The Angiotensin Receptor Neprilysin Inhibitor LCZ696 in Heart Failure With Preserved Ejection Fraction: A Phase 2 Double-Blind Randomised Controlled Trial

Study Questions:

What is the safety and efficacy of LCZ696, a first-in-class angiotensin-receptor neprilysin inhibitor, in patients with heart failure with preserved ejection fraction (HFPEF)?


This was a multicenter, phase 2, double-blind, randomized (1:1), controlled trial (PARAMOUNT) of LCZ696 titrated to 200 mg twice daily versus valsartan titrated to 160 mg twice daily. Patients were at least 40 years of age, had a left ventricular EF (LVEF) ≥45%, New York Heart Association class II-III symptoms, an N-terminal pro–B-type natriuretic peptide (NT-proBNP) >400 pg/ml, and an estimated glomerular filtration rate ≥30 with potassium ≤5.2 mmol/L. Patients received therapy for 36 weeks. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers were stopped in all patients 24 hours prior to randomization. The primary endpoint was change in NT-proBNP at 12 weeks, and echocardiogram measures were secondary measures.


There were 301 patients enrolled, 149 of whom received LCZ696 and 152 valsartan. Mean LVEF was 58%, mean age was 71 years, and 57% were female. Baseline characteristics in the groups were similar, but LCZ696 patients had a slightly lower NT-proBNP (828 [460-1,341] vs. 939 [582-1,490]). The change in NT-proBNP was greater with LCZ696 therapy compared with valsartan (ratio of change, 0.77 [0.64-0.92], p = 0.005) at 12 weeks, but was not significantly greater at 36 weeks (ratio of change, 0.88 [0.65-1.09], p = 0.20). Patients with diabetes appeared to have greater reduction in NT-proBNP with LCZ696 (interaction, p = 0.02), and blood pressure effects of LCZ696 appeared greater. There were no significant differences in echo parameters studied after 12 weeks of therapy.


The authors concluded that patients with HFPEF had greater early reductions in NT-proBNP.


LCZ696 is an angiotensin-receptor neprilysin inhibitor, inhibiting both neprilysin and the angiotensin receptor. Inhibition of neprilysin has been shown to increase active natriuretic peptides (C-type, atrial, and BNPs, but not NT-proBNP), possibly improving chronic HF symptoms in HFPEF through improved myocardial relaxation. In this early phase study, improvements in NT-proBNP were noted. More studies are needed to see if this medication will lead to improved HF outcomes, and/or outcomes that are superior to that of standard evidence-based therapies.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Biological Markers, Heart Failure, Blood Pressure, Neprilysin

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