Table 1.

Table of Studies Which Led to the Development of Combined Angiotensin Receptor Blocker and Neprilysin Inhibitor

Study and Year	Population	Study Drug	Comparator	Primary Outcome(s)	Results
Exogenous Natriuretic Peptides
VMAC Investigators (2002)15	AHF (N=489)	Nesiritide	Nitroglycerin or placebo	Change in PCWP in those undergoing RHC (N=246) Change in patient-assessed symptoms after 3 hours	Change in PCWP nesiritide vs nitroglycerin (−8.2 vs −6.3 mmHg; P=0.03). Improved symptoms vs placebo (P=0.03) but not vs nitroglycerin
ASCEND-HF (2011)17	AHF (N=7141)	Nesiritide	Placebo	Change in breathlessness at 6 and 24 hours Rehospitalisation with HF or death at 30 days	More patients reported an improvement in breathlessness in the nesiritide group but there was no difference in the primary endpoints.
TRUE-AHF (2017)18	AHF (N=2157)	Ularitide	Placebo	Cardiovascular death during follow up (15 months) Clinical endpoint in first 48 hours of treatment classifying patients as “worse”, “unchanged” or “improved”	Greater reductions in SBP and NTproBNP with ularitide but no effect on primary endpoints.
Neprilysin Inhibitors
Northridge et al (1989)20	Healthy controls (N=16) CHF (N=6)	UK69,578	Placebo	Physiological effects	Increase in plasma ANP levels and urinary sodium levels and decrease in plasma renin levels vs placebo (P<0.01, P<0.01 and P<0.05 respectively)
Gros et al (1989)21	Healthy controls (N=8)	Acetorphan	Placebo	Physiological effects	Increase in plasma ANP levels and urine volume and sodium concentration.
Kahn et al (1990)22	CHF (N=12)	Sinorphan	Pre-treatment	Physiological effects	Increase in ANP levels (P<0.01) and decrease in renin levels and PCWP (P<0.04) compared to pre-treatment.
Good et al (1995)23	CHF (N=12)	Candoxatrilat	Placebo	Physiological effects	Increase in ANP levels and urine volume and sodium concentration vs placebo
Cleland et al (1998)24	CHF (N=279)	Ecadotril	Placebo	Safety and tolerability of varying doses	Dose-dependent increases in cGMP but no effect on renin, ang II, NTproANP, or symptoms. Possibility of drug-induced pancytopenia causing death in 2 patients in ecadotril arm.
Dual ACE and Neprilysin Inhibition
Liao et al (2003)25	Healthy controls (N=47)	Omapatrilat	Placebo	Pharmacokinetics	Dose-dependent increases in urinary ANP and cGMP levels and decrease in SBP.
IMPRESS (2000)26	CHF (N=573)	Omapatrilat	Placebo	Improvement in ETT at 12 weeks. Composite of death or comorbid events due to HF (secondary endpoint)	No effect on ETT. 48% RRR of death, HF hospitalisation or worsening HF (P=0.035) – study not powered to detect secondary endpoint
OVERTURE (2002)27	CHF (N=5770)	Omapatrilat	Enalapril	Composite of death or hospitalisation with HF requiring IV treatment	Primary endpoint occurred in 32% vs 34% in the omapatrilat and enalapril groups (P=0.187): omapatrilat was noninferior (but not superior) to enalapril
OCTAVE (2004)28	Hypertension (N=25,302)	Omapatrilat	Enalapril	Reduction in SBP at 8 weeks Need for new antihypertensive treatment at 24 weeks	Between group difference of 3.6 mmHg in favour of omapatrilat at week 8 with fewer new antihypertensives started by week 24 (P<0.001). Angio-oedema occurred in 2.17% the omapatrilat group (vs 0.68%; P<0.001) two of whom had airway compromise.

Abbreviations: AHF, acute heart failure; CHF, chronic heart failure; ACE, angiotensin-converting enzyme; PCWP, pulmonary capillary wedge pressure; RHC, right heart catheterisation; HF, heart failure; SBP, systolic blood pressure; NTproBNP, N-terminal pro-B-type Natriuretic Peptide; ANP, atrial natriuretic peptide; NTproANP, N-terminal pro-ANP; ang II, angiotensin II; cGMP, cyclic guanosine monophosphate; ETT, exercise treadmill test; RRR, relative risk reduction.