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

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.

[1]  C. Cannon,et al.  Biomarkers and Coronary Lesions Predict Outcomes after Revascularization in Non-ST-Elevation Acute Coronary Syndrome. , 2017, Clinical chemistry.

[2]  L. Wallentin,et al.  Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease. , 2017, Clinical chemistry.

[3]  C. Held,et al.  Growth Differentiation Factor 15 Predicts All-Cause Morbidity and Mortality in Stable Coronary Heart Disease. , 2017, Clinical chemistry.

[4]  J. Spertus,et al.  Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention. , 2016, JAMA.

[5]  E. Hagström,et al.  Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study. , 2016, European heart journal.

[6]  Marc P. Bonaca,et al.  Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. , 2015, European heart journal.

[7]  Baris Gencer,et al.  ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation , 2011 .

[8]  M. Valgimigli,et al.  Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. , 2015, The New England journal of medicine.

[9]  Braunwald,et al.  Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. , 2014, The New England journal of medicine.

[10]  R. de Caterina,et al.  Growth Differentiation Factor 15, a Marker of Oxidative Stress and Inflammation, for Risk Assessment in Patients With Atrial Fibrillation: Insights From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial , 2014, Circulation.

[11]  C. Held,et al.  Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non–ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization: A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial , 2014, Circulation.

[12]  L. Lind,et al.  GDF-15 for Prognostication of Cardiovascular and Cancer Morbidity and Mortality in Men , 2013, PloS one.

[13]  R. Vasan,et al.  Biomarkers of cardiovascular stress and incident chronic kidney disease. , 2013, Clinical chemistry.

[14]  K. Unsicker,et al.  The multiple facets of the TGF-β family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1. , 2013, Cytokine & growth factor reviews.

[15]  L. Lind,et al.  Change in growth differentiation factor 15 concentrations over time independently predicts mortality in community-dwelling elderly individuals. , 2013, Clinical chemistry.

[16]  A. Zarbock,et al.  GDF‐15 prevents platelet integrin activation and thrombus formation , 2013, Journal of thrombosis and haemostasis : JTH.

[17]  U. Haberkorn,et al.  Growth Differentiation Factor‐15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin‐6–Dependent Inflammatory Response to Vascular Injury , 2012, Journal of the American Heart Association.

[18]  A. Khera,et al.  Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multiethnic population: observations from the Dallas Heart Study. , 2012, Clinical chemistry.

[19]  L. Lind,et al.  Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study. , 2009, European heart journal.

[20]  W. Ahmad Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. , 2009 .

[21]  A. Skene,et al.  Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. , 2009, American heart journal.

[22]  E. Antman,et al.  Prasugrel versus clopidogrel in patients with acute coronary syndromes. , 2007, The New England journal of medicine.

[23]  A. Siegbahn,et al.  Growth Differentiation Factor 15 for Risk Stratification and Selection of an Invasive Treatment Strategy in Non–ST-Elevation Acute Coronary Syndrome , 2007, Circulation.

[24]  R. Califf,et al.  Prognostic Value of Growth-Differentiation Factor-15 in Patients With Non–ST-Elevation Acute Coronary Syndrome , 2007, Circulation.

[25]  K. Unsicker,et al.  Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions , 2004, Cell and Tissue Research.

[26]  Salim Yusuf,et al.  Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study , 2001, The Lancet.