Влияние системного воспаления на эффект антиагрегантной терапии у больных с острым коронарным синдромом

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Abstract

Purpose. The aim of this study was to determine whether there is an association between antiplatelet therapy resistance and systemic inflammation in patients with acute coronary syndrome (ACS).

Methods. We included 122 patients with ACS hospitalized at Moscow City Hospital 23. We measured platelet function using simultaneous light transmittance aggregometry (spontaneous aggregation and ADP-induced), Thromboelastography Platelet Mapping (TEG-PM), Multiplate aggregometry and VerifyNow Aspirin and P2Y12 assays. The following markers of systemic inflammation were estimated: white blood cell count and plasma levels of high sensitivity C-reactive protein (hsCRP), soluble CD40-ligand (sCD40L), sP-selectin, von Willebrand factor, fibrinogen. All patients received aspirin at 250–325 mg and a loading dose of clopidogrel (300–600 mg) on arrival, followed by 125 mg of aspirin and 75 mg of clopidogrel per day. For the following analysis, the patients were separated into two groups. Both groups received atorvastatin: one group at 20 mg per day (n=18) and the second at 80 mg per day (n=24) for at least 7 days.

Results. We found that high white blood cell counts were associated with increased levels of 5 or 10 .M ADPinduced platelet aggregation and decreased percentages of P2Y12-inhibition (VerifyNow) (p=0.002, 0.004, and 0.017, respectively). High plasma levels of sP-selectin were associated with high levels of ADPtest (Multiplate) and decreased percentages of P2Y12-inhibition (VerifyNow) (p=0.046 and 0.047, respectively). Patients with elevated levels of plasma von Willebrand factor had increased 5 .M ADP-induced platelet aggregation (p=0,044). Kaplan–Meier survival analysis with a logrank significance test showed an association between a high risk of reinfarction during follow-up (1–22 months after ACS) and high levels both of 10 .M ADP-induced platelet aggregation and of HPR ADP (p=0.014 and 0.006, respectively). We found that this association remains significant among patients with high levels of hs-CRP (p=0.021), while in the group of patients with low levels of hs-CRP this relationship was not significant. Among patients receiving atorvastatin at 20 mg, the association between a high risk of reinfarction and high levels of platelet aggregation also remained significant (p=0.003). In contrast, among patients receiving atorvastatin at 80 mg, this association disappeared.

Conclusions. High on-treatment platelet reactivity is associated with several laboratory signs of systemic inflammation and predicts a poor prognosis in patients with ACS. High-dose statin therapy can overcome the association between high on-treatment platelet reactivity and poor prognosis in patients with ACS.

References

Васильева Е. Ю., Касьянова О. В., Шпектор А. В. Уровень С-реактивного белка и эффективность терапии аспирином у пациентов с ишемической болезнью сердца // Кардиологоия. 2006. Т. 45, № 1. С. 66-67.
Barragan P., Bouvier J. L., Roquebert P. O. et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator- stimulated phosphoprotein phosphorylation // Catheter. Cardiovasc. Interv. 2003. Vol. 59. P. 295-302.
Bhindi R., Ormerod O., Newton J. et al. Interaction between statins and clopidogrel: is there anything clinically relevant? // QJM. 2008. Vol. 101, № 12. P. 915-925.
Bonello L., Tantry U. S., Marcucci R. et al. Working Group on High On-Treatment Platelet Reactivity. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate // J. Am. Coll. Cardiol. 2010. Vol. 56. P. 919-933.
Campbell C. L., Steinhubl S. R. Variability in response to aspirin: do we understand the clinical relevance? // J. Thromb. Haemost. 2005. Vol. 3, №4. P. 665-669.
Cuisset T., Frere C., Quilici J. et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting // J. Am. Coll. Cardiol. 2006. Vol. 48, № 7. P. 1339-1345.
Farrй A. J., Tamargo J., Mateos-Cбceres P. J. et al. Old and new molecular mechanisms associated with platelet resistance to antithrombotics // Pharm. Res. 2010. Vol. 27, № 11. P. 2365-2373.
Hamm C. W., Bassand J. P., Agewall S. et al. 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 European Society of Cardiology // Eur. Heart J. 2011. Vol. 32. P. 2999-3054.
Hulot J. S., Collet J. P., Montalescot G. Thienopyridine-associated drug-drug interactions: pharmacologic mechanisms and clinical relevance // Curr. Cardiol. Rep. 2011. Vol. 13. P. 451-458.
Krasopoulos G., Brister S. J., Beattie W. S. et al. Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis // BMJ. 2008. Vol. 336. № 7637. P. 195-198.
Levine G. N., Bates E. R., Blankenship J. C. et al. 2011 ACCF/AHA/SCAI gui deline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions // Circulation. 2011. Vol. 124. e574-e651.
Matetzky S., Shenkman B., Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction // Circulation. 2004. Vol. 109, № 25. P. 3171-3175.
Ridker P. M., Cushman M., Stampfer M. J. et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men // N. Engl. J. Med. 1997. № 336. P. 973-979.
Ridker P. M., Danielson E., Fonseca F. A. et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial./ JUPITER Trial Study Group // Lancet. 2009. Vol. 373, № 9670. P. 1175-1182.
Ridker P. M., Hennekens C. H., Buring J. E. et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women // N. Engl. J. Med. 2000. Vol. 342. P. 836-843.
Ridker P. M., Pfeffer M. A., Braunwald E. et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein / The Cholesterol and Recurrent Events (CARE) Investigators // Circulation. 1999. Vol. 100. P. 230-235.
Riesen W. F., Engler H., Risch M. et al. Short-term effects of atorvastatin on C-reactive protein // Eur. Heart J. 2002. Vol. 23. P. 794-799.
Sakkinen P., Abbott R. D., Curb J. D. et al. C-reactive protein and myocardial infarction // J. Clin. Epidemiol. 2002. Vol. 55. Р. 445-451.
Sposito A. C., Santos S. N., de Faria E. C. et al. Timing and dose of statin therapy define its impact on inflammatory and endothelial responses during myocardial infarction // Arterioscler. Thromb. Vasc. Biol. 2011. Vol. 31, № 5. P. 1240-1246.
Stefanadi E., Tousoulis D., Antoniades C. et al. Early initiation of low-dose atorvastatin treatment after an acute ST-elevated myocardial infarction, decreases inflammatory process and prevents endothelial injury and activation // Int. J. Cardiol. 2009. Vol. 133, № 2. P. 266-268.
Tafreshi M. J., Zagnoni L. G., Gentry E. J. Combination of clopidogrel and statins: a hypothetical interaction or therapeutic dilemma? // Pharmacotherapy. 2006. Vol. 26, № 3. P. 388-394.
Van de Werf F., Bax J., Betriu A. et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology // Eur. Heart J. 2008. Vol. 29. P. 2909-2945.
Vasilieva E., Kasyanova O., Shpektor A. The antiplatelet effect of atorvastatin in patients with acute coronary syndrome depends on the hs-CRP level // Acute Card. Care. 2008. Vol. 10, № 3. P. 181-184.
Wenaweser P., Eshtehardi P., Abrecht L. et al. A randomised determination of the Effect of Fluvastatin and Atorvastatin on top of dual antiplatelet treatment on platelet aggregation after implantation of coronary drug-eluting stents // Thromb. Haemost. 2010. Vol. 104, № 3. P. 554-562.
Wright R. S., Anderson J. L., Adams C. D. et al. 2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/ non-ST-elevation myocardial infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines // Circulation. 2011. Vol. 123. P. 2022-2060

Chief Editor

Leo A. Bockeria, MD, PhD, DSc, Professor, Academician of Russian Academy of Sciences, President of Bakoulev National Medical Research Center for Cardiovascular Surgery