Heart Online First, published on May 26, 2016 as 10.1136/heartjnl-2014-306775 Review The neprilysin pathway in heart failure: a review and Heart: first published as 10.1136/heartjnl-2014-306775 on 20 May 2016. Downloaded from guide on the use of sacubitril/valsartan Pardeep S Jhund, John J V McMurray BHF Cardiovascular Research ABSTRACT and the sympathetic nervous system, and the action Centre, Institute of Inhibition of neurohumoural pathways such as the renin of vasopressin, lead to increased ventricular preload Cardiovascular and Medical Sciences, University of angiotensin aldosterone and sympathetic nervous and afterload and elevated wall stress which in turn Glasgow, Glasgow, UK systems is central to the understanding and treatment of lead to production of pre-pro B-type natriuretic heart failure (HF). Conversely, until recently, potentially peptide (BNP) which is cleaved to BNP and Correspondence to beneficial augmentation of neurohumoural systems such N-terminal proBNP (NT-proBNP). The release of Dr Pardeep S Jhund, British as the natriuretic peptides has had limited therapeutic natriuretic peptides may also be determined by the Heart Foundation Cardiovascular Research success. Administration of synthetic natriuretic peptides levels of other neurohormones such as angiotensin 6 Centre, University of Glasgow, has not improved outcomes in acute HF but modulation II and endothelin. The peptide BNP acts to 126 University Place, Glasgow of the natriuretic system through inhibition of the promote natriuresis and vasodilation (NT-proBNP is G12 8TA, UK; pardeep.jhund@ enzyme that degrades natriuretic (and other vasoactive) physiologically inactive). Atrial stretch leads to the glasgow.ac.uk peptides, neprilysin, has proven to be successful. After production of pre-proatrial or A-type natriuretic Received 5 October 2015 initial failures with neprilysin inhibition alone or dual peptide and ultimately atrial natriuretic peptide Accepted 14 April 2016 neprilysin-angiotensin converting enzyme (ACE) (ANP) which has similar biological properties to inhibition, the Prospective comparison of angiotensin BNP.5 Urodilatin (which is structurally related to receptor neprilysin inhibitor (ARNI) with ACEI to ANP), is derived from the same precursor in the Determine Impact on Global Mortality and morbidity in kidneys.7 C-type natriuretic peptide (CNP) is Heart Failure trial (PARADIGM-HF) trial demonstrated released from endothelial cells and acts in a para- that morbidity and mortality can be improved with the crine fashion but is only found in low concentra- angiotensin receptor blocker neprilysin inhibitor tions in circulating blood.5 Two strategies have been sacubitril/valsartan (formerly LCZ696). In comparison to employed to try and improve outcomes in HF-REF the ACE inhibitor enalapril, sacubitril/valsartan reduced via modulation of this pathway. The first is the the occurrence of the primary end point (cardiovascular administration of exogenous natriuretic peptides. death or hospitalisation for HF) by 20% with a 16% Nesiritide, a recombinant human BNP, initially reduction in all-cause mortality. These findings suggest showed promising beneficial effects on haemo- that sacubitril/valsartan should replace an ACE inhibitor dynamics and natriuresis in patients with HF-REF.8 or angiotensin receptor blocker as the foundation of However, in a large-scale randomised controlled http://heart.bmj.com/ treatment of symptomatic patients (NYHA II–IV) with HF trial, nesiritide failed to improve outcomes (though and a reduced ejection fraction. This review will explore it did improve dyspnoea).9 Although carperitide the background to neprilysin inhibition in HF, the results (recombinant ANP) is used as a treatment for acute of the PARADIGM-HF trial and offer guidance on how to HF in Japan, there is no robust evidence supporting use sacubitril/valsartan in clinical practice. this practice.10 The second strategy is to inhibit the breakdown of natriuretic peptides. ANP, BNP, CNP and urodilatin are cleaved and inactivated by a mem- on September 26, 2021 by guest. Protected copyright. The renin angiotensin aldosterone system (RAAS) brane bound endopeptidase, neprilysin (as well as system is at the core of the pathophysiology of insulin degrading enzyme). Neprilysin is found in a heart failure (HF) and its modulation is central to number of tissues but in especially high concentra- altering the disease process in HF with reduced tions in the kidney. Natriuretic peptides are also ejection fraction (HF-REF). Successive randomised cleared via the natriuretic peptide clearance receptor controlled trials have demonstrated that blockade (NPRC and NPRC3). of RAAS improves morbidity and mortality in – patients with HF-REF.1 3 The prognosis of INITIAL NEPRILYSIN INHIBITORS HF-REF has been improved as a consequence, Initial attempts at inhibiting neprilysin using an although it remains poor4 as it remains a complex oral (racecodotril11) and intravenous (candoxatri- syndrome involving a multitude of neurohormonal lat12) formulation were successful in promoting pathways. Therefore, further therapies to improve natriuresis and increasing urinary excretion of ANP. outcomes in these patients are needed. A further neprilysin inhibitor (ecadotril) had similar effects.13 However, a study of chronic use THE NATRIURETIC PEPTIDE SYSTEM of the oral prodrug candoxatril showed that the The natriuretic peptide system counter regulates initial reduction in blood pressure was not sus- the detrimental effects of the upregulation of RAAS tained and therefore development was stopped.14 To cite: Jhund PS, that occurs in HF-REF, inhibits secretion of argin- This might be explained by the finding that neprily- McMurray JJV. Heart 15–17 Published Online First: ine vasopressin and modulates the autonomic sin also breaks down angiotensin II. Therefore [please include Day Month nervous system in ways that are likely to be benefi- inhibiting neprilysin alone, while raising natriuretic Year] doi:10.1136/heartjnl- cial in this syndrome.5 Sodium and water retention peptides levels, also increases angiotensin II levels 2014-306775 and vasoconstriction caused by activation of RAAS (and other substrates for neprilysin such as Jhund PS, McMurray JJV. Heart 2016;0:1–6. doi:10.1136/heartjnl-2014-306775 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& BCS) under licence. Review endothelin, vasopressin, bradykinin, etc) potentially counteract- angio-oedema was expected to be lower than with omapatri- – Heart: first published as 10.1136/heartjnl-2014-306775 on 20 May 2016. Downloaded from ing the actions of the former peptides. lat.19 21 Given twice daily, sacubitril/valsartan leads to sustained neprilysin and RAAS inhibition over a 24 h period addressing DUAL NEPRILYSIN AND ACE INHIBITION one limitation of the OVERTURE trial in which omapatrilat The solution to the problem of lone neprilysin inhibition was given as a single large dose once daily.22 That approach may appeared to be dual blockade of RAAS and the natriuretic have contributed to the significant early postdose hypotension peptide system (figure 1). As ACE inhibitors are known to seen with omapatrilat but did not provide sustained inhibition improve outcomes it seemed logical to combine an ACE inhibitor of ACE and neprilysin over 24 h. The systemic exposure deliv- with a neprilysin inhibitor. The combined ACE and neprilysin ered by sacubitril/valsartan 97 mg/103 mg (200 mg LCZ696) is inhibitor omapatrilat was studied in a large randomised con- equivalent to 160 mg of valsartan and neprilysin is almost com- – trolled trial against enalapril 10 mg twice daily in the pletely inhibited for up to 12 h.19 21 Omapatrilat Versus Enalapril Randomized Trial of Utility in The Prospective comparison of ARNI with ACEI to Reducing Events (OVERTURE) trial.18 The primary end point, Determine Impact on Global Mortality and morbidity in Heart death from any cause or HF hospitalisations were not reduced by Failure trial (PARADIGM-HF) was conducted to test whether omapatrilat. Although other secondary end points suggested a 97 mg/103 mg twice daily of sacubitril/valsartan was superior to benefit with omapatrilat (death from any cause or cardiovascular enalapril 10 mg twice daily in reducing the primary end point – (CV) hospitalisation was 9% lower in the omapatrilat group) the of CV death or HF hospitalisation.22 24 All randomised patients rate of angio-oedema was much higher in the omapatrilat group. completed a run-in period of 6–8 weeks during which it was Both ACE and neprilysin break down bradykinin and omapatrilat required that the target dose of both drugs was tolerated prior also inhibits aminopeptidase P which also catabolises bradykinin. to randomisation. Each treatment period (enalapril and sacubi- Therefore, unintended excessive potentiation of bradykinin and tril/valsartan) included a washout period to avoid simultaneous resultant high rates of serious angio-oedema led to the discon- neprilysin and ACE inhibition and the potential risk of tinuation of the clinical development of this drug. angio-oedema (patients with a history of angio-oedema were also excluded). The trial was terminated early, on the recom- ANGIOTENSIN RECEPTOR BLOCKER NEPRILYSIN mendation of the Data Monitoring Committee, due to a sus- INHIBITORS tained and highly significant reduction in the risk of the primary Combining an angiotensin receptor blocker (ARB) and a nepri- composite end point (CV death or HF hospitalisation) and in lysin inhibitor