News:Antiplatelets: Clopidogrel-to-Ticlopidine Crossover Study Demonstrates Drug Specific Resistance

September 19, 2007 By Scott P. Williams [mailto:swilliams@perfuse.org]

The study examines data from 143 individuals to determine whether patient resistance to clopidogrel or ticlopidine (both thienopyrdines) represents a drug-specific or class-specific issue. Patients enrolled in the single site study underwent percutaneous coronary intervention (PCI) between November 2005 and May 2006. The patients were admitted to treat either stable angina (SA; 76 patients) or ST-segment elevation myocardial infarction (STEMI; 67 patients).

Venous blood samples were collected from the patients at three time points. At the baseline time point (T0) a sample was collected prior to the administration of either thienopyridne. At the second time point, (T1), a blood sample was collected when patients achieved a clopidogrel steady state. The steady state was achieved by giving patients a 300 mg loading dose of clopidogrel, followed by 75 mg per day doses of the drug for 5 to 7 days. The final time point, (T2), was defined by a ticlopidine steady state, in which ticlopidine was substituted for clopidogrel. The third blood sample was obtained after patients received a 500 mg loading dose, followed by twice daily 250 mg doses for 7 to 10 days. At all three time points the researchers used light transmission aggregometry to measure platelet aggregation (PA). Resistance to clopidogrel or ticlopidine was defined as an absolute difference in PA between T0 and (T1 or T2) equal to or less than 10%.

In addition to receiving the experimental doses of clopidogrel and ticlopidine, SA patients received 100 mg of aspirin per day for at least 7 days and were given clopidogrel at least 6 hours prior to PCI. Similarly, STEMI patients received 250 mg of aspirin intravenously, 50 to 70 U/kg of heparin and glycoprotein IIb/IIIa inhibitors. Following PCI, all patients received thienopyridines for 1 to 6 months and were prescribed 100 mg doses of aspirin once per day, indefinitely.

Results of the study indicate that thienopyrdine resistance appears to be a drug specific problem, rather than a class effect. Of the 143 patients in the study, 30 (21%) demonstrated clopidogrel resistance and 28 (19%) showed ticlopidine resistance. Only 5 (3.5%) patients demonstrated a class effect resistance to thienopyrdines, while the other 48 (34%) patients were responsive to either clopidogrel or ticlopidine.

The research team acknowledges that the study is limited by the fact that all patients received clopidogrel before ticlopidine, and suggest that a randomized crossover study would strengthen their conclusions. Additionally, the paper notes that an inflammatory environment in STEMI patients may have influenced platelet activity, and in turn patient responsiveness to both drugs may have been influenced.

The study’s conclusion that poor patient response to clopidogrel or ticlopidine is often a drug specific problem suggests routine testing for clopidogrel responsiveness in future clinical trials could yield valuable clinical data on the optimal use of thienopyridines following PCI.

References


 * 1) ref1 pmid=17868803