sacubitril/valsartan

Sacubitril/valsartan can be used instead of an ACE inhibitor or an angiotensin receptor blocker in people with heart failure and a reduced left ventricular ejection fraction (LVEF),{{cite journal | vauthors = Chang HY, Chen KC, Fong MC, Feng AN, Fu HN, Huang KC, Chong E, Yin WH | title = Recovery of left ventricular dysfunction after sacubitril/valsartan: predictors and management | journal = Journal of Cardiology | volume = 75 | issue = 3 | pages = 233–241 | date = March 2020 | pmid = 31563433 | doi = 10.1016/j.jjcc.2019.08.005 | doi-access = free }} alongside other standard therapies (e.g. beta-blockers) for heart failure. To investigate its use for heart failure in those with a preserved LVEF (HFpEF), Novartis funded the PARAGON-HF trial which was designed to investigate the use of sacubitril/valsartan in the treatment of HFpEF patients with a LVEF of 45% or more. Concluding in 2019, it failed to show significance for reducing hospitalisation related to heart failure or reducing death from cardiovascular causes, and therefore appearing to show limited benefit to those with HFpEF.{{cite journal | vauthors = Solomon SD, McMurray JJ, Anand IS, Ge J, Lam CS, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Düngen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP | title = Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction | journal = The New England Journal of Medicine | volume = 381 | issue = 17 | pages = 1609–1620 | date = October 2019 | pmid = 31475794 | doi = 10.1056/NEJMoa1908655 | doi-access = free | hdl = 2445/175935 | hdl-access = free }}

There is moderate evidence to suggest that treating people with HFpEF using MRA and ARNI may reduce the rate of people being hospitalized due to heart failure, however, there is no evidence that this type of treatment improves the person's quality of life or rate of survival due to cardiovascular disease.{{cite journal | vauthors = Martin N, Manoharan K, Davies C, Lumbers RT | title = Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 5 | pages = CD012721 | date = May 2021 | pmid = 34022072 | pmc = 8140651 | doi = 10.1002/14651858.CD012721.pub3 }} Evidence is lacking to support the use of ACE Inhibitors, ARBs or ARNIs in people with HFpEF at this time, and that the mainstay pharmacological therapy for HFpEF still remains the treatment of co-morbidities such as hypertension or other triggers for decompensation. Patients who exhibit symptoms of NYHA Class II or III heart failure and are still symptomatic despite maximally tolerated dose of an ACE inhibitor or ARB alone, may be considered for sacubitril/valsartan dual therapy to decrease the risk of cardiovascular-related and all-cause mortality. Mortality benefits have only been observed to date in those with LVEF less than 35%.

Common adverse effects [>1%] include hyperkalaemia [high potassium levels in the blood, a known side effect of Valsartan], hypotension [low blood pressure, common in vasodilators and extracellular fluid volume reducers], a persistent dry cough and renal impairment [reduced kidney function].{{cite journal | vauthors = McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR | title = Angiotensin-neprilysin inhibition versus enalapril in heart failure | journal = The New England Journal of Medicine | volume = 371 | issue = 11 | pages = 993–1004 | date = September 2014 | pmid = 25176015 | doi = 10.1056/NEJMoa1409077 | hdl-access = free | hdl = 2336/552372 | s2cid = 11383 }}{{cite journal | vauthors = Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E | title = Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure | journal = The New England Journal of Medicine | volume = 380 | issue = 6 | pages = 539–548 | date = February 2019 | pmid = 30415601 | doi = 10.1056/NEJMoa1812851 | s2cid = 53280900 | doi-access =free }}

Angioedema, a rare but more serious reaction, can occur in some patients [<1%] and involves swelling of the face and lips. Angioedema is more common in black (African American) patients. Sacubitril/Valsartan should not be taken within 36 hours of an Angiotensin Converting Enzyme Inhibitor to reduce the risk of developing Angioedema.

The side effect profile in trials of sacubitril/valsartan compared to valsartan alone or enalapril [an angiotensin converting enzyme inhibitor] is very similar, with the incidence of hypotension slightly higher in sacubitril/valsartan, the risk comparable for angioedema, and the chance of hyperkalaemia, renal impairment and cough slightly lower.

Sacubitril/valsartan is contraindicated in pregnancy because it contains valsartan, a known risk for birth defects.{{cite web | title=Entresto- sacubitril and valsartan tablet, film coated | website=DailyMed | date=14 June 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=000dc81d-ab91-450c-8eae-8eb74e72296f | access-date=21 September 2020 | archive-date=19 April 2020 | archive-url=https://web.archive.org/web/20200419215543/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=000dc81d-ab91-450c-8eae-8eb74e72296f | url-status=live }}

Valsartan blocks the angiotensin II receptor type 1 (AT₁). This receptor is found on both vascular smooth muscle cells, and on the zona glomerulosa cells of the adrenal gland which are responsible for aldosterone secretion. In the absence of AT₁ blockade, angiotensin causes both direct vasoconstriction and adrenal aldosterone secretion, the aldosterone then acting on the distal tubular cells of the kidney to promote sodium reabsorption which expands extracellular fluid (ECF) volume. Blockade of (AT₁) thus causes blood vessel dilation and reduction of ECF volume.{{cite book| vauthors = Mutschler E, Schäfer-Korting M |title=Arzneimittelwirkungen|language=de|location=Stuttgart|publisher=Wissenschaftliche Verlagsgesellschaft|year=2001|edition=8|page=579|isbn=978-3-8047-1763-3 }}{{cite journal | vauthors = Zouein FA, de Castro Brás LE, da Costa DV, Lindsey ML, Kurdi M, Booz GW | title = Heart failure with preserved ejection fraction: emerging drug strategies | journal = Journal of Cardiovascular Pharmacology | volume = 62 | issue = 1 | pages = 13–21 | date = July 2013 | pmid = 23714774 | pmc = 3724214 | doi = 10.1097/FJC.0b013e31829a4e61 }}

Sacubitril is a prodrug that is activated to sacubitrilat (LBQ657) by de-ethylation via esterases.{{cite web|url=http://spo.escardio.org/eSlides/view.aspx?eevtid=46&fp=13|title=HFpEF in the Future: New Diagnostic Techniques and Treatments in the Pipeline|vauthors=Solomon SD|location=Boston|page=48|access-date=26 January 2012|archive-date=12 September 2014|archive-url=https://web.archive.org/web/20140912012635/http://spo.escardio.org/eSlides/view.aspx?eevtid=46&fp=13|url-status=live}} Sacubitrilat inhibits the enzyme neprilysin,{{cite journal | vauthors = Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, Maahs S, Ksander G, Rigel DF, Jeng AY, Lin TH, Zheng W, Dole WP | title = Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) | journal = Journal of Clinical Pharmacology | volume = 50 | issue = 4 | pages = 401–414 | date = April 2010 | pmid = 19934029 | doi = 10.1177/0091270009343932 | s2cid = 24853279 }} a neutral endopeptidase that degrades vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Thus, sacubitril increases the levels of these peptides, causing blood vessel dilation and reduction of ECF volume via sodium excretion.{{cite news| vauthors = Schubert-Zsilavecz M, Wurglics M |title=Neue Arzneimittel 2010/2011|language=de }}

Despite these actions, neprilysin inhibitors have been found to have limited efficacy in the treatment of hypertension and heart failure when taken on their own.{{cite journal | vauthors = Bevan EG, Connell JM, Doyle J, Carmichael HA, Davies DL, Lorimer AR, McInnes GT | title = Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension | journal = Journal of Hypertension | volume = 10 | issue = 7 | pages = 607–613 | date = July 1992 | pmid = 1321186 | doi = 10.1097/00004872-199207000-00002 | s2cid = 23507064 }}{{cite journal | vauthors = Richards AM, Wittert GA, Crozier IG, Espiner EA, Yandle TG, Ikram H, Frampton C | title = Chronic inhibition of endopeptidase 24.11 in essential hypertension: evidence for enhanced atrial natriuretic peptide and angiotensin II | journal = Journal of Hypertension | volume = 11 | issue = 4 | pages = 407–416 | date = April 1993 | pmid = 8390508 | doi = 10.1097/00004872-199304000-00011 | s2cid = 25333484 }} This is attributed to a reduction in enzymatic breakdown of angiotensin II by the reduction of neprilysin activity, which results in an increase in systemic angiotensin II levels and the negation of the positive effects of this drug family in cardiovascular disease treatment. Combined treatment with a neprilysin inhibitor and an angiotensin converting enzyme (ACE) inhibitor has been shown to be effective in reducing angiotensin II levels, and demonstrated superiority in lowering blood pressure compared to ACE inhibition alone.{{cite journal | vauthors = Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E | title = Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial | journal = American Journal of Hypertension | volume = 17 | issue = 2 | pages = 103–111 | date = February 2004 | pmid = 14751650 | doi = 10.1016/j.amjhyper.2003.09.014 | doi-access = free }} However, due to an increase in bradykinins from the inhibition of both ACE and neprilysin, there was a threefold increase in relative risk of angioedema compared with ACE inhibition alone following this combination treatment. The combination of a neprilysin inhibitor with an angiotensin receptor blocker instead of the ACE inhibitor has been shown to have a comparable risk of angioedema, whilst also demonstrating superiority in treating moderate-severe heart failure to ACE inhibitor treatment.

Neprilysin also has a role in clearing the protein amyloid beta from the cerebrospinal fluid, and its inhibition by sacubitril has shown increased levels of AB_1-38 in healthy subjects (Entresto 194/206 for two weeks). Amyloid beta is considered to contribute to the development of Alzheimer's disease, and there exist concerns that sacubitril may promote the development of Alzheimer's disease.{{cite journal | vauthors = Patel N, Gluck J | title = Is Entresto good for the brain? | journal = World Journal of Cardiology | volume = 9 | issue = 7 | pages = 594–599 | date = July 2017 | pmid = 28824789 | pmc = 5545143 | doi = 10.4330/wjc.v9.i7.594 | doi-access = free }}

Sacubitril is the molecule that is metabolically activated by de-ethylation by esterases. The active form of the molecule, sacubitrilat, is responsible for the molecule's drug lowering effects.{{cite journal |vauthors=Abdin A, Schulz M, Riemer U, Hadëri B, Wachter R, Laufs U, Bauersachs J, Kindermann I, Vukadinović D, Böhm M |title=Sacubitril/valsartan in heart failure: efficacy and safety in and outside clinical trials |journal=ESC Heart Fail |volume= 9|issue= 6|pages= 3737–3750|date=August 2022 |pmid=35921043 |doi=10.1002/ehf2.14097 |pmc=9773772 |url=}}

Sacubitril/valsartan is co-crystallized sacubitril and valsartan, in a one-to-one molar ratio. One sacubitril/valsartan complex consists of six sacubitril anions, six valsartan dianions, 18 sodium cations, and 15 molecules of water, resulting in the molecular formula C₂₈₈H₃₃₀N₃₆Na₁₈O₄₈·15H₂O and a molecular mass of 5748.03 g/mol.{{cite journal | vauthors = Monge M, Lorthioir A, Bobrie G, Azizi M | title = New drug therapies interfering with the renin-angiotensin-aldosterone system for resistant hypertension | journal = Journal of the Renin-Angiotensin-Aldosterone System | volume = 14 | issue = 4 | pages = 285–289 | date = December 2013 | pmid = 24222656 | doi = 10.1177/1470320313513408 | doi-access = free }}

The substance is a white powder consisting of thin hexagonal plates. It is stable in solid form as well as in aqueous (water) solution with a pH of 5 to 7, and has a melting point of about {{convert|138|C|F}}.{{Cite journal| vauthors = Feng L, Karpinski PH, Sutton P, Liu Y, Hook DF, Hu B, Blacklock TJ, Fanwick PE, Prashad M, Godtfredsen S, Ziltener C |title=LCZ696: a dual-acting sodium supramolecular complex| journal=Tetrahedron Letters| volume=53|issue=3| year=2012| pages=275–276 | doi= 10.1016/j.tetlet.2011.11.029}}

During its development by Novartis, Entresto was known as LCZ696. It was approved under the FDA's priority review process on 7 July 2015. It was also approved in Europe in 2015. In 2022, Novartis sold its India marketing rights of Sacubitril Valsartan to JB Pharma, under the brand name Azmarda.{{cite news|url=https://medicaldialogues.in/partner/jbcpl/azmarda-sacubitril-valsartan|title=Azmarda (Sacubitril Valsartan): Overview, Indications, Clinical Evidence & Dosage|date=30 June 2022|work=Medical Dialogues|access-date=30 June 2022|archive-date=5 July 2022|archive-url=https://web.archive.org/web/20220705000846/https://medicaldialogues.in/partner/jbcpl/azmarda-sacubitril-valsartan|url-status=live}}

There was controversy over the PARADIGM-HF trial—the Phase III trial on the basis of which the drug was approved by the FDA. For example, both Richard Lehman, a physician who writes a weekly review of key medical articles for the BMJ Blog and a December 2015, report from the Institute for Clinical and Economic Review (ICER) found that the risk–benefit ratio was not adequately determined because the design of the clinical trial was too artificial and did not reflect people with heart failure that doctors usually encounter.{{cite news | url=http://resource.nlm.nih.gov/101672986 | vauthors=Ollendorf DA, Tarlochan Sandhu A, Chapman R, Heidenreich PA, Russo E, Shore KK, Synnott P, Travers K, Weissberg J, Pearson SD | title=CardioMEMS HF System (St. Jude Medical, Inc.) and Sacubitril/Valsartan (Entresto, Novartis AG) for management of congestive heart failure: effectiveness, value, and value-based price benchmarks : final report | date=1 December 2015 | id=101672986 | access-date=4 October 2019 | archive-date=29 August 2021 | archive-url=https://web.archive.org/web/20210829043221/https://collections.nlm.nih.gov/catalog/nlm:nlmuid-101672986-pdf | url-status=live }}{{rp|28}}[http://blogs.bmj.com/bmj/2014/09/08/richard-lehmans-journal-review-8-september-2014/#more-32277 Richard Lehman's journal review—8 September 2014. NEJM 4 Sep 2014.] {{Webarchive|url=https://web.archive.org/web/20210516220729/https://blogs.bmj.com/bmj/2014/09/08/richard-lehmans-journal-review-8-september-2014/#more-32277 |date=16 May 2021 }} Vol 371. The BMJ, 8 September 2014. In 2019, the PIONEER-HF and PARAGON-HF trials studied the effect of sacubitril/valsartan in 800 patients recently hospitalised with severe heart failure and 4800 patients with less severe symptoms of heart failure respectively. The medication consistently demonstrated similar levels of safety, with higher rates of very low blood pressure, compared to current treatments across all three trials in a variety of patients, however it has only shown effectiveness in those with more advanced heart failure. In December 2015, Steven Nissen and other thought leaders in cardiology said that the approval of sacubitril/valsartan had the greatest impact on clinical practice in cardiology in 2015, and Nissen called the drug "truly a breakthrough approach."Roger Sergel for Medpage Today. [http://www.medpagetoday.com/Cardiology/CHF/55415 5 Game-Changers in Cardiology in 2015: Entresto] {{Webarchive|url=https://web.archive.org/web/20210627214226/https://www.medpagetoday.com/Cardiology/CHF/55415 |date=27 June 2021 }}

One 2015 review stated that sacubitril/valsartan represents "an advancement in the chronic treatment of heart failure with reduced ejection fraction" but that widespread clinical success with the drug will require taking care to use it in appropriate patients, specifically those with characteristics similar to those in the clinical trial population.{{cite journal | vauthors = Lillyblad MP | title = Dual Angiotensin Receptor and Neprilysin Inhibition with Sacubitril/Valsartan in Chronic Systolic Heart Failure: Understanding the New PARADIGM | journal = The Annals of Pharmacotherapy | volume = 49 | issue = 11 | pages = 1237–1251 | date = November 2015 | pmid = 26175499 | doi = 10.1177/1060028015593093 | s2cid = 28918702 }} Another 2015 review called the reductions in mortality and hospitalization conferred by sacubitril/valsartan "striking", but noted that its effects in heart failure people with hypertension, diabetes, chronic kidney disease, and the elderly needed to be evaluated further.{{cite journal | vauthors = Bavishi C, Messerli FH, Kadosh B, Ruilope LM, Kario K | title = Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials | journal = European Heart Journal | volume = 36 | issue = 30 | pages = 1967–1973 | date = August 2015 | pmid = 25898846 | doi = 10.1093/eurheartj/ehv142 | doi-access = free }}

The wholesale cost to the National Health Service (NHS) in the UK is approximately {{GBP|1,200}} per person per year as of 2017.{{cite web|title=Entresto|url=http://www.mims.co.uk/drugs/cardiovascular-system/heart-failure/entresto|website=MIMS|access-date=25 July 2017|archive-date=5 August 2017|archive-url=https://web.archive.org/web/20170805222559/http://www.mims.co.uk/drugs/cardiovascular-system/heart-failure/entresto|url-status=live}} The wholesale cost in the United States is {{US$|4,560}} per year {{as of|2015|lc=yes}}. One industry-funded analysis found a cost of {{US$|45,017}} per quality-adjusted life year (QALY).{{cite journal | vauthors = Gaziano TA, Fonarow GC, Claggett B, Chan WW, Deschaseaux-Voinet C, Turner SJ, Rouleau JL, Zile MR, McMurray JJ, Solomon SD | title = Cost-effectiveness Analysis of Sacubitril/Valsartan vs Enalapril in Patients With Heart Failure and Reduced Ejection Fraction | journal = JAMA Cardiology | volume = 1 | issue = 6 | pages = 666–672 | date = September 2016 | pmid = 27438344 | doi = 10.1001/jamacardio.2016.1747 | doi-access = free }} Similar class generic drugs without sacubitril, such as valsartan alone, cost approximately {{US$|48}} a year.{{cite news |url=https://www.nytimes.com/2014/08/31/business/new-novartis-drug-shows-striking-efficacy-in-treating-heart-failure.html |title=New Novartis Drug Effective in Treating Heart Failure |vauthors=Pollack A |newspaper=The New York Times |date=30 August 2014 |access-date=3 March 2017 |archive-date=5 May 2021 |archive-url=https://web.archive.org/web/20210505133259/https://www.nytimes.com/2014/08/31/business/new-novartis-drug-shows-striking-efficacy-in-treating-heart-failure.html |url-status=live }}

In 2023, the Institute for Clinical and Economic Review (ICER) identified Entresto (sacubitril/valsartan) as one of five high-expenditure drugs that experienced significant net price increases without new clinical evidence to justify the hikes. Specifically, Entresto's wholesale acquisition cost rose by 7%, leading to an additional $72 million in costs to U.S. payers.{{Cite web |title=Institute for Clinical and Economic Review Announces Most Significant Drug-Price Hikes Unsupported by New Clinical Evidence in US |url=https://icer.org/news-insights/press-releases/icer-announces-most-significant-drug-price-hikes-unsupported-by-new-clinical-evidence-in-us/?mkt_tok=NjM4LVBYUi0zMTgAAAGYMxe5Fv3mzhJbiVnr0V4g2FUAcS3PgZOZSYRvQcW3_VFPXIet0TCD7bWAyVVeW2Q62e3AynO8rDpP8sIoIbs_qux8kQcMBBD4cDSe3Q |access-date=2025-02-06 |website=ICER |language=en-US}}

The PARADIGM-HF trial (in which Milton Packer was one of the principal investigators) compared treatment with sacubitril/valsartan to treatment with enalapril.{{cite news|vauthors=Husten L|title=Novartis Trial Was Stopped Early Because Of A Significant Drop In Cardiovascular Mortality|url=https://www.forbes.com/sites/larryhusten/2014/03/31/novartis-trial-was-stopped-early-because-of-a-significant-drop-in-cardiovascular-mortality/#2226cab84010|work=Forbes|date=31 March 2014|access-date=6 August 2017|archive-date=24 June 2021|archive-url=https://web.archive.org/web/20210624200934/https://www.forbes.com/sites/larryhusten/2014/03/31/novartis-trial-was-stopped-early-because-of-a-significant-drop-in-cardiovascular-mortality/#2226cab84010|url-status=live}} People with heart failure and reduced LVEF (10,513) were sequentially treated on a short-term basis with enalapril and then with sacubitril/valsartan. Those that were able to tolerate both regimens (8442, 80%) were randomly assigned to long-term treatment with either enalapril or sacubitril/valsartan. Participants were mainly white (66%), male (78%), middle aged (median 63.8 +/- 11 years) with NYHA stage II (71.6%) or stage III (23.1%) heart failure.{{cite journal | vauthors = King JB, Bress AP, Reese AD, Munger MA | title = Neprilysin Inhibition in Heart Failure with Reduced Ejection Fraction: A Clinical Review | journal = Pharmacotherapy | volume = 35 | issue = 9 | pages = 823–837 | date = September 2015 | pmid = 26406774 | doi = 10.1002/phar.1629 | s2cid = 6363036 }}

The trial was stopped early after a prespecified interim analysis revealed a reduction in the primary endpoint of cardiovascular death or heart failure in the sacubitril/valsartan group relative to those treated with enalapril. Taken individually, the reductions in cardiovascular death and heart failure hospitalizations retained statistical significance.{{cite journal | vauthors = McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR | title = Angiotensin-neprilysin inhibition versus enalapril in heart failure | journal = The New England Journal of Medicine | volume = 371 | issue = 11 | pages = 993–1004 | date = September 2014 | pmid = 25176015 | doi = 10.1056/NEJMoa1409077 | hdl-access = free | hdl = 2336/552372 | s2cid = 11383 }} Relative to enalapril, sacubitril/valsartan provided reductions{{cite web | title=Sacubitril/Valsartan Combination Drug: 2 Years Later | date=3 March 2017 | vauthors=Drescher CS, Desai AS | publisher=American College of Cardiology | url=https://www.acc.org/latest-in-cardiology/articles/2017/03/03/09/30/sacubitril-valsartan-combination-drug | access-date=20 June 2019 | archive-date=24 June 2021 | archive-url=https://web.archive.org/web/20210624200924/https://www.acc.org/latest-in-cardiology/articles/2017/03/03/09/30/sacubitril-valsartan-combination-drug | url-status=live }} in:

• the composite endpoint of cardiovascular death or hospitalization for heart failure (incidence 21.8% vs 26.5%)
• cardiovascular death (incidence 13.3% vs 16.5%)
• first hospitalization for worsening heart failure (incidence 12.8% vs 15.6%), and
• all-cause mortality (incidence 17.0% vs 19.8%)

Limitations of the trial include scarce experience with initiation of therapy in hospitalized patients and in those with NYHA heart failure class IV symptoms.{{cite journal | vauthors = Havakuk O, Elkayam U | title = Angiotensin Receptor-Neprilysin Inhibition | journal = Journal of Cardiovascular Pharmacology and Therapeutics | volume = 22 | issue = 4 | pages = 356–364 | date = July 2017 | pmid = 28587583 | doi = 10.1177/1074248416683049 | s2cid = 4066142 }}{{cite journal | vauthors = Perez AL, Kittipibul V, Tang WH, Starling RC | title = Patients Not Meeting PARADIGM-HF Enrollment Criteria Are Eligible for Sacubitril/Valsartan on the Basis of FDA Approval: The Need to Close the Gap | journal = JACC. Heart Failure | volume = 5 | issue = 6 | pages = 460–463 | date = June 2017 | pmid = 28571599 | doi = 10.1016/j.jchf.2017.03.007 | doi-access = free }} Additionally the trial compared a maximal dose of valsartan (plus sacubitril) with a sub-maximal dose of enalapril, and was thus not directly comparable with current gold-standard use of ACE inhibitors in heart failure, diminishing the validity of the trial results.{{Cite web|url=https://blogs.bmj.com/bmj/2014/09/08/richard-lehmans-journal-review-8-september-2014/|title=Richard Lehman's journal review—8 September 2014|date=8 September 2014|website=The BMJ|access-date=20 May 2019|archive-date=11 February 2018|archive-url=https://web.archive.org/web/20180211144219/http://blogs.bmj.com/bmj/2014/09/08/richard-lehmans-journal-review-8-september-2014/|url-status=live}}{{cite journal | vauthors = Ahn R, Prasad V | title = Do Limitations in the Design of PARADIGM-HF Justify the Slow Real World Uptake of Sacubitril/Valsartan (Entresto)? | journal = Cardiovascular Drugs and Therapy | volume = 32 | issue = 6 | pages = 633–635 | date = December 2018 | pmid = 30232657 | doi = 10.1007/s10557-018-6830-x | s2cid = 52298581 }}

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