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.

Carvedilol (Fig. 1) is a novel multiple action drug that has recently been introduced to the market for the treatment of mild to moderate hypertension (7,8,2426). In extensive clinical trials conducted worldwide, comparisons to all major classes of antihypertensive agents, including captopril, nifedipine, and atenolol, have demonstrated that once-daily therapy with carvedilol is both highly efficacious and possesses a favorable side effect profile. Clinical trials are currently in progress to establish the utility of carvedilol in angina and congestive heart failure.Carvedilol is both a competitive P-adrenoceptor antagonist (76,93,94) and an arterial vasodilator (73). At higher concentrations, carvedilol is also a calcium channel antagonist (73,75,93,94). The vasodilatory actions result primarily from a,-adrenoceptor blockade (73,75,76), although in certain vascular beds, calcium channel blockade may also contribute to vasodilation (96,124). In addition to these actions on the heart and vasculature, carvedilol has also been shown to possess significant antioxidant and antiproliferative actions. These multiple actions are responsible for the antihypertensive efficacy of the drug in animals (93,94,105,106) and in humans (7,8,24-26), and may also work in conjunction to provide effective therapy in angina and congestive heart failure.The antihypertensive response produced by carvedilol is associated with a decrease in peripheral vascular resistance with either no change or only a moderate reduction in heart rate. The reduction in peripheral vascular resistance produced by carvedilol is indicative of arterial vasodilation (7,8,108), and the lack of reflex tachycardia is a direct consequence of the P-adrenoceptor blocking property of the drug (7).Carvedilol has been shown in animal models to protect all the major organ systems that comprise the cardiovascular system, specifically the kidney, heart, vasculature, and brain.

Nitroxyl (HNO) is a reactive nitrogen molecule that has potential therapeutic benefits for patients with acute heart failure. The results of the first‐in‐human study for BMS‐986231, a novel HNO donor, are reported. The aim of this sequential cohort study was to evaluate the safety, tolerability, and pharmacokinetic profile of BMS‐986231 after 24‐ and 48‐hour intravenous infusions in healthy volunteers. Eighty subjects were randomized and dosed. Seven cohorts (stratum A) received BMS‐986231 0.1, 0.33, 1, 3, 5, 10, and 15 μg/kg/min or placebo, infused over 24 hours. An additional cohort (stratum B) received 10 μg/kg/min or placebo, infused over 48 hours. Adverse events (AEs) were reported for 30 days after completion of infusion. Blood/urine samples were collected at regular intervals; other parameters (blood pressure, heart rate/rhythm, cardiac index) were also assessed. Headaches were the most commonly reported drug‐related AE (48%) in those who received BMS‐986231, although their severity was reduced by hydration. No other significant drug‐related AEs were noted. BMS‐986231 was associated with dose‐dependent and well‐tolerated reductions in systolic and diastolic blood pressure versus baseline; cardiac index, as measured noninvasively, was increased. BMS‐986231 had no clinically significant effect on heart rate/rhythm or laboratory parameters. Its mean elimination half‐life was 0.7‐2.5 hours. BMS‐986231 was safe and well‐tolerated for up to 24 hours (15 μg/kg/min) or 48 hours (10 μg/kg/min), with a favorable hemodynamic profile observed. Ongoing studies continue to evaluate the potential benefit of BMS‐986231 in patients with acute heart failure.

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