抗血小板药物治疗的实验室检测

基于一级和二级预防实验结果,当前国内外的缺血性心脑血管疾病防治指南均推荐应用抗血小板药物（Ⅰ级证据）。但值得注意的是约一半患者对抗血小板药物存在＂抵抗＂或＂无效＂的认识,针对上述患者的临床发现存在滞后性。本文重点讨论一些当前国内外用于抗血小板药物（阿司匹林和氯吡格雷）疗效评价实验室方法的优缺点。一些方法已应用于基础和临床研究且有证据支持可预测抗血小板药物的疗效。但至今尚无任何一项研究是通过上述实验室方法检测抗血小板药物来说明改变治疗的临床转归。因此未来的发展应是寻找更加有药物特异性和非特异性的实验室方法,并探讨这些实验室指标与药物临床效果的量化联系。     

High platelet reactivity and clinical outcome - fact and fiction

In patients suffering from acute coronary syndromes or undergoing percutaneous coronary intervention, oral antiplatelet treatment is routinely administered with the primary aim of inhibiting platelet-mediated thrombus formation and subsequent abrupt vessel occlusion. Simultaneous inhibition of blood platelet cyclooxygenase-1 by aspirin and of the P2Y12 receptor by clopidogrel or prasugrel is currently recommended in this setting. Inter-individual response variability to aspirin and especially to clopidogrel is the subject of much debate as evidence has grown over the years linking an attenuated response to treatment with the occurrence of ischaemic events. Consequently, the clinical entity of high (on-treatment) platelet reactivity (HPR) was born and subsequently characterised in numerous studies over the last decade. Until recently, alternative treatment options were limited in patients exhibiting HPR. At present the antiplatelet therapy landscape is changing with the advent of prasugrel and ticagrelor as alternative and more potent treatment options. Different tests for monitoring platelet function are available and are being increasingly employed in research projects and clinical routine. These tests may prove useful for achieving optimal platelet inhibition for the individual patient, and several centres now incorporate such testing in day-to-day practice. Widespread adoption of this practice and incorporation into clinical guidelines awaits the results of ongoing trials in which treatment is changed based on platelet function monitoring. This review aims to summarise available facts and fiction in relation to platelet function testing and reactivity with a particular focus on P2Y12 receptor inhibition in patients undergoing coronary stent placement.     

Antiplatelet therapies and the role of antiplatelet resistance in acute coronary syndrome

Acute coronary syndrome is the number one killer in the industrialized world and, as such, continues to be one of the most well-studied disease states in all of medicine. Advancements in antiplatelet therapies for use in patients undergoing percutaneous coronary intervention have improved outcomes dramatically. However, a proportion of patients on long-term antiplatelet therapy continue to have cardiovascular events. Resistance to antiplatelet drugs may explain some of these events and this topic has become one of major interest and rapid evolution. This review describes the pathogenesis of acute coronary syndromes, outlines the evidence behind the use of the available antiplatelet agents, and examines the current data surrounding antiplatelet resistance.     

Peri-operative platelet function testing: the potential for reducing ischaemic and bleeding risks

The pivotal role of platelet activation and reactivity during atherothrombotic event occurrence associated with acute coronary syndromes (ACS) or percutaneous coronary interventions (PCI) is well established. Numerous translational research studies have established a threshold level of platelet reactivity during dual antiplatelet therapy above which a higher risk for ischaemic event occurrence has been observed. The clinical validity of these threshold values in reducing ischemic event occurrence with modified P2Y12 receptor therapy is currently under investigation in large-scale clinical trials. The association between on-treatment platelet reactivity measured by an ex vivo assay and the occurrence of bleeding events is less established. Currently, there is limited evidence of an association between platelet inhibition and coronary artery bypass grafting (CABG)- related bleeding in patients on clopidogrel therapy indicating that preoperative platelet function monitoring may guide both the timing of elective CABG and the administration of blood products in patients needing surgery. However, in the absence of a large-scale prospective clinical trial, routine platelet function monitoring and modification of timing of surgery based on platelet function monitoring are currently not recommended.     

Clopidogrel response variability and the advent of personalised antiplatelet therapy. A bench to bedside journey

Platelet-mediated thrombosis is a dreaded clinical event and is the primary cause of acute coronary syndromes and post-percutaneous intervention (PCI) ischaemic events. There has been a long standing interest in the ex vivo quantification of platelet reactivity to assess the risk of thrombosis. Early studies demonstrated platelet activation and heightened platelet reactivity in acute coronary syndromes and after PCI. However, a demonstration that heightened reactivity actually precipitated the ischaemic event was lacking. Our knowledge of platelet receptor physiology and the advent of novel inhibitors have significantly advanced the field. The P2Y12 receptor has been shown to play a pivotal role in the amplification of platelet activation by multiple agonists and its inhibition has resulted in improved clinical outcomes. The most widely used drug to block P2Y12 receptor, clopidogrel is associated with resistance in selected patients and these patients have been shown to be at increased risk for post-PCI ischaemic event occurrence in multiple studies. Importantly, a threshold of high platelet reactivity has been demonstrated, and beyond this threshold ischaemic events occur precipitously. Based on the current evidence, it is rational to quantify the intensity of the ADP-P2Y12 interaction in the patient at the greatest risk for thrombosis-the PCI patient. However, there is only evidence from small clinical trials demonstrating the clinical efficacy of changing an antiplatelet regimen based on an ex vivo platelet function measurement. Moreover, there are numerous patients with vulnerable coronary anatomy that have not yet experienced plaque rupture; the prognostic role of a measurement of platelet reactivity in the latter group has never been studied. Large-scale trials are ongoing that will investigate the role of personalised antiplatelet therapy in the PCI patient.     

Clopidogrel withdrawal: is there a "rebound" phenomenon?

Dual antiplatelet therapy with aspirin and clopidogrel is routinely indicated in patients with acute coronary syndromes and following percutaneous coronary intervention to reduce the risk of cardiovascular mortality and ischaemic events. Although clinical guidelines recommend aspirin lifelong and clopidogrel for between one and 12 months, depending upon the indication, the optimal duration of clopidogrel therapy actually remains contentious. Premature cessation of clopidogrel in patients receiving drug-eluting stents is a clear risk factor for stent thrombosis, but recent clinical studies have also demonstrated a link between "appropriate" cessation of clopidogrel and clustering of adverse clinical events. It has been suggested that this may be due to a "rebound" prothrombotic and/ or proinflammatory response associated with clopidogrel withdrawal. This review will examine the definition and concept of a "rebound" phenomenon associated with clopidogrel cessation as well as the likely mechanisms behind this effect. Within the context of clinical event clustering after clopidogrel cessation, we will also discuss (i) the clinical importance of clopidogrel and the increasing uncertainty surrounding optimal duration of therapy, (ii) the antiplatelet and anti-inflammatory properties of clopidogrel and, in particular, its influence on arachidonic acid pathways traditionally thought to be mediated predominantly by aspirin and (iii) the role of newer, more potent antiplatelet agents and potential changes to antiplatelet therapy prescribing guidelines in the future.     

Strategies for antiplatelet targets and agents

Platelets play a key role in thrombosis and haemostasis, which can be either beneficial or deleterious depending on the circumstance. Antiplatelet therapy is the ‘cornerstone’ in the prevention and treatment of thrombotic deseases. Platelet activation is a complex process known as transmembrane signaling which then serves to activate the platelet via a cascade of biochemical interactions. Currently available strategies of antiplatelet therapy are generally based on the signaling pathway of platelet activation, which possess the characters that mono-agent, mono-target, and mainly irreversible inhibition. Therefore, both established and novel antiplatelet agents have their own pros and cons and such problems as resistance, drug-drug interaction, discontinuation and monitoring, etc. have been appeared. Due to the problems existing in current antiplatelet agents, future new strategies for antiplatelet targets, agent-developing and treatment might probably include three aspects: targeting the factors associated with platelet hyperactivity, developing novel antiplatelet agents with multiple targets, mild and reversible properties from natural products, and keeping healthy lifestyle and emphasizing prevention.     

Antiplatelet resistance in stroke

Although the exact prevalence of antiplatelet resistance in ischemic stroke is not known, estimates about the two most widely used antiplatelet agents - aspirin and clopidogrel - suggest that the resistance rate is high, irrespective of the definition used and parameters measured. Inadequate antiplatelet responsiveness correlates with an increased risk of recurrent ischemic vascular events in patients with stroke and acute coronary syndrome. It is not currently known whether tailoring antiplatelet therapy based on platelet function test results translates into a more effective strategy to prevent secondary vascular events after stroke. Large-scale clinical trials using a universally accepted definition and standardized measurement techniques for antiplatelet resistance are needed to demonstrate whether a 'platelet-function test-guided antiplatelet treatment' strategy translates into improved stroke care. This article gives an overview of the clinical importance of laboratory antiplatelet resistance, describes the challenges for platelet-function test-guided antiplatelet treatment and discusses practical issues about the management of patients with aspirin and/or clopidogrel resistance.     

血小板活化状态检测在颅内动脉瘤支架置入术中的应用

目的探讨流式检测血小板活化状态对颅内动脉瘤支架置入术治疗的患者调整抗血小板药物的临床价值。方法对66例颅内动脉瘤患者行支架置入术治疗,术前给予常规抗血小板治疗[阿司匹林（100 mg,1次/d）＋氯吡格雷（75 mg,1次/d）]。利用流式细胞术方法监测血小板活化状态,血小板激活率〈20%,减少氯吡格雷药量;血小板激活率〉50%,增加氯吡格雷药量;血小板激活率为20%~50%,不调整药量。所有患者阿司匹林药量均不调整。结果氯吡格雷剂量未调整32例,调整为35 mg 6例、150 mg 26例、225 mg 1例,改用西洛他唑1例。药物调整后用药不当发生率（1.5%,1/66）较调整前（51.5%,34/66）明显降低（P〈0.05）。35例患者出院后随访1年,1例调整用药前即发生再缺血事件,调整用药方案后随访6个月未见再狭窄;4例药物调整前有明显的临床出血症状,调整用药方案后临床症状消失。结论流式细胞术是一种检测血小板活化状态有效的方法。流式检测结果对临床调整抗血小板药物治疗具有重要的指导作用。     

Individualized antithrombotic therapy in high risk patients after coronary stenting. A double-edged sword between thrombosis and bleeding

Dual antiplatelet therapy with aspirin and clopidogrel is currently the standard therapy after coronary stent implantation to prevent a life-threatening stent thrombosis. However, a variety of procedural and individual factors contribute to the individual patient risk and have to be taken into account to allow for an individual recommendation for both the duration and intensity of the antiplatelet therapy. Obviously, the benefit of the prevention of stent thrombosis by antithrombotic therapy has to outweigh the risk of severe bleeding complications. Depending on the individual clinical situation and procedural characteristics (stent type, length, angiographic result etc.), the recommended duration of the combined antiplatelet therapy currently varies from four weeks to at least one year. These recommendations are mainly based on large, prospective, randomized trials and evidence-based guidelines. However, in a subgroup of high-risk patients there is insufficient evidence for the benefit of conventional dual antiplatelet regimen. These include i) patients with an indication for anticoagulation, ii) patients with urgent need for an operation requiring a perioperative withholding of antiplatelet therapy, as well as iii) clopidogrel low responders. This review aims to provide a stratification to define patient collectives who may benefit from more individualized antithrombotic regimens on behalf of currently available literature and guidelines.     

Warfarin for atrial fibrillation: the end of an era?

BACKGROUND: Warfarin has been in routine clinical use for more than 50 years; however, it was not proven to be of benefit in both primary and secondary prevention of stroke for patients with non-valvular atrial fibrillation (AF) until about a decade ago. Despite its efficacy in reducing the risk of stroke in patients with AF by about 60%, with an absolute reduction of about 3% per year, there have always been barriers to its use. These barriers have included the need for monitoring the degree of anticoagulation with blood tests to measure the international normalised ratio, frequent dose adjustments to maintain this ratio within quite a narrow therapeutic range, and the risk of bleeding should the upper limits of this range be exceeded. Aspirin has also been used but is less effective. RECENT DEVELOPMENTS: New oral drugs are being tested; these may be as effective at reducing stroke risk as warfarin in patients with AF. Direct thrombin inhibitors such as ximelagatran are not inferior to warfarin and, based on results from the SPORTIF III and V trials, are perhaps safer, with no need for long-term monitoring and dose adjustment. However, the side-effect of raised amounts of the liver enzyme alanine amino-transferase in 6% of patients needs to be resolved. In the ACTIVE trial, the efficacy of a combination of antiplatelet drugs (aspirin plus clopidogrel) is being tested against dose-adjusted warfarin; and in AMADEUS, the factor-Xa inhibitor and pentasaccharide idraparinux is being assessed in a similar way. Several surgical procedures and devices are also being developed to control AF rhythm and prevent stroke. WHERE NEXT?: The place of these new drugs in the management of AF needs to be established. In the short term, it seems that ximelagatran will replace warfarin in patients for whom there is evidence of a favourable risk-to-benefit ratio. The SPORTIF population consists of patients with AF plus at least one risk factor. More information about the effect of raised liver enzymes will probably not be available until phase IV studies are completed. Combination antiplatelet drugs need to be tested further--perhaps even triple therapy with aspirin, clopidogrel, and dipyridamole--if the results of ACTIVE are encouraging. The place of surgical procedures and devices to control rhythm and prevent stroke is unclear. Whatever happens, there is a high probability that the days of warfarin are numbered.     

Serumkonzentration von Antiepileptika Praktische Richtlinien zur Messung und sinnvollen Interpretation

The clinical relevance of being informed on the serum concentration of antiepileptic drugs has been judged very differently during the last decades. Therefore the Commission on the treatment of epilepsy (German section of the International League against Epilepsy) had the task to outline the importance of therapeutic monitoring of anticonvulsant serum concentrations. The possibility of determining the serum concentration of anticonvulsants induced the elaboration of "therapeutic drug level ranges". The usefulness of determining serum concentrations of antiepileptic drugs in clinical management of patients with epilepsy depends decisively on the following questions: Can the efficacy of antiepileptic drug treatment be increased by serum concentration monitoring? Can the rate of adverse effects of antiepileptic drugs be reduced by serum concentration monitoring? Clinical experience suggests numerous indications of therapeutic drug monitoring, scientific studies however, supporting these empirical guidelines are not available. Therefore, therapeutic drug monitoring may be restricted for some special situations which have to be justified in every single case. Tailored determinations with specific purposes are e.g.: resistance to therapy, including suspected irregular intake; suspected intoxication, particularly during combined therapy; the possibility of significant changes in the dosage-serum concentration relationship (interactions with other drugs, unusual pharmacokinetics in childhood, in pregnancy etc.).     

Safety of early antiplatelet administration in patients with acute ischemic stroke treated with alteplase (SEAPT-24)

ObjectivesAlteplase, a tissue-type plasminogen activator, is recommended for ischemic stroke patients presenting within 4.5 h. Due to bleeding risks, current guidelines advise delaying antiplatelet therapy for 24 h after alteplase. However, specific scenarios may require antiplatelet therapy to be given within the 24 h window. This study aimed to examine the safety of early antiplatelet therapy administration within the first 24 h after alteplase.Materials and methodsThis study is a retrospective, observational study of adult patients with acute ischemic stroke who received alteplase across a multi-hospital system. Patients were grouped based on early antiplatelet therapy (within 24 h window) or as recommended per guidelines. The occurrence of bleeding events, including symptomatic intracranial hemorrhage and/or gastrointestinal bleeding, in-hospital mortality, unfavorable outcomes (modified Rankin score 3–6), and hospital length of stay, were compared between groups.ResultsPatients were predominantly African American (72%) and female (53%) with a median age of 62 years. Median baseline NIHSS scores were higher in the early group (5 vs. 7; p = 0.04), and patients in the early group were more likely to undergo endovascular therapy (26% vs. 8%, p < 0.0001). In patients treated with alteplase only and who did not undergo endovascular therapy, there was no difference in symptomatic intracranial hemorrhage (1.4% vs. 0%, p = 0.1), gastrointestinal bleeding, in-hospital mortality, unfavorable outcomes, or length of stay.ConclusionsIn our retrospective analysis, early administration of antiplatelet therapy (< 24 h post-alteplase) did not increase the risk of symptomatic intracranial hemorrhage, gastrointestinal bleeding, or unfavorable outcomes in patients who received alteplase alone for management of acute ischemic stroke. Prospective studies are needed to validate these findings.     

Clinical consequences of aspirin and clopidogrel resistance: an overview

The aim of this review is to introduce the concept of personalized medicine in secondary stroke prevention with antiplatelet medication. In the last years, many studies have been conducted regarding aspirin resistance and genotyping of clopidogrel metabolism. A review of the currently published data on this issue emphasizes the importance of focusing on the individualizing approach in antiplatelet therapy to achieve maximal therapeutic beneficial effect. However, many authors suggest that, before new information from ongoing trials become available, good clinical practice should dictate the use of low dose of aspirin that was shown to be effective in the prevention of stroke and death in patients with ischemic cerebrovascular disease, because higher doses do not have significantly better efficacy than lower doses in secondary stroke prevention, but lower‐dose aspirin is associated with less side effects. On the other hand, many factors are associated with clopidogrel resistance, and recent genetic studies showed that the CYP2C19*2 genotype (loss‐of‐function allele) is related to poor metabolism of clopidogrel, but larger studies are needed to definitively confirm or rule out the clinical significance of this genetic effect. The aim of personalized approach in secondary stroke prevention is to take the most appropriate medicine in the right dose in accordance with the clinical condition of the patient and associated risk factors.     

Resistance to anti-platelet agents

In the last few years, the concept of resistance to antiplatelet agents has been largely emphasized in the medical literature, although its definition is still uncertain. The real prevalence of resistance to aspirin appears to be rather low. In contrast, resistance to clopidogrel (a P2Y12 inhibitor), which is mostly due to inefficient metabolism of the pro-drug clopidogrel to its active metabolite, is a rather frequent condition, which is associated with lower clinical efficacy of the drug. The proposed solution to the problem of clopidogrel resistance, based on monitoring the pharmacological response with platelet function tests, is cumbersome, not effective in all treated patients and not practicable yet, because the most appropriate laboratory test has not yet been identified. The use of new P2Y12 inhibitors, such as prasugrel and ticagrelor, which adequately inhibit P2Y12-dependent platelet function in the vast majority of treated subjects, appears the best solution to the problem of clopidogrel resistance.     

Ischaemic stroke and bleeding rates in 'real-world' atrial fibrillation patients

Stroke prevention guidelines recommend oral anticoagulants (OAC) for atrial fibrillation (AF) patients at moderate/high risk of stroke, and antiplatelet or no therapy for those at low/moderate risk. Outcomes for AF patients receiving antiplatelet/no therapy in 'real-life' clinical practice were explored. This study compared clinical event rates (stroke/bleeding) for AF patients treated with OAC therapy, antiplatelets or no therapy in usual clinical practice to event rates in OAC-treated AF patients from optimally-monitored 'real-life' settings (anticoagulation clinics). We searched biomedical literature (1994-2010) using PubMed to identify 'real-world' studies of clinical event rates for AF patients receiving OAC therapy, antiplatelets, or no therapy; event rates were extracted for each treatment and setting. We identified 136 studies of thromboembolic events and 86 of bleeding events. Ischaemic stroke rates (30 studies) were higher for AF patients receiving no therapy (median: 4.45/100 person-years; range: 0.25-5.9) or antiplatelet-therapy (median: 4.45/100 person-years; range: 2.0-10) compared to OAC-treated patients monitored in anticoagulation clinics (median: 1.72/100 person-years; range: 0.97-2.00), or from a non-specialized setting (median 1.66/100 person-years; range: 0-4.9). Major bleeding rates (32 studies) for patients receiving antiplatelet/no therapy were similar to OAC-treated patients from both clinical settings. As in randomised clinical trials, AF patients in 'real-world' clinical practice receiving antiplatelet/no therapy have higher rates of ischaemic stroke than OAC-treated patients. Antiplatelet/no therapy was associated with similar bleeding rates to OAC therapy. Increasing utilisation of anticoagulants in clinical practice could improve patient outcomes.     

Clopidogrel resistance?

Clopidogrel is an effective inhibitor of platelet activation and aggregation due to its selective and irreversible blockade of the P2Y(12) receptor. Combination antiplatelet therapy with clopidogrel and aspirin is an important strategy for patients with acute coronary syndromes and those undergoing percutaneous interventions. Despite significant benefits demonstrated with combination antiplatelet treatment in large clinical trials, the occurrence of adverse ischemic events, including stent thrombosis, remains a serious clinical problem. Recent studies have demonstrated distinct response variability and nonresponsiveness to clopidogrel therapy based on ex vivo platelet function measurements. Small scale investigations have suggested that nonresponsiveness may be associated with a heightened risk for adverse clinical events. The above findings have stimulated a close examination of clopidogrel metabolism.     

Efficacy of cilostazol-based dual antiplatelet treatment in patients undergoing carotid artery stenting

Background: It is essential that patients undergoing carotid artery stenting (CAS) receive optimal antiplatelet inhibition. Although a reduction in platelet reactivity and improved clinical outcomes occur when using adjunctive cilostazol with dual antiplatelet therapy, this can lead to an increased risk of hemorrhagic complications. Therefore, our current study examined patients undergoing CAS and evaluated the impact of cilostazol-based dual antiplatelet treatment on the outcomes.

Methods: Between 2010 and 2015, 137 consecutive patients underwent CAS. From 2010 to 2011 (period 1), 28 patients underwent CAS in conjunction with aspirin and clopidogrel dual antiplatelet treatment (DAPT). From 2010 to 2013 (period 2), 44 patients underwent a preoperative assessment of their platelet function, with the clopidogrel-resistant patients receiving adjunctive cilostazol in addition to the aspirin and clopidogrel. From 2013 to 2015 (period 3), 65 patients underwent CAS in conjunction with cilostazol and clopidogrel treatment. In all patients, the incidence of new ipsilateral ischemic lesions observed by diffusion-weighted imaging on the day after CAS, and ischemic or hemorrhagic events occurring within 30 days were assessed.

Results: Clopidogrel resistance was identified in 43% of the patients in period 1, in 16% in period 2, and in 5% in period 3 (P < 0.001). The on-treatment platelet reactivity results indicated that the PRU value during cilostazol-based DAPT was significantly lower than that observed for the standard DAPT (P < 0.05). New ipsilateral ischemic lesions decreased by 9% and 8% in periods 2 and 3, respectively, versus a 25% decrease in period 1 (P = 0.047). However, there were no significant differences noted for any of the hemorrhagic or thromboembolic events.

Conclusions: Compared to the standard aspirin and clopidogrel dual antiplatelet therapy, cilostazol-based dual antiplatelet treatment reduces the rate of clopidogrel resistance and suppresses new ischemic lesions without hemorrhagic complications.     

Genetic variability in response to clopidogrel therapy and its clinical implications

This article concentrates on individual genetic differences responsible for variations of action of clopidogrel, which have been found to be partially responsible for increased cardiovascular events in patients with coronary artery disease under dual antiplatelet therapy. According to these results, genotyping for the relevant gene polymorphisms, especially for the CYP2C19 loss-of-function alleles, has been discussed to be an effective method of individualising and optimising clopidogrel treatment. However, due to the facts that 1) there are no prospective studies demonstrating a clinical benefit of personalising antiplatelet therapy based on genotyping; 2) CYP2C19 polymorphisms account for only approximately 12% of variability in clopidogrel platelet response; 3) the positive predictive value of CYP2C19 loss-of-function polymorphisms for cardiovascular events in patients with acute coronary syndrome undergoing percutaneous coronary intervention is only approximately 12% - 20%; 4) it is likely that other clinical factors and risk constellations might be of greater clinical importance; and 5) it is unknown whether a specific genetic polymorphism is capable of influencing outcome for the individual patient; genetic profiling cannot be recommended for routine use at present but will remain of considerable scientific interest.     

Impact of the proton pump inhibitors and CYP2C19*2 polymorphism on platelet response to clopidogrel as assessed by four platelet function assays

Background

Previous studies suggested a possible negative interference of proton pump inhibitors (PPIs) on clopidogrel’s antiplatelet effect because of the competitive inhibition of the CYP 2C19 isoenzyme. Moreover, carriers of the loss-of-function allele of CYP2C19 polymorphism (CYP2C19*2) display significantly lower responses to clopidogrel. In this study, we investigated the association between CYP2C19*2 genotype, PPI intake and clopidogrel resistance in patients with coronary artery disease (CAD) and their effect on clinical outcome.

Methods

We recruited 95 patients with CAD receiving chronic clopidogrel therapy in combination with aspirin. Platelet reactivity was simultaneously assessed by INNOVANCE PFA-100 P2Y, ADP-induced light transmission aggregometry (LTA), flow-cytometric vasodilator-stimulated phosphoprotein (VASP)-phosphorylation assay and multiple electrode aggregometry (Multiplate). Cardiovascular outcomes were recorded during 1-year follow-up period.

Results

Only platelet reactivity assessed by measuring platelet phosphorylated-VASP demonstrated a significant higher platelet reactivity in carriers of CYP2C19*2 (p = 0.023). The other methods displayed higher - but not statistically significant - platelet reactivity in patients carrying the CYP2C19*2 variant as compared with non-carriers. Patients on PPIs demonstrated almost similar suppression of platelet reactivity in comparison with those not treated with PPIs by all platelet function assays. In logistic regression analysis none of the platelet function assays measurements were related with clinical outcomes. Similarly neither CYP2C19*2 genetic variant nor PPI treatment were associated with adverse clinical events.

Conclusions

PPI co-administration did not influence clopidogrel’s antiplatelet effect on laboratory testing by all platelet function assays used. On the contrary, patients carrying CYP2C19*2 genotype had significantly higher residual platelet reactivity as estimated by VASP-phosphorylation assay.