冠心病患者阿司匹林抵抗的相关因素

目的观察冠心病患者发生阿司匹林抵抗的发生率,并探讨冠心病患者出现阿司匹林抵抗现象的相关因素。方法60例病情稳定的冠心病住院患者,每日口服拜阿司匹林100 mg,连服7 d,分别以二磷酸腺苷（ADP）和花生四烯酸（AA）为诱导剂,检测血小板聚集功能。结果阿司匹林抵抗（AR）发生率为20%;阿司匹林半敏感（ASR）者占13%。与阿司匹林敏感（AS）者相比,伴有高脂血症、糖尿病的冠心病患者AR较多（50%vs15%,P<0.05）,两组年龄、性别、吸烟和并发高血压病统计无显著性差异。结论伴有高脂血症、糖尿病的冠心病患者发生阿司匹林抵抗较多,阿司匹林抵抗与年龄、性别、吸烟和并发高血压病等因素无关。     

Profile and prevalence of aspirin resistance in patients with cardiovascular disease

We determined the prevalence and clinical predictors of aspirin resistance by prospectively studying 325 patients with stable cardiovascular disease who were receiving aspirin (325 mg/day for > or =7 days) but no other antiplatelet agents. We also compared the detection of aspirin resistance with optical platelet aggregation, a widely accepted method, with a newer, more rapid method, the platelet function analyzer (PFA)-100, a whole blood test that measures platelet adhesion and aggregation ex vivo. Blood samples were analyzed in a blinded fashion for aspirin resistance by optical aggregation using adenosine diphosphate (ADP) and arachidonic acid, and by PFA-100 using collagen and/or epinephrine and collagen and/or ADP cartridges to measure aperture closure time. Aspirin resistance was defined as a mean aggregation of > or =70% with 10 microM ADP and a mean aggregation of > or =20% with 0.5 mg/ml arachidonic acid. Aspirin semiresponders were defined as meeting one, but not both of the above criteria. Aspirin resistance by PFA-100 was defined as having a normal collagen and/or epinephrine closure time (< or =193 seconds). By optical aggregation, 5.5% of the patients were aspirin resistant and 23.8% were aspirin semiresponders. By PFA-100, 9.5% of patients were aspirin resistant. Of the 18 patients who were aspirin resistant by aggregation, 4 were also aspirin resistant by PFA-100. Patients who were either aspirin resistant or aspirin semiresponders were more likely to be women (34.4% vs 17.3%, p = 0.001) and less likely to be smokers (0% vs 8.3%, p = 0.004) compared with aspirin-sensitive patients. There was a trend toward increased age in patients with aspirin resistance or aspirin semiresponders (65.7 vs 61.3 years, p = 0.06). There were no differences in aspirin sensitivity by race, diabetes, platelet count, renal disease, or liver disease.     

Effect of atorvastatin and pravastatin on platelet inhibition by aspirin and clopidogrel treatment in patients with coronary stent thrombosis

We sought to determine a potential interaction between statins and antiplatelet therapy with aspirin and clopidogrel. Previous laboratory studies have shown a possible drug-drug interaction of statins metabolized by cytochrome P450 3A4 and clopidogrel (prodrug metabolized by cytochrome P450 3A4), resulting in an impaired inhibitory effect of clopidogrel on platelet aggregation. However, conclusive prospective data assessing this potentially relevant interaction are lacking. In 73 patients, 23 with previous coronary stent thrombosis (ST) (ST group) and 50 without coronary ST (control group), platelet aggregation was measured 3 times in monthly intervals using light transmission aggregometry (adenosine diphosphate [ADP] and arachidonic acid induction). Measurements were carried out with aspirin monotherapy (100 mg/day), dual antiplatelet therapy with aspirin plus clopidogrel (75 mg/day), and additional treatment of 20 mg/day of atorvastatin or 40 mg/day of pravastatin. ADP (5 and 20 micromol)-induced platelet aggregation was significantly decreased with clopidogrel (p <0.001) but remained stable under additional treatment with atorvastatin or pravastatin in the 2 groups. Patients with previous ST showed a higher ADP-induced aggregation level than control subjects. This difference was not influenced by clopidogrel or statin treatment. In conclusion, patients with previous ST show a higher aggregation level than control subjects independent of statin treatment. Atorvastatin and pravastatin do not interfere with the antiaggregatory effect of aspirin and clopidogrel. In conclusion, drug-drug interaction between dual antiplatelet therapy and atorvastatin or pravastatin seems not to be associated with ST.     

Effects of triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol) on platelet aggregation and P-selectin expression in patients undergoing coronary artery stent implantation

The purpose of this study was to determine the effect of the addition of cilostazol to aspirin plus clopidogrel on platelet aggregation after intracoronary stent implantation. Twenty patients who underwent coronary stent placement were randomly assigned to therapy with aspirin plus clopidogrel (dual-therapy group, n = 10) or aspirin plus clopidogrel plus cilostazol (triple-therapy group, n = 10). A loading dose of clopidogrel (300 mg) and cilostazol (200 mg) was administered immediately after stent placement, and clopidogrel (75 mg/day) and cilostazol (100 mg twice daily) were given for 1 month. Platelet aggregation in response to adenosine diphosphate (ADP; 5 and 20 micromol/L) or collagen and P-selectin (CD-62P) expression was assayed at baseline, 2 hours, 24 hours, 1 week, and 1 month after stent placement. Inhibition of ADP-induced platelet aggregation was significantly higher in patients receiving triple therapy than those receiving dual therapy from 24 hours after stent placement, and inhibition of collagen-induced platelet aggregation was significantly higher in the triple-therapy group beginning 1 week after stent placement. P-Selectin expression was significantly lower in the triple-therapy than dual-therapy group at 1 week and 30 days. In conclusion, compared with dual antiplatelet therapy, triple therapy after coronary stent placement resulted in more potent inhibition of platelet aggregation induced by ADP and collagen. These findings suggest that triple therapy may be used clinically to prevent thrombotic complications after coronary stent placement.     

2型糖尿病对阿司匹林和氯吡格雷双联抗血小板药物治疗效应的分析

目的:本研究通过前瞻性连续入选在我院因稳定性冠心病行经皮冠状动脉介入治疗(PCI)的患者,分析探讨糖尿病对阿司匹林和氯吡格雷双联抗血小板药物效应的影响。方法:2008年8月至2011年11月前瞻性连续入选稳定性冠心病患者。入院后服用氯吡格雷前测定花生四烯酸(AA)诱导的血小板聚集率和基线二磷酸腺苷(ADP)诱导的血小板聚集率,之后给予氯吡格雷300 mg负荷量口服,继续服用氯吡格雷75 mg/d至1 d后,再次测定服用氯吡格雷后ADP诱导的血小板聚集率。结果:入选了355例稳定性冠心病患者,其中合并2型糖尿病103例,非糖尿病252例。阿司匹林抵抗的发生率18.6%,糖尿病组与非糖尿病组阿司匹林抵抗的发生率未见明显差异(20.4%vs.17.9%,P=0.578),将患者基线特征纳入Logistic回归模型进行校正后结果显示,糖尿病并未增高阿司匹林抵抗的风险(OR=1.3,95%CI=0.7～2.7,P=0.439)。氯吡格雷抵抗的发生率为20.8%;糖尿病组氯吡格雷抵抗的发生率明显高于非糖尿病组(33.0%vs.15.9%,P<0.001);Logistic回归校正后结果显示,糖尿病是氯吡格雷抵抗的独立危险因素(OR=5.7,95%CI=2.9～11.1,P<0.001)。结论:双联抗血小板药物基础上,糖尿病未增高阿司匹林抵抗的风险;但是糖尿病明显增高了氯吡格雷抵抗的风险。     

择期行CABG术患者中抗血小板药物对血小板聚集率的影响

目的：探讨择期行冠状动脉旁路移植手术(Coronary artery bypass graft,CABG)的冠心病(Coronary artery diseas,CAD)患者停用阿司匹林和氯吡格雷后,抗血小板药物作用持续时间。方法： 24例经冠状动脉造影(Coronary arteriography,CAG)提示需行CABG术的冠心病患者,连续口服100 mg肠溶阿司匹林和75mg氯吡格雷一周,观察停药后1,2,3,4,5,6,7,9天血小板聚集率的变化。采用光学血小板聚集仪(light transmission aggregometer, LTA)测定花生四烯酸诱导的血小板聚集率(arachidonic acid induced platelet aggregation, PL-AA)和二磷酸腺苷诱导的血小板聚集率(adenosine diphosphate induced platelet aggregation,PL-ADP)。结果：停药后第一天AA诱导的血小板聚集抑制效应最强(5.4±1.6%),血小板功能在停药后第四天恢复至正常水平(76.6±4.0%);停药后第一天ADP诱导的血小板聚集抑制效应最强(29.5±12.1%),在停药后第七天恢复至正常水平(69.7±3.5%)。结论：冠心病患者口服100mg阿司匹林和75mg氯吡格雷一周后,停药后AA诱导的血小板聚集功能第四天恢复至正常;ADP诱导的血小板聚集功能在第七天恢复至正常。     

Profile and prevalence of aspirin resistance in Indian patients with coronary artery disease

BACKGROUND: Aspirin resistance is considered to be an enigma and the data available on aspirin resistance is scarce. This study was initiated to prospectively evaluate the prevalence of aspirin resistance in patients with stable coronary artery disease by using an established method of optical platelet aggregation. METHODS AND RESULTS: We studied 50 patients who were on 150 mg of aspirin for the previous 7 days. Fasting blood samples were assessed using optical platelet aggregation (Chronolog Corp, USA). The mean platelet aggregation with 10 microm of adenosine diphosphate in our patient group was 49.42 +/- 23.29% and with 0.5 mg/ ml of arachidonic acid it was 13.58 +/- 21.40%. Aspirin resistance was defined as a mean aggregation of > or =70% with 10 microm of adenosine diphosphate and a mean aggregation of > or =20% with 0.5 mg/ml of arachidonic acid. Aspirin semi responders were defined as those meeting only one of the criteria. Based on these criteria, 2.08% patients were found to be aspirin-resistant, 39.58% were aspirin semi responders and 58.33% were aspirin responders. Females tended to be more aspirin semi responsive (p = 0.08). All other parameters tested, namely, age, smoking, diabetes mellitus, hypertension, obesity, lipids, hemoglobin, platelet count, ejection fraction and drug intake did not show any statistically significant difference among the groups. Thus, in our group 41.66% patients showed inadequate response to aspirin. Conclusions: This study shows that aspirin resistance and aspirin semi responsiveness do occur in the Indian patients and there are no reliable clinical predictors for this condition. The diagnosis therefore relies primarily on laboratory tests.     

Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention

Increased platelet inhibition is achieved when clopidogrel is added to aspirin (acetylsalicylic acid [ASA]). A broad variability in platelet inhibition profiles during the early phases of treatment has been demonstrated and may be attributed to ASA resistance. However, the influence of ASA sensitivity on platelet function profiles of patients on long-term dual antiplatelet therapy has yet to be explored. A total of 135 patients who had previously undergone percutaneous coronary intervention on long-term (>1 month) ASA and clopidogrel therapy was included. The PFA-100 system was used to define ASA resistance. Platelet aggregation, after adenosine diphosphate (6 and 20 micromol/L) and collagen (6 microg/ml) stimuli, and platelet activation (glycoprotein IIb/IIIa activation and P-selectin expression), after adenosine diphosphate (2 micromol/L) and thrombin receptor-activating peptide (50 micromol/L) stimuli, were assessed by light transmittance aggregometry and flow cytometry, respectively. Patient variability in response to treatment was defined by the coefficient of variability. ASA resistance was found in 60 of 135 patients (44%). Patients with diabetes were more frequently ASA resistant. Collagen/epinephrine- and collagen/adenosine diphosphate-coated cartridges on the PFA-100 had shorter closure times in the ASA-resistant population compared with ASA-sensitive patients. Platelet aggregation and activation were significantly higher in ASA-resistant patients. A broad variability (coefficient of variation >0.25) in patient response to treatment was observed in ASA-resistant and -sensitive patients. In conclusion, ASA resistance is associated with increased platelet reactivity in patients on long-term dual antiplatelet treatment.     

心血管病患者中的阿司匹林抵抗

目的　前瞻性地评价心血管病患者发生阿司匹林抵抗 (AR)的流行病学概况 ,并探讨其预测因子。方法　 35 2例病情稳定的心血管病住院患者 ,每日服用阿司匹林 10 0mg ,连服 7天 ,服用最后一剂后 2 4h内抽取的空腹静脉血为血样 ,分别用二磷酸腺苷 (ADP)、花生四烯酸 (AA)诱导血小板凝集试验 (PAgT) ,检测血小板聚集率。结果　患者中AR发生率为 3.98% ,阿司匹林半敏感 (ASR)者占 2 5 .9% ,且AR或ASR患者中的女性较AS者多(35 .2 %vs 18.2 % ,P =0 .0 0 1) ,而AS者中吸烟者较AR或ASR者多 (0 %vs 9.5 % ,P =0 .0 0 2 )。结论　阿司匹林用于抗血小板治疗及预防动脉硬化事件的心血管病患者 ,若有AR存在可选择其他安全有效的抗血小板制剂长期服用 ,预测AR及抗血小板治疗个体化 ,将是抗血小板治疗未来的方向     

Effect of 150-mg vs 300-mg loading doses of clopidogrel on platelet function in Japanese patients undergoing coronary stent placement

BACKGROUND: The loading dose of ticlopidine is 500 mg in both the US and Europe and 200 mg in Japan. A lower loading dose of clopidogrel might achieve adequate platelet inhibition in Japanese patients. METHODS AND RESULTS: Platelet aggregation was serially measured at baseline, and 2, 4, 6, and 8 h after 150-mg (n=20) and 300-mg (n=20) clopidogrel loading. Platelets were stimulated with 5 and 20 micromol/L adenosine diphosphate (ADP) and aggregation was assessed by optical aggregometry. Pretreatment ADP-induced platelet aggregation in the 150-mg clopidogrel group did not differ from that of the 300-mg group. The administration of 300-mg clopidogrel loading dose resulted in lower platelet aggregation 2 h after the administration (5 micromol/L ADP: 53+/-9% vs 61+/-12%, p<0.05 and 20 micromol/L ADP: 61+/-10% vs 68+/-9%, p<0.05). A lower platelet aggregation induced with 20 micromol/L ADP was still observed 4 h after the 300-mg clopidogrel loading (58+/-10% vs 65+/-9%, p<0.05). CONCLUSIONS: The 150-mg clopidogrel loading does not achieve rapid platelet inhibition. The 300-mg loading dose should be used to suppress platelet function rapidly even in Japanese patients undergoing coronary stent placement.     

Antiplatelet effect of 50-mg maintenance dose of clopidogrel compared to 200 mg ticlopidine: a preliminary study

In the United States and Europe, patients with coronary stents are maintained on 75 mg clopidogrel. Because the maintenance dose of ticlopidine in patients with coronary stents is 100 mg twice daily in Japan and 250 mg twice daily in the United States and Europe, in Japanese patients a lower dose of clopidogrel may achieve an antiplatelet effect comparable to 200 mg ticlopidine. Platelet aggregation was evaluated in 104 consecutive patients on 50 mg clopidogrel plus aspirin (n = 54) and 200 mg ticlopidine plus aspirin (n = 50). Platelets were stimulated with adenosine diphosphate (5 and 20 μmol/l) and aggregation was assessed by optical aggregometry. There was no significant difference in platelet aggregation induced with 5 (37% ± 11% vs 38% ± 15%, not significant) and 20 μmol/l adenosine diphosphate (48% ± 13% vs 51% ± 12%, not significant) between 50 mg clopidogrel and 200 mg ticlopidine. In Japanese patients, there is the possibility that a maintenance dose of 50 mg clopidogrel on platelet inhibition is comparable to 200 mg ticlopidine.     

瑞舒伐他汀和阿托伐他汀对氯吡格雷抗血小板活性的影响

目的观察瑞舒伐他汀和阿托伐他汀对氯吡格雷抗血小板活性的影响。方法选择60例冠心病患者接受阿司匹林100mg/d、氯吡格雷75 mg/d及低分子肝素5000 U/12 h治疗,5 d后随机分为阿托伐他汀20mg/d(阿托伐他汀组,30例)和瑞舒伐他汀10 mg/d(瑞舒伐他汀组,30例)。在服用氯吡格雷之前(基线值)、加用他汀类药物之前及服用他汀类药物3d后,用全血阻抗法分别测定不同浓度二磷酸腺苷(5、10、20μmol/L)诱导的血小板聚集率。结果与基线值比较,服用氯吡格雷5 d后和加服他汀类药物治疗3 d后,2组患者血小板聚集率明显降低,差异有统计学意义(P<0.05);与治疗前比较,阿托伐他汀组患者血小板聚集率有所升高,而瑞舒伐他汀组患者血小板聚集率有所下降,但差异无统计学意义(P>0.05)。结论经细胞色素3A4途径代谢的阿托伐他汀及不经细胞色素3A4代谢的瑞舒伐他汀,短期内对氯吡格雷抗血小板活性无影响。     

Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance.

We evaluated the response to clopidogrel among aspirin-resistant versus aspirin-sensitive patients undergoing elective coronary stenting. Patients (n = 150) treated with aspirin but not clopidogrel had blood samples drawn at baseline and 24 h after clopidogrel loading. Depending on the definition used, 9% to 15% were resistant to aspirin and 24% to clopidogrel. About half of the aspirin-resistant patients were also resistant to clopidogrel. As a group, aspirin-resistant patients had lower response to clopidogrel (assessed by platelet aggregation and activation markers) than aspirin-sensitive patients. Both aspirin- and clopidogrel-resistant patients had higher incidence of creatine kinase-MB elevation than the respective sensitive patients. OBJECTIVES: We sought to evaluate the response to clopidogrel among aspirin-resistant versus aspirin-sensitive patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Wide variability has been reported in response to aspirin and clopidogrel. There are limited data on the simultaneous responses to both drugs. METHODS: Elective PCI patients (n = 150) who received aspirin for > or = 1 week but not clopidogrel were included. All patients received bivalirudin during PCI. Blood samples were drawn at baseline and 20 to 24 h after a 300-mg clopidogrel dose. Aspirin resistance was defined by > or = 2 of 3 criteria: rapid platelet function analyzer-ASA score > or = 550, 5 micromol/l adenosine diphosphate (ADP)-induced aggregation > or = 70%, and 0.5 mg/ml arachidonic acid-induced aggregation > or = 20%. Clopidogrel resistance was defined as baseline minus post-treatment aggregation < or = 10% in response to 5 and 20 micromol/l ADP. RESULTS: Nineteen (12.7%) patients were resistant to aspirin and 36 (24%) to clopidogrel. Nine (47.4%) of the aspirin-resistant patients were also clopidogrel resistant. Aspirin-resistant patients were more likely to be women and have diabetes than were aspirin-sensitive patients. They also had lower response to clopidogrel, assessed by platelet aggregation and activation markers (flow cytometry-determined PAC-1 binding and P-selectin expression). Elevation of creatine kinase-myocardial band after stenting occurred more frequently in aspirin-resistant versus aspirin-sensitive patients (38.9% vs. 18.3%; p = 0.04) and in clopidogrel-resistant versus clopidogrel-sensitive patients (32.4% vs. 17.3%; p = 0.06). CONCLUSIONS: Aspirin-resistant patients as a group have reduced response to clopidogrel. Furthermore, we have identified a unique group of dual drug-resistant patients who may be at increased risk for thrombotic complications after PCI.     

P2Y12 gene H2 haplotype is not associated with increased adenosine diphosphate-induced platelet aggregation after initiation of clopidogrel therapy with a high loading dose.

A large variability in the antiplatelet response to clopidogrel has been consistently reported. Recently, a P2Y12 haplotype was shown to be associated with enhanced adenosine diphosphate (ADP)-induced platelet aggregation in healthy volunteers. The aim of this study was to test in patients (n = 416) scheduled for coronary artery stenting whether P2Y12 haplotype H2 carriage is associated with increased ADP-induced platelet aggregation after administration of a 600 mg loading dose of clopidogrel. Blood was drawn from the arterial sheath at least 2 h after administration of 100 mg aspirin and 600 mg clopidogrel. ADP-induced platelet aggregation was assessed in platelet-rich plasma with light-transmission aggregometry. P2Y12 haplotypes (H1/H2) and P2Y12 C32T genotypes were determined with TaqMan assays. Haplotype combinations and genotypes were not associated with parameters of ADP-induced platelet aggregation after administration of a 600 mg loading dose of clopidogrel. Maximal ADP (5 mumol/l)-induced platelet aggregation was similar in patients carrying haplotype H2 and homozygous carriers of haplotype H1 (43.9 +/- 21.4 versus 43.2 +/- 21.1%, respectively; P = 0.77). Carriage of P2Y12 H2 haplotype does not seem to affect the platelet response to a 600 mg loading dose of clopidogrel in coronary artery disease patients prior to stenting.     

Feasibility of intravenous administration of aspirin in acute coronary syndrome

s To compare the clinical effects of intravenously and orally administered aspirin in the treatment for acute coronary syndrome (ACS),and to evaluate the adverse effects of intravenous administration of aspirin.Methods One hundred and twenty-five patients with unstable angina pectoris or acute myocardial infarction were randomized into three groups:group 1 received intravenous aspirin (300mg/d,n =40),while groups 2 (n =42) and 3 (n =43) received orally administered aspirin (100mg/d and 300mg/ d,respectively).The control group included 30 patients with no heart disease or blood disease,and they had never taken aspirin and clopidogrel.Blood samples were taken at 2nd and 7th day of hospitalization.Platelet aggregation and the level ofplatelet activation marker CD62p were measured and compared among the groups.Patients were followed up for 6 months for the occurrence of major adverse cardiovascular events.Results There were no statistically significant differences in the decrease in adenosine diphosphate (ADP)-induced platelet aggregation rate (12.01±10.45%,6.76±14.62% and 9.73±16.72% for group 1,group2 and group 3,respectively),the decrease in arachidonic acid (AA)-induced platelet aggregation rate (6.73±11.34%,6.95±12.45% and 7.57±13.11%,respectively),and the decrease in CD62p level (10.89±18.62%,8.92±11.57% and 7.05±15.67%,respectively).At six months,there were 4 deaths (10%) in group 1,4 deaths (9.5%) in group 2 and 5 deaths (11.6%) in group 3 (P＞0.05).Conclusions Intravenous administration of aspirin provides a new approach as an anti-platelet treatment for ACS patients,especially those who can not tolerate oral administration of aspirin.(J Geriatr Cardiol 2008;5:212-216)     

Pharmacodynamic effects of EV-077 in patients with diabetes mellitus and coronary artery disease on aspirin or clopidogrel monotherapy: results of an in vitro pilot investigation

Patients with diabetes mellitus (DM) have increased propensity to generate thromboxane A₂ (TXA₂) and other eicosanoids which can contribute to their heightened platelet reactivity. EV-077 is a potent thromboxane receptor antagonist and thromboxane synthase inhibitor and thus represents an attractive therapy in patients with DM. However, the effects of EV-077 on pharmacodynamic (PD) profiles in patients with DM and coronary artery disease (CAD) while on antiplatelet therapy is poorly explored and represented the aim of this in vitro pilot investigation. Patients with DM and stable CAD (n = 10) on low-dose aspirin (81 mg/day) were enrolled and then switched to clopidogrel (75 mg/day) monotherapy for 7–10 days. PD assessments were conducted while on aspirin and on clopidogrel using light transmittance aggregometry following stimuli with U-46619 [TXA₂ stable analogue (7 μM)], arachidonic acid [AA (1 mM)], collagen (3 μg/mL) and adenosine diphosphate [ADP (5 μM and 20 μM)] with and without in vitro EV-077. EV-077 completely inhibited U-46619-stimulated platelet aggregation (p = 0.005 for both aspirin and clopidogrel) and also showed a significant reduction of collagen-induced aggregation (aspirin p = 0.008; clopidogrel p = 0.005). EV-077 significantly reduced AA-induced platelet aggregation in clopidogrel (p = 0.009), but not aspirin (p = 0.667) treated patients. Ultimately, EV-077 significantly reduced ADP-mediated platelet aggregation in both aspirin (ADP 5 μM p = 0.012; ADP 20 μM p = 0.032) and clopidogrel (ADP 5 μM p = 0.007; ADP 20 μM p = 0.008) treated patients. In conclusion, in DM patients with CAD on aspirin or clopidogrel monotherapy, in vitro EV-077 exerts potent platelet inhibitory effects on multiple platelet signaling pathways. These data support that EV-077 has only additive platelet inhibiting effects on top of standard antiplatelet therapies. These findings warrant further investigation in ex vivo settings.     

A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is characterised by in situ thrombosis and increased thromboxane (Tx) A2 synthesis; however, there are no studies of antiplatelet therapy in IPAH. The aim of the current study was to determine the biochemical effects of aspirin (ASA) and clopidogrel on platelet function and eicosanoid metabolism in patients with IPAH. A randomised, double-blind, placebo-controlled crossover study of ASA 81 mg once daily and clopidogrel 75 mg once daily was performed. Plasma P-selectin levels and aggregometry were measured after exposure to adenosine diphosphate, arachidonic acid and collagen. Serum levels of TxB2 and urinary metabolites of TxA2 and prostaglandin I2 (Tx-M and PGI-M, respectively) were assessed. A total of 19 IPAH patients were enrolled, of whom nine were being treated with continuous intravenous epoprostenol. ASA and clopidogrel significantly reduced platelet aggregation to arachidonic acid and adenosine diphosphate, respectively. ASA significantly decreased serum TxB2, urinary Tx-M levels and the Tx-M/PGI-M ratio, whereas clopidogrel had no effect on eicosanoid levels. Neither drug significantly lowered plasma P-selectin levels. Epoprostenol use did not affect the results. In conclusion, aspirin and clopidogrel inhibited platelet aggregation, and aspirin reduced thromboxane metabolite production without affecting prostaglandin I2 metabolite synthesis. Further clinical trials of aspirin in patients with idiopathic pulmonary arterial hypertension should be performed.     

Response to aspirin and clopidogrel monitored with different platelet function methods

Laboratory non-response to aspirin or clopidogrel is defined as an inability to cause in vitro detectable platelet function inhibition. It would be beneficial to monitor response to aspirin or clopidogrel with widely available and routinely used platelet function methods, like the platelet function analyzer (PFA-100) or the fully automated coagulation analyzer BCT. The aim of this study was to assess the potential of the coagulation analyzer BCT and the platelet function analyzer PFA-100 in monitoring the response of aspirin and clopidogrel. A group of 125 consecutive patients with arterial occlusive disease treated either with aspirin 100 mg/day (82 patients) or clopidogrel 75 mg/day (43 patients) as only antiplatelet drug were investigated. For the first time platelet-enriched plasma (PRP), not adjusted to a fixed predetermined concentration of platelets, was used for aggregation studies and the effect of clopidogrel alone without combination of aspirin treatment on platelet function was investigated. Response to aspirin was observed in 85% (70/82) of patients using PFA-100, while performing the arachidonic acid-induced aggregation on the BCT showed an inhibitory effect to aspirin in 91% (75/82) of patients. Non-response to aspirin was assessed with both platelet function methods in 7% (6/82) of patients. Clopidogrel response was observed in 58% (25/43) of patients when performing ADP-induced aggregation on the BCT. On the PFA-100 the antiplatelet effect of clopidogrel could not be detected. In conclusion, measurement of platelet aggregation on the BCT using native platelet-enriched plasma allows the quantification of individual inhibitory effects to aspirin as well as to clopidogrel, while the PFA-100 seems only suitable to investigate the degree of platelet inhibition induced by aspirin but not by clopidogrel.     

应用血栓弹力图评价糖尿病对急性冠状动脉综合征患者血小板抑制率的影响

目的 了解糖尿病对双联抗血小板治疗的急性冠状动脉综合征患者血小板抑制率的影响.方法 选择自2011年12月至2012年7月在我院住院的急性冠状动脉综合征患者90例为研究对象.入院后均给予标准双联抗血小板治疗,并于入院即刻及入院第7天应用血栓弹力图仪测定花生四烯酸（AA）和二磷酸腺苷（ADP）诱导的血小板抑制率,根据是否合并糖尿病,将患者分为糖尿病组和非糖尿病组,比较两组患者AA和ADP诱导的血小板抑制率的差异及血糖、糖化血红蛋白与血小板抑制率的相关性.结果 90例急性冠状动脉综合征患者中合并糖尿病患者38例,非糖尿病患者52例,入院第7天,前者AA诱导的血小板抑制率为74.2％ ±20.2％,ADP诱导的血小板抑制率为42.6％±18.5％,后者分别为78.5％±21.3％和60.7％±27.5％,两组患者之间AA抑制率差异无统计学意义,而ADP抑制率在糖尿病患者中低于非糖尿病患者（P＜0.05）.糖化血红蛋白与ADP诱导的血小板抑制率呈明显负相关（r=-0.286,P＜0.05）,与AA抑制率无明显相关性.空腹血糖与AA和ADP抑制率均无明显相关性.结论 糖尿病患者ADP诱导的血小板抑制率降低,且与糖化血红蛋白呈负相关,而AA诱导的血小板抑制率无明显变化.     

Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: enhanced inhibitory effects of combination therapy

OBJECTIVES: We sought to compare the inhibitory effects of the combination of two doses of aspirin plus clopidogrel with either drug alone on platelet aggregation and activation. BACKGROUND: Enhanced platelet inhibitory effects of clopidogrel by aspirin on platelet aggregation and activation are suggested by experimental studies but have not been shown in humans. METHODS: The effects of clopidogrel 75 mg or aspirin 100 (300) mg on platelet aggregation and activation by flow cytometry after stimulation with various agonists were determined in 30 patients with a past history of myocardial infarction. RESULTS: Clopidogrel alone or in combination with aspirin markedly inhibited adenosine diphosphate (ADP)-mediated platelet aggregation compared with monotherapy with aspirin (24.6 +/- 3.3% or 26.6 +/- 2.7% vs. 44.7 +/- 2.9%; p < 0.001). Combined treatment significantly inhibited collagen-induced aggregation compared with aspirin and clopidogrel (16.4 +/- 2.4%, 36.5 +/- 4.2% and 59.3 +/- 5.1%, respectively;, p < 0.001) and resulted in considerable inhibition of aggregation induced by thrombin receptor agonist peptide (TRAP, p < 0.03). Clopidogrel with or without aspirin significantly suppressed expression of platelet activation markers CD 62p, CD 63 and PAC-1 after stimulation with ADP or thrombin (p < 0.001). In addition, the combined treatment was more effective than either agent alone after activation with low dose thrombin (p < 0.05). Both doses of aspirin equally potentiated the platelet inhibitory effects of clopidogrel. CONCLUSIONS In this prospective clinical ex vivo platelet study, clopidogrel was more effective than aspirin in inhibiting ADP-mediated platelet aggregation and activation. Clopidogrel in combination with aspirin showed synergistic inhibitory effects after stimulation with collagen and thrombin compared with monotherapies. Thus, this dual antiplatelet treatment strategy deserves further evaluation in clinical trials for secondary prevention of acute myocardial infarction or unstable angina.