Citations

Atrial fibrillation (AF) is an important comorbidity in patients with end-stage renal disease (ESRD) undergoing dialysis that portends increased health care utilization, morbidity, and mortality in this already high-risk population. Patients with ESRD have a particularly high stroke risk, which is further compounded by AF. However, the role of anticoagulation for stroke prophylaxis in ESRD and AF is debated. The ESRD population presents a unique challenge because of the combination of elevated stroke and bleeding risks. Warfarin has been traditionally used in this population, but it is associated with significant risks of minor and major bleeding, particularly intracranial, thus leading many clinicians to forgo anticoagulation altogether. When anticoagulation is prescribed, rates of adherence and persistence are poor, leaving many patients untreated. The direct oral anticoagulants (DOACs) may offer an alternative to warfarin in ESRD patients, but these agents have not been extensively studied in this population and uncertainties regarding comparative effectiveness (versus warfarin, each other, and no treatment) remain. In this review, we discuss the current evidence on the risk and benefits of anticoagulants in this challenging population and comparisons between warfarin and DOACs, and review future directions including options for non-pharmacologic stroke prevention.

Abstract Aims This study was designed to evaluate the safety, tolerability and haemodynamic effects of BMS-986231, a novel second-generation nitroxyl donor with potential inotropic, lusitropic and vasodilatory effects in patients hospitalized with decompensated heart failure and reduced ejection fraction (HFrEF). Methods and results Forty-six patients hospitalized with decompensated HFrEF were enrolled into four sequential dose-escalation cohorts in this double-blind, randomized, placebo-controlled Phase 2a study. Patients with baseline pulmonary capillary wedge pressure (PCWP) of ≥20 mmHg and a cardiac index of ≤2.5 L/min/m2 received one 6-h i.v. infusion of BMS-986231 (at 3, 5, 7 or 12 µg/kg/min) or placebo. BMS-986231 produced rapid and sustained reductions in PCWP, as well as consistent reductions in time-averaged pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure and right atrial pressure. BMS-986231 increased non-invasively measured time-averaged stroke volume index, cardiac index and cardiac power index values, and decreased total peripheral vascular resistance. There was no evidence of increased heart rate, drug-related arrhythmia or symptomatic hypotension with BMS-986231. Analyses of adverse events throughout the 30-day follow-up did not identify any toxicities specific to BMS-986231, with the potential exception of infrequent mild-to-moderate headaches during infusion. There were no treatment-related serious adverse events. Conclusions BMS-986231 demonstrated a favourable safety and haemodynamic profile in patients hospitalized with advanced heart failure. Based on preclinical data and these study's findings, it is possible that the haemodynamic benefits may be mediated by inotropic and/or lusitropic as well as vasodilatory effects. The therapeutic potential of BMS-986231 should be further assessed in patients with heart failure.