A randomized, double-blind, placebo-controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure

Abstract

AimsThe aim of this study was to evaluate the haemodynamic effects of serelaxin (30 µg/kg/day 20-h infusion and 4-h post-infusion period) in patients with acute heart failure (AHF).Methods and resultsThis double-blind, multicentre study randomized 71 AHF patients with pulmonary capillary wedge pressure (PCWP) ≥18 mmHg, systolic blood pressure (BP) ≥115 mmHg, and estimated glomerular filtration rate ≥30 mL/min/1.73 m2 to serelaxin (n = 34) or placebo (n = 37) within 48 h of hospitalization. Co-primary endpoints were peak change from baseline in PCWP and cardiac index (CI) during the first 8 h of infusion. Among 63 patients eligible for haemodynamic analysis (serelaxin, n = 32; placebo, n = 31), those treated with serelaxin had a significantly higher decrease in peak PCWP during the first 8 h of infusion (difference vs. placebo: −2.44 mmHg, P = 0.004). Serelaxin showed no significant effect on the peak change in CI vs. placebo. Among secondary haemodynamic endpoints, a highly significant reduction in pulmonary artery pressure (PAP) was observed throughout the serelaxin infusion (largest difference in mean PAP vs. placebo: −5.17 mmHg at 4 h, P < 0.0001). Right atrial pressure, systemic/pulmonary vascular resistance, and systolic/diastolic BP decreased from baseline with serelaxin vs. placebo and treatment differences reached statistical significance at some time points. Serelaxin administration improved renal function and decreased N-terminal pro-brain natriuretic peptide levels vs. placebo. Treatment with serelaxin was well tolerated with no apparent safety concerns.ConclusionThe haemodynamic effects of serelaxin observed in the present study provide plausible mechanistic support for improvement in signs and symptoms of congestion observed with this agent in AHF patients.ClinicalTrials.gov identifier NCT01543854.

Renal Hemodynamic Effects of Serelaxin in Patients With Chronic Heart Failure

“…Central hemodynamic studies of serelaxin in patients with AHF showed that serelaxin decreased the mean pulmonary artery pressure and pulmonary capillary wedge pressure, indicating cardiac unloading. 9,10 However, in these studies, serelaxin did not increase cardiac index. An increase in cardiac index as an explanation for the increase in RPF with serelaxin in this study is, therefore, unlikely.…”

“…The following formulas were used: infusion rate (mg/h) for IOTH=1.2×eGFR (mL/min) and infusion rate (mg/h) for PAH=5.5×eGFR (mL/min). For pooled time intervals (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) hours, 0-24 hours, and 24-28 hours), plasma concentration in the above formula was replaced by the time-weighted average plasma concentration (area under the curve divided by time). Baseline plasma clearance was derived using the 0-hour IOTH/ PAH concentration measurement.…”

Focused echocardiography and lung ultrasound protocol for guiding treatment in acute heart failure

“…Cardiac filling pressures, considered the driving force behind pulmonary congestion, have shown potential to decrease rapidly following aggressive AHF treatment initiation,27, 28 while pulmonary decongestion can be assessed in real time with LUS 14. Echo‐derived filling pressures and LUS have also displayed prognostic significance prior to discharge, making them potential treatment targets during AHF hospitalizations 16, 17, 29.…”

Therapeutic Effects of Serelaxin in Acute Heart Failure

“…10 A separate study addressed the hemodynamic effects of serelaxin in patients with AHF (NYHA III-IV class) and SBP >115 mmHg. 22 Serelaxin was administered at 30μg · kg -1 · day -1 for 20 h and hemodynamic parameters were monitored for 24 h and blood pressures for 44 h. Compared with the placebo-treated patients (n=37) receiving standard therapy, treatment with serelaxin exerted a rapid (<30 min) hemodynamic improvement measured by a reduction in pulmonary capillary wedge-pressure (PCWP), pulmonary artery pressure (PAP), SVR and pulmonary vascular resistance (PVR) without significant change in CI. Meanwhile, serelaxin administration improved renal function and reduced both SBP and diastolic blood pressure by 7-10 mmHg.…”