Platelet function analysis: at the edge of meaning.

Thromb Haemost 2009; 101: 217–219 Anti-platelet agents are a cornerstone in the treatment of symptomatic coronary artery disease and acute coronary syndromes. Despite the proven benefits of acetylsalicylic acid (ASA) and clopidogrel, ischaemic events still occur in patients receiving dual anti-platelet therapy. Over the course of the last 10 years, a series of published studies has examined the effects of anti-platelet therapy on ex-vivo assays of platelet function and has clearly established substantial inter-individual variability in the degree of inhibition of platelet function observed in individuals taking ASA or clopidogrel or both (1–3). Individuals who display residual platelet function in ex-vivo assays despite standard doses of anti-platelet therapy have been classified as “non-responders” or “resistant” to anti-platelet medications (4, 5). A major unknown is whether patients who are non-responsive to anti-platelet medications, as judged by testing ex vivo, are at higher risk of suffering an ischaemic event and, if so, whether tailoring anti-platelet medications based on ex-vivo functional assays will result in protection from ischaemic events. A recent, small study supports the use of a tailored approach based on ex-vivo platelet function testing to dose-adjust clopidogrel and reduce ischaemic events following percutaneous coronary intervention (PCI) (6). However, the most compelling evidence of a benefit from higher platelet inhibition comes from studies of prasugrel, a novel P2Y12 receptor antagonist that more completely inhibits ex-vivo platelet function than does clopidogrel when assessed by light transmittance aggregometry (LTA) (7). In the Trial to Assess Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombosis in Myocardial Infarction (TRITON-TIMI) 38 trial (NCT00699998), dual antiplatelet therapy with prasugrel and ASA reduced ischaemic events as compared to clopidogrel and ASA, albeit at the expense of increased bleeding (8). One possibility is that the improved ischaemic outcomes in TRITON reflect a reduction in the number of patients that are “non-responders” to dual anti-platelet therapy. Several point-of-care assays of platelet function have been developed in recent years to rapidly screen individuals on antiplatelet therapy. The ideal test would be capable of distinguishing individuals at risk of ischaemic and bleeding events and could be used to guide dose adjustments in therapy. The clinical data indicating that a significant number of patients respond incompletely to clopidogrel, the reduction in ischaemic outcomes but increased bleeding with prasugrel in the TRITON trial, and the availability of point-of-care assays would suggest the time is right to use platelet function analysis to individualize anti-platelet therapy. Indeed, the most recent guidelines for PCI from the American College of Cardiology/American Heart Association/ Society for Coronary Angiography and recommend that platelet function be monitored in patients undergoing high-risk procedures and that the dose of clopidogrel be increased in patients identified as non-responsive (9). However, before widespread use of platelet function assays is adopted, several key issues need to be resolved. First, for each platelet function assay, the reliability of the test in predicting ischaemic and bleeding risk must be determined. This may require defining non-responsiveness in a manner that includes individuals who may benefit from higher doses of therapy and excludes those at risk of bleeding. Second, the optimal timing for platelet function analysis needs to be determined (i.e. on admission, prior to balloon inflation, following PCI). Third, the strategy of dose-adjustment based on ex-vivo platelet function results must be prospectively evaluated to assure that an improvement in clinical outcomes can be realized. In this issue of Thrombosis and Haemostasis, Gremmel et al. (10) provide fundamental information on the performance of four commonly used platelet function assays. Their findings are a key step in addressing the value and importance of the tests. Gremmel et al. compared the results of four platelet function assays to those of the “gold standard” LTA in a group of patients presenting for elective percutaneous stent implantation. A total of 80 patients were enrolled following stent placement in the coronary, peripheral or cerebrovascular bed. All patients were treated with ASA (100 mg/day for at least 2 weeks) and received a 300 mg loading dose of clopidogrel 24 hours before the procedure followed by 75 mg daily. Blood was sampled 24 hours after the intervention and stored in a manner consistent with the requirements of each assay. Each assay was performed by a