Abhinav Sharma1, Susanna R Stevens1, Joseph Lucas1, Mona Fiuzat1, Kirkwood F Adams2, David J Whellan3, Mark P Donahue4, Dalane W Kitzman5, Ileana L Piña6, Faiez Zannad7, William E Kraus4, Christopher M O'Connor8, G Michael Felker9. 1. Duke Clinical Research Institute, Durham, North Carolina. 2. Division of Cardiology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina. 3. Division of Cardiology, Thomas Jefferson University, Philadelphia, Pennsylvania. 4. Division of Cardiology, Duke University School of Medicine, Durham, North Carolina. 5. Division of Cardiology, Wake Forest School of Medicine, Winston-Salem, North Carolina. 6. Division of Cardiology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York. 7. INSERM, CIC 1433, Université de Lorraine, CHRU, Nancy, France. 8. Inova Heart and Vascular Institute, Fairfax, Virginia. 9. Duke Clinical Research Institute, Durham, North Carolina. Electronic address: Michael.felker@dm.duke.edu.
Abstract
OBJECTIVES: This study sought to determine the relationship between growth differentiation factor (GDF)-15 and clinical outcomes in ambulatory patients with heart failure and reduced ejection fraction (HFrEF). BACKGROUND: The prognostic utility of GDF-15, a member of the transforming growth factor-β cytokine family, among patients with HF is unclear. METHODS: We assessed GDF-15 levels in 910 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial, a randomized clinical trial of exercise training in patients with HFrEF. Median follow-up was 30 months. Cox proportional hazard models assessed the relationships between GDF-15 and clinical outcomes. RESULTS: The median GDF-15 concentration was 1,596 pg/ml. Patients in the highest tertile of GDF-15 were older and had measurements of more severe HF (higher N-terminal pro-B-type natriuretic peptide [NT-proBNP] concentrations and lower peak oxygen uptake on cardiopulmonary exercise testing [CPX]). GDF-15 therapy was a significant predictor of all-cause death (unadjusted hazard ratio [HR]: 2.03 when GDF-15 was doubled; p < 0.0001). This association persisted after adjustment for demographic and clinical and biomarkers including high sensitivity troponin T (hs-TnT) and NT-proBNP (HR: 1.30 per doubling of GDF-15; p = 0.029). GDF-15 did not improve discrimination (as measured by changes in c-statistics and the integrated discrimination improvement) in addition to baseline variables, including hs-TnT and NT-proBNP or variables found in CPX testing. CONCLUSIONS: In demographically diverse, well-managed patients with HFrEF, GDF-15 therapy provided independent prognostic information in addition to established predictors of outcomes. These data support a possible role for GDF-15 in the risk stratification of patients with chronic HFrEF. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437).
RCT Entities:
OBJECTIVES: This study sought to determine the relationship between growth differentiation factor (GDF)-15 and clinical outcomes in ambulatory patients with heart failure and reduced ejection fraction (HFrEF). BACKGROUND: The prognostic utility of GDF-15, a member of the transforming growth factor-β cytokine family, among patients with HF is unclear. METHODS: We assessed GDF-15 levels in 910 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial, a randomized clinical trial of exercise training in patients with HFrEF. Median follow-up was 30 months. Cox proportional hazard models assessed the relationships between GDF-15 and clinical outcomes. RESULTS: The median GDF-15 concentration was 1,596 pg/ml. Patients in the highest tertile of GDF-15 were older and had measurements of more severe HF (higher N-terminal pro-B-type natriuretic peptide [NT-proBNP] concentrations and lower peak oxygen uptake on cardiopulmonary exercise testing [CPX]). GDF-15 therapy was a significant predictor of all-cause death (unadjusted hazard ratio [HR]: 2.03 when GDF-15 was doubled; p < 0.0001). This association persisted after adjustment for demographic and clinical and biomarkers including high sensitivity troponin T (hs-TnT) and NT-proBNP (HR: 1.30 per doubling of GDF-15; p = 0.029). GDF-15 did not improve discrimination (as measured by changes in c-statistics and the integrated discrimination improvement) in addition to baseline variables, including hs-TnT and NT-proBNP or variables found in CPX testing. CONCLUSIONS: In demographically diverse, well-managed patients with HFrEF, GDF-15 therapy provided independent prognostic information in addition to established predictors of outcomes. These data support a possible role for GDF-15 in the risk stratification of patients with chronic HFrEF. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437).
Authors: Clyde W Yancy; Mariell Jessup; Biykem Bozkurt; Javed Butler; Donald E Casey; Mark H Drazner; Gregg C Fonarow; Stephen A Geraci; Tamara Horwich; James L Januzzi; Maryl R Johnson; Edward K Kasper; Wayne C Levy; Frederick A Masoudi; Patrick E McBride; John J V McMurray; Judith E Mitchell; Pamela N Peterson; Barbara Riegel; Flora Sam; Lynne W Stevenson; W H Wilson Tang; Emily J Tsai; Bruce L Wilkoff Journal: J Am Coll Cardiol Date: 2013-06-05 Impact factor: 24.094
Authors: Christopher M O'Connor; David J Whellan; Daniel Wojdyla; Eric Leifer; Robert M Clare; Stephen J Ellis; Lawrence J Fine; Jerome L Fleg; Faiez Zannad; Steven J Keteyian; Dalane W Kitzman; William E Kraus; David Rendall; Ileana L Piña; Lawton S Cooper; Mona Fiuzat; Kerry L Lee Journal: Circ Heart Fail Date: 2011-11-23 Impact factor: 8.790
Authors: Tibor Kempf; Rüdiger Horn-Wichmann; Georg Brabant; Timo Peter; Tim Allhoff; Gunnar Klein; Helmut Drexler; Nina Johnston; Lars Wallentin; Kai C Wollert Journal: Clin Chem Date: 2006-12-21 Impact factor: 8.327
Authors: Inder S Anand; Tibor Kempf; Thomas S Rector; Heike Tapken; Tim Allhoff; Franziska Jantzen; Michael Kuskowski; Jay N Cohn; Helmut Drexler; Kai C Wollert Journal: Circulation Date: 2010-09-20 Impact factor: 29.690
Authors: Gregg C Fonarow; Nancy M Albert; Anne B Curtis; Wendy Gattis Stough; Mihai Gheorghiade; J Thomas Heywood; Mark L McBride; Patches Johnson Inge; Mandeep R Mehra; Christopher M O'Connor; Dwight Reynolds; Mary Norine Walsh; Clyde W Yancy Journal: Circulation Date: 2010-07-26 Impact factor: 29.690
Authors: Alan S Maisel; Padma Krishnaswamy; Richard M Nowak; James McCord; Judd E Hollander; Philippe Duc; Torbjørn Omland; Alan B Storrow; William T Abraham; Alan H B Wu; Paul Clopton; Philippe G Steg; Arne Westheim; Catherine Wold Knudsen; Alberto Perez; Radmila Kazanegra; Howard C Herrmann; Peter A McCullough Journal: N Engl J Med Date: 2002-07-18 Impact factor: 91.245
Authors: Lesley H Curtis; David J Whellan; Bradley G Hammill; Adrian F Hernandez; Kevin J Anstrom; Alisa M Shea; Kevin A Schulman Journal: Arch Intern Med Date: 2008-02-25
Authors: Christopher M O'Connor; David J Whellan; Kerry L Lee; Steven J Keteyian; Lawton S Cooper; Stephen J Ellis; Eric S Leifer; William E Kraus; Dalane W Kitzman; James A Blumenthal; David S Rendall; Nancy Houston Miller; Jerome L Fleg; Kevin A Schulman; Robert S McKelvie; Faiez Zannad; Ileana L Piña Journal: JAMA Date: 2009-04-08 Impact factor: 56.272
Authors: G Michael Felker; Mona Fiuzat; Vivian Thompson; Linda K Shaw; Megan L Neely; Kirkwood F Adams; David J Whellan; Mark P Donahue; Tariq Ahmad; Dalane W Kitzman; Ileana L Piña; Faiez Zannad; William E Kraus; Christopher M O'Connor Journal: Circ Heart Fail Date: 2013-10-08 Impact factor: 8.790
Authors: Kai M Eggers; Tibor Kempf; Bo Lagerqvist; Bertil Lindahl; Sylvia Olofsson; Franziska Jantzen; Timo Peter; Tim Allhoff; Agneta Siegbahn; Per Venge; Kai C Wollert; Lars Wallentin Journal: Circ Cardiovasc Genet Date: 2009-12-11
Authors: David D Berg; Christian T Ruff; Petr Jarolim; Robert P Giugliano; Francesco Nordio; Hans J Lanz; Michele F Mercuri; Elliott M Antman; Eugene Braunwald; David A Morrow Journal: Circulation Date: 2019-02-05 Impact factor: 29.690
Authors: Marat Fudim; Jacob P Kelly; Aaron D Jones; Omar F AbouEzzeddine; Andrew P Ambrosy; Stephen J Greene; Yogesh N V Reddy; Kevin J Anstrom; Brooke Alhanti; Gregory D Lewis; Adrian F Hernandez; G Michael Felker Journal: Am Heart J Date: 2019-11-16 Impact factor: 4.749
Authors: Justin B Echouffo-Tcheugui; Natalie Daya; Kunihiro Matsushita; Dan Wang; Chiadi E Ndumele; Mahmoud Al Rifai; Ron C Hoogeveen; Christie M Ballantyne; Elizabeth Selvin Journal: Clin Chem Date: 2021-03-31 Impact factor: 8.327