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SummaryPatients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Previous studies have suggested that patients with CKD have less therapeutic benefit of antiplatelet therapy. However, the relation between renal function and platelet reactivity is still under debate. On-treatment platelet reactivity was determined in parallel by ADP- and AA-induced light transmittance aggregometry (LTA) and the VerifyNow® System (P2Y12 and Aspirin) in 988 patients on dual antiplatelet therapy, undergoing elective coronary stenting. Patients were divided into two groups according to the presence or absence of moderate/severe CKD (GFRClinical Trial Registration: www.clinicaltrials.gov: NCT00352014.

Background Previous studies have suggested that women do not accrue equal therapeutic benefit from antiplatelet medication as compared with men. The physiological mechanism and clinical implications behind this gender disparity have yet to be established. Methods On-treatment platelet reactivity was determined in 717 men and 234 women on dual antiplatelet therapy, undergoing elective coronary stent implantation. Platelet function testing was performed using arachidonic acid and adenosine diphosphate-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 and Aspirin assays. Also the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischaemic stroke was evaluated. Results Women had higher baseline platelet counts than men. Women exhibited a higher magnitude of on-aspirin platelet reactivity using LTA, but not using the VerifyNow Aspirin assay. The magnitude of on-clopidogrel platelet reactivity was significantly higher in women as compared with men with both tests used. The cut-off value to identify patients at risk as well as the incidence of clinical endpoints was similar between women and men (16/234[6.8%] vs. 62/717[8.6%], p = 0.38). Conclusion Although the magnitude of platelet reactivity was higher in women, the absolute difference between genders was small and both the cut-off value to identify patients at risk and the incidence of the composite endpoint were similar between genders. Thus, it is unlikely that the difference in platelet reactivity accounts for a worse prognosis in women.

Summary. Background: The pathophysiology of stent thrombosis (ST) has evolved from the identification of single causative factors to a complex multifactorial model. Objectives: The aim of the present study was to investigate whether patients with a history of ST exhibit heightened platelet reactivity to clopidogrel and aspirin. Patients/methods: Pretreatment and on-treatment platelet reactivity to clopidogrel and aspirin, as well as dual antiplatelet therapy resistance, was determined in 84 patients with a history of definite ST (cases: 41 early ST; 43 late ST) and in 103 control patients with a previously implanted coronary stent but no ST after the index procedure. Platelet function was evaluated with optical aggregometry, the VerifyNow P2Y12 and aspirin assays, the PFA-100 Innovance P2Y* cartridge, the flow cytometric vasodilator-stimulated phosphoprotein assay and urine 11-dehydrothromboxane B2 measurement before and after the administration of a 600-mg loading dose of clopidogrel and 100 mg of aspirin. The study was registered at ClinicalTrials.gov, number NCT01012544. Results: Patients with a history of early ST clearly demonstrated higher on-clopidogrel platelet reactivity than controls. Patients with both early and late ST exhibited heightened on-aspirin platelet reactivity status, and dual antiplatelet therapy resistance was more frequent. Conclusions: Patients with a history of early ST exhibit a poor response to clopidogrel. Furthermore, both early and late ST are strongly and independently associated with heightened on-aspirin platelet reactivity, and dual antiplatelet therapy resistance is more frequent.

Background The TRITON-TIMI 38 study has identified three subgroups of patients with a higher risk of bleeding during treatment with the thienopyridine prasugrel: patients with a history of stroke or transient ischaemic attack (TIA), patients >= 75 years and patients with a body weight = 75 years and a history of stroke were independent predictors of a higher on-treatment platelet reactivity. In contrast, a body weight = 75 years and patients with previous stroke, onclopidogrel platelet reactivity is increased. In contrast, in patients with a low body weight, on-clopidogrel platelet reactivity is decreased, suggesting that a stronger response to a thienopyridine might only lead to more bleeds in patients with low body weight

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.

SummaryNovel P2Y12 inhibitors are in development to overcome the occurrence of atherothrombotic events associated with poor responsiveness to the widely used P2Y12 inhibitor clopidogrel. Cangrelor is an intravenously administered P2Y12 inhibitor that does not need metabolic conversion to an active metabolite for its antiplatelet action, and as a consequence exhibits a more potent and consistent antiplatelet profile as compared to clopidogrel. It was the objective of this study to determine the contribution of variation in the P2Y12 receptor gene to platelet aggregation after in vitro partial P2Y12 receptor blockade with the direct antagonist cangrelor. Optical aggregometry was performed at baseline and after in vitro addition of 0.05 and 0.25 μM cangrelor to the platelet-rich plasma of 254 healthy subjects. Five haplotype-tagging (ht)-SNPs covering the entire P2Y12 receptor gene were genotyped (rs6798347C>t, rs6787801T>c, rs9859552C>a, rs6801273A>g and rs2046934T>c [T744C]) and haplotypes were inferred. The minor c allele of SNP rs6787801 was associated with a 5% lower 20 μM ADP-induced peak platelet aggregation (0.05 μM cangrelor, p

Summary. Background: No randomized comparisons are yet available evaluating the effect of pre-hospital high dose tirofiban on the incidence of early stent thrombosis after primary percutaneous coronary intervention (PCI). Objectives: The aim of this analysis was to evaluate whether routine pre-hospital administration of high-dose tirofiban in ST-segment elevation myocardial infarction (STEMI) decreases the incidence of early stent thrombosis after primary PCI. Patients/methods: The Ongoing Tirofiban in Myocardial Evaluation (On-TIME) 2 trial was a prospective multicenter study of consecutive STEMI patients referred for primary PCI in which patients were randomized to pre-hospital no high-dose tirofiban/placebo. We examined the incidence of Academic Research Consortium definite and probable early stent thrombosis and determined predictors and outcome of early stent thrombosis. Results: Primary PCI was performed in 1203 out of 1398 patients (86.1%). In 1073 patients (89.2%) a coronary stent was placed. Early stent thrombosis occurred in 39 patients (3.6%). Pre-hospital initiation of high-dose tirofiban significantly reduced early stent thrombosis (2.1% vs. 5.2%, P = 0.006) and was associated with a lower incidence of urgent repeat PCI (1.9% vs. 5.2%, P = 0.005). Early stent thrombosis, as well as pre-hospital initiation of high-dose tirofiban, was independently associated with 30-day mortality. Conclusions: Pre-hospital initiation of high-dose tirofiban reduces the 30-day incidence of stent thrombosis in STEMI patients treated with primary PCI and stenting. Early stent thrombosis and pre-hospital initiation of high-dose tirofiban were independent predictors of 30-day mortality.

Anticoagulation after coronary stenting is essential to prevent stent thrombosis. Drug-eluting stents, which are the preferred therapy, may be associated with a higher tendency for stent thrombosis.Patients who underwent coronary stent placement and presented with late stent thrombosis are described.Eight patients with stent thrombosis are presented. Early discontinuation of the antithrombotic medication is associated with the occurrence of these complications.Long-term antithrombotic therapy seems essential to prevent stent thrombosis, especially for patients treated with drug-eluting stents.

The antiplatelet agent clopidogrel in combination with aspirin has been shown to reduce thrombotic events in patients with acute coronary syndromes and/or who are undergoing percutaneous coronary intervention. However, a large interindividual response variability to clopidogrel has been described. The reported rates of inadequate clopidogrel response vary considerably depending on the definition and methodologies used to measure the inhibition of platelet function. Recently, several (small) studies have demonstrated the clinical relevance of an inadequate response to clopidogrel. Moreover, several factors have been associated with a high interindividual variability in response to clopidogrel. These are: dosing, impaired intestinal absorption, cytochrome P450 3A4 and 3A5 activity, drug–drug interactions, polymorphisms of the receptors involved in the process of arterial thrombosis and hemostasis, and the method of measurement of platelet function. Future research for the evaluation of clopidogrel resistance should be based on the assessment of selective P2Y12 receptor inhibition (e.g., the vasodilator-stimulated phosphoprotein-assay or the measurement of stabilization of platelet aggregates) with quick and simple tests. Only then can we reveal the true prevalence and impact of clopidogrel resistance.

The relevance of P2Y12-receptor gene variation for the outcome of clopidogrel-treated patients undergoing elective coronary stent implantation: A clinical follow-up

Summary. Background: Early coronary stent thrombosis occurs most frequent after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Objectives: To identify the specific predictors of, respectively, acute and subacute stent thrombosis in patients after primary PCI for STEMI. Patients/Methods: Consecutive STEMI patients with angiographically confirmed early stent thrombosis were enrolled and compared in a 2 : 1 ratio with a matched control group. Clinical outcome was collected up to 1 year. Results: Of 5842 STEMI patients treated with primary PCI, 201 (3.5%) presented with a definite early stent thrombosis. Of these, 97 (1.7%) had acute stent thromboses and 104 (1.8%) had subacute stent thromboses. Postprocedurally discovered dissection, undersizing and smaller stent diameter were the strongest predictors for acute stent thrombosis. No glycoprotein IIb/IIIa therapy and the use of drug-eluting stents were also associated with acute stent thrombosis. Lack of clopidogrel therapy in the first 30 days after the index PCI was the strongest predictor for subacute stent thrombosis. Mortality rates at 1-year follow-up were lower for acute stent thrombosis than for subacute stent thrombosis (8.3% vs. 13.2%, P = 0.294). The incidence of definite recurrent stent thrombosis at 1-year follow up was significantly lower after a first definite acute stent thrombosis than after a first definite subacute stent thrombosis (6.4% vs. 19.3%, P = 0.007 at 1 year). Conclusions: The specific risk factors for, respectively, acute and subacute stent thrombosis after primary PCI vary greatly. Mortality rates are high for both categories of stent thrombosis. However, recurrent stent thrombosis occurs more frequently after subacute stent thrombosis.

Both peak and late aggregation are capable of identifying patients at risk for atherothrombotic events

Background: Multiple platelet function tests claim to be P2Y12-pathway specific and capable of capturing the biological activity of clopidogrel. Objectives: The aim of the present study was to determine which platelet function test provides the best reflection of the in vivo plasma levels of the active metabolite of clopidogrel (AMC). Patients/methods: Clopidogrel-naive patients scheduled for elective percutaneous coronary intervention (PCI) received a 600 mg loading dose of clopidogrel and 100 mg of aspirin. For pharmacokinetic analysis, blood was drawn at 0, 20, 40, 60, 90, 120, 180, 240 and 360 min after clopidogrel loading and peak plasma concentrations (C-max) of the AMC were quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Platelet function testing was performed at baseline and 360 min after the clopidogrel loading. Results: The VASP-assay, the VerifyNow P2Y12-assay and 20 mu mol L-1 adenosine diphosphate (ADP)-induced light transmittance aggregometry (LTA) showed strong correlations with C-max of the AMC (VASP: R2 = 0.56, P

Item does not contain fulltext AIMS: Glycoprotein IIb/IIIa blocking agents seem to improve percutaneous coronary intervention (PCI) results in patients with ST-elevation myocardial infarction (STEMI). We aimed to compare the effect of pre-hospital administration of tirofiban in STEMI patients with and without diabetes mellitus (DM) treated with primary PCI. METHODS AND RESULTS: We performed a pre-specified sub-analysis of the randomised On-Time II trial (n=984) and it's open label run-in phase (n=414), which investigated pre-hospital administration of high dose tirofiban in STEMI patients treated with primary PCI. Two-hundred and twenty (16%) diabetic patients (known DM or Hba1C >/=6.2%) were included, 101 in the placebo group and 119 in the tirofiban group. In patients with DM, randomisation to tirofiban resulted in a lower residual ST deviation (5.1+/-8.5 mm vs. 6.2+/-5.6 mm, p=0.003), a reduced infarct size (CK 1694+/-1925 U/L vs. CK 2040+/-1829 U/L, p=0.02) and a trend towards lower one-year mortality (4.6% vs. 11.6%, p=0.07). The beneficial effects of tirofiban were more pronounced in diabetic patients compared to patients without diabetes. CONCLUSIONS: Pre-hospital administration of tirofiban in diabetic STEMI patients treated with primary PCI improves ST resolution and reduces myocardial infarct size. Tirofiban seems particularly beneficial in patients with diabetes. 01 augustus 2010

BackgroundInadequate platelet inhibition despite aspirin and clopidogrel therapy during and after a percutaneous coronary intervention is associated with an impaired clinical outcome. Cangrelor, a direct and reversible P2Y12 inhibitor that is currently in development, has the potential to achieve higher levels of inhibition of ADP-induced platelet aggregation than clopidogrel. The aim of the present study was to compare the magnitude of platelet inhibition in clopidogrel-pretreated patients before and after the in vitro addition of a subtherapeutic dose of cangrelor. MethodsBlood samples were drawn from patients pretreated with clopidogrel and aspirin who were undergoing elective percutaneous coronary intervention (n=39). Platelet function analysis with ‘classical’ light transmittance aggregometry (both peak and late aggregation [at 6 min]) was performed before and after the in vitro addition of cangrelor (0.25 μmol/l) to platelet-rich plasma (PRP). After an incubation period of five minutes, platelet aggregation was induced by 5 and 20 μmol/l ADP. ResultsThe in vitro addition of 0.25μmol/l cangrelor to the PRP from clopidogrel-treated subjects resulted in an additional reduction in ADP-induced platelet aggregation. For ADP concentrations of 5 and 20 μmol/l, peak aggregation showed a decrease of 75 and 85%, respectively (p

Multiple studies have demonstrated the effectiveness of dual or triple antiplatelet therapy with aspirin, clopidogrel and glycoprotein (GP) IIb/IIIa therapy in patients with acute coronary syndromes as well as in patients undergoing coronary stent implantation. In the last few years, it is becoming clear that not all patients receive the full benefits with the current standard dosages of antiplatelet therapy. Specifically, numerous studies have revealed a wide interindividual variability in the response to these antiplatelet agents and, more importantly, both nonresponsiveness as well as a heightened residual platelet reactivity have been linked to the occurrence of adverse cardiovascular events. Therefore, assays that identify those patients with an impaired responsiveness or a heightened platelet reactivity despite dual antiplatelet therapy may contribute to better risk stratification and will probably improve clinical outcome when appropriate action is initiated. Likewise, a considerable number of patients do not achieve the minimal inhibition of aggregation threshold with the current recommended weight-adjusted dosages of GP IIb/IIIa therapy. Identifying and optimizing the absolute degree of platelet inhibition in this subgroup of patients will probably improve clinical outcome. The VerifyNow platform is one of the most user friendly point-of-care platelet function test systems because it produces rapid results at the patient bedside. The purpose of the present paper is to give insight into the principal mechanisms of the VerifyNow system, to discuss its clinical utility for the monitoring of antiplatelet therapy and to discuss the proposed cut-off levels to segregate responders from non-responders for the different types of antiplatelet therapy.

Contains fulltext : 70744.pdf (Publisher’s version ) (Closed access)

BackgroundIn patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI, few data exist on the magnitude of platelet activation, aggregation and dosing of glycoprotein (GP) IIb/IIIa receptor inhibitors. Methods Sixty STEMI patients were randomised to abciximab, to high-dose tirofiban or to no additional GP IIb/IIIa inhibitor treatment. Platelet activation (P-selectin expression) was measured using flow cytometry and the level of inhibition of platelet aggregation was assessed using the Plateletworks assay. Additionally, the PFA-100 with the collagen/adenosine-diphosphate cartridge (CADP) was used to compare the levels of platelet inhibition. All measurements were performed at baseline (T0), immediately after (T1), 30 minutes (T2), 60 minutes (T3) and 120 minutes (T4) after primary PCI. Results The level of platelet activation in both GP IIb/IIIa receptor inhibitor treated groups was significantly lower compared with the control group at all time points after primary PCI (p=0.04). Also the administration of the currently recommended dose of abciximab resulted in significantly lower levels of inhibition of aggregation compared with high-dose tirofiban (p

A 69-year-old man with a history of coronary artery bypass grafting and a recent inferoposterior myocardial infarction presented to the hospital for diagnostic coronary angiography. Physical examination, laboratory analyses, coronary angiography, echocardiography, and CT scan were performed. A giant aneurysm of the aortocoronary venous bypass graft, associated with compression of the right side of the heart, was revealed. After surgical resection and replacement of the venous graft the patient died due to right ventricular failure. (Neth Heart J 2007;15:252-4.17923880Neth Heart J 2007;15:252-4.)

Multiple studies have demonstrated that the addition of clopidogrel to lifelong aspirin therapy is effective in reducing the composite endpoint of death from cardiovascular causes, non-fatal myocardial infarction, or stroke in patients undergoing percutaneous coronary intervention (PCI) [1,2]. However, the problem with the one size fits all 75 mg/day clopidogrel maintenance therapy is the wide variability in individual responses to it [3]. Therefore, it has been demonstrated that an individual risk-stratification with platelet function tests may identify patients who are at a high risk for the occurrence of atherothrombotic events [4–7]. Light transmission aggregometry (LTA) is generally considered to be the gold standard method of measurement of platelet function and it has been suggested that the focus of interpretation of the results from LTA in clopidogrel-treated patients should be the absolute level of late aggregation instead of peak aggregation [8]. The rationale behind this theory is the following. Two platelet surface adenosine diphosphate (ADP) receptors have now been characterized: the Gq-protein coupled P2Y1 receptor, which is responsible for platelet shape change, phospholipase C activation and calcium release from internal stores, and the Giprotein coupled P2Y12 receptor, which is responsible for the inhibition of adenylyl cyclise [9]. The active metabolite of clopidogrel selectively inhibits ADP binding to P2Y12 but not P2Y1. Platelets from patients with a P2Y12 deficiency and platelets from patients with a structural defective P2Y12 are still capable of changing shape and aggregating (although this aggregation is rapidly reversible with loosely bound platelets with few contact points), and fail to attenuate PGE1-induced cAMP production. Therefore, it has been hypothesized that P2Y1 is mainly responsible for the maximal amplitude of platelet aggregation whereas P2Y12 is responsible for the stabilization of aggregation [10–12]. The aim of the present study was to investigate whether a difference exist between ADP-induced peak aggregation and late aggregation in patients who have been treated with an aspirin and clopidogrel maintenance dose for a long period of time (> 5 days). Classical LTA induced by four different concentrations (2, 5, 10 and 20 lmol L) of ADP was performed in 164 patients who were on a maintenance of 75 mg of clopidogrel for >five days. All patients were also on ‡80 mg of aspirin for at least seven days. The local Institutional Review Board approved the protocol and written informed consent was obtained before elective PCI. LTA was quantified in non-adjusted platelet-rich plasma (PRP) at maximal (peak) aggregation and after 360 s (late aggregation) with an APACT 4004 four-channel light transmission aggregometer (LABiTec, Arensburg, Germany). Samples were centrifuged for 10 min at 150 · g to obtain native PRP and the platelet count was assessed on a routine cellcounter (LH 750, Beckman Coulter, Krefeld, Germany). Samples tubes containing 3.2% of citrate were used for the analysis of platelet function. Both peak and late aggregation at 360 s were highly variable between subjects (mean ± SD were 27 ± 11% vs. 12 ± 9%, 46 ± 12% vs. 23 ± 16%, 55 ± 13% vs. 34 ± 21%, and 61 ± 12% vs. 44 ± 22% for 2, 5, 10, and 20 lmol L of ADP, respectively). Furthermore, as illustrated in Fig. 1, peak aggregation was strongly correlated with late aggregation (r 1⁄4 0.72, 0.76, 0.86, and 0.93, all P < 0.01, for 2, 5, 10, and 20 lmol L of ADP, respectively). Multiple studies have demonstrated that patients with an inadequate response to clopidogrel therapy have an increased risk of developing atherothrombotic events [4–6]. However, to date, there is no predefined cutoff level to segregate clopidogrel poor responders from clopidogrel responders. As a consequence, the multiple studies linking clopidogrel poor response with a higher incidence of atherothrombotic events have all used different definitions to allocate clopidogrel poor responsiveness. In addition, some of them use the absolute change from baseline (off-drug aggregation) whereas others use one single measurement after a certain (but adequate) clopidogrel pretreatment period. Importantly, several of these studies are Correspondence: JochemW. van Werkum, Department of Cardiology, St Antonius Hospital, PO Box 2500, 3435 CM Nieuwegein, the Netherlands. Tel.: +31 306099111; fax: +31 306034420; e-mail:w.van.werkum@ antonius.net

A drug-eluting stent was implanted in four patients, a man aged 67 and a woman aged 42 with acute myocardial infarction, a woman aged 41 with unstable angina pectoris and a man aged 41 with stable angina pectoris. All suffered stent thrombosis after discontinuation (in three cases prematurely) of clopidogrel therapy. Reasons for discontinuation included allergic reaction, a dental procedure and refusal of reimbursement by the insurer. In order to restore stent patency they were treated by percutaneous coronary intervention and all patients suffered irreversible myocardial damage. Combination therapy using acetylsalicylic acid and clopidogrel during and after angioplasty for the prevention of long- and short-term complications is necessary. Stent thrombosis after drug-eluting stent implantation usually occurs within 1-4 weeks following discontinuation ofantiplatelet medication. These cases stress the importance of antiplatelet therapy after stent implantation. Physicians, dentists and patients must be aware of the risk of the early discontinuation ofantiplatelet therapy.

A 69-year-old female patient with hypertension and diabetes mellitus presented in September 2002 with an acute coronary syndrome. Coronary angiography demonstrated significant one-vessel disease (figure 1A) with a preserved left ventricular function.