Natriuretic Peptide-Based Inclusion Criteria in a Heart Failure Clinical Trial: Insights From COMMANDER HF.

Objectives: This study investigated the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) trial.

Background: Heart failure (HF) trials that select patients based on history of HF hospitalization alone are susceptible to regional variations in event rates. Elevated plasma concentrations of natriuretic peptides (NPs) as selection criteria may help HF ascertainment and risk enrichment.

Effects of Elamipretide on Left Ventricular Function in Patients With Heart Failure With Reduced Ejection Fraction: The PROGRESS-HF Phase 2 Trial.

Background: Elamipretide, a novel mitochondrial modulating agent, improves myocardial energetics; however, it is unknown whether this mechanistic benefit translates into improved cardiac structure and function in heart failure (HF) with reduced ejection fraction (HFrEF). The objective of this study was to evaluate the effects of multiple subcutaneous doses of elamipretide on left ventricular end systolic volume (LVESV) as assessed by cardiac magnetic resonance imaging.

Methods: We randomized 71 patients with HFrEF (LVEF ≤ 40%) in a double-blind, placebo-controlled trial in a 1:1:1 ratio to receive placebo, 4 mg or 40 mg elamipretide once daily for 28 consecutive days.

Preoperative Noncoronary Cardiovascular Assessment and Management of Kidney Transplant Candidates.

The pretransplant risk assessment for patients with ESKD who are undergoing evaluation for kidney transplant is complex and multifaceted. When considering cardiovascular disease in particular, many factors should be considered. Given the increasing incidence of kidney transplantation and the growing body of evidence addressing ESKD-specific cardiovascular risk profiles, there is an important need for a consolidated, evidence-based model that considers the unique cardiovascular challenges that these patients face.

Assessment and management of coronary artery disease in kidney and pancreas transplant candidates.

: Patients with end-stage renal disease (ESRD) undergoing evaluation for kidney and/or pancreas transplantation represent a population with unique cardiovascular (CV) profiles and unique therapeutic needs. Coronary artery disease (CAD) is common in patients with ESRD, mediated by both the overrepresentation and higher prognostic value of traditional CV risk factors amongst this population, as well as altered cardiovascular responses to failing renal function, likely mediated by dysregulation of the renin-angiotensin-aldosterone system (RAAS) and abnormal calcium and phosphate metabolism. Within the ESRD population, obstructive CAD correlates highly with adverse coronary events, including during the peri-transplant period, and successful revascularization may attenuate some of that increased risk.

Medication dosing for heart failure with reduced ejection fraction - opportunities and challenges.

Multiple drug classes have shown incremental benefits in heart failure with reduced ejection fraction. Most of these trials were designed to achieve specific doses of the investigational agent. Clinical practice guidelines recommend using the same target dosing of therapies, as tolerated.

Safety and Tolerability of the Chymase Inhibitor Fulacimstat in Patients With Left Ventricular Dysfunction After Myocardial Infarction-Results of the CHIARA MIA 1 Trial.

The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose.

Rationale and design of the phase 2b clinical trials to study the effects of the partial adenosine A1-receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced (PANTHEON) and preserved (PANACHE) ejection fraction.

Despite major advances in the treatment of chronic heart failure (HF) with reduced ejection fraction (HFrEF), morbidity and mortality associated with the condition remain high, suggesting the need for additional treatment options, particularly haemodynamically neutral treatments that do not alter blood pressure, heart rate, or renal function. HF with preserved ejection fraction (HFpEF) is also associated with high morbidity and mortality and adequate treatment options are limited; thus there is a critical unmet need for the development of novel therapies for HFpEF. Chronic HFrEF and HFpEF are both systemic disorders that affect not only the heart but several other tissues and organs including skeletal muscle, leading to exercise intolerance and dyspnoea.

A Critical Appraisal of Short-Term End Points in Acute Heart Failure Clinical Trials.

The prevalence of heart failure continues to grow, and this is accompanied by an increase in hospitalization for acute heart failure. Hospitalization for heart failure results in a trajectory shift of the syndrome and is associated with worsening outcomes, increased mortality risk, and high costs. Numerous clinical trials over the past 2 decades have had limited success, with no single agent shown to improve mortality risk.

Rivaroxaban in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease.

Background: Heart failure is associated with activation of thrombin-related pathways, which predicts a poor prognosis. We hypothesized that treatment with rivaroxaban, a factor Xa inhibitor, could reduce thrombin generation and improve outcomes for patients with worsening chronic heart failure and underlying coronary artery disease.

Methods: In this double-blind, randomized trial, 5022 patients who had chronic heart failure, a left ventricular ejection fraction of 40% or less, coronary artery disease, and elevated plasma concentrations of natriuretic peptides and who did not have atrial fibrillation were randomly assigned to receive rivaroxaban at a dose of 2.

A new educational program in heart failure drug development: the Brescia international master program.

: Despite recent advances in chronic heart failure treatment, prognosis of acute heart failure patients remains poor with a heart failure rehospitalization rate or death reaching approximately 25% during the first 6 months after discharge. In addition, about half of these patients have preserved ejection fraction for which there are no evidence-based therapies. Disappointing results from heart failure clinical trials over the past 20 years emphasize the need for developing novel approaches and pathways for testing new heart failure drugs and devices.

Mobile health applications in cardiovascular research.

Cardiovascular disease is the leading cause of mortality and morbidity globally. With widespread and growing use of smart phones and mobile devices, the use of mobile health (mHealth) in transmission of physiologic parameters and patient-referred symptoms to healthcare providers and researchers, as well as reminders and care plan applications from providers to patients, has potential to revolutionize both clinical care and the conduct of clinical trials with improved designs, data capture, and potentially lower costs. In randomized early phase proof-of-concept studies, focusing on lifestyle intervention, there is evidence that mHealth technology can improve outcomes.

Expanded algorithm for managing patients with acute decompensated heart failure.

Heart failure is a complex disease process, the manifestation of various cardiac and noncardiac abnormalities. General treatment approaches for heart failure have remained the same over the past decades despite the advent of novel therapies and monitoring modalities. In the same vein, the readmission rates for heart failure patients remain high and portend a poor prognosis for morbidity and mortality.

Predictors of Post-discharge Mortality Among Patients Hospitalized for Acute Heart Failure.

Acute Heart Failure (AHF) is a " multi-event disease" and hospitalisation is a critical event in the clinical course of HF. Despite relatively rapid relief of symptoms, hospitalisation for AHF is followed by an increased risk of death and re-hospitalisation. In AHF, risk stratification from clinically available data is increasingly important in evaluating long-term prognosis.

Dual Vasopressin V1a/V2 Antagonism: The Next Step in Neurohormonal Modulation in Patients With Heart Failure?

Stimulation of the V1a receptor for arginine vasopressin produces myocardial and vascular effects similar to those of angiotensin II while stimulation of the V2 receptor causes fluid retention. There are no data with sustained blockade of the V1a receptor while single-dose experiments suggest benefit. Acute and chronic administration of selective V2 receptor antagonists reliably relieves dyspnea and produces diuresis without adverse effects on renal function or neurohormonal stimulation, either as adjunctive or alternative therapy to loop diuretics, but has not been shown to improve outcomes as adjunctive therapy.

Acute Dyspnea and Decompensated Heart Failure.

The majority of patients hospitalized with acute heart failure (AHF) initially present to the emergency department (ED). Correct diagnosis followed by prompt treatment ensures optimal outcomes. Paradoxically, identification of high risk is not the unmet need, given nearly all ED AHF patients are hospitalized; rather, it is identification of low-risk.

Regional Validation and Recalibration of Clinical Predictive Models for Patients With Acute Heart Failure.

Background: Heart failure clinical practice guidelines recommend applying validated clinical predictive models (CPMs) to support decision making. While CPMs are now widely available, the generalizability of heart failure CPMs is largely unknown.

Methods And Results: We identified CPMs derived in North America that predict mortality for patients with acute heart failure and validated these models in different world regions to assess performance in a contemporary international clinical trial (N=4133) of patients with acute heart failure treated with guideline-directed medical therapy.

Plasma renin activity, response to aliskiren, and clinical outcomes in patients hospitalized for heart failure: the ASTRONAUT trial.

Aims: The direct renin inhibitor, aliskiren, is known to reduce plasma renin activity (PRA), but whether the efficacy of aliskiren varies based on an individual's baseline PRA in patients hospitalized for heart failure (HF) is presently unknown. We characterized the prognostic value of PRA and determined if this risk is modifiable with use of aliskiren.

Methods And Results: This pre-specified neurohormonal substudy of ASTRONAUT analysed all patients hospitalized for HF with ejection fraction (EF) ≤40% with available baseline PRA data (n = 1306, 80.

Lessons learned in acute heart failure.

Acute heart failure (HF) is a global pandemic with more than one million admissions to hospital annually in the US and millions more worldwide. Post-discharge mortality and readmission rates remain unchanged and unacceptably high. Although recent drug development programmes have failed to deliver novel therapies capable of reducing cardiovascular morbidity and mortality in patients hospitalized for worsening chronic HF, hospitalized HF registries and clinical trial databases have generated a wealth of information improving our collective understanding of the HF syndrome.

Pre-discharge and early post-discharge troponin elevation among patients hospitalized for heart failure with reduced ejection fraction: findings from the ASTRONAUT trial.

Aims: Troponin levels are commonly elevated among patients hospitalized for heart failure (HF), but the prevalence and prognostic significance of early post-discharge troponin elevation are unclear. This study sought to describe the frequency and prognostic value of pre-discharge and post-discharge troponin elevation, including persistent troponin elevation from the inpatient to outpatient settings.

Methods And Results: The ASTRONAUT trial (NCT00894387; http://www.

Renin-angiotensin blockade in heart failure with preserved ejection fraction: a systematic review and meta-analysis.

Studies with angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in patients with heart failure with preserved ejection fraction (HFpEF) have yielded inconsistent results. To conduct a systematic review and meta-analysis of all evidence for ACE-I and ARBs in patients with HFpEF, we searched PubMed, Ovid SP, Embase, and Cochrane database to identify randomized trials and observational studies that compared ACE-I or ARBs against placebo or standard therapy in HFpEF patients. Random-effect models were used to pool the data, and I testing was performed to assess the heterogeneity of the included studies.

Dose of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and Outcomes in Heart Failure: A Meta-Analysis.

Background: The association between angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) doses on outcomes in patients with heart failure (HF) with reduced ejection fraction is uncertain. The objective of this study was to investigate the effect of dose of ACEI and ARBs on outcomes and drug discontinuation in patients with HF with reduced ejection fraction.

Methods And Results: MEDLINE, Ovid SP, and Embase were searched from the inception of these databases till August 2016.