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• W2035618259 abstract "Clopidogrel and aspirin are now in routine use in patients at-risk of vascular ischemic events. The drugs are often used in combination and recent data from the Percutaneous Coronary Intervention-Clopidogrel as Adjunctive Reperfusion Therapy (PCI-CLARITY) study [1] has confirmed that the drugs are particularly useful when administered to patients with acute coronary syndromes in advance of percutaneous coronary intervention (PCI). Platelets contribute to vascular and stent thrombosis following activation and aggregation. Following their initial deposition platelets contribute further to thrombosis and vascular injury via procoagulant and pro-inflammatory activities. Both aspirin and clopidogrel limit these processes. Aspirin inhibits the enzyme cyclo-oxygenase, an enzyme involved in the synthesis of thromboxane A2 (TXA2) which is an important mediator of platelet aggregation. Clopidogrel reduces the platelet activation brought about by adenosine diphosphate (ADP). Clopidogrel is a prodrug that is converted into a metabolite that acts as an antagonist at P2Y12 receptors on platelets. Aspirin and clopidogrel used together reduce the impact of both of these important mediators of platelet function. But do the drugs always achieve the protection that is intended? The answer to this question would appear to be no, as judged by the growing number of reports that describe variable effects of the drugs, particularly clopidogrel, in different people in relation to unwanted clinical consequences. In this issue of the Journal Cuisset et al. [2] describe a study involving 106 patients with acute coronary syndromes who had been treated with clopidogrel and aspirin prior to undergoing PCI with stenting. The authors measured platelet aggregation to ADP as a measure of the effectiveness of clopidogrel, and to arachidonic acid (the precursor of TXA2) as a measure of the effectiveness of the aspirin. The measurements were performed at the time of stenting. Patients were divided into quartiles based on these two measures with patients in the highest quartile (quartile 4) defined as ‘low-responders’. Twelve recurrent cardiovascular ischemic events occurred during the 1-month follow-up after PCI. Clinical outcome was significantly associated with platelet response, particularly to clopidogrel. Nine of the 12 events were in patients in quartile 4 for ADP-induced platelet aggregation with the remainder in quartile 3. Further, low platelet response to aspirin also significantly correlated with clopidogrel low response. The study that is described is the latest in a series of small studies of platelet low-response to clopidogrel linked to adverse clinical outcomes. Matetzky et al. [3] studied 60 patients who also underwent PCI with stenting. In this case there were eight cardiovascular ischemic events during 6 months of follow-up of which seven were in patients in the lowest quartile of response to clopidogrel (measured as ADP-induced aggregation), one was in the next lowest and none in the next two quartiles. Earlier Baragan et al. [4] had compared platelet reactivity in 16 patients who went on to have subacute stent thrombosis with 30 other stented patients who did not. The patients were taking either clopidogrel or ticlopidine, a related thienopyridine, and measurements were made of vasodilator stimulated phosphoprotein (VASP) phosphorylation which provides a direct measure of the action of ADP at P2Y12 receptors. These authors found a highly significant difference in platelet reactivity between these two groups which implied a much reduced effect of the drugs in the patients with thrombosis. Müller et al. [5] also reported two cases of stent thrombosis in patients who they defined as non-responders to clopidogrel, and there is also a recent case report of a patient with stent thrombosis in whom there was no effect of clopidogrel on ADP-induced platelet aggregation apparently in consequence of a failure to metabolize clopidogrel to its active metabolite [6]. Very recent reports also support a relationship between residual platelet aggregation after clopidogrel treatment and event rate following PCI. In the Clopidogrel effect on platelet REactivity in patients with Stent Thrombosis (CREST) study [7] 20 patients who experienced stent thromboses were found to have high platelet reactivity following clopidogrel therapy judged using a number of different measures, compared with 100 patients who did not have stent thrombosis. The Excelsior study is a prospective study of 802 consecutive patients in which ADP-induced platelet aggregation was measured at the time of PCI, and it has been reported that the main finding is that patients above the median for platelet aggregation exhibited a 6.5-fold higher risk of 30-day major adverse coronary events compared with those below the median [8]. This growing body of evidence of a relationship between levels of inhibition of platelet aggregation and adverse clinical outcomes may be added to soon when the ongoing Trial to assess Improvement in Therapeutic outcomes by Optimizing platelet inhibitioN with prasugrel (TRITON) TIMI-38 study is completed. This is a large comparative study of clopidogrel and another agent, prasugrel, in 13 000 patients with acute coronary syndromes. It has also been announced that a study (OASIS-7) is being contemplated in which clinical outcomes and platelet function will be assessed in 12 000 patients following administration of different doses of clopidogrel and aspirin. Why is it that platelets behave differently following treatment with clopidogrel? It is certainly not just an experimental artefact as differences in platelet reactivity have been observed using a range of experimental methodologies and conditions [9-11] and are reproducible in different individuals [10]. Differences in baseline platelet responses to ADP before instigation of any treatment may contribute to clopidogrel's effectiveness [10-13]. However, added to this there is growing evidence for differences in the rate of absorption of clopidogrel and in conversion of the drug to its active metabolite [14-16]. This may be associated with gene sequence variations in one of the enzymes (CYP3A4) responsible for its metabolism [17] although apparently not in CYP3A5 [18]. The possibility of interference by certain statins which share the same CYP3A4 metabolic pathway has been examined but the results are controversial [19, 20]. Although an attractive concept, common polymorphisms of the P2Y12 receptor appear not to be responsible for the drugs different effects [18, 21, 22]. It is not just ADP-induced aggregation that can remain high in patients who experience thrombotic consequences despite treatment with aspirin and clopidogrel. For example, shear-induced platelet aggregation has been reported to be more extensive in patients with stent thrombosis [3, 23], as well as platelet responses to epinephrine [3] and to arachidonate as reported in this issue by Cuisset et al. [2]. This may also be a consequence of the limited effectiveness of clopidogrel in these patients in that ADP plays a central role in platelet function [24]. If and when the relationship between levels of inhibition of platelet aggregation and clinical outcomes is clearly established, what can be done to offer more protection to patients who respond poorly? One possibility is to increase the dose of the drug. The conventional recommended maintenance dose for clopidogrel is 75 mg day−1, but with this dose it takes 3–5 days for maximal platelet inhibition to be achieved. When more rapid inhibition of platelet function is required, for example in the run up to PCI, a loading dose of 300 mg is added to this regimen, and more recently there have been several studies in which a 600 mg loading dose has been used to increase further the rate of onset of platelet inhibition [25-29]. Even more recently a dose of 900 mg was tested, although this did not appear to produce any more active metabolite or inhibition of platelet function than the 600 mg dose [30]. If residual platelet function still persists at the time of PCI, it would be possible to increase platelet inhibition further by infusion of a GPIIb/IIIa antagonist, a procedure that is already established as providing additional inhibition of platelet function in such patients [31]. There might also be a case for testing the benefit of administering additional aspirin over and above the 160 mg used by Cuisset et al. [2], given the residual aggregation with arachidonate that was still observed in some patients. Hopefully this is something that the proposed OASIS-7 trial will look at. For the future there is clearly scope for drugs that are more efficacious than clopidogrel, and such drugs are in the pipeline. Prasugrel is an agent that is similar to clopidogrel but which is metabolized very differently. Its active metabolite is produced much more quickly (<30 min) despite a much lower loading dose of the drug being administered (60 mg vs. 300 mg clopidogrel) and its effect on platelets is much less variable [32-34]. Another drug that is also in development is AZD6140. This differs from clopidogrel and prasugrel in that it acts directly at P2Y12 receptors without the necessity for conversion to an active metabolite; this also effects rapid and consistent inhibition of platelet function after oral administration [35]. Another agent, cangrelor, also a direct acting P2Y12 antagonist, is also being developed [36]. This is an infusible drug that may prove useful for direct application during procedures such as PCI. The overall challenge is to provide drugs that exert a rapid and consistent effect on platelet function in all those in whom this is required. Hopefully it will not be too long before this aim is achieved." @default.
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• W2035618259 title "Variable therapeutic effectiveness of clopidogrel in acute coronary syndromes" @default.
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