Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel

Andrew L. Frelinger III; Alan D. Michelson; Stephen D. Wiviott; Dietmar Trenk; Franz-Josef Neumann; Debra L. Miller; Joseph A. Jakubowski; Timothy M. Costigan; Carolyn H. McCabe; Elliott M. Antman; Eugene Braunwald

doi:10.1160/TH11-03-0185

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2011; 106(02): 219-226
DOI: 10.1160/TH11-03-0185

Theme Issue Article

Schattauer GmbH

Intrinsic platelet reactivity before P2Y₁₂ blockade contributes to residual platelet reactivity despite high-level P2Y₁₂ blockade by prasugrel or high-dose clopidogrel

Results from PRINCIPLE-TIMI 44

Andrew L. Frelinger III

¹Center for Platelet Research Studies, Division of Hematology/Oncology, Children’s Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

²Center for Platelet Function Studies, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA

,

Alan D. Michelson

¹Center for Platelet Research Studies, Division of Hematology/Oncology, Children’s Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

²Center for Platelet Function Studies, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA

,

Stephen D. Wiviott

³TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

,

Dietmar Trenk

⁴Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany

,

Franz-Josef Neumann

⁴Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany

,

Debra L. Miller

⁵Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA

,

Joseph A. Jakubowski

⁵Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA

,

Timothy M. Costigan

⁵Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA

,

Carolyn H. McCabe

³TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

,

Elliott M. Antman

³TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

,

Eugene Braunwald

³TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

› Institutsangaben

Abstract

Summary

It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y₁₂ 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-treatment platelet reactivity is maintained after more potent P2Y₁₂ inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, twophase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous 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). 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 reactivity 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 P2Y₁₂ blockade with high-dose clopidogrel or even higher level P2Y₁₂ 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 therapeutic strategies.

keywords

Antiplatelet agents - cardiology - clinical trials - antiplatelet drugs - platelet pharmacology

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Referenzen

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