The Influence Of Atorvastatin Or Rosuvastatin On Antiplatelet Function Of Clopidogrel

Objective: Platelet activation, aggregation and atherothrombotic play a crucial role in acute coronary syndromes and percutaneous coronary interventions. Clopidogrel inhibits platelet P2Y12 Adenosine diphosphate (ADP) receptor, thus preventing ADP-induced platelet aggregation. Clopidogrel can significant decrease adverse cardiovascular events and the incidence of stent reocclusion in combination with aspirin.Statins have the effection of anti-cholesterol as well as slowing atherosclerosis progression. Many clinical trails have demonstrated that statins can decrease the incidence of cardiocerebral vascular events. Statins are frequently given in conjunction with clopidogrel for therapy of acute coronary syndromes.Clopidogrel is an inactive thienopyridine prodrug. In order to exert its antiplatelet action, clopidogrel requires conversion in the liver into an active metabolite in vivo through cytochrome (CY) P450, mainly theisoenzyme CYP3A4 and CYP3A5. Some statins, such as atorvastatin, lovastatin, simvastatin and cerivastatin, were found to metabolize by the liver cytochrome P3A4. So some researchers thought that it was possible for the statins to reduce the metabolism of clopidogrel to its active metabolite and attenuate its antiplatelet function.Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4). Rosuvastatin is metabolized by CYP2C9 slowly, almost not by CYP3A4. In this random control study, we compared the influence of two statins, which are metabolized through different enzyme, on antiplatelet function of clopidogrel.Methods: A total of 60 patients who were diagnosed as coronary heart disease in the second hospital of Hebei Medical University were enrolled between February 2008 and August 2008. 41 patients were with unstable angina and 19 patients were with ST or non-ST elevated acute coronary syndromes. The criteria for exclusion include as the followings: platelet count>300×109/L or<100×109/L; high risk of bleeding tendency; contraindication to aspirin, clopidogrel, statins and low molecular weight heparin; receiving the therapy of statins, or antagonist of platelet membrane glycoproteinⅡb/Ⅲa receptor or clopidogrel within a month.All the patients received standard antiplatelet treatment including aspirin 100 mg/d, clopidogrel 75mg/d and low molecular heparin 5000U/12h by hypodermic injection for five days. Five days after receiving the above medications, patients were randomized to receive atorvastatin 20mg/d as atorvastatin group (n = 30), rosuvastatin 10mg/d as rosuvastatin group (n = 30). Blood samples were obtained at the day before clopidogrel therapy, the day before statin therapy and 3 days after statin therapy. Platelet aggregation was measured with whole blood impedance method induced by adenosine diphosphate (ADP) at 5, 10, and 20μmol/L with a mobile four-channel impedance aggregometer (Chronolog-Log Corporation), which allowed measurement of aggregation beginning 1 hour after blood sampling.Statistical analysis: Continuous variables were expressed as the mean value±standard deviation (SD). Categorical variables were summarized as frequency and compared using chi-square test. Student's t-test was performed to determine the differences between the two groups. The comparison of determination values before and after administration was evaluated by repeated measure variance analysis. All the statistical analysis was performed using the Statistical Package for Social Sciences software (SPSS13.0). Statistical significance was defined as P<0.05.Results: Baseline clinical characteristics and levels of The maximal platelet aggregation rate (MPAR) at the baseline were comparable between two groups(all P>0.05,Table 1,2). After 5-day clopidogrel treatment, the platelet aggregation induced by ADP was lower than before. But after 3-day statin treatment, atorvastatin in addition to clopidogrel led to a small increase to platelet aggregation, and rosuvastatin led to a small decrease, which was not significant. (all P>0.05). The comparation of MPAR between two groups for the three time points was not significantly different (all P>0.05).Conclusion: Neither atorvastatin (CYP3A4-MET) nor rosuvastatin (non-CYP3A4-MET) attenuated the antiplatelet effects of clopidogrel in the early days during short-term co-medication. And no significant difference was found for antiplatelet effects of clopidogrel between atorvastatin and rosuvastatin.