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.

In patients with AHF after initial clinical stabilization, both baseline and post-baseline CI measurements are positively related to PPP. This was the most closely related non-invasive blood pressure variable to CI.

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Background: Growth differentiation factor 15 (GDF-15) appears to have a role in regulating inflammation and apoptosis and is up-regulated following injury to the liver, kidney, heart and lung. Elevated baseline (BL) levels of GDF-15 and increases over time have been shown to be associated with adverse events in heart failure (HF). GDF-15 was decreased following LVAD implantation and cardiac unloading in end stage HF. As previously reported, serelaxin improved Pulmonary Capillary Wedge Pressure (PCWP), mean Pulmonary Artery Pressure (mPAP), and Pulmonary Vascular Resistance (PVR) during a 20 h infusion period (all p<0.005 vs. placebo [PBO]). A post-hoc analysis was performed to explore serelaxin effects on GDF-15 in acute HF (AHF) and whether GDF-15 is associated with pulmonary hemodynamics. Methods: Following serelaxin (30 ug/kg/d) or PBO infusion for 20 h in AHF patients, PCWP, mPAP, PVR, NTproBNP (Roche Diagnostics) and GDF-15 (pre-commercial kit, Roche Diagnostics) were measured in 32 serelaxin and 31 PBO treated patients. The effect of serelaxin on GDF-15 and NTproBNP was analyzed and the potential association of GDF-15 or NTproBNP with selected hemodynamic indices was explored combining treatment data from the two treatment arms. Results: Following the 20 h infusion period, serelaxin reduced GDF-15 vs BL (BL median 3192 pg/ml) by 16% (serelaxin vs PBO p=0.021) and reduced NTproBNP (BL median 3262 pg/ml) by 13% (serelaxin vs PBO p=0.021). GDF-15 at BL and 20 h was significantly associated with BL and 20 h NTproBNP (both p<0.001), mPAP (both p<0.025), and PVR (both p<0.001). At 20 h GDF-15 and PCWP were significantly associated (p<0.02) but their association at BL was not statistically significant (p=0.70). The association of NTproBNP at BL and 20 h was not statistically significant for BL or 20 h PCWP, mPAP or PVR (all p >0.05). Conclusions: In this small invasive hemodynamic study in patients with AHF, serelaxin significantly reduced GDF-15 and NTproBNP and had favorable effects on pulmonary hemodynamics. GDF-15 levels at BL and 20 h showed a strong correlation with BL and 20 h values of mPAP and PVR. Additional studies measuring GDF-15 levels in acute HF patients with pulmonary congestion appear warranted.