Impact of anemia on the relationships of growth differentiation factor 15 with mortality and cardiovascular events in patients with suspected or known coronary artery disease: the ANOX study
Authors: Wada H , Suzuki M , Matsuda M , Ajiro Y , Shinozaki T , Sakagami S , Yonezawa K , Shimizu M , Funada J , Takenaka T , Wada M , Iguchi M , Abe M , Akao M , Hasegawa K 
Published: November 2020

Abstract

Background
Growth differentiation factor 15 (GDF-15) is a stress-responsive cytokine that plays an important role in the regulation of the inflammatory response, growth and cell differentiation. An elevated GDF-15 was found in various conditions including anemia and stable coronary artery disease (CAD), and it was reported to predict mortality and cardiovascular (CV) events in general population and in patients with established CAD. However, the impact of anemia on the relationships of GDF-15 with mortality and CV events in patients with suspected or known CAD is unclear.

Methods
Serum GDF-15 levels were measured in 2,418 patients with suspected or known CAD undergoing elective coronary angiography, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict CV events (ANOX) study, and followed up for 3 years. Anemia was defined as a hemoglobin level of less than 13 g/dL in men and &lt;12 g/dL in women. Patients were divided into 2 groups according to the presence (anemic, n=882) or absence (non-anemic, n=1,536) of anemia. The primary outcome was all-cause death. The secondary outcomes were CV death, and major adverse CV events (MACE) defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke.

Results
During the follow-up, 164 anemic and 90 non-anemic patients died from any cause, 64 anemic and 24 non-anemic patients died from CV disease, and 96 anemic and 69 non-anemic patients developed MACE. After adjustment for established risk factors, GDF-15 levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.75; 95% confidence interval [CI], 1.51–2.04), CV death (HR, 1.67; 95% CI, 1.30–2.13), and MACE (HR, 1.46; 95% CI, 1.18–1.81) in anemic, while GDF-15 levels were also significantly associated with all-cause death (HR, 1.47; 95% CI, 1.27–1.69), CV death (HR, 1.56; 95% CI, 1.18–1.99), and MACE (HR, 1.25; 95% CI, 1.004–1.50) in non-anemic patients. Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of GDF-15 levels further improved the prediction of all-cause death (P&lt;0.001 for continuous net reclassification improvement [NRI], P&lt;0.001 for integrated discrimination improvement [IDI]), CV death (P=0.026 for NRI, P=0.023 for IDI), and MACE (P=0.025 for NRI, P=0.042 for IDI) in anemic, whereas it did not improved the prediction of all-cause death (P=0.072 for NRI, P=0.079 for IDI), CV death (P=0.289 for NRI, P=0.179 for IDI) or MACE (P=0.397 for NRI, P=0.230 for IDI) in non-anemic patients.

Conclusions
The GDF-15 level significantly improved the prediction of all-cause death, CV death, and MACE in anemic, but not in non-anemic patients with suspected or known CAD. The relationships of GDF-15 with mortality and CV events seem to be remarkable in the presence of anemia.

Funding Acknowledgement
Type of funding source: Public Institution(s). Main funding source(s): The ANOX study is supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization.