摘要
多项临床试验证明,阿司匹林用于心脑血管血栓栓塞性疾病的一级以及二级预防,能够有效地预防心肌梗死、脑卒中以及心血管死亡的发生。其通过不可逆抑制血栓素A2 (TXA2)的合成发挥抑制血小板聚集的作用。但临床发现,有部分患者正规服用阿司匹林后仍出现血栓栓塞事件,即阿司匹林抵抗现象(Aspirin Resistance,AR)。本研究旨在观察阿司匹林抵抗的发生率,相关危险因素,及其与血小板P-选择素之间的相关性。
方法入选冠心病患者50例(男26例,女24例),测定干预前P-选择素水平,给予阿司匹林100mg 1/晚连续口服2周,比浊法测定血小板聚集率,分为抵抗及敏感(Aspirin Sensitive, AS)两组,测定干预后P-选择素(P-selection, P-选择素)表达。
结果本研究AR的发生率为18%(9/50),男女无明显差异(P=0.385)。AR与AS两组患者间低密度脂蛋白水平(3.65±1.17 vs 2.93±1.03,P=0.018)、高血压患病率(66.7%vs 29.2%,P=0.03)、总胆固醇水平(5.43±1.6 vs 5.09±1.63,P=0.042)及血红蛋白水平(130±7.9 vs 139±14.75,P=0.05)均有显著差异。Logistic多元回归分析则显示,低密度脂蛋白水平(OR=3.26)及高血压(OR=3.89)是阿司匹林抵抗的独立危险因素(P<0.05)。两组患者服药后血小板P-选择素表达有显著性差异,AR组患者服药后血小板P-选择素水平显著高于AS组(2.97±1.64 vs 2.48±1.01,P=0.003)。阿司匹林干预前,AR与AS组P-选择素水平无显著差异(3.36±1.55 vs3.34±1.10,P=0.982),干预后则有显著差异(2.97±1.64 vs 2.48±1.01,P=0.003)。在AR组,干预前后P-选择素水平无明显差异(3.36±1.55 vs 2.97±1.64,P=0.08),在AS组,干预前后P-选择素水平有明显差异(3.34±1.10 vs 2.48±1.01,P=0.03)。AR组干预后P-选择素与血小板聚集率呈正相关(r=0.472,P=0.037),而AS组干预后P-选择素与血小板聚集率无明显相关性(r=0.014,P=0.931)。
结论阿司匹林抵抗的发生率为18%,在男、女性别无显著差异。低密度脂蛋白水平和高血压是发生阿司匹林抵抗的独立危险因素,而与患者年龄、体重、血糖、血小板、白细胞、血红蛋白等指标均无显著相关性。阿司匹林通过不可逆乙酰化环氧合酶-1,抑制TXA2合成,从而抑制血小板活化的同时间接抑制血小板表面P-选择素的表达。血小板P-选择素表达与阿司匹林抵抗之间呈正相关。
It is proved that aspirin can effectually prenvent the happening of myocardial infarction, cerebral apoplexy and other death of circulating system in many clinical trails. It is now used for the first-level and second-level prevention for thromboembolic disease. However, some patients still suffer from thromboembolic disease after regularly taking of aspirin because the existence of aspirin resistance. Our objective is to find out the prevalence and risk factors of aspirin resistance, and to investigate the correlationship between aspirin resistance and P-selection in platelet.
Methods 50 patients with coronary disease(male 26, female 24) intook aspirin 100mg/d for two weeks. Platelet aggregation (PAG) induced with adenosine diphosphate (ADP) were detected. According to PAG, CHD patients was divided into two subgroups: aspirin-resistant subgroup and aspirin-sensitive subgroup. P-selection expression was detected before and after treatment.
Results 9 patients(18%) showed AR.The prevalence was similar in male and famale(P=0.385). The blood LDL-C level(3.65±1.17 vs 2.93±1.03mmol/L, P=0.018), hypertension(66.7% vs 29.2%, P=0.03), total cholesterol level (5.43±1.6 vs 5.09±1.63mmol/L, P=0.042)and hemoglobin level(130±7.9 vs 139±14.75g/L, P=0.05)was higher in AR, compared with Aspirin sensitive patients. Logistic regression revealed that blood LDL-C level (or=3.26) and hypertension (or=3.89) were the independent factors of AR (P<0.05). The expression of P-selection was significantly higher in AR patients than in AS (2.97±1.64 vs 2.48±1.01, P=0.003). P-selection has no significant change in AR or AS groups before aspirin interference while they showed difference after interference respectively(2.97±1.64vs2.48±1.01, P=0.003). Group comparison revealed that P-selection level had no much difference before and after interference in AR subgroup(3.36±1.55 vs 2.97±1.64, P=0.08), compared with its significant deviation in AS subgroup(3.34±1.10 vs 2.48±1.01, P=0.03). Positive correlation was shown between PS and PAG in AR subgroup.
Conclusion The incidence rate of AR is 18% and there is no significant difference between male and female. The blood LDL-C level and hypertension are the independent factors of AR. The trail also reveals that AR has no relationship with the age, weight, blood glouse, platelet, leukocyte and hemoglobin. P-selection expression can be used as an effective standard of measuring AR. Aspirin reduces the activation and aggregation of platelets and inhibit the expression of P-selection indirectly by irreversibly acetylating cyclooxygenase-1 (COX-1),and thereby reduces TXA2 produced by platelets. Positive correlation exists between PS expression and AR.
引文
1 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 [J]. Ann Pharmacotherapy,2007, 41(5):737-741.
2 Hobikoglu G, Norgaz T, Aksu H, et al. High frequency of aspirin resistance in patients with acute coronary syndrome. Tohoku J Exp Med,2005,207 (1):59-64.
3 Angelino D, Fernandez-Ortiz A, Bernardo E, et al. Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention. Am J Cardiol,2006,97 (1):38-43.
4 王春波,胡大一,史旭波等.服用小剂量阿司匹林患者的阿司匹林抵抗.中国危重病急救医学,2006,18(4)：219-223.
5 Mirkhel A, Peyster E, Sundeen J, et al. Frequency of aspirin resistance in a community hospital. Am J Cardiol,2006,98(5):577-579.
6 Blake G J, Ridker P M, Novel clinical markers of vascular wall inflammation [J]. Circ Res, 2001,89(9):763-771.
7 Fijnheer F, Moore KL, Garabt M, et al. Structure and function of P-selectingly coprotein-ligand in unstable coronary disease[J]. Leuk Lymphoma,2005,29(122):11-15.
8 Gum PA, Kotter, Marchant K, Poggio ED, et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease [J]. Am J Cardiol,2001,88:230-235.
9 Howard PA. Aspirin resistance. Ann Pharmacother,2002,36 (100):1620-1624.
10 Cipolin F, Printer C. Overexpression of functionally coupled cycloxygenase-2 and prostaglandin E synthesis in synptomatic atherrosclerotic plaque as a basis of prostaglandin E2-dependent plaqueinstability[J]. Circulation,2001,104:921-927.
11 Macchi L, Sorel N, Christiaens L, et al. Aspirin resistance:definitions, mechanisms, prevalence, and clinical significance[J]. CurrPharm Des,2006,12 (2):251-258.
12 Hovens MM,Snoep JD, Eikenboom JC, et al. Prevalence of persistent platelet reactivity despite use of aspirin:asystematic review[J]. Am Heart J,2007,153(2):175-181.
13 Pamukcu B. Oflaz H, Onur I,et al. Aspirin-resistant platelet aggregation in a cohort of patients with coronary heart disease [J]. Blood Coagul Fibrinolysis,2007,18 (5):461-465.
14 Sadiq PA. Puri A, DixitM, et al. Profile and prevalence of aspirin resistance in Indian patients with coronary artery disease [J]. Indian Heart J,2005,57 (6):658-661.
15 Christiaens L, Macchi L, Herpin D, et al. Resistance to aspirin invitroatrestand during exercise in patients with angiographically proven coronary artery disease. Thromb Res.2002; 108 (2-3):115-119.
16 Payne DA, Jones CI, Hayes PD, et al. Platelet inhibition by aspirin is diminished in patients during carotid surgery:a form of transient aspirin resistance thromb haemost.2004; 92 (1) 89-96.
17 Maalej N, Folts JD. Increased shear stress overcomes the antithrombotic platelet inhibitory effect of aspirin in stenosed dog coronary arteries. Circulation 1996;93:1201-1205.
18辛晓敏,金玉英,张云平,等.阿司匹林抵抗与尿11-脱氢-血栓素B2的检测与相关性研究[J].中华检验医学杂志,2005,28(9)：919-921.
19 Eikelboom JW, Hirsh J, Weitz J, et al. Aspirin resistant thromboxane bio-synthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events[J].Circulation,2002,105:1650-1655.
20 Francis JL. Platelet Function Analyzer(PFA-100). In:Platelets. Michelson AD(ed.). Amsterdam:Academic Press,2002,325-335.
21 Blake G J, Ridker P M. Novel clinical markers of vascular wall inflammation [J]. Circ Res, 2001,89(9):763-771.
22 Jean-Francois T, Chahrour W, Yacoub D, et al. Recombinant P-selectingly coprotein-ligand-1 delays thrombin induced platelet aggregation:a new role for P-selectin in early aggregation. British J Pharmacology,2006,148:299-305.
23 Kabbani SS, Watkins MW, Holoch PA, et al. Platelet reactivity in coronary ostial blood:a reflection of the thrombotic state accompanying plaque rupture and of the adequacy of anti-thrombotic therapy [J].Thromb Thrombolysis,2001,12 (2):171-176.
24 Stellbaum C, Willich T, Boltzen U, et al.Clopidogrel-mediated reduction of circulating tissue factor in patients with stable coronary artery disease [J].Eur J Haematol,2007,78(4):347-352.
25 Van Der Zee PM, Biro E, Ko Y, et al. P-selection and CD63-exposing platelet micropaticles reflect platelet activation in perapheral aterial disease and myocardial infarction[J]. Clin Chem,2006,52(4):657-664.
26 Helgason CM, Bolin KM, Hoff JA, et al. Development of aspirin resistance in persons with previous ischemic stroke. Stroke,1994; 25:2331-2336.
1. NEngI J Med.2005;353:2372-2383.
2. Weber A-A, Aspirin and activated platelets. In:The Eicosanoids. Curtis-Prior P(ed.). London:John Wiley& Sons,2004.
3. Shimokawa T, Smith WL. Prostaglandin endoperoxide synthase. The aspirin acetylation region. J Biol Chem 1992; 267:12387-12392.
4. Metha J, Metha P, Burger C, et al. Platelet aggregation studies in coronary artery disease[J]. Atherosclerosis,1978,31:169-175.
5. Howard PA. Aspirin resistance. Ann Pharmacother,2002,36 (100):1620-1624.
6. Gum PA, Kottke-Marchant K, Poggio ED, et al. Profile and prevalence of aspirin resistance in patients with cardiovascur disease. Am J Cardiol,2001,88 (3):230-235.
7. 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 [J]. Ann Pharmacotherapy,2007,41 (5):737-741.
8. Hobikoglu G, Norgaz T, Aksu H, et al. High frequency of aspirin resistance in patients with acute coronary syndrome. Tohoku J Exp Med,2005,207 (1):59-64.
9. Angelino D, Fernandez-Ortiz A, Bernardo E, et al. Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention. Am J Cardiol,2006,97 (1):38-43.
10.王春波,胡大一,史旭波等.服用小剂量阿司匹林患者的阿司匹林抵抗.中国危重病急救医学,2006,18(4)：219-223.
11. Mirkhel A, Peyster E, Sundeen J, et al. Frequency of aspirin resistance in a community hospital. Am J Cardiol,2006,98(5):577-579.
12. Bhatt D, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nature Rev 2003; 2: 15-28.
13. Tran H, Anand S, Hankey G, et al. Aspirin resistance.Thrombosis Research,2007,120 (3): 337-346.
14. Hankey GJ. Eikeboom JW. Aspirin Resistance BMJ,2004,328(3):477.
15. Cattaneo M. Resistance to antiplatelet drugs:molecular mechanisms and laboratory detection[J]. J Thromb Haemost,2007,5(Suppl 1):230-237.
16. Weber A A, Przytulski B, Schanz A, et al. Towards a definition of aspirin resistance:a typological approach. Platelets,2002,13(1):37-40.
17. Patrono E, Morris ST. Jardine AG, et al. Cardiac and vescular abnormalities in renal transplant patients:diferential efects of cyclesporine and asathioprine[J]. J Nephrol.2000,13(3):185-192.
18. Pulcinelli FM, Riondino S. More on:aspirin resistance:position paper of the Working Group on Aspirin Resistance. Proposal for a laboratory Test Guiding Algorithm [J]. J Thromb Haemost,2006, 4(2):485-487.
19. Cotter G, Shemesh E, Zehavi M, et al. Lack of aspirin effect:aspirin resistance or resistance to taking aspirin?[J]. Am Heart J,2004,147(2):293-300.
20. Schwartz KA, Schwartz DE, Ghosheh K, et al. Complian ce as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction. Am J Cardiol,2005, 95(8):973-975.
21. Hart RG, Leonard AD, Talbert RL, et al. Aspirin dosage and thromboxane synthesis in patients with vascular disease[J]. Pharmo-otherapy,2003,23:579-584.
22. Topol EJ. A guide to therapeutic decision-making in patients with non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol 2003;41:S 123-129.
23. Lee PY, Chen WH, Ng W, et al. Low-dose aspirin increases aspirin resistance in patients with coronary artery disease[J]. Am J Med,2005,118(7):723-727.
24. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ,2002,324(7329):71-86.
25. Cox D, Maree AO, DooleyM, et al. Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers [J]. Stroke,2006,37 (8):2153-2158.
26. Karha J, Rajagopa V, Kottke-Marchant K, et al. Lack of effect of enteric coating on aspirin-induced inhibition of platelet aggregation in healthy volunteers[J]. Am Heart J,2006,151 (5):976.e7-976. e11.
27. Adebayo GI, Williams J, Healy S. Aspirin esterase activity-evidence for skewed distribution in healthy volunteers [J]. Eur J InternMed,2007,18 (4):299-303.
28. Capone ML, Sciulli MG, Tacconelli S, et al. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects[J]. J Am Coll Cardiol,2005,45 (8):1295-1301.
29. MacDonald TM, Wei L. Effect ibuprofen on cardioprotective effect of aspirin[J]. Lancet, 2003,361(9368):573-574.
30. Payne DA, Jones CI, Hayes PD, et al. Platelet inhibition by aspirin is diminished in patients duringcarotid surgery:A form of transient aspirin resistance?Thromb Haemost,2004,92(1):89-96.
31. Zimmermann N, Wenk A, Kim U, et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery [J]. Circulation,2003,108(5):542-547.
32. Rentrop KP. Thrombi in acute coronary syndromes:revisited and revised. Circulation 2000;101:1619-1626.
33. Poulsen TS, Mickley H. Is the antiplatelet effect of aspirin affected by systemic inflammation? [J]. Ann Hematol,2004,83 (11):728.
34. Cipollone F, Prontera C, Pina B, et al. Overexp ression of functionally coupled cyclooxygenase-2 and prostaglandin Esynthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E2dependent plaque instability[J]. Circulation,2001,104 (8):921-927.
35.谭真,黄德嘉,张敏,等.美洛昔康与小剂量阿司匹林联用对心血管病患者前列环素-血栓烷A2平衡的影响[J].心脏杂志,2005,17(4)：376-379,382.
36. Chanrasekharan NV, DaiH, Roos KL, et al.Cox-3, a cyclgelase-1 variant inhibited by acetam inophen and other analgesic/antipyretic drugs; cloning, structure, and expression[J]. Pree Nail Aead Sci,2002,99(21):13926-13931.
37. Kis B, Snipes JA, Busija DW. Acetaminophen and the cyclooxygenase-3 puzzle:sorting out facts, fictions, and uncertainties[J]. J Pharmacol Exp Ther,2005,315:1-7.
38. Davies NM, Good RL, Roupe KA, et al. Cyclooxygenase-3:axiom, dogma, anomaly, enigma or splice error?-not as easyasl,2,3[J]. J Pharm Pharm Sei,2004,7:217-226.
39. Poulsen TS, Mickley H. Is the antiplatelet effect of aspirin affected by systemic inflammation? [J]. Ann Hematol,2004,83 (11):728.
40. Marrow JD. Quantification of isoprostance as indices of oxidant stress and the risk of atherosclerosis in humans [J]. Arterioseler Thromb Vasc Biol,2005,2005 (2):279-286.
41. Wang TH, BhattDL, Topol EJ, et al. Aspirin and clopidogrel resistance:an emerging clinical entity[J]. Eur Heart J,2006,27 (7):647-654.
42. Maree AO, Curton RT, Chubb A, et al. Cyclooxygenase-1 haplocytemodulates platelet response to aspirin [J]. J Thromb Haemost,2005,3(10):2340-2345.
43. Cooke GE, Liu-Stratton Y, Ferketion AK, et al. Effect of platelet antigen polymorphism on platelet inhibition by aspirin, clopidogrel, or their combination [J]. J Am Coll Cardiol,2006,47 (3):541-546.
44. Jefferson BK, Foster JH, Mccarthy JJ, et al. Aspirin resistance and a single gene[J]. Am J Cardiol, 2005,95 (6):805-808.
45. Fontana P, Nolli S, Reber G, et al. Biological efects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers[J]. J Thromb Haemost,2006,4(4):813-819.
46. PulcineUi FM, Pignatelli P, Celestini A, et al. Inhibition of platelet aggregation by aspirin progressively decreases in long-term treated patients[J]. J Am Cardiol,2004,43(6):979-984.
47. Pulcinelli FM, Riondino S, Celestini A, et al. Persistent production of platelet thromboxane A2 in patients chronically treated with aspirin[J]. J Thromb Haemost,2005,3(12):2784-2789.
48. FitzGerald GA. Parsing an enigma:the pharmacodynamics of aspirin resistance. Lancet 2003;361: 542-544.
49. Michelson AD, CattaneoM, Eikelboom JW, et al. Aspirin resistance:position paper of the Working Group on Aspirin Resistance[J]. J Thromb Haemost,2005,3(6):1309-1311.
50. Gum PA, Kottke, Marchant K, Welsh PA, et al. Aprospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease[J]. J Am Coll Cardiol,2003,41 (6):961-965.
51. Ivandic BT, Giannitsis E, Schlick P, et al. Determination of aspirin responsiveness by use of whole blood platelet aggregometry[J]. Clin Chem,2007,53 (4):614-619.
52. Fritsma GA, Ens GE, Alvord MA, et al. Monitoring the antiplatelet action of aspirin. Jaapa,2001, 14(5):57-62.
53. Tohgi H, Konno S, Tamura K, et al. Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxaneA2 and prostacyclin [J]. Stroke,1992,23:1400-1403.
54. Eikelboom JW, Hirsh J, Weitz J I, et al. Aspirin resistant thromboxane biosynthesis and risk of myocardial infarction,stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation,2002,105 (14):1650-1655.
55. Coma-Canella, Velasco A, Castano S. Prevalence of aspirin resistance measured by PFA-100. Int J Cardiol,2005,101:71-76.
56. FeuringM, SchultzA, Losel R, et al. Monitoring acetylsalicylic acid effects with the platelet function analyzer PFA-100 [J]. Semin Thromb Hemost,2005,31 (4):411-415.
57. Coleman JL, Wang JC, Simon DI. Determination of individual response to aspirin therapy using the Accumetrics Ultegra RPFA-ASA system [J]. Point Care,2004,3 (2):77-82.
58. Koscielny J, Aslan T, Meyer O, et al. Use of the platelet reactivity index by Grotemeyer, platelet function analyzer, and retention test Homburg to monitor therapy with antiplatelet drugs. Semin Thromb Hemosst,2005,31 (4):464-469.
59. Michelson AD, Barmard MR, Krueger LA, et al. Evaluation of platelet function by flow cytometry [J]. Methods,2000,21 (3):259-270.
60. Ahnadi CE, Boughrassa FF, Chapman-Montgomery ES, et al. Comparison of two methods to assess variability of platelet response to anti-platelet therapies in patients with acute coronary syndrome undergoing angioplasty[J]. Thromb Haemost,2004,92 (6):1207-1213.
61. Lordkipanidze M, Pharand C, Schanpaert 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[J]. Eur Heart J,2007,28(14):1702-1708.
62. Harrison P, Segal H, Silver L, et al. Lack of reproducibility of assessment of aspirin responsiveness by optical aggregometry and two platelet function tests[J]. Platelets,2008,19(2):119-124.
63. Macchi L, Sorel N, Christiaens L, et al. Aspirin resistance:definitions, mechanisms, prevalence, and clinical significance [J]. CurrPharm Des,2006,12 (2):251-258.
64. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
65. 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.
66. Kra Sopoulos G, Brister S J, Beattie S, et al. Aspirin "resistance" and risk of cardiovascular morbidity:systematic review and meta-analysis [J]. BMJ,2008,336 (7637):195-198.
67. Bradbury J. Aspirin resistance may increase death risk in some patients with heart disease [J]. Lancet,2002,359 (9312):1128.
68. Snoep J D, Howwen M, Eikenboom J C, et al. Association of laborato redefined aspirin resistance with a higher risk of recurrent cardiovascular events:a systematic review and meta-analysis[J]. Arch Intern Med,2007,167 (15):1593-1599.
69. Pulcin Elli F M, Pignatell I P, Cel estinia, et al. Inhibition of platelet aggregation by aspirin progressively decreases in long-term treated patients [J]. J Am Coll Cardio,2004,43:979-984.
70. Coma-can Ella, Velasca. Variability in individual responsiveness to aspirin:clinical implications and treatment [J]. Cardiovasc Hemato ID is ord Drug Targets.2007,7 (4):274-287.
71. Peters RJ, Mehta SR, Fox KA, 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[J]. Circulation,2003,108 (14) 1682-1687.
72. Sanderson S, Emery J,Baglin T, et al. Narrative review:aspirin resistance and its clinical implications [J]. Ann InternMed,2005,142 (5):370-380.
73. Gasparyan AY, Watson T, Lip GY. The role of aspirinin cardiovascular prevention:implications of aspirin resistance[J]. J Am Coll Cardio,2008,51 (19):1829-1843.
74. Fitzgerald GA. Parsing an enigma:the pharmacodynamics of aspirin resistance[J]. Lancet,2003, 361 (9357):542-544.
75. Schwartz KA, Schwartz DE, Ghosheh K, et al. Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction[J]. Am J Cardiol,2005, 95(8):973-975.
76. Ellahham S. Role of antiplatelet agents in the primary and secondary prevention of atherothrombotic events in high risk-patients[J]. South Med J,2008,101(3):273-283.
