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- Racial differences in resistance to P2Y12 receptor antagonists in Type-2 diabetic subjects. [JOURNAL ARTICLE]
- J Pharmacol Exp Ther 2014 Jul 22.
Although resistance to the P2Y12 antagonist clopidogrel is linked to altered drug metabolism, some studies suggest that these pharmacokinetic abnormalities only partially account for drug resistance. To circumvent pharmacokinetic complications and target P2Y12 receptor function we applied the direct P2Y12 antagonist 2-methylthio-AMP to purified platelets, ex vivo. Platelets were purified from healthy and Type-2 Diabetes (T2DM) patients and stimulated with thrombin or the selective protease activated receptor agonists, PAR1-activating peptide (PAR1-AP) or PAR4-AP. Platelet activation as measured by αIIbβ3 activation and P-selectin expression was monitored in 141 subjects. Our results demonstrate that compared to healthy subjects, platelets from diabetic patients are resistant to inhibition by 2-methylthio-AMP, demonstrating P2Y12 pharmacodynamic defects amongst diabetic patients. Inhibition of thrombin-mediated αIIbβ3 activation by 2-methylthio-AMP was lower in diabetic platelets versus healthy platelets. Sub-group analysis revealed a racial difference in the resistance to 2-methylthio-AMP. We found no resistance in platelets from diabetic African-Americans; they were inhibited by 2-methylthio-AMP equally as well as platelets from healthy African-Americans. In contrast, platelets from Caucasian diabetics, were resistant to P2Y12 antagonism compared to healthy Caucasians. Multivariable analysis demonstrated that other variables such as obesity, age or gender could not account for the differential resistance to 2-methylthio-AMP among races. These results suggest that in addition to altered drug metabolism, P2Y12 receptor function itself is altered in the Caucasian diabetic population. The racial difference in platelet function in T2DM is a novel finding, which may lead to differences in treatment as well as potentially lead to new targets for anti-platelet therapy.
- Platelet function in Takotsubo cardiomyopathy. [JOURNAL ARTICLE]
- J Thromb Thrombolysis 2014 Jul 23.
Takotsubo cardiomyopathy (TK) includes a transient left ventricular dysfunction without obstructive coronary disease, sometimes after stressful situations with elevated cathecolamines. Since catecholamines activate platelets we aimed to study the platelet influence in a TK setting. We included 32 patients with a TK diagnosis, 13 with an acute coronary syndrome (ACS) and 18 healthy volunteers. Once consent informed was obtained, blood samples were extracted and processed (at admission and after 3 months follow-up). Clinical, ecg, echocardiographic and angiographic features were thoroughly recorded.Previous treatment before admission was similar between groups. No differences were observed in clinical features or any of the acute markers studied regarding platelet reactivity between TK compared to ACS. After follow-up, aggregation levels and platelet reactivity showed differences, mainly due to the antithrombotic therapy prescribed at discharge, but similar to volunteers. Circulating epinephrine during the acute phase was significantly higher in TK (p < 0.001). Patients with higher levels of epinephrine had elevated platelet activation and aggregation after 3 months. No differences were observed in Takotsubo acute platelet aggregation compared to patients with ACS, in spite of higher blood levels of adrenaline. Takotsubo patients had elevated platelet aggregation and activation compared with ACS patients at 3 months follow-up because they were less frequently on chronic clopidogrel and ASA. However, they had similar platelet aggregation and activation levels to healthy volunteers despite treatment with low-dose ASA. Takotsubo patients who had higher levels of adrenaline in the acute phase displayed increased platelet reactivity during follow-up.
- Interplay between Genetic and Clinical Variables Affecting Platelet Reactivity and Cardiac Adverse Events in Patients Undergoing Percutaneous Coronary Intervention. [JOURNAL ARTICLE]
- PLoS One 2014; 9(7):e102701.
Several clinical and genetic variables are associated with influencing high on treatment platelet reactivity (HTPR). The aim of the study was to propose a path model explaining a concurrent impact among variables influencing HTPR and ischemic events. In this prospective cohort study polymorphisms of CYP2C19*2, CYP2C19*17, ABCB1, PON1 alleles and platelet function assessed by Multiple Electrode Aggregometry were assessed in 416 patients undergoing percutaneous coronary intervention treated with clopidogrel and aspirin. The rates of major adverse cardiac events (MACE) were recorded during a 12-month follow up. The path model was calculated by a structural equation modelling. Paths from two clinical characteristics (diabetes mellitus and acute coronary syndrome (ACS)) and two genetic variants (CYP2C19*2 and CYP2C19*17) independently predicted HTPR (path coefficients: 0.11 0.10, 0.17, and -0.10, respectively; p<0.05 for all). By use of those four variables a novel score for prediction of HTPR was built: in a factor-weighted model the risk for HTPR was calculated with an OR of 3.8 (95%CI: 3.1-6.8, p<0.001) for a score level of ≥1 compared with a score of <1. While MACE was independently predicted by HTPR and age in the multivariate model (path coefficient: 0.14 and 0.13, respectively; p<0.05), the coexistence of HTPR and age ≥75 years emerged as the strongest predictor of MACE. Our study suggests a pathway, which might explain indirect and direct impact of variables on clinical outcome: ACS, diabetes mellitus, CYP2C19*2 and CYP2C19*17 genetic variants independently predicted HTPR. In turn, age ≥75 years and HTPR were the strongest predictors of MACE.
- Prognostic Role of Platelet Reactivity in Patients with Acute Coronary Syndromes. [JOURNAL ARTICLE]
- Cardiol Rev 2014 Jul 21.
Despite dual antiplatelet treatment with aspirin and clopidogrel, patients with acute coronary syndromes (ACS) remain at risk for recurrent cardiovascular events. This may be due, at least in part, to an incomplete response to clopidogrel, which is more frequent in ACS patients compared to stable patients because of massive platelet activation and increased platelet turnover. Currently, numerous laboratory-based methods and point-of-care tests are available to assess platelet reactivity. Several studies have tried to establish a standardized definition of high on-treatment platelet reactivity (HTPR) and to evaluate a correlation between this aggregometric phenomenon and clinical outcomes. Indeed a strong relationship between HTPR and ischemic events was found, especially in high-risk ACS patients undergoing percutaneous coronary revascularization. Therefore, evaluation of platelet reactivity in this subset of patients may guide physicians to choose the best antiplatelet regimen for the individual patient avoiding both ischaemic and bleeding complications. This was the rationale for tailored antiplatelet therapy pursued by utilization of different clopidogrel regimens, more potent P2Y12 receptor antagonists or more extensive administration of glycoprotein IIb/IIIa inhibitors. To date, data from randomized studies addressing the concept of tailored antiplatelet therapy did not show any clinical benefit from a strategy based on platelet reactivity monitoring. However, as predominantly elective and stable patients were included into the latter studies, these results cannot be completely transferred into an ACS setting. This review summarizes current evidence about the potential role of platelet reactivity in the therapeutic management of patients with ACS.
- Dual antiplatelet therapy after noncardioembolic ischemic stroke or transient ischemic attack: pros and cons. [Journal Article, Review]
- J Clin Neurol 2014 Jul; 10(3):189-96.
Dual antiplatelet therapy simultaneously blocks different platelet activation pathways and might thus be more potent at inhibiting platelet activation and more effective at reducing major ischemic vascular events compared to antiplatelet monotherapy. Aspirin plus clopidogrel dual therapy is now the standard therapy for patients with acute coronary syndrome and for those undergoing percutaneous coronary intervention. However, dual antiplatelet therapy carries an increased risk of bleeding. Patients with ischemic stroke or transient ischemic attack (TIA) are generally older and likely to have a fragile cerebrovascular bed, which further increases the risk of systemic major bleeding events and intracranial hemorrhage. Clinical trials and meta-analyses suggest that in comparison to antiplatelet monotherapy, dual antiplatelet therapy initiated early after noncardioembolic ischemic stroke or TIA further reduces the rate of recurrent stroke and major vascular events without significantly increasing the rate of major bleeding events. In contrast, studies of long-term therapy in patients with noncardioembolic ischemic stroke or TIA have yielded inconsistent data regarding the benefit of dual antiplatelet therapy over monotherapy. However, the harm associated with major bleeding events, including intracranial hemorrhage, which is generally more disabling and more fatal than ischemic stroke, is likely to increase with dual antiplatelet therapy. Physicians should carefully assess the benefits and risks of dual antiplatelet therapy versus antiplatelet monotherapy when managing patients with ischemic stroke or TIA.
- Clopidogrel, CYP2C19 and proton pump inhibitors: What we know and what it means. [Journal Article]
- J Clin Pharmacol 2014 Aug; 54(8):884-8.
- The clopidogrel conundrum. [Journal Article]
- J Clin Pharmacol 2014 Aug; 54(8):841-2.
- Comparison of loading with maintenance dose of clopidogrel on platelet reactivity in Chinese with different CYP2C19 genotypes prior to percutaneous coronary intervention. [Journal Article]
- Chin Med J (Engl) 2014 Jul; 127(14):2571-7.
Whether two clopidogrel pretreatment strategies prior to elective percutaneous coronary intervention (PCI): a 300 mg loading dose (LD) in clopidogrel naїve patients and a 75 mg maintenance dose (MD) once daily in patients on chronic clopidogrel therapy play the same role in the platelet inhibition in Chinese with different CYP2C19 genotypes remains unknown. We aim to evaluate the impact on platelet inhibition by clopidogrel pretreatment strategy and its interaction effect with CYP2C19 genotype.Chinese patients undergoing PCI (n = 840) were assigned to 2×2 groups in the trial according to different clopidogrel pretreatment strategies (470 patients in LD, 370 patients in MD) and CYP2C19 genotypes (494 carriers of any CYP2C19 *2 or *3 loss-of-function allele, 346 non-carriers). The primary outcome was platelet aggregation (PA) as measured by the 10 µmol/L adenosine diphosphate induced light transmission aggregation.Compared with MD group, LD strategy showed a significantly higher PA-((59.22 ± 11.67)% vs. (52.83 ± 12.17)%, P < 0.01), similar PA difference was observed in CYP2C19 loss-of-function carriers compared with non-carriers ((59.41 ± 10.91)% vs. (52.10 ± 12.90)%, P < 0.01). LD patients in either the CYP2C19 loss-of-function allele carrier or non-carrier group showed a significantly higher PA compared with MD group ((61.50 ± 10.61)% vs. (56.84 ± 10.74)%, P < 0.01; (56.06 ± 12.34)% vs. (46.88 ± 11.78)%, P < 0.01, respectively). A quantitative interaction effect was observed between clopidogrel pretreatment strategy and CYP2C19 genotype (P = 0.001).The 300 mg LD strategy results in a decreased effect on platelet inhibition compared with the 75 mg MD in Chinese patients receiving clopidogrel prior to PCI, especially in the CYP2C19 *2 or *3 loss-of-function allele non-carriers.
- Switching Patients from Clopidogrel to Prasugrel in Acute Coronary Syndrome: Impact of the Clopidogrel Loading Dose on Platelet Reactivity. [JOURNAL ARTICLE]
- J Interv Cardiol 2014 Jul 19.
The present study aimed to assess the pharmacodynamic response of a prasugrel 60-mg loading dose (LD) alone compared with prasugrel 60 mg added to clopidogrel 600 mg.Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) commonly receive a clopidogrel LD prior to angiography. Switching these patients to prasugrel may be desirable because higher platelet inhibition is expected.In this open-label, multicenter, nonrandomized trial, 75 patients were categorized into 2 treatment strategies: Those who received a clopidogrel 600-mg LD and received a reloading dose of prasugrel 60 mg (clopidogrel/prasugrel group) and those who did not receive a clopidogrel LD and received a prasugrel 60-mg LD (prasugrel group). Platelet reactivity was assessed using VerifyNow P2Y12 reaction units (PRU) and Platelet Reactivity Index vasodilator-stimulated phosphoprotein phosphorylation (PRI-VASP) at 3 different times: at the sheath insertion prior to prasugrel LD, 4 hours after prasugrel LD, and at discharge.Four hours after prasugrel LD, platelet reactivity did not differ between the clopidogrel/prasugrel group and the prasugrel group according to the VerifyNow assay (median PRU 23 [5-71] vs. 54 [5-91], respectively; P = 0.18) and the VASP assay (median PRI 8.67 [4.51-16.85] versus 8.03 [4.82-21.72], respectively; P = 1.0). No significant differences in PRU and PRI were observed at discharge. Few bleeding events were reported without any significant differences between the 2 groups.Platelet reactivity with prasugrel 60 mg added to a clopidogrel 600-mg LD was not significantly different compared with prasugrel 60 mg alone in ACS patients undergoing PCI.
- Dipyridamole-induced headache and lower recurrence risk in secondary prevention of ischaemic stroke: a post hoc analysis. [JOURNAL ARTICLE]
- Eur J Neurol 2014 Jul 8.
Our objective was to investigate the association between recurrent stroke risk and headache induced by extended-release dipyridamole (ER-DP) when administered alone or with low-dose aspirin (ASA+ER-DP).This was a post hoc analysis of prospectively collected data on recurrent stroke risk and headache as an adverse event or reason for treatment discontinuation from the PRoFESS (N = 20 332) and ESPS2 (N = 6602) trials. Hazard ratios (HRs) for recurrent stroke were calculated using the Cox model.In PRoFESS, the 2.5-year recurrent stroke risk in patients receiving ASA+ER-DP was 8.2% in those with headache within 7 days of starting treatment and 9.4% in those without [HR 0.85, 95% confidence interval (CI) 0.73-0.98; P = 0.03]. Recurrent stroke risk was 5.0% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.2% in those who did not (HR 0.52, 95% CI 0.35-0.77; P = 0.001). No such difference was observed in clopidogrel-treated patients. In ESPS2, risk of recurrent stroke was 6.2% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.8% in patients who did not (HR 0.62, 95% CI 0.31-1.27; P = 0.19) and 7.3% in patients who discontinued ER-DP due to headache by day 90 versus 13.2% in those who did not (HR 0.53, 95% CI 0.27-1.04; P = 0.06).Patients taking ASA+ER-DP in PRoFESS who developed headache had significantly reduced stroke recurrence risk versus those without headache. Similar (non-significant) findings for ASA+ER-DP and ER-DP in ESPS2 suggest that dipyridamole-induced headache may reflect better cerebrovascular function.