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J Am Coll Cardiol, 2007; 49:1505-1516, doi:10.1016/j.jacc.2006.11.044 (Published online 26 March 2007).
© 2007 by the American College of Cardiology Foundation
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STATE-OF-THE-ART PAPER

Variability in Individual Responsiveness to Clopidogrel

Clinical Implications, Management, and Future Perspectives

Dominick J. Angiolillo, MD, PhD, FACC*,1,*, Antonio Fernandez-Ortiz, MD, PhD{dagger}, Esther Bernardo, BSc{dagger}, Fernando Alfonso, MD, PhD{dagger}, Carlos Macaya, MD, PhD{dagger}, Theodore A. Bass, MD, FACC* and Marco A. Costa, MD, PhD, FACC*

* Division of Cardiology, University of Florida-Shands Jacksonville, Jacksonville, Florida
{dagger} Cardiovascular Institute, San Carlos University Hospital, Madrid, Spain.

Manuscript received August 9, 2006; revised manuscript received November 13, 2006, accepted November 28, 2006.

* Reprint requests and correspondence: Dr. Dominick J. Angiolillo, Division of Cardiology, University of Florida–Shands Jacksonville, 655 West 8th Street, Jacksonville, Florida 32209. (Email: dominick.angiolillo{at}jax.ufl.edu).

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes and/or undergoing percutaneous coronary interventions. Clopidogrel, in combination with aspirin, is currently the antiplatelet treatment of choice for prevention of stent thrombosis, and clinical trials have shown that, in high-risk patients, prolonged dual antiplatelet treatment is more effective than aspirin alone in preventing major cardiovascular events. However, despite the use of clopidogrel, a considerable number of patients continue to have cardiovascular events. Numerous in vitro studies have shown that individual responsiveness to clopidogrel is not uniform in all patients and is subject to inter- and intraindividual variability. Notably, there is a growing degree of evidence that recurrence of ischemic complications may be attributed to poor response to clopidogrel. The mechanisms leading to poor clopidogrel effects are not fully elucidated and are likely multifactorial. Although the gold standard definition to assess antiplatelet drug response has not been fully established, there is sufficient evidence to support that persistence of enhanced platelet reactivity despite the use of clopidogrel is a clinically relevant entity. This paper reviews the impact of individual response variability to clopidogrel on clinical outcomes and current and future directions for its management.

Abbreviations and Acronyms
  ACS = acute coronary syndrome
  ADP = adenosine diphosphate
  ATP = adenosine triphosphate
  cAMP = cyclic adenosine monophosphate
  CYP = cytochrome P450
  GP = glycoprotein
  GTP = guanosine triphosphate
  LTA = light transmittance aggregometry
  MFI = median fluorescence intensity
  NSTE-ACS = non–ST-segment elevation acute coronary syndrome
  PCI = percutaneous coronary intervention
  PGE1 = prostaglandin E1
  STEMI = ST-segment elevation myocardial infarction
  VASP-P = vasodilator-stimulated phosphoprotein-phosphorylation




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