Valentina Carubelli1, Yuhui Zhang2, Marco Metra1, Carlo Lombardi1, G Michael Felker3, Gerasimos Filippatos4,5, Christopher M O'Connor6, John R Teerlink7,8, Phillip Simmons9, Robert Segal9, Gabriella Malfatto10, Maria Teresa La Rovere11, Dianfu Li12, Xiumin Han13, Zuyi Yuan14, Yali Yao15, Benjamin Li16, Lit Fui Lau17, Giuseppe Bianchi9, Jian Zhang2. 1. Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University and Civil Hospital of Brescia, Brescia, Italy. 2. Heart Failure Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Beijing, China. 3. Duke University School of Medicine and Duke Clinical Research Institute, Durham, NC, USA. 4. National and Kapodistrian University of Athens, Athens, Greece. 5. Medical School, University of Cyprus, Nicosia, Cyprus. 6. Inova Heart and Vascular Institute, Falls Church, VA, USA. 7. Section of Cardiology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA. 8. School of Medicine, University of California, San Francisco, CA, USA. 9. Windtree Therapeutics, Inc., Warrington, PA, USA. 10. IRCCS Istituto Auxologico Italiano, Department of Cardiovascular, Neural and Metabolic Sciences, S. Luca Hospital, Milan, Italy. 11. Istituti Clinici Scientifici Maugeri IRCCS, Department of Cardiology, Institute of Montescano, Pavia, Italy. 12. Jiangsu Provincial People's Hospital, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 13. The General Hospital of Shenyang Military Region of Chinese People's Liberation Arm, Shenyang, China. 14. The First Affiliated Hospital of Xi'An Jiaotong University, Xi'an, China. 15. The First Hospital of Lanzhou University, Lanzhou, China. 16. Lee's Pharmaceutical Limited, Taipei, Taiwan. 17. CVie Therapeutics Limited, Taipei, Taiwan.
Abstract
AIM: Istaroxime is a first-in-class agent which acts through inhibition of the sarcolemmal Na+ /K+ pump and activation of the SERCA2a pump. This study assessed the effects of a 24 h infusion of istaroxime in patients hospitalised for acute heart failure (AHF). METHODS AND RESULTS: We included patients hospitalised for AHF with left ventricular ejection fraction ≤40% and E/e' > 10. Patients were randomised to a 24 h intravenous infusion of placebo or istaroxime at doses of 0.5 μg/kg/min (cohort 1: placebon = 19; istaroxime n = 41) or 1.0 μg/kg/min (cohort 2: placebon = 20, istaroxime n = 40). The primary endpoint of change in E/e' ratio from baseline to 24 h decreased with istaroxime vs. placebo (cohort 1: -4.55 ± 4.75 istaroxime 0.5 μg/kg/min vs. -1.55 ± 4.11 placebo, P = 0.029; cohort 2: -3.16 ± 2.59 istaroxime 1.0 μg/kg/min vs. -1.08 ± 2.72 placebo, P = 0.009). Both istaroxime doses significantly increased stroke volume index and decreased heart rate. Systolic blood pressure increased with istaroxime, achieving significance with the high dose. Self-reported dyspnoea and N-terminal pro-brain natriuretic peptide improved in all groups without significant differences between istaroxime and placebo. No significant differences in cardiac troponin absolute values or clinically relevant arrhythmias were observed during or after istaroxime infusion. Serious cardiac adverse events (including arrhythmias and hypotension) did not differ between placebo and istaroxime groups. The most common adverse events were injection site reactions and gastrointestinal events, the latter primarily with istaroxime 1.0 μg/kg/min. CONCLUSIONS: In patients hospitalised for AHF with reduced ejection fraction, a 24 h infusion of istaroxime improved parameters of diastolic and systolic cardiac function without major cardiac adverse effects.
RCT Entities:
AIM: Istaroxime is a first-in-class agent which acts through inhibition of the sarcolemmal Na+ /K+ pump and activation of the SERCA2a pump. This study assessed the effects of a 24 h infusion of istaroxime in patients hospitalised for acute heart failure (AHF). METHODS AND RESULTS: We included patients hospitalised for AHF with left ventricular ejection fraction ≤40% and E/e' > 10. Patients were randomised to a 24 h intravenous infusion of placebo or istaroxime at doses of 0.5 μg/kg/min (cohort 1: placebo n = 19; istaroxime n = 41) or 1.0 μg/kg/min (cohort 2: placebo n = 20, istaroxime n = 40). The primary endpoint of change in E/e' ratio from baseline to 24 h decreased with istaroxime vs. placebo (cohort 1: -4.55 ± 4.75 istaroxime 0.5 μg/kg/min vs. -1.55 ± 4.11 placebo, P = 0.029; cohort 2: -3.16 ± 2.59 istaroxime 1.0 μg/kg/min vs. -1.08 ± 2.72 placebo, P = 0.009). Both istaroxime doses significantly increased stroke volume index and decreased heart rate. Systolic blood pressure increased with istaroxime, achieving significance with the high dose. Self-reported dyspnoea and N-terminal pro-brain natriuretic peptide improved in all groups without significant differences between istaroxime and placebo. No significant differences in cardiac troponin absolute values or clinically relevant arrhythmias were observed during or after istaroxime infusion. Serious cardiac adverse events (including arrhythmias and hypotension) did not differ between placebo and istaroxime groups. The most common adverse events were injection site reactions and gastrointestinal events, the latter primarily with istaroxime 1.0 μg/kg/min. CONCLUSIONS: In patients hospitalised for AHF with reduced ejection fraction, a 24 h infusion of istaroxime improved parameters of diastolic and systolic cardiac function without major cardiac adverse effects.
Authors: Mohit M Hulsurkar; Satadru K Lahiri; Jason Karch; Meng C Wang; Xander H T Wehrens Journal: Expert Opin Ther Targets Date: 2022-04-25 Impact factor: 6.797
Authors: Abdelrahman N Emara; Noha O Mansour; Mohamed Hassan Elnaem; Moheb Wadie; Inderpal Singh Dehele; Mohamed E E Shams Journal: J Clin Med Date: 2022-05-31 Impact factor: 4.964
Authors: S M Kamel; C J M van Opbergen; C D Koopman; A O Verkerk; B J D Boukens; B de Jonge; Y L Onderwater; E van Alebeek; S Chocron; C Polidoro Pontalti; W J Weuring; M A Vos; T P de Boer; T A B van Veen; J Bakkers Journal: Nat Commun Date: 2021-12-09 Impact factor: 14.919
Authors: Beatrice Badone; Carlotta Ronchi; Francesco Lodola; Anika E Knaust; Arne Hansen; Thomas Eschenhagen; Antonio Zaza Journal: Int J Mol Sci Date: 2021-12-16 Impact factor: 5.923