Angiotensin Receptor Neprilysin Inhibitor LCZ696 Research Articles

The angiotensin receptor neprilysin inhibitor LCZ696 attenuates renal fibrosis via ASK1/JNK/p38 MAPK-mediated apoptosis in unilateral ureteral obstruction.

The angiotensin receptor neprilysin inhibitor LCZ696 affords superior cardioprotection and renoprotection compared with renin-angiotensin blockade monotherapy, but the underlying mechanisms remain elusive. Herein, we evaluated whether LCZ696 attenuates renal fibrosis by inhibiting ASK1/JNK/p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis in a rat model of unilateral ureteral obstruction (UUO) and in vitro. Rats with UUO were treated daily for 7 days with LCZ696, valsartan, or the selective ATP competitive inhibitor of apoptosis signal-regulating kinase 1 (ASK1), GS-444217. The effects of LCZ696 on renal injury were examined by assessing the histopathology, oxidative stress, intracellular organelles, apoptotic cell death, and MAPK pathways. H2O2-exposed human kidney 2 (HK-2) cells were also examined. LCZ696 and valsartan treatment significantly attenuated renal fibrosis caused by UUO, and this was paralleled by downregulation of proinflammatory cytokines and decreased inflammatory cell influx. Intriguingly, LCZ696 had stronger effects on renal fibrosis and inflammation than valsartan. UUO-induced oxidative stress triggered mitochondrial destruction and endoplasmic reticulum stress, which resulted in apoptotic cell death; these effects were reversed by LCZ696. Both GS-444217 and LCZ696 hampered the expression of death-associated ASK1/JNK/p38 MAPKs. In H2O2-treated HK-2 cells, LCZ696 and GS-444217 increased cell viability but decreased the production of intracellular reactive oxygen species and MitoSOX and apoptotic cell death. Both agents also deactivated H2O2-stimulated activation of ASK1/JNK/p38 MAPKs. These findings suggest that LCZ696 protects against UUO-induced renal fibrosis by inhibiting ASK1/JNK/p38 MAPK-mediated apoptosis.

Effect of Neprilysin Inhibition for Ischemic Mitral Regurgitation after Myocardial Injury.

Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 ± 13.8 µL versus 525.1 ± 23.6 µL; p < 0.05), while valsartan did not (471.2 ± 8.9 µL; p > 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 ± 2.7 µm vs. 48.8 ± 7.5 µm; p < 0.05). Transforming growth factor-β and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT.

Renal protective effects and mechanisms of the angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome

AimsThis study investigated the renal protective effects and mechanisms of angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome. Materials and methodsMice were divided into abdominal aortic ligation alone, or treatment with LCZ696 or valsartan, whilst those undergoing sham surgery served as controls. Rat proximal renal tubular epithelial cells from the NRK-52E line were treated with control solution, LCZ696 or valsartan, in the presence or absence of Ang II for 24 h. Key findingsCompared to controls, abdominal aortic ligation significantly increased plasma NT-proBNP and urine neutrophil gelatinase-associated lipocalin (NGAL), which were associated with reduced renal length and velocity time integral on ultrasonography. Histology revealed wrinkling of the glomerular capillary wall and sclerosis of the glomerulus, dilatation of the Bowman's capsule, accompanied by diffuse renal tubular atrophy and fibrosis, accompanied by lower kidney index and higher percentage area of fibrosis. Increases in NGAL and decreased ANP protein and mRNA expression levels were observed. These abnormalities were significantly prevented by LCZ696 and to a lesser extent by valsartan. Cellular experiments demonstrated a central role of Ang II/transforming growth factor-β1/Smad2/3/connective tissue growth factor-dependent signaling leading to type IV collagen deposition. This upregulation was reversed by LCZ696 in a greater extent than valsartan treatment alone, accompanied by a significant improvement in NGAL. SignificanceLCZ696 can reduce kidney injury to a level beyond valsartan therapy alone in mice with cardiorenal syndrome, which can be speculated by effects on epithelial-mesenchymal transition and fibrosis through downregulating the TGF-β1/Smad2/3/CTGF/Collagen IV pathway.

ADAM10 inhibition improves survival and augments cardiac function after myocardial infarction

Abstract Background and purpose Following myocardial infarction (MI), adverse fibrotic remodeling with extensive deposition of extracellular matrix (ECM) components has substantial consequences for the contractility of the ventricle finally leading to terminal heart failure (HF). Recently, inhibition of ECM-remodeling enzymes is discussed as potential treatment option for HF, especially following MI. The metalloprotease ADAM10 plays a crucial role in the development of the cardiovascular system and HF patients show elevated serum levels of the ADAM10 substrates CXCL16 and FasL. However, the causal role of ADAM10 in cardiovascular diseases has not been investigated. Here we evaluate the so far unknown role of ADAM10 in heart failure and after MI. Methods and results Our study capitalized from human atrial tissue biopsies, a cardiomyocyte-specific ADAM10 knockout (ADAM10 KO) mouse model as well as pharmacological ADAM10 inhibition following MI. ADAM10 expression analysis revealed elevated protein levels in HF patients compared to non-failing hearts. Upon MI, ADAM10 KO and pharmacological ADAM10 inhibition (GI254023X) significantly improved overall survival, significantly enhanced cardiac function (fractional area shortening - FAS, ejection fraction - EF) and significantly reduced infarct sizes. Compared to the high potential angiotensin receptor neprilysin inhibitor (ARNi) LCZ696, ADAM10 inhibition and combined ADAM10i/LCZ696 treatment resulted in preservation of cardiac function that was superior to sole LCZ696 treatment. Mechanistically, this functional improvement was due to reduced shedding of the ADAM10 substrate Notch1, induction of angiogenesis and an ADAM10-dependend inactivation of the NLRP3 inflammasome Conclusion Our data suggest that ADAM10 targeting is highly efficient for improving post-infarction cardiac function. Due to its overexpression in heart tissue of HF patients, ADAM10 could be a potential molecular target to improve therapy after MI. In terms of overall survival and pathophysiological remodeling following MI, our data suggest a greater potential of the ADAM10i/LCZ696 combinatorial therapy than sole LCZ696 treatment. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Heart Foundation/ German Foundation of Heart Research

1797-P: Effect of LCZ696 and Its Components Sacubitril and Valsartan on Insulin Secretion and Glucose Homeostasis in Mice

In type 2 diabetes, HbA1c decreases upon treatment of heart failure with the angiotensin receptor-neprilysin (NEP) inhibitor LCZ696 (LCZ). We sought to determine whether the components of LCZ, the NEP inhibitor sacubitril (SAC) and angiotensin receptor blocker valsartan (VAL), enhance insulin secretion and if so, their effects are additive when combined in LCZ. C57BL/6 mice fed high fat diet (HFD) received injections of vehicle (VEH) or low-dose streptozotocin (3 × 30 mg/kg; STZ), the latter to induce diabetes. Mice were continued for 8 weeks on HFD alone (CTL) or supplemented with LCZ (114 mg/kg/d), SAC (48 mg/kg/d) or VAL (54 mg/kg/d). All drugs significantly reduced body weight gain in both VEH and STZ groups, with LCZ being more effective than SAC (Table). SAC and VAL, but not LCZ, lowered fed and fasting plasma glucose and increased insulin release during an IV glucose tolerance test (IVGTT) in STZ mice only (Table). In VEH and STZ mice, insulin sensitivity was similar among the 4 treatment groups; however, SAC enhanced glucose disposal during IVGTT (Table). None of the treatments altered pancreatic ß- and α-cell mass or lipolysis (not shown). In sum, SAC and VAL exert beneficial anti-obesity, glycemic and insulinotropic effects when given alone in obese and/or diabetic mice. Additional studies are needed to understand why, when SAC and VAL are combined in LCZ, only anti-obesity effects are observed. Disclosure N. Esser: None. C.R. Schmidt: None. B. Barrow: None. L. Cronic: None. D.J. Hackney: None. S.M. Mongovin: None. R.L. Hull: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation (LCZ696BUSNC09T)

The angiotensin II receptor-neprilysin inhibitor LCZ696 attenuates the progression of proteinuria in type 2 diabetic rats

We examined the effects of the angiotensin receptor-neprilysin inhibitor LCZ696 on overt proteinuria and renal injury in type 2 diabetic Otsuka-Long- Evans-Tokushima-Fatty (OLETF) rats. Aged OLETF rats were also treated with either valsartan or valsartan plus hydralazine for comparison. LCZ696 caused greater attenuation of the progression of proteinuria than either valsartan alone or valsartan combined with hydralazine. Reduced glomerular injury and tubulointerstitial fibrosis were also observed in LCZ696-treated rats. Moreover, LCZ696 prevented increases in blood urea nitrogen (BUN) and creatinine levels. These data suggest that LCZ696 elicits a reno-protective effect against type 2 diabetes with overt proteinuria.

Sacubitril/Valsartan versus enalapril in nonischemic heart failure in Paradigm-Hf trial

<strong>Background :</strong>We compared the angiotensin receptor–neprilysin inhibitor LCZ696 (sacubitril/valsartan) with enalapril in patients who had nonischemic heart failure with a reduced ejection fraction.

Cost Effectiveness of the Angiotensin Receptor Neprilysin Inhibitor Sacubitril/Valsartan for Patients with Chronic Heart Failure and Reduced Ejection Fraction in the Netherlands: A Country Adaptation Analysis Under the Former and Current Dutch Pharmacoeconomic Guidelines

ObjectivesTo describe the adaptation of a global health economic model to determine whether treatment with the angiotensin receptor neprilysin inhibitor LCZ696 is cost effective compared with the angiotensin-converting enzyme inhibitor enalapril in adult patients with chronic heart failure with reduced left ventricular ejection fraction in the Netherlands; and to explore the effect of performing the cost-effectiveness analyses according to the new pharmacoeconomic Dutch guidelines (updated during the submission process of LCZ696), which require a value-of-information analysis and the inclusion of indirect medical costs of life-years gained. MethodsWe adapted a UK model to reflect the societal perspective in the Netherlands by including travel expenses, productivity loss, informal care costs, and indirect medical costs during the life-years gained and performed a preliminary value-of-information analysis. ResultsThe incremental cost-effectiveness ratio obtained was €17,600 per quality-adjusted life-year (QALY) gained. This was robust to changes in most structural assumptions and across different subgroups of patients. Probability sensitivity analysis results showed that the probability that LCZ696 is cost-effective at a €50,000 per QALY threshold is 99.8%, with a population expected value of perfect information of €297,128. On including indirect medical costs of life-years gained, the incremental cost-effectiveness ratio was €26,491 per QALY gained, and LCZ696 was 99.46% cost effective at €50,000 per QALY, with a population expected value of perfect information of €2,849,647. ConclusionsLCZ696 is cost effective compared with enalapril under the former and current Dutch guidelines. However, the (monetary) consequences of making a wrong decision were considerably different in both scenarios.

Angiotensin receptor neprilysin inhibitor LCZ696: pharmacology, pharmacokinetics and clinical development.

Heart failure still has a significant disease burden with poor outcomes worldwide despite advances in therapy. The standard therapies have been focused on blockade of renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid antagonists and the sympathetic nervous system with β-blockers. The natriuretic peptide system is a potential counter-regulatory system that promotes vasodilatation and natriuresis. Angiotensin receptor neprilysin inhibitors are a new class drug capable of blocking the renin-angiotensin-aldosterone system and enhancing the natriuretic peptide system to improve neurohormonal balance. The success of the PARADIGM-HF trial with LCZ696 and its approval for heart failure treatment is likely to generate a paradigm shift. This review summarises the current knowledge of LCZ696 with a focus on pharmacology, pharmacokinetics and pharmacodynamics, mechanisms of action, clinical efficacy and safety.

A COST-EFFECTIVENESS ANALYSIS IN THE US OF LCZ696 (SACUBITRIL/VALSARTAN) VERSUS RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM INHIBITION FOR HEART FAILURE PATIENTS WITH REDUCED EJECTION FRACTION

The angiotensin receptor neprilysin inhibitor LCZ696 (sacubitril/valsartan) reduced all-cause death and HF hospitalizations compared to enalapril. We assessed the cost-effectiveness of LCZ696 relative to enalapril in the US. Using PARADIGM-HF trial data, a two-state Markov model was developed for

Influenza Vaccination in Patients With Chronic Heart Failure: The PARADIGM-HF Trial

ObjectivesThis study sought to examine the prevalence and predictors of influenza vaccination among participants in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) study and investigate associations between receiving influenza vaccine and cardiovascular death or heart failure hospitalizations, all-cause hospitalizations, and cardiopulmonary or influenza-related hospitalizations. BackgroundInfluenza is associated with an increased risk for cardiovascular events in patients with heart failure. MethodsWe used data from the PARADIGM-HF trial in which patients with heart failure were randomized to the angiotensin receptor neprilysin inhibitor LCZ696 (sacubitril/valsartan) or enalapril. We assessed predictors of receiving influenza vaccination, and examined the relationship between influenza vaccination and outcomes in a propensity-adjusted model. ResultsOf 8,099 study participants, 1,769 (21%) received influenza vaccination. We observed significant regional variation in vaccination rates, with highest rates in the Netherlands (77.5%), Great Britain (77.2%), and Belgium (67.5%), and lowest rates in Asia (2.6%), with intermediate rates in North America (52.8%). Top predictors of vaccination included enrolling country, white race, implanted defibrillator, older age, lower New York Heart Association functional class, lower heart rate, and a history of diabetes mellitus. Influenza vaccination was associated with a reduced risk for all-cause mortality in propensity-adjusted (hazard ratio: 0.81; 95% confidence interval: 0.67 to 0.97; p = 0.015) models. ConclusionsInfluenza vaccination rates varied widely in patients with heart failure with reduced ejection fraction enrolled in the PARADIGM-HF trial, and vaccination was associated with reduced risk for death, although whether this association was causal cannot be determined.

Abstract 17955: Reduction in 30-day Rehospitalization After Discharge From a Heart Failure Admission in Patients Receiving LCZ696 versus Enalapril: PARADIGM-HF

Introduction: The angiotensin receptor neprilysin inhibitor LCZ696 reduced cardiovascular death, heart failure hospitalization and all-cause mortality in patients with heart failure and reduced ejection fraction compared with enalapril. Hypothesis: We hypothesized that LCZ696 would reduce 30-day readmission after a heart failure hospitalization. Methods: PARADIGM-HF randomized 8399 patients with HF and reduced ejection fraction to either LCZ696 200mg bid or Enalapril 10mg bid. We assessed the risk of 30-day readmission for any cause following investigator reported and adjudicated hospitalization for heart failure. Admission and discharge dates were available for 2800 hospitalizations (95%) in 1638 patients. Results: Of 2800 HF hospitalizations, 1545 occurred in 871 patients in the enalapril group and 1255 occurred in 767 patients in the LCZ arm. Overall, 10.5% of these HF hospitalizations were followed by a repeat hospitalization for any cause within 30 days of discharge, and this occurred significantly less frequently in the LCZ arm (8.7%) relative to the enalapril arm (12.0%), in both unadjusted models and a random-effects logistic regression model accounting for the repeated HF hospitalizations experienced by some patients. We observed similar results in a sensitivity analysis restricted only to the first HF hospitalization for each patient. Further adjustment for baseline characteristics did not alter these findings. Similar effect sizes were observed for adjudicated heart failure hospitalizations. Conclusion: In patients admitted with heart failure in PARADIGM-HF, LCZ reduced 30-day readmissions for any-cause.

PARAMETER Study: LCZ696 Safe and Effective in Reducing Systolic and Pulse Pressure

Results of the PARAMETER study demonstrated that the angiotensin receptor neprilysin inhibitor LCZ696 reduced central aortic systolic and pulse pressure more effectively than olmesartan in older patients with systolic hypertension and arterial stiffness. Both treatments were safe and well tolerated without significantly variability in key safety parameters between the groups.

Angiotensin receptor neprilysin inhibitor LCZ696: a novel targeted therapy for arterial hypertension?

The need for novel antihypertensive therapies represents a continuous challenge. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that has been shown to enhance endogenous natriuretic peptide (NP) actions on neurohormonal activation. This effect seems to be additive to that of the renin-angiotensin-aldosterone system (RAAS) suppression, as impressively suggested in the PARADIGM HF study. LCZ696 has been shown to be effective in reducing blood pressure in several small studies; however, its effectiveness and safety remain to be proved in larger studies. This review summarizes the role of RAAS and NP system in the pathophysiology of hypertension and reviews the current data on the antihypertensive effects of LCZ696.

Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances.

This review describes the role of neprilysin (also known as neutral endopeptidase or enkephalinase) in the degradation of natriuretic and other vasoactive peptides, including bradykinin and adrenomedullin. The initial development of neprilysin inhibitors, then angiotensin converting enzyme-neprilysin inhibitors and, most recently, the angiotensin receptor neprilysin inhibitor (ARNI) LCZ696 (sacubitril valsartan) as an extension of the nurohumoral basis for the treatment of heart failure is also summarised. Finally, the implications of the compelling benefits of LCZ696 compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) is discussed.

Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction.

Increases in serum creatinine with renin-angiotensin-aldosterone system (RAAS) inhibitors can lead to unnecessary discontinuation of these agents. The dual-acting angiotensin receptor neprilysin inhibitor LCZ696 improves clinical outcome patients with heart failure with reduced ejection fraction, and pilot data suggest potential benefit in heart failure with preserved ejection fraction (HFpEF). The effects of LCZ696 on renal function have not been assessed. A total of 301 HFpEF patients were randomly assigned to LCZ696 or valsartan in the PARAMOUNT trial. We studied renal function [creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and urinary albumin to creatinine ratio (UACR)] at baseline, 12 weeks, and after 36 weeks of treatment. Worsening renal function (WRF) was determined as an serum creatinine increase of >0.3 mg/dL and/or >25% between two time-points. Mean eGFR at baseline was 65.4 ± 20.4 mL/min per 1.73 m(2) . The eGFR declined less in the LCZ696 group than in the valsartan group (-1.5 vs. -5.2 mL/min per 1.73 m(2) ; P = 0.002). The incidence of WRF was lower in the LCZ696 group (12%) than in the valsartan group (18%) at any time-point, but this difference was not statistically significant (P = 0.18). Over 36 weeks, the geometric mean of UACR increased in the LCZ696 group (2.4-2.9 mg/mmol), whereas it remained stable in the valsartan group (2.1-2.0 mg/mmol; P for difference between groups = 0.016). In patients with HFpEF, therapy with LCZ696 for 36 weeks was associated with preservation of eGFR compared with valsartan therapy, but an increase in UACR.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

The angiotensin receptor neprilysin inhibitor LCZ696 improves systolic cardiac function compared to angiotensin converting enzyme inhibition (ACEi) in a rat model of myocardial infarction

The angiotensin receptor neprilysin inhibitor LCZ696 improves systolic cardiac function compared to angiotensin converting enzyme inhibition (ACEi) in a rat model of myocardial infarction

Elevation in high-sensitivity troponin T in heart failure and preserved ejection fraction and influence of treatment with the angiotensin receptor neprilysin inhibitor LCZ696.

Elevated high-sensitivity troponin is associated with increasing disease severity in patients with stable heart failure with reduced ejection fraction, but less is known about the association in heart failure with preserved ejection fraction. We examined the prevalence of elevated high-sensitivity troponin T (hs-TnT) in 298 patients with heart failure with preserved ejection fraction enrolled in the Prospective comparison of angiotensin receptor neprilysin inhibitor with angiotensin receptor blocker on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial, in which the angiotensin receptor neprilysin inhibitor LCZ696 reduced markers of heart failure severity compared with valsartan. We assessed the association between hs-TnT and cardiac structure and function, and the effect of LCZ696, compared with valsartan, on hs-TnT over 36 weeks. Elevated hs-TnT in the myocardial injury range (>0.014 μg/L) was found in 55% of patients and was associated with older age, history of diabetes mellitus, higher N-terminal pro-brain natriuretic peptide, lower estimated glomerular filtration rate, and larger left atrial size, left ventricular volume, and mass. LCZ696 treatment reduced hs-TnT to a greater extent at 12 weeks (12% reduction; P=0.05) and at 36 weeks (14% reduction; P=0.03) compared with valsartan. Troponin T was elevated in a substantial number of patients enrolled in a heart failure with preserved ejection fraction clinical trial and was associated with abnormalities of cardiac structure, function, and elevated baseline N-terminal pro-brain natriuretic peptide. Decreases in hs-TnT with LCZ696 in parallel with improvement in N-terminal pro-brain natriuretic peptide and left atrial size suggest that the angiotensin receptor neprilysin inhibitor LCZ696 may reduce this measure of myocardial injury in heart failure with preserved ejection fraction. http://www.clinicaltrials.gov. Unique identifier: NCT00887588.

Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure

BackgroundWe compared the angiotensin receptor–neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients.MethodsIn this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less 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. 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.ResultsThe trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, 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). 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.ConclusionsLCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.)