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Among 15 studies of 4762 patients with stroke or TIA treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles (*2, *3, and *8) were at increased risk of stroke in comparison with noncarriers (12.0% versus 5.8%; risk ratio, 1.92, 95% confidence interval, 1.57-2.35; P<0.001). Composite vascular events were also more frequent in carriers of CYP2C19 loss-of-function alleles than in noncarriers (13.7% versus 9.4%; risk ratio, 1.51, 95% confidence interval, 1.10-2.06; P=0.01), whereas bleeding rates were similar (2.4% versus 3.1%; risk ratio, 0.89, 95% confidence interval, 0.58-1.35; P=0.59). There was no evidence of statistical heterogeneity among the included studies for stroke, but there was for composite vascular events. Genetic variants other than CYP2C19 were not associated with clinical outcomes, with the exception that significant associations of PON1, P2Y12, and COX-1 with outcomes were observed in 1 study.
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1. Clopidogrel is one of the most important antithrombotic drugs but has different efficacies in different populations. The aim of the present study was to evaluate the contribution of CYP2C19 genetic polymorphisms to the inhibition of ADP-induced platelet aggregation by clopidogrel in healthy Chinese volunteers. 2. Eighteen healthy male volunteers (six CYP2C19*1/CYP2C19*1, six CYP2C19*1/CYP2C19*2and*3 and six CYP2C19*2/CYP2C19*2and*3) were enrolled in the study. Each subject took 300 mg clopidogrel on the first day and then 75 mg once daily for 2 consecutive days. Blood samples were taken to measure ADP-induced platelet aggregation at baseline and 4, 24 and 72 h after administration of the first dose of clopidogrel. 3. There were significant decrease in 2 and 5 micromol/L ADP-induced platelet aggregation at 4, 24 and 72 h after clopidogrel among the three CYP2C19 genotypes compared with baseline (P < 0.001). The change in 5 micromol/L ADP-induced platelet aggregation in subjects with the CYP2C19*1/CYP2C19*1 genotype was greater than that in subjects with the CYP2C19*2/CYP2C19*2and*3 genotype at 4 h (49.0 +/- 15.5 vs 29.7 +/- 17.4%, respectively; P = 0.029), 24 h (48.7 +/- 20.5 vs 25.0 +/- 17.6%, respectively; P = 0.035) and 72 h (45.5 +/- 15.2 vs 26.5 +/- 15.8%, respectively; P = 0.030) after clopidogrel administration. 4. In conclusion, CYP2C19*2 and CYP2C19*3 genetic polymorphisms reduced clopidogrel inhibition of ADP-induced platelet aggregation, with the degree of inhition dependent on the genetic polymorphism present.
The results may have important clinical implications for understanding the role of P2Y12 receptor in upper airway diseases such as allergic rhinitis and non-allergic rhinitis.
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Previous studies have compared bivalirudin and unfractionated heparin (UFH) plus the routine use of glycoprotein IIb/IIIa inhibitors. They have demonstrated that bivalirudin can decrease bleeding complications without a significant increase in ischemic complications, resulting in a better net clinical outcome, as defined by the efficacy (ischemic complications) or safety (bleeding complications) end point. The aim of the present study was to compare bivalirudin and UFH plus protamine in patients undergoing elective percutaneous coronary intervention and pretreated with clopidogrel and aspirin. We randomly assigned 850 patients with stable or unstable coronary artery disease to bivalirudin or UFH followed by protamine at the end of the percutaneous coronary intervention. The primary end point was in-hospital major bleeding. The main secondary end points were the 1-month composite of death, myocardial infarction, unplanned target vessel revascularization; and the 1-month net clinical outcome. The rate of major bleeding (primary end point) was 0.5% in patients randomized to bivalirudin and 2.1% in patients randomized to UFH (p = 0.033). At 30 days, the rate of major bleeding was 0.9% in the bivalirudin arm and 2.8% in the UFH arm (p = 0.043). The composite of death, myocardial infarction, and target vessel revascularization rate and the net clinical outcome rate was 2.8% and 6.4% (p = 0.014) and 3.3% and 7.8% (p = 0.004), respectively, in the bivalirudin and UFH arms. In conclusion, in percutaneous coronary intervention patients pretreated with clopidogrel and aspirin, bivalirudin was associated with less major bleeding and fewer ischemic complications and a better net clinical outcome than UFH.
A total of 418 consecutive patients with ACS (44.7% STEMI, 34.2% NSTEMI, 21.1% unstable angina) from 17 centers (52.9% with catheterization facilities) were enrolled in the study (78.0% males, 63.9 ± 12.9 years).
Patients on dual antiplatelet therapy - although at an increased risk of postoperative bleeding complications - can be managed safely with local haemostatic measures and without the need to discontinue antiplatelet therapy.
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To assess the impact of impaired renal function (IRF) and timing of catheterization (immediate versus delayed intervention) on outcomes in intermediate/high risk NSTE-ACS patients.
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Viabahn stent grafts were placed in a total of 91 limbs in 61 patients (66% men; mean age, 69 ± 12 years) during the study period. Indication for intervention was either claudication (n = 59) or critical limb ischemia (n = 32), with the majority (70%) classified as TransAtlantic Inter-Society Consensus II C (n = 33) or D (n = 31) lesions. Mean follow-up was 38.3 months (range, 1-91 months). Postprocedural pharmacologic regimens included aspirin, clopidogrel, and warfarin (47%); indefinite aspirin and clopidogrel (46%); or aspirin and temporary clopidogrel (7%). Primary and secondary patency rates were 60%, 44%, and 36% and 95%, 82%, and 74% at 1 year, 3 years, and 5 years, respectively. Kaplan-Meier analysis demonstrated more aggressive antiplatelet/anticoagulation regimens to be associated with improved primary patency and freedom from reintervention. Cox proportional hazards analysis demonstrated TransAtlantic Inter-Society Consensus II D lesions, tobacco use, coronary artery disease, and smaller stent diameter to be independent risk factors for stent graft failure. Bleeding events were limited to those in the aspirin, clopidogrel, and warfarin group (11.6% [n = 5]; P = .052), although the majority of these events were not life-threatening, and only two cases required blood transfusion.
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The 11,478 patients who received thienopyridines during hospitalisation experienced a significant increase in major bleeding (2.8% with thienopyridines, 2.2% without thienopyridines; p=0.002). No significant interaction with glycoprotein IIb/IIIa inhibitors and thienopyridines was seen with regard to bleeding. Thienopyridines with unfractionated heparin did not alter bleeding risk, but thienopyridines with low molecular weight heparin was associated with a significant excess of bleeding (2.1% with thienopyridines, 1.3% without thienopyridines; p=0.004). There was no significant difference in major bleeding with thienopyridines in patients who did or did not undergo revascularisation.
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The acute coronary syndrome (ACS) is one of the most frequent diagnoses in cardiology. The therapeutic corner-stones of ACS are PCI (percutaneous coronary intervention) and inhibition of blood coagulation. Current antiplatelet therapy consists of aspirin in combination with clopidogrel and glycoprotein IIb/IIIa blockade if needed. Prasugel is a new antiplatelet agent that is in the process of being approved for routine clinical use. In terms of antithrombotic therapy latest developments focus on drugs with anti-factor Xa activity, such as fondaparinux, or direct anti-thrombin activity, such as bivalirudin. This review discusses latest developments in the field of anti-platelet and anti-thrombotic therapy for ACS.
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To (a) describe the use of GI prophylaxis in patients on DAPT with ASA and clopidogrel and (b) assess the incidence of adverse outcomes that occurred during readmissions within 6 months of the index hospitalization.
A structured literature search of English-language articles was conducted by using MEDLINE, EMBASE, and the Cochrane Collaboration Database for the period of January 1, 1990-April 30, 2007. Studies were included if they met the following criteria: randomized controlled trials, prospective observational trials, or retrospective trials; characteristics and outcomes of patients who were exposed to clopidogrel within 7 days before CABG were analyzed; at least 20 patients were enrolled; and reported outcomes were related to transfusion requirements, resource utilization, clinical events, or hemorrhage-related reoperation rates. Patients were considered exposed to clopidogrel if they discontinued the drug within a specified time frame that was designated in each study. The rates of the outcomes were compared between those patients exposed and those not exposed to clopidogrel.
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The purpose of this study was to evaluate if Nurse-led Early Triage (NET) in the coronary care unit (CCU) can improve time to assessment and management of NSTE-ACS patients.
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Lower hematocrit was associated with higher P2Y12 reaction unit (PRU) and a higher rate of HTPR (P < .001) as measured by VN assay. No differences were seen among the 4 groups in platelet reactivity measured by LTA using ADP 5 μM (P = .23) and ADP 20 μM (P = .21). In a multivariable logistic regression model, baseline hematocrit was independently associated with PRU ≥208 (odds ratio [OR] 0.92, 95% CI 0.86-0.97, P = .005) but had no correlation with LTA ADP 5 μM ≥46% (OR 1.0, 95% CI 0.95-1.06, P = .88) or LTA ADP 20 μM ≥59% (OR 1.03, 95% CI 0.97-1.09, P = .39). In a logistic regression model, the addition of VN assay results, hematocrit, and interaction between the hematocrit and assay results had shown a significant influence on the area under curve for prediction of 1-year major adverse cardiac events compared with baseline clinical variables only for PRU (0.63 vs 0.76, P = .006) but not with LTA (0.64 vs 0.74, P = .13).
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Cangrelor appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed. Vorapaxar in addition to standard oral antiplatelet therapy was effective in patients with prior MI, but was not safe in patients with a prior stroke. Low dose rivaroxaban decreased cardiovascular events and mortality in patients post-ACS compared to placebo, although bleeding was increased.
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Of 96 patients who had neurovascular stent placement, 5.2% were resistant to aspirin and 36.5% were resistant to clopidogrel. Periprocedural thromboembolic complications were seen in 7 patients (7.3%). In a multivariate logistic regression model, clopidogrel resistance, higher diastolic blood pressure, and lack of statin use were significantly associated with periprocedural thromboembolic complication. There was a nonsignificant decrease in thromboembolic complications in patients whose clopidogrel dosage was tailored to the assay.
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The mechanical injury was exerted by pinching the abdominal aorta with hemostatic forceps for either 15 (moderate injury) or 60 (severe injury) seconds. Thrombus formation was monitored for 20min in real time using a fluorescent microscope coupled to a CCD camera. In the moderate injury, thrombus formation peaked at approximately 1min after injury and resolved within 3min, with the mean AUC (area under the curve) of 165.2±17.29mm(2), whereas a larger thrombus was observed upon the severe injury, with the mean AUC of 600.5±37.77mm(2). Using scanning electron microscopy and HE staining, a complete deformation of the endothelium in the moderate injury model and the exposure of the media in the severe injury model were observed. The model was also evaluate for its application on the effects of antithrombotic drugs targeting GP IIb-IIIa (eptifibatide), ADP receptor P2Y1 (MRS2500) and P2Y12 (clopidogrel), and thrombin (hirudin) on thrombus formation.
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In 2005, the Food and Drug Administration approved Qualaquin (quinine) for treatment of malaria and later ordered unapproved quinine formulations off the market. In 2009, labeling for Qualaquin added a warning for use for leg cramps, as serious hematologic reactions could occur. We examined quinine use trends among Medicare beneficiaries focusing on indications for use and associations with adverse hematologic outcomes.
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The three methods of measuring response to clopidogrel identify different patients as poor responders. Poor response to clopidogrel assessed by VerifyNow P2Y12 predicts myocardial necrosis. Measurement of [TxB2]S-P demonstrates a wide variation in aspirin response in patients taking dual antiplatelet therapy.
CEA can be performed in the subacute period without significantly increasing the operative risk. The urgent best medical treatment was associated with significant reduction in the risk of early NR in CEA patients. It seems that urgent aggressive best medical treatment may obviate the need for urgent CEA.
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Among 5673 patients with ACS previously on home warfarin, 1357 (24%) were not discharged on warfarin. In the subset of 1247 patients who underwent coronary stenting, 60% were prescribed triple anticoagulation therapy (aspirin, clopidogrel, and warfarin), 31% were given aspirin and clopidogrel without warfarin, and 3% received warfarin and aspirin without clopidogrel. Factors associated with a decision not to continue warfarin at the time of hospital discharge included in-hospital red blood cell transfusion, non-white race, prior stroke, and discharge clopidogrel use. The decision to continue warfarin at discharge correlated with perceived bleeding risk and was unaffected by patients' stroke risk.