Impaired thrombolytic status predicts adverse cardiac events in patients undergoing primary percutaneous coronary intervention

Christos Christopoulos; Mohamed Farag; Keith Sullivan; David Wellsted; Diana A. Gorog

doi:10.1160/TH16-09-0712

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2017; 117(03): 457-470
DOI: 10.1160/TH16-09-0712

Coagulation and Fibrinolysis

Schattauer GmbH

Impaired thrombolytic status predicts adverse cardiac events in patients undergoing primary percutaneous coronary intervention

Christos Christopoulos^*

¹Postgraduate Medical School, University of Hertfordshire, Hertfordshire, UK

²Department of Cardiology, East and North Hertfordshire NHS Trust, Hertfordshire, UK

,

Mohamed Farag^*

¹Postgraduate Medical School, University of Hertfordshire, Hertfordshire, UK

²Department of Cardiology, East and North Hertfordshire NHS Trust, Hertfordshire, UK

,

Keith Sullivan

¹Postgraduate Medical School, University of Hertfordshire, Hertfordshire, UK

,

David Wellsted

¹Postgraduate Medical School, University of Hertfordshire, Hertfordshire, UK

,

Diana A. Gorog

¹Postgraduate Medical School, University of Hertfordshire, Hertfordshire, UK

²Department of Cardiology, East and North Hertfordshire NHS Trust, Hertfordshire, UK

³National Heart & Lung Institute, Imperial College, London, UK

› Institutsangaben

Abstract

Summary

Antithrombotic medications reduce thrombosis but increase bleeding. Identification of ST-elevation myocardial infarction (STEMI) patients at risk of recurrent thrombosis could allow targeted treatment with potent antithrombotic medications, with less potent agents in others, to reduce bleeding. Conventional platelet function tests assess platelet reactivity only, yet there is increasing evidence that endogenous thrombolytic potential determines outcome following thrombus initiation. We investigated whether assessing both platelet reactivity and endogenous thrombolysis, could identify STEMI patients at high-risk of recurrent thrombotic events. Thrombotic status was assessed in STEMI patients, before and after primary percutaneous coronary intervention (PPCI), at discharge and at 30 days; with 12 months’ followup. The time to form an occlusive thrombus under high shear (occlusion time, OT), and time to restore flow by endogenous thrombolysis (lysis time, LT) was measured using the point-of-care Global Thrombosis Test (GTT) in the cardiac catheterisation laboratory. Impaired endogenous thrombolysis (prolonged LT ≥ 3000 s), seen in 13 % patients pre-PPCI, was related to major adverse cardiac events, MACE (HR: 3.31, 95 %CI: 1.02–10.78, p = 0.045), driven by cardiovascular death (HR: 4.17, 95 %CI: 0.99–17.51, p = 0.05). Enhanced (rapid) endogenous thrombolysis (LT < 1000 s) was associated with spontaneous reperfusion, ST-segment resolution and Thrombolysis In Myocardial Infarction 3 flow pre-PPCI. Baseline OT was shorter in those with MACE (especially recurrent myocardial infarction and stroke) than those without (253 ± 150 s vs 354 ± 134 s, p=0.017). Endogenous thrombolysis, when impaired, is associated with increased cardiovascular risk, and when enhanced, with spontaneous reperfusion. Endogenous thrombolysis may be a novel target for pharmacological intervention, and allow targeting of potent antithrombotic medications to high-risk patients.

Keywords

Percutaneous coronary intervention - thrombosis - endogenous thrombolysis - myocardial infarction - coronary reperfusion

Volltext

Referenzen

References
1 Naghavi M, Libby P, Falk E. et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation 2003; 108: 1772-1778.
2 Kastrati A, Neumann FJ, Schulz S. et al. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med 2011; 365: 1980-1989.
3 Patti G, Pasceri V, D’Antonio L. et al. Comparison of safety and efficacy of bivalirudin versus unfractionated heparin in high-risk patients undergoing percutaneous coronary intervention (from the Anti-Thrombotic Strategy for Reduction of Myocardial Damage During Angioplasty-Bivalirudin vs Heparin study). Am J Cardiol 2012; 110: 478-484.
4 Steg PG, van’t Hof A, Hamm CW. et al. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013; 369: 2207-2217.
5 Shahzad A, Kemp I, Mars C. et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; 384: 1849-1858.
6 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
7 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
8 Roe MT, Armstrong PW, Fox KA. et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012; 367: 1297-1309.
9 Gorog DA, Sweeny JM, Fuster V.. Antiplatelet drug ’resistance.’Part 2: laboratory resistance to antiplatelet drugs-fact or artifact?. Nat Rev Cardiol 2009; 06: 365-373.
10 Gorog DA, Fuster V.. Platelet function tests in clinical cardiology: unfulfilled expectations. J Am Coll Cardiol 2013; 61: 2115-2129.
11 Swan HJ.. Acute myocardial infarction: a failure of timely, spontaneous thrombolysis. J Am Coll Cardiol 1989; 13: 1435-1437.
12 Okafor O, Gorog D.. Endogenous fibrinolysis: an important mediator of thrombus formation and cardiovascular risk. J Am Coll Cardiol 2015; 65: 1683-1699.
13 Saraf S, Christopoulos C, Salha IB. et al. Impaired endogenous thrombolysis in acute coronary syndrome patients predicts cardiovascular death and nonfatal myocardial infarction. J Am Coll Cardiol 2010; 55: 2107-2115.
14 Sharma S, Farrington K, Kozarski R. et al. Impaired thrombolysis: a novel cardiovascular risk factor in end-stage renal disease. Eur Heart J 2013; 34: 354-363.
15 Steg PG, James SK, Atar D. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569-2619.
16 O’Gara PT, Kushner FG, Ascheim DD. et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61: e78-140.
17 Yamamoto J, Yamashita T, Ikarugi H. et al. Görög Thrombosis Test: a global in-vitro test of platelet function and thrombolysis. Blood Coagul Fibrinolysis 2003; 14: 31-39.
18 de Lemos JA, Antman EM, Giugliano RP. et al. ST-segment resolution and infarct-related artery patency and flow after thrombolytic therapy. Thrombolysis in Myocardial Infarction (TIMI) 14 investigators. Am J Cardiol 2000; 85: 299-304.
19 Mehran R, Rao SV, Bhatt DL. et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123: 2736-2747.
20 Connelly LM.. Pilot studies. Medsurg Nurs 2008; 17: 411-412.
21 Saraf S, Wellsted D, Sharma S, Gorog DA.. Shear-induced global thrombosis test of native blood: pivotal role of ADP allows monitoring of P2Y12 antagonist therapy. Thromb Res 2009; 124: 447-451.
22 Niespialowska-Steuden M, Okafor O, Collins P. et al. NOAC but not VKA Favorably affect endogenous thrombolytic status: a novel mechanism of action. J Am Coll Cardiol 2014. 63 (12_S).
23 Farag M, Okafor O, Niespialowska-Steuden M. et al. Comparative effect of novel oral anticoagulants on global thrombotic status in patients with atrial fibrillation. J Am Coll Cardiol 2015. 65 (10_S).
24 Rosser G, Tricoci P, Morrow D. et al. PAR-1 antagonist vorapaxar favorably improves global thrombotic status in patients with coronary disease. J Thromb Thrombolysis 2014; 38: 423-429.
25 Alexander JH, Lopes RD, James S. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365: 699-708.
26 Oldgren J, Budaj A, Granger CB. et al. Dabigatran vs placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011; 32: 2781-2789.
27 Mega JL, Braunwald E, Wiviott SD. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9-19.
28 Johansson L, Jansson JH, Boman K. et al. Tissue plasminogen activator, plasminogen activator inhibitor-1, and tissue plasminogen activator/plasminogen activator inhibitor-1 complex as risk factors for the development of a first stroke. Stroke 2000; 31: 26-32.
29 Belalcazar LM, Ballantyne CM, Lang W. et al. Metabolic factors, adipose tissue, and plasminogen activator inhibitor-1 levels in type 2 diabetes: findings from the look AHEAD study. Arterioscler Thromb Vasc Biol 2011; 31: 1689-1695.
30 Erkol A, Oduncu V, Turan B. et al. The value of plasma D-dimer level on admission in predicting no-reflow after primary percutaneous coronary intervention and long-term prognosis in patients with acute ST segment elevation myocardial infarction. J Thromb Thrombolysis 2014; 38: 339-347.
31 Kikkert WJ, Claessen BE, Stone GW. et al. D-dimer levels predict ischemic and hemorrhagic outcomes after acute myocardial infarction: a HORIZONS-AMI biomarker substudy. J Thromb Thrombolysis 2014; 37: 155-164.
32 Hansen CH, Ritschel V, Halvorsen S. et al. Markers of thrombin generation are associated with myocardial necrosis and left ventricular impairment in patients with ST-elevation myocardial infarction. Thromb J 2015; 13: 31.
33 Sambola A, García Del Blanco B, Ruiz-Meana M. et al. Increased von Willebrand factor, P-selectin and fibrin content in occlusive thrombus resistant to lytic therapy. Thromb Haemost 2016; 115: 1129-1137.
34 Zalewski J, Bogaert J, Sadowski M. et al. Plasma fibrin clot phenotype independently affects intracoronary thrombus ultrastructure in patients with acute myocardial infarction. Thromb Haemost 2015; 113: 1258-1269.
35 Denorme F, Wyseure T, Peeters M. et al. Inhibition of Thrombin-Activatable Fibrinolysis Inhibitor and Plasminogen Activator Inhibitor-1 Reduces Ischemic Brain Damage in Mice. Stroke 2016; 47: 2419-2422.
36 Benamer H, Tafflet M, Bataille S. et al. Female gender is an independent predictor of in-hospital mortality after STEMI in the era of primary PCI: insights from the greater Paris area PCI Registry. EuroIntervention 2011; 06: 1073-1079.
37 Pancholy SB, Shantha GP, Patel T, Cheskin LJ.. Sex differences in short-term and long-term all-cause mortality among patients with ST-segment elevation myocardial infarction treated by primary percutaneous intervention: a meta-analysis. JAMA Intern Med 2014; 174: 1822-1830.
38 van der Meer MG, Nathoe HM, van der Graaf Y. et al. Worse outcome in women with STEMI: a systematic review of prognostic studies. Eur J Clin Invest 2015; 45: 226-235.
39 Gorog DA, Yamamoto J, Saraf S. et al. First direct comparison of platelet reactivity and thrombolytic status between Japanese and Western volunteers: possible relationship to the „Japanese paradox“. Int J Cardiol 2011; 152: 43-48.
40 Stone GW, Witzenbichler B, Weisz G. 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: 614-623.
41 Ahn SG, Lee SH, Yoon JH. et al. Different prognostic significance of high on-treatment platelet reactivity as assessed by the VerifyNow P2Y12 assay after coronary stenting in patients with and without acute myocardial infarction. JACC Cardiovasc Interv 2012; 05: 259-267.
42 Nesbitt WS, Westein E, Tovar-Lopez FJ. et al. A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat Med 2009; 15: 665-673.
43 Jackson SP.. The growing complexity of platelet aggregation. Blood 2007; 109: 5087-5095.
44 Patti G, Nusca A, Mangiacapra F. et al. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study. J Am Coll Cardiol 2008; 52: 1128-1133.
45 Aradi D, Vorobcsuk A, Lenkey Z. et al. Low platelet disaggregation predicts poor response to 150 mg clopidogrel in patients with elevated platelet reactivity. Platelets 2010; 21: 1-10.
46 Brass L.. Thrombus formation: stability matters. Blood 2006; 108: 2883-2884.