Growth Differentiation Factor 15 at 1 Month After an Acute Coronary Syndrome Is Associated With Increased Risk of Major Bleeding

Daniel Lindholm, Emil Hagström, Stefan K James, Richard C Becker, Christopher P Cannon, Anders Himmelmann, Hugo A Katus, Gerald Maurer, José Luis López-Sendón, Philippe Gabriel Steg, Robert F Storey, Agneta Siegbahn, Lars Wallentin, Daniel Lindholm, Emil Hagström, Stefan K James, Richard C Becker, Christopher P Cannon, Anders Himmelmann, Hugo A Katus, Gerald Maurer, José Luis López-Sendón, Philippe Gabriel Steg, Robert F Storey, Agneta Siegbahn, Lars Wallentin

Abstract

Background: Growth differentiation factor-15 (GDF-15) is related to major bleeding when measured at initial presentation in patients with acute coronary syndromes (ACSs) treated with dual antiplatelet therapy. It is unknown whether follow-up measurements provide additional information. The objective of this study was to investigate whether GDF-15 measured 1 month after an ACS provides additional information beyond the baseline levels with regard to the risk of major bleeding.

Methods and results: GDF-15 was measured at baseline and at 1 month after an ACS in 4049 patients included in the PLATelet inhibition and patient Outcomes (PLATO) trial. The association between 1-month GDF-15 level and non-coronary artery bypass grafting surgery-related major bleeding was assessed by a multivariable Cox model, adjusting for baseline GDF-15, age, anemia, impaired renal function, history of gastrointestinal bleeding, and sex. Elevated GDF-15 (>1800 ng/L) at 1 month was associated with an increased risk of non-coronary artery bypass grafting-related major bleeding (3.9% versus 1.2%; hazard ratio, 3.38; 95% CI, 1.89-6.06), independent of baseline GDF-15. Patients who had elevated GDF-15 levels at baseline and subsequent nonelevated GDF-15 at 1 month had a similar risk as patients who had nonelevated levels at both measurements.

Conclusions: GDF-15 at 1 month after an ACS is related to the risk of bleeding during DAPT and provides additional information on the bleeding risk beyond baseline GDF-15 levels. GDF-15 levels may therefore be useful as part of decision support concerning long-term antithrombotic treatment in patients post-ACS.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Keywords: biomarker; bleeding; ischemic heart disease.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
GDF‐15 at baseline and at 1 month. A, Log2‐transformed GDF‐15 levels. B, Waterfall plot indicating relative change in GDF‐15 levels between baseline and 1 month (please note that data are truncated at ∼+100%; a few patients had >100% relative increase in GDF‐15). The plot is an ordered bar plot, where each patient's % change in GDF‐15 from baseline to 1 month is plotted. Although GDF‐15 levels were only slightly lower on the population level (A), some patients had substantial relative changes in GDF‐15 (B). GDF‐15 indicates growth differentiation factor‐15.
Figure 2
Figure 2
Probability of non‐CABG‐related major bleeding in relation to GDF‐15 assessed from baseline (black) and from the 1‐month follow‐up visit (blue). The dashed line indicates a GDF‐15 level of 1800 ng/L, which was used as a cutoff to define GDF‐15 elevation in this study. CABG indicates coronary artery bypass grafting. CABG indicates coronary artery bypass grafting; GDF‐15 indicates growth differentiation factor‐15.
Figure 3
Figure 3
Kaplan‐Meier estimates of non‐CABG‐related major bleeding from the 1‐month follow‐up visit according to 1‐month GDF‐15 levels (ng/L). CABG indicates coronary artery bypass grafting.
Figure 4
Figure 4
Kaplan–Meier estimates of non‐CABG‐related major bleeding from the 1‐month follow‐up visit according to 1‐month GDF‐15 levels in (A) patients with nonelevated (≤1800 ng/L) baseline GDF‐15 levels and (B) patients with elevated (>1800 ng/L) baseline GDF‐15 levels. CABG indicates coronary artery bypass grafting.

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