To assess platelet function profiles in diabetic and nondiabetic patients on aspirin and clopidogrel therapy, two patient populations were included to investigate the 1) acute effects of a 300-mg clopidogrel loading dose (group 1, n ‫؍‬ 52) and 2) long-term effects of clopidogrel (group 2, n ‫؍‬ 120) on platelet function in diabetic compared with nondiabetic patients already on aspirin treatment. Patients were stratified according to the presence of type 2 diabetes. Platelet aggregation was assessed using light transmittance aggregometry (groups 1 and 2). Platelet activation (P-selectin expression and PAC-1 binding) was determined using wholeblood flow cytometry (group 2). Clopidogrel response was also assessed. In group 1, platelet aggregation was significantly increased in diabetic (n ‫؍‬ 16) compared with nondiabetic (n ‫؍‬ 36) patients at baseline and up to 24 h following a 300-mg loading dose (P ‫؍‬ 0.005). In group 2, platelet aggregation and activation were increased in diabetic (n ‫؍‬ 60) compared with nondiabetic (n ‫؍‬ 60) subjects (P < 0.05 for all platelet function assays). Diabetic subjects had a higher number of clopidogrel nonresponders (P ‫؍‬ 0.04). Diabetic patients have increased platelet reactivity compared with nondiabetic subjects on combined aspirin and clopidogrel treatment. Reduced sensitivity to antiplatelet drugs may contribute to the increased atherothombotic risk in diabetic patients. Diabetes 54:2430 -2435, 2005 D iabetes is commonly associated with accelerated atherosclerosis, clinically resulting in premature coronary artery disease (CAD), increased risk of cerebrovascular disease, and severe peripheral vascular disease (1). Patients with type 2 diabetes have a two-to fourfold increase in the risk of CAD, and diabetic patients without prior myocardial infarction have the same risk for a subsequent acute coronary event as nondiabetic patients with a previous myocardial infarction (2,3). Recurrent ischemic events are also more frequent in patients with type 2 diabetes than in nondiabetic patients (4 -6). Platelet dysfunction, among other mechanisms, contribute to the increased risk of atherothrombotic complications in the diabetic population (7-9). Such altered platelet function is revealed by hypersensitivity to aggregants observed in in vitro studies.Platelets from diabetic subjects are also less sensitive to aspirin (10 -11). Importantly, reduced sensitivity, or "poor response," to aspirin has been associated with an increased risk of ischemic events (12-15). Combining clopidogrel to aspirin enhances platelet inhibition and has been associated with a reduction in ischemic events compared with the use of aspirin alone (16 -19). However, the magnitude of antiplatelet effects may be depressed in diabetic patients. The aim of this study was to compare platelet function profiles in diabetic and nondiabetic patients on combined aspirin and clopidogrel therapy. RESEARCH DESIGN AND METHODSTwo patient populations were included to investigate the 1) acute effects of a 300-mg loading dose of...

Background-After treatment with clopidogrel, patients with type 2 diabetes mellitus (T2DM) have reduced platelet inhibition compared with patients who are not diabetic. Whether platelet inhibition can be enhanced by increasing clopidogrel maintenance dosage in T2DM patients is unknown. The aim of this pilot study was to assess the functional impact of a high maintenance dose in T2DM patients with suboptimal clopidogrel-induced antiplatelet effects. Methods and Results-T2DM patients on chronic dual antiplatelet therapy were screened to identify suboptimal clopidogrel responders. The latter were randomized to 30-day treatment with a standard (75 mg; nϭ20) or high (150 mg; nϭ20) daily maintenance dose. Platelet function was assessed at 3 time points: baseline, 30 days after randomization, and 30 days after resuming standard dosing. Platelet function parameters included adenosine diphosphate-induced (20 and 5 mol/L) maximal and late platelet aggregation, inhibition of platelet aggregation, platelet disaggregation, and P2Y 12 reactivity index. A total of 64 T2DM patients were screened to identify 40 suboptimal responders. After randomization, maximal adenosine diphosphate-induced (20 mol/L) platelet aggregation was significantly reduced in the 150-mg group compared with the 75-mg group (Pϭ0.002; primary end point). However, suboptimal clopidogrel response was still present in 60% of patients on the 150-mg regimen. All other platelet function parameters showed enhanced clopidogrel-induced antiplatelet effects with 150 mg, which returned to baseline values after resumption of standard dosing. Conclusions-A 150-mg maintenance dose of clopidogrel is associated with enhanced antiplatelet effects compared with 75 mg in high-risk T2DM patients. However, enhanced ex vivo platelet reactivity continues to persist, the clinical implications of which are unknown and need to be evaluated in large-scale clinical trials. (Circulation. 2007;115:708-716.)

High platelet reactivity determined in T2DM patients with coronary artery disease while on chronic dual antiplatelet therapy is associated with a higher risk of long-term adverse cardiovascular events, suggesting the need for tailored antithrombotic drug regimens in these high-risk patients.

The P2Y12-dependent and -independent pathways of platelet reactivity are altered in T2DM compared with nondiabetic patients, and ITDM have greater ADP-induced platelet aggregation compared with NITDM.

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes and/or undergoing percutaneous coronary interventions. Clopidogrel, in combination with aspirin, is currently the antiplatelet treatment of choice for prevention of stent thrombosis, and clinical trials have shown that, in high-risk patients, prolonged dual antiplatelet treatment is more effective than aspirin alone in preventing major cardiovascular events. However, despite the use of clopidogrel, a considerable number of patients continue to have cardiovascular events. Numerous in vitro studies have shown that individual responsiveness to clopidogrel is not uniform in all patients and is subject to inter- and intraindividual variability. Notably, there is a growing degree of evidence that recurrence of ischemic complications may be attributed to poor response to clopidogrel. The mechanisms leading to poor clopidogrel effects are not fully elucidated and are likely multifactorial. Although the gold standard definition to assess antiplatelet drug response has not been fully established, there is sufficient evidence to support that persistence of enhanced platelet reactivity despite the use of clopidogrel is a clinically relevant entity. This paper reviews the impact of individual response variability to clopidogrel on clinical outcomes and current and future directions for its management.

The β1-adrenergic-receptor (ADRB1) antagonist metoprolol reduces infarct size in acute myocardial infarction (AMI) patients. The prevailing view has been that metoprolol acts mainly on cardiomyocytes. Here, we demonstrate that metoprolol reduces reperfusion injury by targeting the haematopoietic compartment. Metoprolol inhibits neutrophil migration in an ADRB1-dependent manner. Metoprolol acts during early phases of neutrophil recruitment by impairing structural and functional rearrangements needed for productive engagement of circulating platelets, resulting in erratic intravascular dynamics and blunted inflammation. Depletion of neutrophils, ablation of Adrb1 in haematopoietic cells, or blockade of PSGL-1, the receptor involved in neutrophil–platelet interactions, fully abrogated metoprolol's infarct-limiting effects. The association between neutrophil count and microvascular obstruction is abolished in metoprolol-treated AMI patients. Metoprolol inhibits neutrophil–platelet interactions in AMI patients by targeting neutrophils. Identification of the relevant role of ADRB1 in haematopoietic cells during acute injury and the protective role upon its modulation offers potential for developing new therapeutic strategies.

Objectives-Metabolic activity of cytochrome P450 (CYP) 3A4 has been associated with clopidogrel response variability.Because metabolic activity of CYP3A4 is genetically regulated, we hypothesized that genetic variations of this enzyme may contribute to clopidogrel response variability. Methods and Results-The CYP3A4*1B, CYP3A4*3, IVS7ϩ258AϾG, IVS7ϩ894CϾT, and IVS10ϩ12GϾA polymorphisms of the CYP3A4 gene were assessed in 82 patients in a steady phase of clopidogrel therapy. Glycoprotein (platelet glycoprotein (GP) IIb/IIIa receptor activation and platelet aggregation were assessed. A cohort of 45 clopidogrel-naïve patients was studied to determine the modulating effects of these polymorphisms after loading dose (300 mg) administration. Only the IVS7ϩ258AϾG, IVS7ϩ894CϾT, and IVS10ϩ12GϾA polymorphisms were sufficiently polymorphic. During the steady phase of clopidogrel treatment, IVS10ϩ12A allele carriers had reduced GP IIb/IIIa activation (Pϭ0.025) and better responsiveness (Pϭ0.02); similarly, clopidogrel-naïve patients carriers of the IVS10ϩ12A allele had reduced GP IIb/IIIa activation during the first 24 hours after a loading dose (Pϭ0.025), increased platelet inhibition (Pϭ0.006), and a more optimal drug response (Pϭ0.003). This polymorphism did not influence platelet aggregation profiles. No association was observed between the other polymorphisms and clopidogrel responsiveness. Key Words: clopidogrel Ⅲ platelet Ⅲ polymorphism T reatment with clopidogrel is associated with a broad variability in antiplatelet effects. [1][2][3][4] This may be partly attributed to the levels of clopidogrel's active metabolite. 5 Clopidogrel in fact is an inactive pro-drug that requires oxidation by the hepatic cytochrome P450 3A4 (CYP3A4) to generate an active metabolite. 6 -7 The active metabolite of clopidogrel inhibits platelet activation through an irreversible blockage of the platelet adenosine diphosphate (ADP) P2Y 12 receptor. The P2Y 12 receptor inhibits adenylyl cyclase and in turn decreases platelet cAMP (cAMP) levels and cAMPmediated phosphorylation of the vasodilator-stimulated phosphoprotein, critical for inhibition of glycoprotein (GP) IIb/ IIIa receptor activation. 8 Conclusions-The See page 1681Drugs that are substrates or inhibit CYP3A4 can potentially interfere with the conversion of clopidogrel into its active metabolite. 9 -11 Accordingly, the metabolic activity of the CYP3A4 enzyme, which varies considerably among individuals, 12 has shown to influence platelet reactivity after a clopidogrel loading dose. 13 Because genetic predisposition is the major determinant of heterogeneity in metabolic activity of the CYP3A4 enzyme, 12,14 -15 we hypothesized that single-nucleotide polymorphisms (SNPs) of CYP3A4 may account for interindividual variability of platelet reactivity in patients treated with clopidogrel. In the present study we examined the influence of SNPs of the CYP3A4 enzyme on platelet reactivity and responsiveness to clopidogrel in patients with coronary artery disease. Materials and Methods Detail...

In DM patients with coronary artery disease taking maintenance aspirin and clopidogrel therapy, impaired renal function is associated with reduced clopidogrel-induced antiplatelet effects and a greater prevalence of HPPR.