TY - JOUR
T1 - Effects of the chymase inhibitor fulacimstat on adverse cardiac remodeling after acute myocardial infarction—Results of the Chymase Inhibitor in Adverse Remodeling after Myocardial Infarction (CHIARA MIA) 2 trial
AU - GROUP investigators of the CHIARA MIA 2 trial
AU - Duengen, Hans Dirk
AU - Kim, Raymond J.
AU - Zahger, Doron
AU - Orvin, Katia
AU - Kornowski, Ran
AU - Admon, Dan
AU - Kettner, Jiri
AU - Shimony, Avraham
AU - Otto, Christiane
AU - Becka, Michael
AU - Kanefendt, Friederike
AU - Romo, Andres Iniguez
AU - Hasin, Tal
AU - Ostadal, Petr
AU - Rojas, Gonzalo Calvo
AU - Senni, Michele
AU - Podpera, Ivo
AU - Linkova, Hana
AU - Hajek, Petr
AU - Bauersachs, Johann
AU - Menck, Niels
AU - Fuisting, Jan
AU - Oumbe Tiam, Sadrack
AU - Martinez Selles, Manuel
AU - Miro Palau, Vicente
AU - Roque, Mercedes
AU - Ibanez, Borja
AU - Arbel, Yaron
AU - Nikolsky, Eugenia
AU - Nodari, Savina
AU - Silvio Marenzi, Gian Carlo
AU - Achilli, Felice
AU - Reimers, Bernhard
N1 - Funding Information:
The authors are grateful to the following clinical investigators for reviewing the study protocol, enrolment of patients, and collection of data: Ivo Podpera, Hana Linkova, Petr Hajek, Johann Bauersachs, Niels Menck, Jan Fuisting, Sadrack Oumbe Tiam, Manuel Martinez Selles, Vicente Miro Palau, Mercedes Roque, Borja Ibanez, Yaron Arbel, Eugenia Nikolsky, Savina Nodari, Gian Carlo Silvio Marenzi, Felice Achilli, and Bernhard Reimers. The authors wish to thank Andrea-Viviana Scalise and Thomas Viethen for ongoing medical review; Mark Enzler (Swiss BioQuant AG) and Richard Abbott (Bayer AG) for performing bioanalysis of plasma PK samples, Wilfried Dinh for valuable scientific contributions to the study design, and Michele Parker from the MRI core laboratory. We are grateful to all patients participating in this study. Funding: The study was funded by its sponsor Bayer AG.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85084081354&partnerID=8YFLogxK
U2 - 10.1016/j.ahj.2020.01.012
DO - 10.1016/j.ahj.2020.01.012
M3 - Article
AN - SCOPUS:85084081354
VL - 224
SP - 129
EP - 137
JO - American Heart Journal
JF - American Heart Journal
SN - 0002-8703
ER -