Impact of anemia on platelet response to clopidogrel in patients undergoing percutaneous coronary stenting

High residual platelet reactivity (HRPR) on clopidogrel is a predictor of recurrent ischemic events in patients undergoing percutaneous coronary interventions (PCI). Significant intraindividual variability in platelet aggregation on repeat testing has been reported. To understand factors contributing to the variability in platelet aggregation testing, we examined clinical and laboratory elements linked to HRPR in 255 consecutive patients tested ≥12 hours after PCI using light transmission aggregometry (LTA) in response to adenosine diphosphate 5 μmol/L and VerifyNow P2Y12 assay (VNP2Y12; Accumetrics). HRPR was defined as >46% residual aggregation for LTA and >236 P2Y12 response units (PRUs) for VNP2Y12. On multivariate analysis the only variable independently associated with HRPR with both LTA and VNP2Y12 was laboratory-defined anemia. Prevalences of HRPR by LTA were 34.3% in anemic patients, 15.6% in patients with normal hemoglobin levels, and 59.8% versus 25.9% by VNP2Y12 (p <0.005 for the 2 comparisons). In a subgroup of 50 patients, testing was done before and after the clopidogrel loading dose. At baseline there were no differences in platelet aggregation with either assay; however, absolute decrease in reactivity after the clopidogrel load was significantly less in anemic patients compared to patients with normal hemoglobin (change in residual aggregation by LTA 15.8 ± 5.8% vs 28.8 ± 3.2%, p <0.05; change in PRU by VNP2Y12 56.5 ± 35.5 vs 145.0 ± 14.2 PRUs, p <0.05, respectively). In conclusion, anemia is an important contributor to apparent HRPR on clopidogrel and may explain some of the intraindividual variability of platelet aggregation testing.     

Effects of rosuvastatin on platelet inhibition by clopidogrel in cardiovascular patients

Statin interference has been suggested among the mechanisms of reduction of the antiplatelet effect of clopidogrel. We thus sought to assess the influence of rosuvastatin on clopidogrel antiplatelet action in high-risk (HR) cardiovascular patients. To set the level of platelet inhibition by combined antithrombotic treatments we retrospectively studied two populations of HR patients, one under aspirin alone, the other under aspirin plus rosuvastatin, before and after addition of clopidogrel. The effects of rosuvastatin compared with atorvastatin were then prospectively investigated in patients who underwent percutaneous coronary intervention (PCI), under clopidogrel and aspirin treatment. Light transmission platelet aggregation (LTA) was studied in response to adenosine diphosphate (ADP) (5 μM) or arachidonic acid (0.5 mM). The inhibitory effect of clopidogrel in reducing ADP-induced LTA was similar in the two HR groups of patients. No difference in ADP-induced platelet aggregation was observed in the two PCI groups of patients with either atorvastatin or rosuvastatin. In conclusion, rosuvastatin does not interfere with the antiplatelet effect of clopidogrel in patients with cardiovascular disease.     

血栓弹力图法和光密度比浊法对双联抗血小板治疗患者的血小板聚集率检测的比较

目的分析血栓弹力图法（TEG法）和光密度比浊法（LTA法）对经双联抗血小板治疗的急性冠脉综合征（ACS）患者的血小板聚集率检测的相关性。方法募集2010年9月至2012年9月,在解放军总医院住院期间行氯吡格雷和阿司匹林双联抗血小板治疗的ACS患者共93名。在患者经口服双联抗血小板药物稳定剂量后取血,分别采用LTA法和TEG法,检测腺苷二磷酸（ADP）和花生四烯酸（AA）诱导的血小板聚集率,并对不同方法的检测指标进行相关回归分析。结果在93名ACS受试者中,应用LTA法和TEG法检测的ADP诱导的血小板聚集率分别为（59.3±21．34）％和（63．67±28．15）％,两者之间的相关系数为0．814（P〈0．0001）,回归方程为^Y（燃）=0．2＋0．617血栓弹力图法oLTA法和TGA法检测的AA诱导的血小板聚集率分别为（40．87±35．16）％和（46．02±39．26）％,两者的相关系数为0．965（P〈0．0001）,回归方程为“Y（＆{虫{击）=1．077Xm＆#女目＊＋O．02。结论在双联抗血小板治疗的ACS患者中,采用TEG法和u．A法检测的血小板功能具有较好的一致性。     

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。     

Poor responsiveness to antiplatelet drugs in acute coronary syndromes: clinical relevance and management

Cardiovascular diseases are the most common cause of mortality and morbidity in Western countries, accounting for more than 40% of total mortality. An optimal pharmacological management in these patients is of major importance and antiplatelet agents remain the cornerstone of acute coronary syndrome (ACS) therapy at hospital admission and during percutaneous coronary interventions (PCI). The recently described poor biological responses to aspirin and clopidogrel have been source of major concern, especially in era of drug eluting stent implantation. Indeed, insufficient platelet inhibition at the time of PCI has been consistently associated with an increased risk of complications and recurrence of ischemic events. Despite the lack of uniformly accepted definitions of aspirin and clopidogrel poor response, we sought to describe the current evidence and gaps in knowledge. While trials on the potential benefit of an increased antiplatelet maintenance dose after PCI have shown only marginal benefits, the strengthening of the initial antiplatelet regimens by additional loading doses of clopidogrel, by the administration of glycoprotein IIb/IIIa receptor inhibitors or phosphodiesterase inhibitors might further improve outcomes during ACS and PCI in patients with poor responsiveness to conventional dual antiplatelet therapy. Overall, tailoring the antiplatelet treatment on the basis of the individual biological response improves the short-term outcome after PCI. New and more potent antiplatelet drugs may overcome the clinical consequences of the poor response to antiplatelet agents.     

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.     

Evolving pattern of platelet P2Y12 inhibition in patients with acute coronary syndromes

Abstract

Dual antiplatelet therapy consisting of clopidogrel in addition to aspirin has previously been the standard of care for patients with acute coronary syndromes (ACS) but international guidelines have been evolving over the last 4 years with the introduction of prasugrel and ticagrelor. In October 2009, prasugrel was approved in the UK by the National Institute of Health and Clinical Excellence (NICE) for use in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), diabetic patients with non-ST-elevation (NSTE) ACS undergoing PCI and patients with stent thrombosis while other ACS patients were to continue receiving clopidogrel. Ticagrelor was approved in October 2011 by NICE for use in patients with moderate-to-high risk NSTE ACS and STEMI undergoing primary PCI and was recommended in preference to clopidogrel in European guidelines. These recommendations were adopted in our region, constituting a population of 1.8 million. We studied the effect of changing patterns of P2Y₁₂ inhibitor usage on levels of platelet inhibition during maintenance therapy. Patients admitted to Northern General Hospital, Sheffield, with NSTE ACS or STEMI managed with primary PCI were enrolled over two periods of time: May 2010 to November 2011 (T1); and October 2012 to February 2013 (T2). Venous blood samples were obtained at 1 month after the onset of ACS. Light transmittance aggregometry (LTA) was performed and maximum aggregation response to ADP 20?μM was determined. A total of 116 patients were enrolled in T1 of whom 82 were receiving clopidogrel and 34 were receiving prasugrel. Twenty-nine patients were enrolled in T2, all of whom were receiving ticagrelor. Mean LTA results according to treatment with clopidogrel, prasugrel and ticagrelor were 57?±?18%, 41?±?20%, and 31?±?12%, respectively. Prasugrel was associated with significantly lower platelet aggregation responses than clopidogrel (p?<?0.001) and ticagrelor was associated with significantly lower platelet aggregation responses than both prasugrel (p?=?0.015) and clopidogrel (p?<?0.001). We conclude that international guidelines and NICE approval have led to increasing levels of P2Y₁₂ inhibition in ACS patients in this UK centre between May 2010 and February 2013. Ticagrelor was associated with significantly greater P2Y₁₂ inhibition than both clopidogrel and prasugrel during maintenance therapy.     

经皮冠状动脉介入术后氯吡格雷抵抗的临床观察

目的观察因急性冠脉综合征（ACS）行冠状动脉介入治疗（PCI）患者应用氯吡格雷后血小板聚集率的变化及氯吡格雷抵抗的发生情况。方法ACS患者37例,予氯吡格雷负荷量300mg,继予75mg/d维持,在服用氯吡格雷前,服药后2、4、6、24、48h以及服药后30d取血,测定ADP诱导的血小板聚集率,观察血小板聚集率变化并根据抑制程度判断氯吡格雷抵抗发生率。结果给药后2、4、6、24、48h及30d时,氯吡格雷抵抗的发生率分别为62%、46%、32%、38%、49%和43%,氯吡格雷抵抗者用药后血小板抑制率明显低于反应者,其中1例抵抗者出现亚急性支架内血栓形成。结论PCI治疗的部分患者中存在氯吡格雷抵抗。     

Effect of glycemic control on response to antiplatelet therapy in patients with diabetes mellitus and ST-segment elevation myocardial infarction

Impaired glycemic control (GC) is a troubling clinical condition with an unclear prognostic value that is frequent in diabetics, especially in the setting of acute coronary syndrome. Residual platelet reactivity can be also affected by GC. We evaluated the relation between response to dual antiplatelet therapy and GC in diabetics with STEMI treated with primary coronary angioplasty (PCI). Sixty diabetic patients were prospectively enrolled in the study. All patients were treated with clopidogrel and aspirin. Platelet reactivity (whole blood aggregation and phosphorylation of vasodilator-stimulated phosphoprotein, VASP) were assessed serially before and 24 hours, 7 days, and 30 days after the PCI. Blood glucose >8.5 mmol/L on admission was an independent predictor of a impaired clopidogrel response measured with platelet reactivity index (PRI) >50% on admission (OR 7.8, 95% CI 1.4-17.7, p<0.02) and 24 hours after PCI (OR 13.1, 95% CI 3.4-28.1, p<0.01). In conclusion, diabetic patients with STEMI and glycemia >8.5 mmol/L on admission is related to a poorer response to clopidogrel. There were no interaction between glycated hemoglobin level or glycemia on admission and platelet reactivity measured with collagen, arachidonic acid or thrombin receptor agonist peptide-induced aggregation. Further clinical studies of the role of GC in the efficacy of antiplatelet agents are warranted.     

经皮冠状动脉介入术患者的氯吡格雷抵抗和心血管事件

目的：观察因急性冠脉综合征（ACS）行冠状动脉介入治疗（PCI）出现氯吡格雷抵抗及心血管事件的发生情况。方法：因ACS入院患者42例，予氯吡格雷负荷量300mg，继予75mg／d维持，在服用氯吡格雷前，服药后2h、4h、6h、24h、48h和服药后30d取血，测定ADP诱导的血小板聚集率，根据其抑制程度判断是否为氯吡格雷抵抗，观察氯吡格雷抵抗者心血管事件的发生情况。结果：给药后2h、4h、6h、24h、48h和30d时，氯吡格雷抵抗的发生率分别为59．5％、52．4％、38．1％、38．1％、47．6％和41．5％，16例24h时存在氯吡格雷抵抗者有3例出现心血管事件，虽未达统计学差异，但发生率明显高于无抵抗组。结论：PCI治疗的部分患者中存在氯格雷抵抗，并可能与心血管事件发生有关。     

Measuring aspirin resistance, clopidogrel responsiveness, and postprocedural markers of myonecrosis in patients undergoing percutaneous coronary intervention

Aspirin and clopidogrel are proven to prevent thromboembolic events during percutaneous coronary intervention (PCI). Enzyme release of creatine kinase-MB (CK-MB) enzyme during PCI has been associated with an increased risk of future adverse cardiac events. This study examined the correlation between measurements of aspirin resistance and the level of inhibition of the thienopyridine-specific P2Y12 platelet receptor and CK-MB release after PCI. We prospectively studied 330 patients with elective PCI treated with drug-eluting stents. Patients were pretreated with aspirin and clopidogrel. Patients with positive CK-MB or acute coronary syndrome and those on glycoprotein IIb/IIIa inhibitors were excluded. Serum assays of aspirin resistance (Ultegra Rapid Platelet Function Assay-ASA, Accumetrics) and clopidogrel resistance (Rapid Platelet Function Assay P2Y12, Accumetrics) were performed before PCI. Serum troponinI and CK-MB levels were measured at 8, 16, and 24 hours after PCI. Aspirin resistance unit (ARU) measurement > or =550 was detected in 12 patients (3.7%). Mean platelet reactivity unit (PRU; measurement of inhibition of P2Y12 activity) was 192.2 +/- 95.4 (lower PRU, more inhibition of P2Y12 receptor). There was no correlation between level of ARU or PRU and troponin I or CK-MB release after PCI at any time point. Only multivessel coronary disease was found to be a predictor of any increase in CK-MB in a multivariate analysis (odds ratio 2.2, 95% confidence interval 1.4 to 3.3, p = 0.0003). A positive correlation was found between levels of ARU and PRU. Target vessel revascularization/major adverse cardiac event rate at 6 months was 8.2% with no correlation between ARU or PRU and release of cardiac enzymes or occurrence of adverse cardiac events. In conclusion, this study does not support routine measurements of aspirin and clopidogrel resistance in stable patients undergoing PCI.     

Optimizing antiplatelet therapy in acute coronary syndrome and percutaneous coronary intervention

Dual antiplatelet therapy with aspirin and clopidogrel is the standard of care for patients with acute coronary syndrome (ACS) and those undergoing percutaneous coronary intervention (PCI). It is well established that inhibition of platelet aggregation reduces the risk of recurrent thrombotic events and stent thrombosis. However, some patients show a reduced antiplatelet response to standard clopidogrel loading (300 mg) and maintenance (75 mg day^?1) doses, which has been associated with poorer patient outcomes. Pharmacodynamic and pharmacokinetic studies show that higher‐than‐standard clopidogrel dosing strategies facilitate more rapid platelet inhibition of a greater intensity as a result of greater plasma concentrations of the clopidogrel active metabolite. Recently completed studies suggest that in patients with ACS undergoing PCI, higher‐than‐standard clopidogrel dosing regimens provide greater inhibition of platelet function and improved clinical outcomes with a small but significant increase in major bleeding. Newer, more potent antiplatelet agents such as prasugrel and ticagrelor are other alternative strategies that result in more rapid, greater inhibition of platelet function and better outcomes than standard‐dose clopidogrel. Whether platelet reactivity‐guided therapy or genotyping for cytochrome P450 polymorphisms is useful in managing patients needs to be further defined. Most importantly, early and effective antiplatelet therapy results in the best short‐ and long‐term outcomes for patients with ACS or those undergoing PCI. © 2011 Wiley‐Liss, Inc.     

Evidence of platelet sensitization to ADP following discontinuation of clopidogrel therapy in patients with stable coronary artery disease

Epidemiological studies have linked clopidogrel discontinuation with an increased incidence of ischemic events. This has led to the hypothesis that clopidogrel discontinuation may result in a pharmacological rebound. We evaluated the impact of clopidogrel discontinuation on platelet function. Platelet aggregation was measured by light transmission aggregometry (LTA) in response to adenosine diphosphate (ADP) 0.5, 1, 1.5, 2.5, 5 and 10?µM and by VerifyNow® P2Y₁₂, in 37 clinically stable coronary artery disease (CAD) patients scheduled to discontinue clopidogrel treatment, and 37 clinically stable CAD patients not taking clopidogrel. Platelet function was assessed the day before clopidogrel cessation and 1, 3, 7, 14, 21 and 28 days after. Clopidogrel had been initiated a median of 555 days (ranging from 200 to 2280 days) before the treating cardiologist recommended its discontinuation. All participants were taking aspirin, most commonly 80?mg daily although a minority was prescribed 325?mg daily. Following clopidogrel discontinuation, VerifyNow® P2Y₁₂ did not detect any rebound platelet activity, but ADP-induced LTA showed platelet sensitization to ADP, particularly at low ADP levels. Increased platelet activity was detectable seven days after clopidogrel cessation and remained higher than in controls 28 days after discontinuation. No clinical event occurred in any of the participants during the 28 days following clopidogrel cessation. In conclusion, platelet sensitization to ADP as a consequence of chronic clopidogrel administration may partially explain the recrudescence of ischemic events following clopidogrel discontinuation in otherwise stable coronary artery patients.     

血栓弹力图评价急性冠脉综合征患者氯吡格雷抗血小板效果

目的：利用血栓弹力图评价老年急性冠脉综合征（ACS）非血运重建患者不同剂量氯吡格雷的抗血小板效果。方法：60例老年ACS未进行血运重建的患者被随机分为：甲组（30例,冠状动脉造影术后予氯吡格雷75mg／d维持）,乙组（30例,冠脉造影术后予氯吡格雷50mg／d维持）,两组冠脉造影术前均予氯吡格雷300mg口服。冠脉造影术前24h内及造影术后一周后分别测定两组患者肝肾功能及以血栓弹力图法测定血小板抑制率。并观察3个月内两组的主要心脏不良事件及不良反应。结果：与治疗前比较,治疗一周后两组患者ADP诱导的血小板抑制率[甲组：（25．8±11．4）％比（75．2±12．3）％,乙组：（24．2±13．3）％比（64．8±17．5）％]和花生四烯酸（AA）诱导的血小板抑制率[甲组：（16．7±21．6）％比（82．7±25．4）％,乙组：（23．8±22．2）％比（80．2±22．7）％,P〈0．053均明显升高,两组比较无显著差异（P〉0．05）。3个月内两组的心脏不良事件及不良反应无显著差异（P〉0．05）。结论：对非血运重建的急性冠脉综合征老年患者,低剂量氯吡格雷同样有效。     

Residual platelet reactivity is associated with clinical and laboratory characteristics in patients with ischemic heart disease undergoing PCI on dual antiplatelet therapy

A residual platelet reactivity (RPR) on antiplatelet therapy in patients with ischemic heart disease (IHD) has been reported to be associated with adverse clinical events by some Authors. However, scarce data are present on the clinical parameters associated with this phenomenon. No study, at our knowledge, was designed with the specific aim to examine the relationship between clinical characteristics and RPR. We sought to evaluate the clinical and laboratory characteristics associated with RPR in patients with IHD undergoing coronary revascularization on dual (aspirin plus clopidogrel) antiplatelet therapy. We included in the study 868 patients undergoing a coronary angiography: 386 with acute coronary syndromes undergoing a primary coronary revascularization and 482 IHD patients scheduled to undergo an elective coronary angiography. We measured platelet function by both platelet aggregation with two agonists [0.5 mg/mL arachidonic acid (AA); 2 and 10 microM adenosine 5'-diphosphate (ADP)] and a point-of-care assay (PFA-100) on venous blood samples collected within 24 h from the end of the procedure. In patients with acute coronary syndromes and elective PCI diabetes is independently associated with RPR [group A: OR=2.9 (1.5-5.7) by 10 microM ADP, OR=5.3 (1.1-27.8) by PFA-100; group B: OR=4.0 (1.6-10.0) by 10 microM ADP]; reduced left ventricular systolic function [OR=3.7 (2.2-6.5) by AA-PA, OR=2.7 (1.6-4.6) by PFA-100], chronic use of aspirin [OR=0.2 (0.1-0.4) by AA-PA, OR=0.3 (0.2-0.5) by PFA-100] and loading dose of clopidogrel [OR=0.2 (0.06-0.5) by 10 microM ADP] were independent variables significantly associated with RPR in patients undergoing elective PCI. In addition, inflammatory status was found to be significantly associated with RPR in both groups of patients. These results provide indications for the selection of patients for whom the evaluation of platelet reactivity could be useful.     

长期负荷量硫酸氢氯吡格雷显著降低血小板高反应性患者PCI术后心血管缺血事件发生率

目的 观察长期负荷量使用硫酸氢氯吡格雷对血小板高反应性患者PCI术后心血管缺血事件发生率的影响。方法 采用血栓弹力仪检测硫酸氢氯吡格雷的药物效果,筛选PCI术后对硫酸氢氯吡格雷药物不敏感患者（血小板高反应性患者）作为研究对象,随机分为对照组及试药组,每组患者各60例,对照组每天服用100 mg阿司匹林及75 mg硫酸氢氯吡格雷,试药组服用100 mg阿司匹林以及150 mg硫酸氢氯吡格雷,检测6个月后硫酸氢氯吡格雷的药物效果,同时观察两组6个月内心血管事件的发生率。结果 6个月内试药组心血管病病死率、支架内血栓再形成率、再发心肌梗死和再发不稳定心绞痛发生率分别为0%、10%、23%以及6%,对照组为3%、20%、36%以及17%,试药组显著低于对照组,试药组硫酸氢氯吡格雷所致血小板抑制率明显高于对照组,两组患者出血风险无显著性差异。结论对于血小板高反应性患者,长期加倍剂量服用硫酸氢氯吡格雷可降低心血管缺血事件发生率。     

Lack of early augmentation of platelet reactivity after coronary intervention in patients treated with bivalirudin

To determine whether a regimen of aspirin pretreatment, bivalirudin during the procedure and clopidogrel (600 mg) immediately after percutaneous coronary intervention (PCI) was associated with platelet activation during and shortly after (1 and 2 h) PCI, we characterized platelet function in 10 patients with the use of flow cytometry in the absence of agonist and in response to thrombin (10 nM), ADP (1 μM), the collagen-mimetic convulxin (5 ng/ml), and platelet activating factor (10 nM). Activation of platelets in peripheral blood was rare (<0.5% of platelets) before, during and after PCI. Platelet reactivity in response to each of the agonists was lower after the PCI compared with that in blood taken before the PCI. Accordingly, platelet activation and platelet reactivity were not increased after elective PCI when patients were treated during the procedure with aspirin and bivalirudin and immediately after the procedure with a 600 mg loading dose of clopidogrel.     

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.     

Impact of Mild Hypothermia on Platelet Responsiveness to Aspirin and Clopidogrel: an In Vitro Pharmacodynamic Investigation

The combination of percutaneous coronary intervention (PCI) and therapeutic hypothermia in comatose patients after cardiac arrest due to an acute coronary syndrome has been reported to be safe and effective. However, recent investigations suggest that hypothermia may be associated with impaired response to clopidogrel and greater risk of thrombotic complications after PCI. This investigation aimed to evaluate the effect of hypothermia on the pharmacodynamic response of aspirin and clopidogrel in patients (n?=?20) with ST elevation myocardial infarction undergoing primary PCI. Higher platelet reactivity (ADP stimulus) was observed in samples incubated at 33 °C compared with those at 37 °C (multiple electrode aggregometry, 235.2?±?31.4 AU×min vs. 181.9?±?30.2 AU×min, p?<?0.001; VerifyNow P2Y12, 172.9?±?20.3 PRU vs. 151.0?±?19.3 PRU, p?=?0.004). Numerically greater rates of clopidogrel poor responsiveness were also observed at 33 °C. No differences were seen in aspirin responsiveness. In conclusion, mild hypothermia was associated with reduced clopidogrel-mediated platelet inhibition with no impact on aspirin effects. Clinical relevance: Mild therapeutic hypothermia is associated with impaired response to clopidogrel therapy, which might contribute to increase the risk of thrombotic events in ACS comatose patients undergoing PCI.     

Effectiveness and safety of reduced-dose enoxaparin in non-ST-segment elevation acute coronary syndrome followed by antiplatelet therapy alone for percutaneous coronary intervention

Adjunctive pharmacotherapy for stabilizing patients with acute coronary syndrome/non-ST-segment elevation myocardial infarction (ACS/NSTEMI) and for subsequent percutaneous coronary intervention (PCI) includes a combination of anticoagulant and antiplatelet agents. However, all anticoagulants have been shown to paradoxically activate platelets and induce other prothrombotic activities, increase bleeding, and/or cause thrombocytopenia. A single-center experience of 1,400 consecutive patients presenting with ACS/NSTEMI managed using decreased-dose anticoagulation (enoxaparin) and dual-antiplatelet therapy (aspirin and clopidogrel) followed by triple-antiplatelet therapy (aspirin, clopidogrel, and eptifibatide) alone, without additional anticoagulation, during subsequent PCI was retrospectively analyzed. Patients received a median of 3 doses of enoxaparin at a mean dose of 0.51 mg/kg. The final dose was administered 10.8 hours (mean) before PCI. Medical management "failed" in 8 patients (0.6%), and each required emergency PCI. The overall technical success rate was 99.8%. One major adverse clinical event (0.1%) occurred within 24 hours after PCI. Non-Q-wave myocardial infarction occurred in 1.8% of patients, major and minor bleeding complications, in 0.1% and 2.1%, respectively, and thrombocytopenia in 1.3%. Five additional major adverse clinical events (0.4%) occurred within 30 days after PCI, none involving target vessel thrombosis. In conclusion, for patients with ACS/NSTEMI, reduced-dose enoxaparin combined with dual-antiplatelet therapy followed by triple-antiplatelet therapy alone (without additional anticoagulation) during subsequent PCI appears safe and may prove efficacious.