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Oral antiplatelet drugs are a cornerstone of modern pharmacotherapy in cardiovascular atherothrombotic diseases. The efficacy of acetylsalicylic acid ASA, aspirin and clopidogrel in decreasing the risk of adverse events in coronary heart disease patients has been well established in the past 20 years. Despite chronic oral antiplatelet therapy, a number of atherothombotic events continue to occur. The present position paper, conveyed within a group of clinical cardiologists with expertise in thrombosis appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, has been further elaborated and endorsed by the Working Group on Thrombosis of the European Society of Cardiology. It aims at summarizing the main findings in this complex area, issuing opinions in cases of high controversy, and fostering future research in this area to obtain reliable laboratory and clinical data for the resolution of the many problems still open. The efficacy of acetylsalicylic acid ASA, aspirin and clopidogrel in decreasing the risk of adverse events in coronary heart disease CHD patients 1—4 has been well established in the past 20 years. The present position paper, conveyed within a group of clinical cardiologists with expertise in thrombosis appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, and published in a previous version in the Polish Cardiology Journal, 5 has been further elaborated and endorsed by the Working Group on Thrombosis of the European Society of Cardiology. This position paper aims at summarizing the main findings in this complex area, issuing opinions in cases of high controversy, and fostering future research in this area to obtain reliable laboratory and clinical data for the resolution of the many problems still open. ASA is a non-selective cyclooxygenase inhibitor. At doses used in cardiology, ASA efficiently blocks the constitutive isoenzyme cyclooxygenase COX -1 present in blood platelets. ASA acetylates a serine in the amino acid chain near the enzyme active site, thus preventing the contact with arachidonic acid and hence stopping thromboxane TX A 2 synthesis. The effect is irreversible throughout the entire life span of platelet in the circulation, and therefore lasts from 7 to 10 days. Moreover, ASA blocks exclusively one amplification pathway of platelet activation, while many other pathways stimulated by adenosine diphosphate ADP , adrenaline, thrombin, shear stress, and high-dose collagen remain largely unaffected. It is metabolized by esterases present in the blood and in the liver, explaining its short half-time, in the order of 15 min. It has recently been shown that enteric-coated formulations of ASA are absorbed worse than standard plain formulations in the moderately acidic intestinal environment, and provoke a lesser antiplatelet effect. A second oral antiplatelet drug, clopidogrel, is a pro-drug, and its active form, a thiol derivative, is produced through oxidation to 2-oxy-clopidogrel and hydrolysis, in a process mainly dependent on the cytochrome P isoenzymes 3A4, 3A5, 2B6, and 2C19 and, to a lesser extent, on isoenzymes 1A1 and 1A2. The active form of the drug binds selectively and irreversibly to the P2Y 12 receptor on the external surface of the platelet membrane, blocking the interaction of the receptor with ADP. As for ASA, clopidogrel platelet receptor occupancy lasts for the entire life span of platelet, i. It should be at first pointed out that atherothrombosis is a complex process, and the blockade of only one of its mechanisms—platelet function—albeit important, cannot completely abolish the entire process and its consequences. For this reason, one cannot expect that antiplatelet drugs, despite their careful use according to current guidelines in secondary prevention, can save all patients from all atherothrombotic complications. The same happens for lipid-lowering and blood pressure-lowering drugs. Measurement of the action of antiplatelet drugs has not reached such a status of standardization and is still a research tool after more 30 years of intense work. Such results are understandable, as the drug response tested in a group of healthy individuals or patients mostly shows a normal distribution: 12 at a certain given dose, the majority of patients will respond to the drug, a small percentage will respond more than the average, and some patients will respond less. The number of low-responders will usually decrease but drug-related adverse events will also somewhat increase hand-in-hand with a dose escalation. This can be obtained already at a dose as small as 30 mg used chronically. In the case of clopidogrel, the dose—response curve has all the characteristics of a normal distribution, 12 with higher antiplatelet effect occurring at a loading dose of mg and a maintenance dose of mg a day. Yet, a clinical problem related to the use of antiplatelet agents is achieving an effective and clinically relevant inhibition of platelet function with acceptable safety. The high interindividual variability 17 is problematic and might be overcome to some extent, at least in the case of clopidogrel, by increasing loading and maintenance doses. On the one hand, it may refer to a mere assessment of cases occurring while on treatment. It can be imagined, on the other hand, that—in a given patient—a target lipid, blood pressure, and platelet function level if we could work out such a measure for platelets is achieved with appropriate therapies, but the patient still develops a cardiovascular ischaemic event. The estimates of such treatment failures in the latter strict sense can be easily given with antihypertensive or lipid-lowering therapies, but this is certainly very problematic with antiplatelet treatments. The definitions of clinical resistance or treatment failure related to oral antiplatelet agents are imprecise ways of linking the presence of cardiovascular atherothrombotic events with a possibly inappropriate response to antiplatelet drugs. We therefore propose stopping using such designations in relation to clinical events. The description of all methods used to measure platelet reactivity in the laboratory is beyond the scope of the current article. Such methods have been described in detail elsewhere. This is intended to be only a temporary proposition, which can be changed with the possible inclusion of newer methods and the better assessment of current ones. The methodological problems related with the tests have effectively been described in a recent study where six different tests were compared in a group of patients with stable CHD. All patients were on chronic ASA therapy. The results with the various tests hardly correlated with one another. Secondly, for all the above-mentioned methods, investigators or device producers have established cut-off values, which could help classifying patients as normal responders or low responders. At present, the majority of such cut-off values relate to optical aggregation induced with arachidonic acid, 26 or impedance aggregometry in whole blood with the same agonist. We are actually in the even more worrisome situations that we do not know whether populations separated by such cut-offs are actually different at all in terms of outcomes. The search for such an association link and of possible new cut-off values is ongoing. This is an index of the maximum capacity of platelets to produce thromboxane, and is therefore exquisitely sensitive to the biochemical effect of ASA. As, however, platelet function including platelet aggregation depends on the TX pathway to a variable extent, according to the type of activating stimulus and possibly to inter-individual variability, this test cannot be automatically translated into the clinical use to identify low functional platelet responses to ASA. Measurements of the urinary output of the hepatic metabolites of TX, such as dehydro-TXB 2 , may reflect also extra-platelet production of TX. First, the proposed functional test for clopidogrel is platelet aggregation induced by ADP. Such values were worked-out as being above the 75th percentile of aggregation values in a control group. Secondly, a method to assess the biochemical effect of clopidogrel is the flow cytometric analysis of vasodilator-stimulated phosphoprotein VASP phosphorylation. Other methods for monitoring the effects of antiplatelet agents are less specific. The results obtained with these devices or systems describe the reactivity of platelet as a whole, and such results can only by far approximation be attributed to the specific pathways blocked by ASA and clopidogrel. Some of these tests all non-automated aggregation tests are extremely difficult to standardize and subjects to a large variability. The biochemical tests can assess whether the drug hits its molecular target; the functional tests can assess the extent by which they change platelet function. Both questions are relevant, but neither one is sufficient to guide possible therapeutic decisions. As to clopidogrel, such propositions can be put forward by analogy. These may include changes in the enzyme structure due to gene polymorphisms , 44 , 45 or the transient inaccessibility of the enzyme due to the blockade of the active site by non-steroidal anti-inflammatory agents e. Here the main reason for a low response to the antiplatelet drug is the limited availability of the active drug at the level of its target. Adding ASA in vitro to the blood sample should block or significantly reduce the aggregation as well as TXB 2 concentration. One should here also consider the increased production of new, more active platelets, which cannot be blocked with once daily ASA administration in a relatively small dose. It is important to mention at this point that one of the reasons for incomplete platelet blockade with clopidogrel or aspirin can be simply patient's non-compliance. Such situations can be ascertained with a good approximation in vitro. For the assessment of ASA-specific effects, the proposed test is the use of aggregation induced by arachidonic acid and of TXB 2 concentrations in serum or in the supernatant after aggregation. To detect the reason for this, more specific tests for a given drug should be used. The above-mentioned frequency of ASA resistance is obtained from different studies using different laboratory protocols. Such impossibility is mainly due to the absence of a univocal definition and of established laboratory methods. Every day the practitioner encounters patients with cardiovascular events due to atherothrombosis despite treatment with oral antiplatelet agents. A special category includes rare but severe cases of stent thrombosis, likely more frequent in patients implanted with drug-eluting stents. This concern is also reflected in the recent European Society of Cardiology Guidelines for non-ST-elevation Acute Coronary Syndromes, which do not recommend the routine use of such monitoring. This category comprises patients after unprotected left main stenting, left main bifurcation or stenting of the last patent coronary vessel Class IIb, Level of Evidence: C. Recent clinical data show that the new thienopyridine prasugrel exerts a more potent antiplatelet action than clopidogrel, which can translate into a lower incidence of stent thrombosis, although the risk of severe bleeding is also increased. In order to accept the possibility of a selective approach in individual patients, such a proposition should be specifically tested in randomized, prospective trials. In certain situations and in certain groups of patients, a high residual platelet activity is connected with a poor prognosis. The in vitro platelet reactivity is also closely connected with individual compliance. This recommendations derives from the Antiplatelet Trialist's Collaboration meta-analysis, 9 where it was shown that such low doses of ASA retain the same efficacy as higher doses with lesser risk of bleeding, and from the CURE trial. Such trials are still designed to monitor the antiplatelet effect of ASA and clopidogrel, but without the guidance from an in vitro individual evaluation of platelet reactivity. The main combined aim of such trials is to investigate whether increasing the dose of antiplatelet agents would improve the clinical outcome. Patients are then prospectively followed for the evaluation of clinical endpoints during 2 years. The primary composite endpoint of the study is cardiac death, non-fatal myocardial infarction, or stent thrombosis at a 6 month follow-up. The primary endpoint was the occurrence of peri-procedural myocardial infarction, as defined by an increase in Troponin I or T greater than three times the upper limit of normal within 48 h, which was attained in This resulted in a significant reduction of major adverse cardiovascular events within 30 days in the tirofiban group compared with the placebo group Promising results in this direction, although in small patient groups, have recently been reported. In the absence of such outcome data, and for the vagueness of some current recommendations on the method to be used, any such recommendation, even in the setting of potentially lethal situations, appears premature and de facto impossible to implement in practical terms at the current stage of knowledge. In academic centres with experience in platelet reactivity tests, individual antiplatelet dosing might be implemented in individual cases e. Those actions should be undertaken as a research activity, and are currently not based on evidence of efficacy. Such an assessment of the prognostic implications of results of laboratory tests is preliminary to any practical intervention trial. Such an approach should also define sensitivity and specificity of each laboratory methods with regard to clinical events, which hopefully would lead to the clinical use of the best such test s in the future. Currently ongoing research could also indicate particular groups of patients where a higher residual platelet function is found despite chronic treatment with antiplatelet drugs. Such patients might have a higher potential for profiting from platelet function monitoring or might require an upper titration of the dose even without the setting up of cumbersome platelet function monitoring. Such studies could allow a preliminary assessment of the cost-effectiveness of platelet reactivity tests. Conflict of interest: L. Google Scholar. Google Preview. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Advertisement intended for healthcare professionals. Sign in through your institution. ESC Publications. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Preamble: aims and scope. Interindividual variability of antiplatelet agents. Evaluation of the effect of acetylsalicylic acid. Evaluation of the effect of clopidogrel. Non-specific methods for measuring platelet reactivity. Proceeding in situations with incomplete response to antiplatelet drugs. Journal Article. Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Wiktor Kuliczkowski , Wiktor Kuliczkowski. Oxford Academic. Adam Witkowski. Lech Polonski. Cezary Watala. Krzysztof Filipiak. Andrzej Budaj. Jacek Golanski. Dariusz Sitkiewicz. Jerzy Pregowski. Jacek Gorski. Marian Zembala , Marian Zembala. Grzegorz Opolski. Kurt Huber. Harald Arnesen. Steen D. Revision received:. Select Format Select format. Permissions Icon Permissions. Abstract Oral antiplatelet drugs are a cornerstone of modern pharmacotherapy in cardiovascular atherothrombotic diseases. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. Google Scholar Crossref. Search ADS. Addition of clopidogrel to aspirin in 45, patients with acute myocardial infarction: randomised placebo-controlled trial. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17, cases of suspected acute myocardial infarction: ISIS Resistance to oral antiplatelet drugs—a Position Paper of the Working Group on antiplatelet drug resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society. Google Scholar PubMed. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Variability in platelet responsiveness to clopidogrel among individuals. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. Screening for aspirin resistance in stable coronary artery patients by three different tests. Platelet function tests and flow cytometry to monitor antiplatelet therapy. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. Resistance to aspirin in patients after coronary artery bypass grafting is transient: impact on the monitoring of aspirin antiplatelet therapy. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Increased thromboxane biosynthesis in a human preparation of platelet activation: biochemical and functional consequences of selective inhibition of thromboxane synthase. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome. The significance of vasodilator-stimulated phosphoprotein for risk stratification of stent thrombosis. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. More on aspirin resistance: position paper of the Working Group on Aspirin Resistance. Proposal for a Laboratory Test Guiding Algorithm. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Contribution of gene sequence variations of the hepatic cytochrome P 3A4 enzyme to variability in individual responsiveness to clopidogrel. CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Aspirin use post-acute coronary syndromes: intolerance, bleeding and discontinuation. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review. Biological assessment of aspirin efficacy on healthy individuals: heterogeneous response or aspirin failure? High-dose aspirin in addition to daily low-dose aspirin decreases platelet activation in patients before and after percutaneous coronary intervention. Identification of low responders to a mg clopidogrel loading dose in patients undergoing coronary stenting. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Incidence and clinical impact of dual nonresponsiveness to aspirin and clopidogrel in patients with drug-eluting stents. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous coronary interventions. Results of a randomized study. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. Guidelines for percutaneous coronary interventions. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate? Rationale for the study and protocol design. Cilostazol could ameliorate platelet responsiveness to clopidogrel in patients undergoing primary percutaneous coronary intervention. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study. Poor responsiveness to clopidogrel: drug-specific or class-effect mechanism? Evidence from a clopidogrel-to-ticlopidine crossover study. Baseline platelet reactivity in acute myocardial infarction treated with primary angioplasty—influence on myocardial reperfusion, left ventricular performance, and clinical events. Residual platelet reactivity is an independent predictor of myocardial injury in acute myocardial infarction patients on antiaggregant therapy. High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-ST elevation acute coronary syndromes. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects. Reduced blood platelet sensitivity to aspirin in coronary artery disease: are dyslipidaemia and inflammatory states possible factors predisposing to sub-optimal platelet response to aspirin? Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events CURE Trial. Unstable angina, stroke, myocardial infarction and death in aspirin non-responders. A prospective, randomized trial. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. Published on behalf of the European Society of Cardiology. All rights reserved. For permissions please email: journals. Download all slides. Views 2, More metrics information. Total Views 2, Email alerts Article activity alert. Advance article alerts. New issue alert. Receive exclusive offers and updates from Oxford Academic. More on this topic CardioPulse Articles. Optimal antiplatelet therapy in out-hospital cardiac arrest with mild therapeutic hypothermia. Questions and answers on antithrombotic therapy: a companion document of the ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Antiplatelet therapy prescription patterns for acute coronary syndrome: a decade analysed. Non-vitamin K oral anticoagulants in valvular heart disease before surgery: a tale of bridging vs. Citing articles via Web of Science Prognosis after switching to electronic cigarettes following percutaneous coronary intervention: a Korean nationwide study. Major clinical outcomes in symptomatic vs. Peerless performance: celebrating the backstage champions of scientific publishing. More from Oxford Academic. Cardiovascular Medicine. Clinical Medicine. Medicine and Health. Looking for your next opportunity? Advanced Gastroenterologist. Assistant Professor. View all jobs. Authoring Open access Purchasing Institutional account management Rights and permissions. Get help with access Accessibility Contact us Advertising Media enquiries.

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