Clopidogrel Resistance, Low Response Not Clearly Defined
Resistance can lead to stent thrombosis, inflammation, post-PCI ischemic events, post-PCI myonecrosis.
Clopidogrel resistance is an important predictor of adverse cardiovascular events, but resistance or nonresponsiveness has not been clearly defined.
“There are a series of definitions in the literature, and obviously when we’re working with different definitions, we’re going to have a different prevalence of clopidogrel [Plavix, Bristol-Myers Squibb] response or nonresponse,” said Dominick J. Angiolillo, MD, Associate Director of Cardiovascular Research at the University of Florida School of Medicine.
Angiolillo highlighted five published papers that each have a different definition of nonresponsiveness or low responsiveness to clopidogrel: an absolute change in platelet aggregation from baseline of less than 10%; a relative change in platelet aggregation from baseline of less than 10%; the lowest quartile of relative reduction of platelet aggregation; a platelet aggregation two standard deviations below the mean; and a relative change in platelet aggregation from baseline of less than 40%.
Varying definitions can lead to differences in rate measurements of 6% to 35%. “The definition of clopidogrel resistance is more than just a laboratory curiosity,” Angiolillo said. Clopidogrel resistance can lead to stent thrombosis, inflammation, post-PCI ischemic events or post-PCI myonecrosis.
Factors in poor response
Several factors contribute to variability in clopidogrel response, Angiolillo said. Low response can be attributed clinically to failure to prescribe or patient noncompliance. The dose may be too low or be poorly absorbed. Patients with acute coronary syndromes, diabetes mellitus, insulin resistance or elevated body mass index may respond poorly to clopidogrel, Angiolillo said.
Several genetic factors, including polymorphisms of CYP3As, GPIa, P2Y12 or GPIIIa, can contribute to clopidogrel resistance. Angiolillo listed cellular factors that play a role in clopidogrel response variability: accelerated platelet turnover; reduced CYP3A metabolic activity; increased ADP exposure; upregulation of the P2Y12 pathway; upregulation of the P2Y1 pathway; and upregulation of other P2Y-independent pathways.
Increasing the clopidogrel dose may reduce resistance and improve outcome, Angiolillo said. In ARMYDA-2 (Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty), patients assigned 300-mg clopidogrel had a 12% rate of death, myocardial infarction (MI) and target vessel revascularization at 30 days compared with a 4% rate among patients assigned the 600-mg dose (P = .041).
CURRENT/OASIS 7 trial
Angiolillo said the CURRENT/OASIS 7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions) trial is enrolling patients with unstable angina or non-ST elevation MI with a planned early invasive strategy. The trial will investigate efficacy of a higher vs. a lower loading dose of clopidogrel.
In the trial, patients will be randomized to either a 600-mg loading dose followed by 150 mg from day 2 to day 7 and 75 mg from day 8 to day 30, or a 300-mg loading dose of clopidogrel followed by 75 mg from day 2 to day 7 and 75 mg from day 8 to day 30.
“The novelty in this trial is the higher maintenance dose of clopidogrel,” Angiolillo said.