Comparison of the influence of ticagrelor and clopidogrel on inflammatory biomarkers and vascular endothelial function for patients with ST-segment elevation myocardial infarction receiving emergency percutaneous coronary intervention: study protocol for a randomized controlled trial

Zhenhua Li, Yueyan Li, Tao Zhang, Wei Miao, Guohai Su, Zhenhua Li, Yueyan Li, Tao Zhang, Wei Miao, Guohai Su

Abstract

Background: The Platelet Inhibition and Patient Outcomes (PLATO, Eur J Prev Cardiol 22(6):734-42, 2015) trial shows that, in patients who have an acute coronary syndrome, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death, but the reason is still uncertain. Both inflammation and vascular endothelian cell dysfunction play important roles in the pathophysiology of atherosclerotic plaques, but whether ticagrelor has superior anti-inflammatory effect and can improve vascular endothelial cell function to a great extent is unknown.

Methods/design: Patients with STEMI who are scheduled to undergo emergency percutaneous coronary intervention (PCI) will be randomly assigned to receive a loading dose of ticagrelor 180 mg as the treatment group or clopidogrel 600 mg as the control group. After PCI, the treatment group will be treated with ticagrelor 90 mg twice daily while the control group will be treated with clopidogrel 75 mg once daily. The vascular endothelial function will be tested by circulating endothelial cells, and levels of inflammation will be tested by CD40 ligand (CD40L), high sensitivity C-reactive protein (hsCRP) and P-selectin. The estimated enrollment sample size will be 350 patients, including 175 in the treatment group and 175 in the control group.

Discussion: This study will compare the influence of ticagrelor and clopidogrel on inflammatory biomarkers and vascular endothelial function firstly for STEMI patients receiving emergency PCI and will provide evidence to identify whether ticagrelor inhibits inflammation and improves vascular endothelial cell function to a greater extent than clopidogrel or not.

Trial registration: This trial was registered with Clinicaltrials.gov (identifier: NCT02123004) on 20 April 2014.

Figures

Fig. 1
Fig. 1
Study procedure

References

    1. Patel MR, Becker RC, Wojdyla DM, Emanuelsson H, Hiatt WR, Horrow J, et al. Cardiovascular events in acute coronary syndrome patients with peripheral arterial disease treated with ticagrelor compared with clopidogrel: data from the PLATO Trial. Eur J Prev Cardiol. 2015;22(6):734–42. doi: 10.1177/2047487314533215.
    1. Ridker PM. Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity. Nutr Rev. 2007;65(12 Pt 2):S253–9. doi: 10.1301/nr.2007.dec.S253-S259.
    1. Lucas AR, Korol R, Pepine CJ. Inflammation in atherosclerosis: some thoughts about acute coronary syndromes. Circulation. 2006;113(17):e728–32. doi: 10.1161/CIRCULATIONAHA.105.601492.
    1. Khuseyinova N, Koenig W. Biomarkers of outcome from cardiovascular disease. Curr Opin Crit Care. 2006;12(5):412–9. doi: 10.1097/01.ccx.0000244119.16377.75.
    1. Tousoulis D, Antoniades C, Koumallos N, Stefanadis C. Pro-inflammatory cytokines in acute coronary syndromes: from bench to bedside. Cytokine Growth Factor Rev. 2006;17(4):225–33. doi: 10.1016/j.cytogfr.2006.04.003.
    1. Jawien J. New insights into immunological aspects of atherosclerosis. Pol Arch Med Wewn. 2008;118(3):127–31.
    1. Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med. 2002;8(11):1211–7. doi: 10.1038/nm1102-1211.
    1. Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol. 2003;23(12):2131–7. doi: 10.1161/.
    1. Ruggeri ZM. Platelets in atherothrombosis. Nat Med. 2002;8(11):1227–34. doi: 10.1038/nm1102-1227.
    1. Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest. 2005;115(12):3378–84. doi: 10.1172/JCI27196.
    1. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357(24):2482–94. doi: 10.1056/NEJMra071014.
    1. Yeh ET, Khan BV. The potential role of antiplatelet agents in modulating inflammatory markers in atherothrombosis. J Thromb Haemost. 2006;4(11):2308–16. doi: 10.1111/j.1538-7836.2006.02202.x.
    1. Muhlestein JB. Effect of antiplatelet therapy on inflammatory markers in atherothrombotic patients. Thromb Haemost. 2010;103(1):71–82. doi: 10.1160/TH09-03-0177.
    1. Frelinger AL, 3rd, Jakubowski JA, Li Y, Barnard MR, Fox ML, Linden MD, et al. The active metabolite of prasugrel inhibits ADP-stimulated thrombo-inflammatory markers of platelet activation: influence of other blood cells, calcium, and aspirin. Thromb Haemost. 2007;98(1):192–200.
    1. Kodama M, Yamasaki Y, Sakamoto K, Yoshioka R, Matsuhisa M, Kajimoto Y, et al. Antiplatelet drugs attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes. Thromb Res. 2000;97(4):239–45. doi: 10.1016/S0049-3848(99)00168-1.
    1. Redondo S, Santos-Gallego CG, Ganado P, Garcia M, Rico L, Del Rio M, et al. Acetylsalicylic acid inhibits cell proliferation by involving transforming growth factor-beta. Circulation. 2003;107(4):626–9. doi: 10.1161/01.CIR.0000045664.75269.A5.
    1. Martin T, Cardarelli PM, Parry GC, Felts KA, Cobb RR. Cytokine induction of monocyte chemoattractant protein-1 gene expression in human endothelial cells depends on the cooperative action of NF-kappa B and AP-1. Eur J Immunol. 1997;27(5):1091–7. doi: 10.1002/eji.1830270508.
    1. Roebuck KA. Regulation of interleukin-8 gene expression. J Interferon Cytokine Res. 1999;19(5):429–38. doi: 10.1089/107999099313866.
    1. Serebruany VL, Midei MG, Meilman H, Malinin AI, Lowry DR. Platelet inhibition with prasugrel (CS-747) compared with clopidogrel in patients undergoing coronary stenting: the subset from the JUMBO study. Postgrad Med J. 2006;82(968):404–10. doi: 10.1136/pgmj.2006.047696.
    1. Braun OO, Johnell M, Varenhorst C, James S, Brandt JT, Jakubowski JA, et al. Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease. Thromb Haemost. 2008;100(4):626–33.
    1. Jennings LK. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost. 2009;102(2):248–57.
    1. Feldman M, Jialal I, Devaraj S, Cryer B. Effects of low-dose aspirin on serum C-reactive protein and thromboxane B2 concentrations: a placebo-controlled study using a highly sensitive C-reactive protein assay. J Am Coll Cardiol. 2001;37(8):2036–41. doi: 10.1016/S0735-1097(01)01289-X.
    1. Azar RR, Kassab R, Zoghbi A, Aboujaoude S, El-Osta H, Ghorra P, et al. Effects of clopidogrel on soluble CD40 ligand and on high-sensitivity C-reactive protein in patients with stable coronary artery disease. Am Heart J. 2006;151(2):521. doi: 10.1016/j.ahj.2005.10.021.
    1. Saw J, Madsen EH, Chan S, Maurer-Spurej E. The ELAPSE (Evaluation of Long-Term Clopidogrel Antiplatelet and Systemic Anti-Inflammatory Effects) study. J Am Coll Cardiol. 2008;52(23):1826–33. doi: 10.1016/j.jacc.2008.08.047.
    1. Steinhubl SR, Badimon JJ, Bhatt DL, Herbert JM, Luscher TF. Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med. 2007;12(2):113–22. doi: 10.1177/1358863X07077462.
    1. Chen YG, Xu F, Zhang Y, Ji QS, Sun Y, Lu RJ, et al. Effect of aspirin plus clopidogrel on inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin Med J (Engl) 2006;119(1):32–6.
    1. Sluimer JC, Kolodgie FD, Bijnens AP, Maxfield K, Pacheco E, Kutys B, et al. Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions: relevance of compromised structural integrity for intraplaque microvascular leakage. J Am Coll Cardiol. 2009;53(17):1517–27. doi: 10.1016/j.jacc.2008.12.056.
    1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340(2):115–26. doi: 10.1056/NEJM199901143400207.
    1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362(6423):801–9. doi: 10.1038/362801a0.
    1. Woywodt A, Streiber F, de Groot K, Regelsberger H, Haller H, Haubitz M. Circulating endothelial cells as markers for ANCA-associated small-vessel vasculitis. Lancet. 2003;361(9353):206–10. doi: 10.1016/S0140-6736(03)12269-6.
    1. Bull TM, Golpon H, Hebbel RP, Solovey A, Cool CD, Tuder RM, et al. Circulating endothelial cells in pulmonary hypertension. Thromb Haemost. 2003;90(4):698–703.
    1. Mutin M, Canavy I, Blann A, Bory M, Sampol J, Dignat-George F. Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood. 1999;93(9):2951–8.
    1. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001;89(1):E1–7. doi: 10.1161/hh1301.093953.
    1. Damani S, Bacconi A, Libiger O, Chourasia AH, Serry R, Gollapudi R, et al. Characterization of circulating endothelial cells in acute myocardial infarction. Sci Transl Med. 2012;4(126):126ra33. doi: 10.1126/scitranslmed.3003451.
    1. Ziemianin B, Olszanecki R, Uracz W, Marcinkiewicz E, Gryglewski RJ. Thienopyridines: effects on cultured endothelial cells. J Physiol Pharmacol. 1999;50(4):597–604.
    1. Vishnevetsky D, Kiyanista VA, Gandhi PJ. CD40 ligand: a novel target in the fight against cardiovascular disease. Ann Pharmacother. 2004;38(9):1500–8. doi: 10.1345/aph.1D611.
    1. Hancock WW, Buelow R, Sayegh MH, Turka LA. Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes. Nat Med. 1998;4(12):1392–6. doi: 10.1038/3982.
    1. McClung JA, Kruger AL, Ferraris A, Vanella L, Tsenovoy P, Weiss MB, et al. Usefulness of clopidogrel to protect against diabetes-induced vascular damage. Am J Cardiol. 2010;105(7):1014–8. doi: 10.1016/j.amjcard.2009.11.034.
    1. Nanhwan MK, Ling S, Kodakandla M, Nylander S, Ye Y, Birnbaum Y. Chronic treatment with ticagrelor limits myocardial infarct size: an adenosine and cyclooxygenase-2-dependent effect. Arterioscler Thromb Vasc Biol. 2014;34(9):2078–85. doi: 10.1161/ATVBAHA.114.304002.
    1. Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol. 2007;50(19):1844–51. doi: 10.1016/j.jacc.2007.07.053.
    1. Husted S, Storey RF, Harrington RA, Emanuelsson H, Cannon CP. Changes in inflammatory biomarkers in patients treated with ticagrelor or clopidogrel. Clin Cardiol. 2010;33(4):206–12. doi: 10.1002/clc.20732.
    1. Fuster V. Understanding the coronary disease process and the potential for prevention: a summary. Prev Med. 1999;29(6 Pt 2):S9–10.
    1. Ayala TH, Schulman SP. Pathogenesis and early management of non-ST-segment elevation acute coronary syndromes. Cardiol Clin. 2006;24(1):19–35. doi: 10.1016/j.ccl.2005.09.006.
    1. Packard KA, Campbell JA, Knezevich JT, Davis EM. Emerging antiplatelet therapy for coronary artery disease and acute coronary syndrome. Pharmacotherapy. 2012;32(3):244–73. doi: 10.1002/j.1875-9114.2012.01021.x.
    1. Krishna V, Diamond GA, Kaul S. Do platelet function testing and genotyping improve outcome in patients treated with antithrombotic agents?: the role of platelet reactivity and genotype testing in the prevention of atherothrombotic cardiovascular events remains unproven. Circulation. 2012;125(10):1288–303. doi: 10.1161/CIRCULATIONAHA.111.075242.
    1. Serebruany V, Cherala G, Williams C, Surigin S, Booze C, Kuliczkowski W, et al. Association of platelet responsiveness with clopidogrel metabolism: role of compliance in the assessment of “resistance”. Am Heart J. 2009;158(6):925–32. doi: 10.1016/j.ahj.2009.10.012.
    1. Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382(9892):614–23. doi: 10.1016/S0140-6736(13)61170-8.
    1. Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol. 2013;62(24):2261–73. doi: 10.1016/j.jacc.2013.07.101.
    1. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57. doi: 10.1056/NEJMoa0904327.
    1. Steg PG, Harrington RA, Emanuelsson H, Katus HA, Mahaffey KW, Meier B, et al. Stent thrombosis with ticagrelor versus clopidogrel in patients with acute coronary syndromes: an analysis from the prospective, randomized PLATO trial. Circulation. 2013;128(10):1055–65. doi: 10.1161/CIRCULATIONAHA.113.002589.
    1. Braunwald E. Unstable angina: an etiologic approach to management. Circulation. 1998;98(21):2219–22. doi: 10.1161/01.CIR.98.21.2219.
    1. Armstrong EJ, Morrow DA, Sabatine MS. Inflammatory biomarkers in acute coronary syndromes. Part I: introduction and cytokines. Circulation. 2006;113(6):e72–5. doi: 10.1161/CIRCULATIONAHA.105.595520.
    1. Vilahur G, Badimon L. Ischemia/reperfusion activates myocardial innate immune response: the key role of the toll-like receptor. Front Physiol. 2014;5:496. doi: 10.3389/fphys.2014.00496.

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