cardiovascularКардиоваскулярная терапия и профилактикаCardiovascular Therapy and Prevention1728-88002619-0125«SILICEA-POLIGRAF» LLC10.15829/1728-8800-2012-6-71-77cardiovascular-2031Research ArticleМНЕНИЕ ПО ПРОБЛЕМЕOPINION ON A PROBLEMРезистентность к антитромбоцитарным препаратам у больных ишемической болезнью сердцаAntiplatelet drug resistance in patients with coronary heart diseaseСулимовВ. А.SulimovV. A.moros@list.ruМорозЕ. В.MorozE. V.moros@list.ruГБОУ ВПО Первый Московский государственный медицинский университет им. И. М. Сеченова на базе Факультетской терапевтической клиники им. В. Н. Виноградова и Университетской клинической больницы №1, МоскваI. M. Sechenov First Moscow State Medical University, V. N. Vinogradov Faculty Clinic of Internal Medicine, University Clinical Hospital No. 1, Moscow2012201220121167177Copyright © Сулимов В.А., Мороз Е.В., 20122012Сулимов В.А., Мороз Е.В.Sulimov V.A., Moroz E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cardiovascular.elpub.ru/jour/article/view/2031

В лечении ишемической болезни сердца (ИБС) лидирующее положение занимает коронарная ангиопластика. Имеется большая доказательная база необходимости проведения двойной антиагрегантной терапии (клопидогрел и аспирин) у таких больных перед операцией и в дальнейшем. Появление тромботических осложнений при использовании этих антиагрегантов обозначило проблему резистентности к ним. Распространенность резистентности к ацетилсалициловой кислоте (АСК) колеблется от 5% до 45%, к клопидогрелу от 20% до 45% в зависимости от применяемого метода и категории больных; резистентность к двойной антитромбоцитарной терапии колеблется в пределах 6-8%. В настоящее время «золотым стандартом» оценки функциональной активности тромбоцитов является оптическая агрегометрия. Для оценки резистентности к АСК в качестве индуктора агрегации используется арахидоновая кислота, вычисляется абсолютное значение агрегации. Для оценки резистентности к клопидогрелу исследуют АДФиндуцированную агрегацию тромбоцитов, показатель является относительным. На развитие резистентности к АСК влияют биологические, клинические и генетические факторы. Резистентность к клопидогрелу усугубляют такие факторы, как лекарства, гипергликемия, атеросклероз; значимым является полиморфизм гена CYP2С19*2. Выявление пациентов, резистентных к антитромбоцитарным препаратам, позволит вовремя скорректировать антиагрегантную терапию и снизить вероятность развития сердечно-сосудистых событий. Возможными путями преодоления такой резистентности служит удвоение нагрузочной и поддерживающей дозы клопидогрела, применение новых антиагрегантных препаратов.

Coronary angioplasty is an important component of coronary heart disease (CHD) management. There is a substantial evidence of the need for dual antiaggregant therapy (clopidogrel and aspirin) in this clinical group, both before and after the intervention. The development of thrombotic complications during antiaggregant therapy suggests the antiplatelet drug resistance. The prevalence of this condition varies from 5% to 45% for aspirin, and from 20% to 45% for clopidogrel, depending on the assessment method and the specific clinical group. For dual antiplatelet therapy, the resistance prevalence is 6-8%. Presently, the gold standard method of the platelet functional activity assessment is optical aggregometry. To assess the resistance to aspirin, arachidonic acid is used as an aggregation inductor, with the calculation of absolute aggregation levels. To assess the resistance to clopidogrel, ADP is used as an aggregation inductor, and the relative aggregation parameters are calculated. The development of aspirin resistance is influenced by biological, clinical, and genetic factors. The clopidogrel resistance is associated with certain medications, hyperglycemia, atherosclerosis, and CYP2C19*2 gene polymorphism. Identification of the patients resistant to antiplatelet drugs enables the clinicians to adjust the antiplatelet treatment reasonably early and to reduce the risk of cardiovascular events. The possible methods of overcoming antiplatelet drug resistance are to double the loading and maintenance doses of clopidogrel and to use new agents.

резистентностьацетилсалициловая кислотаклопидогрелишемическая болезнь сердцаresistanceacetylsalicylic acidclopidogrelcoronary heart diseaseReferencesYusuf S, Zhao F, Mehta SR, et. al. The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345: 494-502.Yusuf S, Zhao F, Mehta SR, et. al. The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345: 494-502.Steinhubl SR, Berger PB, Mann JT for the CREDO Investigators. Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention. A Randomized Controlled Trial. JAMA. 2002; 288: 2411-20.Steinhubl SR, Berger PB, Mann JT for the CREDO Investigators. Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention. A Randomized Controlled Trial. JAMA. 2002; 288: 2411-20.Gratsianskaya N. Antiplatelet therapy in coronary heart disease. Some of the problems and achievements. Atherothrombosis 2011; 1(4): 2-52. Russian (Грацианский Н.А. Антитромбоцитарная терапия при коронарной болезни сердца. Некоторые проблемы и достижения. Атеротромбоз 2011; 1 (4): 2-52).Gratsianskaya N. Antiplatelet therapy in coronary heart disease. Some of the problems and achievements. Atherothrombosis 2011; 1(4): 2-52. Russian (Грацианский Н.А. Антитромбоцитарная терапия при коронарной болезни сердца. Некоторые проблемы и достижения. Атеротромбоз 2011; 1 (4): 2-52).Kuliczkowski W. Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Grjup on antiplatelet drug resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society. Eur Heart J 2009; 30: 426-35.Kuliczkowski W. Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Grjup on antiplatelet drug resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society. Eur Heart J 2009; 30: 426-35.Gori AM, Marcucci R, Migliorini A, et. al. Incidence and clinical impact of dual nonresponsiveness to aspirin and clopidogrel in patients with drug– eluting stents. JACC 2008; 52(9): 734-9.Gori AM, Marcucci R, Migliorini A, et. al. Incidence and clinical impact of dual nonresponsiveness to aspirin and clopidogrel in patients with drug– eluting stents. JACC 2008; 52(9): 734-9.Snoep JD, Hovens MM, Eikenboom JC. Clopidogrel nonresponsiveness in patient undergoing percutaneous intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007; 154: 221-31.Snoep JD, Hovens MM, Eikenboom JC. Clopidogrel nonresponsiveness in patient undergoing percutaneous intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007; 154: 221-31.Combescure С, Reny JL, Daali Y, et al. Clinical implications of clopidogrel non-response in cardiovascular patients a systematic review and metaanalisys. J Thromb Haemost 2009; 7: 1747-9.Combescure С, Reny JL, Daali Y, et al. Clinical implications of clopidogrel non-response in cardiovascular patients a systematic review and metaanalisys. J Thromb Haemost 2009; 7: 1747-9.Gurbel PA, Richard C, Michelson AD. Platelet function monitoring in patients with coronary artery disease. JACC 2007; 50 (19): 1822-34.Gurbel PA, Richard C, Michelson AD. Platelet function monitoring in patients with coronary artery disease. JACC 2007; 50 (19): 1822-34.Methods of clinical laboratory tests. Тhe book: A Reference Guide, edited by V.V. Menshikov. Moscow: Labora 2008; 156-7. Russian (Методики клинических лабораторных исследований. В кн.: Справочное пособие под редакцией В.В.Меньшикова. Москва: Лабора 2008; 156-7).Methods of clinical laboratory tests. Тhe book: A Reference Guide, edited by V.V. Menshikov. Moscow: Labora 2008; 156-7. Russian (Методики клинических лабораторных исследований. В кн.: Справочное пособие под редакцией В.В.Меньшикова. Москва: Лабора 2008; 156-7).Cipollone F, Rocca B, Patrono C. Ciclooxygenase-2 expression and inhibition in atherothrombosis. Arterioscler Thromb Vasc Biol 2004; 24(2): 246-55.Cipollone F, Rocca B, Patrono C. Ciclooxygenase-2 expression and inhibition in atherothrombosis. Arterioscler Thromb Vasc Biol 2004; 24(2): 246-55.Law WC, Gurbel PA, Watkins PB, et al. Atorvastatin reduses the ability of clopidogrel to inhibit plateletaggregation: a new drug-drug interaction. Circulation 2003; 107: 32.Law WC, Gurbel PA, Watkins PB, et al. Atorvastatin reduses the ability of clopidogrel to inhibit plateletaggregation: a new drug-drug interaction. Circulation 2003; 107: 32.Serebrunay VL, Gurbel PA, Alexander JH, et al. Statins do not affect platelet inhibition with clopidogrel during coronary stenting. Atherosclerosis 2001; 159: 239-41.Serebrunay VL, Gurbel PA, Alexander JH, et al. Statins do not affect platelet inhibition with clopidogrel during coronary stenting. Atherosclerosis 2001; 159: 239-41.Sirotkina O. Molecular and genetic mechanisms of platelet activation and sensitivity to antiplatelet drugs in patients with cardiovascular disease. Biomedical and social security problems in emergency situations 2010; 4(1):69-76. Russian (Сироткина О.В. Молекулярно генетические механизмы активации тромбоцитов и чувствительности к антиагрегантным препаратам у больных сердечно-сосудистыми заболеваниями. Медико-биологические и социальные проблемы безопасности в чрезвычайных ситуациях 2010; 4(1): 69-76).Sirotkina O. Molecular and genetic mechanisms of platelet activation and sensitivity to antiplatelet drugs in patients with cardiovascular disease. Biomedical and social security problems in emergency situations 2010; 4(1):69-76. Russian (Сироткина О.В. Молекулярно генетические механизмы активации тромбоцитов и чувствительности к антиагрегантным препаратам у больных сердечно-сосудистыми заболеваниями. Медико-биологические и социальные проблемы безопасности в чрезвычайных ситуациях 2010; 4(1): 69-76).Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-7.Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-7.Mega JL, Simon T, Anderson J, et al. CYP2С19*2 Genetic Variants and Clinical Outcomes With Clopidogrel: Meta-Analysis. Circulation 2009; 120: S598-9.Mega JL, Simon T, Anderson J, et al. CYP2С19*2 Genetic Variants and Clinical Outcomes With Clopidogrel: Meta-Analysis. Circulation 2009; 120: S598-9.Bhatt DL, Cryer B, Contant CF, et al. on Behalf of the COGENT Investigators. The COGENT Trial. Slide set. http://www.clinicaltrialresults.orgBhatt DL, Cryer B, Contant CF, et al. on Behalf of the COGENT Investigators. The COGENT Trial. Slide set. http://www.clinicaltrialresults.orgFerguson AD, Dokainish H, Lakkis N. Aspirin and clopidogrel response variability: review of the published literature. Tex Heart Inst J 2008; 35(3): 313-20.Ferguson AD, Dokainish H, Lakkis N. Aspirin and clopidogrel response variability: review of the published literature. Tex Heart Inst J 2008; 35(3): 313-20.Csiszar A, Stef G, Pacher P, et al. Oxidative stress-induced isoprostane formation may contribute to aspirin resistance in platelets. Prostaglandins Leukot Essent Fatty Acids 2002; 66: 557-8.Csiszar A, Stef G, Pacher P, et al. Oxidative stress-induced isoprostane formation may contribute to aspirin resistance in platelets. Prostaglandins Leukot Essent Fatty Acids 2002; 66: 557-8.Gori AM, Marcucci R, Migliorini A, et al. Incidence and clinical impact of dual nonresponsiveness to aspirin and clopidogrel in patients with drugeluting stents. JACC 2008 Aug 26; 52(9): 734-9.Gori AM, Marcucci R, Migliorini A, et al. Incidence and clinical impact of dual nonresponsiveness to aspirin and clopidogrel in patients with drugeluting stents. JACC 2008 Aug 26; 52(9): 734-9.Montalescot G, Wiviott SD, Braunwald E, et al. for the TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 723-31.Montalescot G, Wiviott SD, Braunwald E, et al. for the TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 723-31.Cannon CP, Harrington RA, James S. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010; 375: 283-93.Cannon CP, Harrington RA, James S. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010; 375: 283-93.

The authors declare that there are no conflicts of interest present.