A novel fifteen minute test for assessment of individual time-dependent clotting responses to aspirin and clopidogrel using modified thrombelastography

Background: A rapid, reliable, point of care test reflecting patient specific responses to antiplatelet therapy would be of great clinical value in percutaneous coronary intervention (PCI). The aim of this study was to establish whether modified thrombelastography (TEG) can be employed as a 15 minute test of individual patient responses to aspirin and clopidogrel using a novel parameter, percentage clotting inhibition (%CIn).

Methods and results: Thirty healthy volunteers and 10 patients undergoing elective PCI were recruited into four groups: 10 volunteers received a single 300?mg dose of aspirin [A1]: 10 volunteers received aspirin 75?mg daily for 7 days [A2]: 10 volunteers received a 600?mg dose of clopidogrel [C1]: 10 patients received a 600?mg loading dose of clopidogrel prior to elective PCI [C2]. In all cases the area under the clotting response curve was measured at 15 minutes (AUC15) and used to calculate a novel parameter, percentage clotting inhibition (%CIn). Large differences were demonstrated in both aspirin and clopidogrel groups in response to therapy as assessed by both the area under the curve at 15 minutes and %CIn. Furthermore, the technique demonstrated important heterogeneity of time-dependent responses between individuals.

Conclusion: Modified TEG, employing AUC15 and %CIn, is a promising tool for assessing responses to aspirin and clopidogrel. Further data are now required to assess the potential of this test to optimise individual therapy in PCI patients in order to detect and treat those patients with relative hypo-responsiveness to anti-platelet drugs.     

A novel fifteen minute test for assessment of individual time-dependent clotting responses to aspirin and clopidogrel using modified thrombelastography

BACKGROUND: A rapid, reliable, point of care test reflecting patient specific responses to antiplatelet therapy would be of great clinical value in percutaneous coronary intervention (PCI). The aim of this study was to establish whether modified thrombelastography (TEG) can be employed as a 15 minute test of individual patient responses to aspirin and clopidogrel using a novel parameter, percentage clotting inhibition (%CIn). METHODS AND RESULTS: Thirty healthy volunteers and 10 patients undergoing elective PCI were recruited into four groups: 10 volunteers received a single 300 mg dose of aspirin [A1]: 10 volunteers received aspirin 75 mg daily for 7 days [A2]: 10 volunteers received a 600 mg dose of clopidogrel [C1]: 10 patients received a 600 mg loading dose of clopidogrel prior to elective PCI [C2]. In all cases the area under the clotting response curve was measured at 15 minutes (AUC15) and used to calculate a novel parameter, percentage clotting inhibition (%CIn). Large differences were demonstrated in both aspirin and clopidogrel groups in response to therapy as assessed by both the area under the curve at 15 minutes and %CIn. Furthermore, the technique demonstrated important heterogeneity of time-dependent responses between individuals. CONCLUSION: Modified TEG, employing AUC15 and %CIn, is a promising tool for assessing responses to aspirin and clopidogrel. Further data are now required to assess the potential of this test to optimise individual therapy in PCI patients in order to detect and treat those patients with relative hypo-responsiveness to anti-platelet drugs.     

Single high-dose bolus tirofiban with high-loading-dose clopidogrel in primary coronary angioplasty

Glycoprotein IIb/IIIa inhibitor therapy during primary percutaneous coronary intervention (PCI) decreases the incidence of major adverse cardiac events. These effects directly result from the level of platelet inhibition. It was shown that standard dosing of tirofiban is insufficient for optimal platelet inhibition. We sought to determine the efficacy and safety of single high-dose bolus (HDB) tirofiban with high-dose clopidogrel loading in primary PCI in acute ST elevation myocardial infarction. A total of 100 patients (mean age 55.2 ± 9.9 years, male/female = 86/14) undergoing primary PCI, pretreated with clopidogrel (450 mg) and aspirin (325 mg), were consecutively randomized into two groups. Group I (n = 50) received a standard dose bolus of tirofiban (10 μg/kg/3 min) with 24-h infusion at a rate of 0.15 μg/kg/min. Group II received single HDB tirofiban (25 μg/kg/3 min). The assessed angiographic, clinical, and echocardiographic endpoints were: initial and final Thrombolysis in Myocardial Infarction (TIMI) grade flow (TGF), corrected TIMI frame count (CTFC), ST-segment resolution (STR) at 90 min, in-hospital bleeding complications, echocardiographic left ventricular ejection fraction (LVEF), death, reinfarction, and repeat target vessel revascularization at 1 month. Platelet function inhibition was measured using PFA-100 (Behring-Dade, Liederbach, Germany) with a test cartridge unit containing a membrane coated with 2 μg of equine Type I collagen and 50 μg adenosine diphosphate before, and 10 min, 2, 4, 6, 12, and 24 h after the bolus of the tirofiban in the first 10 cases of each group. There were no significant differences in baseline characteristics between groups. Initial TGF III was more frequent (24% vs 8%, P = 0.029) and the value of CTFC was lower (75 ± 34 vs 89 ± 25, P = 0.03) in group II. Postprocedural TGF, CTFC, STR, bleeding complications, and LVEF at 1 month were not different between the two groups. There was a higher rate of reinfarction in group II (8%) compared with group I (2%), but this difference was not statistically significant (P > 0.05). The results of platelet function analyses showed that group II patients had significantly prolonged platelet function assay closure times (299 ± 6 s) compared with group patients (236 ± 97 s) at 10 min after the bolus dose (P = 0.04). However, after the first dose between 2 and 24 h, PFA closure times were significantly prolonged in patients with tirofiban infusion. High-dose bolus of tirofiban seems to be safe and more effective than conventional dose at the periprocedural time, whereas continuous infusion of tirofiban may be necessary in the first 24 h before stable and safe antiplatelet status is reached with clopidogrel. However, safety and efficacy of HDB tirofiban and high-loading-dose clopidogrel together with tirofiban infusion requires further studies with a larger population.     

Relation of low response to clopidogrel assessed with point-of-care assay to periprocedural myonecrosis in patients undergoing elective coronary stenting for stable angina pectoris

Impaired responses to antiplatelet therapy assessed by laboratory tests are associated with an increased risk of recurrent ischemic events after percutaneous coronary intervention (PCI). This study was designed to determine the relation between responses to aspirin and clopidogrel as assessed by a point-of-care assay (Verify Now, Accumetrics, San Diego, California) and periprocedural myocardial infarction (PMI) in patients undergoing elective PCI for stable angina. One hundred twenty-two consecutive patients undergoing elective coronary stenting prospectively received aspirin 500 mg and clopidogrel 600 mg >or=12 hours before PCI. Clopidogrel response was measured with P2Y12 reaction units (PRUs) and percent inhibition P2Y12 from baseline (percent inhibition P2Y12) and aspirin response with aspirin reaction units (ARUs). Troponin T level was considered positive if it was >0.03 ng/ml. Responses to aspirin and clopidogrel were correlated (r=0.42, p <0.0001). PMI occurred in 27 patients (22%) who showed significantly lower percent inhibition P2Y12 (25.3+/-26 vs 38.3+/-25, p=0.01) and a trend toward higher PRU values (221+/-87 vs 193+/-94, p=0.21). We did not find any difference for aspirin response as assessed by ARUs in patients with or without PMI (460+/-82 vs 454+/-73, p = 0.82). Stratification of percent inhibition P2Y12 isolated a quartile of clopidogrel nonresponders (inhibition P2Y12 <15%) with significantly higher incidence of PMI (44% vs 15%, odds ratio 4.6, 95% confidence interval 1.9 to 11.5, p=0.001). In conclusion, point-of-care assessment of clopidogrel response reliably predicted PMI after low- to medium-risk elective PCI for stable angina.     

非ST抬高急性冠脉综合征患者经皮冠脉介入治疗术后氯吡格雷使用方法的探讨

目的探讨非sT抬高急性冠脉综合征（NSTACS）患者经皮冠脉介入治疗术（PCI）后氯吡格雷用药的方法。方法选择我院符合标准的NSTACS患者75例,分成两组,A组42例服用氯吡格雷（波立维）75mg／d,12个月后停用,为直接停药组;B组33例服用氯吡格雷75mg／d,12个月后改为37．5mg／d,2周后停药,为渐停药组。检测两组患者在停（减）药前、停（减）药后2周的高敏C-反应蛋白（hs—CRP）。结果两组患者的hs—CRP水平停（减）药前差异无统计学意义（P〉0．05）,A组停（减）药2周后与停（减）药前差异有统计学意义（P〈0．01）。两组患者的hs—CRP水平停（减）药2周后差异有统计学意义（P〈0．05）。两组PCI术后12个月主要不良心血管事件间差异无统计学意义（P〉0．05）。结论氯吡格雷长期与阿司匹林等合用能够持续降低炎症水平,渐停法优于直接停药法。     

Clopidogrel treatment surrounding percutaneous coronary intervention: When should it be started and stopped?

Clopidogrel pretreatment before percutaneous coronary intervention (PCI) has been shown to decrease major adverse cardiovascular events (MACE) at 1 month. This benefit has been demonstrated in patients spanning the entire spectrum of coronary artery disease. Subsequent dual antiplatelet therapy with aspirin and clopidogrel after stent placement is necessary for the prevention of stent thrombosis. The duration of clopidogrel therapy after stent placement is dependent upon the type of stent placed, and is recommended for a minimum of 4 weeks after bare-metal stent placement, 3 months after sirolimus-eluting stent placement, and 6 months after paclitaxel-eluting stent placement. A longer course of therapy with clopidogrel (12 months) has been recommended by the most recent American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions guidelines for PCI based upon incremental reduction in cardiovascular complications (primarily myocardial infarction). This article reviews the data presently available regarding pretreatment with clopidogrel before PCI, and the strength of evidence supporting long-term dual antiplatelet therapy.     

Relation of aspirin resistance to coronary flow reserve in patients undergoing elective percutaneous coronary intervention

Previous studies have shown that more complete platelet inhibition improves the coronary flow reserve (CFR), a measure of microvascular integrity, in patients undergoing percutaneous coronary intervention (PCI). We hypothesized that patients with aspirin resistance would have impaired CFR after elective PCI. We used VerifyNow Aspirin to determine the response to aspirin in 117 consecutive patients who underwent elective single-lesion PCI. The assay results are expressed quantitatively in Aspirin Reaction Units based on the degree of platelet aggregation. All patients received a 300-mg loading dose of clopidogrel >12 hours before and a 75-mg maintenance dose the morning of PCI. CFR was estimated using the Thrombolysis In Myocardial Infarction frame count method. Of the 117 patients, 22 (18.8%) were aspirin resistant. The clinical, angiographic, and procedural characteristics of the aspirin-sensitive and -resistant patients were balanced. All patients underwent successful PCI with <50% residual diameter stenosis and Thrombolysis In Myocardial Infarction grade 3 flow after PCI. Aspirin-resistant patients had a lower CFR than the aspirin-sensitive patients (1.42 +/- 0.35 vs 1.80 +/- 0.64, p = 0.018). Univariate correlates of CFR included the Aspirin Reaction Unit (r = -0.227, p = 0.014) and post-PCI creatine kinase-MB elevation (p = 0.048). Multivariate linear regression analysis revealed the Aspirin Reaction Unit to be the only independent determinant of CFR after PCI (r2 = 0.051, p = 0.014). Thus, aspirin resistance was associated with impaired CFR in patients who underwent elective PCI, implicating insufficient aspirin-induced platelet inhibition as a cause of microvascular dysfunction by distal atherothrombotic embolization and/or spasm.     

Effects of high-dose statin administered prior to coronary angioplasty on the incidence of cardiac events in patients with acute coronary syndrome

INTRODUCTION: Statins given after acute coronary syndrome without ST elevation (NSTE-ACS) reduce the incidence of major adverse cardiac events (MACE) in long-term follow-up. AIM: To evaluate the effects of high-dose statin administered in patients with NSTE ACS and increased CRP level prior to percutaneous coronary intervention (PCI) on the incidence of MACE in long-term follow-up. METHODS: The study involved 140 consecutive patients with NSTE ACS and increased CRP level at baseline. Patients from group A (n=54) did not receive statin before PCI, whereas subjects in group B (n=86) were given 80 mg of atorvastatin. Patients in both groups received typical cardiological therapy including aspirin, thienopyridine and low molecular weight heparin. After PCI all patients received 40 mg of atorvastatin. Incidence of MACE (death, myocardial infarction (MI), re-PCI) during long-term followup was evaluated in both groups. RESULTS: Study groups did not differ with respect to demographic parameters and rate of ischaemic heart disease risk factors. Also, no differences occurred regarding CRP level (group A vs. B: hsCRP 10.8+/-1.8 mg/l vs. 8.2+/-2.8 mg/l; p=NS) and TIMI Risk Score (group A vs. B: 4.3+/-0.71 vs. 4.37+/-0.79; p=NS). During long-term follow-up the incidence of MI (9.25% vs. 1.2%, p=0.03), composite endpoint: death + MI (14.8% vs. 2.32%, p=0.013) and death + MI + re PCI (25.9% vs. 8.1%, p=0.006) was significantly higher in group A than group B. CONCLUSIONS: Administration of high-dose statin in NSTE ACS patients before PCI was associated with significant reduction of MACE in long-term follow-up. This effect was observed despite the same therapy given after PCI.     

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。     

Effects of folate supplementation in hyperhomocysteinemic pigs.

OBJECTIVES: The aim of this study was to evaluate the therapeutic effects of folic acid in the pig model of hyperhomocysteinemia. BACKGROUND: We have previously shown that pigs fed a methionine-rich diet develop hyperhomocysteinemia, arterial lesions and thrombotic events. Elevated homocysteine level is an independent risk factor for atherosclerosis that can be markedly lowered with daily folic acid administration. However, it is not known whether this treatment can prevent arterial lesions. METHODS: Three groups of pigs were studied: 8 control subjects received a standard diet; 8 received a methionine-rich diet for four months; 8 received a methionine-rich diet for 1 month and then the methionine-rich diet + 5 mg/day folic acid for 3 months. At month 4 after hemodynamic investigation, all the pigs were sacrificed. RESULTS: Control animals developed few usual vascular streaks. All the pigs fed a methionine-rich diet without folic acid treatment developed hyperhomocysteinemia (10.3+/-1.3 micromol/liter at basal state, 18.2+/-2.5 micromol/liter at one month and 14.6+/-3.8 micromol/liter at four months), hemodynamic abnormalities and diffuse arterial lesions with smooth muscle cell hyperplasia, endothelial alterations and elastic lamina dislocation. In this group, one pig died of venous thromboembolism and one of myocardial infarction. The pigs fed a methionine-rich diet + folic acid displayed similar arterial lesions and two had thrombotic events (one myocardial infarction and one pulmonary embolism), despite normalization of homocysteine levels (10.9+/-1.3 micromol/liter at basal state, 19.5+/-2.5 micromol/liter at one month and 11.4+/-3.8 micromol/liter at four months). CONCLUSIONS: In the pig model of hyperhomocysteinemia, 5 mg/day folic acid did not prevent arterial lesions or thrombotic events.     

Aspirin, but not clopidogrel, reduces collateral conductance in a rabbit model of femoral artery occlusion.

OBJECTIVES: The objective of this study was to test the potential of aspirin and clopidogrel to influence collateral artery growth (arteriogenesis). BACKGROUND: Aspirin and clopidogrel are antiplatelet agents commonly used in the treatment of ischemic cardiovascular disease. Both inhibit platelet aggregation; however, they differ mechanistically because aspirin acts via cyclooxygenase (COX) inhibition, while clopidogrel noncompetitively antagonizes the P2Y12 adenosine diphosphate receptor. We hypothesized that aspirin, due to its anti-inflammatory effects through inhibition of COX activity could inhibit arteriogenesis. Given that clopidogrel does not affect COX activity, it would be less likely to interfere with collateral artery growth. METHODS: Fifty-four New Zealand White rabbits received either saline, aspirin (10 mg/kg), or clopidogrel (10 mg/kg) for seven days after femoral artery ligation. Maximal collateral conductance was assessed with fluorescent microspheres under maximal vasodilation; cellular migration and proliferation (Ki-67) was evaluated by quantitative immunohistology. RESULTS: Collateral conductance was significantly reduced by aspirin treatment, whereas clopidogrel had a neutral effect (saline: 0.94 +/- 0.04; clopidogrel: 0.94 +/- 0.05; aspirin: 0.64 +/- 0.03 ml x min(-1) x 100 mm Hg(-1) x g(-1); p < 0.001). Ki-67 proliferation indexes were consistent with these results (saline: 23.1 +/- 2.9%; clopidogrel: 23.5 +/- 1.1%; aspirin: 19.2 +/- 1.1% Ki-67-positive cells). Immunohistochemistry showed COX expression in collateral arteries and a significantly decreased monocyte/macrophage accumulation in the perivascular tissue after aspirin treatment. Cell adhesion molecule expression on monocytes after activation was significantly reduced by aspirin, which might explain the reduced migratory ability. CONCLUSIONS: In summary, clopidogrel had a neutral effect on natural arteriogenesis. Aspirin significantly inhibited collateral artery growth, probably due to its anti-inflammatory effect. Additional studies are needed to substantiate these results before translation into clinical practice.     

Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation.

OBJECTIVES: This study sought to determine the prevalence of platelet aspirin resistance using methods that directly indicate the degree of platelet cyclooxygenase inhibition. BACKGROUND: Aspirin resistance in platelets may be overestimated by nonspecific laboratory measurements that do not isolate cyclooxygenase activity. METHODS: Arachidonic acid (AA)-induced light-transmittance platelet aggregation (LTA) and thrombelastography (TEG) platelet mapping were performed on the blood of healthy subjects (n = 6) before and 24 h after receiving 325 mg aspirin, and on 223 patients reporting compliance with long-term daily aspirin treatment (n = 203 undergoing percutaneous intervention [PCI] and n = 20 with a history of stent thrombosis). Aspirin resistance was defined as >20% aggregation by LTA or >50% aggregation by TEG. RESULTS: In healthy subjects, AA-induced aggregation by LTA was 82 +/- 10% before and 2 +/- 1% at 24 h after aspirin (p < 0.001), and aggregation by TEG was 86 +/- 14% before and 5 +/- 7% at 24 h after aspirin (p < 0.001). In compliant patients, AA-induced aggregation by LTA was 3 +/- 2% before PCI and 3 +/- 2% after PCI (p = NS), and aggregation by TEG was 5 +/- 9% before PCI and 6 +/- 14% after PCI (p = NS). Seven PCI patients were noncompliant, and all were aspirin sensitive after in-hospital aspirin treatment. Among 223 patients, only one patient ( approximately 0.4%) was resistant to aspirin treatment. CONCLUSIONS: Platelet aspirin resistance assessed by methods that directly indicate inhibition of cyclooxygenase is rare in compliant patients with coronary artery disease.     

Tailoring clopidogrel dose according to multiple electrode aggregometry decreases the rate of ischemic complications after percutaneous coronary intervention

Multiple studies have shown a correlation between high on-treatment platelet reactivity (HPR) and ischemic complications after percutaneous coronary interventions (PCI); however, the role of platelet reactivity testing in order to adjust clopidogrel dose is debated. We sought to determine whether a strategy incorporating platelet reactivity testing with the Multiplate analyzer to tailor the dose of clopidogrel is superior to standard clopidogrel treatment after PCI. Between May 2008 and June 2009, 192 consecutive patients undergoing PCI were randomized to a tailored treatment strategy using the Multiplate analyzer or to uniform administration of 75 mg clopidogrel. In the tailored group, platelet function was assessed 24 h after clopidogrel loading, and patients with HPR (>46 U) received an additional 600 mg loading dose and 150 mg clopidogrel thereafter for one month. The primary endpoint was the composite of cardiac death, myocardial infarction, ischemic stroke or definite/probable stent thrombosis during six months. In the tailored group, a repeated loading dose of 600 mg clopidogrel significantly decreased platelet reactivity in patients with HPR (61.0 U [IQR: 52.5-71.5] vs. 21.5 U [15.8-30.5]; P < 0.0001) that remained unchanged during the maintenance phase on 150 mg clopidogrel (25.0 U [IQR: 19.8-27.0]; P = 0.20). The incidence of the primary endpoint was significantly higher in the standard clopidogrel group as compared to the Multiplate-tailored arm (5.3% vs. 0%, P = 0.03). In parallel, MACCE-free survival significantly improved in patients with Multiplate-tailored therapy (Kaplan-Meier log-rank: P = 0.02). Increasing the dose of clopidogrel according to the Multiplate assay may reduce ischemic complications in patients on clopidogrel after PCI.     

冠状动脉植入药物支架术后高维持剂量氯吡格雷治疗的近期疗效

目的:对比观察植入药物洗脱支架(durg eluting stent,DES)患者术后服用高维持剂量氯吡格雷150 mg/d的有效性及安全性。方法:前瞻性入选我院2007年1月~12月120例成功行DES植入术的患者。所有患者于术前顿服600 mg负荷量氯吡格雷,术后在服用阿司匹林基础上随机接受每日75 mg(n=60)或150 mg(n=60)维持量的氯吡格雷治疗30 d,30 d后所有患者接受每日75 mg的氯吡格雷治疗直至术后1年。分别检测2组服药前、服药后15和30 d二磷酸腺苷(ADP)诱导的血小板最大凝集率,随访术后30 d和9月主要临床心血管事件(包括死亡、心肌梗死、紧急靶血管血运重建、脑卒中等)和出血事件的发生情况。结果:氯吡格雷150 mg组与75 mg组患者术前ADP诱导的血小板聚集率和最大聚集时间比较无显著性差异,而术后15和30 d比较差异有显著性(P0.05)。氯吡格雷150 mg组30 d和9月主要临床心血管事件发生率较75 mg组显著减少(P0.05,P0.01)。2组30 d和9月出血事件差异均无统计学意义。结论:植入DES患者术后服用高维持剂量氯吡格雷150 mg较之常规维持剂量75 mg预治疗能更大程度抑制血小板凝集,同时降低DES植入术的患者术后近期发生不良事件的风险,可显著改善临床预后。     

The effects of prior beta-blocker therapy on serum C-reactive protein levels after percutaneous coronary intervention

BACKGROUND: There are no studies in the literature related to the effect of beta blockers (BB) on changes in C-reactive protein (CRP) levels after percutaneous coronary intervention (PCI). HYPOTHESIS: We designed a prospective randomized study to investigate the impact of BB therapy on CRP in patients who underwent elective PCI. METHODS: In all, 300 patients with coronary artery disease were included. Patients were randomized to either a metoprolol or to a control group before PCI. Blood samples for CRP levels were obtained before BB treatment, and at the 6th, 24th, and 36th h after PCI. RESULTS: Of 300 patients, 150 received metoprolol 100 mg/day (mean age, 59.0 +/- 10.2 years; 106 men, 44 women), and 150 received no BB (mean age, 59.8 +/- 9.8 years; 114 men, 36 women) and served as the control group. Baseline clinical characteristics of both groups were similar. Basal CRP levels between the two groups were similar. Of the patients included in the study, 40.8% in the BB group and 39.6% in the control group had elevated basal CRP levels. The CRP levels increased above baseline values in 85% of patients in the BB group and in 89.3% of patients in the control group (p > 0.05) during follow-up. The CRP levels in patients in the BB group at the 6th, 24th, and 36th h were lower than those in the control group; however, this difference did not reach statistical significance. CONCLUSIONS: Prior BB therapy seems to have no effect on CRP levels after PCI.     

Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin

There is a need for a rapid antithrombotic effect after the administration of antiplatelet drugs in the setting of acute coronary syndromes and percutaneous interventions. Clopidogrel, a new thienopyridine derivative, is an efficient antiplatelet agent. However, the standard regimen of clopidogrel (75 mg/d) requires 2 to 3 days before significant antithrombotic effects. Patients with stable arterial disease on chronic aspirin therapy (n=20) were treated with clopidogrel either with a front-loaded regimen, 300 mg the first day and 75 mg/d the next 7 days, or with a standard regimen, 75 mg/d for 8 days. Blood thrombogenicity was assessed by quantification of platelet-thrombus formation in an ex vivo perfusion chamber, by ADP-induced platelet aggregation, and by ADP-induced fibrinogen binding. At 2 hours, mean total thrombus area with the standard regimen was not significantly reduced. In contrast, at 2 hours, the mean total thrombus area with the front-loaded regimen was significantly decreased by 23.1+/-8.5% versus baseline (P<0.05). ADP-induced platelet aggregation (with 5 and 10 micromol/L) was also significantly (P<0.05) reduced with the front-loaded regimen at 2 hours, with the mean platelet aggregation being 82.2+/-4.4% and 81.8+/-4.5%, respectively, versus baseline. Similarly, flow cytometry demonstrated a significant decrease (P<0. 05) in the ADP-induced fibrinogen binding (with 0.12 and 0.6 micromol/L) at 2 hours in this front-loaded regimen group (36.1+/-2. 0% and 53.2+/-9.3%). With the standard regimen, platelet activity was not significantly reduced at 2 hours. Our data suggest that a front-loaded regimen of clopidogrel added to aspirin achieves a significant antithrombotic effect at 2 hours in patients with known atherosclerotic disease on chronic aspirin therapy. This provides a rationale for using front-loaded clopidogrel in combination with aspirin in percutaneous coronary interventions.     

Does pre-treatment with aspirin and loading dose clopidogrel obviate the need for glycoprotein IIb/IIIa antagonists during elective coronary stenting? A focus on peri-procedural myonecrosis.

AIMS: Although full platelet inhibition with aspirin and thienopyridines before coronary stenting has significantly reduced the risk of acute stent thrombosis, peri-procedural myonecrosis still occurs frequently and is associated with increased death rate. Whether further inhibition of platelet aggregation by a glycoprotein IIb/IIIa antagonist may provide an additional cardioprotection is unknown. METHODS AND RESULTS: A total of 200 patients pre-treated with aspirin and a loading dose of clopidogrel (450 mg) were randomized just before coronary intervention (percutaneous coronary intervention, PCI) to treatment with or without abciximab. Platelet aggregation was assessed in samples collected during the procedure and the degree of platelet aggregation inhibition was correlated with cardiac enzyme release post-PCI. Abciximab treatment achieved a more complete inhibition of aggregation than dual oral antiplatelet therapy alone (median value of 1 vs. 50%, normal 100%). Any pathological increase in creatinine kinase-MB (CK-MB) post-PCI was present in 21% of the abciximab group and in 22% of the no-abciximab group (P = 0.9). Also the occurrence of clinically relevant myonecrosis [myocardial infarction (MI) = CK-MB > 3x upper limit of normal] was not significantly influenced by treatment assignment: 9 vs. 10% (P = 0.9). In a multiple logistic regression model including clinical, angiographic, and procedural characteristics, post-PCI myonecrosis was not correlated with the degree of platelet aggregation inhibition but with procedural features (such as long inflation time) and with the presence of multi-vessel disease. There were no cases of acute or subacute stent thrombosis. At 6 months, major adverse cardiac events, including cardiac death, non-fatal MI, or target lesion revascularization occurred in 13% of abciximab patients and in 16% of the control patients (P = 0.6). CONCLUSIONS: In the studied patients scheduled for elective coronary stenting and pre-treated with aspirin and a loading dose of clopidogrel, further inhibition of platelet aggregation by abciximab does not afford additional cardioprotection. Our data suggest that distal athero-embolization rather than thrombo-embolization is involved in the phenomenon of myonecrosis post-elective stenting.     

Clinical and prognostic implications of the initial response to aspirin in patients with acute coronary syndrome

Increased platelet reactivity and decreased response to antiplatelet drugs may result in recurrent ischemic events after acute coronary syndrome (ACS). We evaluated laboratory response to aspirin in patients with ACS before and after percutaneous coronary intervention (PCI) and assessed its effect on major adverse clinical events. Sixty-three consecutive patients with ACS were tested for response to aspirin by light transmittance aggregometry (LTA) and the IMPACT-R test (with arachidonic acid) before and 2 to 4 days after PCI and clopidogrel loading. Patients were followed for clinical events up to 15 months from PCI. Response to aspirin improved significantly after PCI and clopidogrel treatment (mean arachidonic acid-induced LTA decreased from 34.9 ± 3.35% before PCI to 15.2 ± 2.2% and surface coverage increased from 2.2 ± 0.27% to 6.2 ± 0.6%, p <0.0001 for the 2 methods). Improved response to aspirin after PCI correlated with response to clopidogrel (LTA and IMPACT-R, p <0.01). Patients with good laboratory response to aspirin before but not after PCI had a significantly lower major cardiovascular event rate during 15-month follow-up in multivariate analysis. In conclusion, laboratory response to aspirin is highly dynamic in patients with ACS. Improved response to aspirin after PCI may result from stabilization of coronary artery disease and/or clopidogrel treatment. Laboratory response to aspirin before PCI and clopidogrel loading is a sensitive marker for platelet reactivity that correlates with clinical outcome in patients with ACS.     

Impact of a 600-mg loading dose of clopidogrel on 30-day outcome in unselected patients undergoing percutaneous coronary intervention

On the basis of biologic studies of platelet reactivity, the recent American College of Cardiology and American Heart Association guidelines recommend a 600-mg loading dose (LD) of clopidogrel in patients who undergo percutaneous coronary intervention (PCI). There is, however, a lack of studies addressing the clinical impact of such a clopidogrel LD. The aim of this study was to compare the clinical efficacy and safety of a 600-mg LD of clopidogrel with that of a 300-mg LD in an unselected cohort of patients who underwent PCI. A cohort of 4,105 unselected patients who underwent PCI were included in the study and divided according to the LD used: the high-LD group (600 mg) included 3,146 patients, and the low-LD group (300 mg) included 959. The primary end point was the rate of major adverse cardiovascular events (MACEs) at 1 month. Patients in the low-LD group more often had diabetes mellitus and histories of myocardial infarction (36.8% vs 31.9%, p = 0.01). Left ventricular ejection fractions were similar (0.49 +/- 0.14 vs 0.48 +/- 0.14, p = 0.25). Angiographic and procedural characteristics were identical between the 2 groups. Patients in the high-LD group had fewer MACEs after 1 month (2.9% vs 5.2%, p <0.001). In multivariate analysis, an LD of 600 mg was significantly associated with MACEs at 1-month follow-up, with an odds ratio of 0.62 (95% confidence interval 0.41 to 0.95, p = 0.03). In conclusion, a 600-mg LD was associated with a significant decrease in the rate of post-PCI MACEs at 1 month, without any in-hospital increase in bleeding complications. The results of this study therefore support the current guidelines of a 600-mg LD of clopidogrel in patients who undergo PCI.     

PCI术后长期应用双联抗血小板治疗225例

目的观察PC／术后长期氯吡格雷片伍用肠溶阿司匹林双联抗血小板治疗的效果。方法对225例PCI术后患者进行1年随访观察,其中女性82例,男性143例,年龄（57．0±11．5）岁。术前常规准备,术前3d服用氯吡格雷片75mg,qd和肠溶阿司匹林片0．1g,qd;术中常规操作;术后低分子肝素5000U,q12h,IH,连用3d;出院后双联抗血小板治疗1年。于术后1个月、半年、1年复诊;如出现心前区闷痛、晕厥、牙龈出血、黑便、黄染等及时复诊。结果225例患者中多支病变66例、双支病变117例、单支病变42例。共置人支架351枚,高压后扩张67例。8例患者术前白细胞少于4．0×10^9／L,给予常规量治疗并严密观察,未出现进一步下降。个别患者出现牙龈及皮下淤斑（术后1个月、半年和1年分别为1．77％、3．11％和2．22％,P〉0．05）,消化道出血2例,无颅内出血。无死亡。结论PCI术前双联抗血小板治疗（DAPT）,术后长期应用安全,可起到显著抗血小板作用,对白细胞影响较小,长期应用副作用小,未出现急性冠脉事件,可改善患者生活质量。