# Sacubitril/valsartan (combination) Drug · id `cardio:sacubitril-valsartan` · Cardiovascular Atlas · release `5dcd9b263fe17744` (public) > General information from published sources, not medical advice, and not reviewed by clinicians. Check the cited source before relying on anything here. The atlas's own text and curation may be reused under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0, https://creativecommons.org/licenses/by-nc/4.0/): credit the atlas, and do not use it commercially. See the atlas About page. Text quoted from a source stays under that source's own terms, given as the source's reuse\_basis. The atlas's reuse terms do not cover it. The downloads list each quotation with its source in third\_party\_quotations. Also called: Sacubitril and valsartan; LCZ696 Browse, organ or system: Heart Browse, condition area: Heart failure ## In plain language 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. ## 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. ## Claims, with the population each applies to ## Context: People whose heart failure has a reduced ejection fraction (2022 AHA/ACC/HFSA, as summarized by the ACC) Recipient: Recipient not specified; Population: People whose heart failure has a 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) ### 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. - Category: Recommendation - Evidence stage: Guidance - Certainty: Certainty not assessed - Applies to: Recipient: Recipient not specified; Population: People whose heart failure has a 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) - 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 - Source problem: a cited source is corrected. Check the sources before relying on this claim. - Sources: 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, 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.) Locator: Key perspective 2, sentence 2. Retrieved 2026-10-15T13:50:22Z. Source state: Corrected. Snapshot hash: 9bf3f8d91011b793cc049e80db09ae5624271eb6cdb688f5331c7f8aa1556cad. How it applies: ARNI recommended as first-line RASi in HFrEF. 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, 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.) Locator: Key perspective 2, sentence 3. Retrieved 2026-10-15T13:50:22Z. Source state: Corrected. Snapshot hash: 9bf3f8d91011b793cc049e80db09ae5624271eb6cdb688f5331c7f8aa1556cad. How it applies: ACE inhibitor or ARB when an ARNI is not feasible. 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, 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.) Locator: Key perspective 1, classification list (HFrEF). Retrieved 2026-10-15T13:50:22Z. Source state: Corrected. Snapshot hash: 9bf3f8d91011b793cc049e80db09ae5624271eb6cdb688f5331c7f8aa1556cad. How it applies: HFrEF means an ejection fraction of 40% or less. 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, 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.) Locator: CommentsCorrectionsList, three ErratumIn entries. Retrieved 2026-10-15T13:48:58Z. Source state: Corrected. Snapshot hash: 359253a28c2add87ff845ef77e0400c1886971358eacddb04f09833df0707f1f. How it applies: Shows that corrections exist. What they change is unknown. ## 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). ### 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. - Category: Effect - Evidence stage: Interventional - Certainty: Certainty not assessed - Applies to: 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). - 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 - Sources: 1. Supports: Angiotensin-neprilysin inhibition versus enalapril in heart failure (Publication, edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched.) Locator: Abstract, RESULTS, sentence 1. Retrieved 2026-10-14T18:18:45Z. Source state: Current. Snapshot hash: 8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4. How it applies: The trial was stopped early for overwhelming benefit. Abstract of the paper from PubMed; the full text was not read. 2. Supports: Angiotensin-neprilysin inhibition versus enalapril in heart failure (Publication, edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched.) Locator: Abstract, RESULTS, sentence 2. Retrieved 2026-10-14T18:18:45Z. Source state: Current. Snapshot hash: 8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4. How it applies: Primary outcome counts and hazard ratio. Abstract of the paper from PubMed; the full text was not read. 3. Supports: Angiotensin-neprilysin inhibition versus enalapril in heart failure (Publication, edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched.) Locator: Abstract, RESULTS, sentence 3. Retrieved 2026-10-14T18:18:45Z. Source state: Current. Snapshot hash: 8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4. How it applies: Death from any cause and from cardiovascular causes. Abstract of the paper from PubMed; the full text was not read. 4. Supports: Angiotensin-neprilysin inhibition versus enalapril in heart failure (Publication, edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched.) Locator: Abstract, RESULTS, sentence 5. Retrieved 2026-10-14T18:18:45Z. Source state: Current. Snapshot hash: 8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4. How it applies: Adverse events in each direction. Abstract of the paper from PubMed; the full text was not read. 5. Background: Angiotensin-neprilysin inhibition versus enalapril in heart failure (Publication, edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched.) Locator: Abstract, METHODS, sentence 1. Retrieved 2026-10-14T18:18:45Z. Source state: Current. Snapshot hash: 8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4. How it applies: Who was randomized, the doses and the background therapy. Abstract of the paper from PubMed; the full text was not read. 6. Background: Angiotensin-neprilysin inhibition versus enalapril in heart failure (Publication, edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched.) Locator: Abstract, METHODS, sentence 2. Retrieved 2026-10-14T18:18:45Z. Source state: Current. Snapshot hash: 8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4. How it applies: How the primary outcome was defined. Abstract of the paper from PubMed; the full text was not read. 7. Background: Angiotensin-neprilysin inhibition versus enalapril in heart failure (Publication, edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched.) Locator: Abstract, CONCLUSIONS, sentence 2. Retrieved 2026-10-14T18:18:45Z. Source state: Current. Snapshot hash: 8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4. How it applies: Funding statement and registry number. Abstract of the paper from PubMed; the full text was not read. 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, edition ClinicalTrials.gov API v2 record, last update posted 2016-08-15.) Locator: protocolSection.armsInterventionsModule.armGroups\[0\].description. Retrieved 2026-10-14T18:18:42Z. Source state: Current. Snapshot hash: b03ff7af4d62f600eef30fdb79e0e6010be9fc5de1ee648d6903dcf0a5ba8978. How it applies: The registry arm description gives the single-blind run-in before randomization. 9. Background: Angiotensin-neprilysin inhibition versus enalapril in heart failure (Publication, edition PubMed record (abstract and bibliographic data) from NCBI E-utilities. The full text and the version of record were not fetched.) Locator: ChemicalList, NameOfSubstance C549068. Retrieved 2026-10-14T18:18:45Z. Source state: Current. Snapshot hash: 8df25f03ed91739238d89bd55142cb9ea4eea56f61a0b38be60a0047662736b4. How it applies: PubMed indexes the trial drug as the sacubitril and valsartan drug combination. ## Connected pages - PARADIGM-HF: lower rate of cardiovascular death or hospitalization for heart failure than enalapril: Heart failure with reduced ejection fraction (HFrEF) (`cardio:hfref`) [a claim, not a settled fact; see claim `cardio:claim-paradigm-hf-primary-effect` and its context] - Files under this front: Medicines (`cardio:front-medicines`) - Contained in: Sacubitril/valsartan (Entresto) (`cardio:entresto`) - Investigated in: PARADIGM-HF (`cardio:paradigm-hf`) ## Provenance Content hash: 0e27d3301c858347e89a59c3a55345565de31cb24d5df3db19767b07383f8872 Last substantive edit: 2026-10-14 Evidence last checked: 2026-10-14