A 68-year-old man was admitted for acute ST-elevation inferior myocardial infarction after right coronary artery stenting (3.0 x 18mm drug-eluting stent) four months ago. He had been taking 81 mg of aspirin and 75 mg of clopidogrel orally on a daily basis. He is treated for hypertension and hypercholesterolemia, but not diabetes. He does not smoke. The angiogram demonstrated thrombosis in the stent. He underwent thromboaspiration, intravascular ultrasound of the thrombosed stent and balloon high-pressure inflations with a 3.5 x 15mm NC balloon. Did this patient have clopidogrel (Plavix)/aspirin (ASA) resistant platelets? Should the future doses of clopidogrel/ASA be increased over the standard doses on presumption of insufficient platelet response to dual antiplatelet therapy? Should platelet function be routinely tested?
Definition of Platelet Resistance
It has been thought that platelet resistance to clopidogrel or aspirin is associated with, or even promotes, acute stent thrombosis. Although we have considerable literature on the subject of platelet function, testing and resistance, the use of the point-of-care platelet function assays often results in ambiguous clinical decision-making. Because thrombosis results from multiple pathways, treatment failure (e.g. subacute thrombosis) alone is not sufficient evidence of drug resistance. The definition of drug resistance is nonresponsive to antiplatelet agent with persistent activity of the specific target of the antiplatelet agent. Platelets respond to some stimuli but not to the ‘resistant’ agent. The detection of non-responsiveness to clopidogrel has been tested mostly by light transmission aggregometry studies using ADP. ADP is an agonist which causes platelets to clump. The clumps block the transmitted light through a test tube. The reduction of light is the measure of a global platelet function, namely the abilities to aggregate (clump) and agglutinate (stick to vessels). Early investigations suggested platelet resistance was an absolute change in aggregometry of Platelet Function Assays
A large number of platelet function assays are available as commercial point-of-care testing systems (Table 1). The use of different point-of-care assays provides slightly different information on platelet function.1
Is There Evidence for Post Treatment Platelet Reactivity Associated with Long-Term Ischemic Events?
Platelet resistance to clopidogrel has been most commonly studied in patients undergoing percutaneous coronary intervention. Wide variations in response to therapy, ranging from 5-44% potential resistance, are reported. Differences in the prevalence of platelet resistance between studies, dosing, definitions, laboratory methods or insufficient time allowed before blood sampling to detect maximal effect has made clear understanding of in-vivo results difficult. Clopidogrel response variability has multiple proposed etiologies and has been reviewed in detail by Gurbel et al.2
Preliminary evidence suggests a potential threshold effect of platelet reactivity and associated increase risk of post-discharge ischemic events.3 There was a linkage between post-treatment platelet reactivity to ADP and occurrence of ischemic events, with a threshold of approximately 50% peri-procedural platelet aggregation response to ADP. This data is yet to be tested in a large trial.
The major limitations of focusing on platelet function to predict risk is that the measurement of platelet function in isolation fails to account for the multiplicity of additional clinical factors which may be significant contributors. None of the current studies using point-of-care platelet assay assessed platelet-fibrin interaction, kinetics of thrombin generation or measurements of platelet-fibrin clot strength, all contributing to thrombosis and important clinical events. Methods that measure coagulation and platelet interactions might prove to be better predictive tools. From review of available platelet function studies, it is difficult to correlate results with clinical outcomes and hence limited the use of the platelet function information to guide therapy. One recommendation for the potential use of platelet function testing would be to determine level of platelet reactivity in a patient with recently restenotic or acutely thrombosed stent.
Adequate Platelet Response to Clopidogrel
Current available data indicates 4-30% of patients treated with conventional dose of clopidogrel do not display adequate antiplatelet response. Variability of clopidogrel platelet response appears to be multi-factorial, related to either extrinsic or intrinsic mechanisms. Extrinsic mechanisms include under-dosing of platelets, undergoing stenting in acute coronary artery syndromes or drug-drug interactions with other agents reducing platelet function drug interaction. Intrinsic mechanisms include genetic polymorphisms, excessive release of adenosine or ADP, or up-regulation of other platelet activation pathways.
The optimal level of clopidogrel-induced platelet inhibition, which would correlate with thrombosis prevention, is not available. At this moment, it is not justified to routinely look for platelet resistance in the clinical setting. Several key questions remain:
1. Do laboratory tests and resistance to aspirin, clopidogrel, and GP IIb/IIIa antagonists predict clinical events? So far, data are not overwhelmingly positive.
2. What are the clinically meaningful definitions of aspirin, clopidogrel, and GP III resistance linking point-of-care testing? How can these issues be sorted out for standardization of platelet function testing?
There are two scenarios in which it makes sense to apply the results of platelet function testing in our patients at high risk of thrombotic complications after stenting. For a patient with recent subacute stent thrombosis treated with thromboaspiration with or without restenting, test platelet function and if clopidogrel/ASA resistance is detected, increase or change the dual antiplatelet regimen. For a patient with a recently implanted stent who requires surgery which might be complicated by bleeding, and the risk of stent thrombosis after cessation of dual antiplatelet therapy (clopidogrel/ASA) is high, we could test the platelet function. If already high (i.e. minimally inhibited platelets) on a normal dose of clopidogrel, proceed with surgery as needed. If platelet function is greatly impaired, then the timing of surgery must be balanced against the timing of clopidogrel withdrawal. Based on available data, daily clinical practice cannot yet be guided by point-of-care platelet function testing.
1. Werkum JW, Hackeng CM, de Korte FI, et al. Point-of-care platelet function testing in patients undergoing PCI between a rock and a hard place. Neth Heart J 2007 September; 15(9): 299–305.
2. Gurbel PA, Becker RC, Mann KG, et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007 Nov 6;50(19):1822-1834.
3. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005 Nov 15;46(10):1820-1826.