219 © Schattauer 2011 Thrombosis and Haemostasis 106.2/2011 Theme Issue Article Intrinsic platelet reactivity before P2Y 12 blockade contributes to residual platelet reactivity despite high-level P2Y 12 blockade by prasugrel or high-dose clopidogrel Results from PRINCIPLE-TIMI 44 Andrew L. Frelinger III 1,2 ; Alan D. Michelson 1,2 ; Stephen D. Wiviott 3 ; Dietmar Trenk 4 ; Franz-Josef Neumann 4 ; Debra L. Miller 5 ; Joseph A. Jakubowski 5 ; Timothy M. Costigan 5 ; Carolyn H. McCabe 3 ; Elliott M. Antman 3 ; Eugene Braunwald 3 1 Center for Platelet Research Studies, Division of Hematology/Oncology, Children’s Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA; 2 Center for Platelet Function Studies, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA; 3 TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 4 Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany; 5 Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA Summary It was the objective of this study to determine whether the intrinsic pla- telet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y 12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treat- ment platelet reactivity is maintained after more potent P2Y 12 in- hibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, two- phase crossover study of prasugrel compared with high-dose clopido- grel in 201 patients undergoing cardiac catheterisation for planned per- cutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18–24 h) and MD (15 d). Correspondence to: Alan D. Michelson, MD Director, Center for Platelet Research Studies Children’s Hospital Boston Karp 08213, 300 Longwood Avenue Boston, MA 02115–5737, USA Tel.: +1 617 919 2116, Fax: +1 617 730 4631 E-mail: alan.michelson@childrens.harvard.edu Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18–24 h and 15 day reac- tivity to ADP (correlations 0.24–0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y 12 blockade with high-dose clopidogrel or even higher level P2Y 12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to thera- peutic strategies. Keywords Antiplatelet agents, cardiology, clinical trials, antiplatelet drugs, pla- telet pharmacology Financial support: Daiichi Sankyo Company Limited (Tokyo, Japan) and Eli Lilly and Company (Indiana- polis, IN) sponsored the PRINCIPLE-TIMI 44 trial. The present analysis had no funding. Received: March 18, 2011 Accepted after minor revision: June 17, 2011 Prepublished online: June 28, 2011 doi:10.1160/TH11-03-0185 Thromb Haemost 2011; 106: 219–226 Introduction Patient-to-patient variability in residual platelet function during clopidogrel therapy has been well described (1). Multiple studies indicate high residual platelet reactivity, also referred to as clopido- grel “resistance” or “non-responsiveness”, is associated with poor clinical outcomes (1–5). However, we (6) and others (2) have sug- gested that a portion of platelet function following treatment with standard dose clopidogrel (300 mg loading dose [LD], 75 mg daily maintenance dose [MD]) is accounted for by pretreatment platelet reactivity – and that clopidogrel “resistance” or “non-responsive- ness” may therefore not be appropriate terms. More potent P2Y 12 antagonism is now being used more fre- quently in patients, either high-dose clopidogrel (600 mg LD, 150 mg daily MD) or the recently Food and Drug Administration (FDA)-approved prasugrel (7–9). However, it remains unknown whether the relationship between platelet reactivity prior to expo- sure to thienopyridines and residual on-treatment platelet reactiv- ity (2, 6) is maintained in patients after this more potent P2Y 12 in- hibition – or whether more potent P2Y 12 antagonism can over- Platelet function testing: From bench to bedside For personal or educational use only. No other uses without permission. 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