TY - JOUR
T1 - Endothelin-1, Outcomes in Patients With Heart Failure and Reduced Ejection Fraction, and Effects of Dapagliflozin
T2 - Findings From DAPA-HF
AU - Ern Yeoh, Su
AU - Docherty, Kieran F
AU - Campbell, Ross T
AU - Jhund, Pardeep S
AU - Hammarstedt, Ann
AU - Heerspink, Hiddo J L
AU - Jarolim, Petr
AU - Køber, Lars
AU - Kosiborod, Mikhail N
AU - Martinez, Felipe A
AU - Ponikowski, Piotr
AU - Solomon, Scott D
AU - Sjöstrand, Mikaela
AU - Bengtsson, Olof
AU - Greasley, Peter J
AU - Sattar, Naveed
AU - Welsh, Paul
AU - Sabatine, Marc S
AU - Morrow, David A
AU - McMurray, John J V
PY - 2023/5/30
Y1 - 2023/5/30
N2 - BACKGROUND: ET-1 (endothelin-1) is implicated in the pathophysiology of heart failure and renal disease. Its prognostic importance and relationship with kidney function in patients with heart failure with reduced ejection fraction receiving contemporary treatment are uncertain. We investigated these and the efficacy of dapagliflozin according to ET-1 level in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure).METHODS: We investigated the incidence of the primary outcome (cardiovascular death or worsening heart failure), change in kidney function, and the effect of dapagliflozin according to baseline ET-1 concentration, adjusting in Cox models for other recognized prognostic variables in heart failure including NT-proBNP (N-terminal pro-B-type natriuretic peptide). We also examined the effect of dapagliflozin on ET-1 level.RESULTS: Overall, 3048 participants had baseline ET-1 measurements: tertile 1 (T1; ≤3.28 pg/mL; n=1016); T2 (>3.28-4.41 pg/mL; n=1022); and T3 (>4.41 pg/mL; n=1010). Patients with higher ET-1 were more likely male, more likely obese, and had lower left ventricular ejection fraction, lower estimated glomerular filtration rate, worse functional status, and higher NT-proBNP and hs-TnT (high-sensitivity troponin-T). In the adjusted Cox models, higher baseline ET-1 was independently associated with worse outcomes and steeper decline in kidney function (adjusted hazard ratio for primary outcome of 1.95 [95% CI, 1.53-2.50] for T3 and 1.36 [95% CI, 1.06-1.75] for T2; both versus T1; estimated glomerular filtration rate slope: T3, -3.19 [95% CI, -3.66 to -2.72] mL/min per 1.73 m2 per y, T2, -2.08 [95% CI, -2.52 to -1.63] and T1 -2.35 [95% CI, -2.79 to -1.91]; P=0.002). The benefit of dapagliflozin was consistent regardless of baseline ET-1, and the placebo-corrected decrease in ET-1 with dapagliflozin was 0.13 pg/mL (95% CI, 0.25-0.01; P=0.029).CONCLUSIONS: Higher baseline ET-1 concentration was independently associated with worse clinical outcomes and more rapid decline in kidney function. The benefit of dapagliflozin was consistent across the range of ET-1 concentrations measured, and treatment with dapagliflozin led to a small decrease in serum ET-1 concentration.REGISTRATION: URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT03036124.
AB - BACKGROUND: ET-1 (endothelin-1) is implicated in the pathophysiology of heart failure and renal disease. Its prognostic importance and relationship with kidney function in patients with heart failure with reduced ejection fraction receiving contemporary treatment are uncertain. We investigated these and the efficacy of dapagliflozin according to ET-1 level in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure).METHODS: We investigated the incidence of the primary outcome (cardiovascular death or worsening heart failure), change in kidney function, and the effect of dapagliflozin according to baseline ET-1 concentration, adjusting in Cox models for other recognized prognostic variables in heart failure including NT-proBNP (N-terminal pro-B-type natriuretic peptide). We also examined the effect of dapagliflozin on ET-1 level.RESULTS: Overall, 3048 participants had baseline ET-1 measurements: tertile 1 (T1; ≤3.28 pg/mL; n=1016); T2 (>3.28-4.41 pg/mL; n=1022); and T3 (>4.41 pg/mL; n=1010). Patients with higher ET-1 were more likely male, more likely obese, and had lower left ventricular ejection fraction, lower estimated glomerular filtration rate, worse functional status, and higher NT-proBNP and hs-TnT (high-sensitivity troponin-T). In the adjusted Cox models, higher baseline ET-1 was independently associated with worse outcomes and steeper decline in kidney function (adjusted hazard ratio for primary outcome of 1.95 [95% CI, 1.53-2.50] for T3 and 1.36 [95% CI, 1.06-1.75] for T2; both versus T1; estimated glomerular filtration rate slope: T3, -3.19 [95% CI, -3.66 to -2.72] mL/min per 1.73 m2 per y, T2, -2.08 [95% CI, -2.52 to -1.63] and T1 -2.35 [95% CI, -2.79 to -1.91]; P=0.002). The benefit of dapagliflozin was consistent regardless of baseline ET-1, and the placebo-corrected decrease in ET-1 with dapagliflozin was 0.13 pg/mL (95% CI, 0.25-0.01; P=0.029).CONCLUSIONS: Higher baseline ET-1 concentration was independently associated with worse clinical outcomes and more rapid decline in kidney function. The benefit of dapagliflozin was consistent across the range of ET-1 concentrations measured, and treatment with dapagliflozin led to a small decrease in serum ET-1 concentration.REGISTRATION: URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT03036124.
KW - Benzhydryl Compounds/adverse effects
KW - Endothelin-1/pharmacology
KW - Heart Failure/diagnosis
KW - Humans
KW - Male
KW - Stroke Volume
KW - Ventricular Dysfunction, Left/drug therapy
KW - Ventricular Function, Left
KW - heart failure
KW - biomarkers
KW - SGLT-2 inhibitor
KW - kidney
KW - endothelin-1
UR - http://www.scopus.com/inward/record.url?scp=85160841821&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.122.063327
DO - 10.1161/CIRCULATIONAHA.122.063327
M3 - Journal article
C2 - 37039015
SN - 1524-4539
VL - 147
SP - 1670
EP - 1683
JO - Circulation
JF - Circulation
IS - 22
ER -