Effects of sacubitril/valsartan according to polypharmacy status in PARAGON-HF.

Aims: Patients with heart failure (HF) and preserved ejection fraction (HFpEF) have a particularly high prevalence of comorbidities, often necessitating treatment with many medications. The aim of this study was to evaluate the association between polypharmacy status and outcomes in PARAGON-HF.

Methods And Results: In this post hoc analysis, baseline medication status was available in 4793 of 4796 patients included in the primary analysis of PARAGON-HF.

Independent prognostic importance of blood urea nitrogen to creatinine ratio in heart failure.

Aim: Blood urea nitrogen (BUN) to creatinine ratio is associated with worse outcomes in acute heart failure (HF) but little is known about its importance in chronic HF.

Methods And Results: We combined individual patient data from clinical trials (HF with reduced ejection fraction [HFrEF]: PARADIGM-HF, ATMOSPHERE and DAPA-HF, and HF with preserved ejection fraction [HFpEF]: PARAGON-HF and I-PRESERVE). The primary outcome examined was a composite time to first HF hospitalization or cardiovascular death; its components and all-cause death were also examined.

Changes in mid-regional pro-adrenomedullin during treatment with sacubitril/valsartan.

Aims: Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment.

Methods And Results: Mid-regional pro-adrenomedullin (MR-proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with heart failure with preserved ejection fraction (HFpEF) randomized to treatment with Sac/Val or valsartan.

Duration of Heart Failure With Preserved Ejection Fraction and Outcomes With Sacubitril/Valsartan: Insights From the PARAGON-HF Trial.

Objective: In this post hoc analysis of the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) trial, we evaluated clinical outcomes and responses to sacubitril/valsartan by duration of heart failure (HF) with left ventricular ejection fraction ≥ 45% at initial diagnosis.

Methods And Results: The primary outcome was a composite of total hospitalizations due to HF and cardiovascular deaths, analyzed by using a semiparametric proportional rates method, stratified by geographic region. Among 4784 (99.

Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).

Background: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive.

Methods: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months.

Importance of cystatin C in estimating glomerular filtration rate: the PARADIGM-HF trial.

Aims: The 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation combining creatinine and cystatin C provides a better estimation of glomerular filtration rate (GFR) compared to the creatinine-only equation.

Methods And Results: CKD-EPI creatinine-cystatin C equation (creatinine-cystatin) was compared to creatinine-only (creatinine) equation in a subpopulation of Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF). Patients were categorized according to difference in eGFR using the two equations: Group 1 (<-10 mL/min/1.

Anthropometric measures and adverse outcomes in heart failure with reduced ejection fraction: revisiting the obesity paradox.

Aims: Although body mass index (BMI) is the most commonly used anthropometric measure, newer indices such as the waist-to-height ratio, better reflect the location and amount of ectopic fat, as well as the weight of the skeleton, and may be more useful.

Methods And Results: The prognostic value of several newer anthropometric indices was compared with that of BMI in patients with heart failure (HF) and reduced ejection fraction (HFrEF) enrolled in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure. The primary outcome was HF hospitalization or cardiovascular death.

Urinary cGMP (Cyclic Guanosine Monophosphate)/BNP (B-Type Natriuretic Peptide) Ratio, Sacubitril/Valsartan, and Outcomes in Heart Failure With Reduced Ejection Fraction: An Analysis of the PARADIGM-HF Trial.

Background: The ratio of ucGMP (urinary cyclic guanosine monophosphate) to BNP (B-type natriuretic peptide) is thought to reflect the responsiveness of tissues to natriuretic peptides.

Methods: We examined the relationship between ucGMP/BNP ratio and clinical outcomes, the effect of sacubitril/valsartan, compared with enalapril, on the ucGMP/BNP ratio, and the efficacy of sacubitril/valsartan on clinical outcomes according to baseline ucGMP/BNP ratio in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). ucGMP/BNP ratio was available at baseline (N=2031), 1 month (N=1959), and 8 months after randomization (N=1746).

Investigator-reported ventricular arrhythmias and mortality in heart failure with mildly reduced or preserved ejection fraction.

Aims: Few reports have examined the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) or their relationship with mortality in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF).

Methods And Results: Data from the PARAGON-HF, TOPCAT, I-Preserve, and CHARM-Preserved trials were merged. VT/VF, reported as adverse events, were identified.

Associations Between New York Heart Association Classification, Objective Measures, and Long-term Prognosis in Mild Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial.

Importance: Heart failure (HF) treatment recommendations are centered on New York Heart Association (NYHA) classification, such that most apparently asymptomatic patients are not eligible for disease-modifying therapies.

Objectives: To assess within-patient variation in NYHA classification over time, the association between NYHA class and an objective measure of HF severity (N-terminal pro-B-type natriuretic peptide [NT-proBNP] level), and their association with long-term prognosis in the PARADIGM-HF trial.

Design, Setting, And Participants: All patients in PARADIGM-HF were in NYHA class II or higher at baseline and were treated with sacubitril-valsartan during a 6- to 10-week run-in period before randomization.

Effect of sacubitril/valsartan on investigator-reported ventricular arrhythmias in PARADIGM-HF.

Aims: Sudden death is a leading cause of mortality in heart failure with reduced ejection fraction (HFrEF). In PARADIGM-HF, sacubitril/valsartan reduced the incidence of sudden death. The purpose of this post hoc study was to analyse the effect of sacubitril/valsartan, compared to enalapril, on the incidence of ventricular arrhythmias.

Diagnostic criteria for apathy in neurocognitive disorders.

Introduction: Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed.

Methods: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019.

Global Differences in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial.

Methods: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region.

Cardiac and Noncardiac Disease Burden and Treatment Effect of Sacubitril/Valsartan: Insights From a Combined PARAGON-HF and PARADIGM-HF Analysis.

Background: The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction.

Methods: We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399] and PARAGON-HF [Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796]).

Dynamic changes in cardiovascular and systemic parameters prior to sudden cardiac death in heart failure with reduced ejection fraction: a PARADIGM-HF analysis.

Aims: Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time-point. We investigated independent predictors of SCD addressing the impact of integrating time-varying covariates to improve prediction assessment.

Methods And Results: We studied 8399 patients enrolled in the PARADIGM-HF trial and identified independent predictors of SCD (n = 561, 36% of total deaths) using time-updated multivariable-adjusted Cox models, classification and regression tree (CART), and logistic regression analysis.

Relationship between duration of heart failure, patient characteristics, outcomes, and effect of therapy in PARADIGM-HF.

Aims: Little is known about patient characteristics, outcomes, and the effect of treatment in relation to duration of heart failure (HF). We have investigated these questions in PARADIGM-HF. The aim of the study was to compare patient characteristics, outcomes, and the effect of sacubitril/valsartan, compared with enalapril, in relation to time from HF diagnosis in PARADIGM-HF.

Prognostic value of brain natriuretic peptide vs history of heart failure hospitalization in a large real-world population.

Background: In heart failure (HF) patients, both natriuretic peptides (NP) and previous HF hospitalization (pHFH) have been used to predict prognosis.

Hypothesis: In a large real-world population, both NP levels and pHFH have independent and interdependent predictive value for clinical outcomes of HFH and all-cause mortality.

Methods: Linked electronic health records and insurance claims data from Decision Resource Group were used to identify HF patients that had a BNP or NT-proBNP result between January 2012 and December 2016.

Measuring Apathy in Alzheimer's Disease in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): A Comparison of Instruments.

Background: Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver.

Objective: The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2.

Neurobiologic Rationale for Treatment of Apathy in Alzheimer's Disease With Methylphenidate.

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting.

The prevalence and importance of frailty in heart failure with reduced ejection fraction - an analysis of PARADIGM-HF and ATMOSPHERE.

Aims: Frailty, characterized by loss of homeostatic reserves and increased vulnerability to physiological decompensation, results from an aggregation of insults across multiple organ systems. Frailty can be quantified by counting the number of 'health deficits' across a range of domains. We assessed the frequency of, and outcomes related to, frailty in patients with heart failure and reduced ejection fraction (HFrEF).

Covariate adjusted reanalysis of the I-Preserve trial.

Background: The CHARM-Preserved trial suggested that the renin-angiotensin system (RAS) inhibitor candesartan might have been beneficial in heart failure with preserved ejection fraction (HFpEF); however, this hypothesis was not supported by the findings of I-Preserve with irbesartan.

Aims: To re-analyse the results of I-Preserve, adjusting for imbalances in baseline variables that may have influenced the trial outcomes.

Methods: Cox proportional hazards models with covariate adjustment for baseline variables, including age, sex, medical history, physiological and laboratory variables.

Comparison of BNP and NT-proBNP in Patients With Heart Failure and Reduced Ejection Fraction.

Background: Both BNP (B-type natriuretic peptide) and NT-proBNP (N-terminal pro B-type natriuretic peptide) are widely used to aid diagnosis, assess the effect of therapy, and predict outcomes in heart failure and reduced ejection fraction. However, little is known about how these 2 peptides compare in heart failure and reduced ejection fraction, especially with contemporary assays. Both peptides were measured at screening in the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure).