Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: enhanced inhibitory effects of combination therapy

Moshfegh, Khatereh; Redondo, Maurice; Julmy, Friedgard; Wuillemin, Walter A.; Gebauer, Mathias; Haeberli, André; Meyer, Beat J.

doi:10.1016/s0735-1097(00)00817-2

Cited by 170 publications

(115 citation statements)

References 29 publications

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“…Clopidogrel and aspirin synergistically inhibit platelet function through two different pathways: the P2Y 12 subtype ADP receptor for clopidogrel and the cyclooxygenase-1 enzyme for aspirin (16,17). The addition of clopidogrel to aspirin was accompanied by a significant reduction in platelet aggregation compared with baseline values; however, this still resulted in suboptimal platelet inhibition in diabetic patients.…”

Section: Discussionmentioning

confidence: 99%

Platelet Function Profiles in Patients With Type 2 Diabetes and Coronary Artery Disease on Combined Aspirin and Clopidogrel Treatment

et al. 2005

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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...

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Section: Discussionmentioning

confidence: 99%

Platelet Function Profiles in Patients With Type 2 Diabetes and Coronary Artery Disease on Combined Aspirin and Clopidogrel Treatment

et al. 2005

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“…However, rather than an additive effect, the two drugs used together were synergistic [22,23]. A potent synergism between clopidogrel and anticoagulants [using either a direct thrombin inhibitor (Bivalirudin), a FXa inhibitor or a synthetic LMW heparin] has also been observed ( Fig.…”

Section: Combination Antithrombotic Therapymentioning

confidence: 97%

Therapeutic approaches in arterial thrombosis

Phillips

Conley

Sinha

et al. 2005

Journal of Thrombosis and Haemostasis

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Summary. The current standard of care for the treatment of arterial thrombosis includes anticoagulants and three classes of antiplatelet agents -aspirin, thienopyridines and glycoprotein IIb-IIIa antagonists. Although these drugs have had a significant impact on morbidity and mortality in several patient populations, up to 15% of the high risk patients with acute coronary syndrome continue to suffer from ischemic events. This problem may occur, in part, because the platelets in many patients are non-responsive to aspirin and clopidogrel. Murine models now indicate that platelets are not only responsible for arterial occlusion, they are also involved in the progression of atherosclerotic disease. New opportunities have emerged identifying potential targets and strategies for drug discovery suited to address these deficiencies by more effectively modulating platelet adhesion, thrombus growth, thrombus stability and the pro-inflammatory activity of platelets. In addition, a growing need has emerged for the development of bedside devices capable of bringing personalized medicine to patients being treated with antithrombotic drugs in order to measure the pharmacodynamic activities of new therapies, to assess the activities achieved by combined antithrombotic therapy, and to identify patients that fail to respond.

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“…However as shown in table 2, the performance of the tests is subject to considerable variation, which may affect the results. The variation in agonist concentration may influence the results obtained by optical platelet aggregation, since Moshfegh et al (2000) have demonstrated a clear dose-response relationship ( fig. 4) between the concentration of agonist used and the degree of aggregation measured.…”

Section: Important Bias Potentially Affecting Interpretation!mentioning

confidence: 99%

Existence of a Clinically Relevant Interaction between Clopidogrel and HMG‐CoA Reductase Inhibitors? Re‐evaluating the Evidence

Poulsen

Vinholt

Mickley

et al. 2005

Basic Clin Pharma Tox

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Abstract:Clopidogrel is an inactive prodrug, which requires activation by the cytochrome P450 3A4 system in order to exert its antiplatelet action. Some statins (atorvastatin, lovastatin and simvastatin) also requires metabolism by the cytochrome P450 3A4 system. From a theoretical point of view, a clinical relevant interaction may exist between clopidogrel and cytochrome P450 3A4 metabolized statins. Nine studies have investigated the existence of this potential interaction. Seven studies have used results based on platelet function as surrogate endpoints and two studies have dealt with objective clinical events including mortality, acute myocardial infarction and stroke. However the studies have yielded conflicting results. This controversy is primarily caused by substantial differences in study design and methods used for assessment of the antiaggregatory effect of clopidogrel. Most studies have included too few patients, and there appears to be no consensus regarding the definition of and optimal way of measuring the platelet inhibitory effect of clopidogrel. Therefore an adequately powered prospective study, ensuring elimination of identified possible confounders and with the use of a well-defined surrogate ex vivo parameter should be performed.

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Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: enhanced inhibitory effects of combination therapy

Cited by 170 publications

References 29 publications

Platelet Function Profiles in Patients With Type 2 Diabetes and Coronary Artery Disease on Combined Aspirin and Clopidogrel Treatment

Platelet Function Profiles in Patients With Type 2 Diabetes and Coronary Artery Disease on Combined Aspirin and Clopidogrel Treatment

Therapeutic approaches in arterial thrombosis

Existence of a Clinically Relevant Interaction between Clopidogrel and HMG‐CoA Reductase Inhibitors? Re‐evaluating the Evidence

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