Growth Differentiation Factor 15, a Marker of Oxidative Stress and Inflammation, for Risk Assessment in Patients With Atrial Fibrillation

Abstract

Background— Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation. Methods and Results— The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment, and other biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile range, 977–2052 ng/L). Annual rates of stroke or systemic embolism ranged from 0.9% to 2.03% ( P <0.001); of major bleeding, from 1.22% to 4.53% ( P <0.001); and of mortality, from 1.34% to 7.19% ( P <0.001) in the lowest compared with the highest GDF-15 quartile. The prognostic information provided by GDF-15 was independent of clinical characteristics and clinical risk scores. Adjustment for the other cardiac biomarkers attenuated the prognostic value for stroke, whereas the prognostic value for mortality and major bleeding remained. Apixaban consistently reduced stroke, mortality, and bleeding, regardless of GDF-15 levels. Conclusions— GDF-15 is a risk factor for major bleeding, mortality, and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00412984.

Growth Differentiation Factor 15, Its 12-Month Relative Change, and Risk of Cardiovascular Events and Total Mortality in Patients with Stable Coronary Heart Disease: 10-Year Follow-up of the KAROLA Study

“…In patients with atrial fibrillation GDF-15 was also shown to be associated with death independently of NT-proBNP and cardiac troponin (22 ).…”

EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication

“…GDF15). [302][303][304] Many of these studies have been performed in selected clinical trial cohorts, and the prognostic role in risk stratification requires prospective testing in unselected large 'real-world' cohorts with a broad range of stroke risk and renal function. As in the case of AF prediction, evidence for the additive value of biomarkers for stroke risk prediction from large prospective nonanticoagulated 'real-world' cohorts is limited.…”

New Biomarkers and Risk Stratification in Atrial Fibrillation

“…Thus, the article by Wallentin et al 14 in the current issue of Circulation is a timely addition to the literature on GDF-15 in AF and describes its systematic analysis in 14 798 patients enrolled in the ARISTOTLE trial. GDF-15 provided prognostic information for stroke, mortality and major bleeding independent of clinical characteristics and clinical risk scores.…”

“…However, the data from Wallentin et al 14 suggest that used in combination with clinical risk assessment, GDF-15 may prove to be yet another useful biomarker to improve risk stratification for bleeding and mortality in patients with AF who are receiving anticoagulation therapy. Thus, GDF-15 joins the club of a plethora of biomarkers in AF, only few of which have managed practical application.…”

“…Given the caveat that GDF-15 may be nonspecific, this analysis by Wallentin et al 14 was performed in an anticoagulated trial cohort, so the issues of generalizability to the general AF population remain, given that many patients in an unselected population with AF suitable for anticoagulation were ineligible for trial participation. 15 Thus, additional studies are needed in non-anticoagulated AF populations as well as in real-world cohorts that have a broad range of stroke risk and comorbidities.…”