Hans-Dirk Duengen1, Raymond J Kim2, Doron Zahger3, Katia Orvin4, Ran Kornowski4, Dan Admon5, Jiri Kettner6, Avraham Shimony3, Christiane Otto7, Michael Becka8, Friederike Kanefendt9, Andres Iniguez Romo10, Tal Hasin11, Petr Ostadal12, Gonzalo Calvo Rojas13, Michele Senni14. 1. Department of Internal Medicine, Cardiology, Charité-Universitaetsmedizin, Berlin, Germany. 2. Duke Cardiovascular Magnetic Resonance Center, Duke University Medical Center, Durham, United States. 3. Department of Cardiology, Soroka University Medical Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel. 4. Rabin Medical Center - Beilinson Campus, Cardiology Division, Petah Tikva, Israel. 5. Hadassah Hebrew University Hospital Ein Kerem, Heart Institute, Jerusalem, Israel. 6. Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic. 7. Experimental Medicine Cardiovascular, Bayer AG, Wuppertal, Germany. Electronic address: christiane.otto@bayer.com. 8. Research and Clinical Sciences Statistics, Bayer AG, Wuppertal, Germany. 9. Clinical Pharmacokinetics, Bayer AG, Wuppertal, Germany. 10. Hospital Alvaro Cunqueiro, Servicio de la Cardiologia, Vigo, Spain. 11. Shaare Zedek Medical Center, Department of Cardiology, Jerusalem, Israel. 12. Na Homolce Hospital, Prague, Czech Republic. 13. Hospital Clinic de Barcelona, Barcelona, Spain. 14. Division of Cardiology, Cardiovascular Department, Papa Giovanni XXIII Hospital, Bergamo, Italy.
Abstract
BACKGROUND:Adverse cardiac remodeling is a major risk factor for the development of post myocardial infarction (MI) heart failure (HF). This study investigates the effects of the chymase inhibitor fulacimstat on adverse cardiac remodeling after acute ST-segment-elevation myocardial infarction (STEMI). METHODS: In this double-blind, randomized, placebo-controlled trial patients with first STEMI were eligible. To preferentially enrich patients at high risk of adverse remodeling, main inclusion criteria were a left-ventricular ejection fraction (LVEF) ≤45% and an infarct size >10% on day 5 to 9 post MI as measured by cardiac MRI. Patients were then randomized to 6 months treatment with either 25 mg fulacimstat (n = 54) or placebo (n = 53) twice daily on top of standard of care starting day 6 to 12 post MI. The changes in LVEF, LV end-diastolic volume index (LVEDVI), and LV end-systolic volume index (LVESVI) from baseline to 6 months were analyzed by a central blinded cardiac MRI core laboratory. RESULTS: Fulacimstat was safe and well tolerated and achieved mean total trough concentrations that were approximately tenfold higher than those predicted to be required for minimal therapeutic activity. Comparable changes in LVEF (fulacimstat: 3.5% ± 5.4%, placebo: 4.0% ± 5.0%, P = .69), LVEDVI (fulacimstat: 7.3 ± 13.3 mL/m2, placebo: 5.1 ± 18.9 mL/m2, P = .54), and LVESVI (fulacimstat: 2.3 ± 11.2 mL/m2, placebo: 0.6 ± 14.8 mL/m2, P = .56) were observed in both treatment arms. CONCLUSION: Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on cardiac remodeling.
RCT Entities:
BACKGROUND: Adverse cardiac remodeling is a major risk factor for the development of post myocardial infarction (MI) heart failure (HF). This study investigates the effects of the chymase inhibitor fulacimstat on adverse cardiac remodeling after acute ST-segment-elevation myocardial infarction (STEMI). METHODS: In this double-blind, randomized, placebo-controlled trial patients with first STEMI were eligible. To preferentially enrich patients at high risk of adverse remodeling, main inclusion criteria were a left-ventricular ejection fraction (LVEF) ≤45% and an infarct size >10% on day 5 to 9 post MI as measured by cardiac MRI. Patients were then randomized to 6 months treatment with either 25 mg fulacimstat (n = 54) or placebo (n = 53) twice daily on top of standard of care starting day 6 to 12 post MI. The changes in LVEF, LV end-diastolic volume index (LVEDVI), and LV end-systolic volume index (LVESVI) from baseline to 6 months were analyzed by a central blinded cardiac MRI core laboratory. RESULTS:Fulacimstat was safe and well tolerated and achieved mean total trough concentrations that were approximately tenfold higher than those predicted to be required for minimal therapeutic activity. Comparable changes in LVEF (fulacimstat: 3.5% ± 5.4%, placebo: 4.0% ± 5.0%, P = .69), LVEDVI (fulacimstat: 7.3 ± 13.3 mL/m2, placebo: 5.1 ± 18.9 mL/m2, P = .54), and LVESVI (fulacimstat: 2.3 ± 11.2 mL/m2, placebo: 0.6 ± 14.8 mL/m2, P = .56) were observed in both treatment arms. CONCLUSION:Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on cardiac remodeling.
Authors: Carlos M Ferrario; Leanne Groban; Hao Wang; Che Ping Cheng; Jessica L VonCannon; Kendra N Wright; Xuming Sun; Sarfaraz Ahmad Journal: Mol Cell Endocrinol Date: 2020-12-10 Impact factor: 4.369