血栓弹力图评价脑梗死患者阿司匹林、氯吡格雷及其联合应用抗血小板治疗的作用研究

目的探讨采用血栓弹力图测定血小板抑制率评价脑梗死患者口服阿司匹林、氯吡格雷单药及其合用双联抗血小板治疗的作用。方法 98例住院的急性脑梗死患者按口服抗血小板药物分为阿司匹林组(39例)、氯吡格雷组(37例)及氯吡格雷+阿司匹林组(22例)。在患者服药21 d时,采用血栓弹力图仪(TEG-5000)检测花生四烯酸(AA)途径和二磷酸腺苷(ADP)途径诱导的血小板抑制率值,并与正常对照组(52人)进行比较。结果阿司匹林组和阿司匹林+氯吡格雷组AA途径诱导的血小板抑制率均显著高于正常对照组及氯吡格雷组(均P 0. 05)。氯吡格雷组和阿司匹林+氯吡格雷组ADP途径诱导的抑制率均明显高于正常对照组(均P 0. 05)。结论血栓弹力图可用于评价临床抗血小板药物的效果。服用阿司匹林能起到很好的抗血小板作用,氯吡格雷的效果稍差;而阿司匹林联合氯吡格雷的抗血小板作用更强。     

缺血性脑卒中患者阿司匹林或氯吡格雷及其联合应用抗血小板治疗的研究

目的 研究缺血性脑卒中患者阿司匹林或氯吡格雷及其联合应用抗血小板治疗的效果.方法 180例缺血性脑卒中患者分为阿司匹林组(阿司匹林肠溶片100 mg/d)、氯吡格雷组(氯吡格雷75 mg/d)和联合用药组(阿司匹林肠溶片+氯吡格雷,剂量相同);每组60例.在治疗前、治疗14 d后,用血栓弹力图检测患者的花生四烯酸(AA)和二磷酸腺苷(ADP)途径诱导的血小板抑制率.结果 治疗后,3组AA、ADP途径诱导的血小板抑制率显著高于治疗前(均P＜0.05);3组间AA、ADP途径诱导的血小板抑制率的差异有统计学意义(均P＜0.05).联合用药组和阿司匹林组AA途径诱导的血小板抑制率显著高于氯吡格雷组(均P＜0.05);联合用药组和氯吡格雷组ADP途径诱导的血小板抑制率显著高于阿司匹林组(均P＜0.05);联合用药组与阿司匹林组AA途径、联合用药组与氯吡格雷组ADP途径诱导的血小板抑制率的差异无统计学意义.结论 阿司匹林和氯吡格雷对缺血性脑卒中患者均有显著的抗血小板作用;而阿司匹林联合氯吡格雷能从两个途径抑制血小板聚集,抗血小板的效果更好.     

缺血性卒中患者因氯吡格雷低反应性改为高维持量及替格瑞洛后血小板抑制率变化

目的探讨用血栓弹力图评价符合双抗治疗的缺血性脑血管病患者,因氯吡格雷低反应性,改为高维持剂量及改服替格瑞洛后血小板抑制率的变化。方法选择符合双抗治疗的缺血性脑血管病患者联合应用抗血小板制剂(阿司匹林肠溶片100 mg/qd+氯吡格雷75 mg/qd)前及后7 d,用血栓弹力图检测患者的花生四烯酸(AA)和二磷酸腺苷(ADP)途径诱导的血小板抑制率,筛选出氯吡格雷低反应性者96例,随机分为3组,常规剂量组(氯吡格雷75 mg/qd,32例)、高维持量组(氯吡格雷150 mg/qd,32例)和替格瑞洛组(替格瑞洛90 mg/bid,32例),3组阿司匹林继续按原剂量服用。分组后3组按新方案治疗7 d,再次复查血栓弹力图。结果分组后高维持量组及替格瑞洛组ADP诱导的血小板抑制率较常规剂量组有显著性差异(P0.05),3组均未发生出血等严重不良事件,替格瑞洛组发生1例轻度呼吸困难。替格瑞洛组高于同一时间点高维持量组ADP途径诱导的血小板抑制率(P0.05)。结论针对常规剂量氯吡格雷的低反应性,替格瑞洛及双倍剂量的氯吡格雷均能有效降低血小板的高反应性,并且替格瑞洛的作用更为明显,且未增加出血等不良事件的发生。     

短暂性脑缺血发作与轻型卒中抗血小板治疗

目的：探讨短暂性脑缺血发作与轻型卒中抗血小板治疗效果。方法选取63例缺血性脑卒中患者为研究对象,并随机分成A、B、C 3组,每组21例,C组采用氯吡格雷治疗,B组采用阿司匹林治疗,A组采用氯吡格雷联合阿司匹林治疗,对比3组治疗前后血栓弹力图（TEG）检测二磷酸腺苷（ADP）及花生四烯酸（AA）途径诱导的血小板抑制率。结果治疗后3组患者ADP、AA途径诱导的血小板抑制率均明显高于治疗前（P＜0.05）,AA途径诱导下血小板抑制率中 A组和B组显著高于C组（P＜0.05）,ADP途径诱导的血小板抑制率中A组、C组显著高于B组（P＜0.05）。结论氯吡格雷联合阿司匹林从两个途径抑制血小板聚集的效果优于单用阿司匹林或氯吡格雷,且出血风险低,值得推广应用。     

应用血栓弹力图指导急性非心源性卒中患者选择敏感抗血小板聚集药物的临床研究

目的 应用血栓弹力图（thromboelastography,TEG）指导急性非心源性卒中患者选择敏感抗血小板聚 集药物,并评价临床治疗效果。 方法 连续选取首都医科大学附属北京朝阳医院西区神经内科2013年1月至2014年12月期间急性非心 源性卒中住院患者162例,分为个体化治疗组54例（阿司匹林100 mg联合氯吡格雷75 mg应用14 d,后 根据TEG结果选择阿司匹林或氯吡格雷单抗）,阿司匹林组（n =54）,氯吡格雷组（n =54）。三组患者 均于住院第7天抽静脉血,应用TEG仪检测花生四烯酸（arachidonic acid,AA）途径诱导的血小板抑制 率和二磷酸腺苷（adenosine diphosphate,ADP）受体途径诱导的血小板抑制率,并于入院时、第14天、3 个月行美国国立卫生研究院卒中量表（National Institutes of Health Stroke Scale,NIHSS）评分及日常生 活能力量表（Activity of Daily Living Scale,ADL）评分。比较三组之间基线资料及AA途径、ADP途径 诱导的血小板抑制率,并评估14 d及3个月NIHSS评分、ADL评分及再发缺血性卒中及脑出血发生事件。 结果 三组之间在年龄、性别、高血压、糖尿病、高血脂、吸烟、饮酒、既往卒中、冠状动脉粥样性 心脏病以及入院时NIHSS评分、ADL评分方面比较差异无显著性（P＞0.05）。个体化治疗组AA及ADP 途径诱导的血小板抑制率中位数分别为93.2%（77.45%,98.35%）、50.4%（27.62%,67.25%）,阿 司匹林组AA途径及氯吡格雷组ADP诱导的血小板抑制率中位数分别为73.05%（40.8%,92.75%）、 20.5%（5.1%,53.5%）,个体化治疗组AA或ADP途径诱导血小板抑制率较阿司匹林组及氯吡格雷组 相比差异有显著性（P＜0.05）。个体化治疗组、阿司匹林组、氯吡格雷组三组患者入院第14天NIHSS 评分中位数分别为3（2,4）、3.5（3,4）、4（3,4）,ADL评分中位数分别为80（70,90）、75（70,85）、 70（65,85）;第3个月NIHSS评分中位数分别为2（2,3）、3（2,3）、3（2,3）,ADL评分中位数分别为90 （85,95）、87.5（80,90）、85（80,90）,三组间两两比较个体化治疗组优于阿司匹林组及氯吡格雷组 （P＜0.05）,阿司匹林组与氯吡格雷组比较差异无显著性（P ＞0.05）。随访3个月三组均无脑出血发 生,个体化治疗组有1例再发缺血性事件,阿司匹林组有3例、氯吡格雷组有4例再发缺血性事件。 结论 急性非心源性卒中患者急性期给予双抗治疗后根据TEG结果选择敏感抗血小板聚集药物能 提高患者临床预后,不增加出血风险。     

吸烟状态对氯吡格雷疗效的影响

目的通过血栓弹力图检测,观察吸烟状态是否会对缺血性卒中患者的氯吡格雷疗效产生影响。方法回顾性连续纳入2013年1月-2014年10月首次发病的急性非心源性栓塞所致的缺血性脑血管病并接受氯吡格雷治疗的患者202例,分为吸烟组和不吸烟组。连续服用氯吡格雷每日75 mg,5 d后,抽取外周静脉血,用血栓弹力图仪测定氯吡格雷对血小板的抑制率。结果与非吸烟组相比,吸烟组患者氯吡格雷诱导的二磷酸腺苷抑制率更高(55.29%±25.92%vs 53.25%±27.02%,P=0.589),出现氯吡格雷反应低下(二磷酸腺苷抑制率30%)的患者比例更低(15.8%vs 19.5%,P=0.498),但差异无统计学意义。结论在非心源性栓塞的缺血性卒中患者中,吸烟有提高氯吡格雷反应性,增强其抗血小板聚集作用的趋势。但吸烟者中氯吡格雷治疗后血小板反应的变异性仍有待进一步研究证实。     

阿司匹林抵抗的危险因素分析和临床干预

目的探讨脑梗死患者阿司匹林抵抗的危险因素,研究阿司匹林抵抗者抗血小板药物调整后阿司匹林抵抗的发生情况及预后。方法选取269例新发脑梗死患者,口服阿司匹林100 mg/d,经血栓弹力图筛选出阿司匹林抵抗者90例,分析其危险因素,并将其随机分为3组:A组口服阿司匹林200 mg/d;B组口服阿司匹林100 mg/d+氯吡格雷75 mg/d;C组口服阿司匹林100 mg/d。1 m后复测血栓弹力图,比较血小板抑制率的变化。随访12 m观察血管事件和死亡的发生情况。结果阿司匹林抵抗的发生率为33.5%。单因素分析显示,阿司匹林抵抗组(AR)与阿司匹林敏感组(AS)年龄比较差异有统计学意义(P=0.029);Logistic回归分析显示,年龄是脑梗死患者阿司匹林抵抗的危险因素(OR=1.026,95%CI 1.002 1.049,P=0.030)。A组和B组患者AA诱导的血小板抑制率明显升高(P0.05),且B组患者血小板抑制率升高更明显;C组患者AA诱导的血小板抑制率较前无明显改变(P0.05)。随访12 m后3组患者总体缺血性事件发生率比较差异有统计学意义(P=0.002),C组总体缺血性事件发生率明显高于A组和B组;3组患者出血性事件发生率比较差异无统计学意义(P0.05)。结论年龄是脑梗死患者阿司匹林抵抗的危险因素;阿司匹林加量或联合氯吡格雷治疗可以有效改善阿司匹林抵抗现象,并可减少或避免缺血性事件发生。     

氯吡格雷在急性脑梗死的糖尿病患者中血小板抑制效应的研究

目的用血栓弹力图(thromboelastograms,TEG)评价合并糖尿病的急性脑梗死患者正规使用氯吡格雷后血小板抑制率的变化及氯吡格雷抵抗情况。方法收集住院的急性脑梗死患者80例,其中糖尿病患者33例,非糖尿病患者47例,所有患者予以顿服氯吡格雷负荷量300 mg继以75 mg/d维持,在服用氯吡格雷3 d后和7 d后空腹抽取肘静脉血标本,用血栓弹力图(thromboelastograms,TEG)测定10μmol/L二磷酸腺苷(adenosine diphosphate,ADP)受体途径诱导的血小板抑制率,分析比较两组患者临床特征、血小板抑制率的差异和氯吡格雷抵抗情况。结果糖尿病组的空腹血糖(Fasting plasma glucose,FPG)和糖化血红蛋白(%)显著高于非糖尿病组,差异具有统计学意义(P<0.05)。糖尿病组3 d后和7 d的血小板抑制率显著低于非糖尿病组,差异具有统计学意义(P<0.05)。糖尿病组3 d和7 d后分别有11例(33.3%)、12例(36.4%)患者出现氯吡格雷抵抗的现象,显著高于非糖尿病组的6例(12.8%)、5例(10.6%),差异具有统计学意义(P<0.05)。结论糖尿病患者的血小板抑制率明显低于非糖尿病患者,更容易发生氯吡格雷抵抗现象。     

CYP2C19基因多态性与急性脑梗死患者氯吡格雷抵抗的关系

目的探讨CYP2C19基因多态性与急性脑梗死患者氯吡格雷抵抗的关系。方法检测118例急性脑梗死患者的CYP2C19基因,根据基因型分为野生型组、突变杂合型组及突变纯合型组。使用血栓弹力图测定二磷酸腺苷(ADP)诱导的血小板聚集抑制率,比较各组结果。结果根据基因分型,将患者分为野生型组45例(38.1%),突变杂合型组54例(45.8%)及突变纯合型组19例(16.1%)。与野生型组比较,突变纯合型组与突变杂合型组的血小板抑制率均显著下降(均P0.01),氯吡格雷抵抗率明显增高(P0.05~0.01)。与突变杂合型组比较,突变纯合型组的血小板抑制率显著下降(P0.01),氯吡格雷抵抗率差异无统计学意义。Logistic多元回归分析显示,携带CYP2C19突变杂合型等位基因及突变纯合型等位基因与血小板抑制率呈正相关,是氯吡格雷抵抗的独立危险因素(OR=2.13,95%CI:1.78~4.28,P=0.013;OR=4.44,95%CI:3.31~6.41,P=0.001)。结论 CYP2C19突变型等位基因是氯吡格雷低应答的独立危险因素。     

CYP2C19基因型与复发性脑梗死患者氯吡格雷抵抗的关系研究

目的通过CYP2C19基因检测及血小板聚集率综合评估氯吡格雷抵抗,指导复发性脑梗死患者合理用药。方法对2018年1-10月就诊于嘉兴市第二医院神经内科,诊断为复发性脑梗死的患者进行CYP2C19基因测序,分别收集氯吡格雷快代谢、中代谢、慢代谢基因型患者各30例,比较3组患者年龄、性别、BMI、吸烟、高血压、糖尿病及高脂血症等一般临床资料。3组均给予常规剂量氯吡格雷75 mg/d治疗,检测患者使用氯吡格雷前及使用7 d后的血小板聚集率。根据血小板聚集抑制率判断氯吡格雷抵抗情况,分析CYP2C19基因型与患者氯吡格雷抵抗的关系。筛选出氯吡格雷抵抗者(血小板聚集抑制率10%)分至氯吡格雷抵抗组,改用西洛他唑100 mg 2次/日,氯吡格雷半反应(10%≤血小板聚集抑制率30%)及氯吡格雷敏感(血小板聚集抑制率≥30%)者分至非氯吡格雷抵抗组,继续氯吡格雷75 mg/d治疗。3个月后再次检测血小板聚集率,比较不同药物的血小板聚集抑制情况,并观察终点事件发生情况(主要终点:再发脑梗死;次要终点:脑出血和死亡)。结果最终入组患者90例,其中男性49例(54.4%),年龄40～89岁,平均年龄68.27±10.14岁。快、中、慢代谢3组糖尿病(P=0.036)和氯吡格雷抵抗发生率(P0.001)差异均有统计学意义,其中慢代谢组合并糖尿病比率高于中代谢组(P=0.010),慢代谢组氯吡格雷抵抗发生率高于快代谢组(P0.001)及中代谢组(P=0.006)。氯吡格雷抵抗组患者22例(24.4%),非氯吡格雷抵抗组患者68例(75.6%)。Logistic回归分析提示,吸烟(OR 7.792,95%CI 1.899～31.968,P=0.004)、糖尿病(OR 4.466,95%CI 1.122～17.778,P=0.034)及CYP2C19基因慢代谢(OR 13.713,95%CI 2.352～79.959,P=0.004)是复发性脑梗死患者氯吡格雷抵抗的独立危险因素。非氯吡格雷抵抗组(49.51%±4.33%vs 63.73%±7.84%,P0.001)和氯吡格雷抵抗组(55.42%±6.63%vs 76.95%±7.42%,P0.001)患者3个月后的血小板平均聚集率较7 d时均下降,差异有统计学意义。3个月后较非氯吡格雷抵抗组,氯吡格雷抵抗组血小板聚集抑制率更高(21.53%±4.30%vs 14.23%±6.90%,P0.001)。入组患者随访3个月均无终点事件发生。结论吸烟、合并糖尿病及CYP2C19慢代谢基因型是复发性脑梗死患者氯吡格雷抵抗的独立危险因素。西洛他唑能有效抑制血小板聚集,可以作为氯吡格雷抵抗的复发性脑梗死患者的替代性用药。     

The additive antiplatelet action of clopidogrel in patients with coronary artery disease treated with aspirin

We searched for additional anti-platelet effects of clopidogrel in coronary artery disease (CAD) patients treated with aspirin. Response to clopidogrel was also stratified according to aspirin resistance. Out of 76 screened aspirin-treated CAD male patients, five were aspirin-resistant based on arachidonic acid (AA) and ADP aggregometry. These five patients and 15 aspirin-sensitive patients entered the proper study. Platelet function was assessed at baseline and after one week of additional clopidogrel treatment using aggregometry, flow cytometry (ADP, TRAP-6) and platelet reactivity index (PRI) based on VASP (vasodilatorstimulated phosphoprotein) expression. We evaluated the same markers in 15 healthy men after aspirin treatment. In healthy subjects aspirin did not affect resting or ADP-induced activated GPIIb/IIIa and P-selectin expression. The P-selectin expression on ADP-activated platelets was increased (p < 0.01) in aspirin treated ASA-resistant CAD patients as compared to ASA-sensitive group or aspirin-treated healthy subjects. Clopidogrel significantly decreased ADP and AA-induced platelet aggregation and overcame aspirin resistance in four of five patients. Expression of ADP-induced activation markers was significantly lowered after clopidogrel in all patients. Out of 20 patients, five did not respond to clopidogrel (<10% inhibition of ADP aggregation), and this group showed no change in expression of ADP-induced activation markers after clopidogrel. Clopidogrel treatment significantly reduced PRI only in the clopidogrel-sensitive group. In conclusion, the addition of clopidogrel to aspirin provides greater inhibition of platelets and can overcome aspirin resistance. Flow cytometric analysis of platelets is useful for monitoring of clopidogrel therapy.     

Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement

Dual antiplatelet therapy with aspirin and clopidogrel decreases the rate of stent thrombosis in patients undergoing percutaneous coronary intervention (PCI). However, despite intensified antiplatelet treatment, up to 4.7% of the patients undergoing coronary stenting develop thrombotic stent occlusion, suggesting incomplete platelet inhibition due to clopidogrel resistance. We evaluated the percentage of clopidogrel non-responders among 105 patients with coronary artery disease (CAD) undergoing elective PCI. All patients were treated regularly with aspirin 100 mg/d and received a loading dose of 600 mg clopidogrel followed by a maintenance dose of 75 mg/d before PCI. Clopidogrel non-responders were defined by an inhibition of ADP (5 and 20 Mol/L) induced platelet aggregation that was less than 10% when compared to baseline values 4 h after clopidogrel intake. Semi-responders were identified by an inhibition of 10 to 29%. Patients with an inhibition over 30% were regarded as responders. We found that 5 (ADP 5 Mol/L) to 11% (ADP 20 Mol/L) of the patients were non-responders and 9 to 26% were semi-responders. Among the group of non-responders there were two incidents of subacute stent thrombosis after PCI. We conclude that a subgroup of patients undergoing PCI does not adequately respond to clopidogrel, which may correspond to the occurrence of thromboischemic complications. Point-of-care testing may help to identify these patients who may then benefit from an alternative antiplatelet therapy.     

Increased platelet sensitivity among individuals with aspirin resistance - platelet aggregation to submaximal concentration of arachidonic acid predicts response to antiplatelet therapy

Aspirin 'resistance' (AR) is a phenomenon of uncertain etiology describing decreased platelet inhibition by aspirin. We studied whether (i) platelets in AR demonstrate increased basal sensitivity to a lower degree of stimulation and (ii) platelet aggregation with submaximal stimulation could predict responses to aspirin. Serum thromboxane B(2) (TxB(2)) levels and platelet aggregation with light transmission aggregometry (LTA) were measured at baseline and 24 hours after 325 mg aspirin administration in 58 healthy subjects. AR was defined as the upper sixth of LTA (> or = 12%) to 1.5 mM AA. Baseline platelet aggregation with submaximal concentrations of agonists [ADP 2 microM, arachidonic acid (AA) 0.75 mM, collagen 0.375 and 0.5 microg/ml] was greater in AR subjects compared with non-AR subjects, but not with higher concentrations (ADP 5 microM and 20 microM, AA 1.5 mM and collagen 1 microg/ml). Post-aspirin platelet aggregation was elevated in AR subjects with both submaximal and maximal stimulation. Baseline and post-aspirin serum TxB(2) were higher in AR subjects and decreased further with ex-vivo COX-1 inhibition, suggesting incompletely suppressed COX-1 activity. Pre-aspirin platelet aggregation to 0.75 AA demonstrated a dichotomous response with 29/58 subjects having aggregation < or = 15% and 29/58 subjects having aggregation > or = 75%. In the high aggregation group 28% had AR compared to 6% in the non-AR group (p = 0.04). In conclusion, platelets in AR subjects demonstrate increased basal sensitivity to submaximal stimulation, which could predict responses to antiplatelet therapy.     

Residual cyclooxygenase-1 activity and epinephrine reduce the antiplatelet effect of aspirin in patients with acute myocardial infarction

Aspirin treatment is essential in patients with acute myocardial infarction (AMI) to block platelet thromboxane (TXA)? synthesis. Epinephrine is known to enhance platelet reactivity induced by other agonists and to be elevated in patients with AMI due to stress. Our objective was to study the influence of epinephrine on platelet TXA? synthesis in patients treated with aspirin for AMI at early onset (within 48 hours) and the potential biochemical mechanisms involved in the functional response. Washed platelets from 45 patients with AMI and 10 aspirin-free controls were stimulated with arachidonic acid (AA) or AA + epinephrine, and aggregation and TXA? synthesis were evaluated. Full platelet aggregation was recorded in 8/45 patients (18%) with a partial TXA? inhibition (86%) vs. the aspirin-free controls. Platelets from the remaining 37 patients did not aggregate to AA and had TXA? inhibition >95%. However, when platelets were simultaneously stimulated with AA + epinephrine, in 25/37 patients a large intensity of aggregation (73%) was observed and a 5.5-fold increase in TXA? synthesis, although this remained residual (<5% of aspirin-free controls). This residual-TXA? was critical in the functional response, as demonstrated by the complete inhibition by TXA? receptor blockade or additional aspirin in vitro. The phosphatidylinositol-3-kinase activity and the cytosolic calcium levels participated in this platelet response elicited by a receptor cooperation mechanism, while the Rho/p160(ROCK) pathway or the blockade of the ADP receptors (P2Y1, P2Y12) were without effect. Residual-cyclooxygenase -1 activity and epinephrine enhance TXA?-dependent platelet function, which may reduce the clinical benefit of aspirin in patients with AMI.     

氯吡格雷与阿司匹林联合应用在急性脑梗死治疗中的疗效评定

目的观察急性脑梗死患者血小板上α颗粒膜糖蛋白(CD62p)及溶酶体颗粒膜糖蛋白(CD63)的表达,通过血小板活化的变化,探讨阿司匹林与氯吡格雷联合用药与阿司匹林单药治疗的疗效差异。方法将60例脑梗死患者随机分为两个亚组:单药组(阿司匹林0.15 g/d)和联合用药组(阿司匹林0.10 g/d+氯吡格雷75 mg/d),30例健康体检者为对照组。使用流式细胞术检测所有病例CD62p、CD63阳性率,对单药组和联合用药组治疗前后的CD62p、CD63阳性率进行比较,同时进行NIHSS评分。结果脑梗死组血小板CD62p、CD63阳性率显著高于对照组(P<0.01)。单药组和联合用药组在治疗一周和二周后CD62p、CD63阳性率和NIHSS评分均较治疗前显著下降(P<0.01)。联合用药组治疗二周后与单药组比较CD62p、CD63阳性率和NIHSS评分明显降低,差异有统计学意义(P<0.01)。结论抗血小板治疗对脑梗死有效,阿司匹林+氯吡格雷联合治疗的总体疗效明显优于单用阿司匹林,CD62p、CD63可以衡量抗血小板治疗效果。     

Antiplatelet activity of clopidogrel in coronary artery bypass graft surgery patients

Clopidogrel is a recently introduced platelet ADP receptor antagonist, belonging to the thienopyridine derivatives, like its analogue ticlopidine. Its potential advantage is to be safer than ticlopidine. At 75 mg/od clopidogrel significantly inhibits platelet aggregation in ambulatory patients with symptomatic atherosclerotic disease and it prevents the recurrence of ischemic events more efficiently than aspirin. Its adequate dose in more acute situations remained to be determined. Therefore, sixty two patients with coronary artery disease were randomly assigned in four groups treated, within 24 h after coronary artery bypass graft, by clopidogrel 50 mg/od, 75 mg/od or 100 mg/od or by ticlopidine 250 mg/bid which was considered as the reference. The tolerance of clopidogrel was fairly good during the whole period of the study. Bleeding time and ex-vivo platelet aggregation induced by ADP 2 microM and 5 microM were performed at day -1, +9 and +28 after surgery. Like ticlopidine, the three dose levels of clopidogrel significantly inhibited ex-vivo platelet activity and prolonged the bleeding time at day 28. However, unlike ticlopidine, the inhibitory effects of clopidogrel were not significant at day 9, especially with 75 mg/od, a dose which was found to significantly protect patients in a chronic situation. Hence, although the clinical outcome for patients included in this limited study was the same in the four groups, these results suggest that the dose regime of clopidogrel should be more extensively investigated during the early period following coronary artery bypass graft, facing an overproduction of young and hyperreactive platelets. By analogy, the dose regime should be also investigated in other situations with an acute risk of arterial thrombotic occlusion.