冠状动脉支架术后抗血小板药物抵抗的诊断及干预研究
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摘要
研究背景和目的抗血小板治疗可显著降低冠状动脉支架术后血栓事件的发生率,但约5%~35%的病人由于存在抗血小板药物抵抗而导致血栓事件风险明显增高。目前对抗血小板药物抵抗的诊断方法尚不普及、诊断标准不统一,且缺乏理想的干预手段。本研究旨在筛选简便、可靠的抗血小板药物抵抗诊断方法,分析抗血小板药物抵抗与临床高危因素的相关性并初步探索对抗血小板药物抵抗进行临床干预的有效性和安全性。
方法2006年6月至2007年2月,前瞻性入选行冠状动脉支架术病人305例,分别于抗血小板药物治疗前及治疗后24h测定血小板功能,主要指标包括CD62P、血小板活化复合物(PAC)-1的表达及20μmol/L ADP诱导的血小板聚集率(IPA),以治疗前后20μmol/L ADP诱导的IPA变化值小于10%作为诊断氯吡格雷抵抗(CR)金标准。病人入选后随机分入优化抗血小板治疗组(n=154)及标准治疗组(n=151)。标准治疗组所有病例均采用标准阿司匹林、氯吡格雷两联抗血小板治疗;优化治疗组病人根据血小板功能检查结果分为CR和非CR,非CR病人抗血小板治疗方案与标准治疗组相同,CR病人在常规两联治疗基础上加用西洛他唑6个月。研究主要终点为随访1年时的死亡、心肌梗死(MI)和缺血性卒中复合终点。次要终点包括(1)随访1年时的死亡、MI、症状驱动的血运重建、缺血性卒中及外周动脉闭塞的复合终点。(2)TIMI出血事件发生率。(3)亚急性支架内血栓(SAT)及迟发性支架内血栓发生率。
结果(1)入选病人CR发生率为23.8%。受试者操作特征曲线(ROC)分析表明,CD62P及PAC-1诊断CR的价值不大,而用药后测定的20μmol/L ADP诱导的IPA与金标准相比,曲线下面积(AUC)为0.878,临界值为>71.8%,诊断CR的敏感性和特异性分别为77.8%和85.2%。(2)多因素分析结果显示,年龄≥65岁[比值比(OR)=10.31, 95%可信区间(CI)= 4.265- 24.926, P<0.001]、糖尿病(OR=9.3, 95%CI= 3.413-25.344, P<0.001)、既往缺血病史(OR=7.139, 95%CI=2.658-19.180, P<0.001)、肌钙蛋白T(TnT)阳性(OR=7.6, 95%CI=1.505-38.391, P=0.014)、多支病变(OR=2.355, 95%CI=1.054- 5.261, P=0.037)是CR的临床预测因素。以临床预测因素个数≥2作为CR判别标准,与金标准相比AUC为0.899,敏感性和特异性分别达86.5%和79.7%。(3)优化治疗组主要终点事件风险较标准治疗组下降37%(5.8%比9.3%),但差异无统计学显著意义(P=0.257)。优化治疗组与标准治疗组的死亡(1.9%比2.6%, P=0.489)、MI(2.6%比4.6%,P=0.340)及缺血性卒中(1.3%比2.0,P=0.491)发生率均无显著差别。两组心性死亡、MI、缺血性卒中、缺血驱动的血运重建及下肢动脉闭塞的复合终点事件发生率无显著差异[9.7%(15/154)比14.6(22/151),P=0.197],但在优化治疗组中有降低趋势。两组支架血栓及出血事件均无差异。优化治疗组和对照组CR病例数分别为41例(26.6%)和33例(21.9%),在两联抗血小板治疗基础上加用西洛他唑可显著降低CR病人的IPA[(77.5±12.1)%比(64.5±12.1)%,P<0.001]。优化治疗组CR病人的主要终点事件与对照组CR病人相比无统计学显著意义[19.5%(8/41)比36.4%(12/33), P=0.105],但有降低趋势[相对风险(RR)= 54%,95%CI:0.25-1.16]。
结论用药后单次测定20μmol/L ADP诱导的IPA可作为CR的诊断标准。年龄≥65岁、糖尿病、既往缺血病史、TnT阳性、多支病变是CR的临床预测因素,存在危险因素越多,临床存在CR的风险越高。根据IPA测定值调整抗血小板治疗方案(对CR病人进行强化的三联抗血小板治疗)可能有利于改善长期预后,但其有效性和安全性还需大样本临床研究证实。
Background and Objectives Antiplatelet therapy significantly decreases the incidence of thrombotic events after coronary stenting. However, about 5%~35% of patients were associated with an increased risk of thrombotic events because of antiplatelet resistance. At present, there was no uniform diagnosis standard of antiplatelet resistance, as well as effective therapeutic methods. The present study was aimed to screen effective and convenient diagnosis measures of aniplatelet resistance, to analyze the relationship between antiplatelet resistance and clinical risk factors, and to explore the efficacy and safety of optimal anitplatelet therapy in managing antiplatelet resistance.
Methods Between June 2006 and February 2007, a total of 305 patients who underwent coronary stenting were prospectively enrolled. Expression of platelet CD62P, platelet activated complex -1(PAC-1) and 20μmol/L ADP induced platelet aggregation (IPA) were assayed before and 24 h after administration of antiplatelet agents. An absolute reduction of IPA <10% compared with baseline was served as the golden standard of the diagnosis of clopidogrel resistance (CR). Enrolled patients were randomly assigned to receive optimal (optimal group, n=154) or standard antiplatelet therapy (standard group, n=151). The antiplatelet regimen of standard group was dual antiplatelet therapy with aspirin and clopidogrel. Antiplatelet therapy for the patients in optimal group depended on the results of IPA assay: patients with CR were received cilostazol for 6 months in addition to dual anitplatelet therapy, whereas non-CR patients received standard dual antiplatelet therapy. The primary endpoint was the composite of death, myocardial infarction (MI) and stroke at 1 year. The secondary end points was the composite of death, MI, ischemic driven revascularization, stroke and peripheral artery occlusions, TIMI hemorrhagic events, subacute and late stent thrombosis.
Results (1) The incidence of CR was 23.8%. Recipient operation characteristic curve showed that CD62P and PAC-1 were not valuable in diagnosis of CR. However, post therapy IPA induced by 20μmol/L ADP was valuable for the diagnosis of CR with an area under curve of 0.878 and cutoff value of 71.8%. The sensitivity and specificity were 77.8% and 85.2%, respectively. (2) Multivariate analysis demonstrated that≥65 years old (OR=10.31, 95%CI= 4.265- 24.926, P<0.001), diabetes (OR=9.3, 95%CI= 3.413-25.344, P<0.001), history of ischemic events (OR=7.139, 95%CI= 2.658-19.180, P<0.001), positive TnT (OR=7.6, 95%CI=1.505-38.39, P=0.014) and multivessel disease (OR=2.355, 95%CI=1.054- 5.261, P=0.037) were predictors of CR. Two or more risk above mentioned risk factors strongly predicted CR (AUC 0.899, sensitivity of 86.5% and specificity of 79.7%). (3) Patients in optimal group were associated with a 37% reduction in the risk of primary events compared with their counterparts in standaardl group (5.8% vs. 9.3%, P=0.257). The rates of death (1.9% vs. 2.6%, P=0.489), M(I2.6% vs. 6%, P=0.340)and ischemic stroke(1.3% vs. 2.0,P=0.491)were not significantly different between the two groups. Optimal group was also associated with a tendency of decreased incidence of secondary end points [9.7%(15/154) vs. 14.6(22/151),P=0.197]. There was no difference in the rates of stent thrombosis and hemorrhagic events between the two groups. 41(26.6%)patients in the optimal group and 33(21.9%) in the standardl group were diagnosed as CR according to IPA assay. In CR patients, IPA were significantly reduced after cilostazol treatment [(77.5±12.1)% vs. (64.5±12.1)%,P<0.001]. CR patients in optimal group had a lower but not statistically significant incidence of primary events [19.5%(8/41)比36.4%(12/33), RR= 54%,95%CI:0.25-1.16, P=0.105].
Conclusions IPA induced by 20μmol/L ADP after antiplatelet treatment is reasonable to be served as the diagnosis standard of CR. Clinical risk factors such as≥65 years old, diabetes, history of ischemic events, TnT positive and multivessel coronary artery disease are predictors of CR and the number of the risk factors are associated with the risk of CR. Adjusting antiplatelet regimen according to IPA assay results might be effective in improving long-term outcomes for patients undergoing coronary stenting, especially for those diagnosed as CR. However, the effectiveness and safety need further confirmation by clinical trials with large sample size.
方法2006年6月至2007年2月,前瞻性入选行冠状动脉支架术病人305例,分别于抗血小板药物治疗前及治疗后24h测定血小板功能,主要指标包括CD62P、血小板活化复合物(PAC)-1的表达及20μmol/L ADP诱导的血小板聚集率(IPA),以治疗前后20μmol/L ADP诱导的IPA变化值小于10%作为诊断氯吡格雷抵抗(CR)金标准。病人入选后随机分入优化抗血小板治疗组(n=154)及标准治疗组(n=151)。标准治疗组所有病例均采用标准阿司匹林、氯吡格雷两联抗血小板治疗;优化治疗组病人根据血小板功能检查结果分为CR和非CR,非CR病人抗血小板治疗方案与标准治疗组相同,CR病人在常规两联治疗基础上加用西洛他唑6个月。研究主要终点为随访1年时的死亡、心肌梗死(MI)和缺血性卒中复合终点。次要终点包括(1)随访1年时的死亡、MI、症状驱动的血运重建、缺血性卒中及外周动脉闭塞的复合终点。(2)TIMI出血事件发生率。(3)亚急性支架内血栓(SAT)及迟发性支架内血栓发生率。
结果(1)入选病人CR发生率为23.8%。受试者操作特征曲线(ROC)分析表明,CD62P及PAC-1诊断CR的价值不大,而用药后测定的20μmol/L ADP诱导的IPA与金标准相比,曲线下面积(AUC)为0.878,临界值为>71.8%,诊断CR的敏感性和特异性分别为77.8%和85.2%。(2)多因素分析结果显示,年龄≥65岁[比值比(OR)=10.31, 95%可信区间(CI)= 4.265- 24.926, P<0.001]、糖尿病(OR=9.3, 95%CI= 3.413-25.344, P<0.001)、既往缺血病史(OR=7.139, 95%CI=2.658-19.180, P<0.001)、肌钙蛋白T(TnT)阳性(OR=7.6, 95%CI=1.505-38.391, P=0.014)、多支病变(OR=2.355, 95%CI=1.054- 5.261, P=0.037)是CR的临床预测因素。以临床预测因素个数≥2作为CR判别标准,与金标准相比AUC为0.899,敏感性和特异性分别达86.5%和79.7%。(3)优化治疗组主要终点事件风险较标准治疗组下降37%(5.8%比9.3%),但差异无统计学显著意义(P=0.257)。优化治疗组与标准治疗组的死亡(1.9%比2.6%, P=0.489)、MI(2.6%比4.6%,P=0.340)及缺血性卒中(1.3%比2.0,P=0.491)发生率均无显著差别。两组心性死亡、MI、缺血性卒中、缺血驱动的血运重建及下肢动脉闭塞的复合终点事件发生率无显著差异[9.7%(15/154)比14.6(22/151),P=0.197],但在优化治疗组中有降低趋势。两组支架血栓及出血事件均无差异。优化治疗组和对照组CR病例数分别为41例(26.6%)和33例(21.9%),在两联抗血小板治疗基础上加用西洛他唑可显著降低CR病人的IPA[(77.5±12.1)%比(64.5±12.1)%,P<0.001]。优化治疗组CR病人的主要终点事件与对照组CR病人相比无统计学显著意义[19.5%(8/41)比36.4%(12/33), P=0.105],但有降低趋势[相对风险(RR)= 54%,95%CI:0.25-1.16]。
结论用药后单次测定20μmol/L ADP诱导的IPA可作为CR的诊断标准。年龄≥65岁、糖尿病、既往缺血病史、TnT阳性、多支病变是CR的临床预测因素,存在危险因素越多,临床存在CR的风险越高。根据IPA测定值调整抗血小板治疗方案(对CR病人进行强化的三联抗血小板治疗)可能有利于改善长期预后,但其有效性和安全性还需大样本临床研究证实。
Background and Objectives Antiplatelet therapy significantly decreases the incidence of thrombotic events after coronary stenting. However, about 5%~35% of patients were associated with an increased risk of thrombotic events because of antiplatelet resistance. At present, there was no uniform diagnosis standard of antiplatelet resistance, as well as effective therapeutic methods. The present study was aimed to screen effective and convenient diagnosis measures of aniplatelet resistance, to analyze the relationship between antiplatelet resistance and clinical risk factors, and to explore the efficacy and safety of optimal anitplatelet therapy in managing antiplatelet resistance.
Methods Between June 2006 and February 2007, a total of 305 patients who underwent coronary stenting were prospectively enrolled. Expression of platelet CD62P, platelet activated complex -1(PAC-1) and 20μmol/L ADP induced platelet aggregation (IPA) were assayed before and 24 h after administration of antiplatelet agents. An absolute reduction of IPA <10% compared with baseline was served as the golden standard of the diagnosis of clopidogrel resistance (CR). Enrolled patients were randomly assigned to receive optimal (optimal group, n=154) or standard antiplatelet therapy (standard group, n=151). The antiplatelet regimen of standard group was dual antiplatelet therapy with aspirin and clopidogrel. Antiplatelet therapy for the patients in optimal group depended on the results of IPA assay: patients with CR were received cilostazol for 6 months in addition to dual anitplatelet therapy, whereas non-CR patients received standard dual antiplatelet therapy. The primary endpoint was the composite of death, myocardial infarction (MI) and stroke at 1 year. The secondary end points was the composite of death, MI, ischemic driven revascularization, stroke and peripheral artery occlusions, TIMI hemorrhagic events, subacute and late stent thrombosis.
Results (1) The incidence of CR was 23.8%. Recipient operation characteristic curve showed that CD62P and PAC-1 were not valuable in diagnosis of CR. However, post therapy IPA induced by 20μmol/L ADP was valuable for the diagnosis of CR with an area under curve of 0.878 and cutoff value of 71.8%. The sensitivity and specificity were 77.8% and 85.2%, respectively. (2) Multivariate analysis demonstrated that≥65 years old (OR=10.31, 95%CI= 4.265- 24.926, P<0.001), diabetes (OR=9.3, 95%CI= 3.413-25.344, P<0.001), history of ischemic events (OR=7.139, 95%CI= 2.658-19.180, P<0.001), positive TnT (OR=7.6, 95%CI=1.505-38.39, P=0.014) and multivessel disease (OR=2.355, 95%CI=1.054- 5.261, P=0.037) were predictors of CR. Two or more risk above mentioned risk factors strongly predicted CR (AUC 0.899, sensitivity of 86.5% and specificity of 79.7%). (3) Patients in optimal group were associated with a 37% reduction in the risk of primary events compared with their counterparts in standaardl group (5.8% vs. 9.3%, P=0.257). The rates of death (1.9% vs. 2.6%, P=0.489), M(I2.6% vs. 6%, P=0.340)and ischemic stroke(1.3% vs. 2.0,P=0.491)were not significantly different between the two groups. Optimal group was also associated with a tendency of decreased incidence of secondary end points [9.7%(15/154) vs. 14.6(22/151),P=0.197]. There was no difference in the rates of stent thrombosis and hemorrhagic events between the two groups. 41(26.6%)patients in the optimal group and 33(21.9%) in the standardl group were diagnosed as CR according to IPA assay. In CR patients, IPA were significantly reduced after cilostazol treatment [(77.5±12.1)% vs. (64.5±12.1)%,P<0.001]. CR patients in optimal group had a lower but not statistically significant incidence of primary events [19.5%(8/41)比36.4%(12/33), RR= 54%,95%CI:0.25-1.16, P=0.105].
Conclusions IPA induced by 20μmol/L ADP after antiplatelet treatment is reasonable to be served as the diagnosis standard of CR. Clinical risk factors such as≥65 years old, diabetes, history of ischemic events, TnT positive and multivessel coronary artery disease are predictors of CR and the number of the risk factors are associated with the risk of CR. Adjusting antiplatelet regimen according to IPA assay results might be effective in improving long-term outcomes for patients undergoing coronary stenting, especially for those diagnosed as CR. However, the effectiveness and safety need further confirmation by clinical trials with large sample size.
引文
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38. Weber AA, Zimmermann KC, Kirchrath JM et al. Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet 1999; 353:900.
39. Maree AO, Curtin RJ, Chubb A, et al. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost. 2005;3(10):2340-5.
40. Jefferson BK, Foster JH, McCarthy JJ, et al. Aspirin resistance and a single gene. Am J Cardiol. 2005;95(6):805-8.
41. Fontana P, Dupont A, Gandrille S, et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation. 2003; 108(8):989-95.
42. Hetherington SL, Singh RK, Lodwick D, et al. Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arterioscler Thromb Vasc Biol. 2005;25(1):252-7.
43. Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation. 2004; 109(2): 166-71.
44. Pamukcu B, Oflaz H, Nisanci Y. The role of platelet glycoprotein IIIa polymorphism in the high prevalence of in vitro aspirin resistance in patients with intracoronary stent restenosis. Am Heart J. 2005; 149(4):675-80.
45. Barragan P, Bouvier JL, Roquebert PO, et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003;59:295–302.
46. Michelson AD. Platelet function testing in cardiovascular diseases. Circulation 2004;110:e489–93.
47. Smith JW, Steinhubl SR, Lincoff AM, et al. Rapid platelet-function assay: an automated and quantitative cartridge-based method. Circulation 1999;99:620–5.
48. von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation. 2005 ;112(19): 2946-50.
49. Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol. 2006;48(5):931-8.
50. Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose ofclopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation, 2005, 111(16):2099-2106.
51. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol. 2006;47(1):e1-121.
52. Silber S, Albertsson P, Avilés FF, et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J. 2005;26(8):804-47.
53. von Beckerath N, Kastrati A, Wieczorek A, et al. A double-blind randomized study on platelet aggregation in patients treated with a daily dose of 150 or
75 mg of clopidogrel for 30 days. Eur Heart J 2007; 28: 1814-9.
54. Angiolillo DJ, Shoemaker SB, Desai B, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation. 2007;115(6):708-16.
55. Campo G, Valgimigli M, Gemmati D, et al. Poor responsiveness to clopidogrel: drug-specific or class-effect mechanism? Evidence from a clopidogrel-to-ticlopidine crossover study. J Am Coll Cardiol. 2007;50(12):1132-7.
56. Lee SW, Park SW, Hong MK, et al. Comparison of cilostazol and clopidogrel after successful coronary stenting. Am J Cardiol. 2005;95(7):859-62.
57. Jakubowski JA, Winters KJ, Naganuma H, et al. Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev. 2007 ;25(4):357-74.
58. Lee SW, Park SW, Hong MK, et al. Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis. J Am Coll Cardiol, 2005, 46(10):1833-1837.
59.韩雅玲,苏庆丰,李毅,等.冠状动脉介入治疗术后三联抗血小板治疗的近期疗效.中华医学杂志, 2006, 86 (31):1093-1096.
60. Born GVR. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962;194:927–929.
61. O’Brien JR. Platelet aggregation. Part II: some results of a new method. J Clin Pathol 1962;15:452– 455.
62. Muller I, Besta F, Schulz C, et al. Prevalence of clopidogrel nonresponders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89:783-7.
63. Wenaweser P, Dorffler-Melly J, Imboden K, et al. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol 2005;45:1748 - 52.
64. Lev EI, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006; 47:27– 33.
65. Geisler T, Langer H, Wydymus M, et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006;27:2420 -5.
66. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading dose ofclopidogrel on platelet reactivity and clinical outcomes in patients with non–ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006;48: 1339- 45.
67. Michelson AD, Barnard MR, Krueger LA, et al. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001;104:1533–7.
68. Smith JW, Steinhubl SR, Lincoff AM, et al. Rapid platelet-function assay: an automated and quantitative cartridge-based method. Circulation 1999;99:620–5.
69. Kereiakes DJ, Mueller M, HowardW, et al. Efficacy of abciximab induced platelet blockade using a rapid point of care assay. J Thromb Thrombolysis 1999;7:265–76.
70. Coller BS, Lang D, Scudder LE. Rapid and simple platelet function assay to assess glycoprotein IIb/IIIa receptor blockade. Circulation 1997;95:860–7.
71. Harrison P. The role of PFA-100 testing in the investigation and management of haemostatic defects in children and adults. Br J Haematol 2005;130:3-10.
72. Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction. J Lab Clin Med 2001;138:152–63.
73. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000;284(7):835-42.
74. Prabhakaran S, Wells KR, Lee VH, et al. Prevalence and risk factors for aspirin and clopidogrel resistance in cerebrovascular stenting. AJNR Am J Neuroradiol. 2008;29(2):281-5.
75. Angiolillo DJ, Bernardo E, Ramirez C, et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. J Am Coll Cardiol 2006;48:298–304.
76. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007 Aug 14;50(7):e1-e157.
77. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand JP, Hamm CW, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J. 2007 ;28(13):1598-660.
78. Kannan S. Inflammation: a novel mechanism for the transport of extracellular nucleotide-induced arachidonic acid by S100A8/A9 for transcellular metabolism. Cell Biol Int 2003;27:593–5.
79. Lee SW, Park SW, Kim YH, et al. Comparison of triple versus dual antiplatelet therapy after drug-eluting stent implantation (from the DECLARE-Long trial). Am J Cardiol. 2007;100(7):1103-8. 80. Lee SW, Park SW, Kim YH, et al. Drug-eluting stenting followed bycilostazol treatment reduces late restenosis in patients with diabetes mellitus the DECLARE-DIABETES Trial (A Randomized Comparison of Triple Antiplatelet Therapy with Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in Diabetic Patients). J Am Coll Cardiol. 2008;51(12):1181-7.
81. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA. 2006 5;295(13):1531-8.
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33. Davis JW, Hartman CR, Lewis HD et al. Cigarette smoking-induced enhancement of platelet functiotion: lack of prevention by aspirin in men with coronary artery disease. J Lab Clin Med 1985; 105:479–483.
34. Kawasaki T, Ozeki Y, Igawa T et al. Increased platelet sensitivity to collagenin individuals resistant to low-dose aspirin. Stroke 2000;31:591–595.
35. Macchi L, Christiaens L, Brabant S et al. Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. Thromb Res 2002; 107:45–49.
36. Valles J, Santos MT, Aznar 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; 97:350–355.
37. Cipollone F, Ciabattoni G, Patrignani P et al. Oxidant stres and aspirin-insensitive thromboxane biosynthesis in severe unstable angina. Circulation 2000;102:1007–1013.
38. Weber AA, Zimmermann KC, Kirchrath JM et al. Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet 1999; 353:900.
39. Maree AO, Curtin RJ, Chubb A, et al. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost. 2005;3(10):2340-5.
40. Jefferson BK, Foster JH, McCarthy JJ, et al. Aspirin resistance and a single gene. Am J Cardiol. 2005;95(6):805-8.
41. Fontana P, Dupont A, Gandrille S, et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation. 2003; 108(8):989-95.
42. Hetherington SL, Singh RK, Lodwick D, et al. Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arterioscler Thromb Vasc Biol. 2005;25(1):252-7.
43. Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation. 2004; 109(2): 166-71.
44. Pamukcu B, Oflaz H, Nisanci Y. The role of platelet glycoprotein IIIa polymorphism in the high prevalence of in vitro aspirin resistance in patients with intracoronary stent restenosis. Am Heart J. 2005; 149(4):675-80.
45. Barragan P, Bouvier JL, Roquebert PO, et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003;59:295–302.
46. Michelson AD. Platelet function testing in cardiovascular diseases. Circulation 2004;110:e489–93.
47. Smith JW, Steinhubl SR, Lincoff AM, et al. Rapid platelet-function assay: an automated and quantitative cartridge-based method. Circulation 1999;99:620–5.
48. von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation. 2005 ;112(19): 2946-50.
49. Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol. 2006;48(5):931-8.
50. Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose ofclopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation, 2005, 111(16):2099-2106.
51. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol. 2006;47(1):e1-121.
52. Silber S, Albertsson P, Avilés FF, et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J. 2005;26(8):804-47.
53. von Beckerath N, Kastrati A, Wieczorek A, et al. A double-blind randomized study on platelet aggregation in patients treated with a daily dose of 150 or
75 mg of clopidogrel for 30 days. Eur Heart J 2007; 28: 1814-9.
54. Angiolillo DJ, Shoemaker SB, Desai B, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation. 2007;115(6):708-16.
55. Campo G, Valgimigli M, Gemmati D, et al. Poor responsiveness to clopidogrel: drug-specific or class-effect mechanism? Evidence from a clopidogrel-to-ticlopidine crossover study. J Am Coll Cardiol. 2007;50(12):1132-7.
56. Lee SW, Park SW, Hong MK, et al. Comparison of cilostazol and clopidogrel after successful coronary stenting. Am J Cardiol. 2005;95(7):859-62.
57. Jakubowski JA, Winters KJ, Naganuma H, et al. Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev. 2007 ;25(4):357-74.
58. Lee SW, Park SW, Hong MK, et al. Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis. J Am Coll Cardiol, 2005, 46(10):1833-1837.
59.韩雅玲,苏庆丰,李毅,等.冠状动脉介入治疗术后三联抗血小板治疗的近期疗效.中华医学杂志, 2006, 86 (31):1093-1096.
60. Born GVR. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962;194:927–929.
61. O’Brien JR. Platelet aggregation. Part II: some results of a new method. J Clin Pathol 1962;15:452– 455.
62. Muller I, Besta F, Schulz C, et al. Prevalence of clopidogrel nonresponders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89:783-7.
63. Wenaweser P, Dorffler-Melly J, Imboden K, et al. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol 2005;45:1748 - 52.
64. Lev EI, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006; 47:27– 33.
65. Geisler T, Langer H, Wydymus M, et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006;27:2420 -5.
66. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading dose ofclopidogrel on platelet reactivity and clinical outcomes in patients with non–ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006;48: 1339- 45.
67. Michelson AD, Barnard MR, Krueger LA, et al. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001;104:1533–7.
68. Smith JW, Steinhubl SR, Lincoff AM, et al. Rapid platelet-function assay: an automated and quantitative cartridge-based method. Circulation 1999;99:620–5.
69. Kereiakes DJ, Mueller M, HowardW, et al. Efficacy of abciximab induced platelet blockade using a rapid point of care assay. J Thromb Thrombolysis 1999;7:265–76.
70. Coller BS, Lang D, Scudder LE. Rapid and simple platelet function assay to assess glycoprotein IIb/IIIa receptor blockade. Circulation 1997;95:860–7.
71. Harrison P. The role of PFA-100 testing in the investigation and management of haemostatic defects in children and adults. Br J Haematol 2005;130:3-10.
72. Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction. J Lab Clin Med 2001;138:152–63.
73. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000;284(7):835-42.
74. Prabhakaran S, Wells KR, Lee VH, et al. Prevalence and risk factors for aspirin and clopidogrel resistance in cerebrovascular stenting. AJNR Am J Neuroradiol. 2008;29(2):281-5.
75. Angiolillo DJ, Bernardo E, Ramirez C, et al. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. J Am Coll Cardiol 2006;48:298–304.
76. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007 Aug 14;50(7):e1-e157.
77. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand JP, Hamm CW, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J. 2007 ;28(13):1598-660.
78. Kannan S. Inflammation: a novel mechanism for the transport of extracellular nucleotide-induced arachidonic acid by S100A8/A9 for transcellular metabolism. Cell Biol Int 2003;27:593–5.
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