Impact of vasodilators on diuretic response in patients with congestive heart failure: A mechanistic trial of cimlanod (BMS‐986231)

Abstract

AimTo investigate the effects of Cimlanod, a nitroxyl donor with vasodilator properties, on water and salt excretion after an administration of an intravenos bolus of furosemide.Methods and resultsIn this randomized, double‐blind, mechanistic, crossover trial, 21 patients with left ventricular ejection fraction <45%, increased plasma concentrations of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and receiving loop diuretics were given, on separate study days, either an 8 h intravenous (IV) infusion of cimlanod (12 μg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the 4 h after the bolus of furosemide during infusion of cimlanod compared with placebo. Median NT‐proBNP at baseline was 1487 (interquartile range: 847–2665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure without affecting cardiac power index consistent with its vasodilator effects. Urine volume in the 4 h post‐furosemide was lower with cimlanod (1032 ± 393 ml) versus placebo (1481 ± 560 ml) (p = 0.002), as were total sodium excretion (p = 0.004), fractional sodium excretion (p = 0.016), systolic blood pressure (p < 0.001), estimated glomerular filtration rate (p = 0.012), and haemoglobin (p = 0.010), an index of plasma volume expansion.ConclusionsFor patients with heart failure and congestion, vasodilatation with agents such as cimlanod reduces the response to diuretic agents, which may offset any benefit from acute reductions in cardiac preload and afterload.

New cimlanod trial provides insights into mechanistic effects of vasodilators in heart failure

“…The STAND-UP AHF trial 12 demonstrated that cimlanod was well tolerated, provided expected vasodilatory and decongestive effects, but those benefits did not persist beyond 48-h duration of treatment, while the StandUP Imaging trial 13 showed improvements in left ventricular end-systolic dimensions and stroke volume indices comparable to nitroglycerin, without additional inotropic or lusitropic effects, in a small cohort of chronic HF patients. The most recent cimlanod study published by Pellicori et al 14 in this issue of the Journal is timely, building upon the STAND-UP programme and offers both the mechanistic insights into the limitations of vasodilator therapy in acutely decompensated HF and an explanation of the potential lack of benefit noted in clinical trials as well as previous observations of deleterious effects on renal function. 14 This elegant study evaluated the more mechanistic effects of cimlanod on both the arterial and venous vasculature, renal function, and diuresis.…”

“…The most recent cimlanod study published by Pellicori et al 14 in this issue of the Journal is timely, building upon the STAND-UP programme and offers both the mechanistic insights into the limitations of vasodilator therapy in acutely decompensated HF and an explanation of the potential lack of benefit noted in clinical trials as well as previous observations of deleterious effects on renal function. 14 This elegant study evaluated the more mechanistic effects of cimlanod on both the arterial and venous vasculature, renal function, and diuresis. 14 Patients with left ventricular systolic dysfunction (left ventricular ejection fraction <40%) were administered intravenous furosemide after an infusion of the study drug or placebo.…”

“…14 This elegant study evaluated the more mechanistic effects of cimlanod on both the arterial and venous vasculature, renal function, and diuresis. 14 Patients with left ventricular systolic dysfunction (left ventricular ejection fraction <40%) were administered intravenous furosemide after an infusion of the study drug or placebo. As expected, cimlanod was associated with reductions in blood pressure and systemic vascular resistance.…”

“…Cimlanod also produced favourable effects on left ventricular filling pressures, left ventricular systolic function and natriuretic peptide levels. 14 Intuitively, these haemodynamic effects as well as reductions in preload and afterload, as achieved by cimlanod, would be of benefit to patients with acute HF. Intriguingly, however, measures of blood volume increased with lower levels of urine volume and sodium excretion noted, implying the use of cimlanod impacts renal function and reduces the effectiveness of loop diuretic therapy in this setting.…”

“…Intriguingly, however, measures of blood volume increased with lower levels of urine volume and sodium excretion noted, implying the use of cimlanod impacts renal function and reduces the effectiveness of loop diuretic therapy in this setting. 14 Potential mechanisms for this observation include reductions in renal perfusion in the setting of arteriolar vasodilatation. Reduction in renal perfusion exacerbates salt and water retention in acutely decompensated HF due to impaired diuretic delivery, increased sodium retention and reduced sodium filtration.…”