Javed Butler1, Muhammad Shahzeb Khan2, Stefan D Anker3, Gregg C Fonarow4, Raymond J Kim5, Savina Nodari6, Christopher M O'Connor7, Burkert Pieske8, Elisabeth Pieske-Kraigher8, Hani N Sabbah9, Michele Senni10, Adriaan A Voors11, James E Udelson12, Jim Carr13, Mihai Gheorghiade14, Gerasimos Filippatos15. 1. Department of Medicine, University of Mississippi Medical Center, Jackson, Missisippi, USA. 2. Department of Medicine, Cook County Hospital, Chicago, Illinois, USA. 3. Department of Cardiology (CVK), Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Germany. 4. Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA. 5. Duke Cardiovascular Magnetic Resonance Center, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA. 6. Cardiology Section, Department of Clinical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. 7. Inova Heart and Vascular Institute, Falls Church, Virginia, USA. 8. Department of Internal Medicine and Cardiology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany; Department of Internal Medicine and Cardiology, German Heart Center Berlin, and German Centre for Cardiovascular Research (DZHK), Partner site Berlin, and Berlin Institute of Health (BIH), Berlin, Germany. 9. Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, Michigan, USA. 10. Cardiovascular Department, ASST Papa Giovanni XXIII, Bergamo, Italy. 11. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 12. Division of Cardiology and the Cardiovascular Center, Tufts Medical Center, Boston, Massachusetts, USA. 13. Stealth BioTherapeutics, Newton, Massachusetts, USA. 14. Department of Medicine, Bluhm Cardiovascular Institute, Northwestern University Feingerg School of Medicine, Chicago, Illinois, USA. 15. National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece. Electronic address: geros@otenet.gr.
Abstract
BACKGROUND:Elamipretide, a novel mitochondrial modulating agent, improves myocardial energetics; however, it is unknown whether this mechanistic benefit translates into improved cardiac structure and function in heart failure (HF) with reduced ejection fraction (HFrEF). The objective of this study was to evaluate the effects of multiple subcutaneous doses of elamipretide on left ventricular end systolic volume (LVESV) as assessed by cardiac magnetic resonance imaging. METHODS: We randomized 71 patients with HFrEF (LVEF ≤ 40%) in a double-blind, placebo-controlled trial in a 1:1:1 ratio to receive placebo, 4 mg or 40 mg elamipretide once daily for 28 consecutive days. RESULTS:The mean age (standard deviation) of the study population was 65 ± 10 years, 24% were females, and the mean EF was 31% ± 7%. The change in LVESV from baseline to week 4 was not significantly different between elamipretide 4 mg (89.4 mL to 85 mL; difference, -4.4 mL) or 40 mg (77.9 mL to 76.6 mL; difference, -1.2 mL) compared with placebo (77.7 mL to 74.6 mL; difference, -3.8 mL) (4 mg vs placebo: difference of means, -0.3; 95% CI, -4.6 to 4.0; P = 0.90; and 40 mg vs placebo: difference of means, 2.3; 95% CI, -1.9 to 6.5; P = 0.28). Also, no significant differences in change in LVESV and LVEF were observed between placebo and either of the elamipretide groups. Rates of any study drug-related adverse events were similar in the 3 groups. CONCLUSIONS:Elamipretide was well tolerated but did not improve LVESV at 4 weeks in patients with stable HFrEF compared with placebo.
RCT Entities:
BACKGROUND: Elamipretide, a novel mitochondrial modulating agent, improves myocardial energetics; however, it is unknown whether this mechanistic benefit translates into improved cardiac structure and function in heart failure (HF) with reduced ejection fraction (HFrEF). The objective of this study was to evaluate the effects of multiple subcutaneous doses of elamipretide on left ventricular end systolic volume (LVESV) as assessed by cardiac magnetic resonance imaging. METHODS: We randomized 71 patients with HFrEF (LVEF ≤ 40%) in a double-blind, placebo-controlled trial in a 1:1:1 ratio to receive placebo, 4 mg or 40 mg elamipretide once daily for 28 consecutive days. RESULTS: The mean age (standard deviation) of the study population was 65 ± 10 years, 24% were females, and the mean EF was 31% ± 7%. The change in LVESV from baseline to week 4 was not significantly different between elamipretide 4 mg (89.4 mL to 85 mL; difference, -4.4 mL) or 40 mg (77.9 mL to 76.6 mL; difference, -1.2 mL) compared with placebo (77.7 mL to 74.6 mL; difference, -3.8 mL) (4 mg vs placebo: difference of means, -0.3; 95% CI, -4.6 to 4.0; P = 0.90; and 40 mg vs placebo: difference of means, 2.3; 95% CI, -1.9 to 6.5; P = 0.28). Also, no significant differences in change in LVESV and LVEF were observed between placebo and either of the elamipretide groups. Rates of any study drug-related adverse events were similar in the 3 groups. CONCLUSIONS: Elamipretide was well tolerated but did not improve LVESV at 4 weeks in patients with stable HFrEF compared with placebo.
Authors: Mario G Pavez-Giani; Pablo I Sánchez-Aguilera; Nils Bomer; Shigeki Miyamoto; Harmen G Booij; Paula Giraldo; Silke U Oberdorf-Maass; Kirsten T Nijholt; Salva R Yurista; Hendrik Milting; Peter van der Meer; Rudolf A de Boer; Joan Heller Brown; Herman W H Sillje; B Daan Westenbrink Journal: Int J Mol Sci Date: 2021-04-23 Impact factor: 5.923
Authors: Danielle L Kirkman; Austin T Robinson; Matthew J Rossman; Douglas R Seals; David G Edwards Journal: Am J Physiol Heart Circ Physiol Date: 2021-04-09 Impact factor: 5.125