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Sunday 17 December 2017
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Neprilysin/angiotensin inhibition in heart failure

The lifetime risk of developing heart failure (HF) is 1 in 5.1 Once patients develop HF their prognosis is poor. Patients with HF due to left ventricular dysfunction, or reduced ejection fraction (HFREF), are admitted to hospital frequently, have a high symptom burden and are at risk of death from progressive HF.2 While the natural history of HFREF is of progressive deterioration, many patients will die suddenly and can do so at any time during the course of their disease.2 The prognosis of HF is therefore worse than many types of cancer.3
The background to neprilysin inhibition in heart failure
The pathophysiology of HFREF is characterised by activation of neurohormonal mechanisms that lead to detrimental changes and worsening of ventricular function. Therapies used to treat heart failure aim to modulate the maladaptive activation of these systems. In response to the low cardiac output in HFREF, the renin–angiotensin–aldosterone system is activated in an effort to retain sodium and water, bolstering the circulation. However, this response becomes maladaptive with angiotensin II having multiple detrimental effects too. The angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers counteract this system and have been shown in randomised trials to improve morbidity and mortality.4 Similarly, blocking aldosterone with a mineralocorticoid receptor antagonist improves morbidity and mortality.4
The sympathetic nervous system is also activated, and consequently beta blockers have also been shown to improve morbidity and mortality in HFREF. In patients with HFREF, the sodium and water retention that occurs due to the activation of these neurohormonal systems leads to a stretching of the ventricle and in response produces pre-pro B-type natriuretic peptide, which is cleaved to B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP). BNP is a peptide and it promotes natriuresis and vasodilation. NT-proBNP is inactive. The atria also stretch and produce pre-pro-atrial or A-type natriuretic peptide, which then makes atrial natriuretic peptide (ANP). ANP has similar properties to BNP.5 In addition to BNP and ANP, C-type natriuretic peptide (CNP) is released from endothelial cells and acts locally. Therefore attempts have been made to augment these peptides, therefore promoting vasodilatation and natriuresis, by inhibiting their breakdown. Neprilysin is the enzyme responsible for the breakdown of these peptides and the history of neprilysin inhibition is long and full of unsuccessful drugs. 
Initial neprilysin inhibitors did not sustain their effects on blood pressure (possible due to the fact that neprilysin also breaks down angiotensin II and therefore inhibition of neprilysin upregulates angiotensin II levels).6 To counteract this, a neprilysin inhibitor was combined with an ACE inhibitor (given that ACE inhibitors were known to improve outcomes in HFREF and a way to mitigate angiotensin II production was needed it was logical to combine the two). However, in a large outcomes study, the rate of angioedema in the group randomised to the combined ACE/neprilysin inhibitor omapatrilat was higher than in the ACE inhibitor arm.7 As ACE and neprilysin are responsible for the breakdown of bradykinin, the dual inhibition of these enzymes led to an increase in bradykinin-mediated angioedema. Compounding this interaction was the finding that omapatrilat also inhibited aminopeptidase P, which also breaks down bradykinin. As a logical conclusion to these issues, combining a neprilysin inhibitor with an angiotensin receptor blocker was a potential solution. The combined angiotensin receptor–neprilysin inhibitor sacubitril/valsartan was designed as such a solution. It is administered twice a day, giving 24-hour neprilysin inhibition.
Evidence underlying the use of sacubitril/valsartan
To examine the efficacy of sacubitril/valsartan in the treatment of HFREF, the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) was designed.8–10 Patients with heart failure and an ejection fraction of ≤40% were randomised to 97/103mg twice-daily of sacubitril/valsartan or enalapril 10mg twice daily (the evidence-based dose from the trials demonstrating the benefit of enalapril in HFREF). The primary endpoint of the trial was the first occurrence of cardiovascular death or heart failure hospitalisation.
The trial was designed with a run-in period; all patients had to tolerate the target dose of enalapril and sabuitril/valsartan before randomisation. Each treatment period during this run-in phase (enalapril and sacubitril/valsartan) included a washout period. This was done to minimise inhibition of both neprilysin and ACE at the same time, which could potentially increase the risk of angioedema through inhibition of bradykinin breakdown. The Data Monitoring Committee recommended terminating the trial early as a sustained and highly significant reduction in the risk of the primary composite endpoint (cardiovascular death or heart failure hospitalisation) and in cardiovascular mortality was observed in the sacubitril/valsartan group compared with the enalapril group. In the final analysis, sacubitril/valsartan reduced the occurrence of the primary endpoint by 20% and all-cause mortality by 16%. Importantly, it also reduced deaths from worsening heart failure and sudden deaths.10 It was not only the first hospitalisation for heart failure that was reduced but also recurrent hospitalisation for heart failure (that is, the total number of hospitalisations for heart failure) by 21% and 23%, respectively.11 In addition to improving morbidity and mortality, quality of life was also better preserved on sacubitril/valsartan compared to enalapril.10 
Sacubitril/valsartan: licensing and guidelines
Sacubitril/valsartan is licensed by the Food and Drug Administration (FDA)12 in the USA and the European Medicines Agency13 for the treatment of HFREF in place of an ACE inhibitor or angiotensin receptor blocker. While the PARADIGM-HF trial stipulated that patients be on stable HF medications (that is, an ACE inhibitor or angiotensin receptor blocker) for four weeks, the FDA labelling advice gives information on how to start the drug in ACE inhibitor or angiotensin receptor blocker-naïve patients.12 This extends outside of the evidence base, but is probably logical given that it would be impossible to conduct a trial in patients with new-onset HFREF. The guidelines for the treatment of HFREF in the USA14 and Europe4 have taken slightly differing stances. 
In the US guidelines, sacubitril/valsartan has been given a IB recommendation and is recommended for the treatment of HFREF as an alternative to ACE inhibitors or angiotensin receptor blockers. In the European Society of Cardiology guidelines,4 sacubitril/valsartan has similarly been given a IB recommendation but, in contrast, has more tightly followed the inclusion criteria of the trial when determining the eligible population. In these guidelines sacubitril/valsartan “is recommended as a replacement for an ACE-I to further reduce the risk of HF hospitalisation and death in ambulatory patients with HFREF who remain symptomatic despite optimal treatment with an ACE-I, a beta-blocker and an MRA” and in addition they “should have elevated natriuretic peptides (plasma BNP ≥150 pg/ml or plasma NT-proBNP ≥600pg/ml, or if HF hospitalisation within the last 12 months, plasma BNP ≥100pg/ml or plasma NT-proBNP ≥400pg/ml) and able to tolerate enalapril 10mg bid.” 
Using sacubitril/valsartan in clinical practice
Whether following the US or European guidelines, the use of sacubitril/valsartan in day-to-day clinical practice is the same. Sacubitril/valsartan should not be prescribed with another angiotensin receptor blocker or renin inhibitor due the risk of renal impairment and hyperkalaemia. It must not be given with an ACE inhibitor because of the risk of renal impairment, hyperkalaemia and angioedema. As the risk of angioedema increases with concomitant ACE inhibition sacubitril/valsartan must not be started for at least 36 hours after discontinuing an ACE inhibitor.12,13 The starting dose of sacubitril/valsartan is 24/26mg twice daily in those unable to tolerate a maximal dose of and ACE inhibitor or angiotensin receptor blocker or who have not had one of these in the past, those with renal impairment (eGFR <30ml/min/m2), moderate hepatic impairment, and the elderly. Otherwise the starting dose should be 49/51mg twice daily. The dose should be doubled every two to four weeks as tolerated by the patient to the maximum dose of 97/103mg twice daily. It is important that patients should also continue all their other guidelines recommended, evidence-based drugs such as a beta-blocker, mineralocorticoid receptor antagonist, ivabradine and digoxin. 
They should also receive cardiac resynchronisation therapy or an implantable cardioverter defibrillator as appropriate. The drug should be monitored much in the same way as we currently do with ACE inhibitors and angiotensin receptor blockers. Blood pressure should be monitored. Symptomatic hypotension leading to treatment discontinuation was uncommon in PARADIGM-HF but the drug should not be initiated in those with a systolic blood pressure of <100mmHg.12,13 Renal function should also be monitored and although renal function may decline slightly after starting sacubitril/valsartan treatment discontinuation due to renal dysfunction was lower with sacubitril/valsartan compared to enalapril in PARADIGM-HF.10
Sacubitril/valsartan has been licensed and recommended in the major guidelines to treat patients with HFREF. It should be considered in all such patients to improve morbidity, mortality and quality of life if they continue to be symptomatic despite optimal guideline recommended treatment.
1 Lloyd-Jones DM et al; Framingham Heart Study. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation 2002;106(24):3068–72.
2 McMurray JJ. Clinical practice. Systolic heart failure. N Engl J Med 2010;362(3):228–38.
3 Stewart S et al. Population impact of heart failure and the most common forms of cancer: a study of 1 162 309 hospital cases in Sweden (1988 to 2004). Circ Cardiovasc Qual Outcomes 2010;3(6):573–80.
4 Ponikowski P et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129–200. 
5 Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol 2007;50:2357–68.
6 Bevan EG et al. Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension. J Hypertens 1992;10:607–13.
7 Packer M et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002;106:920–6.
8 McMurray JJV et al; on behalf of the PARADIGM-HF Committees, Investigators. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to determine impact. Eur J Heart Fail 2013;15:1062–73. 
9 McMurray JJ V et al. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail 2014;16:817–25. 
10 McMurray JJ V et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. 
11 Packer M et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131:54–61.
12 US Food and Drug Administration. Entresto (sacubitril and valsartan). Highlights of prescribing information. (accessed February 2017).
13 European Medicines Agency. Entresto. (accessed February 2017).
14 Yancy CW et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: An update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A report of the American College of Cardiology/American Heart Association Task Force on Clinic. J Am Coll Cardiol 2016;68:1476–88. 

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