Growth differentiation factor 15 and all-cause and cause-specific mortality in patients with suspected or known coronary artery disease: The ANOX and EXCEED-J Studies

Background Growth differentiation factor 15 (GDF-15) is a stress responsive member of the transforming growth factor ꞵ (TGF-ꞵ) cytokine superfamily. The circulating GDF-15 level is an independent predictor of cardiovascular (CV) and cancer mortality and morbidity in community-dwelling individuals, and is also an independent marker of all-cause mortality and cardiovascular events in patients with coronary artery disease (CAD). However, the prognostic value of GDF-15 for cause-specific mortality in patients with CAD are not fully confirmed. Methods Serum GDF-15 levels were measured in 3,255 patients enrolled in the EXCEED-J Study and 2,418 patients enrolled in the ANOX Study with suspected or known CAD. The outcomes were all-cause death, CV death, cancer death, and other non-CV death. Patients were followed up over a 6-year period. Results During the follow-up, 518 (15.9%) deaths occurred, including 169 (5.2%) CV deaths, 117 (3.6%) cancer deaths, 170 (5.2%) other non-CV deaths, and 60 (1.8%) undetermined deaths in the EXCEED-J Study, while 536 (22.2%) deaths occurred, including 166 (6.9%) CV deaths, 128 (5.3%) cancer deaths, 198 (8.2%) other non-CV deaths, and 44 (1.8%) undetermined deaths in the ANOX Study. After adjustment for potential clinical confounders (i.e., age, sex, body mass index, hypertension, dyslipidemia, diabetes, current smoker, estimated glomerular filtration rate, the Gensini score, previous myocardial infarction, previous stroke, previous heart failure hospitalization, atrial fibrillation, valvular heart disease, peripheral artery disease, chronic obstructive pulmonary disease, malignancies, anemia, antihypertensive drug use, statin use, and aspirin use) and established CV biomarkers (i.e., N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin I, and high-sensitivity C-reactive protein), log-transformed (Ln-) GDF-15 levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.58; 95% confidence interval [CI], 1.40–1.78), CV death (HR, 1.40; 95% CI, 1.14–1.72), cancer death (HR, 1.65; 95% CI, 1.29–2.12), and other non-CV death (HR, 1.92; 95% CI, 1.55–2.37) in the EXCEED-J Study; and significantly associated with all-cause death (HR, 1.77; 95% CI, 1.56–2.01), CV death (HR, 1.48; 95% CI, 1.16–1.87), cancer death (HR, 2.32; 95% CI, 1.83–2.95), and other non-CV death (HR, 1.74; 95% CI, 1.40–2.15) in the ANOX Study. The addition of Ln-GDF-15 to the model with potential clinical confounders and established CV biomarkers significantly improved the prediction of all-cause death, cancer death, and other non-CV death (P<0.05 for both continuous net reclassification improvement and integrated discrimination improvement for all comparisons), but not that of CV death, in both studies. Conclusions The GDF-15 level independently predicted all-cause, cancer, and other non-CV mortality, but not CV mortality, in patients with suspected or known CAD.