Skip to main content

Advertisement

SpringerLink
Log in

Relationship between biomarkers and subsequent bleeding risk in ST-segment elevation myocardial infarction patients treated with paclitaxel-eluting stents: a HORIZONS-AMI substudy

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Major bleeding complications in STEMI patients result in significant mortality, morbidity and healthcare cost. Identification of patients at increased risk of bleeding is therefore essential. New biomarkers might be of incremental value to identify patients at risk for bleeding after primary PCI. A total of 26 biomarkers were measured at enrolment and analyzed at a central core laboratory in 464 STEMI patients in the HORIZONS-AMI trial. We investigated the relationship between tertiles of biomarker and in hospital non-CABG major bleeding. In hospital non-CABG major bleeding occurred in 3.7 % of patients (n = 17). Increasing levels of cystatin C and D-dimer at admission were associated with higher rates of in hospital major bleeding. After adjustment for a risk score for bleeding, the odds ratio for in hospital major bleeding was 3.13 for cystatin C > 2.04 mg/L (p = 0.046) and 3.28 for ESAM > 34 ng/mL (p = 0.037). In this exploratory analysis of the HORIZONS-AMI biomarker substudy, high cystatin C and ESAM levels were associated with a higher risk of major bleeding. Larger studies are warranted to confirm the prognostic value of cystatin C and ESAM for major bleeding in STEMI patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

MI:

Myocardial infarction

pPCI:

Primary percutaneous coronary intervention

STEMI:

ST-segment elevation myocardial infarction

GPI:

Glycoprotein IIb/IIIa inhibitor

CABG:

Coronary artery bypass grafting

BMS:

Bare metal stent

IL:

Interleukin

CT-1:

Cardiotrophin-1

MCP-1:

Monocyte chemotactic protein-1

CCL23:

Chemokine ligand 23

CRP:

C-reactive protein

BNP:

B-type natriuretic peptide

proANP:

Pro-atrial natriuretic peptide

MMP-9:

Matrix metalloproteinase 9

PAPP-A:

Pregnancy-associated protein A

ESAM:

Endothelial cell-selective adhesion molecule

ICAM:

Inter-cellular adhesion molecule

VCAM:

Vascular cell adhesion molecule

vWF:

Von Willebrand factor

PLGF:

Placental growth factor

CGRP:

Calcitonin gene-related peptide

hFABP:

heart-type fatty acid binding protein

MPO:

Myeloperoxidase

References

  1. Antithrombotic Trialists' Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324(7329):71–86

    Google Scholar 

  2. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345(7):494–502. doi:10.1056/NEJMoa010746

    Article  PubMed  CAS  Google Scholar 

  3. Mehta SR, Yusuf S, Peters RJG, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht HJr, Zhao F, Chrolavicius S, Copland I, Fox KAA (2001) Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 358(9281):527–533. doi:10.1016/s0140-6736(01)05701-4

    Article  PubMed  CAS  Google Scholar 

  4. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Kirtane AJ, Parise H, Mehran R (2008) Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 358(21):2218–2230. doi:10.1056/NEJMoa0708191

    Article  PubMed  CAS  Google Scholar 

  5. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361(11):1045–1057. doi:10.1056/NEJMoa0904327

    Article  PubMed  CAS  Google Scholar 

  6. Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH, Antman EM (2009) Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 373(9665):723–731

    Article  PubMed  CAS  Google Scholar 

  7. Lindsey JB, Marso SP, Pencina M, Stolker JM, Kennedy KF, Rihal C, Barsness G, Piana RN, Goldberg SL, Cutlip DE, Kleiman NS, Cohen DJ (2009) Prognostic impact of periprocedural bleeding and myocardial infarction after percutaneous coronary intervention in unselected patients: results from the EVENT (evaluation of drug-eluting stents and ischemic events) registry. JACC Cardiovasc Interv 2(11):1074–1082. doi:10.1016/j.jcin.2009.09.002

    Article  PubMed  Google Scholar 

  8. Suh JW, Mehran R, Claessen BE, Xu K, Baber U, Dangas G, Parise H, Lansky AJ, Witzenbichler B, Grines CL, Guagliumi G, Kornowski R, Wohrle J, Dudek D, Weisz G, Stone GW (2011) Impact of in-hospital major bleeding on late clinical outcomes after primary percutaneous coronary intervention in acute myocardial infarction: the HORIZONS-AMI (Harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol 58(17):1750–1756. doi:10.1016/j.jacc.2011.07.021

    Article  PubMed  Google Scholar 

  9. Budaj A, Eikelboom JW, Mehta SR, Afzal R, Chrolavicius S, Bassand JP, Fox KAA, Wallentin L, Peters RJG, Granger CB, Joyner CD, Yusuf S (2009) Improving clinical outcomes by reducing bleeding in patients with non-ST-elevation acute coronary syndromes. Eur Heart J 30(6):655–661

    Article  PubMed  Google Scholar 

  10. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S (2006) Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 114(8):774–782

    Article  PubMed  Google Scholar 

  11. Moscucci M, Fox KA, Cannon CP, Klein W, Lopez-Sendon J, Montalescot G, White K, Goldberg RJ (2003) Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 24(20):1815–1823

    Article  PubMed  CAS  Google Scholar 

  12. Mehran R, Pocock SJ, Nikolsky E, Clayton T, Dangas GD, Kirtane AJ, Parise H, Fahy M, Manoukian SV, Feit F, Ohman ME, Witzenbichler B, Guagliumi G, Lansky AJ, Stone GW (2010) A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 55(23):2556–2566

    Article  PubMed  Google Scholar 

  13. Mehran R, Brodie B, Cox DA, Grines CL, Rutherford B, Bhatt DL, Dangas G, Feit F, Ohman EM, Parise H, Fahy M, Lansky AJ, Stone GW (2008) The harmonizing outcomes with revascularization and stents in acute myocardial infarction (HORIZONS-AMI) trial: study design and rationale. Am Heart J 156(1):44–56. doi:10.1016/j.ahj.2008.02.008

    Article  PubMed  CAS  Google Scholar 

  14. Stone GW, Lansky AJ, Pocock SJ, Gersh BJ, Dangas G, Wong SC, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Möckel M, Ochala A, Kellock A, Parise H, Mehran R (2009) Paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction. N Engl J Med 360(19):1946–1959. doi:10.1056/NEJMoa0810116

    Article  PubMed  CAS  Google Scholar 

  15. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Fahy M, Parise H, Mehran R (2001) Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 377(9784):2193–2204. doi:10.1016/s0140-6736(11)60764-2

    Article  Google Scholar 

  16. Claessen BE, Stone GW, Mehran R, Witzenbichler B, Brodie BR, Wohrle J, Witkowski A, Guagliumi G, Zmudka K, Henriques JP, Tijssen JG, Sanidas EA, Chantziara V, Hakim D, Leon S, Xu K, Dangas GD (2012) Relationship between biomarkers and subsequent clinical and angiographic restenosis after paclitaxel-eluting stents for treatment of STEMI: a HORIZONS-AMI substudy. J Thromb Thrombolysis. doi:10.1007/s11239-012-0706-x

    Google Scholar 

  17. World Health Organization (1968) Nutritional anaemias. Report of a WHO scientific group. World Health Organization Tech Rep Ser 405:5–37

  18. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41

    Article  PubMed  CAS  Google Scholar 

  19. Ishida T, Kundu RK, Yang E, Hirata Ki, Ho YD, Quertermous T (2003) Targeted disruption of endothelial cell-selective adhesion molecule inhibits angiogenic processes in vitro and in vivo. J Biol Chem 278(36):34598–34604

    Article  PubMed  CAS  Google Scholar 

  20. Yokota T, Oritani K, Butz S, Kokame K, Kincade PW, Miyata T, Vestweber D, Kanakura Y (2009) The endothelial antigen ESAM marks primitive hematopoietic progenitors throughout life in mice. Blood 113(13):2914–2923

    Article  PubMed  CAS  Google Scholar 

  21. Wegmann F, Petri BÝ, Khandoga AG, Moser C, Khandoga A, Volkery S, Li H, Nasdala I, Brandau O, Fassler R, Krombach F, Vestweber D (2006) ESAM supports neutrophil extravasation, activation of Rho, and VEGF-induced vascular permeability. J Exp Med 203(7):1671–1677

    Article  PubMed  CAS  Google Scholar 

  22. Rudd MA, Johnstone MT, Rabbani LE, George D, Ware JA, Loscalzo J (1991) Thrombolytic therapy causes an increase in vascular permeability that is reversed by 1-deamino-8-D-vasopressin. Circulation 84(6):2568–2573. doi:10.1161/01.cir.84.6.2568

    Article  PubMed  CAS  Google Scholar 

  23. Nasdala I, Wolburg-Buchholz K, Wolburg H, Kuhn A, Ebnet K, Brachtendorf G, Samulowitz U, Kuster B, Engelhardt B, Vestweber D, Butz S (2002) A transmembrane tight junction protein selectively expressed on endothelial cells and platelets. J Biol Chem 277(18):16294–16303

    Article  PubMed  CAS  Google Scholar 

  24. O’Connor MN, Salles II, Cvejic A, Watkins NA, Walker A, Garner SF, Jones CI, Macaulay IC, Steward M, Zwaginga JJ, Bray SL, Dudbridge F, de Bono B, Goodall AH, Deckmyn H, Stemple DL, Ouwehand WH (2009) Functional genomics in zebrafish permits rapid characterization of novel platelet membrane proteins. Blood 113(19):4754–4762

    Article  PubMed  Google Scholar 

  25. Stalker TJ, Wu J, Morgans A, Traxler EA, Wang L, Chatterjee MS, Lee D, Quertermous T, Hall RA, Hammer DA, Diamond SL, Brass LF (2009) Endothelial cell specific adhesion molecule (ESAM) localizes to platelet–platelet contacts and regulates thrombus formation in vivo. J Thromb Haemost 7(11):1886–1896

    Article  PubMed  CAS  Google Scholar 

  26. Abrahamson M, Olafsson I, Palsdottir A, Ulvsback M, Lundwall A, Jensson O, Grubb A (1990) Structure and expression of the human cystatin C gene. Biochem J 268(2):287–294

    PubMed  CAS  Google Scholar 

  27. Grubb A (1992) Diagnostic value of analysis of cystatin C and protein HC in biological fluids. Clin Nephrol 38(Suppl 1):S20–S27

    PubMed  CAS  Google Scholar 

  28. Shimizu-Tokiwa A, Kobata M, Io H, Kobayashi N, Shou I, Funabiki K, Fukui M, Horikoshi S, Shirato I, Saito K, Tomino Y (2002) Serum cystatin c is a more sensitive marker of glomerular function than serum creatinine. Nephron 92(1):224–226

    Article  PubMed  CAS  Google Scholar 

  29. Schnabel RB, Schulz A, Messow CM, Lubos E, Wild PS, Zeller T, Sinning CR, Rupprecht HJ, Bickel C, Peetz D, Cambien F, Kempf T, Wollert KC, Benjamin EJ, Lackner KJ, Münzel TF, Tiret L, Vasan RS, Blankenberg S (2010) Multiple marker approach to risk stratification in patients with stable coronary artery disease. Eur Heart J 31(24):3024–3031. doi:10.1093/eurheartj/ehq322

    Article  PubMed  CAS  Google Scholar 

  30. Ix JH, Shlipak MG, Chertow GM, Whooley MA (2007) Association of cystatin c with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease. Circulation 115(2):173–179. doi:10.1161/circulationaha.106.644286

    Article  PubMed  CAS  Google Scholar 

  31. Windhausen F, Hirsch A, Fischer J, van der Zee PM, Sanders GT, van Straalen JP, Cornel JH, Tijssen JGP, Verheugt FWA, de Winter RJ, Investigators ftIvCTiUCS (2009) Cystatin C for enhancement of risk stratification in non-ST elevation acute coronary syndrome patients with an increased troponin T. Clin Chem 55(6):1118–1125. doi:10.1373/clinchem.2008.119669

    Article  PubMed  CAS  Google Scholar 

  32. Åkerblom A, Wallentin L, Siegbahn A, Becker RC, Budaj A, Buck K, Giannitsis E, Horrow J, Husted S, Katus HA, Steg PG, Storey RF, Åsenblad N, James SK (2012) Cystatin C and estimated glomerular filtration rate as predictors for adverse outcome in patients with ST-elevation and non-ST-elevation acute coronary syndromes: results from the platelet inhibition and patient outcomes study. Clin Chem 58(1):190–199. doi:10.1373/clinchem.2011.171520

    Article  PubMed  Google Scholar 

  33. Silva D, Cortez-Dias N, Jorge C, Marques JS, Carrilho-Ferreira P, Magalhaes A, Martins SR, Goncalves S, da Silva PC, Fiuza M, Diogo AN, Pinto FJ (2012) Cystatin C as prognostic biomarker in ST-segment elevation acute myocardial infarction. Am J cardiol 109(10):1431–1438. doi:10.1016/j.amjcard.2012.01.356

    Article  PubMed  CAS  Google Scholar 

  34. Fox KA, Antman EM, Montalescot G, Agewall S, SomaRaju B, Verheugt FW, Lopez-Sendon J, Hod H, Murphy SA, Braunwald E (2007) The impact of renal dysfunction on outcomes in the ExTRACT-TIMI 25 trial. J Am Coll Cardiol 49(23):2249–2255

    Article  PubMed  CAS  Google Scholar 

  35. Liani M, Salvati F, Golato M, Tresca E (1996) Platelet glycoproteins GPIb and GPIIb/IIIa abnormalities in uremia. Nephron 72(4):716

    Article  PubMed  CAS  Google Scholar 

  36. Bazinet A, Almanric K, Brunet C, Turcotte I, Martineau J, Caron S, Blais N, Lalonde L (2005) Dosage of enoxaparin among obese and renal impairment patients. Thromb Res 116(1):41–50. doi:10.1016/j.thromres.2004.10.004

    Article  PubMed  CAS  Google Scholar 

  37. Darlington A, Ferreiro JL, Ueno M, Suzuki Y, Desai B, Capranzano P, Capodanno D, Tello-Montoliu A, Bass TA, Nahman NS, Angiolillo DJ (2011) Haemostatic profiles assessed by thromboelastography in patients with end-stage renal disease. Thromb Haemost 106(1):67–74. doi:10.1160/th10-12-0785

    Article  PubMed  CAS  Google Scholar 

  38. Berger PB, Best PJM, Topol EJ, White J, DiBattiste PM, Chan AW, Kristensen SD, Herrmann HC, Moliterno DJ (2005) The relation of renal function to ischemic and bleeding outcomes with 2 different glycoprotein IIb/IIIa inhibitors: the Do Tirofiban and ReoPro give similar efficacy outcome (TARGET) trial. Am Heart J 149(5):869–875. doi:10.1016/j.ahj.2004.12.002

    Article  PubMed  CAS  Google Scholar 

  39. Sreedhara R, Itagaki I, Hakim RM (1996) Uremic patients have decreased shear-induced platelet aggregation mediated by decreased availability of glycoprotein IIb–IIIa receptors. Am J Kidney Dis 27(3):355–364

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The HORIZONS-AMI trial was supported by the Cardiovascular Research Foundation, with grant support from Boston Scientific and the Medicines Company. Dr. Stone has served as a consultant to the Medicines Company and Boston Scientific. Dr. Dangas and Dr. Mehran have received speaker grants from Sanofi Aventis, Bristol-Meiers Squibb, The Medicines Co, Eli Lilly, Daichi Snakyo, and honoraria from Astra Zeneca, Johnson&Johnson, and Abbott Vascular. Dr. Witzenbichler has received lecture honoraria from Boston Scientific and The Medicines Company. Dr. Witkowski has received honoraria from Medtronic, Abott Vascular and Eli Lilly. Dr. Guagliumi has served as a consultant to Boston Scientific, Volcano, Cordis and St. Jude and is receiving grant support from Abott Vascular, Medtronic, Boston Scientific and Lightlab. The other authors report no conflicts.

Author information

Authors and Affiliations

  1. Cardiovascular Research Foundation, New York, NY, USA

    Bimmer E. Claessen, Gregg W. Stone, Roxana Mehran, Elias A. Sanidas, Vasiliki Chantziara, Ke Xu & George D. Dangas

  2. Columbia University Medical Center, New York, NY, USA

    Gregg W. Stone, Elias A. Sanidas & Vasiliki Chantziara

  3. Mount Sinai Medical Center, New York, NY, USA

    Roxana Mehran & George D. Dangas

  4. Academic Medical Center—University of Amsterdam, Amsterdam, Netherlands

    Wouter J. Kikkert, Bimmer E. Claessen, José P. S. Henriques & Jan G. P. Tijssen

  5. Ospedali Reuniti di Bergamo, Bergamo, Italy

    Giulio Guagliumi

  6. Charité Universitatsmedizin Campus Benjamin Franklin, Berlin, Germany

    Bernhard Witzenbichler

  7. University of Ulm, Ulm, Germany

    Jochen Wöhrle

  8. LeBauer CV Research Foundation, Greensboro, NC, USA

    Bruce R. Brodie

  9. National Institute of Cardiology, Warsaw, Poland

    Adam Witkowski

  10. Szpital Jana Pawla II, Krakow, Poland

    Krzysztof Zmudka

  11. Mount Sinai Medical Center, Cardiovascular Institute, One Gustave L. Levy Place, P.O. Box 1030, New York, NY, 10029, USA

    George D. Dangas

Authors
  1. Wouter J. Kikkert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bimmer E. Claessen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gregg W. Stone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roxana Mehran
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bernhard Witzenbichler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bruce R. Brodie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jochen Wöhrle
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Adam Witkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giulio Guagliumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Krzysztof Zmudka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. José P. S. Henriques
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jan G. P. Tijssen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Elias A. Sanidas
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Vasiliki Chantziara
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ke Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. George D. Dangas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George D. Dangas.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kikkert, W.J., Claessen, B.E., Stone, G.W. et al. Relationship between biomarkers and subsequent bleeding risk in ST-segment elevation myocardial infarction patients treated with paclitaxel-eluting stents: a HORIZONS-AMI substudy. J Thromb Thrombolysis 35, 200–208 (2013). https://doi.org/10.1007/s11239-012-0837-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-012-0837-0

Keywords

Search

Navigation