Growth differentiation factor 15 predicts poor prognosis in patients with heart failure and reduced ejection fraction and anemia: results from RED-HF

Thor Ueland,Lars Gullestad,Pål Aukrust,James B Young,Marc A Pfeffer,John J V Mcmurray,Lei Kou,Karl Swedberg,Akshay S Desai,Dirk Jan Van Veldhuisen,Inderjit S Anand

doi:10.1007/s00392-021-01944-6

Abstract

AimsWe aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and anemiaMethods and resultsSerum GDF-15 was assessed in 1582 HFrEF and mild-to-moderate anemia patients who where followed for 28 months in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial, an overall neutral RCT evaluating the effect darbepoetin alfa on clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Association between baseline and change in GDF-15 during 6 months follow-up and the primary composite outcome of all-cause death or HF hospitalization were evaluated in multivariable Cox-models adjusted for conventional clinical and biochemical risk factors. The adjusted risk for the primary outcome increased with (i) successive tertiles of baseline GDF-15 (tertile 3 HR 1.56 [1.23–1.98] p < 0.001) as well as with (ii) a 15% increase in GDF-15 levels over 6 months of follow-up (HR 1.68 [1.38–2.06] p < 0.001). Addition of change in GDF-15 to the fully adjusted model improved the C-statistics (p < 0.001). No interaction between treatment and baseline or change in GDF-15 on outcome was observed. GDF-15 was inversely associated with several indices of anemia and correlated positively with ferritin.ConclusionsIn patients with HF and anemia, both higher baseline serum GDF-15 levels and an increase in GDF-15 during follow-up, were associated with worse clinical outcomes. GDF-15 did not identify subgroups of patients who might benefit from correction of anemia but was associated with several indices of anemia and iron status in the HF patients.Graphic abstract

Highlights

Anemia is common in patients with heart failure (HF) and is associated with a high incidence of hospitalization and death [1,2,3]
Anemia in HF patients is associated with impaired renal function, potentially causing impaired erythropoietin production, and patients with HF often have systemic inflammation, which may lead to bone marrow suppression [2, 3]
Of the 2278 patients enrolled in the RED-HF study, baseline measurement of Growth differentiation factor-15 (GDF-15) was available for 1582 (69%)

Summary

Introduction

Anemia is common in patients with heart failure (HF) and is associated with a high incidence of hospitalization and death [1,2,3]. Anemia in HF patients is associated with impaired renal function, potentially causing impaired erythropoietin production, and patients with HF often have systemic inflammation, which may lead to bone marrow suppression [2, 3]. High levels of GDF-15 are reported in patients with HF and anemia, correlated with iron status [10]. It has been suggested that GDF-15 may influence erythropoiesis by suppressing hepcidin expression, a major regulator of iron status [11]. In the large Valsartan Heart Failure Trial (Val-HeFT, n = 1734), baseline GDF15 was independently associated with mortality even after adjusting for multiple clinical and biochemical prognostic variables including BNP, hs-CRP, and hs-Troponin [16]

Methods

Results

Conclusion