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Clopidogrel resistance "Live" – the risk of stent thrombosis should be evaluated before procedures
Zuzana Motovska, Petr Widimsky, Iuri Marinov, Robert Petr, Jaroslava Hajkova, Jan Kvasnicka, the PRAGUE-8 study Investigators
Thrombosis Journal , 2009, DOI: 10.1186/1477-9560-7-6
Abstract: Every year, millions of people undergo percutaneous coronary intervention (PCI) with intracoronary stent implantation. Dual antiplatelet therapy – aspirin plus clopidogrel – is recommended for the reduction of acute and subacute stent thrombosis [1,2]. Despite combined antiplatelet therapy, stent thrombosis persists at a rate of 0.5–2% in elective cases, and up to 6% in patients with acute coronary syndromes [3]. Stent thrombosis is a life-threatening event [4]. In addition, also in cases of immediate reperfusion therapy by means of emergency PCI, patients with stent thrombosis have developed a major myocardial infarction, with consequent significant decline in left ventricular function – a strong negative predictor of long-term survival [3]. "Retrospective" laboratory testing in patients with stent thrombosis has shown that poor response ("resistance") to antiplatelet therapy is a risk factor for this event [5-7].A 67-year old woman was admitted to Cardiocentre for an elective coronary angiography, because of changes on the ECG (new negative T waves in leads I, aVL, V1-V3) and new anteroapical hypokinesis seen by echocardiography. She was a cigarette smoker, with a history of diabetes, hypertension, hypercholestrolemia on statin therapy (atorvastatin), and with known coronary artery disease on aspirin. The patient fulfilled the inclusion criteria of the PRAGUE-8 trial (see section methods) [8]. After signing of informed consent, she was randomized into group B of this study, and also participated in the vasodilator stimulated phosphoprotein (VASP) phosphorylation state and genetic laboratory substudies. In the laboratory substudy, the time course of platelet inhibition after clopidogrel (600 mg loading dose followed by 75 mg per day) was investigated.On the second day of hospitalization, the patient underwent a coronary angiography, which showed an 80% stenotic lesion on her left anterior descending artery. The lesion was treated with ad hoc performed PCI with the
Boosting platelet inhibition in poor responder to aspirin and clopidogrel undergoing percutaneous coronary intervention: role of tirofiban
Gianluca Campo, Luca Fileti, Marco Valgimigli, et al
Journal of Blood Medicine , 2010, DOI: http://dx.doi.org/10.2147/JBM.S7236
Abstract: oosting platelet inhibition in poor responder to aspirin and clopidogrel undergoing percutaneous coronary intervention: role of tirofiban Review (3494) Total Article Views Authors: Gianluca Campo, Luca Fileti, Marco Valgimigli, et al Published Date May 2010 Volume 2010:1 Pages 61 - 69 DOI: http://dx.doi.org/10.2147/JBM.S7236 Gianluca Campo1, Luca Fileti1, Marco Valgimigli1, Jlenia Marchesini1, Antonella Scalone1, Roberto Ferrari1,2 1Cardiovascular Institute, Azienda Ospedaliera Universitaria S Anna, Ferrara, Italy; 2Cardiovascular Research Centre, Salvatore Maugeri Foundation, IRCCS Gussago (BS), Italy Abstract: Nowadays, aspirin (acetylsalicylic acid) and clopidogrel form the cornerstone in prevention of cardiovascular events and their clinical effectiveness has been well established. The thienopyridine clopidogrel is a prodrug that, after hepatic metabolization, strongly inhibits adenosine diphosphate-induced platelet aggregation. Aspirin is a non-steroidal anti-inflammatory drug that exerts its anti-platelet action through the irreversible acetylation of platelet cyclooxygenase (COX)-1, blocking thromboxane A2 production. However, despite dual-antiplatelet therapy, some patients still develop recurrent cardiovascular ischemic events. Many studies have clearly showed that a marked variability exists in the responsiveness to aspirin and clopidogrel, being the poor responder patients at higher risk of short (peri-procedural) and long-term ischemic complications. In particular, these patients showed a major recurrence of myocardial infarction and, after stent implantation, of stent thrombosis. The mechanisms of aspirin and clopidogrel poor response are numerous and not fully elucidated, and are likely multifactorial (eg, genetic polymorphisms, elevated baseline platelet reactivity, drug interaction). How to improve the short- and long-term outcome of these patients is currently unknown. Recently published and ongoing clinical trials are evaluating different strategies for the acute and chronic treatments (eg, reload of clopidogrel, double clopidogrel maintenance dose, switching to prasugrel). In this paper, we reviewed all available evidence on aspirin and clopidogrel resistance and focused our attention on tirofiban, a glycoprotein IIb/IIIa inhibitor that may be used to obtain a better platelet inhibition in poor responder patients during the acute phase and in particular during percutaneous coronary intervention.
Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance - The BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy
Horst Neubauer, Andreas FC Kaiser, Heinz G Endres, Jan C Krüger, Andreas Engelhardt, Sebastian Lask, Fenena Pepinghege, Andreas Kusber, Andreas Mügge
BMC Medicine , 2011, DOI: 10.1186/1741-7015-9-3
Abstract: Platelet function testing using whole blood aggregometry (Chronolog 590) was performed 48 hours following coronary stenting (for either acute coronary syndromes or stable coronary artery disease) on 504 patients. The antiplatelet therapy included a loading dose of 600 mg clopidogrel and 500 mg ASA, followed by 75 mg clopidogrel and 100 mg ASA once daily. Clopidogrel low responders (CLR: >5 ohm; adenosine diphosphate (ADP) 5 μM) and/or ASA low responders (ALR: >0 ohm; arachidonic acid 10 μM) were treated according to a structured therapy plan: in the case of CLR, the maintenance + dose was doubled (repeated loading dose followed by 150 mg daily), and when still ineffective ticlopidine or prasugrel, if available and not contraindicated, were used. ALR was treated by increasing the dose to 300 mg in a first step or to 500 mg ASA when the first modification did not take effect sufficiently. In addition, ADP receptor antagonist 2-methylthioadenosine 5'-monophosphate triethylammonium salt (MeSAMP) testing and ASA incubation were performed to rule out either a platelet ADP-receptor defect or an ASA pharmacokinetic resistance.Of the total cohort of 504 patients, we detected 30.8% clopidogrel low-responders and 19.4% aspirin low-responders. For ALR, with a dose adjustment of 300 mg ASA daily, 94.6% of ALR were effectively treated and the residual 5.4% by administration of daily dosages of 500 mg ASA. This means that after modification of the ASA maintenance dose, all initial ALRs had an adequate antiplatelet response.The results for clopidogrel revealed that 69% of the CLR were treated effectively by increasing the clopidogrel dose to 150 mg daily. When prasugrel was not available or contraindicated, 12.7% of the remaining low responders showed an adequate result after being switched to ticlopidine. Consequently, by applying the therapy algorithm, we were able to reduce the CLR prevalence by 86.6%. On including prasugrel in the therapy plan, we were finally able to eliminate
Antiplatelet and anticoagulant therapy in elective percutaneous coronary intervention
Jurri?n M ten Berg, HW Plokker, Freek WA Verheugt
Trials , 2001, DOI: 10.1186/cvm-2-3-129
Abstract: The acute success rate of percutaneous coronary intervention (PCI) has increased ever since its introduction, despite a widening scope of indications [1,2,3]. Nevertheless, abrupt vessel closure during or shortly after balloon angioplasty still occurs in 2-5% of the patients [4,5,6,7,8]. Abrupt closure may result in myocardial infarction (10-35%) and death (2-5%) despite urgent reintervention [4,5,6,7,8]. Stents are nowadays placed in more than 50% of elective interventions, partly because they are very effective in avoiding vessel closure [7,9]. Stenting, however, is associated with a unique and devastating complication, namely (sub)acute thrombosis, which occurs in 1-4% of the procedures [10,11]. Unfortunately, the majority of patients who experience this complication suffer from myocardial infarction and/or die [10,11]. Thrombosis plays a major role in acute vessel closure both after balloon angioplasty and after stenting. This review will address the value of antiplatelet and anticoagulant therapy to prevent thrombotic complications after PCI. We will focus on agents that are routinely available and commonly used. As the role of thrombosis differs for stented and non-stented lesions, the therapeutic options during and after balloon angioplasty and stenting are discussed separately. In addition, the unique pathophysiology of late thrombotic closure after intracoronary brachytherapy and the extended need for antithrombotic therapy will be discussed.Studies using angioscopy [12,13,14] and post-mortem observations [15,16,17] suggest that balloon angioplasty very often leads to rupture of the obstructing plaque and to dissection of the vessel wall followed by mural thrombus formation. The etiology of abrupt vessel closure is multifactorial: dissection leading to an occlusive 'flap', spasm, elastic recoil and intramural hematoma may all play a role. Mural thrombosis is considered an important associated cause in this process [6,18,19], particularly when the target les
Triple antiplatelet therapy for preventing vascular events: a systematic review and meta-analysis
Chamila Geeganage, Robert Wilcox, Philip MW Bath
BMC Medicine , 2010, DOI: 10.1186/1741-7015-8-36
Abstract: Completed randomized controlled trials investigating the effect of triple versus dual antiplatelet therapy in patients with ischaemic heart disease (IHD), cerebrovascular disease or peripheral vascular disease were identified using electronic bibliographic searches. Data were extracted on composite VEs, myocardial infarction (MI), stroke, death and bleeding and analysed with Cochrane Review Manager software. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using random effects models.Twenty-five completed randomized trials (17,383 patients with IHD) were included which involving the use of intravenous (iv) GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban), aspirin, clopidogrel and/or cilostazol. In comparison with aspirin-based therapy, triple therapy using an intravenous GP IIb/IIIa inhibitor significantly reduced composite VEs and MI in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) (VE: OR 0.69, 95% CI 0.55-0.86; MI: OR 0.70, 95% CI 0.56-0.88) and ST elevation myocardial infarction (STEMI) (VE: OR 0.39, 95% CI 0.30-0.51; MI: OR 0.26, 95% CI 0.17-0.38). A significant reduction in death was also noted in STEMI patients treated with GP IIb/IIIa based triple therapy (OR 0.69, 95% CI 0.49-0.99). Increased minor bleeding was noted in STEMI and elective percutaneous coronary intervention (PCI) patients treated with GP IIb/IIIa based triple therapy. Stroke events were too infrequent for us to be able to identify meaningful trends and no data were available for patients recruited into trials on the basis of stroke or peripheral vascular disease.Triple antiplatelet therapy based on iv GPIIb/IIIa inhibitors was more effective than aspirin-based dual therapy in reducing VEs in patients with acute coronary syndromes (STEMI and NSTEMI). Minor bleeding was increased among STEMI and elective PCI patients treated with a GP IIb/IIIa based triple therapy. In patients undergoing elective PCI, triple therapy had no beneficial effect and
A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility  [PDF]
Nikola Sprigg, Laura J. Gray, Tim England, Mark R. Willmot, Lian Zhao, Gillian M. Sare, Philip M. W. Bath
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002852
Abstract: Background Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke. Methodology/Principal Findings A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p<0.01). Conclusions/Significance Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates, and their severity, and a trend to increased discontinuations. However, the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy. Trial Registration Controlled-Trials.com ISRCTN83673558
Aspirin and clopidogrel hyporesponsiveness and nonresponsiveness in patients with coronary artery stenting  [cached]
Rakesh K Sharma,Hanumanth K Reddy,Vibhuti N Singh,et al
Vascular Health and Risk Management , 2009,
Abstract: Rakesh K Sharma1, Hanumanth K Reddy1, Vibhuti N Singh2, Rohit Sharma1, Donald J Voelker1, Girish Bhatt11Medical Center of South Arkansas, El Dorado, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 2Bayfront Medical Center, St. Petersburg, University of South Florida, Tampa, FL, USAAbstract: Patients undergoing coronary artery stenting receive an antiplatelet regimen to reduce the risk of antithrombotic complications. Current guidelines recommend the use of acetyl salicylic acid (aspirin) and clopidogrel as evidenced by large clinical trials. There has been a concern about variable responses of patients to aspirin and clopidogrel which may predispose them to subacute stent thrombosis or late stent thrombosis. Up to 25% of patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) were found to have hyporesponsiveness or resistance to clopidogrel which may predispose them to recurrent events. Dual antiplatelet regimen is a standard therapy in these patients and there is always a concern about variable responses to aspirin and clopidogrel predisposing them to acute coronary syndrome (ACS). Prevalence of this hyporesponsiveness or resistance may be due to noncompliance, genetic mutations, co-morbid situations and concomitant use of other drugs. This issue is of considerable importance in the era of coronary drug eluting stents when a long-term dual antiplatelet regimen is needed. This paper is a review for clinicians taking care of such patients with hyporesponsiveness or nonresponsiveness to dual antiplatelet regimen.Keywords: aspirin, clopidogrel, acute coronary syndrome, coronary artery stenting
Aspirin and clopidogrel hyporesponsiveness and nonresponsiveness in patients with coronary artery stenting
Rakesh K Sharma, Hanumanth K Reddy, Vibhuti N Singh, et al
Vascular Health and Risk Management , 2009, DOI: http://dx.doi.org/10.2147/VHRM.S6787
Abstract: spirin and clopidogrel hyporesponsiveness and nonresponsiveness in patients with coronary artery stenting Review (6560) Total Article Views Authors: Rakesh K Sharma, Hanumanth K Reddy, Vibhuti N Singh, et al Published Date November 2009 Volume 2009:5 Pages 965 - 972 DOI: http://dx.doi.org/10.2147/VHRM.S6787 Rakesh K Sharma1, Hanumanth K Reddy1, Vibhuti N Singh2, Rohit Sharma1, Donald J Voelker1, Girish Bhatt1 1Medical Center of South Arkansas, El Dorado, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 2Bayfront Medical Center, St. Petersburg, University of South Florida, Tampa, FL, USA Abstract: Patients undergoing coronary artery stenting receive an antiplatelet regimen to reduce the risk of antithrombotic complications. Current guidelines recommend the use of acetyl salicylic acid (aspirin) and clopidogrel as evidenced by large clinical trials. There has been a concern about variable responses of patients to aspirin and clopidogrel which may predispose them to subacute stent thrombosis or late stent thrombosis. Up to 25% of patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) were found to have hyporesponsiveness or resistance to clopidogrel which may predispose them to recurrent events. Dual antiplatelet regimen is a standard therapy in these patients and there is always a concern about variable responses to aspirin and clopidogrel predisposing them to acute coronary syndrome (ACS). Prevalence of this hyporesponsiveness or resistance may be due to noncompliance, genetic mutations, co-morbid situations and concomitant use of other drugs. This issue is of considerable importance in the era of coronary drug eluting stents when a long-term dual antiplatelet regimen is needed. This paper is a review for clinicians taking care of such patients with hyporesponsiveness or nonresponsiveness to dual antiplatelet regimen.
Advances in antiplatelet technologies to improve cardiovascular disease morbidity and mortality: a review of ticagrelor  [cached]
Davis EM,Knezevich JT,Teply RM
Clinical Pharmacology: Advances and Applications , 2013,
Abstract: Estella M Davis, Jon T Knezevich, Robyn M Teply Department of Pharmacy Practice, Creighton University School of Pharmacy and Health Professions, Omaha, NE, USA Abstract: Antiplatelet therapy is widely used with proven benefit for the prevention of further ischemic cardiac complications in patients with acute coronary syndrome. Treatment guidelines for acute coronary syndrome and percutaneous coronary intervention now recommend the use of oral antiplatelet agents including ticagrelor, prasugrel, or clopidogrel in combination with aspirin to comprise dual antiplatelet therapy for the prevention of recurrent ischemic events. The limitations of conventional antiplatelet therapy with clopidogrel or prasugrel include the potential for low response to clopidogrel identified through platelet reactivity or genetic testing, increased risk of bleeding with prasugrel, or slower return to normal platelet activity in patients who received either prasugrel or clopidogrel prior to emergent or planned surgical procedures. This review will discuss the pharmacokinetic and pharmacodynamic properties of ticagrelor in comparison to conventional P2Y12 receptor inhibitors and its utility in patients identified as low responders to clopidogrel. Completed clinical studies and substudies comparing ticagrelor to clopidogrel and ongoing clinical trials evaluating ticagrelor in acute coronary syndrome patients will also be reviewed. Keywords: ticagrelor, antiplatelet, acute coronary syndrome, ST elevation myocardial infarction, non-ST elevation MI, percutaneous coronary intervention
Bleeding tendency in dual antiplatelet therapy with aspirin/clopidogrel: rescue of the template bleeding time in a single-center prospective study
Raul Altman, Ana J Rivas, Claudio D Gonzalez
Thrombosis Journal , 2012, DOI: 10.1186/1477-9560-10-3
Abstract: In a single-center prospective study, 100 patients under long-term aspirin/clopidogrel treatment, the effect of therapy was assayed by template bleeding time (BT) and the inhibition of platelet aggregation (IPA) by light transmission aggregometry (LTA). Arachidonic acid (0.625 mmol/L) and adenosine diphosphate (ADP; 2, 4, and 8 μmol/L) were used as platelet agonists.Bleeding episodes (28 nuisance, 2 hematuria [1 severe], 1 severe proctorrhagia, 1 severe epistaxis) were significantly more frequent in patients with longer BT. Template BT ≥ 24 min was associated with bleeding episodes (28 of 32). Risk of bleeding increased 17.4% for each 1 min increase in BT. Correlation was found between BT and IPAmax in response to ADP 2 μmol/L but not to ADP 4 or 8 μmol/L.In patients treated with dual aspirin/clopidogrel therapy, nuisance and internal bleeding were significantly associated with template BT and with IPAmax in response to ADP 2 μmol/L but not in response to ADP 4 μmol/L or 8 μmol/L.Until recently, long-term antiplatelet therapy for the prevention of atherothrombotic disease was limited to aspirin (ASA). The availability of thienopyridines, particularly clopidogrel (CLOP), represented an important addition to the physician's armamentarium. The combination of CLOP and ASA in patients with acute coronary syndrome (ACS) reduces the risk of reinfarction, stroke, and death by 20% compared with ASA alone [1]. Nevertheless, the current therapy options for these patients are suboptimal. Despite the use of available antiplatelet therapies, the recurrence of ischemic events in patients with ACS is still increasing and bleeding remains an important, and often underappreciated, risk with these therapies. Patient noncompliance because of bleeding contributes to thrombosis events.The exact mechanism of benefit has not yet been elucidated but is clearly related not just to inhibition of platelet aggregation (IPA) but also to modification of the many consequences of the platelet activ
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