Prognostic role of GDF-15 across the spectrum of clinical risk in patients with NSTE-ACS

Thomas A. Zelniker; Petr Jarolim; Michael G. Silverman; Erin A. Bohula; Jeong-Gun Park; Marc P. Bonaca; Benjamin M. Scirica; David A. Morrow

doi:10.1515/cclm-2018-1081

Article

Prognostic role of GDF-15 across the spectrum of clinical risk in patients with NSTE-ACS

Thomas A. Zelniker , Petr Jarolim , Michael G. Silverman , Erin A. Bohula , Jeong-Gun Park , Marc P. Bonaca , Benjamin M. Scirica and David A. Morrow

Published/Copyright: February 2, 2019

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From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 57 Issue 7

Abstract

Background

Growth differentiation factor (GDF)-15 has been shown to predict cardiovascular (CV) outcomes in acute coronary syndrome (ACS) using non-commercial assays. We evaluated the prognostic performance of GDF-15 measured with the first clinically available assay. Furthermore, we evaluated whether GDF-15 was associated with CV death or heart failure (HF) across the spectrum of risk in non-ST-segment elevation (NSTE)-ACS.

Methods

We measured baseline GDF-15 (Roche, Elecsys) in 4330 patients with NSTE-ACS enrolled in MERLIN-TIMI 36. Patients were categorized using a priori thresholds of GDF-15 levels (<1200, 1200–1800, ≥1800 ng/L) and stratified according to estimated clinical risk per TIMI risk score (0–2, 3–4, and ≥5). Cox modeling included age, sex, BMI, smoking, HF, diabetes, renal function, NT-proBNP, hsTnT, and hsCRP.

Results

There were 2286 (53%), 1104 (25%), and 940 (22%) pts with GDF-15 <1200, 1200–1800, and ≥1800 respectively. GDF-15 was significantly associated after multivariable adjustment with CV death/HF modeled either as a categorical (1200–1800 ng/L: Adj hazard ratios [HR] 1.55 [1.09–2.19]; ≥1800 ng/L: Adj HR 1.94 [1.34–2.79]) or continuous variable (Adj HR 1.36 [1.16–1.60] per 1-unit increase in log₂-transformed GDF-15). Notably, there was an interaction (P_interaction=0.003) between TIMI risk score and GDF-15, with GDF-15 identifying the greatest incremental relative risk in those at lowest risk based on the TIMI risk score alone.

Conclusions

Using a clinically available assay, GDF-15 can be applied using established cut-off points to independently predict risk of CV death/HF in patients with NSTE-ACS. This incremental risk appears to be particularly robust among individuals traditionally identified as low risk.

Keywords: automated assay; cardiovascular death; GDF-15; growth differentiation factor 15; heart failure

Corresponding author: David A. Morrow, MD, MPH, TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, 60 Fenwood Rd., Suite 7022-7024W, Boston, MA 02115, USA

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: ZE 1109/1-1

Funding statement: This biomarker substudy was supported by Roche Diagnostics. TAZ is supported by the Deutsche Forschungsgemeinschaft (ZE 1109/1-1). MGS is supported by the John S. Ladue Memorial Fellowship from Harvard Medical School.

Author contributions: T.A.Z. contributed to data interpretation, and drafting of the manuscript. P.J. contributed to data collection, data interpretation, and critical review of the manuscript. M.G.S. contributed to data collection, data interpretation, and critical review of the manuscript. E.A.B. contributed to data interpretation, and critical review of the manuscript. J.G.P. contributed to statistical analysis, and critical review of the manuscript. M.P.B. contributed to study design, data collection, data interpretation, and critical review of the manuscript. B.M.S. contributed to study design, data collection, data interpretation, and critical review of the manuscript. D.A.M. contributed to study design, data collection, data interpretation, and critical review of the manuscript. D.A.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Amsterdam EA, Wenger NK, Brindis RG, Casey Jr. DE, Ganiats TG, Holmes Jr. DR, et al. 2014 AHA/ACC Guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139–228.10.1016/j.jacc.2014.09.017Search in Google Scholar PubMed

2. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267–315.10.1093/eurheartj/ehv320Search in Google Scholar PubMed

3. Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G, et al. The TIMI risk score for unstable angina/ non-ST elevation MI: a method for prognostication and therapeutic decision making. J Am Med Assoc 2000;284: 835–42.10.1001/jama.284.7.835Search in Google Scholar PubMed

4. Fox KA, Dabbous OH, Goldberg RJ, Pieper KS, Eagle KA, Van de Werf F, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). Br Med J 2006;333:1091.10.1136/bmj.38985.646481.55Search in Google Scholar PubMed PubMed Central

5. Adela R, Banerjee SK. GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J Diabetes Res 2015;2015:490842.10.1155/2015/490842Search in Google Scholar PubMed PubMed Central

6. Wollert KC, Kempf T, Wallentin L. Growth differentiation factor 15 as a biomarker in cardiovascular disease. Clin Chem 2017;63:140–51.10.1373/clinchem.2016.255174Search in Google Scholar PubMed

7. Bonaca MP, Morrow DA, Braunwald E, Cannon CP, Jiang S, Breher S, et al. Growth differentiation factor-15 and risk of recurrent events in patients stabilized after acute coronary syndrome: observations from PROVE IT-TIMI 22. Arterioscler Thromb Vasc Biol 2011;31:203–10.10.1161/ATVBAHA.110.213512Search in Google Scholar PubMed

8. Kempf T, von Haehling S, Peter T, Allhoff T, Cicoira M, Doehner W, et al. Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. J Am Coll Cardiol 2007;50:1054–60.10.1016/j.jacc.2007.04.091Search in Google Scholar PubMed

9. Lindholm D, Hagstrom E, James SK, Becker RC, Cannon CP, Himmelmann A, et al. Growth Differentiation factor 15 at 1 month after an acute coronary syndrome is associated with increased risk of major bleeding. J Am Heart Assoc 2017;6: pii: e005580. doi: 0.1161/JAHA.117.005580.0.1161/JAHA.117.005580Search in Google Scholar

10. Wollert KC, Kempf T, Peter T, Olofsson S, James S, Johnston N, et al. Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation 2007;115:962–71.10.1161/CIRCULATIONAHA.106.650846Search in Google Scholar PubMed

11. Wollert KC, Kempf T, Giannitsis E, Bertsch T, Braun SL, Maier H, et al. An automated assay for growth differentiation factor 15. J Appl Lab Med 2017;1:510–21.10.1373/jalm.2016.022376Search in Google Scholar PubMed

12. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Skene A, McCabe CH, Braunwald E, et al. Evaluation of a novel anti-ischemic agent in acute coronary syndromes: design and rationale for the metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndromes (MERLIN)-TIMI 36 trial. Am Heart J 2006;151:1186 e1–9.10.1016/j.ahj.2006.01.004Search in Google Scholar PubMed

13. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. J Am Med Assoc 2007;297:1775–83.10.1001/jama.297.16.1775Search in Google Scholar PubMed

14. Giannitsis E, Becker M, Kurz K, Hess G, Zdunek D, Katus HA. High-sensitivity cardiac troponin T for early prediction of evolving non-ST-segment elevation myocardial infarction in patients with suspected acute coronary syndrome and negative troponin results on admission. Clin Chem 2010;56:642–50.10.1373/clinchem.2009.134460Search in Google Scholar PubMed

15. Gore MO, Seliger SL, Defilippi CR, Nambi V, Christenson RH, Hashim IA, et al. Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay. J Am Coll Cardiol 2014;63:1441–8.10.1016/j.jacc.2013.12.032Search in Google Scholar PubMed PubMed Central

16. Wollert KC, Kempf T, Lagerqvist B, Lindahl B, Olofsson S, Allhoff T, et al. Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome. Circulation 2007;116:1540–8.10.1161/CIRCULATIONAHA.107.697714Search in Google Scholar PubMed

17. Kempf T, Bjorklund E, Olofsson S, Lindahl B, Allhoff T, Peter T, et al. Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction. Eur Heart J 2007;28:2858–65.10.1093/eurheartj/ehm465Search in Google Scholar PubMed

18. Kempf T, Horn-Wichmann R, Brabant G, Peter T, Allhoff T, Klein G, et al. Circulating concentrations of growth-differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay. Clin Chem 2007;53:284–91.10.1373/clinchem.2006.076828Search in Google Scholar PubMed

19. Cook NR, Ridker PM. Advances in measuring the effect of individual predictors of cardiovascular risk: the role of reclassification measures. Ann Intern Med 2009;150:795–802.10.7326/0003-4819-150-11-200906020-00007Search in Google Scholar PubMed PubMed Central

20. Pencina MJ, Steyerberg EW, D’Agostino RB, Sr. Net reclassification index at event rate: properties and relationships. Stat Med 2017;36:4455–67.10.1002/sim.7041Search in Google Scholar PubMed

21. Zhang S, Dai D, Wang X, Zhu H, Jin H, Zhao R, et al. Growth differentiation factor-15 predicts the prognoses of patients with acute coronary syndrome: a meta-analysis. BMC Cardiovasc Disord 2016;16:82.10.1186/s12872-016-0250-2Search in Google Scholar PubMed PubMed Central

22. Daniels LB, Clopton P, Laughlin GA, Maisel AS, Barrett-Connor E. Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: the Rancho Bernardo Study. Circulation 2011;123:2101–10.10.1161/CIRCULATIONAHA.110.979740Search in Google Scholar PubMed PubMed Central

23. Hagstrom E, James SK, Bertilsson M, Becker RC, Himmelmann A, Husted S, et al. Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study. Eur Heart J 2016;37:1325–33.10.1093/eurheartj/ehv491Search in Google Scholar PubMed

24. Wallentin L, Hijazi Z, Andersson U, Alexander JH, De Caterina R, Hanna M, 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. Circulation 2014;130:1847–58.10.1161/CIRCULATIONAHA.114.011204Search in Google Scholar PubMed

25. Hijazi Z, Oldgren J, Lindback J, Alexander JH, Connolly SJ, Eikelboom JW, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016;387:2302–11.10.1016/S0140-6736(16)00741-8Search in Google Scholar PubMed

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2018-1081).

Received: 2018-10-03

Accepted: 2018-12-28

Published Online: 2019-02-02

Published in Print: 2019-06-26

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Supplementary Material

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Keywords for this article

automated assay; cardiovascular death; GDF-15; growth differentiation factor 15; heart failure