Registered Clinical Research For Patients With Clopidogrel Resistance In Acute Myocardial Infarction And In-stent Restenosis (Trial Registration No.ChiCTR-RCS-14004303)

Background/Objects: In acute myocardial infarction(AMI),in-stent restenosis recurrence,with poor response to clopidogrel,patients of high-risk cardiovascular disease groups,have been facing the choice antiplatelet therapy between increasing the dosage of clopidogrel,and switching to new oral antiplatelet drug-ticagrelor.However,there is now still lack of evidence of evidence-based medicine in this regard.By testing the platelet function in cases of AMI or in-stent restenosis,clopidogrel resistance patients were as objects of the study,to explore the clinical characteristics of resistance patients and prediction factors.Meanwhile,analysis and comparison of the antiplatelet effect were done between double-dose clopidogrel and ticagrelor,in order to provide experimental basis for establishment of scientific and rational antiplatelet therapeutic regimen.Method: From April 2014 to November 2014,a series of 102 patients were included for AMI and in-stent restenosis.After receiving standard dose clopidogrel therapy,platelet function were evaluated by devices as VerifyNow,TEG,VASP and PL-11,and simultaneously,blood samples were collected for CYP2C19(*2,*3,*17),ABCB1 genetic testing.Of these,VerifyNow device was set as gold standard.P2Y12 reaction units(PRU)?208 were defined as clopidogrel resistance or high on-clopidogrel treatment platelet reactivity(HTPR).The clopidogrel resistance patients were randomized in a 1:1 ratio to receive either a double-dose clopidogrel of 150 mg daily or a loading-dose ticagrelor of 180 mg followed by 90 mg twice daily using a computer-generated randomisation table.A second platelet function measurement was carried out 24 hours later in patients who received an alternate treatment.Patients who exhibited HTPR after being treated with double-dose clopidogrel were switched to 90 mg ticagrelor twice daily,and a third platelet function measurement was performed 24 hours after administration of ticagrelor.Results: 1.Of the 102 consecutive patients who were on the standard dose of clopidogrel therapy,48(47.06%)were detected to have HTPR,with PRU ? 208.2.Baseline characteristics,gene polymorphism,laboratory characteristics and angiographic characteristics were similar in clopidogrel resistance(n=48)and clopidogrel nonresistance group(n=54).There were signifiant diffrences between treatment groups with regard to gender(P<0.05),age(P<0.01),urea nitrogen(P<0.05),hemoglobin(P<0.01),CK-MB(P < 0.05),GRACE score(P < 0.05)and CYP2C19*2 homozygote genotype(P<0.05).There were correlation between clopidogrel resistance and factors as age,gender,urea nitrogen,glomerular filtration rate,red blood cell count,hemoglobin,GRACE score,GRUSADE score and CYP2C19*2 homozygote genotype.In the further logistic regression analysis,GRACE score,urea nitrogen,CYP2C19*2 homozygote genotype were found to be possibly predictors of clopidogrel resistance(P < 0.05).3.Significantly higher PR values were found in CYP2C19*2 allele carriers than in the non-carriers(P < 0.05),especially in CYP2C19*2 homozygotes.Double-dose clopidogrel significantly reduce platelet reactivity among CYP2C19*2 heterozygotes(P<0.05)but not CYP2C19*2 homozygotes.By contrast,ticagrelor was able to achieve effective antiplatelet function even among the CYP2C19*2 homozygotes which showed no response to high-dose clopidogrel(PRU value 252.40 ± 15.71 vs.11.00 ± 17.90,P<0.05).4.Baseline characteristics,laboratory characteristics and angiographic characteristics were not statistically different between double-dose clopidogrel and ticagrelor groups.After 24 hours,ticagrelor was associated with a significantly lower platelet reactivity than high-dose clopidogrel(44.38 ± 40.26 vs.212.58 ± 52.34 PRU,P<0.01).No patient receiving ticagrelor exhibited HTPR,whereas 15(62.50%)patients after treatment with high-dose clopidogrel remained HTPR(P< 0.05).5.Analysis and comparison by four different methods of platelet function testing,the platelet inhibition ratio detected by VerifyNow was shown to have positive correlation with that by TEG(r=0.234,P < 0.05).By contrast,there were negative correlation between VerifyNow and platelet reactivity index(PRI)measured by VASP or maximum platelet aggregation rate(MAR)by PL-11(r=-0.299,P < 0.01;r=-0.330,P < 0.01).Correlation was also observed between VerifyNow and another indicator—MA-ADP of TEG.The diagnostic values of the detection methods for HTPR were reviewed by applying ROC,the area under ROC curve of PL-11 was 0.644.Conclusion: The present results provide clinical evidence that,Urea nitrogen,GRACE score,CYP2C19*2 homozygote genotype may be independent clopidogrel resistance impact factors.Meanwhile confirmed the importance of CYP2C19*2homozygous genotype as a reliable predictor in the selection of antiplatelet therapy.Ticagrelor is significantly more effective as compared with high-dose clopidogrel in overcoming HTPR and could achieve adequate antiplatelet function irrespective of CYP2C19*2 genotype.TEG,VASP,PL-11 platelet function testing system all showedcorrelation with the "gold standard" VerifyNow in their testing results to some extent,of which PL-11 has the highest sensitivity and specificity.