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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?
Methods:
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.
Results:
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.
Conclusions:
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.
Perspective:
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.
Keywords: Heart Diseases, Natriuretic Peptides, Biomarkers, Proto-Oncogene Proteins, Cardiology, Heart Failure, Neprilysin, Tetrazoles, New York
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