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

Study Questions:

What are the efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in patients with New York Heart Association (NYHA) class II-III heart failure with preserved ejection fraction?


PARAMOUNT (Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fraction) was a phase 2, randomized, double-blind, multicenter trial, in which patients were randomly assigned to LCZ696 or valsartan, treated for 36 weeks, and continued on background therapy at the discretion of treating physicians. A threshold of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels >400 pg/ml was required for inclusion. The primary endpoint was change from baseline NT-proBNP, which is not a substrate for neprilysin degradation, assessed at 12 weeks. Secondary endpoints included changes in echocardiographic indices, as well as NYHA class and quality-of-life scores.


Compared with valsartan at 12 weeks, LCZ696 caused a greater reduction in NT-proBNP levels (ratio LCZ696/valsartan 0.77, 95% confidence interval, 0.64-0.92; p = 0.005). This effect was no longer statistically significant at 36 weeks (p = 0.20). The LCZ696 group also had greater reduction in left atrial volume (p = 0.003) and improvement in NYHA class (p = 0.05) at 36 weeks, although the trial was not powered to examine clinical status or cardiovascular endpoints. Adverse events were similar in both treatment groups.


Among patients with heart failure with preserved ejection fraction, LCZ696 was safe (and not associated with a tendency toward angioedema) and led to a greater reduction in NT-proBNP at 12 weeks (although this effect was no longer significant by 36 weeks), along with evidence of left atrial reverse remodeling and improvement in NYHA functional class.


No single therapy to date has demonstrated convincing benefit in clinical outcomes among patients with heart failure with preserved ejection fraction, a common syndrome that confers substantial morbidity and mortality. The results of the PARAMOUNT study of angiotensin receptor neprilysin inhibition are encouraging and warrant consideration of a definitive trial. The challenge in designing such a trial would be to find a suitable comparator, recognizing the potential limitations of significant confounding from background treatment in a placebo-controlled study.

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

Keywords: Heart Diseases, Natriuretic Peptides, Biological Markers, Proto-Oncogene Proteins, Cardiology, Heart Failure, Neprilysin, Tetrazoles, New York

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