Clopidogrel 150 vs. 75 mg day−1 in patients undergoing percutaneous coronary intervention: a meta‐analysis

Summary. Background: Whether an increase in the daily oral maintenance dose of clopidogrel may improve clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) is still debated. Objectives: This meta‐analysis aimed to estimate the relative effect of a 150‐ vs. 75‐mg daily maintenance dosage of clopidogrel on clinical and laboratory end‐points in patients undergoing PCI. Methods: We searched electronic and printed sources (up to 14 December 2010) for both randomized control trials and observational studies satisfying the predefined inclusion criteria. Results: We retrieved 12 reports of studies including a total of 23 814 patients. Clopidogrel, 150 mg day^?1, was associated with significant reductions in major adverse cardiac and/or cerebrovascular events (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.48–0.94), myocardial infarction (OR, 0.72; 95% CI, 0.60–0.86), target vessel revascularization (OR, 0.27; 95% CI, 0.12–0.62) and stent thrombosis (OR, 0.64; 95% CI, 0.53–0.77) and decreased adenosine diphosphate‐induced maximal platelet aggregation. However, as compared with 75 mg day^?1, the 150‐mg daily maintenance dosage significantly increased the risk of minor bleeding (OR, 1.21; 95% CI, 1.08–1.36). Conclusion: As compared with the currently recommended 75‐mg day^?1 maintenance dosage of clopidogrel, the 150‐mg day^?1 dosage can reduce major adverse cardiac and/or cerebrovascular events but may increase the risk of minor bleeding.     

High on‐aspirin platelet reactivity as measured with aggregation‐based,cyclooxygenase‐1 inhibition sensitive platelet function tests is associated with the occurrence of atherothrombotic events

Summary. Background: High on‐aspirin platelet reactivity (HAPR) is associated with atherothrombotic events following percutaneous coronary intervention (PCI). The aim of the present study was to identify the platelet function test sensitive for platelet cyclooxygenase‐1 inhibition that best predicts atherothrombotic events. Methods and results: Nine hundred and fifty‐one consecutive patients on dual antiplatelet therapy undergoing elective PCI were enrolled. On‐aspirin platelet reactivity was measured in parallel by arachidonic acid (AA)‐induced light transmittance aggregometry (AA‐induced LTA), the VerifyNow® Aspirin Assay (VerifyNow® Aspirin Assay), the arachidonic acid prestimulated IMPACT‐R (IMPACT‐R AA) and the PFA‐100 collagen/epinephrine cartridge (PFA COL/EPI). Cut‐offs for HAPR were established by receiver‐operator characteristic curve analysis. At 1‐year follow‐up, the composite of all‐cause death, non‐fatal acute myocardial infarction, stent thrombosis and ischemic stroke occurred more frequently in patients with HAPR when assessed by LTA [10.1% vs. 6.0%, P = 0.020 (n = 925)] and VerifyNow^® [13.3% vs. 5.9%, P = 0.015 (n = 422)]. The VerifyNow^® ASA assay (AUC = 0.78) and, to a lesser extent, AA‐induced LTA (AUC = 0.73) added significantly to a model consisting of clinical and procedural risk factors in predicting atherothrombotic events. In contrast, the IMPACT‐R (n = 791) and the PFA Collagen/Epinephrine (n = 719) were unable to discriminate between patients with and without primary endpoint at 1‐year follow‐up. None of the platelet function tests was able to identify patients at risk for bleeding. Conclusions: AA‐induced LTA and the VerifyNow^® ASA test were able to identify aspirin‐treated patients undergoing PCI with stenting at risk for atherothrombotic events. The VerifyNow^® Aspirin Assay had the highest predictive accuracy. None of the tests was able to identify patients at higher risk of bleeding.     

Efficacy and safety of a high loading dose of clopidogrel administered prehospitally to improve primary percutaneous coronary intervention in acute myocardial infarction: the randomized CIPAMI trial

Objectives

To compare a loading dose of 600?mg clopidogrel given in the prehospital phase versus clopidogrel administered only after the diagnostic angiogram in patients with STEMI scheduled for primary PCI.

Background

The optimal time and dose for the initiation of clopidogrel therapy in patients with STEMI scheduled for primary PCI has not been studied in prospective randomized trials.

Methods

The primary efficacy endpoint was the TIMI 2/3 patency of the infarct-related artery in the diagnostic angiography immediately prior to PCI.

Results

We randomized 337 patients to prehospital (n?=?166) loading dose versus standard therapy (n?=?171). The time interval between initiation of clopidogrel therapy and diagnostic angiography was 47?min. TIMI 2/3 patency before PCI was not different between the groups (49.3 vs. 45.1%, P?=?0.5). We observed a trend towards a reduction of the combined endpoint death, re-infarction, and urgent target vessel revascularization in the prehospital-treated patients (3.0 vs. 7.0%, P?=?0.09), this difference was significant if patients were classified as treated (4/161 vs. 13/174; 2.5 vs. 7.5%, P?P?=?0.8).

Conclusions

Early inhibition of the platelet ADP-receptor with a high loading dose of 600?mg clopidogrel given in the prehospital phase in patients with STEMI scheduled for primary PCI is safe, did not increase pre-PCI patency of the infarct vessel, but was associated with a trend towards a reduction in clinical events.     

经皮冠状动脉介入治疗术双抗治疗1年后患者单用阿司匹林或氯吡格雷远期预后对比分析

目的:比较经皮冠状动脉介入治疗(PCI)术双抗治疗1年后患者服用阿司匹林或氯吡格雷远期预后差异,并分析原因。方法:回顾性分析2017年8月至12月植入药物涂层支架后采用双抗血小板治疗1年的168例患者的临床资料。依据患者抗血小板治疗1年后服药情况,将其分为阿司匹林组(100 mg/d,85例)和氯吡格雷组(75 mg/d,83例)。继续观察18个月,比较两组患者主要不良心血管事件(MACEs)以及服药期间出血情况。结果:两组患者心血管相关死亡、再发心绞痛、支架内再狭窄等观察终点事件差异无统计学意义,且均未发生严重出血事件。阿司匹林组轻中度出血比例明显高于氯吡格雷组(16.5%vs 4.8%,P=0.015),主要为胃出血事件增多(8.2%vs 1.2%,P=0.032)。Kaplan-Meier生存曲线结果表明,随访期间两组MACEs发生率差异无统计学意义(log rank=0.014,P=0.905),但氯吡格雷组轻中度出血事件明显少于阿司匹林组(log rank=5.986,P=0.014)。发生出血事件的患者中女性比例(61.1%vs 34.0%,P=0.024)以及年龄[(71.89±8.37)岁vs(64.75±9.02)岁,P=0.002)]高于未出血患者。多因素logistic回归分析发现,年龄[Exp(B)=4.771, 95%CI 1.313～17.344,P=0.018]、性别[Exp(B)=0.361, 95%CI 0.129～1.009,P=0.049]为出血事件的独立危险因素。结论:PCI术双抗治疗1年后患者单用氯吡格雷或阿司匹林远期获益相似,但单用氯吡格雷后轻中度出血风险降低;PCI术双抗治疗1年后的高龄女性患者可考虑长期服用氯吡格雷片75 mg/d治疗。     

Bleeding risk with AZD6140, a reversible P2Y12 receptor antagonist,vs. clopidogrel in patients undergoing coronary artery bypass grafting in the DISPERSE2 trial

AZD6140, the first reversible oral P2Y₁₂ receptor antagonist, exhibits greater and more consistent inhibition of platelet aggregation than the irreversible thienopyridine clopidogrel. As a result of its reversible effect, AZD6140 may pose less risk for bleeding when antiplatelet treatment cannot be stopped at least 5 days before coronary artery bypass graft (CABG) surgery or other invasive procedures. The Dose conflrmation Study assessing anti‐Platelet Effects of AZD6140 vs. clopidogRel in NSTEMI (DISPERSE2) trial showed overall comparable bleeding rates with antiplatelet treatment with AZD6140 90 mg twice daily or 180 mg twice daily vs. clopidogrel 75 mg once daily in 984 patients with non‐ST‐elevation acute coronary syndromes. A post hoc exploratory analysis of bleeding outcomes in the subset of 84 patients undergoing CABG in DISPERSE2 suggests reduced risk for total bleeding (41% and 58% vs. 62%), all major bleeding (38% and 50% vs. 62%), and life‐threatening bleeding (22% and 38% vs. 54%) with AZD6140 90 mg (n = 32) and 180 mg (n = 26) vs. clopidogrel (n = 26) respectively. Trends suggested that major bleeding rates were reduced with AZD6140 (combined groups) vs. clopidogrel when treatment was stopped ≤ 5 days prior to surgery (39% vs. 63%, p = 0.15) but not when treatment was stopped > 5 days before surgery (50% vs. 60%). This observation is consistent with the reversible binding of AZD6140 to the P2Y₁₂ receptor. Further prospective studies are planned to assess the relationship between this potential clinical benefit of AZD6140 and the reversibility of its antiplatelet effects.     

Troponin level and efficacy of abciximab in patients with acute coronary syndromes undergoing early intervention after clopidogrel pretreatment

Objective We investigated how does troponin level (TnT) affect the benefit achieved by abciximab in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) after pretreatment with a high loading dose of clopidogrel. Methods The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 2) trial included 2,022 patients with non-ST elevation ACS undergoing PCI who were randomized to abciximab or placebo after pretreatment with 600 mg of clopidogrel. The patients were divided into groups with elevated TnT level (n = 1,049) and no elevated TnT level (n = 973). The primary end point of the trial was the composite of death, myocardial infarction and urgent reintervention at 30 days. Results In patients with elevated TnT level the incidence of the primary end point was 13.1% in the abciximab group Vs. 18.3% in the placebo group [relative risk (RR): 0.70; 95% confidence interval (CI), 0.52–0.95, P = 0.02]. The combined incidence of death or myocardial infarction was 12.9% in the abciximab group vs. 17.9% in the placebo group (RR: 0.71; 95% CI, 0.52–0.96, P = 0.03). In contrast, the incidence of the primary end point in patients with no elevated TnT level was identical in both treatment groups (4.6%). The risk of bleeding was not related to TnT level. Conclusions Baseline troponin level affects the benefit of abciximab in patients with ACS undergoing PCI after pretreatment with a high loading dose of clopidogrel. Abciximab reduces the risk of ischemic events only in patients with ACS and elevated troponin level.     

Combined influence of proton‐pump inhibitors,calcium‐channel blockers and CYP2C19*2 on on‐treatment platelet reactivity and on the occurrence of atherothrombotic events after percutaneous coronary intervention

Summary. Background: The carriage of CYP2C19*2 and the use of proton‐pump inhibitors (PPIs) and calcium‐channel blockers (CCBs) has been associated with the diminished efficacy of clopidogrel. However, previous studies have only assessed the isolated impact of these risk factors for clopidogrel poor response. Objectives: The aim of the present study was to investigate the impact of the combined presence of three risk factors for clopidogrel poor response, that is, the use of CCBs, PPIs and the carriage of CYP2C19*2, on on‐treatment platelet reactivity and the occurrence of atherothrombotic events in 725 patients on dual antiplatelet therapy undergoing elective coronary stenting. Methods: In a prospective, follow‐up study, on‐treatment platelet reactivity was quantified using ADP‐induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. The clinical study endpoint was the composite of all‐cause mortality, myocardial infarction, stent thrombosis and stroke at 1 year after stenting. Results: Patients with either one or more than one risk factor exhibited increased platelet reactivity (mean relative increase one risk factor: 11% and > 1 risk factor: 22%, respectively). Sixty‐four events occurred during follow‐up (8.8% of the study population). Patients with one risk factor for clopidogrel poor response did not have an increased risk of the composite endpoint. However, patients using both CCBs and PPIs and carriers of CYP2C19*2 who used CCBs had a statistically significant increased risk of the composite endpoint [hazard ratio(HR)_adj 2.2 95% CI, 1.0–5.3, P = 0.044 and HR_adj 3.3 95% CI, 1.1–9.8, P = 0.032, respectively]. Conclusions: The presence of more than one of the three investigated risk factors for clopidogrel poor response is associated with an increased risk of adverse cardiovascular events within 1 year after elective coronary stenting.     

Relationship between post‐treatment platelet reactivity and ischemic and bleeding events at 1‐year follow‐up in patients receiving prasugrel

Summary. Background: Post‐treatment platelet reactivity (PR) is associated with ischemic and bleeding events in patients receiving P2Y12 receptor antagonists. Objectives: We aimed to study the relationship between post‐treatment PR after a 60‐mg loading dose (LD) of prasugrel and 1‐year thrombotic and bleeding events. Method: Patients were prospectively included in this multicenter study if they had a successful percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) and received prasugrel. The platelet reactivity index (PRI) was measured using the Vasodilator‐Stimulated Phosphoprotein index (VASP) after a prasugrel LD. Endpoints included the rate of thrombotic events and bleeding events at 1 year. Results: Among the 301 patients enrolled, 9 (3%) were lost to follow‐up at 1 year. The rates of thrombotic and bleeding events at 1 year were of 7.5% and 6.8%, respectively. Receiver‐operating curve (ROC) analysis demonstrated an optimal cut‐off value of 53.5% of PRI to predict thrombotic events at 1 year. Using this cut‐off value we observed that patients exhibiting high on‐treatment platelet reactivity (HTPR) had a higher rate of thrombotic events (22.4% vs. 2.9%; P < 0.001). In parallel the optimal cut‐off value of PRI to predict bleeding was 16%. Patients with a PRI ≤ 16% had a higher rate of bleeding events compared with those with a PRI > 16% (15.6% vs. 3.3%; P < 0.001). In multivariate analysis, the PRI predicted both thrombotic and bleeding events (OR: 1.44, 95% confidence interval [CI]: 1.2–1.72; P < 0.001 and OR: 0.75, 95% CI: 0.59–0.96; P = 0.024 [respectively, per 10% increase]). Conclusion: Platelet reactivity measurement after a prasugrel LD predicts both ischemic and bleeding events at 1 year follow‐up for ACS patients undergoing PCI.     

G‐protein β3 subunit polymorphism and bleeding in the orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction 16 trial

Summary. Background: Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G‐protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41‐amino‐acid deletion) of the human G‐protein β3 (Gβ3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity.Objectives: To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist. Methods: GNB3 genotype distribution was determined in DNA samples from patients in the orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction (OPUS–TIMI) 16 genetic sub‐study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re‐hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm. Results: Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non‐T carriers treated with orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55–1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58–4.35, P < 0.001). Interaction between T allele carriership and treatment was not significant for the primary endpoint (P = 0.18) or MI (P = 0.69). Conclusion: The GNB3 T allele significantly increased bleeding in patients treated with the platelet antagonist orbofiban. Our findings suggest that risk of bleeding associated with an antiplatelet agent is heritable and may be dissociated from risk of thrombosis.     

早期应用替罗非班对行介入治疗的中高危急性冠脉综合征患者血小板聚集率和临床结果的影响

目的 观察早期应用替罗非班对行冠状动脉介入治疗(PCI)的中高危非ST段抬高性急性冠脉综合征(NSTEACS)患者的血小板聚集率(PAR)和临床结果的影响,从而评价其在PCI中的疗效和安全性.方法 100例入院行PCI的中高危NSTEACS患者,随机分为早期应用替罗非班组(47例)和早期未应用替罗非班组(53例).早期应用组在PCI术前至少4h静脉应用替罗非班.早期未应用组术前不使用替罗非班,术后可据临床情况使用,因此它包括PCI术后即刻应用替罗非班(32例)和PCI术后未应用(21例)两个亚组.所有患者入院后均口服阿司匹林、氯吡格雷、他汀类及皮下注射低分子肝索.观察两组PAR、PCI术前术后TIMI血流情况、出血事件与血小板减少症的发生率.结果 与未用药相比,应用替罗非班12h后PAR明显下降(P<0.01);与早期未应用替罗非班组的两亚组相比,早期应用组术前靶血管的TIMI血流3级的获得率明显较高(83.0% vs.60.0% vs.61.5%;P=0.045);术后靶血管的TIMI血流分级三组比较差异无统计学意义.两组出血与血小板减少症的发生率差异均无统计学意义.结论 早期应用替罗非班可安全、有效地抑制PCI患者血小板聚集并改善PCI术前TIMI血流.     

不同维持剂量氯吡格雷对急性冠脉综合征介入治疗术后血小板功能的影响

目的探讨不同维持剂量氯吡格雷在不同时间点对高危急性冠脉综合征（ACS）患者支架术后血小板功能的影响。方法选取60例行药物洗脱支架（DES）植入术的ACS高危患者,随机分为A、B2组（各30例）。术前2组均服用阿司匹林100mg和氯吡格雷600mg,术后在服用阿司匹林基础上,A、B组分别给予氯吡格雷150、75mg／d治疗30d．30d后所有患者接受75mg／d氯吡格雷治疗直至术后1年。分别于服药前,术后第1、2、7、30天采2组患者静脉血,采用比浊法测定血小板聚集率（PA）,同时监测血小板聚集抑制率（PAI）;酶联免疫法测定血浆可溶性P选择素（sP—s）浓度。术后随访3个月,观察2组终点事件发生情况。结果术前和术后第1天2组PA、PAI和sP—S浓度比较无显著性差异（P〉0．05;而术后第2、7、30天上述指标2组间比较均有显著性差异（P〈0．05）。2组组内不同时间点PA、PAI和sP—S比较均有显著性差异（P〈0．05）。随访3个月,A组主要终点事件发生率明显低于B组（13．33％VS3．33％,P〈0．05）,次要终点事件发生率无显著性差异（P〉0．05）。结论经皮冠状动脉介入（PCI）术后,150mg／d维持量氯吡格雷可降低ACS行DES植入术后血小板聚集功能,减少术后近期发生不良事件的风险,且不增加出血事件的发生。     

Genetic testing in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a cost‐effectiveness analysis

Summary. Background: The CYP2C19 genotype is a predictor of adverse cardiovascular events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) treated with clopidogrel. Objectives: We aimed to evaluate the cost‐effectiveness of a CYP2C19*2 genotype‐guided strategy of antiplatelet therapy in ACS patients undergoing PCI, compared with two ‘no testing’ strategies (empiric clopidogrel or prasugrel). Methods: We developed a Markov model to compare three strategies. The model captured adverse cardiovascular events and antiplatelet‐related complications. Costs were expressed in 2010 US dollars and estimated using diagnosis‐related group codes and Medicare reimbursement rates. The net wholesale price for prasugrel was estimated as $5.45 per day. A generic estimate for clopidogrel of $1.00 per day was used and genetic testing was assumed to cost $500. Results: Base case analyses demonstrated little difference between treatment strategies. The genetic testing‐guided strategy yielded the most QALYs and was the least costly. Over 15 months, total costs were $18 lower with a gain of 0.004 QALY in the genotype‐guided strategy compared with empiric clopidogrel, and $899 lower with a gain of 0.0005 QALY compared with empiric prasugrel. The strongest predictor of the preferred strategy was the relative risk of thrombotic events in carriers compared with wild‐type individuals treated with clopidogrel. Above a 47% increased risk, a genotype‐guided strategy was the dominant strategy. Above a clopidogrel cost of $3.96 per day, genetic testing was no longer dominant but remained cost‐effective. Conclusions: Among ACS patients undergoing PCI, a genotype‐guided strategy yields similar outcomes to empiric approaches to treatment, but is marginally less costly and more effective.     

The role of clopidogrel in the management of acute coronary syndromes

BACKGROUND: Despite significant advances in the management of coronary heart disease, myocardial infarction (MI) is still associated with a mortality rate of 45%. Acetylsalicylic acid (ASA) has been the oral antiplatelet drug of choice until recently. Thienopyridines such as clopidogrel have been shown to provide significant benefits in the management of acute coronary syndromes (ACS), either as an alternative to or in combination with ASA therapy. OBJECTIVE: The purpose of this article was to review the available scientific literature evaluating the use of clopidogrel in the management of ACS. METHODS: Relevant published data were identified through searches of the English-language literature indexed on MEDLINE and International Pharmaceutical Abstracts through April 2003. Search terms included thienopyridines, platelet aggregation inhibitors, clopidogrel, ticlopidine, acute coronary syndrome, myocardial infarction, and percutaneous coronary intervention. Pertinent conference abstracts were also included. RESULTS: The results of 3 large clinical trials-Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Effect of Pretreatment with Clopidogrel and Aspirin Followed by Long-Term Therapy in Patients Undergoing Percutaneous Coronary Intervention (PCI-CURE), and Clopidogrel for the Reduction of Events During Observation (CREDO)-support prolonged use of clopidogrel (up to 12 months) in combination with ASA in patients with non-ST-segment elevation MI and patients undergoing a percutaneous coronary intervention (PCI). A significant increase in bleeding events was observed in the group that received clopidogrel plus ASA compared with ASA alone in the CURE (major bleeding, P = 0.001; minor bleeding, P < 0.001) and PCI-CURE (minor bleeding, P = 0.03) trials. Use of the combination of clopidogrel and ASA with other antiplatelet and/or anticoagulant agents has not been studied extensively. CONCLUSIONS: Use of the combination of clopidogrel and ASA for up to 9 months is recommended for the medical management of non-ST-segment elevation MI and after a PCI. The increased risk of bleeding must be taken into account, and use of this combination with other agents that affect bleeding risk should be considered carefully.     

Low‐molecular‐weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST‐elevation myocardial infarction: a meta‐analysis

Summary. Background: The aim of the current study was to perform two separate meta‐analyses of available studies comparing low‐molecular‐weight heparins (LMWHs) vs. unfractionated heparin (UFH) in ST‐elevation myocardial infarction (STEMI) patients treated (i) with primary percutaneous coronary intervention (pPCI) or (ii) with PCI after thrombolysis. Methods: All‐cause mortality was the pre‐specified primary endpoint and major bleeding complications were recorded as the secondary endpoints. Relative risk (RR) with a 95% confidence interval (CI) and absolute risk reduction (ARR) were chosen as the effect measure. Results: Ten studies comprising 16 286 patients were included. The median follow‐up was 2 months for the primary endpoint. Among LMWHs, enoxaparin was the compound most frequently used. In the pPCI group, LMWHs were associated with a reduction in mortality [RR (95% CI) = 0.51 (0.41–0.64), P < 0.001, ARR = 3%] and major bleeding [RR (95% CI) = 0.68 (0.49–0.94), P = 0.02, ARR = 2.0%] as compared with UFH. Conversely, no clear evidence of benefits with LWMHs was observed in the PCI group after thrombolysis. Meta‐regression showed that patients with a higher baseline risk had greater benefits from LMWHs (r = 0.72, P = 0.02). Conclusions: LMWHs were associated with greater efficacy and safety than UFH in STEMI patients treated with pPCI, with a significant relationship between risk profile and clinical benefits. Based on this meta‐analysis, LMWHs may be considered as a preferred anticoagulant among STEMI patients undergoing pPCI.     

Influence of high‐density lipoprotein and paraoxonase‐1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy

Summary. Background: The paraoxonase activity of the enzyme paraoxonase‐1 (PON‐1) associated with high‐density lipoprotein (HDL) may significantly influence clopidogrel’s antiplatelet and clinical efficacy as a result of its involvement in the clopidogrel biotransformation to the pharmacologically active thiol metabolite. We evaluated the possible relationships of HDL levels as well as PON‐1 activities and the Q192R genotype with clopidogrel’s antiplatelet efficacy in acute coronary syndrome (ACS) patients. Methods and results: The platelet aggregation, P‐selectin expression and platelet/leukocyte conjugates as well as the clopidogrel response variability (evaluated by the VASP phosphorylation test and expressed as platelet reactivity index, PRI) were assessed in 74 ACS patients undergoing percutaneous coronary intervention (PCI) in relation to the PON‐1 Q192R genotype and to serum HDL‐cholesterol levels, and PON‐1 (paraoxonase and arylesterase) activities. Patients were loaded with 600 mg of clopidogrel followed by 75 mg per day. HDL‐cholesterol levels and PON‐1 activities at baseline (before clopidogrel loading) were not altered at 5‐ and 30‐day post‐clopidogrel loading, whereas baseline platelet activation parameters were significantly attenuated. At 5 days, 17 patients were clopidogrel non‐responders (PRI: 64.2 ± 11.1%). HDL‐cholesterol was inversely associated with platelet activation parameters independently on platelet response variability to clopidogrel whereas a negative association between platelet activation parameters and paraoxonase activity was observed in patients adequately responding to clopidogrel but not in clopidogrel non‐responders. Similarly, the platelet activation markers were significantly higher in PON‐1 Q192Q genotype carriers compared with those having one or two R alleles only in patients adequately responding to clopidogrel. Conclusions: PON‐1 is an important determinant of clopidogrel antiplatelet efficacy only in patients adequately responding to clopidogrel. These findings may be clinically important in ACS patients receiving clopidogrel therapy, especially the first days after the episode.     

Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS‐PCI study

Summary. Background: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies.Objectives: To compare different assays for prediction of events during long‐term follow‐up.Methods: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator‐stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA‐100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12‐month follow‐up.Results: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c‐index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA‐100 (c‐index < 0.70; P > 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c‐index < 0.56; P > 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra‐metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status.Conclusions: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping.     

替格瑞洛治疗氯吡格雷低反应患者的有效性及安全性分析

目的 观察替格瑞洛对氯吡格雷低反应急性冠状动脉综合征(acute coronary syndromes,ACS)患者治疗的有效性及安全性。方法 选择2013年1月至2014年6月应用氯吡格雷75 mg/d治疗的ACS经皮冠状动脉介入治疗(PCI)术后患者493例,用血栓弹力图测定血小板聚集率,根据血小板聚集率筛选出氯吡格雷低反应患者173例,采用数字随机法分为氯吡格雷组(n=87)和替格瑞洛组(n=86)。氯吡格雷组继续服用氯吡格雷(75 mg/d),替格瑞洛组将氯吡格雷替换为替格瑞洛(90 mg,2次/d)。主要终点事件为治疗3天、7天、30天二磷酸腺苷(ADP)诱导的血小板聚集率变化情况,次要终点事件为主要不良心脑血管事件(MACCE)及出血的发生率。结果 替格瑞洛组3天、7天、30天血小板聚集率分别为(56.7±12.5)%、(54.1±12.3)%、(53.2±15.3)%显著低于氯吡格雷组(87.7±14.3)%、(85.4±12.7)、(84.9±10.7)%,差异有统计学意义(P<0.01)。对所有患者随访12个月,替格瑞洛组MACCE及出血的发生率显著低于氯吡格雷组(P<0.05)。而两组出血发生率差异无统计学意义(P＞0.05)。结论 对于经皮冠状动脉介入治疗的氯吡格雷低反应患者接受替格瑞洛治疗后能获得理想的抗血小板效果,且替格瑞洛是有效、安全可信赖的药物。     

Early glycoprotein IIb‐IIIa inhibitors in primary angioplasty‐abciximab long‐term results (EGYPT‐ALT) cooperation: individual patient’s data meta‐analysis

Summary. Background: Even although time to treatment has been shown to be a determinant of mortality in primary angioplasty, the potential benefits are still unclear from early pharmacological reperfusion by glycoprotein (Gp) IIb‐IIIa inhibitors. Therefore, the aim of this meta‐analysis was to combine individual data from all randomized trials conducted on upstream as compared with late peri‐procedural abciximab administration in primary angioplasty. Methods: The literature was scanned using formal searches of electronic databases (MEDLINE and EMBASE) from January 1990 to December 2010. All randomized trials on upstream abciximab administration in primary angioplasty were examined. No language restrictions were enforced. Results: We included a total of seven randomized trials enrolling 722 patients, who were randomized to early (n = 357, 49.4%) or late (n = 365, 50.6%) peri‐procedural abciximab administration. No difference in baseline characteristics was observed between the two groups. Follow‐up data were collected at a median (25th–75th percentiles) of 1095 days (720–1967). Early abciximab was associated with a significant reduction in mortality (primary endpoint) [20% vs. 24.6%; hazard ratio (HR) 95% confidence interval (CI) = 0.65 (0.42–0.98) P = 0.02, P_het = 0.6]. Furthermore, early abciximab administration was associated with a significant improvement in pre‐procedural thrombolysis in myocardial infarction (TIMI) 3 flow (21.6% vs. 10.1%, P < 0.0001), post‐procedural TIMI 3 flow (90% vs. 84.8%, P = 0.04), an improvement in myocardial perfusion as evaluated by post‐procedural myocardial blush grade (MBG) 3 (52.0% vs. 43.2%, P = 0.03) and ST‐segment resolution (58.4% vs. 43.5%, P < 0.0001) and significantly less distal embolization (10.1% vs. 16.2%, P = 0.02). No difference was observed in terms of major bleeding complications between early and late abciximab administration (3.3% vs. 2.3%, P = 0.4). Conclusions: This meta‐analysis shows that early upstream administration of abciximab in patients undergoing primary angioplasty for ST‐segment elevation myocardial infarction (STEMI) is associated with significant benefits in terms of pre‐procedural epicardial re‐canalization and ST‐segment resolution, which translates in to significant mortality benefits at long‐term follow‐up.     

Safety and efficacy of protease‐activated receptor‐1 antagonists in patients with coronary artery disease: a meta‐analysis of randomized clinical trials

Summary. Background: Thrombin receptor antagonists blocking protease‐activated receptor‐1 (PAR‐1) on platelets represent a new class of oral antiplatelet agents for patients with atherothrombotic disease manifestations. Objectives: We investigated the safety and efficacy of PAR‐1 antagonists in patients with coronary artery disease (CAD). Patients/Methods: Randomized, placebo‐controlled trials of the PAR‐1 antagonists atopaxar or vorapaxar in CAD patients were identified. The primary safety endpoint was the composite of Thrombolysis In Myocardial Infarction (TIMI) clinically significant bleeding. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke. Results: A total of 41 647 patients from eight trials were included. PAR‐1 antagonists were associated with higher risks of TIMI clinically significant (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.39–1.57, P < 0.001), major (OR 1.46, 95% CI 1.28–1.67, P < 0.001) and minor (OR 1.67, 95% CI 1.40–2.00, P < 0.001) bleeding than placebo in the fixed‐effects model. PAR‐1 antagonists reduced the composite of death, MI or stroke as compared with placebo (OR 0.87, 95% CI 0.81–0.92, P < 0.001), driven by a lower risk of MI (OR 0.85, 95% CI 0.78–0.92, P < 0.001). Conversely, PAR‐1 antagonists and placebo did not differ in terms of risk of death (OR 0.99, 95% CI 0.90–1.09, P = 0.81) or stroke (OR 0.96, 95% CI 0.84–1.10, P = 0.59). Conclusions: PAR‐1 antagonists decrease ischemic events in patients with CAD as compared with placebo, mainly driven by a reduction in MI, at the cost of an increased risk of clinically significant bleeding.     

Long-term care after percutaneous coronary intervention: focus on the role of antiplatelet therapy

Arterial wall injury caused by percutaneous coronary intervention (PCI) triggers transient platelet activation and mural thrombosis; these effects are superimposed on the preexisting platelet hyperreactivity associated with underlying atherothrombosis. Platelet activation has been implicated in the major complications of PCI: acute and subacute thrombosis and restenosis. Antithrombotic and anticoagulant therapy minimizes thrombotic complications after PCI. Aspirin plus a thienopyridine (ticlopidine or clopidogrel) is more effective than aspirin plus heparin and extended warfarin therapy in preventing periprocedural ischemic events and subsequent stent thrombosis and results in less major and minor bleeding. Dual antiplatelet therapy with aspirin and clopidogrel (the preferred thienopyridine because of its superior hematologic safety) is recommended for at least 4 weeks to prevent subacute stent thrombosis with bare-metal stents and 3 to 6 months to prevent late-stent thrombosis with drug-eluting stents. Coronary atherothrombosis is a diffuse vascular disease, and reduction of the risk of future ischemic events requires strategies that extend beyond the focal treatment of stenotic lesions. Optimal long-term care after PCI requires aggressive systemic pharmacotherapy (antiplatelet agents, statins, beta-blockers, and angiotensin-converting enzyme Inhibitors) in conjunction with therapeutic lifestyle changes (smoking cessation, weight reduction, dietary measures, and exercise). In this context, dual antiplatelet therapy (aspirin plus clopidogrel) is recommended for at least 12 months after PCI for prophylaxis of future atherothrombotic events.