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CLINICAL RESEARCH: ANTIPLATELET THERAPY

Patients With Poor Responsiveness to Thienopyridine Treatment or With Diabetes Have Lower Levels of Circulating Active Metabolite, but Their Platelets Respond Normally to Active Metabolite Added Ex Vivo

David Erlinge, MD, PhD^_*,_*, Christoph Varenhorst, MD, Oscar Ö. Braun, MD, PhD^_*, Stefan James, MD, PhD, Kenneth J. Winters, MD, Joseph A. Jakubowski, PhD, John T. Brandt, MD, Atsuhiro Sugidachi, PhD^||, Agneta Siegbahn, MD, PhD and Lars Wallentin, MD, PhD

^_* Department of Cardiology, Lund University, Lund, Sweden
Uppsala Clinical Research Centre and Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Coagulation Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Lilly Research Laboratories, Indianapolis, Indiana
^|| Daiichi Sankyo Co., Ltd., Tokyo, Japan

Manuscript received April 28, 2008; revised manuscript received June 16, 2008, accepted July 10, 2008.

^_* Reprint requests and correspondence: Dr. David Erlinge, Department of Cardiology, Lund University Hospital, SE-221 85, Lund, Sweden (Email: david.erlinge{at}med.lu.se).

Objectives: We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes.

Background: Low platelet inhibition by clopidogrel is associated with ischemic clinical events. A higher 600-mg loading dose (LD) has been advocated to increase responsiveness to clopidogrel.

Methods: In this study, 110 aspirin-treated patients were randomized to double-blind treatment with clopidogrel 600 mg LD/75 mg maintenance dose (MD) for 28 days or prasugrel 60 mg LD/10 mg MD for 28 days. Pharmacodynamic (PD) response was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The PD poor responsiveness was defined with 4 definitions previously associated with worse clinical outcomes. Active metabolites (AM) of clopidogrel and prasugrel were measured. Clopidogrel AM was added ex vivo.

Results: The proportion of patients with poor responsiveness was greater in the clopidogrel group for all definitions at all time points from 1 h to 29 days. Poor responders had significantly lower plasma AM levels compared with responders. Patients with diabetes were over-represented in the poor-responder groups and had significantly lower levels of AM. Platelets of both poor responders and diabetic patients responded fully to AM added ex vivo.

Conclusions: Prasugrel treatment results in significantly fewer PD poor responders compared with clopidogrel after a 600-mg clopidogrel LD and during MD. The mechanism of incomplete platelet inhibition in clopidogrel poor-responder groups and in diabetic patients is lower plasma levels of its AM and not differences in platelet P2Y₁₂ receptor function.

Key Words: prasugrel • trials • thienopyridine • clopidogrel • platelets • clopidogrel resistance • coronary artery disease

Abbreviations and Acronyms   ADP = adenosine 5'-diphosphate   AM = active metabolite   AUC = area under the curve   LD = loading dose   LTA = light transmission aggregometry   MD = maintenance dose   MPA = maximal platelet aggregation   PCI = percutaneous coronary intervention   PD = pharmacodynamic   PRI = platelet reactivity index   RPA = residual platelet aggregation   VASP = vasodilator-stimulated phosphoprotein

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