Abstract Background Natriuretic peptides (NP) have prognostic value in heart failure (HF), although the clinical importance of changes in NP from baseline is unclear. Objectives The authors assessed ...whether a reduction in N-terminal pro–B-type NP (NT-proBNP) was associated with a decrease in HF hospitalization and cardiovascular mortality (primary endpoint) in patients with HF and reduced ejection fraction, whether treatment with sacubitril/valsartan reduced NT-proBNP below specific partition values more than enalapril, and whether the relationship between changes in NT-proBNP and changes in the primary endpoint were dependent on assigned treatment. Methods In PARADIGM-HF (Prospective Comparison of ARNI Angiotensin Receptor–Neprilysin Inhibitor with ACEI Angiotensin-Converting–Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial), baseline NT-proBNP was measured in 2,080 patients; 1,292 had baseline values >1,000 pg/ml and were reassessed at 1 and 8 months. We related change in NT-proBNP to outcomes. Results One month after randomization, 24% of the baseline NT-proBNP levels >1,000 pg/ml had fallen to ≤1,000 pg/ml. Risk of the primary endpoint was 59% lower in patients with a fall in NT-proBNP to ≤1,000 pg/ml than in those without such a fall. In sacubitril/valsartan-treated patients, median NT-proBNP was significantly lower 1 month after randomization than in enalapril-treated patients, and it fell to ≤1,000 pg/ml in 31% versus 17% of patients treated with sacubitril/valsartan and enalapril, respectively. There was no significant interaction between treatment and the relationship between change in NT-proBNP and the subsequent risk of the primary endpoint. Conclusions Patients who attained a significant reduction in NT-proBNP had a lower subsequent rate of cardiovascular death or HF hospitalization independent of the treatment group. Treatment with sacubitril/valsartan was nearly twice as likely as enalapril to reduce NT-proBNP to values ≤1,000 pg/ml. (Prospective Comparison of ARNI Angiotensin Receptor–Neprilysin Inhibitor with ACEI Angiotensin-Converting–Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) PARADIGM-HF; NCT01035255 .)
•We examine and compare wholesale and agency models of electronic books.•A Pareto zone for the agency model always exists in the decentralized channels.•A Pareto zone exists in the horizontally ...centralized channels except special cases.•We investigate how various parameters affect profit improvement and readers’ welfare.
We model a supply chain consisting of an author, a publisher, a physical bookstore (p-bookstore), and an electronic bookstore (e-bookstore). We employ game theory to examine and compare two types of pricing models of electronic books (e-books): wholesale model and agency model. Furthermore, we consider decentralized and horizontally centralized channels. The p-bookstore and e-bookstore are independent in the former but centralized in the latter. We adopt a simplified linear demand model to study when the publisher and the e-bookstore both benefit from the agency model. We find that a Pareto zone where both the publisher and e-bookstore benefit from the agency model always exists in the decentralized channels. In the agency model, the benefit from e-book sales may be more than the loss in physical book (p-book) sales. By contrast, a Pareto zone exists in the horizontally centralized channels if the wholesale price of p-books is not excessively low and the price elasticity is not extremely large. To check the robustness of our results, we relax model assumptions and conduct numerical studies in the Pareto zone to investigate how various parameters, such as authors royalty rate, affect profit improvement and readers welfare. We show that the publisher and bookstore have great potentials for profit improvement in the Pareto zone. Significant improvement is also observed in readers welfare.
Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that ...circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone.
This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death).
N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint.
At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval CI: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates.
Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction PARAGON-HF; NCT01920711)
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As the real‐time digital counterpart of a physical system or process, digital twins are utilized for system simulation and optimization. Neural networks are one way to build a digital twins model by ...using data especially when a physics‐based model is not accurate or even not available. However, for a newly designed system, it takes time to accumulate enough data for neural network models and only an approximate physics‐based model is available. To take advantage of both models, this paper proposed a model that combines the physics‐based model and the neural network model to improve the prediction accuracy for the whole life cycle of a system. The proposed hybrid model (PhysiNet) was able to automatically combine the models and boost their prediction performance. Experiments showed that the PhysiNet outperformed both the physics‐based model and the neural network model.
The absence of integrated decision-making across the agri-food system is arguably the single biggest obstacle to global food security and breaking through it is perhaps our biggest challenge. To date ...little research has been done which takes a fully integrated view to address this global challenge. Integrated decision making implies change across all parts of the diverse agri-food system, requiring an integrated assessment of all the processes involved from the ecology of the land through to nutrition and health. To address this research need, we propose a theoretical framework for integrated solutions based upon mapping of whole agri-food systems, their quantitative analysis based on enhanced life cycle assessment, the use of emergent data to catalyse viable and commercially attractive innovation and the free access of data to all stakeholders and in particular consumers as the principle engine for change. This integrated framework is conceptualised through theoretical development building from prior research. This theoretical framework involves an iterative methodology of four overlapping steps (Map, Analyse, Visualise and Share), namely the MAVS cycle. It gives a transparent advanced methodology and collaborative decision support to all stakeholders across the agri-food ecosystems. We hypothesize that this framework would provide a mechanism to break down the current barriers that prevent the integrated solutions absolutely necessary for global food security. We also theoretically position the perspective that it would break the “four walls” of information that reside within each organisation, fostering an open system that encourages a more democratized agri-food system, in which sustainability and resource efficiency are embedded.
•A theoretical Map, Analyse, Visualize and Share integrated framework is proposed.•The framework promotes a transparent methodology for collaborative decision support.•A mechanism to break down barriers that prevent integrated solutions is suggested.•An open system embedding sustainability and resource efficiency is fostered.
The angiotensin receptor–neprilysin inhibitor LCZ696 was compared with the ACE inhibitor enalapril in patients with advanced heart failure. LCZ696 was superior to enalapril in all outcomes. ...Neprilysin inhibition may replace ACE inhibition for the treatment of heart failure.
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.
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Long-term treatment with enalapril decreased the relative risk of death by 16% among patients with mild-to-moderate symptoms.
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The effect of angiotensin-receptor blockers (ARBs) on mortality has been inconsistent,
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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 . . .
The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction.
Renal function is frequently impaired in patients ...with heart failure with reduced ejection fraction and may deteriorate further after blockade of the renin–angiotensin system.
In the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, 8,399 patients with heart failure with reduced ejection fraction were randomized to treatment with sacubitril/valsartan or enalapril. The estimated glomerular filtration rate (eGFR) was available for all patients, and the urinary albumin/creatinine ratio (UACR) was available in 1872 patients, at screening, randomization, and at fixed time intervals during follow-up. We evaluated the effect of study treatment on change in eGFR and UACR, and on renal and cardiovascular outcomes, according to eGFR and UACR.
At screening, the eGFR was 70 ± 20 ml/min/1.73 m2 and 2,745 patients (33%) had chronic kidney disease; the median UACR was 1.0 mg/mmol (interquartile range IQR: 0.4 to 3.2 mg/mmol) and 24% had an increased UACR. The decrease in eGFR during follow-up was less with sacubitril/valsartan compared with enalapril (−1.61 ml/min/1.73 m2/year; 95% confidence interval: −1.77 to −1.44 ml/min/1.73 m2/year vs. −2.04 ml/min/1.73 m2/year 95% CI: −2.21 to −1.88 ml/min/1.73 m2/year ; p < 0.001) despite a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol 95% CI: 1.04 to 1.36 mg/mmol vs. 0.90 mg/mmol 95% CI: 0.77 to 1.03 mg/mmol; p < 0.001). The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38).
Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR and improved cardiovascular outcomes, even in patients with chronic kidney disease, despite causing a modest increase in UACR.
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Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with ...heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA
and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF.
In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA
≥6·5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA
, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Time to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups.
There were no significant differences in HbA
concentrations between randomised groups at screening. During the first year of follow-up, HbA
concentrations decreased by 0·16% (SD 1·40) in the enalapril group and 0·26% (SD 1·25) in the sacubitril/valsartan group (between-group reduction 0·13%, 95% CI 0·05-0·22, p=0·0023). HbA
concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0·14%, 95% CI 0·06-0·23, p=0·0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 7% patients) compared with patients receiving enalapril (153 10%; hazard ratio 0·71, 95% CI 0·56-0·90, p=0·0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0·77, 0·58-1·02, p=0·073) in the sacubitril/valsartan group.
Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA
than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF.
Novartis.
BACKGROUND:While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF ...(>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone–system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF.
METHODS:We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF.
RESULTS:Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone–system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio HR 0.84 95% CI, 0.78–0.90), cardiovascular death (HR 0.84 95% CI, 0.76–0.92), heart failure hospitalization (HR 0.84 95% CI, 0.77–0.91), and all-cause mortality (HR 0.88 95% CI, 0.81–0.96). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P=0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions.
CONCLUSIONS:The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone–system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men.
CLINICAL TRIAL REGISTRATION:https://www.clinicaltrials.gov. Unique identifiersNCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).
Patients with heart failure and reduced ejection fraction have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and heart failure ...hospitalizations. In PARADIGM-HF trial (Prospective Comparison of ARNI Angiotensin Receptor-Neprilysin Inhibitor With ACEI Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan reduced morbidity and mortality compared with enalapril. Another major treatment goal is to improve HRQL. Given improvements in mortality with sacubitril/valsartan, this analysis provides comprehensive assessment of impact of therapy on HRQL in survivors only.
Patients (after run-in phase) completed disease-specific HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures analysis of covariance model that adjusted for treatment and baseline values (principal efficacy prespecified at 8 months). Among the 8399 patients enrolled in PARADIGM-HF, 7623 (91%) completed KCCQ scores at randomization with complete data at 8 months for 6881 patients (90% of baseline). At 8 months, sacubitril/valsartan group noted improvements in both KCCQ clinical summary score (+0.64 versus -0.29;
=0.008) and KCCQ overall summary score (+1.13 versus -0.14;
<0.001) in comparison to enalapril group and significantly less proportion of patients with deterioration (≥5 points decrease) of both KCCQ scores (27% versus 31%;
=0.01). Adjusted change scores demonstrated consistent improvements in sacubitril/valsartan compared with enalapril through 36 months.
Change scores in KCCQ clinical summary scores and KCCQ overall summary scores were better in patients treated with sacubitril/valsartan compared with those treated with enalapril, with consistency in most domains, and persist during follow-up beyond 8 months. These findings demonstrate that sacubitril/valsartan leads to better HRQL in surviving patients with heart failure.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.
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