Natriuretic peptides are released in response to cardiac-wall stress and other stimuli of heart failure. These potent natriuretic and vasodilatory peptides also inhibit the renin-angiotensin system and sympathetic drive. The neutral endopeptidase neprilysin is responsible for the degradation of several of these natriuretic peptides. Inhibition of neprilysin increases the level of these natriuretic peptides, thus potentially enhancing the beneficial effects of standard therapies to suppress the renin angiotensin system. In the PARADIGM-HF randomized controlled trial, the ACE inhibitor enalapril at a dose of 10mg twice a day was compared with the experimental drug LCZ696, which was a combination of the ARB valsartan and the neprilysin inhibitor sacubitril. This combination was chosen in response to prior studies that demonstrated combining a neprilysin inhibitor with an ARB reduced the risk of angioedema. A total of 8442 patients with an ejection fraction less than 35%, with NYHA class II (70%), III or IV symptoms, and who were already receiving evidence based therapy for heart failure, were randomly assigned in a double-blind fashion to receive enalapril or LCZ696. The primary end-point was a composite of death from cardiovascular causes and heart failure hospitalization. The trial was stopped early on the recommendation of the data safety monitoring committee at a median follow-up of 27 months due to evidence of an overwhelming benefit with LCZ696. Patients in the LCZ696 group were less likely to die from any cause (17.0% vs. 19.8%, HR 0.84; 95% CI, 0.76 to 0.93; P<0.001) or die from a cardiovascular cause (13.3% vs. 16.5%, HR 0.80; 95% CI, 0.71 to 0.89; P<0.001). LCZ696 also significantly decreased symptoms and improved quality of life indices (P=0.001), and decreased hospitalizations by 21% (P<0.001). The number-needed-to-treat to avoid one primary end-point event was 35. LCZ696 also demonstrated no significant increase in angioedema over enalapril and lower overall rates of renal impairment, hyperkalemia, and cough.

Conclusions: In this large, well-conducted randomized study, LCZ696 was superior to enalapril in reducing mortality among patients with heart failure and a reduced ejection fraction. LCZ696 represents a novel agent for heart failure management that may change the paradigm of best-practices for systolic heart failure therapy.

Summarized by Hussain Contractor and Steven M. Bradley

• McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004.