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This study sought to assess associations between longitudinal change in atrial natriuretic peptide (ANP) and reverse cardiac remodeling following initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF).Neprilysin inhibition results in an increase of several vasoactive peptides that may mediate the beneficial effects of sacubitril/valsartan, including ANP.In a prospective study of initiation and titration of sacubitril/valsartan in patients with HFrEF, blood was collected at scheduled time points into tubes containing protease inhibitors. This pre-specified exploratory analysis included patients in whom ANP was measured at baseline and serially through 12 months of treatment.Among 144 participants (mean age: 64.5 years; left ventricular ejection fraction: 30.8%), following initiation of sacubitril/valsartan, there was an early and significant increase in ANP, with the majority of rise from 99 pg/ml at baseline to 156 pg/ml at day 14 (p 0.001). There was a further trend toward a second increase from day 30 to day 45 (p = 0.07). At maximal rise, ANP had doubled. In longitudinal analyses, early rise in ANP was followed by a subsequent increase in urinary cycle guanosine monophosphate. Larger early increase in ANP was associated with larger later improvements in left ventricular ejection fraction and left atrial volume index (p 0.001 for both).Concentrations of ANP doubled after initiation of sacubitril/valsartan in patients with HFrEF. Larger early increases in ANP were associated with a greater magnitude of subsequent reverse cardiac remodeling. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Aims We sought to determine sex‐based differences in biomarkers, self‐reported health status, and magnitude of longitudinal changes in measures of reverse cardiac remodelling among patients with heart failure with reduced ejection fraction (HFrEF, left ventricular ejection fraction ≤40%) treated with sacubitril/valsartan (S/V). Methods and results This was a subgroup analysis of patients initiated on S/V in the Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure (PROVE‐HF) study. There were 226 (28.5%) women in the study. Though women had lower baseline N‐terminal pro B‐type natriuretic peptide (NT‐proBNP), they had more rapid early reduction in the biomarker after initiation of S/V. Compared to men, women had lower average baseline Kansas City Cardiomyopathy Questionnaire (KCCQ)‐23 Total Symptom score (67.6 vs. 71.9; P = 0.003) but showed greater linear improvement (7.4 vs. 5.5 points; P, A summary of differences between women and men in the PROVE‐HF study.

Background: Treatment with sacubitril-valsartan reduces mortality and heart failure (HF) events in HF with reduced ejection fraction and may reduce HF hospitalization in women with HF with preserved ejection fraction. Methods: EVALUATE-HF randomized 464 participants (109 women) with HF with reduced ejection fraction to sacubitril-valsartan or enalapril for 12 weeks. Documented left ventricular ejection fraction (LVEF) ≤0.40 within the prior 12 months was required, although core laboratory LVEF>0.40 was permitted. Assessments of aortic stiffness (pulse pressure and characteristic impedance, Z c ) were performed at baseline and at trough and 4 hours postdose at weeks 4 and 12. Results: In models of change from baseline adjusted for baseline value, treatment with sacubitril-valsartan produced greater overall reductions in mean arterial pressure (treatment group difference, −3.0±0.8 mm Hg, P P c were greater in the sacubitril-valsartan group (−16±6 dyne×second/cm 5 , P =0.012). Post hoc analyses found evidence of effect modification by LVEF (interaction P =0.036). With LVEFc were greater in the sacubitril-valsartan group (trough, −3±8 dyne×second/cm 5 versus post-dose, −17±8 dyne×second/cm 5 ; interaction P =0.024) with no sex difference (treatment×sex interaction, P =0.3). With LVEF≥0.40, treatment with sacubitril-valsartan was associated with greater overall reductions in Z c in women (women, −80±21 dyne×second/cm 5 versus men, −20±13 dyne×second/cm 5 ; interaction P =0.019). Conclusions: In prespecified analyses that include pre- and postdose assessments at 4 and 12 weeks, treatment with sacubitril-valsartan was associated with greater postdose reductions in aortic Z c . In a post hoc analysis, sacubitril-valsartan was associated with sustained reductions in Z c in women with LVEF≥0.40. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT02874794.

Supplemental Digital Content is available in the text., Background: Among patients with heart failure and reduced ejection fraction (left ventricular (LV) ejection fraction ≤40%), sacubitril/valsartan (S/V) treatment is associated with improved health status and reverse cardiac remodeling. Data regarding racial and ethnic differences in response to S/V are lacking. Methods: This was an analysis from the PROVE-HF study (Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure). Longitudinal changes in NT-proBNP (N-terminal pro-B-type natriuretic peptide), cardiac reverse remodeling, and health status scores were compared between groups using multivariate latent growth curve modeling. Results: Among the 782 patients included in this study, 22.7% were non-Hispanic Black (from here referred to as Black), 14.9% were Hispanic, and 62.4% were non-Hispanic White (from here referred to as White). At baseline, compared with White patients, Black and Hispanic patients had lower NT-proBNP (g=0.34) and differences between groups in baseline values for LV end-diastolic volume index and LV end-systolic volume index were negligible (g

Introduction Sacubitril/valsartan (S/V) promotes reverse cardiac remodeling in patients with HFrEF. Neprilysin inhibition results in increase of several vasoactive peptides that may mediate effects of S/V, however its effects on atrial natriuretic peptide (ANP) are largely unknown. Effects of ANP are mediated by cyclic guanosine monophosphate (cGMP). Hypothesis Longitudinal change in ANP concentration following initiation of S/V is associated with reverse cardiac remodeling. Methods Within a prospective open-label study of initiation and titration of S/V in patients with HFrEF, this pre-specified sub-study included patients in whom ANP was measured from samples collected in protease inhibitors to minimize its degradation. Concentrations of ANP and cGMP were measured at baseline and serially through 12 months of treatment. Echocardiographic assessment of LVEF and left atrial volume index (LAVi) was performed at baseline, 6 and 12 months. Results Among 144 participants (mean age 64.5 years; LVEF 30.8%), median ANP concentration at baseline was 102 pg/mL. Following initiation of S/V, ANP increased steeply and consistently during the first 2 months, with a significant increase in log-transformed ANP concentration at Day 14 (from 4.60 pg/mL to 5.05 pg/mL; Δ = 0.453; P Conclusions Concentrations of ANP increase substantially after initiation of S/V in patients with HFrEF. Larger early increases in ANP after S/V initiation were associated with greater magnitude of reverse cardiac remodeling (PROVE-HF; NCT02887183).

Background Compared to angiotensin-converting enzyme inhibition alone, angiotensin receptor-neprilysin inhibition reduces cardiovascular mortality and heart failure (HF) hospitalization in patients with HF and reduced ejection fraction (HFrEF). The pathophysiologic mechanisms responsible for these clinical benefits remain unclear but may be related to effects on central hemodynamics and cardiac structure and function. We sought to determine whether treatment of HFrEF with sacubitril/valsartan improves central aortic stiffness, cardiac remodeling, biomarkers of wall stress and injury, and quality of life compared with enalapril. Methods EVALUATE-HF was a prospective, randomized, multicenter, double-blind, double-dummy clinical trial of patients aged 50 or older with chronic HF, NYHA I-III symptoms, and EF of 40% or less. Participants were randomized 1:1 to treatment with sacubitril/valsartan (target dose 97/103 mg twice daily) versus enalapril (target dose 10 mg twice daily) for 12 weeks followed by open-label sacubitril/valsartan for 12 weeks (Figure). The primary study outcome was between group difference in change from baseline to week 12 in aortic characteristic impedance (Zc). Other prespecified outcomes included change from baseline to week 12 in levels of cardiac biomarkers and echocardiographic measures of cardiac structure and function as well as change in health-related quality of life assessed by the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Results Between August 17, 2016 and January 26, 2019 we randomized 464 participants at 85 sites in the United States, of whom 231 were randomly assigned to sacubitril/valsartan and 233 to enalapril. For the overall population, mean age was 67.3 +/- 9.1 years, mean EF was 34 +/- 10%, median NTproBNP was 584 [IQR 244, 1467], 109 (23.5%) were female, 115 (24.8%) were black, 313 (67.4%) reported NYHA Class 2, and 391 (84.3%) were previously treated with an ACEi or ARB. We will present the primary results of the EVALUATE-HF study as initially submitted to the 2019 European Society of Cardiology Scientific Sessions, including the effects of sacubitril/valsartan compared with enalapril on change from baseline in central aortic stiffness, cardiac biomarkers, cardiac structure and function. We will also present new data regarding the time course and magnitude of changes in quality of life in both treatment groups during study follow up as well as the relationship of these changes to changes in cardiac structure, function, and biomarkers. Conclusions EVALUATE-HF will provide important mechanistic insights into established clinical benefits of sacubitril/valsartan in HFrEF. We will present detailed quality of life outcomes for the first time at HFSA 2019.

Importance Compared with enalapril, sacubitril-valsartan reduces cardiovascular mortality and heart failure hospitalization in patients with heart failure and reduced ejection fraction (HFrEF). These benefits may be related to effects on hemodynamics and cardiac remodeling. Objective To determine whether treatment of HFrEF with sacubitril-valsartan improves central aortic stiffness and cardiac remodeling compared with enalapril. Design, Setting, and Participants Randomized, double-blind clinical trial of 464 participants with heart failure and ejection fraction of 40% or less enrolled across 85 US sites between August 17, 2016, and June 28, 2018. Follow-up was completed on January 26, 2019. Interventions Randomization (1:1) to sacubitril-valsartan (n = 231; target dosage, 97/103 mg twice daily) vs enalapril (n = 233; target dosage, 10 mg twice daily) for 12 weeks. Main Outcomes and Measures The primary outcome was change from baseline to week 12 in aortic characteristic impedance (Zc), a measure of central aortic stiffness. Prespecified secondary outcomes included change from baseline to week 12 in N-terminal pro–B-type natriuretic peptide, ejection fraction, global longitudinal strain, mitral annular relaxation velocity, mitral E/e′ ratio, left ventricular end-systolic and end-diastolic volume indexes (LVESVI and LVEDVI), left atrial volume index, and ventricular-vascular coupling ratio. Results Of 464 validly randomized participants (mean age, 67.3 [SD, 9.1] years; 23.5% women), 427 completed the study. At 12 weeks, Zc decreased from 223.8 to 218.9 dyne × s/cm5in the sacubitril-valsartan group and increased from 213.2 to 214.4 dyne × s/cm5in the enalapril group (treatment difference, −2.2 [95% CI, −17.6 to 13.2] dyne × s/cm5;P = .78). Of 9 prespecified secondary end points, no significant between-group difference in change from baseline was seen in 4, including left ventricular ejection fraction (34%-36% with sacubitril-valsartan vs 33 to 35% with enalapril; treatment difference, 0.6% [95% CI, −0.4% to 1.7%];P = .24). However, greater reductions from baseline were seen with sacubitril-valsartan than with enalapril in all others, including left atrial volume (from 30.4 mL/m2to 28.2 mL/m2vs from 29.8 mL/m2to 30.5 mL/m2; treatment difference, −2.8 mL/m2[95% CI, −4.0 to −1.6 mL/m2];P Conclusions and Relevance Treatment of HFrEF with sacubitril-valsartan, compared with enalapril, did not significantly reduce central aortic stiffness. The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in HFrEF. Trial Registration ClinicalTrials.gov Identifier:NCT02874794

Antipsychotic agents Asenapine (Saphris—Schering) and iloperidone (Fanapt—Vanda) are new atypical antipsychotic agents that join an already large class of these drugs that includes aripiprazole (Abilify), clozapine (e.g., Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and risperidone (e.g., Risperdal) and its active metabolite paliperidone (Invega). Both new drugs have been approved for the acute treatment of schizophrenia in adults, and asenapine has also been approved for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. The labeled indications for asenapine and iloperidone are more limited than those of their predecessors, with which long-term experience and additional studies have resulted in an extension of the indications for which they were initially approved. Although much remains to be learned regarding the mechanisms through which the antipsychotic agents provide benefit in the treatment of schizophrenia, it is thought that their efficacy is mediated through a combination of antagonist activity at dopamine type 2 and serotonin type 2 receptors. Most of the warnings and precautions associated with using asenapine and iloperidone are similar to those of the other atypical antipsychotic agents. The labeling for all of these agents includes a boxed warning regarding increased mortality in elderly patients with dementia-related psychosis, as well as the statement that these agents have not been approved for treating patients with dementia-related psychosis. Other shared warnings and precautions include the potential for cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, hyperglycemia/diabetes, weight gain, orthostatic hypotension/syncope, hyperprolactinemia, seizures, cognitive and motor impairment, dysphagia, problems associated with body temperature regulation, and leukopenia, neutropenia, and agranulocytosis. The possibility of suicide is inherent in psychiatric illness, and these drugs should be prescribed in the smallest quantities consistent with good patient management to reduce the possibility of overdosage. The labeling for both asenapine and iloperidone, as well as that for selected other atypical antipsychotic agents (e.g., paliperidone, ziprasidone), includes a warning regarding prolongation of the QT interval and the associated risk of cardiac dysrhythmias. Accordingly, the use of these agents should be avoided in patients with congenital long QT syndrome, hypokalemia and/or hypomagnesemia, or a history of cardiac dysrhythmias, as well as in patients being treated with other medications that are known to cause QT prolongation, including Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antidysrhythmic agents, antipsychotic agents (e.g., chlorpromazine, thioridazine, ziprasidone), and antimicrobial agents (e.g., moxifloxacin [Avelox]). Both asenapine and iloperidone are classified in Pregnancy Category C and should only be used during pregnancy if the anticipated benefit outweighs the risk to the fetus. Although it is not known whether the new drugs or their metabolites are excreted in human milk, it is recommended that women treated with either of these agents should not breast feed. The effectiveness and safety of asenapine and iloperidone in patients younger than 18 years of age have not been established. Asenapine and iloperidone are considered on an individual basis below.