• Angiotensin-converting–enzyme (ACE) inhibitors have been the cornerstone of the treatment for heart failure and a reduced ejection fraction for nearly 25 years, since enalapril was shown to reduce the risk of death in two trials. The effect of angiotensin-receptor blockers (ARBs) on mortality has been inconsistent,3,4 and thus, these drugs are recommended primarily for patients who have unacceptable side effects (primarily cough) while receiving ACE inhibitors. Subsequent studies showed that the use of beta-blockers and mineralocorticoid-receptor antagonists, when added to ACE inhibitors, resulted in incremental decreases in the risk of death of 30 to 35% and 22 to 30%, respectively.
• Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. In clinical trials, the combined inhibition of ACE and neprilysin was associated with serious angioedema
• LCZ696, which consists of the neprilysin inhibitor sacubitril (AHU377) and the ARB valsartan, was designed to minimize the risk of serious angioedema.

• Multicenter, double-blind randomized controlled trial of 8442 adult patients with class II, III, or IV heart failure and an ejection fraction ≤40% (changed to ≤35% with an amendment on 15 Dec 2010) to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy.
• Patients were required to have a plasma BNP level of at least 150 pg per milliliter (or an N-terminal pro-BNP [NT-proBNP] level ≥600 pg per milliliter) or, if they had been hospitalized for heart failure within the previous 12 months, a BNP of at least 100 pg per milliliter (or an NT-proBNP ≥400 pg per milliliter). Patients taking any dose of an ACE inhibitor or ARB were considered for participation, but for at least 4 weeks before screening, patients were required to take a stable dose of a beta-blocker and an ACE inhibitor (or ARB) equivalent to at least 10 mg of enalapril daily.
• The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes.
• The secondary outcomes were the time to death from any cause, the change from baseline to 8 months in the clinical summary score on the Kansas City Cardiomyopathy Questionnaire (KCCQ), the time to a new onset of atrial fibrillation, and the time to the first occurrence of a decline in renal function

• Symptomatic hypotension, a systolic blood pressure <100 mm Hg at screening or 95 mm Hg at randomization
• eGFR) <30 ml per minute per 1.73 m²sup> of body-surface area at screening or at randomization or a decrease in the eGFR of more than 25% (which was amended to 35%) between screening and randomization
• Serum potassium level of > 5.2 mmol per liter at screening (or above 5.4 mmol per liter at randomization)
• History of angioedema or unacceptable side effects during receipt of ACE inhibitors or ARBs

Primary Endpoints

• The trial was stopped early according to prespecified rules because the boundary for an overwhelming benefit with LCZ696 had been crossed.
• At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001).
• A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001).
• As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P = 0.001).

Secondary Outcomes

• The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.

• Angiotensin receptor–neprilysin inhibition with LCZ696 was superior to ACE inhibition alone in reducing the risks of death and of hospitalization for heart failure
• The robust findings from this landmark trial provides strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the renin–angiotensin system alone among patients with chronic heart failure.