Individual variations of platelet inhibition after loading doses of clopidogrel

Abstract . Järemo P, Lindahl TL, Fransson SG, Richter A (Linköping University Hospital, Linköping, Sweden). Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002; 252: 233–238. Objective. To investigate individual variations of platelet inhibition after clopidogrel‐loading doses. Setting. Department of Cardiology, Linköping University Hospital, Linköping, Sweden. Subjects. Individuals with stable angina pectoris (n = 18) subject to percutaneous coronary interventions (PCI) and subsequent stenting were investigated. Methods and experimental protocol. A 300‐mg clopidogrel loading dose was administrated immediately after stenting (day 1) followed by an additional 75 mg clopidogrel after 24 h (day 2). The ADP‐evoked platelet fibrinogen binding was analysed to estimate platelet reactivity immediately before angiography and on day 2. A flow cytometry technique was used with two ADP solutions (final concentrations 0.6 and 1.7 μmol L^?1) employed as platelet activating agents. Soluble P‐selectin was used as a marker of platelet activity. Results. When using 1.7 μmol L^?1 ADP to activate platelets four individuals had a strong inhibition (i.e. platelet reactivity <10% of the day 1‐value day 2). In contrast, five patients demonstrated a weak inhibition (i.e. platelet reactivity >60% of the day 1‐value day 2). Similar results were obtained when using 0.6 μmol L^?1 ADP as a platelet‐activating agent. Clopidogrel, however, fails to suppress platelet activity as estimated from soluble P‐selectin. Conclusions. Clopidogrel evoked platelet inhibition exhibits a considerable individual heterogeneity. Some individuals only had weak responses whereas others displayed strong platelet inhibition. The present flow cytometry technique appears suitable for identifying patients with abnormal reactions after clopidogrel exposure.     

The platelet hyporesponsiveness to clopidogrel in acute coronary syndrome patients treated with 75 mg/day clopidogrel may be overcome within 1 month of treatment

Platelets are involved in thrombus formation and inflammation following vascular injury, while clopidogrel exerts antithrombotic and anti-inflammatory actions. We investigated various platelet-derived prothrombotic and proinflammatory mediators as well as the platelet aggregatory response in patients with acute coronary syndromes (ACS) receiving clopidogrel, as a function of the patient responsiveness to drug treatment. Blood samples were obtained from 40 patients with recent (<24?h) ACS before clopidogrel loading 600?mg (followed by a maintenance dose of 75?mg/day) as well as 5-days and 30-days afterwards. Twelve patients exhibited platelet reactivity index (PRI) values higher than 50% evaluated by the Vasodilator Stimulated Phosphoprotein (VASP) test at 5 days and were characterized as nonresponders. The platelet response to adenosine diphosphate (ADP) and thrombin receptor agonist peptide-14 (TRAP) was studied by flow cytometry and light transmission aggregometry. A maximum reduction of ADP- or TRAP-induced platelet aggregation in 28 clopidogrel responding patients was observed at 5 days postclopidogrel loading, whereas in nonresponders, it was achieved at 30-days along with a significant decrease in the PRI values. Similar results were obtained for the membrane expression of CD40L and the production of platelet-derived microparticles. By contrast, the maximum inhibition of P-selectin expression and platelet-leukocyte conjugate formation was observed at 30-days in both patient groups. A maintenance dose of 75?mg clopidogrel differentially affects the platelet aggregation and platelet-derived prothrombotic and proinflammatory mediators in ACS patients within the first month of the treatment, a phenomenon that is highly influenced by the drug response variability. Since these factors may be involved in the major adverse cardiovascular events in ACS patients, especially in those undergoing percutaneous coronary intervention, the above findings may be clinically important.     

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.     

Dynamic platelet adhesion in patients with an acute coronary syndrome: The effect of antiplatelet therapy

Platelet adhesion and aggregation are key functions leading to thrombus formation. The effect of aspirin, clopidogrel, and ticagrelor on platelet aggregation has been well established, however, there is limited data on the effect of these drugs on platelet adhesion. We therefore evaluated the effect of these drugs on platelet adhesion in acute coronary syndrome (ACS) patients. Citrated blood was collected from 50 ACS patients loaded with 325 mg of aspirin (baseline) and at 5 days after the administration of aspirin 100 mg/day and clopidogrel (600 mg loading dose, 75 mg/day) (n = 26) or ticagrelor (180 mg loading dose, 90 mg × 2/day) (n = 24). High on-treatment platelet reactivity (HTPR) to clopidogrel was estimated by vasodilator stimulated phosphoprotein (VASP) phosphorylation assay. Platelet adhesion to collagen was studied for 6 min under high shear stress and was evaluated using the time to platelet recruitment (TPR), the perimeter and average area of each adherent object, number of adherent objects, and the total percent of surface coverage (SC%). Six ACS patients exhibited HTPR to clopidogrel and excluded from the platelet adhesion assays. TPR and SC% values were similar among patient groups at baseline and controls. However, all other adhesion parameters were different in ACS patients, indicating the formation of more aggregates in regard to controls. At 5 days post-treatment with either clopidogrel or ticagrelor, the TPR values were increased and the SC% values were reduced to a similar extent compared with baseline. However, significant differences were observed in the ticagrelor group in the perimeter, number of adherent objects, and the average area of each adherent object indicating a more potent inhibition of adherence-induced platelet aggregation than clopidogrel. In conclusion, aspirin does not affect platelet adherence to collagen, whereas clopidogrel and ticagrelor inhibit to a similar extent dynamic platelet adhesion at 5 days post-treatment in ACS patients. However, ticagrelor exhibits a greater inhibitory effect on reducing adhesion-induced platelet aggregation.     

Comparison of platelet reactivity and clopidogrel response in patients ≤ 75 Years Versus > 75 years undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome

Specific data about the clopidogrel response in elderly patients are lacking. The present study was performed to compare the platelet reactivity and clopidogrel response between patients aged > 75 years and < 75 years undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome. A total of 689 patients were enrolled, including 162 patients aged > 75 years and 527 younger patients. All patients received a loading dose of 600 mg clopidogrel followed by 150 mg/day. Post-treatment platelet reactivity was assessed by adenosine diphosphate 10 μmol/L-induced platelet aggregation and the specific pharmacologic response to clopidogrel by the platelet reactivity index vasoactive stimulated phosphoprotein. High post-treatment platelet reactivity was defined as adenosine diphosphate 10 μmol/L-induced platelet aggregation >70%. Clinical events were recorded during 1 month of follow-up. The patients > 75 years old had a greater rate of both ischemic and bleeding complications (p = 0.04 and p = 0.03, respectively). The post-treatment platelet reactivity in response to both the loading and the maintenance clopidogrel dose was greater in patients > 75 years old than in the younger patients: 50 ± 17% versus 45 ± 17% (p = 0.002) and 57 ± 15% versus 53 ± 16% (p = 0.0005), respectively. The rate of high post-treatment platelet reactivity was significantly greater in patients aged > 75 years after 600 mg and 150 mg clopidogrel: 14% versus 9% (p = 0.04) and 23% versus 15% (p = 0.02), respectively. In contrast, the pharmacologic response to clopidogrel was not impaired in patients > 75 years after loading and maintenance doses: 43 ± 21% versus 46 ± 21% (p = 0.17) and 38 ± 18% versus 39 ± 18% (p = 0.55), respectively. In conclusion, patients aged > 75 years have an impaired prognosis after acute coronary syndrome. They display greater post-treatment platelet reactivity. However, this greater platelet reactivity does not seem to be related to an impaired specific response to clopidogrel.     

Predictors of High On-Treatment Platelet Reactivity Early After Clopidogrel Loading in ST-Elevation Myocardial Infarction

Background:?Given that platelet inhibition is crucial when ST-elevation myocardial infarction (STEMI) patients undergo primary PCI (PPCI), the identification of factors associated with early high on-treatment platelet reactivity may be important. Methods and Results:?Consecutive STEMI patients admitted for PPCI were considered for platelet reactivity assessment 2h after loading with 600mg clopidogrel using the VerifyNow point-of-care P2Y12 assay. A cut-off of ≥235 P2Y12 reaction units indicated high on-treatment platelet reactivity. Out of 92 STEMI patients, 63 (68.5%) were found to have high on-treatment platelet reactivity. Patients with high on-treatment platelet reactivity had received upstream clopidogrel loading and pantoprazol more frequently, had lower admission hemoglobin and tended to have an impaired renal function compared to those with an adequate response to clopidogrel. On multivariate analysis, upstream clopidogrel loading and creatinine clearance <60ml/min were independently associated with higher risk for high on-treatment platelet reactivity (relative risk [RR]=1.55, 95% confidence interval [CI]: 1.11-2.17, P=0.01; RR=1.31, 95% CI: 1.008-1.71, P=0.04, respectively). Conclusions:?In patients with STEMI undergoing PPCI, use of upstream clopidogrel and impaired renal function independently predict high on-treatment platelet reactivity assessed as early as 2h following 600mg of clopidogrel loading dose on point-of-care P2Y12 function assay. (Circ J?2012; 76: 2183-2187).     

不同维持剂量氯吡格雷对择期经皮冠脉介入治疗患者术后血小板聚集率的影响

目的 探讨不同维持剂量氯吡格雷对择期经皮冠脉介入治疗(PCI)患者血小板聚集率的影响及其临床意义.方法 随机双盲将118例择期PCI患者分为A、B两组,术前600 mg负荷剂量相同,术后第1天开始分别给予不同剂量氯吡格雷(波立维、法国赛诺菲-安万特公司生产)75 mg/d或150 mg/d,于术前及术后1天、7天、14天和30天评估血小板聚集率.结果 A、B两组患者术前和术后1天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7天、14天、30天比较差异有显著性.结论 较高剂量的氯吡格雷可以降低择期PCI患者的血小板聚集功能.     

The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting

OBJECTIVES: We determined the effect of clopidogrel dosing on the incidence of nonresponsiveness (NR) and high post-treatment platelet aggregation (post-PA). BACKGROUND: We have reported NR after a 300-mg loading dose. Limited information is available on the comparative effect of a 600-mg loading dose on the incidence of NR and high post-PA. METHODS: Clopidogrel responsiveness and post-PA were measured in patients undergoing stenting (n = 190) randomly treated with either a 300-mg or a 600-mg clopidogrel load. Nonresponsiveness was defined as <10% absolute change in platelet aggregation, and high post-PA was defined as >75th percentile aggregation after 300 mg clopidogrel. RESULTS: Nonresponsiveness was lower after 600 mg compared to the 300-mg dose (8% vs. 28% and 8% vs. 32% with 5 and 20 microM ADP, respectively, p < 0.001). Among the patients with high post-PA after 300 mg clopidogrel, 62% to 65% had NR, whereas after the 600-mg dose, all of the patients with high post-PA had NR. CONCLUSIONS: A 600-mg clopidogrel loading dose reduces the incidence of NR and high post-PA as compared to a 300-mg dose. Higher dosing strategies and methods to confirm platelet inhibition should be further investigated in order to optimally use clopidogrel in patients undergoing stenting.     

Comparison of pharmacodynamics between low dose ticagrelor and clopidogrel after loading and maintenance doses in healthy Korean subjects

The novel antiplatelet agent ticagrelor has been demonstrated to exert a faster and more powerful inhibition of platelet aggregation in comparison to clopidogrel in coronary artery disease patients. However, a ticagrelor dose of 90?mg twice daily might not be suitable for patients of East Asian ethnicity, and has not been fully investigated. The aim of this study was to assess the effects of low loading doses (LD, 90?mg) and maintenance doses (MD, 90?mg daily) of ticagrelor in comparison to clopidogrel (600?mg LD, 75?mg daily MD) in healthy Korean volunteers. Twelve subjects were randomized into two groups, receiving either clopidogrel (600?mg LD, followed by 75?mg MD daily for 5 days) or ticagrelor (90?mg LD, followed by 90?mg MD daily for 5 days). Following a 2-week washout period, the treatments were switched between the groups. Three platelet function assessment methods which included light transmission aggregometry (LTA), the VerifyNow assay and multiple electrode platelet aggregometry (MEA) were then used to serially measure platelet function at various time points (baseline, 0.5, 2, 6, 24, 26, 120 and 122?h). The mean IPA to 10?µM ADP in the ticagrelor group was significantly higher than that for the clopidogrel group at the 0.5, 2, 6, 26 and 122?h time points (p?≤?0.001). However, there was no significant difference between the two groups at the 24- and 120-hour time points (p?>?0.05). The assay results produced by the other two platelet function tests (VerifyNow and MEA) were similar to those obtained by LTA. The low loading and maintenance doses of ticagrelor (90?mg LD, 90?mg daily MD) cause a more rapid and potent inhibition of platelet function when compared to clopidogrel (600?mg LD and 75?mg MD). Additionally, at the lowest value of platelet inhibition strength, oral once-daily administration of ticagrelor was no less efficacious than clopidogrel at the 24- and 120-hour time points. Due to a large diurnal variation occurring with a single daily dose, a lower dose twice-daily could be a better option for patients of East Asian ethnicity.     

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.     

不同负荷剂量氯吡格雷对血小板聚集率的影响

目的比较两种剂量氯吡格雷的起效时间及安全性,为急性冠状动脉（冠脉）综合征患者用药方案提供依据。方法60例急性冠脉综合征使用不同负荷剂量氯吡格雷患者随机分为A组（300mg）和B组（600mg）,均予氯吡格雷75mg／d后续治疗。以腺苷二磷酸（ADP）5μmol／L及20μmol／L作为诱导剂检测服药前及服药后2h和6h的血小板聚集率,并检测服药前及服药后第3天的血自细胞及血小板计数。结果在ADP20μmoL／L诱导的血小板聚集检测中,两组均显示服药后6h比服药后2h达到更高的血小板聚集抑制水平[A组（29．75±12．11）％比（43．63±14．31）％,P〈0．05;B组（28．86±10．24）％比（34．86±10．84）％,P〈0．05]。B组与A组相比,在服药后2h即起到更加明显的血小板聚集抑制作用[（34．86±10．84）％比（43．63±14．31）％,P〈0．05]。服药后3d内所有人选患者均无出血、自细胞减少及血小板减少等事件发生。结论氯吡格雷600mg作为负荷剂量较之300mg可以更快地达到较高水平的血小板抑制作用,且两者安全性相似。     

对氯吡格雷低反应患者换用替格瑞洛后的有效性与安全性评价

目的 探索对氯吡格雷低反应的急性冠状动脉综合征（ACS）患者换用替格瑞洛时,起始使用负荷剂量与无负荷剂量两种方案的有效性与安全性的比较.方法 前瞻性入选154例对氯吡格雷低反应拟换用替格瑞洛的患者,由主诊医师自行决定替格瑞洛是否使用负荷剂量（负荷剂量组180mg负荷量,随后90 mg每日两次维持;非负荷剂量组直接用90 mg每日两次维持）.主要终点事件为腺昔二磷酸（ADP）诱导的血小板聚集率变化情况.次要终点事件包括心源性死亡、心肌梗死、卒中事件发生率、呼吸困难、出血、尿酸变化等不良事件发生率.结果 负荷剂量组由氯吡格雷转换为替格瑞洛3d后,血小板聚集率明显低于非负荷剂量组（17.6±7.2比25.7±18.3,P=0.008）,但30 d后两组血小板聚集率差异无统计学意义.换用替格瑞洛后,两组患者均未发生心源性死亡和脑卒中事件.无负荷剂量组发生心肌梗死事件2例,分别在术后3d（转换为替格瑞洛后2d）和90d;负荷剂量组无心肌梗死事件.无负荷剂量组呼吸困难的发生率明显低于负荷剂量组（12.2％比19.4％,P=0.001）;两组的出血事件发生率差异无统计学意义.结论 与不使用负荷剂量相比,氯吡格雷低反应的患者转换为替格瑞洛时应用负荷剂量后早期血小板抑制作用更显著,且不增加出血事件,但呼吸困难发生率也更高.     

Beneficial effect of a loading dose of 600 mg of clopidogrel on platelet parameters in patients admitted for acute coronary syndrome

INTRODUCTION: Despite the beneficial effect of an aspirin-clopidogrel combination in acute coronary syndrome, the incidence of ischaemic recurrences remains significant and very probably implicates a variability in the response to anti-platelet agents. OBJECTIVE: We sought to demonstrate the evidence for a beneficial effect, in terms of anti-platelet effect, of a higher loading dose of 600 mg of clopidogrel compared to the usual 300 mg in patients admitted to our centre with acute coronary syndrome. MATERIALS AND METHODS: Platelet reactivity was evaluated with the ADP 10_mol test and the degree of platelet activation by the expression of P-selectin. 178 consecutive patients admitted for acute coronary syndrome received 250 mg of intravenous aspirin together with either a loading dose of 300 mg of clopidogrel (n = 104) or 600 mg (n = 74) administered 12 to 24 hours prior to coronary angiography. RESULTS: The patients who received 600 mg of clopidogrel had an average aggregation intensity to ADP and a rate of platelet high reactivity post treatment that was significantly lower [48+20 vs 58+18, p = 0.0011 and 11 patients (15%) vs 26 patients (25%), p = 0.0003 respectively]. The degree of platelet activation evaluated with P-selectin was significantly lower in patients receiving 600mg [0.33 + 0.17 vs 0.50+0.29, p < 0.001]. CONCLUSION: Our study provides evidence for a beneficial effect of a loading dose of 600mg of clopidogrel compared to the usual 300 mg in terms of platelet reactivity and platelet activation post treatment.     

Predictors of high on-clopidogrel platelet reactivity in patients with acute coronary syndrome

High on-clopidogrel platelet reactivity (HPR) is a predictor of ischemic events after percutaneous coronary intervention. We conducted a prospective cohort study to identify variables related to HPR in acute coronary syndrome patients who are at high thrombotic risk. We enrolled 463 patients undergoing urgent coronary angiography. Platelet reactivity was measured 12–36 hours after 600?mg clopidogrel loading with multiple electrode aggregometry (Multiplate® analyzer, Roche, Basel, Switzerland, 6.4?µM ADP). HPR was defined by the consensus cut-off area under the curve >46?U. The rate of HPR was 16.0%. We analyzed simple clinical and laboratory parameters with backward multivariate logistic regression and identified the following predictors of HPR: platelet count (per G/L, OR: 1.0073, 95% CI: 1.0035–1.0112, p?=?0.0002), CRP level (per mg/L, OR: 1.0077, 95% CI: 1.0016–1.01372, p?=?0.01), and active smoking (OR: 0.51, 95% CI: 0.29–0.89, p?=?0.02). We developed and internally validated a risk prediction model demonstrating moderate discriminative capacity (area-under-the-receiver operating characteristic curve?=?0.67). In conclusion, we found a relatively low rate of high on-clopidogrel platelet reactivity (16.0%) even in an acute patient cohort. HPR measured by Multiplate was associated with high platelet count and CRP level on admission and was inversely related to active smoking. The model with rapidly available simple parameters might help to identify individuals at risk for HPR in the acute setting.     

Switching directly to prasugrel from clopidogrel results in greater inhibition of platelet aggregation in aspirin-treated subjects

Prasugrel, a novel P2Y₁₂ antagonist, achieves faster onset and greater inhibition of platelet aggregation than clopidogrel 300 and 600 mg loading doses (LD). We studied the safety, time course, and level of platelet inhibition when switching directly from clopidogrel 75 mg maintenance dose (MD) to a prasugrel 60 mg LD/10 mg MD or 10 mg MD regimen. Healthy subjects (n?=?39) on aspirin (81 mg/d) received a clopidogrel 600 mg LD followed by 10 days of clopidogrel MD (75 mg/d). Subjects were then randomized without a washout period to prasugrel 60 mg LD (n?=?16) followed by 10 days of prasugrel MD (10 mg/d) or to prasugrel MD (10 mg/d, n?=?19) for 11 days. Maximal platelet aggregation (MPA) to 20 µM ADP was measured by turbidimetric aggregometry. In subjects on clopidogrel 75 mg MD, mean MPA decreased from 39 to 12% by 30 minutes, and to 5% by 1 hour after a prasugrel 60 mg LD (p?<?0.001 for both) and from 37 to 28% (p?<?0.001) by 1 hour after a prasugrel 10 mg MD. During prasugrel MD, a new pharmacodynamic steady state MPA of ～24% (p?<?0.01 vs. clopidogrel MD) occurred within four to five days of switching from clopidogrel. Changing from clopidogrel to prasugrel did not increase bleeding episodes or other adverse events. Switching directly from clopidogrel MD to either prasugrel LD or MD was well tolerated and resulted in significantly greater levels of platelet inhibition than a clopidogrel 75 mg MD.     

Platelet function in clopidogrel-treated patients with acute coronary syndrome.

Percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS) is associated with increased risk of thrombotic complications. ACS enhances platelet activation; whether pretreatment with clopidogrel is sufficient to suppress platelet function in patients with ACS is not known. This study assessed platelet function in patients with and without ACS prior to PCI and after pretreatment with a single dose of 600 mg clopidogrel. Blood samples of 402 patients prior to PCI with (n = 119) or without (n = 283) ACS were collected at least 2 h after 600 mg clopidogrel administration. Maximal platelet aggregation in response to ADP (5 and 20 micromol/l), collagen (4 microg/ml) and TRAP (25 micromol/l) was measured with optical aggregometry. Surface expression of glycoprotein IIb/IIIa and P-selectin was assessed with flow cytometry at baseline and after stimulation with 5 and 20 micromol/l ADP. Agonist-induced platelet aggregation did not differ significantly between patients with and without ACS (P > or = 0.15). Parameters of platelet activation (glycoprotein IIb/IIIa and P-selectin surface expression) were significantly higher in ACS patients at baseline and after 5 and 20 micromol/l ADP stimulation (P < 0.0001). Patients with ACS continue to exhibit increased platelet activation after pretreatment with 600 mg clopidogrel. This finding supports the need for additional platelet function inhibition during PCI in patients with ACS.     

Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes.

OBJECTIVES: In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and clopidogrel and assessed the effects of AZD6140 in clopidogrel-pretreated patients. BACKGROUND: Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with clopidogrel may be less well protected. AZD6140 is a reversible oral P2Y(12) receptor antagonist that has been studied in ACS patients in comparison with clopidogrel (DISPERSE-2 study). METHODS: Patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design. One-half the patients allocated AZD6140 received a 270-mg loading dose. Patients randomized to receive clopidogrel were given a 300-mg loading dose unless they had already been treated with clopidogrel. Adenosine diphosphate-induced platelet aggregation was assessed by optical aggregometry on day 1 and at 4-week intervals. RESULTS: AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than clopidogrel (e.g., 4 weeks, 4-h postdose [mean (+/-SD)]: clopidogrel 64% [+/-22%], AZD6140 90 mg 79% [+/-22%], AZD6140 180 mg 95% [+/-8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel. CONCLUSIONS: AZD6140 exhibited greater mean inhibition of platelet aggregation than a standard regimen of clopidogrel in ACS patients. In addition, AZD6140 further suppressed platelet aggregation in clopidogrel pretreated patients.     

Comparison of higher clopidogrel loading and maintenance dose to standard dose on platelet function and outcomes after percutaneous coronary intervention using drug-eluting stents

Adequate antiplatelet therapy is paramount for good clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). The purpose of this study was to determine whether a high-dose regimen of clopidogrel in patients undergoing PCI is superior to standard dosing. A total of 119 patients undergoing PCI were blindly randomized in 2:1 fashion to receive clopidogrel loading 600 mg on the table immediately before PCI and 75 mg 2 times/day for 1 month (high-dose group) versus standard dosing (300 mg loading and 75 mg/day; low-dose group). Platelet aggregation was measured using light transmission aggregometry at baseline, 4 hours, and 30 days. The composite of cardiovascular death, myocardial infarction, and target vessel revascularization was studied at 30 days in addition to major and minor bleeding. Baseline characteristics and baseline platelet aggregation were similar in the 2 groups. Percent inhibitions of platelet activity were 41% and 27% in the high-dose group versus 19% and 10% in the low-dose group at 4 hours and 30 days (p = 0.046 and 0.047, respectively). Composite clinical end points were 10.3% in the high-dose group and 23.8% in the low-dose group (p = 0.04). No difference was noted in major or minor bleeding. In conclusion, a higher loading and maintenance dose of clopidogrel in patients undergoing PCI results in superior platelet inhibition and decreased cardiovascular events without increasing bleeding complications.     

The inhibitory potency of clopidogrel on ADP-induced platelet activation is not attenuated when it is co-administered with atorvastatin (20 mg/day) for 5 weeks in patients with acute coronary syndromes

The antiplatelet potency of clopidogrel may be attenuated by short-term co-administration of lipophilic statins metabolized through the cytochrome P-450, isoform 3A4. We investigated whether the co-administration of atorvastatin (20?mg/day) for 5 weeks, in patients with acute coronary syndromes (ACS) could affect the antiplatelet activity of clopidogrel. Fifty-one patients with the first episode of an ACS were included in the study. All patients underwent percutaneous coronary intervention (PCI) and received a loading dose of 375 mg of clopidogrel, followed by 75 mg/day for at least 3 months. Twenty-six of them presented with low density lipoprotein (LDL) cholesterol levels >100?mg/dl (2.6 mmol/l) (measured within 24 h from the onset of symptoms) and received daily 20 mg/day of atorvastatin. The ADP- or TRAP-induced platelet aggregation, as well as P-selectin and CD40L surface expression, were studied at baseline (within 30 min after admission) and 5 weeks afterwards. Atorvastatin did not influence either the clopidogrel-induced inhibition of platelet aggregation initiated by 5 or 10 microM ADP or the clopidogrel-induced reduction of the membrane expression of P-selectin and CD40L induced by ADP. In conclusion, atorvastatin, even at a dose of 20 mg/day does not affect the antiplatelet efficacy of clopidogrel when co-administered for 5 weeks in ACS patients.     

Comparative antiplatelet efficacy of prasugrel and high-dose clopidogrel in patients with coronary heart disease including acute coronary syndrome

A number of randomized double-blind studies have been conducted for comparative assessment of the pharmacodynamic properties of high loading and maintenance doses of clopidogrel (600-900 mg loading dose and 150 mg maintenance dose) and standard dose of prasugrel (60 mg loading dose and 10 mg maintenance dose) in patients with coronary heart disease, including those with acute coronary syndrome. This review briefly discusses the trials ACAPULCO and PRINCIPLE-TIMI 44. Compared with high dose clopidogrel, prasugrel inhibited P2Y12-mediated platelet aggregation faster and to a greater extent. A difference between effects of clopidogrel and prasugrel emerged as soon as at 30 minutes after the loading dose. Antiplatelet effects of prasugrel were greater than those of clopidogrel both during first 2-4 hours after administration of loading dose, and during maintenance dosing. This may have important clinical implications.