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CLINICAL RESEARCH: ANTIPLATELET THERAPY

Poor Responsiveness to Clopidogrel: Drug-Specific or Class-Effect Mechanism?

Evidence From a Clopidogrel-to-Ticlopidine Crossover Study

Gianluca Campo, MD^_*, Marco Valgimigli, MD, PhD^_*,,_*, Donato Gemmati, MS, Gianfranco Percoco, MD^_*, Linda Catozzi, MS, Alice Frangione, MD^_*, Federica Federici, MS, Fabrizio Ferrari, MD^_*, Matteo Tebaldi, MD^_*, Serena Luccarelli, MD^_*, Giovanni Parrinello, PhD and Roberto Ferrari, MD, PhD^_*,

^_* Cardiovascular Institute, Azienda Ospedaliera Universitaria S. Anna, Ferrara, Italy
Cardiovascular Research Centre, Salvatore Maugeri Foundation, IRCCS, Gussago, Italy
Center Study Haemostasis and Thrombosis, University of Ferrara, Ferrara, Italy
Medical Statistics Unit, University of Brescia, Brescia, Italy

Manuscript received February 12, 2007; revised manuscript received March 28, 2007, accepted April 9, 2007.

^_* Reprint requests and correspondence: Dr. Marco Valgimigli, Cardiovascular Institute, Azienda Ospedaliera Universitaria S.Anna, Corso Giovecca 203, 44100 Ferrara, Italy. (Email: vlgmrc{at}unife.it).

Objectives: This study was designed to investigate whether poor responders to thienopyridines after clopidogrel remain so even after ticlopidine administration (class effect) or whether a drug-specific effect exists between currently available thienopyridines.

Background: Whether clopidogrel poor responders also display inadequate platelet inhibition after ticlopidine administration remains undefined.

Methods: Platelet aggregation (PA) was measured in 143 patients, while they were taking aspirin, with light transmission aggregometry using adenosine diphosphate as an agonist at baseline (T₀) and at clopidogrel steady state (T₁). After T_1, clopidogrel was stopped and substituted with ticlopidine. Then PA was assessed at ticlopidine steady state (T₂). Resistance was defined as an absolute difference between T₀ and after-treatment (T₁ or T₂) PA 10%.

Results: Clopidogrel and ticlopidine responsiveness was normally distributed; PA at T₁ did not differ compared with T₂. Thirty (21%) and 28 (19%) patients were clopidogrel and ticlopidine nonresponders, respectively. Only 5 patients (3.5%) were nonresponders to both clopidogrel and ticlopidine (class effect), whereas 25 patients (83%) who were clopidogrel nonresponders at T₁ were responsive to ticlopidine, reaching a higher level of platelet inhibition at T₂ (PA 69 ± 15 vs. 44 ± 18, p < 0.01) (drug-specific response). On the other hand, 23 patients who were responsive to clopidogrel showed resistance to ticlopidine at T₂ (PA 46 ± 15 vs. 70 ± 15, p < 0.01) (drug-specific response).

Conclusions: Poor responsiveness to either clopidogrel or ticlopidine at steady state was common, whereas nonresponders to both drugs were relatively infrequent (3.5%, 95% confidence interval 1.5% to 7.9%), suggesting that poor response to thienopyridines may frequently be a drug-specific mechanism.

Abbreviations and Acronyms   CI = confidence interval   CYP = cytochrome P450   IPA = inhibition of platelet aggregation   MACE = major adverse cardiac event   PA = platelet aggregation   PCI = percutaneous coronary intervention   SA = stable angina   STEMI = ST-segment elevation myocardial infarction

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