The temporal change of clopidogrel resistance and platelet reactivity and their impact on short term prognosis in patients with acute coronary syndromes

Objectives: Antiagregan and antitrombosit drugs constitute the basis of the treatment of acute coronary syndromes. One of the goals of the antithrombosit therapy is the inhibition of the P2Y12 receptor which is the receptor of adenosine difosfate on platelets. Clopidogrel is a P2Y12 inhibitor. Combination therapy of clopidogrel and aspirin reduce the recurrence of cardiovascular events in acute coronary syndromes. Despite dual antiplatelet therapy occurence of ischemic events create a serious problem which partly can be attributed to the clopidogrel resistance issue. Clopidogrel resistance may degrade over time or changing the therapeutic strategies may overcome the clopidogrel resistance by providing more platelet inhibition. But temporal kinetics of clopidogrel resistance is an unresolved subject yet. Another important point is activated platelets in the development of ACS. Activated platelets are larger, produce more prothrombotic factors and aggregate more easily. Mean platelet volume (MPV) is a surrogate marker of platelet activation. Many studies demonstrated the association between higher MPV and ischemic events. In this study we evaluated the temporal change of clopidogrel resistance and platelet reactivity and their impact on short term prognosis in patients with ACS. Methods: The study was designed as a single centered, cross-sectional, prospective and cohort study. Ninety patients diagnosed with ACS and fulfilling the inclusion criteries were enrolled the study. Blood samples were drawn for evaluation of MPV and clopidogrel resistance after clopidogrel loading dose within 24 hours at the admission. Blood samples were drawn again at the end of one month follow up period. The results were grouped and compared as the basal and follow up values. The amount of ADP induced platelet aggregation was assessed by Multiplate aggregometer as arbitrary unit (AU), and a cut of value of 460 AU was considered as clopidogrel resistance limit. For defining the elevated MPV values, a cut of value of one standard deviation plus mean MPV value (9.33 fl) was used. Distributional adequacy was assessed by Shapiro Wilk test, the differences of averages were tested by student t test and Mann-Whitney U test, categorical data was assessed by chi square test. Bland-Altmann analysis was applied to reveal consistency of recurrent measurements. P value lower than 0.05 was considered as statistically significant. Results: The mean age of the patients was 57.4 and the majority of patients were male (83.3%). The most prevalent type of ACS was STE MI (53.3%). The mean value of MPV was 8.58±0.75 fl at the admission, 8.59±0.71 fl at the end of follow up time and this result wasn't significant (p:089). The mean AU value was 254.76±180.9 AU at the admission, 348.2±175.27 AU at the end of follow up time. The increase of clopidogrel resistance was significant (p: 0.0001). The number of patients who had elevated MPV levels was 13 at the admission and was 12 at the end of follow up period. Eleven of these 13 patients (84.6%) who had elevated MPV values at admission had normalized MPV values by the follow up period. Also the number of clopidogrel resistant patients at the admission was 11 and was 23 at the end of follow up time. The increasing number of clopidogrel resistant patients was significant (p:0.012). Differences in the distribution of MPV and AU values were analysed by Bland –Altmann method both at admission and at the end of follow up period. The agreement rate of MPV values was 96.7% and it was 94.5% for measuring clopidogrel resistance by AU values between two different sampling times. Conclusion: Our study revealed that in terms of MVP values and clopidogrel resistant patients with acute coronary syndrome experience clinically relevant and important variations during 1 month follow up. These results indicate the need for determinants of the temporal variation of clopidogrel resistance to be proven by large scaled trials Key words: Coronary artery disease, acute coronary syndrome, clopidogrel, clopidogrel resistance, mean platelet volume, platelet reactivity.