DOI: 10.25881/20728255_2022_17_4_2_121


Gitelson D.G. 1, Faibushevich A.G.2, Gitelzon E.A.2, Deneka A.Ya.3, Vasiliev A.E.1, Danishian K.I.1

1 National Hematology Research Center, Moscow

2 RUDN University, Moscow

3 Fox Chase Cancer Center, USA


Antiplatelet agents significantly reduced mortality and morbidity of coronary heart disease, cerebrovascular disease and peripheral artery disease. Therefore, antiplatelet agents are an important part of optimal drug therapy in such patients. Acetylsalicylic acid remains the most commonly recommended drug, especially for the prevention of thrombotic complications. Clopidogrel is an alternative to acetylsalicylic acid, as well as an important component of dual antiplatelet therapy for balloon angioplasty and stenting. Ticlopidine is not used in practice according to the guidelines due to numerous side effects and the development of safer and more effective P2Y12 antagonists.

Keywords: antiplatelet, acetylsalicylic acid, ticlopidine, clopidogrel.


1. Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T, et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries Endorsed by: the European Stroke Organization (ESO) The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J. 2018; 39(9): 763-816.

2. Lusis AJ. Atherosclerosis. Nature. 2000; 407(6801): 233-41.

3. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018; 39(3): 213-60.

4. Weiss HJ, Aledort LM. Impaired platelet-connective-tissue reaction in man after aspirin ingestion. Lancet. 1967; 2(7514): 495-7.

5. European Stroke O, Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clement D, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2011; 32(22): 2851-906.

6. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med. 1994; 330(18): 1287-94.

7. Lewis HD, Jr., Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE, 3rd, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1983; 309(7): 396-403.

8. Group TI-C. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988; 2(8607): 349-60.

9. Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, et al. Aspirin, sulfi npyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med. 1985; 313(22): 1369-75.

10. Group TR. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet. 1990; 336(8719): 827-30.

11. Steering Committee of the Physicians’ Health Study Research G. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med. 1989; 321(3): 129-35.

12. Antithrombotic Trialists C. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324(7329): 71-86.

13. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005; 52(13): 1293-304.

14. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Eikelboom JW, et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010; 363(10): 930-42.

15. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001; 345(25): 1809-17.

16. Valles J, Santos MT, Aznar J, Osa A, Lago A, Cosin J, et al. Erythrocyte promotion of platelet reactivity decreases the effectiveness of aspirin as an antithrombotic therapeutic modality: the effect of low-dose aspirin is less than optimal in patients with vascular disease due to prothrombotic effects of erythrocytes on platelet reactivity. Circulation. 1998; 97(4): 350-5.

17. Grove EL, Wurtz M, Hvas AM, Kristensen SD. Increased platelet turnover in patients with previous definite stent thrombosis. J Thromb Haemost. 2011; 9(7): 1418-9.

18. Pascale S, Petrucci G, Dragani A, Habib A, Zaccardi F, Pagliaccia F, et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Blood. 2012: 119(15): 3595-603.

19. Gremmel T, Muller M, Steiner S, Seidinger D, Koppensteiner R, Kopp CW, et al. Chronic kidney disease is associated with increased platelet activation and poor response to antiplatelet therapy. Nephrology Dialysis Transplantation. 2013; 28(8): 2116-22.

20. Frelinger AL, 3rd, Furman MI, Linden MD, Li Y, Fox ML, Barnard MR, 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(25): 2888-96.

21. Raparelli V, Proietti M, Napoleone L, Bucci T, Talerico G, Pignataro FS, et al. Asymptomatic peripheral artery disease and antiplatelet management. Vasa. 2014; 43(5): 309-25.

22. Farid NA, Kurihara A, Wrighton SA. Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol. 2010; 50(2): 126-42.

23. Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996; 334 (17): 1084-9.

24. Bertrand ME, Legrand V, Boland J, Fleck E, Bonnier J, Emmanuelson H, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study. Circulation. 1998; 98(16): 1597-603.

25. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med. 1998; 339(23): 1665-71.

26. Urban P, Macaya C, Rupprecht HJ, Kiemeneij F, Emanuelsson H, Fontanelli A, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation. 1998; 98(20): 2126-32.

27. Cosmi B, Rubboli A, Castelvetri C, Milandri M. Ticlopidine versus oral anticoagulation for coronary stenting. Cochrane Database Syst Rev. 2001(4): CD002133.

28. Steinhubl SR, Tan WA, Foody JM, Topol EJ. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. JAMA. 1999; 281(9): 806-10.

29. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, Investigators C. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation. 2000; 102(6): 624-9.

30. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 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 the European Society of Cardiology (ESC). Eur Heart J. 2016; 37(3): 267-315.

31. Jiang XL, Samant S, Lesko LJ, Schmidt S. Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet. 2015; 54(2): 147-66.

32. Committee CS. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996; 348(9038): 1329-39.

33. Steinhubl SR, Berger PB, Mann JT, Fry ET, DeLago A, Wilmer C, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 288(19): 2411-20.

34. Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003; 108(14): 1682-7.

35. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, et al. Addition of clopidogrel to aspirin and fi brinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005; 352(12): 1179-89.

36. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004; 364(9431): 331-7.

37. Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation. 2005; 111(17): 2233-40.

38. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006; 354(16): 1706-17.

39. Investigators A, Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009; 360(20): 2066-78.

40. Belch JJ, Dormandy J, Committee CW, Biasi GM, Cairols M, Diehm C, et al. Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial. J Vasc Surg. 2010; 52(4): 825-33.

41. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol. 2005; 45(2): 246-51.

42. Gremmel T, Panzer S. Clinical, genetic and confounding factors determine the dynamics of the in vitro response/non response to clopidogrel. Thromb Haemost. 2011; 106(2): 211-8.

43. Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation. 2009; 119(2): 237-42.

44. Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double blind OCLA (Omeprazole Clopidogrel Aspirin) study. J Am Coll Cardiol. 2008; 51(3): 256-60.

45. Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010; 363(20): 1909-17.

46. Hobl EL, Stimpfl T, Ebner J, Schoergenhofer C, Derhaschnig U, Sunder-Plassmann R, et al. Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2014; 63(7): 630-5.

47. Xhelili E, Eichelberger B, Kopp CW, Koppensteiner R, Panzer S, Gremmel T. The Antiplatelet Effect of Clopidogrel Decreases With Patient Age. Angiology. 2016.

48. Gremmel T, Kopp CW, Seidinger D, Koppensteiner R, Panzer S, Sunder-Plassmann R, et al. Differential impact of cytochrome 2C9 allelic variants on clopidogrel-mediated platelet inhibition determined by five different platelet function tests. Int J Cardiol. 2013; 166(1): 126-31.

49. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009; 360(4): 354-62.

50. Olinic DM, Tataru DA, Homorodean C, Spinu M, Olinic M. Antithrombotic treatment in peripheral artery disease. Vasa. 2018; 47(2): 99-108.

For citation

Gitelson D.G. , Faibushevich A.G., Gitelzon E.A., Deneka A.Ya., Vasiliev A.E., Danishian K.I. The studies of first antiplatelet drugs: acetylsalicylic acid, ticlopidine and clopidogrel. Bulletin of Pirogov National Medical & Surgical Center. 2022;17(4-2):121-126. (In Russ.)