Increased platelet aggregation and serum thromboxane levels in aspirin-treated patients with prior myocardial infarction

Summary

The antiplatelet effect of aspirin displays considerable inter-individual variability. We investigated the antiplatelet effect of aspirin in patients with coronary artery disease on aspirin mono-therapy with and without prior myocardial infarction (MI). Further, we investigated whether the effect of aspirin differed between patients with and without aspirin use at the time of MI onset. We performed a study on 231 patients, including 171 with prior MI. Among patients with only one prior MI (116 patients), 59 patients were on aspirin at the time of MI onset. All patients received 75 mg aspirin as mono-therapy. Platelet aggregation was assessed by multiple electrode aggregometry (Multiplate®) and Verify -Now®, and platelet activation was evaluated by soluble P-selectin. Furthermore, we measured serum thromboxane B₂. MI patients had higher median platelet aggregation levels than patients without prior MI when evaluated by Multiplate® (p_{arachidonic acid}<0.0001, p_collagen=0.20). This was not supported by VerifyNow®. Furthermore, MI patients had higher median serum thromboxane B₂ levels than patients without prior MI (p=0.01). Patients on aspirin before MI onset had significantly higher median aggregation levels compared with MI patients not on aspirin when evaluated by Multiplate® (p_collagen=0.02) and VerifyNow® (p<0.0001). In conclusion, patients with prior MI had higher platelet aggregation levels than patients without prior MI when evaluated by Multiplate®, despite same aspirin dose and optimal compliance. Serum thromboxane B₂ levels were higher in MI patients than in patients without prior MI. Finally, patients on aspirin before MI onset had higher aggregation levels compared with patients not on aspirin.

Keywords

Aspirin resistance - ischaemic heart disease - thrombosis - antiplatelet agents

• References

• 1 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992; 326: 310-318.
• 2 Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J. 2002; 324: 71-86.
• 3 Baigent C, Blackwell L, Collins R. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-1860.
• 4 Snoep JD, Hovens MM, Eikenboom JC. et al. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med 2007; 167: 1593-1599.
• 5 Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin „resistance“ and risk of cardiovascular morbidity: systematic review and meta-analysis. Br Med J 2008; 336: 195-198.
• 6 Santopinto J, Gurfinkel EP, Torres V. et al. Prior aspirin users with acute non-ST-elevation coronary syndromes are at increased risk of cardiac events and benefit from enoxaparin. Am Heart J 2001; 141: 566-572.
• 7 Rich JD, Cannon CP, Murphy SA. et al. Prior aspirin use and outcomes in acute coronary syndromes. J Am Coll Cardiol 2010; 56: 1376-1385.
• 8 Mikkelsson J, Eskola M, Nikus K. et al. Failure of aspirin to prevent myocardial infarction and adverse outcome during follow-up – a large series of all-comers. Ann Med 2008; 40: 296-302.
• 9 Alexander JH, Harrington RA, Tuttle RH. et al. Prior aspirin use predicts worse outcomes in patients with non-ST-elevation acute coronary syndromes. PURSUIT Investigators. Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy. Am J Cardiol 1999; 83: 1147-1151.
• 10 Grove EL, Hvas AM, Johnsen HL. et al. A comparison of platelet function tests and thromboxane metabolites to evaluate aspirin response in healthy individuals and patients with coronary artery disease. Thromb Haemost 2010; 103: 1245-1253.
• 11 Patrono C, Ciabattoni G, Pinca E. et al. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 1980; 17: 317-327.
• 12 Patrono C, Rocca B. Drug insight: aspirin resistance--fact or fashion?. Nat Clin Pract Cardiovasc Med 2007; 04: 42-50.
• 13 Tentzeris I, Siller-Matula J, Farhan S. et al. Platelet function variability and non-genetic causes. Thromb Haemost 2011; 105 (Suppl. 01) S60-S66.
• 14 Andersen K, Hurlen M, Arnesen H. et al. Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease. Thromb Res 2002; 108: 37-42.
• 15 Chen WH, Cheng X, Lee PY. et al. Aspirin resistance and adverse clinical events in patients with coronary artery disease. Am J Med 2007; 120: 631-635.
• 16 Cotter G, Shemesh E, Zehavi M. et al. Lack of aspirin effect: aspirin resistance or resistance to taking aspirin?. Am Heart J 2004; 147: 293-300.
• 17 DiChiara J, Bliden KP, Tantry US. et al. Platelet function measured by VerifyNow identifies generalized high platelet reactivity in aspirin treated patients. Platelets 2007; 18: 414-423.
• 18 Dorsch MP, Lee JS, Lynch DR. et al. Aspirin resistance in patients with stable coronary artery disease with and without a history of myocardial infarction. Ann Pharmacother 2007; 41: 737-741.
• 19 Eikelboom JW, Hirsh J, Weitz JI. et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002; 105: 1650-1655.
• 20 Gum PA, Kottke-Marchant K, Poggio ED. et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001; 88: 230-235.
• 21 Gurbel PA, Bliden KP, DiChiara J. et al. Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation 2007; 115: 3156-3164.
• 22 Pamukcu B, Oflaz H, Onur I. et al. Aspirin-resistant platelet aggregation in a cohort of patients with coronary heart disease. Blood Coagul Fibrinolysis 2007; 18: 461-465.
• 23 Kottke-Marchant K, Murugesan G, Gerber C. et al. High prevalence of aspirin resistance in patients with a history of myocardial infarction. Congress of the International Society on Thrombosis and Haemostasis (ISTH) 2003. J Thromb Haemost. 2003 Suppl. 1: Abstract OC243
• 24 Lordkipanidze M, Pharand C, Schampaert E. et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 2007; 28: 1702-1708.
• 25 Cohen M, Adams PC, McBride R. et al. Prospective Comparison of Patient Characteristics and Outcome of Non-prior Aspirin Users versus Aspirin Users with Unstable Angina or Non-Q-Wave Myocardial Infarction Treated with Combination Antithrombotic Therapy. J Thromb Thrombolysis 1997; 04: 275-280.
• 26 Collet JP, Montalescot G, Blanchet B. et al. Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 2004; 110: 2361-2367.
• 27 Hobikoglu GF, Norgaz T, Aksu H. et al. The effect of acetylsalicylic acid resistance on prognosis of patients who have developed acute coronary syndrome during acetylsalicylic acid therapy. Can J Cardiol 2007; 23: 201-206.
• 28 Berent R, Auer J, Franklin B. et al. Platelet response to aspirin 50 and 100 mg in patients with coronary heart disease over a five-year period. Am J Cardiol 2011; 108: 644-650.
• 29 Pulcinelli FM, Pignatelli P, Celestini A. et al. Inhibition of platelet aggregation by aspirin progressively decreases in long-term treated patients. J Am Coll Cardiol 2004; 43: 979-984.
• 30 Spencer FA, Santopinto JJ, Gore JM. et al. Impact of aspirin on presentation and hospital outcomes in patients with acute coronary syndromes (The Global Registry of Acute Coronary Events [GRACE]). Am J Cardiol 2002; 90: 1056-1061.
• 31 Portnay EL, Foody JM, Rathore SS. et al. Prior aspirin use and outcomes in elderly patients hospitalized with acute myocardial infarction. J Am Coll Cardiol 2005; 46: 967-974.
• 32 Frelinger III AL, Furman MI, Linden MD. et al. Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance. Circulation 2006; 113: 2888-2896.
• 33 Wang J, Zhang S, Jin Y. et al. Elevated levels of platelet-monocyte aggregates and related circulating biomarkers in patients with acute coronary syndrome. Int J Cardiol 2007; 115: 361-365.
• 34 Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation 2001; 103: 491-495.
• 35 Freynhofer MK, Brozovic I, Bruno V. et al. Multiple electrode aggregometry and vasodilator stimulated phosphoprotein-phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events. Thromb Haemost 2011; 106: 230-239.
• 36 Gremmel T, Steiner S, Seidinger D. et al. Comparison of methods to evaluate clopidogrelmediated platelet inhibition after percutaneous intervention with stent implantation. Thromb Haemost 2009; 101: 333-339.
• 37 Sibbing D, Morath T, Braun S. et al. Clopidogrel response status assessed with Multiplate point-of-care analysis and the incidence and timing of stent thrombosis over six months following coronary stenting. Thromb Haemost 2010; 103: 151-159.
• 38 Paniccia R, Antonucci E, Maggini N. et al. Assessment of platelet function on whole blood by multiple electrode aggregometry in high-risk patients with coronary artery disease receiving antiplatelet therapy. Am J Clin Pathol 2009; 131: 834-842.
• 39 Paniccia R, Antonucci E, Maggini N. et al. Comparison of methods for monitoring residual platelet reactivity after clopidogrel by point-of-care tests on whole blood in high-risk patients. Thromb Haemost 2010; 104: 287-292.
• 40 Williams CD, Cherala G, Serebruany V. Application of platelet function testing to the bedside. Thromb Haemost 2010; 103: 29-33.