| BackgroundClopidogrel is an inhibitor of P2Y12receptor on the platelet membranin, which blocks its combination with adenosine diphosphate (ADP) to restrain the platelet aggregation. Clopidogrel is administered with aspirin to prevent the recurrent ischemia events in patients suffered from coronary heart disease after percutaneous coronary intervention. It has been demonstrated recently that the dual anti-platelet therapy strategy cannot completely avoid cardiac ischemia events after coronary stent implantation, the residual risk may be related to the insufficient response to the anti-platelet medication, especially because of the individual variability response of clopidogrel.The metabolic enzyme encoded by CYP2C19plays a pivotal role in active metabolite transformation of clopidogrel through CYP450enzymes in the liver. Patients carried loss-of-function (LOF) allele of CYP2C19do not response well to clopidogrel and may experience a higher risk of stent thrombosis and major adverse cardiovascular events than non-carriers. Results of platelet function test and CYP2C19genotype are considered to be manifestations of individual response to clopidogrel and widely used in clinical trials during anti-platelet therapy strategy decision making. However, none of recent prospective studies showed a positive result when individual anti-platelet strategy was randomly administered in patients with high on-treatment platelet reactivity.The RDPAC study aimed to evaluate the impact of CYP2C19genotype, clopidogrel pretreatment dose, and PCI procedure to the platelet aggregation, as well as the predict value of long-term clinical outcome by the genotyping of CYP2C19and phenotyping of platelet function, in order to find the evidence based medicine for optimal clopidogrel therapeutic model.Part1:Impact of clopidogrel pretreatment dose and CYP2C19genotype on platelet aggregation prior to PCI and cardiac enzymes after PCI in patients with coronary heart disease ObjectivesTo evaluate the platelet inhibition effect difference between the two clopidogrelpretreatment strategies:300-mg loading dose (LD) in clopidogrel naive patients or75-mg maintenance dose (MD) in patients received chronic clopidogrel therapy in CHD patients with different CYP2C19genotypes.MethodsCHD patients administered in Fuwai hospital undergoing elective PCI during May2012to May2013were assigned to2X2groups according to different clopidogrel pretreatment strategies (470patients in the LD group versus370patients in the MD group) and CYP2C19genotypes (494carriers of any CYP2C19*2or*3LOF allele versus346non-carriers). The primary outcome was platelet aggregation (PA) as measured by the10μmol/L ADP induced light transmission aggregation prior to PCI and cardiac enzymes (cTNl and CK-MB) after PCI between the different groups.Results1. Compared with the MD group, the LD strategy showed a significantly higher on-treatment PA (59.22±11.67%vs.52.83±12.17%, P<0.001), similar PA difference was observed in the CYP2C19loss-of-function carriers compared with the non-carriers (59.41110.91%vs.52.10%±12.90%P<0.001).2. Patients treated with the LD strategy in either the CYP2C19loss-of-function allele carrier or non-carrier group showed a significantly higher PA compared with the MD group (61.50±10.61%vs.56.84±10.74%, P<0.001;56.06±12.34%vs.46.88±11.78%, P<0.001, respectively), a quantitative interaction effect was observed between the clopidogrel pre-treatment strategy and CYP2C19genotype (P=0.001).3.371patients received coronary stent implantation, both cTNl and CK-MB levels were not significantly different between groups defined by clopidogrel pretreatment strategy or CYP2C19genotype (P>0.05). Part2:Impact of coronary angiography and stent implantation on platelet aggregation in CHD patients under chronic clopidogrel therapyObjectives To evaluate the impact of coronary angiography and stent implantation procedureon platelet aggregation in CHD patients under chronic clopidogrel therapy.Methods CHD patients administered in Fuwai hospital who had been treated with clopidogrel (75mg/day) and aspirin (100mg/day) for at least7consecutive days undergoing elective PCI were prospectively enrolled during May2012to May2013. Based on whether a coronary stent was implanted, all of the included patients were divided into two groups:the coronary angiography (CAG) group and the coronary stent implantation (CSI) group. The differences in PA as measured by the10μmol/L ADP induced light transmission aggregation between the preoperative baseline level and the level at24hours after the procedures in both patient groups were determined.Results1. A total of343patients receiving coronary intervention were enrolled in this study, including173patients in the CAG group and170patients in the CSI group.2. Compared with the preoperative baseline, there was no significant difference in PA after the operation in the CAG group (54.21111.44%vs.53.15±11.80%, P=0.062), while a significant postoperative PA increase was observed in the CSI group (55.59110.47%vs.52.47111.97%, P<0.001).3. Compared with the CAG group, the PA increase in the CSI group was significantly greater (the mean PA increase was2.07%,95%CI:0.40%to3.74%; P=0.010).4.66patients received repetitive PA testing30days after coronary stent implantation, which is significantly lower than the PA24hours after PCI (54.71±11.64%vs.56.68±10.21%, P=0.019) and comparable with the baseline PA before procedure (54.71±11.64%vs.54.26±12.23%, P=0.901) in this subgroup.Part3:Grouping by the phenotype vs. genotype for prediction of clinical efficacy and safety in patients received clopidogrel underwent PCIObjectivesTo evaluate the predictive value of both CYP2C19genotype and platelet function phenotype grouping in clinical outcome and bleeding events of patients received clopidogrel underwent PCI.MethodsCHD patients administered in Fuwai hospital underwent elective PCI and received coronary stent implantation were prospectively enrolled during October2012to May2013. Patients were assigned into groups by genotype of CYP2C19(extensive metabolizers, intermediate metabolizers, and poor metabolizers) and phenotype of platelet function (clopidogrel responders, semi-responders, and non-responders). The rates of major adverse cardiovascular events, cardiovascular symptom events, and bleeding events were recorded during a follow-up period until6months after the last patient first visit and compared among the groups defined previously.Results1.380patients received coronary stent implantation were enrolled in this study, including157(41.3%) clopidogrel extensive metabolizers,176(46.3%) intermediate metabolizers, and47(12.4%) poor metabolizers according to the genotype grouping;98(25.8%) were responders to clopidogrel,149(39.2%) were semi-responders, and133(35.0%) were non-responders according to the phenotype grouping.2. The highest cardiovascular symptom events rate was observed in the poor metabolizers (34.0%) as compared to the intermediate metabolizers (19.1%, HR=2.126,95%CI1.131～3.997, P=0.019) and the extensive metabolizers (15.4%, HR=2.772,95%CI1.359～5.655, P=0.005) when grouping by the CYP2C19genotype, without a statistical difference of the major adverse cardiovascular events rate or bleeding events rate.3. The highest bleeding events rate was observed in the clopidogrel responders (32.7%) as compared to the semi-responders (19.0%, HR=1.919,95%CI1.009～3.650, P=0.047) and non-responders (18.3%, HR=2.119,95%CI1.045～4.292, P=0.037) when grouping by the platelet function phenotype, without a statistical difference of the major adverse cardiovascular events rate or cardiovascular symptom events rate.Conclusions1. The300-mg LD strategy results in a decreased effect on platelet inhibition compared with the75-mg MD in Chinese patients receiving clopidogrel prior to PCI, interacted with the CYP2C19*2or*3LOF allele carriage. The platelet function difference due to clopidogrel pretreatment strategy cannot affect the cardiac enzyme level after PCI.2. Coronary stent implantation causes a transient increased ADP-induced PA, while the coronary angiography procedure does not. The result of platelet function test before PCI is in accordance with the effect of long term anti-platelet medication in patients received chronic clopidogrel therapy.3. Genotyping of CYP2C19is a better predictor of cardiovascular symptom events, while phenotyping of platelet response to clopidogrel is a better predictor of bleeding events in CHD patients received coronary stent implantation. Further study design and clinical practice should take into account both in anti-platelet therapy strategy decision and long term prognosis prediction. |
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