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)?

Methods:

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.

Results:

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.

Conclusions:

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

Perspective:

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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