Inhibition of the renin-angiotensin system with ACE-inhibitors or ARBs has failed to convincingly show that these drugs can improve survival and lower the risk of hospitalisation in patients with heart failure with preserved ejection fraction (HF-PEF). LCZ696 is a novel investigational combination angiotensin-receptor/neprilysin inhibitor (ARNI) consisting of valsartan and AHU-377 in a 1:1 mixture. AHU-377 is a prodrug that, when activated, inhibits the enzyme neprilysin. Neprilysin is a metalloprotease enzyme that is responsible for the degradation of atrial and brain natriuretic peptide and has antiangiotensin effects.
The Prospective Comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection Fraction (PARAMOUNT) Phase-2 trial randomised 149 patients with NYHA class 2-3 heart failure, LVEF of at least 45% and N-terminal-pro-BNP levels >400 pg/mL to LCZ696 (up to 200 mg twice daily) and 152 to valsartan (up to 160 mg twice daily). The primary outcome looking at levels of NT-proBNP, found a reduction in 23% (p=0.005) over 12 weeks in those receiving LCZ696 but only a 15% (p=0.20) drop over 36 weeks among those receiving valsartan. Further subgroup analysis broke patients down by age, with or without diabetes, normal or elevated systolic blood pressure, with or without atrial fibrillation or poor renal function, and with or without a prior HF admission; the LCZ696 group showed significant reductions in levels of NT-proBNP in all of these groups. Furthermore, NYHA class also improved significantly with LCZ696 (p<0.05) at 36 weeks, as did left atrial width (p=0.03), left atrial volume (p=0.003), and left atrial volume index (p=0.007).
In this Phase-2 trial, LCZ696 showed potential benefit in the management of patients with heart failure with preserved ejection fraction.
- Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012; DOI:10.1016/S0140-6736(12)61227-6.