GDF-15 is associated with worse ischemic and bleeding outcomes in the acute phase and during follow-up in patients with acute coronary syndrome: insights from the TRACER trial
Authors: Wassberg C , Batra G , Westerbergh J , Lindback J , Lopes R D , Mahaffey K W , Harrington R A , Held C , Wallentin L 
Published: November 2023

Abstract

Introduction
Growth differentiating factor-15 (GDF-15) is a stress responsive cytokine that increases with age. GDF-15 has been associated with mortality, myocardial infarction (MI), heart failure and bleeding in patients with acute coronary syndrome (ACS) and stable coronary artery disease.

Purpose
The aim of this study was to evaluate the levels of GDF-15 and their associations with risk of cardiovascular events and bleeding in patients with ACS in the acute setting and after one month.

Methods
Venous blood samples were obtained at the index event in 6800 patients and again after one month in 5313 patients with non-ST-segment elevation ACS (NSTE-ACS) randomized to vorapaxar vs placebo on top of dual antiplatelet treatment in the TRACER study. The GDF-15 level was centrally measured by the ROCHE ELISA assay in stored plasma aliquots. The main cardiovascular (CV) endpoint in this substudy was the composite of CV death, MI and ischemic stroke and main safety endpoint was non-procedural major or minor bleeding according to Thrombolysis in Myocardial Infarction (TIMI) classification. Cox-regression models were used to estimate unadjusted and adjusted associations between log-transformed GDF-15 and outcomes. Adjustments were made for study treatment and well-established clinical CV risk factors. All corresponding models but without the biomarker was fitted and a concordance index (c-index) calculated. A likelihood-ratio test was used to test for differences between the two c-indices.

Results
Median concentration of GDF-15 at baseline and after one month were 1226 ng/L and 1181 ng/L, respectively. The correlation between GDF-15 concentrations at baseline and after one month was r=0.80 (Figure 1). The levels of GDF-15 were independently associated with older age, presence of diabetes mellitus, renal dysfunction and smoking. GDF-15 levels both at baseline and after one month were independently associated with higher rate of CV death, MI and ischemic stroke and with non-procedural TIMI major or minor bleeding (Figure 2). At baseline the addition of GDF-15 levels to the multivariable model for subsequent CV death, MI or ischemic stroke increased the c-index from 0.656 to 0.668 (P&lt;0.001), and for bleeding from 0.715 to 0.719 (P=0.037). At one month adding GDF-15 levels increased the c-index from 0.711 to 0.722 (P&lt;0.001) for CV death, MI or ischemic stroke and from 0.735 to 0.783 (P&lt;0.001) for bleeding.

Conclusions
In patients with NSTE-ACS levels of GDF-15 are independently associated with CV death, MI or ischemic stroke and non-procedural bleeding and contribute prognostic information both at the index event and after one month. Levels of GDF-15 remain stable over time and provide similar prognostic information in the acute and follow-up setting.Fig.1 Correlation GDF-15 baseline and 1mFig.2 Non-linear cox-regression