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.     

冠状动脉支架术后三联抗血小板药物治疗对血小板功能的影响

目的探讨三联抗血小板药物治疗对冠状动脉(冠脉)支架术后患者血小板活化和聚集功能的影响。方法120例冠心病行冠脉支架植入术患者,随机分为三联组(阿司匹林、氯吡格雷和西洛他唑)和两联组(阿司匹林和氯吡格雷),三联组于术后第1天起加服西洛他唑。两组分别于术后第1天服用西洛他唑前及第5天测定血小板活化复合物(PAC-1)和CD_(62)p,同时测定5μmol/L及20μmol/L ADP诱导的血小板最大聚集率(MPAR)。结果两组临床基线资料及CD_(62)p、PAC-1和MPAR基线值差异均无统计学意义。分别计算各指标第二次测定值与基线值的差值,两组ΔMPAR差异无统计学意义,但三联组和两联组ΔCD_(62)p和ΔPAC-1分别为[(5.12±11.25)%比(1.08±4.97)%,P＜0.05]和[(12.12±12.30)%比(2.22±15.15)%,P＜0.01]。对急性冠脉综合征(ACS)患者亚组分析结果表明三联组ΔMPAR(5μmol/L)[(8.68±10.35)％比(2.92±13.06)%,P=0.018]、ΔMPAR(20μmol/L)[(11.05±11.14)%比(5.16±13.27)%,P=0.019]、ΔCD_(62)p[(5.57±12.08)％比(1.35±4.42)%,P=0.028】和ΔPAC-1[(11.62±12.73)%比(1.29±15.73)%,P= 0.001]均显著高于两联组。3个月临床随访显示三联组与两联组主要不良心、脑血管事件发生率分别为0和3.3%(2/60),出血发生率分别为5%(3/60)和3.3%(2/60),均无统计学意义。结论三联抗血小板药物治疗与常规两联治疗相比能更有效地抑制冠脉支架术后血小板活化和聚集,但其疗效和安全性还需大规模临床试验证实。     

Cilostazol could ameliorate platelet responsiveness to clopidogrel in patients undergoing primary percutaneous coronary intervention.

BACKGROUND: Cilostazol increases the cyclic adenosine monophosphate levels in platelets and might ameliorate the antiplatelet activity of clopidogrel. This study investigated the additional effect of cilostazol on platelet aggregation measured by a VerifyNow analyzer and soluble CD40 ligand (sCD40L) as a marker of activated platelet in patients undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: Sixty cases of primary PCI were randomly assigned to dual (aspirin and clopidogrel) or triple (dual plus cilostazol) therapy. The antiplatelet effects of aspirin and clopidogrel were evaluated by VerifyNow tests. The plasma sCD40L levels at admission, 24 h and 21 days were measured by the ELISA method. The arachidonic acid induced platelet aggregation was similar in both groups. However, the triple group had a significantly lower P2Y12 reaction unit (dual 208.8+/-69.0 vs triple 168.2+/-79.2, p=0.041) and higher % inhibition of adenosine diphosphate (ADP)-induced platelet aggregation (dual 23.8+/-21.4% vs triple 40.5+/-21.0%, p=0.004). In the multivariate analysis, cilostazol was a negative predictor for low responders to clopidogrel (95% confidence interval 0.067-0.711). The plasma sCD40L levels were not significantly different between the 2 groups at the same point of time. CONCLUSIONS: The addition of cilostazol to the combination of aspirin plus clopidogrel significantly increases the inhibition of ADP-induced platelet aggregation. However, there was no additive effect on aspirin-induced antiplatelet activity or lowering of sCD40L.     

抗血小板治疗预防冠脉支架术后再狭窄的Meta分析

目的:就冠状动脉(冠脉)支架术后有关西洛他唑、氯吡格雷、阿司匹林三联抗血小板治疗对血小板活化和聚集功能及支架内再狭窄的影响相关文献进行系统评价。方法:计算机检索国内外公开发表的有关西洛他唑,氯吡格雷,阿司匹林对血小板聚集率、冠脉支架术后再狭窄率影响的临床随机对照试验文献,按一定标准筛选文献后进行质量评价,共纳入5篇随机对照研究文献。以Cochrane协作网的软件RevMan v5.0进行处理,主要以血小板聚集抑制率,最小管腔直径(MLD),晚期管腔丢失,再狭窄率为评价指标,进行Meta分析。结果:在以二磷酸腺苷(ADP)为诱导剂的血小板聚集抑制率方面,实验组与对照组之间差异无显著意义,在最小血管直径,晚期血管丢失,再狭窄率方面,试验组与对照组之间的差异存在显著意义。结论:三联(西洛他唑+氯吡格雷+阿司匹林)抗血小板药物治疗与常规两联(氯吡格雷+阿司匹林)治疗组相比能更有效地抑制冠脉支架术后的再狭窄,但其疗效和安全性还需要大规模临床试验的证实。     

Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis.

OBJECTIVES: We evaluated safety and efficacy of triple antiplatelet therapy with aspirin, clopidogrel, or ticlopidine and cilostazol after coronary stenting. BACKGROUND: Triple antiplatelet therapy might have beneficial effect to prevent thrombotic complications in patients undergoing coronary stenting. METHODS: Patients undergoing successful coronary stenting were divided into dual antiplatelet therapy (aspirin plus clopidogrel or ticlopidine, group I, n = 1,597) and triple antiplatelet therapy (aspirin plus clopidogrel or ticlopidine plus cilostazol, group II, n = 1,415) groups. The primary end point included death, myocardial infarction, target lesion revascularization, or stent thrombosis within 30 days. The secondary end point was side effects of study drugs, including major bleeding, vascular complication, hepatic dysfunction, and hematological complications. RESULTS: Multi-vessel stenting and the use of long stents were more prevalent in group II than in group I. The primary end point was 0.8% in group I and 0.3% in group II (p = 0.085). Stent thrombosis within 30 days was significantly lower in group II (n = 1, 0.1%) than in group I (n = 9, 0.5%; p = 0.024). The independent predictors of stent thrombosis were primary stenting (odds ratio [OR] 7.9, 95% confidence interval [CI] 2.0 to 30.8, p = 0.003) and triple therapy (OR 0.12, 95% CI 0.015 to 0.98, p = 0.048). The overall adverse drug effects, including major bleeding, neutropenia, and thrombocytopenia, were no different between two groups (1.8% vs. 2.6%, p = 0.104). CONCLUSIONS: Compared with the dual antiplatelet regimen, triple antiplatelet therapy seemed to be more effective in preventing thrombotic complications after stenting without an increased risk of side effects. Triple antiplatelet therapy might be safely applied in patients or lesions with a high risk of stent thrombosis.     

Loading effect of 200 mg cilostazol on platelet inhibition in patients undergoing percutaneous coronary intervention

To date, most studies conducted on cilostazol have examined its effects as an agent of maintenance-dose therapy, but its loading effects on platelet inhibition have never been reported. This study aimed to determine the loading effects of 200 mg cilostazol in addition to aspirin and clopidogrel on platelet inhibition in patients undergoing percutaneous coronary intervention.Sixty consecutive patients undergoing coronary intervention were enrolled and assigned to receive 300 mg of aspirin and clopidogrel with or without 200 mg of cilostazol. All loading doses were given at least 3 hours before percutaneous coronary intervention and followed by dual or triple maintenance-dose therapy. Platelet function tests were performed just before and at 24 hours and 30 days after percutaneous coronary intervention by light transmittance aggregometry and VerifyNow? P2Y12 assay.There were no significant differences in baseline or angiographic characteristics between the 2 groups. The results of platelet function tests revealed that the adjunctive loading dose of 200 mg of cilostazol induced more potent platelet inhibition compared to a dual regimen at each time point. Cilostazol reduced the incidence of high post-treatment platelet reactivity (HPPR).Adjunctive 200 mg cilostazol can improve platelet responsiveness to clopidogrel in the pre- and postprocedural phases, reducing the prevalence of HPPR.     

The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease

Peripheral arterial disease (PAD) is associated with platelet hyperactivity. Aspirin and clopidogrel, two platelet inhibitors, act by different mechanisms. Aspirin inhibits thromboxane A2 synthesis and clopidogrel acts on the P2Y12 platelet ADP receptor. We evaluated the effect of clopidogrel (75 mg/day), aspirin (75 mg/day) and then both drugs on several platelet function indices in patients with PAD (n = 20). There was a significant (P = 0.0001) decrease in ADP-induced aggregation, after clopidogrel but not after taking aspirin. Clopidogrel plus aspirin significantly decreased spontaneous platelet aggregation (SPA) (P = 0.01 to P = 0.002) but SPA was not significantly altered by either aspirin or clopidogrel monotherapy. Similarly, monotherapy did not inhibit serotonin (5HT)-induced aggregation but there was a sigificant inhibition (P = 0.03 to P < 0.02) after combination therapy. ADP (0.8 microM)-induced platelet shape change (PSC) was significantly inhibited by clopidogrel (P = 0.004) or aspirin (P = 0.01). This was also true for 5HT-induced PSC (clopidogrel, P = 0.01; aspirin, P = 0.03). Soluble P-selectin decreased significantly (from 32 +/- 24 to 25 +/- 17 ng/ml, P = 0.04) with combination therapy. Plasma platelet-derived growth factor and intraplatelet 5HT levels were not altered by combination therapy. In PAD, clopidogrel is a more potent inhibitor of ADP-induced platelet activation than aspirin; combination therapy is more effective than clopidogrel or aspirin monotherapy. These potentially clinically relevant findings should be evaluated in appropriately designed trials.     

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.     

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.     

阿托伐他汀或瑞舒伐他汀与氯吡格雷合用在非ST段抬高型急性冠状动脉综合征患者支架置入术后的近期疗效比较

目的比较阿托伐他汀或瑞舒伐他汀与氯吡格雷合用在非ST段抬高型急性冠状动脉综合征(NSTE-ACS)支架置入术后患者的近期疗效。方法共154例NSTE-ACS的患者接受支架置入术后,随机分为服用阿托伐他汀组(74例)及服用瑞舒伐他汀组(80例),术前服用阿司匹林(100mg)5 d、氯吡格雷(75 mg)5 d以上或术前12 h以上顿服氯吡格雷300 mg及阿司匹林片300 mg,于术前服抗血小板药前、手术当天、术后3、7 d及术后1、6个月抽取静脉血测定二磷酸腺苷(ADP)(浓度为10μmol/L)诱导的血小板聚集功能,观察住院期间及6个月的主要不良心脏事件(MACE)。结果两组患者的临床基线资料及服药情况差异无统计学意义,服用氯吡格雷(75 mg)5 d或顿服300 mg能达到明显的血小板聚集率抑制作用,血小板聚集率在阿托伐他汀组由基线的(57.2±10.3)%降至手术当日的(32.5±11.2)%,而瑞舒伐他汀组分别为(59.1±9.8)%和(30.4±10.1)%(均为P<0.01),而且这种抑制作用稳定持续至6个月之后。6个月时两组间总的MACE发生率差异无统计学意义(13.0%比15.0%,P>0.05),两组心原性死亡、非致死性心肌梗死、靶血管重建术、支架内血栓形成及出血事件差异均无统计学意义(均为P>0.05)。结论接受冠脉支架置入术的NSTE-ACS患者,服用阿托伐他汀或瑞舒伐他汀后,短期内未发现对氯吡格雷抗血小板作用产生显著影响,且两组间的近期疗效相近。     

Platelet responsiveness to clopidogrel in patients with coronary syndrome. Comparison of platelet aggregation induced by ADP and flow cytometric analysis of intraplatelet VASP phosphorylation

Although antiplatelet therapy with ASA-clopidogrel reduces the risk of cardiovascular episodes after PCI, a substantial number of events occur during follow-up. Sustained platelet reactivity under dual antiplatelet therapy was recently associated with increased risk of recurrent atherothrombotic events after PCI. Whereas it appears significant to determine clopidogrel responsiveness, the accurate platelet function assay is still under investigation. OBJECTIVES: (i) to determine the proportion of "low-responders" or "resistants" patients during coronary syndrome (ii) to identify determinants of interindividual variability response to clopidogrel (iii) to compare aggregometry and VASP phosphorylation measured by flow cytometry. Patients were treated by clopidogrel (300 mg loading dose and 75 mg maintenance dose) and ASA (160 mg) (N=27). Additional treatment by GPIIbIIIa antagonists was given to high-risk patients (N=9). Platelet function was monitored by ADP aggregometry (5, 10, 20 microM) and VASP phosphorylation before any treatment by clopidogrel (d0) and at least five days after (d5). The platelet reactivity index (PRI), expressed as percentage, is the difference in VASP fluorescence intensity between resting (+ PGE1) and activated (ADP) platelets. At d5, low responsiveness to clopidogrel was defined by either (i) a PRI > 67.3% corresponding to the mean value -2SD measured in untreated patients (dO) (ii) or an absolute change (delta d0-d5) in aggregation (ADP 10 microM) < to 30%. RESULTS: PRI, platelet aggregometry to ADP was significantly reduced following clopidogrel treatment (P < 0.01). A wide inter-individual variability to clopidogrel was observed at d5 (PRI from 11 to 83%). Whatever the platelet function used, a large proportion of patients were detected as "low-responders" (37% by VASP, 44% by ADP aggregometry). Absolute change in ADP aggregation was correlated to the variation of PRI (R = 0.559; P = 0.02). Contrary to ADP aggregometry, PRI was not influenced by GPIIbIIIa antagonists or prior administration of ASA. However, the conformity of the two methods to evaluate clopidogrel responsiveness was only 66%. No differences in platelet aggregometry could be observed at d5 between "low" and "good-responders" defined by VASP analysis. At d5, a higher PRI value could be detected in male and patients with history of dyslipemia. CONCLUSION: During coronary syndrome, impaired platelet responsiveness to clopidogrel was observed in a large proportion of patients whatever the platelet function assay used. VASP analysis was found insensitive to GPIIbIIIa or aspirin administration. Possible mechanisms linking clopidogrel "resistance" measured by VASP assay and enhanced thrombogenicity remain to be characterized. Indeed, clopidogrel "resistance" defined by VASP analysis was not associated with higher platelet aggregation.     

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 antiplatelet agents on subacute thrombosis and restenosis after successful coronary stenting: a randomized comparison of ticlopidine and cilostazol.

BACKGROUND: A prospective randomized study compared the preventive effects of ticlopidine plus aspirin therapy versus cilostazol plus aspirin therapy on subacute thrombosis (SAT) and restenosis after coronary stenting. METHODS AND RESULTS: After successful stenting of 327 coronary lesions in 282 consecutive patients, the patients were randomized to receive ticlopidine (200 mg/day) or cilostazol (200 mg/day). Aspirin (81 mg/day) was administered concomitantly in both groups. SAT occurred in 1 patient in the ticlopidine group (0.7%) and in 8 patients in the cilostazol group (5.6%, p=0.037). Based on follow-up angiography, restenosis occurred in 30 patients (23.3%) in the ticlopidine group and 35 patients (26.9%) in the cilostazol group (NS). The late loss was significantly smaller in the cilostazol group than the ticlopidine group (1.08+/-0.95 mm vs 0.78+/-0.93 mm, respectively, p=0.037). No significant differences between the 2 groups were observed with respect to the rates of total death, non-fatal cardiovascular events, or bleeding complications. CONCLUSION: The ticlopidine group showed significantly less SAT after stenting compared with the cilostazol group. After 6 months of treatment, the inhibition of neointimal proliferation was greater in the cilostazol group than in the ticlopidine group, but the prevention of restenosis was not confirmed.     

二磷酸腺苷介导血小板聚集率指导老年择期冠状动脉介入治疗患者术后抗血小板药物使用

目的 评价以二磷酸腺苷(ADP)介导血小板聚集率指导抗血小板药物在老年择期经皮冠状动脉介人治疗(PCI)患者中使用对心血管事件的影响.方法 选取我院2007-2008年老年择期西罗莫司涂层支架植入患者1230例,年龄60～80岁,平均(67.2±10.2)岁,随机选取615例入ADP组,首剂300 mg负荷量后,根据血小板聚集率调整氯吡格雷使用量,分别于用药前、用药第2天、第3天测定ADP介导的血小板聚集率,达标后(聚集率较用药前降低50%)75 mg/d.若未达标,第2、3天可逐次增加300 mg,累计至900 mg;若仍未达标,则改用氯吡格雷75 mg/d联合西洛他唑100 mg/d、阿司匹林100 mg/d三重抗血小板药物治疗持续1年.其余615例入常规组,以常规剂量和方法使用氯吡格雷(首剂300 mg负荷量后,继之以75 mg/d口服持续1年).分别于用药前、用药第3天测定ADP介导的血小板聚集率;两组患者均持续口服氯吡格雷1年.所有患者均在给药前、后进行安全性实验室检查.随访1年,记录心血管事件(心原性死亡、心肌梗死、血运重建、支架血栓事件)和药物不良事件发生率.结果 1230例患者首剂负荷量300 mg后.达标率44.9%ADP组累计总量至900 mg时,ADP组达标率增至67.5%,约32.5%的患者(203/615)仍未达标;改用氯吡格雷、西洛他唑、阿司匹林三重抗血小板药物治疗.相对于常规负荷剂量氯吡格雷,高负荷剂量氯吡格雷有更好的抑制血小板聚集的效果(常规负荷剂量对高负荷剂量,45%对67.5%,P=0.028).平均随访(10.0±2.4)个月,两组心血管事件发生率差异有统计学意义(2.8%对4.9%,P=0.035),常规组急性和亚急性支架血栓事件多于ADP组(4例对1例).所有患者均未出现大出血,两组间轻微出血病例差异无统计学意义,无药物不良反应.结论 PCI术后患者应该检测血小板对氯吡格雷的反应效果;ADP介导的血小板聚集率指导老年择期PCI患者围术期抗血小板药物使用安全、有效,可明显降低1年的心血管事件发生率.     

西洛他唑预防糖尿病冠心病金属裸支架术后再狭窄的效果

目的观察服用西洛他唑预防糖尿病冠心病金属裸支架术后再狭窄的疗效。方法2004年3月至12月我院收治的157例有糖尿病的冠心病患者,择期植入金属裸支架治疗,术后把患者随机分为两组,治疗组每天服用西洛他唑200mg、阿司匹林100mg和氯吡格雷75mg;氯吡格雷组每天服用阿司匹林100mg和氯吡格雷75mg。持续服用6个月,主要测量血管造影:植入金属裸支架的病变处最小腔内直径(MLD)。其次观察临床不良心脑血管事件(MACCE):死亡、非致死性急性心肌梗死、靶血管重建、脑卒中、急性、亚急性血栓,以及出血等不良事件的发生率。结果6个月时冠状动脉造影随访,西洛他唑组MLD明显大于氯吡格雷组(2·48mmvs1·94mm,P<0·05);再狭窄率(13·1%vs35·3%,P<0·05)明显低于氯吡格雷组。两组的主要心脑血管事件及出血不良事件比较差异无显著性(P>0·05)。结论有糖尿病的冠心病金属裸支架术后应用西洛他唑可减少金属裸支架术后再狭窄率,增加随访期的MLD,而没有增加出血并发症,临床应用安全有效。     

三联抗血小板在老年复杂冠状动脉介入患者术后有效性和安全性对照研究

目的评价西洛他唑、氯吡格雷和阿司匹林三联抗血小板药物在老年复杂冠状动脉介入患者植入多枚药物洗脱支架（DES）术后的疗效和安全性。方法2006年3月至2009年9月人选128例冠状动脉B2／C型病变、采用多DES植入的老年（65-75岁）患者。所有入选患者术后随机分为两组：标准化治疗组（对照组,n=67）和三联抗血小板治疗组（试验组,n=61）。3个月后所有患者接受标准化治疗直至术后12个月。观察两组患者临床特征、冠状动脉病变特点以及支架植入特征,平均随访（20．4±5．1）个月主要心血管事件、支架内血栓和出血事件。结果试验组心肌梗死及再次血运重建发生率均显著低于对照组（6．56％vs11．94％,P=0．043;6．56％vs13．43％,P=0．042）。两组全因病死率差异无统计学意义（1．64％vs2．99％,P=0．615）。试验组主要终点事件绝对风险较对照组降低8．07％（P=0．043）。试验组近期、远期支架内血栓事件发生率显著低于对照组（0．00％vs2．99％,P=0．050;1．64％vs4．48％,P=0．048）：两组间出血发生率差异无统计学意义（P〉0．05）。结论三联抗血小板药物可降低复杂冠状动脉介入老年患者术后发生主要不良心血管事件、支架内血栓形成的风险,并且不增加出血事件的发生风险。     

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.     

Comparative inhibitory effects of cilostazol and ticlopidine on subacute stent thrombosis and platelet function in acute myocardial infarction patients with percutaneous coronary intervention

We compared the effects of ticlopidine and cilostazol on the prevention of subacute stent thrombosis (SAT) in acute myocardial infarction (AMI) patients with stenting. We also analyzed the cause of the difference by measuring platelet aggregation activity. Consecutive patients who underwent successful stenting for AMI between March 2001 and March 2004 were analyzed. In addition to aspirin (100 mg/day), cilostazol (200 mg/day) was administered to 99 cases between March 2001 and May 2002 and ticlopidine (200 mg/day) was administered to 85 cases between June 2002 and February 2004. The incidence of SAT within four weeks after stenting was analyzed. Thirty-eight AMI patients were randomized and their platelet aggregation activity was measured using a laser-scattered aggregometer (18 cases in the cilostazol group and 20 cases in the ticlopidine group). SAT did not occur in the ticlopidine group while 5 cases (5.1%) of SAT occurred in the cilostazol group (P < 0.05). The inhibitory activity of cilostazol for ADP-induced platelet aggregation was lower than that of ticlopidine (P < 0.05). Cilostazol with aspirin after stenting in AMI patients showed more frequent SAT than ticlopidine with aspirin. One of the causes for this difference was speculated to be the weaker inhibitory activity of cilostazol for ADP-induced platelet aggregation.     

Optimal management of platelet function after coronary stenting

Opinion statement Coronary stenting elicits vessel wall damage, and subsequent activation of platelets is implicated as a major component of complications such as acute, subacute, and late stent thrombosis. As such, dual antiplatelet therapy using aspirin and clopidogrel has become a routine adjunct to coronary stenting. Use of aspirin and clopidogrel with or without glycoprotein IIb/IIIa inhibitors after coronary stenting reduces the complication rate and improves long-term outcomes. Dual antiplatelet therapy using aspirin and clopidogrel is recommended for at least 4 weeks with bare metal stents, and for 3 to 6 months with drug-eluting stents for prevention of major adverse cardiac events. After coronary stenting, 1 year of dual antiplatelet therapy is recommended for prevention of future cardiac events. However, despite the use of antiplatelet agents, stent thrombosis occurs in approximately 1% of patients, with an increased likelihood of occurrence in high-risk patients or a lesion subset of patients. Although the incidence of stent thrombosis is low, stent thrombosis usually presents as acute coronary syndrome and the mortality rate is up to 45%. Thus, considering the widespread use of stents, a considerable number of people are inadequately protected from thrombotic events despite current standard antiplatelet therapy using aspirin and clopidogrel. A concern with clopidogrel is the loading time and loading dose required to achieve and maintain optimal inhibition of platelet aggregation. The current recommendation for ensuring maximum antiplatelet activity is administration of a 300-mg loading dose of clopidogrel initiated at least 6 hours prior to percutaneous coronary intervention (PCI), and ideally the day before. If this is not possible, a loading dose of 600 mg of clopidogrel should be administered at least 2 hours before PCI. Recently, new combinations of antiplatelet agents (ie, triple therapy using aspirin, clopidogrel, and cilostazol) and new drugs with potent antiplatelet effects (ie, Prasugrel [currently being developed by Sankyo Pharmaceuticals and Ube Pharmaceuticals in Japan and by Eli Lilly and Co. (Indianapolis, IN) in the United States], Cangrelor [currently being developed by AstraZeneca Pharmaceuticals, Wilmington, DE], and AZD6140) have been evaluated in clinical trials; such treatments may help reduce the number of cardiac events after coronary stenting.     

三联抗血小板药物对缺血性脑血管病患者冠状动脉介入治疗术后的近期疗效

目的探讨既往有缺血性脑血管事件发作史的冠心病患者行经皮冠状动脉介入治疗(PCI)后应用西洛他唑联合阿司匹林和氯吡格雷三联抗血小板治疗方案的近期疗效和安全性。方法回顾性分析有缺血性脑血管病史且接受PCI治疗的冠心病患者共216例,其中80例PCI后应用三联抗血小扳治疗(三联组),136例PCI后应用阿司匹林联合氯吡格雷两联抗血小板治疗(两联组)。观察两组PCI后30天主要不良心脑血管事件(MACCE)、亚急性血栓和出血发生率结果两组临床基线特征及PCI即刻结果无差异,术中均无死亡;三联组患者30天病死率、脑卒中发生率、MACCE发生率均显著低于两联组(P值分别<0．05,<0．05,<0．01)。两组亚急性血栓、30天主要出血事件、脑出血发生率差异均无显著性意义。结论有缺血性脑血管病史患者PCI后应用氯吡格雷、阿司匹林和西洛他唑三联抗血小板治疗后,可显著降低近期死亡、脑卒中及MACCE发生率,且不增加脑出血等副作用。