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Antiplatelet agents are a class of pharmaceuticals that decrease platelet aggregation and thus inhibit thrombus formation. We examined the relationships between plasma concentrations of antiplatelet agents (triflusal, clopidogrel and cilostazol) and the platelet aggregation inhibitory effect after dosing. We used triflusal, cilostazol and clopidogrel for the development of a semi-mechanistic PK/PD model. The drugs chosen are used widely and reflect various mechanisms of antiplatelet agents. Time courses of plasma concentrations of the antiplatelet agents and their platelet aggregation effects were analysed using ADPAT V. Pharmacokinetic profiles were fitted to an extended parent-metabolite pharmacokinetic model, based on a two-compartment model, and the pharmacodynamic effects of the agents were fitted to a platelet aggregation effect model that consisted of the following parameters: Ks , the active-form platelet synthesis rate constant; K, the apparent reaction rate constant of the agent and active-form platelets; Kel-PRP , the apparent rate constant of platelets; and ε, an intrinsic activity parameter. This semi-mechanistic PK/PD model described well the relationship between plasma concentrations of antiplatelet agents and platelet aggregation effects. In addition, the estimated parameters were suitable for the explanation of the agents and also have a good correlation with platelet characteristics, such as platelet half-life and platelet aggregation baseline effects. Specifically, we discovered the strong correlations between estimated K parameter and in vitro drug activity. We conclude that this semi-mechanistic PK/PD model explained drug PK/PD characteristics well and will be useful for accurate predictions of antiplatelet effect in the clinical situations.
The objective of this study was to evaluate the impact of prior single or dual antiplatelet (PAP) use in patients presenting with acute coronary syndromes (ACS).
To compare three glycoprotein IIb/IIIa receptor antagonists (GPIs) in terms of platelet inhibition and major adverse cardiac events (MACEs), and assess the rate of bleeding and MACEs between GPIs and coadministered P2Y12 agents.
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Complete occlusion was obtained in 12/15 aneurysms (80%) and partial occlusion in 3 (20%). Among 13 aneurysms with a side branch, this was patent at the angiographic control in 4 cases, showed decreased filling in 6, and was occluded in 3 (with neurological deficits in 2). All PEDs were patent at follow-up. Post-procedural ischemic complications occurred in 4 (27%) procedures with permanent neurological deficit (modified Rankin score 2) in 3 (21%). No early or delayed aneurysm rupture, no subarachnoid or intraparenchymal hemorrhage and no deaths occurred.
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The antiphosholipid syndrome (APS) is an autoimmune disorder, characterized by the presence of vascular thrombosis and/or pregnancy morbidity in a patient with positive laboratory tests for antiphospholipid antibodies. The patients with APS are in the high risk of rethrombosis. We report the case of 43-year-old female presenting with recurrent acute myocardial infarction with ST-segment elevation because of recurrent coronary thrombosis in coronary left anterior descending artery (LAD) and circumflex coronary artery (Cx) resulting in four percutaneous coronary interventions (PCI), associated with the presence of plasma antiphospholipid antibodies. Patient received seven stents to LAD and the aspiration of thrombus from Cx artery was performed. Pharmacotherapy included full antithrombotic treatment consisted with antiplatelet drugs such as: aspirin, clopidogrel followed by prasugrel, glycoprotein IIb/IIIa receptor antagonists and anticoagulants such as heparin followed by warfarin as well as steroids. At 1-year follow-up, controlled coronary angiography confirmed the good effect of PCI without any signs of stenosis or rethrombosis and highlighted the important role of antithrombotic treatment in patients with APS.
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Ticagrelor improves the clinical outcomes in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). However, few studies have directly compared the efficacy and safety of ticagrelor against clopidogrel, an oral, thienopyridine-class antiplatelet drug. This study compared the efficacy and safety of ticagrelor and clopidogrel in patients with STEMI undergoing PPCI.
Management of perioperative antiplatelet/anticoagulation drugs and appropriate antibiotic prophylaxis for endocarditis are two controversial issues in the safe practice of cutaneous surgery. This article highlights the current best practice based on a literature review on these topics. Antiplatelet agents should be continued perioperatively whenever clinically possible, and discontinued only after consultation with the patient's cardiologist. The exception to this is primary cardiovascular disease, when antiplatelet drugs should be stopped for 1 week before surgery. Warfarin can be continued perioperatively when the international normalised ratio is controlled at < 3. The use of antibiotics in patients at risk of endocarditis has been recently reviewed by the National Institute of Health and Clinical Excellence (NICE), the American Heart Association, and the European Society of Cardiology. The advice has changed significantly over the past few years, and the routine use of antibiotics perioperatively should occur only when there is evidence of infection perioperatively at the site of surgery.
Current guidelines recommend that clopidogrel be given to patients for 12 months after drug-eluting stent (DES) implantation. However, the evidence is insufficient to support the benefit of long-term clopidogrel therapy, especially in Asian patients. The aim of this study was to evaluate whether different durations of clopidogrel use might influence long-term outcomes after DES implantation. A total of 844 patients from 4 medical centers in Korea who had undergone successful DES implantation from November 2004 to April 2006 were enrolled. Patients who were event free at 6-month follow-up were divided into 2 groups by clopidogrel use (575 users, 163 nonusers) and followed. The end point was a composite of death, myocardial infarction, and stent thrombosis. During 1,056.4 patient-years of follow-up (median 2.02), there were 7 deaths, 3 myocardial infarctions, and 2 episodes of stent thrombosis. No significant differences in the primary end point were observed between clopidogrel users and nonusers (cumulative incidence 2.9% vs 2.8%, p = 0.578; adjusted hazard ratio 0.67, 95% confidence interval 0.16 to 2.77). In analysis with time-dependent covariates, the incidence rates of the primary end point during observation periods with and without clopidogrel were similar, although the effect estimates were broad (9.9 with and 10.6 without clopidogrel per 1,000 patient-years; adjusted hazard ratio 0.52, 95% confidence interval 0.09 to 3.17). Interestingly, the effect estimates from propensity score analyses, although they also had wide confidence intervals, were closer to the null than those from conventional Cox analyses. In conclusion, this cohort of Korean patients failed to show an absolute benefit of long-term clopidogrel therapy after DES implantation. The benefit of clopidogrel use beyond 6 months after DES implantation remains uncertain, and hence the decision to use long-term dual-antiplatelet therapy should be based on the risk factors of each patient.
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Red cell distribution width (RDW) was significantly higher in diabetic patients than in control subjects (P=0.008). It was also higher in patients with uncontrolled glycemia (HbA1c >7%) than those with good control (HbA1c ≤7%; P=0.035). Mean platelet volume (MPV) was comparable in both diabetic patients and healthy controls (P=0.238). RDW and MPV did not significantly correlate with fasting plasma glucose, HbA1c, or duration of diabetes. Both aspirin and clopidogrel did not show a significant effect on MPV. Both insulin and oral hypoglycemic agents did not show a significant effect on RDW, mean corpuscular volume, MPV, platelet count, or white blood cell count. Diabetic patients treated with indapamide or the combined thiazides and angiotensin receptor blockers showed no significant difference in RDW when compared with the control subjects.
This prospective study included patients receiving antiplatelet therapy with clopidogrel 75 mg after infrainguinal angioplasty or stenting and who presented to our department during routine follow-up. Clopidogrel responsiveness was tested using the VerifyNow P2Y12 Assay. Patients with residual platelet reactivity units (PRU) ≥ 235 were considered as nonresponders (NR group NR), whereas patients with PRU < 235 were considered as normal (responders [group R]). Primary end points were incidence of resistance to clopidogrel and target limb reintervention (TLR)-free survival, whereas secondary end points included limb salvage rates and the identification of any independent predictors influencing clinical outcomes.
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At angiographic follow-up, the overall graft patency rate was 84% (31/37) in the control group and 93% (42/45) in the clopidogrel group (P value was not significant [ns]). Graft patency rates for left internal mammary artery (LIMA) grafts were 92% (23/25) versus 96% (28/29) (ns), and for saphenous vein grafts were 66% (7/11) versus 87% (14/16) (ns), respectively.
Although Hispanics constitute the largest minority in the United States, it is unknown whether regional differences in quality of care and outcomes exist among Hispanic patients hospitalized with acute myocardial infarction (MI).
High on-treatment platelet reactivity (HTPR) has been linked to cardiovascular (CV) events after a percutaneous coronary intervention. There have been some controversies on whether a high maintenance dose (MD) of clopidogrel is effective for HTPR patients. Thus, we carried out a meta-analysis to assess the efficacy and safety of a high MD of clopidogrel in patients with HTPR.
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Three Bio-Rad Variant™ II HPLC instruments and WB and FP specimens were used. Precision, accuracy, linearity, and readable total area of the 6.5-min (β-thalassemia method) Variant II HbA(2)/HbA(1c) Dual Program were assessed. Hb A(1c) stability was measured using in-house FP QC samples. The INTERHEART (a study of the effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries) and CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) studies provided chromatographs for morphometric analyses and interoperator variability experiments. Statistical analyses were performed to assess long-term sample stability, WB vs FP agreement, and significance of Hb A(1c) peak integration.
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Even though patients who develop ischemic stroke despite taking antiplatelet drugs represent a considerable proportion of stroke hospital admissions, there is a paucity of data from investigational studies regarding the most suitable therapeutic intervention. There have been no clinical trials to test whether increasing the dose or switching antiplatelet agents reduces the risk for subsequent events. Certain issues have to be considered in patients managed for a first or recurrent stroke while receiving antiplatelet agents. Therapeutic failure may be due to either poor adherence to treatment, associated co-morbid conditions and diminished antiplatelet effects (resistance to treatment). A diagnostic work up is warranted to identify the etiology and underlying mechanism of stroke, thereby guiding further management. Risk factors (including hypertension, dyslipidemia and diabetes) should be treated according to current guidelines. Aspirin or aspirin plus clopidogrel may be used in the acute and early phase of ischemic stroke, whereas in the long-term, antiplatelet treatment should be continued with aspirin, aspirin/extended release dipyridamole or clopidogrel monotherapy taking into account tolerance, safety, adherence and cost issues. Secondary measures to educate patients about stroke, the importance of adherence to medication, behavioral modification relating to tobacco use, physical activity, alcohol consumption and diet to control excess weight should also be implemented.
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The authors performed this analysis to examine whether the enhanced clopidogrel responsiveness in current smokers is maintained after adjusting the influence of hemoglobin on VerifyNow P2Y12 reaction unit (PRU).
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A 60-year-old man with angina was scheduled for total gastrectomy, splenectomy, and cholecystectomy. Bare-metal stents were implanted into his left anterior descending coronary artery four weeks before the operation. Aspirin and clopidogrel were administered until one week before the operation and then injection of to 15,000 units of heparin per day was given. Anesthesia was maintained with sevoflurane, remifentanil and fentanyl. At 330 minutes after starting the operation, 2-mm ST segment elevation was observed and it recovered immediately. After the operation, new 9-mm ST segment elevation in leads V2-V6 was observed. Emergent cardiac catheterization showed occlusion of the coronary artery with in-stent thrombosis. An additional stent was implanted and 10,000 units of heparin per day was injected. After five days, new stent thrombosis occurred and an additional stent was implanted. Administration of aspirin, clopidogrel and cilostazol was started immediately. Anesthesiologists should pay attention to the kind of coronary stent, consider the timing of the operation, and continue administration of aspirin.
Recently the reperfusion therapy in the form of Primary Percutaneous Coronary intervention (PPCI) has become the gold standard for the treatment of Acute Myocardial Infarction. In spite of rapid revascularization either with PPCI or thrombolytic therapy, the significant number of patients develops decreased left ventricular function leading to heart failure which can increase long-term mortality and morbidity. The number of strategies are being evolved and evaluated to reduce this post infarct heart failure. They are being developed at the level of optimizing the outcomes of PPCI, protection against the reperfusion injury, and novel therapies like cardiac repair and regeneration and sonothrombolysis. Thrombus aspiration using simple aspiration catheters during PPCI are getting established as a useful adjunct tool to reduce distal embolisation and consequently improving myocardial salvage. The newer antiplatelet drugs like Prasugrel and Ticagrelor may replace the Clopidogrel to reduce ischemic complications. The reduction in reperfusion injury using drugs has shown mixed results. The newer modalities like cardiac repair and regeneration using stem cell therapy looks promising but are yet to be established.
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setting: University practice.study population: A total of 822 patents who underwent VRS during 3 intervals in 1994, 2004, and 2008.observation procedure: Retrospective chart review for 1994 and 2004, but contemporaneous in 2008.main outcome measures: Proportion using antiplatelets or anticoagulants, the incidence of early postoperative intraocular bleeding in patients, and clinical consequence of the hemorrhage.
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ADP-stimulated platelet fibrinogen binding was significantly inhibited by clopidogrel before and after PTA. ERK 1/2 activation was significantly increased post-PTA in both the aspirin/clopidogrel and aspirin/placebo groups (P < .001). There was a statistically significant decrease in PDGF (P = .004), and increase in vWF (P = .026), following loading with clopidogrel. sICAM-1 levels significantly decreased (P = .016) in the aspirin/placebo group following PTA. There were no other significant changes and also there was no statistically significant difference between the two treatment groups for each of ERK 1/2, sICAM-1, sE-selectin, or vWF.
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Clinicians will be able to understand the safety profile of using different doses of clopidogrel and the incidence of bleeding when used alone or in combination with other antiplatelet agents.
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Irrespective of the antiplatelet regimen, early HALT occurred in 10% of our patients undergoing transcatheter aortic S3 implantation. Early HALT is clinically inapparent and reversible by full anticoagulation.
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We sought to assess the effect of clopidogrel on clinical events 1 year after discharge in survivors of ST-elevation myocardial infarction (STEMI) in clinical practice.
Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is used for the prevention of cardiovascular events following percutaneous coronary intervention (PCI). These agents increase the risk of gastrointestinal bleeding. To prevent these events, proton pump inhibitors (PPI) are routinely prescribed. It has been reported that with the exception of pantoprazole and dexlanzoprazole, PPIs can impede conversion of clopidogrel by cytochrome P450 2C19 (CYP2C19) to its active metabolite, a critical step required for clopidogrel efficacy. Changes in CYP2C19 enzyme activity (phenotype) and its correlation with platelet reactivity following PPI therapy has not yet been fully described. In this study we attempted to determine if the [ (13)C]-pantoprazole breath test (Ptz-BT) can evaluate changes in CYP2C19 enzyme activity (phenoconversion) following the administration of PPI in coronary artery disease (CAD) patients treated with DAPT after PCI. Thirty (30) days after successful PCI with stent placement, 59 patients enrolled in the Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE) trial (ClinicalTrials.gov Identifier: NCT00930670) were recruited to participate in this sub study. Patients were randomized to one of 4 antacid therapies (omeprazole, esomeprazole. pantoprazole or ranitidine). Subjects were administered the Ptz-BT and platelet function was evaluated by vasodilator-stimulated phosphoprotein (VASP) phosphorylation and light transmittance aggregometry before and 30 d after treatment with antacid therapy. Patients randomized to esomeprazole and omeprazole had greater high on-treatment platelet reactivity and lowering of CYP2C19 enzyme activity at Day 60 after 30 d of PPI therapy. Patients randomized to ranitidine and pantoprazole did not show any changes in platelet activity or CYP 2C19 enzyme activity. In patients treated with esomeprazole and omeprazole, changes in CYP2C19 enzyme activity (phenoconversion) correlated well with changes in platelet reactivity. Co-administration of omeprazole or esomeprazole in patients treated with clopidogrel results in lower CYP2C19 enzyme activity and increased platelet reactivity as measured by VASP phosphorylation test while patients given pantoprazole or ranitidine did not show any significant changes in CYP2C19 enzyme activity and platelet reactivity.