Table.

Important clinical and preclinical studies of combined NEP inhibitors in cardiovascular disease

Drug	Study or model characteristics	Study endpoints	Key results (NEPi drugs vs comparator)
ACEi+NEPi (vasopeptidase inhibitors)
Sampatrilat⁷⁹	Patients with hypertension	BP, plasma renin activity, urinary cGMP excretion	Good antihypertensive effect. No increase of plasma renin activity
Sampatrilat⁸⁰	Patients with resistant hypertension	BP, plasma renin activity at 8 wks	Sustained antihypertensive effect superior to ACEi. No increase of plasma renin activity
Sampatrilat⁸¹	Preclinical. Rats with HF post-MI	LV hemodynamics and remodeling at 5 wks	Reduced mortality and LV remodeling, improved hemodynamics
Omapatrilat⁸²	Preclinical. Hamsters with HF due to dilated cardiomyopathy.	Survival, LV remodeling and function at 8 wks.	Reduced mortality and LV remodeling, improved hemodynamics
Omapatrilat⁸³	Omapatrilat vs enalapril in patients with hypertension (OCTAVE)	BP control at 24 wks	Antihypertensive effect superior to ACEi, but increase of angioedema
Omapatrilat⁸⁴	Omapatrilat vs lisinopril in NYHA class II-IV systolic HF (IMPRESS)	Exercise capacity at 12 wks, HF death/morbidity at 24 wks	Reduced composite of mortality and HF hospitalizations. No angioedema and fewer AE than ACEi
Omapatrilat⁸⁵	Omapatrilat vs enalapril in in systolic HF NYHA 2-4 (OVERTURE)	Composite of mortality and HF hospitalizations at 62 wks	No difference in primary endpoint
ACEi+NEPi+ECEi
Benazepril+daglutril⁸⁶	Preclinical. Rats with HF post-MI	LV hemodynamics and remodeling after 4 wks treatment	Better preserved LV structure and function than ACEi or ECEi/NEPi alone
NEPi+ECEi
CGS26303⁸⁷	Preclinical. Rats with HF post-MI	LV hemodynamics and remodeling after 30 days treatment	Reduced LV remodeling and filling pressures, increased LV function compared to NEPi alone
Daglutril (SLV-306)⁸⁸	Preclinical. Rats with hypertension (salt sensitive Dahl rats)	LV remodeling and neurohormonal activation at 6 wks	Reduced LV remodeling and ET-1 levels similar to ACEi
Daglutril (SLV-306)⁸⁹	Patients with ADHF	Acute hemodynamics after single-bolus dose	Reduced LV filling pressures, but no clear dose-response
SLV-338⁹⁰	Rats with renovascular (2K1C) hypertension	LV remodeling and BP at 12 wks	BP-independent inhibition of cardiac fibrosis
ARB+NEPi (ARNi)
LCZ-696⁹¹	Preclinical and clinical. Double transgenic hypertensive rats. Healthy human controls.	BP effects in hypertensive rats. Pharmacokinetics in healthy humans.	Double transgenic rats: sustained BP reductions. Humans: well-tolerated, effective blocker of AR and NEP
Valsartan/candoxatril⁹²	Preclinical study in normal rats.	BP effects, tracheal plasma extravasation	Antihypertensive effect of ARNi similar to omapatrilat. No observation of tracheal plasma extravasation /angioedema
LCZ-696⁹³	Patients with mild to moderate hypertension.	BP lowering at 8 wks	Greater reductions in blood pressure with LCZ-696 than ARB alone. Safety endpoints met
LCZ-696⁹⁴	Patients with HF and preserved EF and elevated NT-proBNP (PARAMOUNT)	NT-proBNP changes, symptoms, LV remodeling	Reduced NT-proBNP and left atrial size, improved NYHA-class
LCZ-696⁹⁵	Patients with stable chronic HF and reduced EF (PARADIGM-HF)	Death or HF hospitalization	Ongoing (estimated completion date april 2014)

NEPi indicates neprilysin inhibitor; ACEi, angiotensin-converting enzyme inhibitor; BP, blood pressure; cGMP, cyclic GMP; wks, weeks; HF, heart failure; MI, myocardial infarction; LV, left ventricle; NYHA, New York Heart Association (functional class); AE, adverse events; ET-1, endothelin-1; 2K1C, 2-kidney 1 -clip model; ARNi, angiotensin receptor neprilysin inhibitor; EF, ejection fraction, NT-proBNP, N-terminal pro brain natriuretic peptide.