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Marion Dahlke - One of the best experts on this subject based on the ideXlab platform.
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Population pharmacokinetics of Serelaxin in patients with acute or chronic heart failure, hepatic or renal impairment, or portal hypertension and in healthy subjects.
British journal of clinical pharmacology, 2018Co-Authors: Antoine Soubret, Yinuo Pang, Marion DahlkeAbstract:Aims Serelaxin is a recombinant human relaxin-2 peptide being developed for the treatment of acute heart failure (AHF). The present analyses aimed to evaluate Serelaxin pharmacokinetics following intravenous administration and to identify covariates that may explain pharmacokinetic variability in healthy subjects and patients. Methods Serum concentration-time data for 613 subjects from nine phase I and II studies were analysed using a nonlinear mixed-effects model to estimate population pharmacokinetics and identify significant covariates. A quantile regression analysis was also conducted to assess the relationship between clearance and covariates by including sparse data from a phase III study. Results A three-compartment disposition model was established to describe Serelaxin pharmacokinetics. Three out of 23 covariates, including baseline body mass index (BMI) and estimated glomerular filtration rate (eGFR) and study A1201, were identified as significant covariates for clearance but with a moderate impact on steady-state concentration, reducing the intersubject variability from 44% in the base model to 41% in the final model with covariates. The steady-state volume of distribution (Vss) was higher in patients with AHF (544 ml kg-1 ) or chronic heart failure (434 ml kg-1 ), compared with typical nonheart failure subjects (347 ml kg-1 ). Quantile regression analysis showed that a 20% increase in BMI or a 20% decrease in eGFR decreased Serelaxin clearance by 9.2% or 5.2%, respectively. Conclusions Patients with HF showed higher Vss but similar clearance (and therefore steady-state exposure) vs. non nonheart failure subjects. BMI and eGFR were identified as the main covariates explaining intersubject variability in clearance; however, the impact of these covariates on steady-state concentration was moderate and therefore unlikely to be clinically relevant.
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Pharmacokinetics of Serelaxin in patients with severe renal impairment or end-stage renal disease requiring hemodialysis: A single-dose, open-label, parallel-group study
Journal of clinical pharmacology, 2015Co-Authors: Marion Dahlke, Surendra Machineni, Jasna Canadi, Atef Halabi, Chiaki Tsubouchi, Yinuo PangAbstract:Serelaxin, a recombinant human relaxin-2 hormone, is in clinical development for treating acute heart failure. This open-label, parallel-group study investigated Serelaxin pharmacokinetics (PK) after a single 4-hour intravenous infusion (10 µg/kg) in patients with severe renal impairment (n = 6) or end-stage renal disease (ESRD) requiring hemodialysis (PK on the day of dialysis [n = 6] or during dialysis-free interval [n = 6]), compared with matched healthy subjects (n = 18). In all participants, serum Serelaxin concentration peaked at the end of infusion and subsequently declined with mean terminal elimination half-life of 6.5–8.8 hours. Compared with healthy subjects, a moderate decrease in Serelaxin systemic clearance (37%–52%) and increase in its exposure (30%–115%) were observed in all patients. During the 4-hour hemodialysis in ESRD patients, 30% Serelaxin was removed, with hemodialysis clearance constituting approximately 52% of total systemic clearance. Serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. AntiSerelaxin antibodies were not detected in any participant. Given the shallow dose-response relationship observed with Serelaxin in clinical studies and its wide therapeutic window, the observed PK differences in patients with severe renal impairment compared with healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients.
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pharmacokinetics of Serelaxin in patients with hepatic impairment a single dose open label parallel group study
British Journal of Clinical Pharmacology, 2015Co-Authors: Zhanna Kobalava, Jasna Canadi, Iris Rajman, Yinuo Pang, Svetlana Villevalde, Yulia Kotovskaya, Holger Hinrichsen, Andreas Zaehringer, Marc Petersensylla, Marion DahlkeAbstract:Aims Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of Serelaxin in patients with hepatic impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of Serelaxin. Methods This was an open-label, parallel group study (NCT01433458) comparing the PK of Serelaxin following a single 24 h intravenous (i.v.) infusion (30 μg kg−1 day−1) between patients with mild, moderate or severe hepatic impairment (Child–Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration–time curve AUC(0–48 h) and AUC(0–∞) and serum concentration at 24 h post-dose (C24h)] were compared between each hepatic impairment group and healthy controls. Results A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of Serelaxin increased over the first few hours of infusion, reached steady-state at 12–24 h and then declined following completion of infusion, with a mean terminal half-life of 7–8 h. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No Serelaxin treatment-related antibodies developed during this study. Conclusions The PK and safety profile of Serelaxin were not affected by hepatic impairment. No dose adjustment is needed for Serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment.
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Pharmacokinetics of Serelaxin in patients with hepatic impairment: a single‐dose, open‐label, parallel group study
British journal of clinical pharmacology, 2015Co-Authors: Zhanna Kobalava, Jasna Canadi, Iris Rajman, Yinuo Pang, Marc Petersen-sylla, Svetlana Villevalde, Yulia Kotovskaya, Holger Hinrichsen, Andreas Zaehringer, Marion DahlkeAbstract:Aims Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of Serelaxin in patients with hepatic impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of Serelaxin. Methods This was an open-label, parallel group study (NCT01433458) comparing the PK of Serelaxin following a single 24 h intravenous (i.v.) infusion (30 μg kg−1 day−1) between patients with mild, moderate or severe hepatic impairment (Child–Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration–time curve AUC(0–48 h) and AUC(0–∞) and serum concentration at 24 h post-dose (C24h)] were compared between each hepatic impairment group and healthy controls. Results A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of Serelaxin increased over the first few hours of infusion, reached steady-state at 12–24 h and then declined following completion of infusion, with a mean terminal half-life of 7–8 h. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No Serelaxin treatment-related antibodies developed during this study. Conclusions The PK and safety profile of Serelaxin were not affected by hepatic impairment. No dose adjustment is needed for Serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment.
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safety and tolerability of Serelaxin a recombinant human relaxin 2 in development for the treatment of acute heart failure in healthy japanese volunteers and a comparison of pharmacokinetics and pharmacodynamics in healthy japanese and caucasian popu
The Journal of Clinical Pharmacology, 2015Co-Authors: Marion Dahlke, Masayuki Yamaguchi, Surendra Machineni, Sergej Berger, Jasna Canadi, Iris Rajman, Peter Lloyd, Yinuo PangAbstract:Serelaxin, a recombinant form of the human relaxin-2 hormone, is currently under clinical investigation for treatment of acute heart failure. This double-blind, placebo-controlled, dose-ranging study investigated the effect of Japanese ethnicity on the pharmacokinetics (PK), pharmacodynamics (PD), and safety and tolerability of Serelaxin. Japanese healthy subjects (n = 32) received 10, 30, or 100 µg/kg/day of Serelaxin, or placebo, administered as a 48-hour intravenous infusion. A Caucasian cohort (n = 8) receiving 30 µg/kg/day open-label Serelaxin was included for comparison. In all subjects, serum Serelaxin concentrations increased rapidly after the start of infusion, approached steady state as early as 4 hours, and declined rapidly upon treatment cessation. Serum exposure to Serelaxin increased with increasing doses. Statistical dose proportionality was shown for AUC(inf) over the entire dose range. A significant increase in estimated glomerular filtration rate from baseline to Day 2 (30 and 100 µg/kg/day) and to Day 3 (10 and 100 µg/kg/day) was observed compared with placebo. Serelaxin was well tolerated by all subjects. In conclusion, PK, PD, and safety profiles of Serelaxin were generally comparable between Japanese and Caucasian subjects, suggesting that no dose adjustment will be required in Japanese subjects during routine clinical use of this agent.
Yu-zhen Tan - One of the best experts on this subject based on the ideXlab platform.
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Serelaxin inhibits differentiation and fibrotic behaviors of cardiac fibroblasts by suppressing alk 5 smad2 3 signaling pathway
Experimental Cell Research, 2018Co-Authors: Hai-jie Wang, Yong-li Wang, Hao-ran Shen, Yu-zhen TanAbstract:Abstract Serelaxin, a recombinant form of human relaxin-2, is currently regarded as a novel drug for treatment of acute heart failure. However, whether therapeutic effects of Serelaxin are achieved by inhibiting cardiac fibrosis remains unclear. In this study, we investigate effects of Serelaxin on inhibiting cardiac fibrosis. Cardiac fibroblasts (CFs) were isolated from the hearts of adult rats. Effects of Serelaxin on differentiation of CFs towards myofibroblasts (MFs) and their fibrotic behaviors after induction with TGF-β1 were examined. Synthesis and degradation of collagens, secretion of IL-10, and expression of ALK-5 and p-Smad2/3 of TGF-β1-induced cells were assessed after treatment with Serelaxin. Serelaxin inhibited differentiation of TGF-β1-induced CFs towards MFs, and reduced proliferation and migration of the induced cells. Moreover, Serelaxin down-regulated expression of collagen I/III and TIMP-2, and up-regulated expression of MMP-2 and MMP-9 in the cells. After treatment with Serelaxin, activity of MMP-2 and MMP-9 and secretion of IL-10 increased, expression of ALK-5 and the level of Smad2/3 phosphorylation was reduced significantly. These results suggest that Serelaxin can inhibit differentiation of TGF-β1-induced CFs towards MFs, reduce production of collagens by suppressing ALK-5/Smad2/3 signaling pathway, and enhance extracellular matrix degradation by increasing MMP-2/TIMP-2 ratio and IL-10 secretion. Serelaxin may be a potential therapeutic drug for inhibiting cardiac fibrosis.
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Serelaxin inhibits differentiation and fibrotic behaviors of cardiac fibroblasts by suppressing ALK-5/Smad2/3 signaling pathway.
Experimental cell research, 2017Co-Authors: Hai-jie Wang, Yong-li Wang, Hao-ran Shen, Yu-zhen TanAbstract:Abstract Serelaxin, a recombinant form of human relaxin-2, is currently regarded as a novel drug for treatment of acute heart failure. However, whether therapeutic effects of Serelaxin are achieved by inhibiting cardiac fibrosis remains unclear. In this study, we investigate effects of Serelaxin on inhibiting cardiac fibrosis. Cardiac fibroblasts (CFs) were isolated from the hearts of adult rats. Effects of Serelaxin on differentiation of CFs towards myofibroblasts (MFs) and their fibrotic behaviors after induction with TGF-β1 were examined. Synthesis and degradation of collagens, secretion of IL-10, and expression of ALK-5 and p-Smad2/3 of TGF-β1-induced cells were assessed after treatment with Serelaxin. Serelaxin inhibited differentiation of TGF-β1-induced CFs towards MFs, and reduced proliferation and migration of the induced cells. Moreover, Serelaxin down-regulated expression of collagen I/III and TIMP-2, and up-regulated expression of MMP-2 and MMP-9 in the cells. After treatment with Serelaxin, activity of MMP-2 and MMP-9 and secretion of IL-10 increased, expression of ALK-5 and the level of Smad2/3 phosphorylation was reduced significantly. These results suggest that Serelaxin can inhibit differentiation of TGF-β1-induced CFs towards MFs, reduce production of collagens by suppressing ALK-5/Smad2/3 signaling pathway, and enhance extracellular matrix degradation by increasing MMP-2/TIMP-2 ratio and IL-10 secretion. Serelaxin may be a potential therapeutic drug for inhibiting cardiac fibrosis.
Chrishan S. Samuel - One of the best experts on this subject based on the ideXlab platform.
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Serelaxin enhances the therapeutic effects of human amnion epithelial cell-derived exosomes in experimental models of lung disease.
British journal of pharmacology, 2019Co-Authors: Simon G. Royce, Krupesh P Patel, Weiyi Mao, Dandan Zhu, Rebecca Lim, Chrishan S. SamuelAbstract:BACKGROUND AND PURPOSE There is growing interest in stem cell-derived exosomes for their therapeutic and regenerative benefits given their manufacturing and regulatory advantages over cell-based therapies. As existing fibrosis impedes the viability and efficacy of stem cell/exosome-based strategies for treating chronic diseases, here we tested the effects of the anti-fibrotic drug, Serelaxin, on the therapeutic efficacy of human amnion epithelial cell (AEC)-derived exosomes in experimental lung disease. EXPERIMENTAL APPROACH Female Balb/c mice were subjected to either the 9.5-week model of ovalbumin and naphthalene (OVA/NA)-induced chronic allergic airway disease (AAD) or 3-week model of bleomycin (BLM)-induced pulmonary fibrosis; then administered increasing concentrations of AEC-exosomes (5 μg or 25μg), with or without Serelaxin (0.5mg/kg/day) for 7-days. 1x106 AECs co-administered with Serelaxin over the corresponding time-period were included for comparison in both models, as was pirfenidone-treatment of the BLM model. Control groups received saline/corn oil or saline, respectively. KEY RESULTS Both experimental models presented with significant tissue inflammation, remodelling, fibrosis and airway/lung dysfunction at the time-points studied. While AEC-exosome (5 μg or 25μg)-administration alone demonstrated some benefits in each model, Serelaxin was required for AEC-exosomes (25μg) to rapidly normalise chronic AAD-induced airway fibrosis and airway reactivity, and BLM-induced lung inflammation, epithelial damage and subepithelial/basement membrane fibrosis. Combining Serelaxin with AEC-exosomes (25μg) also demonstrated broader protection compared to co-administration of Serelaxin with 1x106 AECs or pirfenidone. CONCLUSIONS AND IMPLICATIONS Serelaxin enhanced the therapeutic efficacy of AEC-exosomes in treating basement membrane-induced fibrosis and related airway dysfunction.
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Relaxin and fibrosis: Emerging targets, challenges, and future directions.
Molecular and cellular endocrinology, 2019Co-Authors: Anthony Kanai, Chrishan S. Samuel, Elisa M. Konieczko, Robert G. Bennett, Simon G. RoyceAbstract:The peptide hormone relaxin is well-known for its anti-fibrotic actions in several organs, particularly from numerous studies conducted in animals. Acting through its cognate G protein-coupled receptor, relaxin family peptide receptor 1 (RXFP1), Serelaxin (recombinant human relaxin) has been shown to consistently inhibit the excessive extracellular matrix production (fibrosis) that results from the aberrant wound-healing response to tissue injury and/or chronic inflammation, and at multiple levels. Furthermore, it can reduce established scarring by promoting the degradation of aberrant extracellular matrix components. Following on from the review that describes the mechanisms and signaling pathways associated with the extracellular matrix remodeling effects of Serelaxin (Ng et al., 2019), this review focuses on newly identified tissue targets of Serelaxin therapy in fibrosis, and the limitations associated with (se)relaxin research.
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Enhanced Serelaxin signalling in co-cultures of human primary endothelial and smooth muscle cells
British journal of pharmacology, 2016Co-Authors: Mohsin Sarwar, Chrishan S. Samuel, Ross A. D. Bathgate, Dennis R Stewart, Roger J. SummersAbstract:BACKGROUND AND PURPOSE In the phase III clinical trial, RELAX-AHF, Serelaxin caused rapid and long-lasting haemodynamic changes. However, the cellular mechanisms involved are unclear in humans. EXPERIMENTAL APPROACH This study examined the effects of Serelaxin in co-cultures of human primary endothelial cells (ECs) and smooth muscle cells (SMCs) on cAMP and cGMP signalling. KEY RESULTS Stimulation of HUVECs or human coronary artery endothelial cells (HCAECs) with Serelaxin, concentration-dependently increased cGMP accumulation in co-cultured SMCs to a greater extent than in monocultures of either cell type. This was not observed in human umbilical artery endothelial cells (HUAECs) that do not express the relaxin receptor, RXFP1. Treatment of ECs with l-N(G) -nitro arginine (NOARG; 30 μM, 30 min) inhibited Serelaxin-mediated (30 nM) cGMP accumulation in HUVECs, HCAECs and co-cultured SMCs. In HCAECs, but not HUVECs, pre-incubation with indomethacin (30 μM, 30 min) also inhibited cGMP accumulation in SMCs. Pre-incubation of SMCs with the guanylate cyclase inhibitor ODQ (1 μM, 30 min) had no effect on Serelaxin-mediated (30 nM) cGMP accumulation in HUVECs and HCAECs but inhibited cGMP accumulation in SMCs. Serelaxin stimulation of HCAECs, but not HUVECs, increased cAMP accumulation concentration-dependently in SMCs. Pre-incubation of HCAECs with indomethacin, but not l-NOARG, abolished cAMP accumulation in co-cultured SMCs, suggesting involvement of prostanoids. CONCLUSIONS AND IMPLICATIONS In co-cultures, treatment of ECs with Serelaxin caused marked cGMP accumulation in SMCs and with HCAEC also cAMP accumulation. Responses involved EC-derived NO and with HCAEC prostanoid production. Thus, Serelaxin differentially modulates vascular tone in different vascular beds.
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Serelaxin mediated signal transduction in human vascular cells bell shaped concentration response curves reflect differential coupling to g proteins
British Journal of Pharmacology, 2015Co-Authors: Mohsin Sarwar, Chrishan S. Samuel, Ross A. D. Bathgate, D R Stewart, Roger J. SummersAbstract:Background and Purpose In a recently conducted phase III clinical trial, RELAX-AHF, Serelaxin infusion over 48 h improved short- and long-term clinical outcomes in patients with acute heart failure. In this study we used human primary cells from the umbilical vasculature to better understand the signalling mechanisms activated by Serelaxin.
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Serelaxin-mediated signal transduction in human vascular cells: bell-shaped concentration–response curves reflect differential coupling to G proteins
British journal of pharmacology, 2014Co-Authors: Mohsin Sarwar, Chrishan S. Samuel, Ross A. D. Bathgate, D R Stewart, Roger J. SummersAbstract:Background and Purpose In a recently conducted phase III clinical trial, RELAX-AHF, Serelaxin infusion over 48 h improved short- and long-term clinical outcomes in patients with acute heart failure. In this study we used human primary cells from the umbilical vasculature to better understand the signalling mechanisms activated by Serelaxin.
Roger J. Summers - One of the best experts on this subject based on the ideXlab platform.
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Enhanced Serelaxin signalling in co-cultures of human primary endothelial and smooth muscle cells
British journal of pharmacology, 2016Co-Authors: Mohsin Sarwar, Chrishan S. Samuel, Ross A. D. Bathgate, Dennis R Stewart, Roger J. SummersAbstract:BACKGROUND AND PURPOSE In the phase III clinical trial, RELAX-AHF, Serelaxin caused rapid and long-lasting haemodynamic changes. However, the cellular mechanisms involved are unclear in humans. EXPERIMENTAL APPROACH This study examined the effects of Serelaxin in co-cultures of human primary endothelial cells (ECs) and smooth muscle cells (SMCs) on cAMP and cGMP signalling. KEY RESULTS Stimulation of HUVECs or human coronary artery endothelial cells (HCAECs) with Serelaxin, concentration-dependently increased cGMP accumulation in co-cultured SMCs to a greater extent than in monocultures of either cell type. This was not observed in human umbilical artery endothelial cells (HUAECs) that do not express the relaxin receptor, RXFP1. Treatment of ECs with l-N(G) -nitro arginine (NOARG; 30 μM, 30 min) inhibited Serelaxin-mediated (30 nM) cGMP accumulation in HUVECs, HCAECs and co-cultured SMCs. In HCAECs, but not HUVECs, pre-incubation with indomethacin (30 μM, 30 min) also inhibited cGMP accumulation in SMCs. Pre-incubation of SMCs with the guanylate cyclase inhibitor ODQ (1 μM, 30 min) had no effect on Serelaxin-mediated (30 nM) cGMP accumulation in HUVECs and HCAECs but inhibited cGMP accumulation in SMCs. Serelaxin stimulation of HCAECs, but not HUVECs, increased cAMP accumulation concentration-dependently in SMCs. Pre-incubation of HCAECs with indomethacin, but not l-NOARG, abolished cAMP accumulation in co-cultured SMCs, suggesting involvement of prostanoids. CONCLUSIONS AND IMPLICATIONS In co-cultures, treatment of ECs with Serelaxin caused marked cGMP accumulation in SMCs and with HCAEC also cAMP accumulation. Responses involved EC-derived NO and with HCAEC prostanoid production. Thus, Serelaxin differentially modulates vascular tone in different vascular beds.
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Serelaxin mediated signal transduction in human vascular cells bell shaped concentration response curves reflect differential coupling to g proteins
British Journal of Pharmacology, 2015Co-Authors: Mohsin Sarwar, Chrishan S. Samuel, Ross A. D. Bathgate, D R Stewart, Roger J. SummersAbstract:Background and Purpose In a recently conducted phase III clinical trial, RELAX-AHF, Serelaxin infusion over 48 h improved short- and long-term clinical outcomes in patients with acute heart failure. In this study we used human primary cells from the umbilical vasculature to better understand the signalling mechanisms activated by Serelaxin.
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Serelaxin-mediated signal transduction in human vascular cells: bell-shaped concentration–response curves reflect differential coupling to G proteins
British journal of pharmacology, 2014Co-Authors: Mohsin Sarwar, Chrishan S. Samuel, Ross A. D. Bathgate, D R Stewart, Roger J. SummersAbstract:Background and Purpose In a recently conducted phase III clinical trial, RELAX-AHF, Serelaxin infusion over 48 h improved short- and long-term clinical outcomes in patients with acute heart failure. In this study we used human primary cells from the umbilical vasculature to better understand the signalling mechanisms activated by Serelaxin.
Barry H. Greenberg - One of the best experts on this subject based on the ideXlab platform.
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effects of Serelaxin in patients admitted for acute heart failure a meta analysis
European Journal of Heart Failure, 2020Co-Authors: John R. Teerlink, Beth A. Davison, Gad Cotter, Aldo P. Maggioni, Naoki Sato, Ovidiu Chioncel, Georg Ertl, Gerasimos Filippatos, Michael G Felker, Barry H. GreenbergAbstract:Aims: The effectiveness and safety of 48 h intravenous 30 μg/kg/day Serelaxin infusion in acute heart failure (AHF) has been studied in six randomized, controlled clinical trials. Methods and results: We conducted a fixed-effect meta-analysis including all studies of intravenous Serelaxin initiated within the first 16 h of admission for AHF. Endpoints considered were the primary and secondary endpoints examined in the Serelaxin phase III studies. In six randomized controlled trials, 6105 total patients were randomized to receive intravenous Serelaxin 30 μg/kg/day and 5254 patients to control. Worsening heart failure to day 5 occurred in 6.0% and 8.1% of patients randomized to Serelaxin and control, respectively (hazard ratio 0.77, 95% confidence interval 0.67–0.89; P = 0.0002). Serelaxin had no statistically significant effect on length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration resulted in statistically significant improvement in markers of renal function and reductions in both N-terminal pro-B-type natriuretic peptide and troponin. No significant adverse outcomes were noted with Serelaxin. Through the last follow-up, which occurred at an average of 4.5 months (1–6 months), Serelaxin administration was associated with a reduction in all-cause mortality, with an estimated hazard ratio of 0.87 (95% confidence interval 0.77–0.98; P = 0.0261). Conclusions: Administration of intravenous Serelaxin to patients admitted for AHF was associated with a highly significant reduction in the risk of 5-day worsening heart failure and in changes in renal function markers, but not length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration was safe and associated with a significant reduction in all-cause mortality.
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Effects of Serelaxin in patients admitted for acute heart failure: a meta‐analysis
European journal of heart failure, 2019Co-Authors: John R. Teerlink, Beth A. Davison, Gad Cotter, Aldo P. Maggioni, Naoki Sato, Ovidiu Chioncel, Georg Ertl, G. Michael Felker, Gerasimos Filippatos, Barry H. GreenbergAbstract:Aims The effectiveness and safety of 48 h intravenous 30 mu g/kg/day Serelaxin infusion in acute heart failure (AHF) has been studied in six randomized, controlled clinical trials. Methods and results We conducted a fixed-effect meta-analysis including all studies of intravenous Serelaxin initiated within the first 16 h of admission for AHF. Endpoints considered were the primary and secondary endpoints examined in the Serelaxin phase III studies. In six randomized controlled trials, 6105 total patients were randomized to receive intravenous Serelaxin 30 mu g/kg/day and 5254 patients to control. Worsening heart failure to day 5 occurred in 6.0% and 8.1% of patients randomized to Serelaxin and control, respectively (hazard ratio 0.77, 95% confidence interval 0.67-0.89; P = 0.0002). Serelaxin had no statistically significant effect on length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration resulted in statistically significant improvement in markers of renal function and reductions in both N-terminal pro-B-type natriuretic peptide and troponin. No significant adverse outcomes were noted with Serelaxin. Through the last follow-up, which occurred at an average of 4.5 months (1-6 months), Serelaxin administration was associated with a reduction in all-cause mortality, with an estimated hazard ratio of 0.87 (95% confidence interval 0.77-0.98; P = 0.0261). Conclusions Administration of intravenous Serelaxin to patients admitted for AHF was associated with a highly significant reduction in the risk of 5-day worsening heart failure and in changes in renal function markers, but not length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration was safe and associated with a significant reduction in all-cause mortality.
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the Efficacy, Safety, and Tolerability of Additional Serelaxin Administration to Standard Therapy in Asian Patients with Acute Heart Failure: The RELAX-AHF-ASIA trial
Journal of Cardiac Failure, 2018Co-Authors: Naoki Sato, John R. Teerlink, Barry H. Greenberg, Tsushung A. Hua, Carolyn S.p. Lam, Hiroyuki Tsutsui, Jian Zhang, Xingli WangAbstract:Background Acute heart failure (AHF) is associated with a high risk of post-discharge rehospitalisation and mortality. Existing evidence suggested potential therapeutic benefits of Serelaxin in patients with AHF, although corresponding data in Asian patients remained scarce. RELAX-AHF-ASIA, a multinational, randomised, double-blind, placebo-controlled, Phase III trial, evaluated the effects of Serelaxin on symptom relief and clinical outcomes in Asian AHF patients. Methods Patients diagnosed with AHF based on clinical criteria regardless of ejection fraction, with a systolic blood pressure ≥125 mmHg and mild-to-moderate renal dysfunction were randomised within 16 hours of presentation to receive 48-hour intravenous infusion of 30 μg/kg/day Serelaxin or placebo in addition to standard therapy. The patients were followed-up for up to 180 days. A novel trichotomous primary endpoint was used in the RELAX-AHF-ASIA trial. It included: (1) treatment success (moderate/marked improvement in patient-reported dyspnoea and physician-assessed signs of congestion on Day 2); (2) treatment failure (in-hospital worsening of signs and/or symptoms of heart failure [HF] requiring intensification of intravenous HF therapy or mechanical ventilation, renal/circulatory support, rehospitalisation due to HF/renal failure or death through Day 5) and (3) unchanged status. Secondary endpoints included time to in-hospital worsening HF through Day 5 and all-cause and cardiovascular deaths through Day 180. Results Although the trial aimed to randomise 1520 AHF patients, it was prematurely terminated following the neutral read-out of the large phase III RELAX-AHF-2 trial. A total of 876 patients were randomised in the RELAX-AHF-ASIA trial and the final analysis was performed with 870 patients (Serelaxin, 437; placebo, 433). The trial was conducted at 127 centres in 11 countries: (China, 15; India, 7; Japan, 50; Republic of Korea, 14; Malaysia, 7; Philippines, 9; Singapore, 2; Jordan, 3; Lebanon, 4; Taiwan, 10; Thailand, 6). The mean age was 70 years and 64% of patients were men. The demographics and baseline characteristics were well balanced between treatment groups. Due to premature termination of this trial, only exploratory analysis for primary and secondary endpoints was performed. The proportion of patients with treatment failure was less in the Serelaxin group (4.1%) than in the placebo group (8.3%), but the primary endpoint failed to achieve statistical significance. Serelaxin significantly reduced in-hospital worsening HF through Day 5 with a hazard ratio of 0.41 (95% confidence interval: 0.20, 0.84; P=0.0119), using a Cox-regression model. There was no difference in time to cardiovascular mortality and all-cause mortality through Day 180. No new or unexpected safety findings were reported in this trial. The frequency of serious adverse events was similar between groups, and Serelaxin infusion was well tolerated. Conclusion The RELAX-AHF-ASIA as the first randomised clinical trial specifically in Asian AHF patients represents a landmark trial in Asia. Although the trial was prematurely terminated, it demonstrated that Serelaxin was well tolerated and that it improved a novel trichotomous primary endpoint, albeit not statistically, compared with placebo. Exploratory analysis revealed that worsening HF significantly improved with Serelaxin treatment. Although RELAX-AHF-ASIA could not confirm the primary endpoint, it demonstrated that future clinical trials of AHF could be successfully conducted in Asian countries.
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Serelaxin in addition to standard therapy in acute heart failure rationale and design of the relax ahf 2 study
European Journal of Heart Failure, 2017Co-Authors: John R. Teerlink, Beth A. Davison, Gad Cotter, Gerasimos Filippatos, Barry H. Greenberg, Michael G Felker, Piotr Ponikowski, Adriaan A. Voors, Peter S Pang, Claudio GimpelewiczAbstract:Patients admitted for acute heart failure (AHF) experience high rates of in-hospital and post-discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin-2, a hormone with vasodilatory and end-organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX-AHF trial, Serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, Serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all-cause and cardiovascular mortality by 37% through day 180. RELAX-AHF-2 ( ClinicalTrials.gov NCT01870778) is designed to confirm Serelaxin's effect on these clinical outcomes. RELAX-AHF-2 is a multicentre, randomized, double-blind, placebo-controlled, event-driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild-to-moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of Serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that Serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all-cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in-hospital length of stay during index AHF. The results from RELAX-AHF-2 will provide data on the potential beneficial effect of Serelaxin on cardiovascular mortality and WHF in selected patients with AHF.
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Effects of Serelaxin in acute heart failure patients with renal impairment: results from RELAX-AHF
Clinical Research in Cardiology, 2016Co-Authors: Licette C.y. Liu, John R. Teerlink, Beth A. Davison, Gad Cotter, G. Michael Felker, Gerasimos Filippatos, Barry H. Greenberg, Adriaan A. Voors, Yakuan Chen, Piotr PonikowskiAbstract:Background Serelaxin showed beneficial effects on clinical outcome and trajectories of renal markers in patients with acute heart failure. We aimed to study the interaction between renal function and the treatment effect of Serelaxin. Methods In the current post hoc analysis of the RELAX-AHF trial, we included all patients with available estimated glomerular filtration rate (eGFR) at baseline ( n = 1132). Renal impairment was defined as an eGFR
