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Aims: Heart failure (HF) outcomes remain poor despite optimal guideline-directed medical therapy (GDMT). We assessed safety, effectiveness, and transthoracic echocardiographic (TTE) outcomes during the 12 months after Ventura shunt implantation in the RELIEVE-HF open-label roll-in cohort., Methods and Results: Eligibility required symptomatic HF despite optimal GDMT with ≥1 HF hospitalization in the prior year or elevated natriuretic peptides. The safety endpoint was device-related major adverse cardiovascular or neurological events at 30 days, compared to a prespecified performance goal. Effectiveness evaluations included the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline, 1, 3, 6, and 12 months and TTE at baseline and 12 months. Overall, 97 patients were enrolled and implanted at 64 sites. Average age was 70 ± 11 years, 97% were in New York Heart Association class III, and half had left ventricular ejection fraction (LVEF) ≤40%. The safety endpoint was achieved (event rate 0%, p < 0.001). KCCQ overall summary score was improved by 12-16 points at all follow-up timepoints (all p < 0.004), with similar outcomes in patients with reduced and preserved LVEF. At 12 months, left ventricular end-systolic and end-diastolic volumes were reduced (p = 0.020 and p = 0.038, respectively), LVEF improved (p = 0.009), right ventricular end-systolic and end-diastolic areas were reduced (p = 0.001 and p = 0.030, respectively), and right ventricular fractional area change (p < 0.001) and tricuspid annular plane systolic excursion (p < 0.001) improved., Conclusion: Interatrial shunting with the Ventura device was safe and resulted in favourable clinical effects in patients with HF, regardless of LVEF. Improvements of left and right ventricular structure and function were consistent with reverse myocardial remodelling. These results would support the potential of this shunt device as a treatment for HF., (© 2024 European Society of Cardiology.)

Aims: The presence of central sleep apnoea (CSA) is associated with poor prognosis in patients with heart failure (HF). The aim of this analysis was to evaluate if using phrenic nerve stimulation to treat CSA in patients with CSA and HF was associated with changes in HF-specific metrics., Methods and Results: All patients randomized in the remedē System Pivotal Trial and identified at baseline with HF were included (n = 96). Effectiveness data from treatment and former control groups were pooled based on months since therapy activation. Changes from baseline to 6 and 12 months in sleep metrics, Epworth Sleepiness Scale, patient global assessment health-related quality of life, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and echocardiographic parameters are reported. HF hospitalization, cardiovascular death, and the composite of HF hospitalization or cardiovascular death within 6 months are reported by the original randomized group assignment for safety assessment. Sleep metrics and quality of life improved from baseline to 6 and 12 months. At 12 months, MLHFQ scores changed by -6.8 ± 20.0 (P = 0.005). The 6-month rate of HF hospitalization was 4.7% in treatment patients (standard error = 3.3) and 17.0% in control patients (standard error = 5.5) (P = 0.065). Reported adverse events were as expected for a transvenous implantable system., Conclusions: Phrenic nerve stimulation reduces CSA severity in patients with HF. In parallel, this CSA treatment was associated with benefits on HF quality of life., (© 2018 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The TRUE-AHF is a randomized, double-blind, parallel-group, placebo-controlled trial which is evaluating the effects of a 48-h infusion of ularitide (15 ng/kg/min) on the short- and long-term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long-term follow-up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event-driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in-hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE-AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure., Trial Registration: NCT01661634., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Data Monitoring Committees (DMCs) play a crucial role in the conducting of clinical trials to ensure the safety of study participants and to maintain a trial's scientific integrity. Generally accepted standards exist for DMC composition and operational conduct. However, some relevant issues are not specifically addressed in current guidance documents, resulting in uncertainties regarding optimal approaches for communication between the DMC, steering committee, and sponsors, release of information, and liability protection for DMC members. The Heart Failure Association (HFA) of the European Society of Cardiology (ESC), in collaboration with the Clinical Trials Unit of the European Heart Agency (EHA) of the ESC convened a meeting of international experts in DMCs for cardiovascular and cardiometabolic clinical trials to identify specific issues and develop steps to resolve challenges faced by DMCs.The main recommendations from the meeting relate to methodological consistency, independence, managing conflicts of interest, liability protection, and training of future DMC members. This paper summarizes the key outcomes from this expert meeting, and describes the core set of activities that might be further developed and ultimately implemented by the ESC, HFA, and other interested ESC constituent bodies. The HFA will continue to work with stakeholders in cardiovascular and cardiometabolic clinical research to promote these goals., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patient's burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Objectives: Emergency medical research performed under federal regulation 21 § CFR 50.24 provides a means to protect human subjects and investigate novel time-sensitive treatments. Although prospective individual consent is not required for studies conducted under this regulation, consent from a legally authorized representative (LAR) or the patient at the earliest feasible opportunity is required to obtain short- and long-term outcome data. The objective of this study was to determine which demographic, cardiac arrest, and patient outcome characteristics predicted the likelihood of obtaining informed consent following enrollment under exception from informed consent in a multicenter cardiac arrest study., Methods: This investigation was an analysis of data collected during a multisite, randomized, controlled, out-of-hospital cardiac arrest clinical trial performed under 21 § CFR 50.24. Research personnel attempted to obtain informed consent from LARs and subjects for medical records review of primary outcome data, as well as consent for neurologic outcome assessments up to 1 year post-cardiac arrest. Hospital discharge and neurologic status were obtained from public records and/or medical records up until the time consent was formally denied, in accordance with federal regulations and guidance. Local institutional review boards also allowed medical records review for cases where consent was neither obtained nor declined despite multiple consent attempts. Patient demographic, cardiac arrest, and clinical outcome characteristics were analyzed in univariate multinomial regression models, with consent status (obtained, denied, neither obtained nor denied) as the dependent variable. A multivariate multinomial logistic regression was then performed. An exploratory secondary analysis following the same process was performed after assigning patients who neither consented nor declined to the declined consent group., Results: Among a total study population of 1,655 cardiac arrest subjects, 457 were transported and had consent attempted (27.6%). The survival status and neurologic function at the time of hospital discharge were known in 440 of 457 (96%) subjects. In the multivariate analysis, initial rhythm of ventricular fibrillation/ventricular tachycardia (VF/VT) and survival with good neurologic outcome were strong predictors of obtaining consent (odds ratio [OR] = 3.15, 95% confidence interval [CI] = 1.73 to 5.75; OR = 7.64, 95% CI = 2.28 to 25.63, respectively). The exploratory secondary analysis also showed initial rhythm of VF/VT and survival with good neurologic outcome as strong predictors of obtaining consent (OR = 1.86, 95% CI = 1.17 to 2.95; OR = 4.52, 95% CI = 2.21 to 9.26, respectively)., Conclusions: Initial arrest rhythm and survival with good neurologic outcome were highly predictive of obtaining consent in this cardiac arrest trial. This phenomenon could result in underrepresentation of outcome data in the study arm with the worse outcome and represents a significant potential confounder in studies performed under 21 § CFR 50.24. Future revisions to the exception from informed consent regulations should allow access to critical survival data recorded as part of standard documentation, regardless of patient consent status., (© 2015 by the Society for Academic Emergency Medicine.)

The desire to replace the amide backbone of renin inhibitors with a new scaffold led us to explore vinylogous amides (enaminones). An initial attempt proved unsuccessful, a result explained after the fact via docking experiments. Based on this lesson, we designed a different vinylogous amide scaffold which incorporated one or more pyrrolinone rings into the backbone. Three of the four compounds gave IC50S in the 0.6 to 18 microM range. These compounds did not inhibit HIV-1 protease. Taken together, the results reported herein provide insights into the role of hydrogen bonding and steric interactions for binding to renin.