The Prevalence, Risk Factors And Management Strategy Of Clopidogrel Resistance In Patients With Coronary Heart Disease

Objective: Platelet activation and aggregation play an important role in the pathogenesis of arterial thrombosis leading to acute coronary syndromes. Clopidogrel is a new orally administered thienopyridine derivative that selectively and irreversibly inhibits ADP-induced platelet aggregation, is widely used antithrombotic agent in clinical practice, play a major role in acute coronary syndromes (ACS). Clopidogrel specifically inhibits ADP-dependent platelet activation by acting on the P2Y12 receptor on platelets, preventing ADP mediated up regulation of the glycoprotein (GP)Пb/Шa receptor as part of the implication phase of platelet activation, inhibit fibrinogen binding and hence platelet aggregation. Clopidogrel has been proven effective in preventing ischemic events in patients with atherosclerotic vascular disease. The CURE study (Clopidogrel in Unstable angina to prevent Recurrent Events) showed that combination antiplatelet therapy with clopidogrel and aspirin reduces ischemic events compared with aspirin monotherapy. It has a favorable profile of side effects and exhibits faster antiplatelet activities, and has already been used in patients with ACS and undergoing coronary stent implantation. However, many studies had found that there were still some patients did not benefit from it, some individuals had weak response to clopidogrel and some subjects even have no response. This phenomenon is described as clopidogrel resistance.The mechanisms of clopidogrel resistance are multifactorial, including inter-individual variability, drug-drug interactions, genetic polymorphisms of platelet, the baseline response of platelet and so on. Because the differences of testing methods, sample size, laboratory conditions, measurement targets and standard of definition, the prevalence of clopidogrel resistance is variability. Currently, there is no clear and consensual definition of what clopidogrel resistance means, and the main method is to increase the dose of clopidogrel or change of other drugs for clopidogrel low-response patients.The aim of this current study is to observe the efficacy of clopidogrel, to investigate the prevalence and influential factors of clopidogrel resistance in patients with coronary heart disease, explore the management strategy of clopidogrel resistance by measuring ADP (10 and 20μmol/L) induced platelet aggregation, the expression of sCD40L and CD62P in plasma from coronary heart disease patients.Methods: A total of 130 coronary heart disease patients were selected between December 2007 and October 2008, including 93 males and 37 females, with a mean age of 60.09±12.00 years. Blood samples were obtained through venipuncture before clopidogrel administration (baseline) and at 5 days after clopidogrel administration, for measuring platelet aggregation, the expression of sCD40L and CD62P in plasma by ELISA. According to the value change of platelet aggregation prior to and 5 days after clopidogrel administration, patients were divided into clopidogrel resistance group and non-clopidogrel resistance group. The nonresponders were randomly divided into two groups, the maintenance dose group and the high dose group, platelet aggregation and the expression of sCD40L and CD62P in plasma were tested at 5 days after drugs management. Continuous variables were expressed as the mean value±standard deviation (SD), categorical variables were summarized as percentages (%), and categorical variables were compared using chi-square test. Independent-samples t test was performed to determine the differences between two groups. Paired-samples t test was performed to compare differences for platelet aggregation, sCD40L and CD62P in the clopidogrel maintenance dose group and high dose group. The influence of clinical baseline factors was evaluated by stepwise logistic regression analysis. A p value of < 0.05 was considered statistically significant. Results: Clopidogrel resistance was defined by an inhibition of ADP (10 and 20μmol/l) induced platelet aggregation that was less than 10% when compared to baseline values after clopidogrel intake. Among the 130 patients, 19(14.62%) patients were found clopidogrel resistance by measuring ADP (20μmol/L) induced platelet aggregation. 21(16.15%) nonresponders were found by measuring 10μmol/l ADP induced platelet aggregation. 109(83.85%) patients had non- clopidogrel resistance that the platelet aggregation decrease≥10% than baseline. The platelet aggregation decreased between 10% and 29% in 9 (6.92%) patients. Among 19 non-responders that management by drugs, 8(6.15%) patients had no response to clopidogrel after 5 days, there were 5 patients had 75 mg of clopidogrel and 3 patients had 150 mg everyday.The baseline characteristics such as age, smoking history, drinking history, hypertension, diabetes mellitus, and blood fat were not significantly different between clopidogrel resistance group and non-clopidogrel resistance group. The concomitant drug use did not differ significantly between the two groups, including PPI, statins, ACEI, CCB, andβ-receptor block agent. But gender was significant differences between the two groups, the females had higher prevalence.There were no significant differences between clopidogrel resistance group and non-clopidogrel resistance group with respects to baseline platelet aggregation, plasma level of sCD40L and CD62P. After 5 days, there were significant differences between the two groups, platelet aggregation, plasma level of sCD40L and CD62P in clopidogrel resistance group were higher than that in non-clopidogrel resistance group.Clopidogrel resistance patients (19) were managed by two doses; there were no significant differences between clopidogrel maintenance dose group and high dose group with respects to platelet aggregation, plasma level of sCD40L and CD62P after 5 days. In high dose group, platelet aggregation, plasma level of sCD40L and CD62P were significant lower than the baseline level. But ADP induced platelet aggregation has no significant differences in maintenance dose group, only plasma level of sCD40L and CD62P were significant lower than the baseline level.Conclusions: It was found that statins and other commonly used drugs can't influence the antiplatelet effect of clopidogrel. ADP induced platelet aggregation was a simple, shortcut and the best of specificity index to reflect the ant-platelet effective, can work for monitoring therapeutic effect of clopidogrel in clinical.The clopidogrel-induced platelet inhibition is dose-and time-dependent. Increasing the dose of clopidogrel will improve the antiplatelet effect, degrade the prevalence of clopidogrel resistance, so, it is an effective method that can prevent and cure clopidogrel resistance.