Table 1: Summary of Neutral Endopeptidase 24.11 Inhibition Studies.

Study name	Author	Year	N	Main inclusion criteria	Trial drug and dose	Comparison drug and dose	Mean treatment duration	Key findings
OVERTURE[58]	Packer et al.	2002	5,770	CHF (NYHA II–IV) or EF ≤30 % with heart failure hospitalisation within the past year, mean EF 23.5 %	Omapatrilat 40 mg once daily	Enalapril 10 mg twice daily	14.5 months	Non-inferior to enalapril in decreasing mortality and rates of heart failure hospitalisation requiring intravenous therapy Increased risk of angioedema
OCTAVE[62]	Kostis et al.	2004	25,302	Untreated or uncontrolled hypertension	Omapatrilat 10 mg once daily, titrated to maximum 80 mg once daily	Enalapril 5 mg once daily, titrated to maximum 40 mg once daily	24 weeks	Reduced systolic blood pressure by 3.6 mmHg more than enalapril Fewer adjunctive antihypertensive medications needed Increased rate of angioedema, including two patients with airway compromise
PARADIGM-HF[59]	McMurray et al.	2014	8,442	CHF (NYHA Class II–IV) and EF ≤40 % (later changed to EF ≤35 %); mean 30 %	LCZ696 (sacubitril/160 mg valsartan) 200 mg twice daily	Enalapril 10 mg twice daily	27 months	Reduction in composite endpoint of death from cardiovascular causes or hospitalisation for heart failure Symptomatic hypotension more common with LCZ696 LCZ696 not associated with increased risk of angioedema
PARAMOUNT[64]	Solomon et al.	2012	301	CHF (NYHA Class II–IV), EF ≥45 % (mean 58 %), and NT-proBNP >400 pg/ml	LCZ696 200 mg twice daily	Valsartan 160 mg twice daily	36 weeks	Lower NT-proBNP with LCZ696 Similar rates of hypotension and renal impairment
PARAGON[65]	Novartis	Currently recruiting		CHF (NYHA II–IV), EF ≥45%	LCZ696 100 mg twice daily	Valsartan 80 mg twice daily	<57 months	Primary outcome: composite endpoint of cardiovascular death and total heart failure hospitalisations

CHF = congestive heart failure; EF = ejection fraction; NYHA = New York Heart Association