abstract says LCZ696 and does not name sacubitril; the PubMed record indexes LCZ696 as the sacubitril and valsartan drug combination. The abstract gives no counts for the adverse events. No certainty rating was assessed.
    Last checked
    2026-10-14
    Next evidence check due
    Not scheduled
    Sources and citations (9)

    1. Supports Angiotensin-neprilysin inhibition versus enalapril in heart failure

      Publication · The New England journal of medicine · Edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched. · Published 2014-09-11 · DOI: 10.1056/NEJMoa1409077 · PMID: 25176015

      Locator
      Abstract, RESULTS, sentence 1
      How it applies
      The trial was stopped early for overwhelming benefit. Abstract of the paper from PubMed; the full text was not read.
      Retrieved
      Source effective date
      Not reported
      Source state
      Current
      Snapshot hash
      8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4
      Reuse basis
      PubMed record fetched through NCBI E-utilities. Only the hash of the bytes is kept, because publisher copyright may apply to the abstract (https://pubmed.ncbi.nlm.nih.gov/disclaimer/). Short factual quotations under 25 words, with the citation.

    2. Supports Angiotensin-neprilysin inhibition versus enalapril in heart failure

      Publication · The New England journal of medicine · Edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched. · Published 2014-09-11 · DOI: 10.1056/NEJMoa1409077 · PMID: 25176015

      Locator
      Abstract, RESULTS, sentence 2
      How it applies
      Primary outcome counts and hazard ratio. Abstract of the paper from PubMed; the full text was not read.
      Retrieved
      Source effective date
      Not reported
      Source state
      Current
      Snapshot hash
      8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4
      Reuse basis
      PubMed record fetched through NCBI E-utilities. Only the hash of the bytes is kept, because publisher copyright may apply to the abstract (https://pubmed.ncbi.nlm.nih.gov/disclaimer/). Short factual quotations under 25 words, with the citation.

    3. Supports Angiotensin-neprilysin inhibition versus enalapril in heart failure

      Publication · The New England journal of medicine · Edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched. · Published 2014-09-11 · DOI: 10.1056/NEJMoa1409077 · PMID: 25176015

      Locator
      Abstract, RESULTS, sentence 3
      How it applies
      Death from any cause and from cardiovascular causes. Abstract of the paper from PubMed; the full text was not read.
      Retrieved
      Source effective date
      Not reported
      Source state
      Current
      Snapshot hash
      8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4
      Reuse basis
      PubMed record fetched through NCBI E-utilities. Only the hash of the bytes is kept, because publisher copyright may apply to the abstract (https://pubmed.ncbi.nlm.nih.gov/disclaimer/). Short factual quotations under 25 words, with the citation.

    4. Supports Angiotensin-neprilysin inhibition versus enalapril in heart failure

      Publication · The New England journal of medicine · Edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched. · Published 2014-09-11 · DOI: 10.1056/NEJMoa1409077 · PMID: 25176015

      Locator
      Abstract, RESULTS, sentence 5
      How it applies
      Adverse events in each direction. Abstract of the paper from PubMed; the full text was not read.
      Retrieved
      Source effective date
      Not reported
      Source state
      Current
      Snapshot hash
      8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4
      Reuse basis
      PubMed record fetched through NCBI E-utilities. Only the hash of the bytes is kept, because publisher copyright may apply to the abstract (https://pubmed.ncbi.nlm.nih.gov/disclaimer/). Short factual quotations under 25 words, with the citation.

    5. Background Angiotensin-neprilysin inhibition versus enalapril in heart failure

      Publication · The New England journal of medicine · Edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched. · Published 2014-09-11 · DOI: 10.1056/NEJMoa1409077 · PMID: 25176015

      Locator
      Abstract, METHODS, sentence 1
      How it applies
      Who was randomized, the doses and the background therapy. Abstract of the paper from PubMed; the full text was not read.
      Retrieved
      Source effective date
      Not reported
      Source state
      Current
      Snapshot hash
      8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4
      Reuse basis
      PubMed record fetched through NCBI E-utilities. Only the hash of the bytes is kept, because publisher copyright may apply to the abstract (https://pubmed.ncbi.nlm.nih.gov/disclaimer/). Short factual quotations under 25 words, with the citation.

    6. Background Angiotensin-neprilysin inhibition versus enalapril in heart failure

      Publication · The New England journal of medicine · Edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched. · Published 2014-09-11 · DOI: 10.1056/NEJMoa1409077 · PMID: 25176015

      Locator
      Abstract, METHODS, sentence 2
      How it applies
      How the primary outcome was defined. Abstract of the paper from PubMed; the full text was not read.
      Retrieved
      Source effective date
      Not reported
      Source state
      Current
      Snapshot hash
      8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4
      Reuse basis
      PubMed record fetched through NCBI E-utilities. Only the hash of the bytes is kept, because publisher copyright may apply to the abstract (https://pubmed.ncbi.nlm.nih.gov/disclaimer/). Short factual quotations under 25 words, with the citation.

    7. Background Angiotensin-neprilysin inhibition versus enalapril in heart failure

      Publication · The New England journal of medicine · Edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched. · Published 2014-09-11 · DOI: 10.1056/NEJMoa1409077 · PMID: 25176015

      Locator
      Abstract, CONCLUSIONS, sentence 2
      How it applies
      Funding statement and registry number. Abstract of the paper from PubMed; the full text was not read.
      Retrieved
      Source effective date
      Not reported
      Source state
      Current
      Snapshot hash
      8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4
      Reuse basis
      PubMed record fetched through NCBI E-utilities. Only the hash of the bytes is kept, because publisher copyright may apply to the abstract (https://pubmed.ncbi.nlm.nih.gov/disclaimer/). Short factual quotations under 25 words, with the citation.

    8. Background This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure

      Registry · U.S. National Library of Medicine (ClinicalTrials.gov) · Edition ClinicalTrials.gov API v2 record, last update posted 2016-08-15. · NCT: NCT01035255

      Locator
      protocolSection.armsInterventionsModule.armGroups[0].description
      How it applies
      The registry arm description gives the single-blind run-in before randomization.
      Retrieved
      Source effective date
      2016-08-15
      Source state
      Current
      Snapshot hash
      b03ff7af4d62f600eef30fdb79e0e6010be9fc5de1ee648d6903dcf0a5ba8978
      Reuse basis
      Registry record. The raw API JSON is committed at research/snapshots/ce-ctgov-NCT01035255.json. The ClinicalTrials.gov terms page is rendered by JavaScript and its text was not read, so the redistribution basis is unverified. Public text is quote, following Ben's decision of 2026-10-13 (medical-atlas-core issue 2) that registries allow short quotations with attribution. Any quotation stays short.

    9. Background Angiotensin-neprilysin inhibition versus enalapril in heart failure

      Publication · The New England journal of medicine · Edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched. · Published 2014-09-11 · DOI: 10.1056/NEJMoa1409077 · PMID: 25176015

      Locator
      ChemicalList, NameOfSubstance C549068
      How it applies
      PubMed indexes the trial drug as the sacubitril and valsartan drug combination.
      Retrieved
      Source effective date
      Not reported
      Source state
      Current
      Snapshot hash
      8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4
      Reuse basis
      PubMed record fetched through NCBI E-utilities. Only the hash of the bytes is kept, because publisher copyright may apply to the abstract (https://pubmed.ncbi.nlm.nih.gov/disclaimer/). Short factual quotations under 25 words, with the citation.

Context Patients with heart failure with reduced ejection fraction (2022 AHA/ACC/HFSA, as summarized by the ACC)

Recipient
Recipient not specified
Population
Patients with heart failure with reduced ejection fraction, which the ACC summary defines as a left ventricular ejection fraction of 40% or less. The summary gives no age limits.
Care setting
Not stated in the ACC summary.
Geography
Not stated in the ACC summary (issued by American societies; jurisdiction not verified)
Life stage
Not stated in the ACC summary
Gestational age
Not reported
Postnatal age
Not reported
Follow-up
Not applicable (guideline context)
Eligibility: 1 inclusion criterion; exclusion criteria not stated
Included
  • Heart failure with a left ventricular ejection fraction of 40% or less
Excluded
None stated

  • Recommendation Guidance Certainty not assessed

    An ACC summary of the 2022 heart failure guideline of the AHA, ACC and HFSA says an angiotensin receptor-neprilysin inhibitor (ARNI) is now recommended as the first-line renin-angiotensin system inhibitor to reduce illness and death in heart failure with reduced ejection fraction. It prints the class of recommendation as 1a. The summary adds that an ACE inhibitor is recommended when an ARNI is not feasible, and an angiotensin receptor blocker for people who cannot take an ACE inhibitor and when an ARNI is not feasible.

    Source problem. A cited source is corrected. Check the sources before relying on this claim.

    Applies to Recipient not specified
    • Patients with heart failure with reduced ejection fraction, which the ACC summary defines as a left ventricular ejection fraction of 40% or less. The summary gives no age limits.
    • Not stated in the ACC summary.
    • Not stated in the ACC summary (issued by American societies; jurisdiction not verified)
    • Not stated in the ACC summary
    • Gestational age Not reported
    • Postnatal age Not reported
    Follow-up Not applicable (guideline context)
    Certainty method
    Not assessed
    Limitations
    The summary names the ARNI class and not a medicine. Sacubitril/valsartan is the only ARNI recorded in this atlas, and its own page rests on a trial abstract that calls it an ARNI; no source read here names it in the guideline. The class of recommendation is as printed on the ACC page. No recommendation record is written for this statement, because it names the ARNI class and the atlas record is one substance. The source is the ACC summary, not the guideline text. PubMed lists three corrections to the guideline; their text was not read, so it is not known whether they change anything stated here.
    Last checked
    2026-10-15
    Next evidence check due
    Not scheduled
    Sources and citations (4)

    1. Supports 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

      Guideline · Circulation · Edition Published in Circulation 145(18):e895-e1032 (issue date 2022-05-03; electronic publication 2022-04-01). PubMed abstract and bibliographic data only. PubMed lists no PMC copy. The guideline text was not read. PubMed lists 3 corrections to the guideline; their text was not read. The same source also holds a snapshot of the ACC key-perspectives summary page of the guideline (dated Apr 01, 2022), which is an ACC summary and not the guideline text. The recommendation text for this atlas comes from that page. The publisher field is the journal title as PubMed gives it. · Published 2022-05-03 · DOI: 10.1161/CIR.0000000000001063 · PMID: 35363499

      Locator
      Key perspective 2, sentence 2
      How it applies
      ARNI recommended as first-line RASi in HFrEF.
      Retrieved
      Source effective date
      Not reported
      Source state
      Corrected
      Snapshot hash
      9bf3f8d91011b793cc049e80db09ae5624271eb6cdb688f5331c7f8aa1556cad
      Reuse basis
      PubMed record and ACC page. PubMed record fetched through NCBI E-utilities on 2026-10-15. Only the hash of the bytes is kept; nothing is committed. Bibliographic metadata and short quotations from the PubMed abstract, under 25 words each. The full text was not redistributed and the societies' reuse terms were not reviewed. ACC web page fetched with a plain Mozilla/5.0 user agent on 2026-10-15. Only the hash of the bytes is kept; nothing is committed. The ACC's reuse terms were not read, so public text is cite_only: public pages state the summary in the atlas's own words, with a citation and a link, and use no ACC wording. Quote rows are short evidence fragments for the reviewer.

    2. Supports 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

      Guideline · Circulation · Edition Published in Circulation 145(18):e895-e1032 (issue date 2022-05-03; electronic publication 2022-04-01). PubMed abstract and bibliographic data only. PubMed lists no PMC copy. The guideline text was not read. PubMed lists 3 corrections to the guideline; their text was not read. The same source also holds a snapshot of the ACC key-perspectives summary page of the guideline (dated Apr 01, 2022), which is an ACC summary and not the guideline text. The recommendation text for this atlas comes from that page. The publisher field is the journal title as PubMed gives it. · Published 2022-05-03 · DOI: 10.1161/CIR.0000000000001063 · PMID: 35363499

      Locator
      Key perspective 2, sentence 3
      How it applies
      ACE inhibitor or ARB when an ARNI is not feasible.
      Retrieved
      Source effective date
      Not reported
      Source state
      Corrected
      Snapshot hash
      9bf3f8d91011b793cc049e80db09ae5624271eb6cdb688f5331c7f8aa1556cad
      Reuse basis
      PubMed record and ACC page. PubMed record fetched through NCBI E-utilities on 2026-10-15. Only the hash of the bytes is kept; nothing is committed. Bibliographic metadata and short quotations from the PubMed abstract, under 25 words each. The full text was not redistributed and the societies' reuse terms were not reviewed. ACC web page fetched with a plain Mozilla/5.0 user agent on 2026-10-15. Only the hash of the bytes is kept; nothing is committed. The ACC's reuse terms were not read, so public text is cite_only: public pages state the summary in the atlas's own words, with a citation and a link, and use no ACC wording. Quote rows are short evidence fragments for the reviewer.

    3. Background 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

      Guideline · Circulation · Edition Published in Circulation 145(18):e895-e1032 (issue date 2022-05-03; electronic publication 2022-04-01). PubMed abstract and bibliographic data only. PubMed lists no PMC copy. The guideline text was not read. PubMed lists 3 corrections to the guideline; their text was not read. The same source also holds a snapshot of the ACC key-perspectives summary page of the guideline (dated Apr 01, 2022), which is an ACC summary and not the guideline text. The recommendation text for this atlas comes from that page. The publisher field is the journal title as PubMed gives it. · Published 2022-05-03 · DOI: 10.1161/CIR.0000000000001063 · PMID: 35363499

      Locator
      Key perspective 1, classification list (HFrEF)
      How it applies
      HFrEF means an ejection fraction of 40% or less.
      Retrieved
      Source effective date
      Not reported
      Source state
      Corrected
      Snapshot hash
      9bf3f8d91011b793cc049e80db09ae5624271eb6cdb688f5331c7f8aa1556cad
      Reuse basis
      PubMed record and ACC page. PubMed record fetched through NCBI E-utilities on 2026-10-15. Only the hash of the bytes is kept; nothing is committed. Bibliographic metadata and short quotations from the PubMed abstract, under 25 words each. The full text was not redistributed and the societies' reuse terms were not reviewed. ACC web page fetched with a plain Mozilla/5.0 user agent on 2026-10-15. Only the hash of the bytes is kept; nothing is committed. The ACC's reuse terms were not read, so public text is cite_only: public pages state the summary in the atlas's own words, with a citation and a link, and use no ACC wording. Quote rows are short evidence fragments for the reviewer.

    4. Background 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

      Guideline · Circulation · Edition Published in Circulation 145(18):e895-e1032 (issue date 2022-05-03; electronic publication 2022-04-01). PubMed abstract and bibliographic data only. PubMed lists no PMC copy. The guideline text was not read. PubMed lists 3 corrections to the guideline; their text was not read. The same source also holds a snapshot of the ACC key-perspectives summary page of the guideline (dated Apr 01, 2022), which is an ACC summary and not the guideline text. The recommendation text for this atlas comes from that page. The publisher field is the journal title as PubMed gives it. · Published 2022-05-03 · DOI: 10.1161/CIR.0000000000001063 · PMID: 35363499

      Locator
      CommentsCorrectionsList, three ErratumIn entries
      How it applies
      Shows that corrections exist. What they change is unknown.
      Retrieved
      Source effective date
      Not reported
      Source state
      Corrected
      Snapshot hash
      359253a28c2add87ff845ef77e0400c1886971358eacddb04f09833df0707f1f
      Reuse basis
      PubMed record and ACC page. PubMed record fetched through NCBI E-utilities on 2026-10-15. Only the hash of the bytes is kept; nothing is committed. Bibliographic metadata and short quotations from the PubMed abstract, under 25 words each. The full text was not redistributed and the societies' reuse terms were not reviewed. ACC web page fetched with a plain Mozilla/5.0 user agent on 2026-10-15. Only the hash of the bytes is kept; nothing is committed. The ACC's reuse terms were not read, so public text is cite_only: public pages state the summary in the atlas's own words, with a citation and a link, and use no ACC wording. Quote rows are short evidence fragments for the reviewer.

Clinical links

Each link reports what one cited claim says about one population. "Evaluated for" means studied, not shown to work. These links do not show that anything is effective or right for you.

Record details

Record id
cardio:sacubitril-valsartan
Content hash
b395ff7a749a936281944b6558989a959167be730e52f394c7ae3c2d9e657f42