| Objectives:To evaluate the pharmacodynamics(PD)and pharmacokinetics(PK)of ticagrelor and clopidogrel in patients with chronic kidney disease(CKD)and non ST elevation acute coronary syndrome(NSTE-ACS).Materials and methods:This is a prospective,randomized,parallel controlled design study.The patients were hospitalized in the cardiovascular department of General Hospital of Shenyang Military Region from October 2015 to December 2016.Screening will be made to select eligible participants before intervention.Patients who had not been used the P2Y12receptor antagonist within 2 weeks or P2Y12 receptor inhibitor na?ve patients presenting with NSTE-ACS(unstable angina or non-ST segment elevation mycardial infarction).Patients with estimated glomerular filtration rate(eGFR)<60 mL/min/1.73m~2(eGFR was calculated by MRDR formula)who planned percutaneous coronary intervention(PCI)(PCI will be performed over 24 hours after loading dose).Patients who meet the inclusion criteria and none of the exclusion criteria will be consented.Initial background assessments include demographics,cardiovascular risk factors,relevant medical and surgical histories,clinical characteristics,and laboratory data.Each enrolled patient was analyzed by Traditonal Chinese Medicine(TCM)dialectical analysis according to the medical history,symptoms,tongue and pulse.Enrolled patients were randomly assigned in a one-to-one ratio to receive ticagrelor or clopidogrel on top of chronic aspirin treatment.Subjects were randomized to receive ticagrelor(180 mg loading dose,then 90 mg twice daily followed)or clopidogrel(600 mg loading dose,then 75 mg qd followed)in a one-to-one ratio.All patients were given aspirin100 mg per day unless they were intolerant.For those not previously given aspirin,a loading dose of 300 mg was preferred.Platelet function assay by VerifyNow will be performed at the time of pre-dose,2 hours,8 hours,24 hours and 30 days after loading dose.Plasma concentration of ticagrelor and clopidogrel will be measured in a subgroup cohort(10 patients in each group)at presetted time frame(pre-dose,1 hour,2 hours,4 hours,8 hours,12hours and 24hours)after drug administration up to 24 hours.CYP2C19 genetype will be tested in both groups after enrollment.Clinicalfollow-up will be perforemd at 30 days.At the end of the study,data will be collected and analyzed.The primary endpoint was the P2Y12 reaction units(PRU)by Verify Now at 30 days after loading dose.The secondary endpoint included the following:PRU by VerifyNow at the time of 2 hours,8 hoursand 24 hours after loading dose;Inhibition of platelet aggregation(IPA)(calculated by the change of the PRU from baseline)at the time of 2 hours,8 hours,24hours and 30days;The relation between PRU or IPA at 30 days and kidney function.The relationship between CYP2C19 genotype and PRU at 30 days;Rate of high on-treatment platelet reactivity(HPR)at each time point(HPR was defined as PRU>208);The effect of Traditional Chinese medicine(TCM)syndrome differentiation on the PRU and IPA at 30 days after loading dose in clopidogrel and ticagrelor group;Plasma concentration of ticagrelor and clopidogrel at 1 hour,2 hours,4 hours,8 hours,12 hours and 24 hours after loading dose;Comparing the incidences of net adverse events(NACE)(Including death,myocardial,stroke,revascularization,all bleeding)at 30 days after loading dose in clopidogrel and ticagrelor group.Safety endpoint was major bleeding events(BARC 3-5 type)at 30 days.Results:1.The primary endpoint:PRU at 30 days after loading in ticagrelor group was significantly lower than that of clopidogrel group(32.6±35.3 vs.203.7±103.6,p<0.001).2.The secondary endpoint:(1)The PRU at 2 hours,8 hours and 24 hours after the loading dose in ticagrelor group was significantly lower than that of clopidogrel group(134.2±130.8 vs.275.5±275.6,p<0.001;58.1±56.5 vs.233.4±79.2,p<0.001;54.5±52.2 vs.222.4±82.1,p<0.001,respectively).The IPA at 2 hours,8 hours,24 hours and 30d after loading dose in ticagrelor was significantly higher than that of clopidogrel group(56.3±39.7 vs.8.5±1.8,p<0.001;80.5±20.1 vs.19.1±21.2,p<0.001;82.4±16.9 vs.22.6±24.4,p<0.001;87.3±10.4 vs.28.4±33.6,p<0.001).(2)PRU at 30 days after loading dose and eGFR showed negative correlation in clopidogrel group(r=-0.57,p=0.001),but PRU at 30 days and eGFR showed no correlation in ticagrelor group(r=-0.33,p=0.09).IPA at 30 days after loading dose and eGFR showed no correlation in clopidogrel group(r=0.32,p=0.09).There was no correlation between IPA at 30 days and eGFR in ticagrelor group(r=0.32,p=0.10).30 days PRU of CKD 4-5 stage(eGFR<30 mL/min/1.73m~2)was higer than that of CKD 3 stage(eGFR30-60 mL/min/1.73m~2)in clopidogrel group(CKD 4-5 stage:327.4±36.1 vs.CKD 3 stage:184.3±86.1,p=0.001).There was no significant difference in PRU at 30 days after loading dose for different CKD stage in ticagrelor group(CKD4-5 stage:56.5±3.5 vs.CKD 3 stage:38.0±61.9,p=0.68).IPA at 30days of CKD4-5 stage was significantly lower than that of CKD3 stage stages in the clopidogrel group(CKD4-5 stage:9.2±11.1%vs.CKD3 stage:29.3±33.5%,p=0.03).IPA at 30 days after loading dose showed no significant difference for different CKD stages in ticagrelor group(CKD4-5 stage:83.8±3.1%vs.87.8±16.4%,p=0.74).There was significant difference in PRU at 30 days between clopidogrel group and ticagrelor group indifferent CKDstages(p<0.001).PRU at 30days was significantly lower in ticagrelor group than that of clopidogrel group in different CKD stages(p<0.001).IPA at 30 days after loading dose in ticagrelor group was significantly higher than that of clopidogrel group in different stages(p<0.001).(3)PRUat 30 days after loading dose and CYP2C19 genotypes showed no correlation in the clopidogrel group(r=0.14,p=0.47).There was no relation in IPA at 30 days after loading dose and CYP2C19 genotypes in clopidogrel group(r=-0.24,p=0.22).There was no correlation between PRU at 30 days and CYP2C19 genotype in ticagrelor group(r=0.23,p=0.24).IPA at 30 days and CYP2C19 genotype showed no correlation in ticagrelor group(r=-0.30,p=0.13).There was no significant difference in PRU at 30 days after loading dose with or without CYP2C19*2/*3 loss of function(LOF)in clopidogrel group(206.0±103.9 vs.215.7±82.8,p=0.81).There was no statistically significant difference in PRU at 30 days after loading dose with or without CYP2C19*2/*3 LOF in ticagrelor group(46.5±64.7 vs.24.3±47.6,p=0.37).IPA at 30 days after loading dose showed no difference with or without CYP2C19*2/*3 LOF in clopidogrel group(24.5±34.6%vs.28.9±25.1%,p=0.73).There was no statistical differencein IPA at 30 days with or without CYP2C19*2/*3 LOF in ticagrelor group(84.8±17.1%vs.93.3±11.6%,p=0.19).There were statistically significant differences in PRU at 30 days between clopidogrel group and ticagrelor group with or without CYP2C19*2/*3 LOF(p<0.001).IPA at 30 days after loading dose showed significant differences between clopidogrel group and ticagrelor group with or without CYP2C19*2/*3LOF(p<0.001).(4)The incidence of HPR at 2 hours,8 hours,24 hours and 30 days after loading dose was higher in clopidogrel group was higher than that of ticagrelor group(81.5%vs.36.7%,p=0.001;65.5%vs.3.3%,p<0.001;57.1%vs.3.3%,p<0.001;54.8%vs.0,p<0.001,respectively).(5)Four TCM syndrome types were seen in enrolled patients.The syndrome types were Qi deficiency and blood stasis,phlegm obstructing the heart,Qi and Yin deficiency,heart and kidney Yin deficiency(15%,30%,37%and 18%,respectively),Phlegm obstructing heart and Qi and Yin deficiency were more common.There was no statistically significant difference in TCM syndrome type distribution for different stages of CKD(p=0.74).There were no differences in PRU or IPA at 30 days after loading dose among different syndrome types in clopidogrel or ticagrelor group(p>0.05).PRU at 30 days after loading dose in ticagrelor group was lower than that of clopidogrel group in different syndrome types(p<0.05).There was no statistical difference for the IPA at 30 days after loading dose in the patients with Qi deficiency and blood stasis(90.1±7.5%vs.44.0±38.4%,p=0.17)although it seemed that the IPA in the ticagrelor group was higher than that of the clopidogrel group.IPA at 30 days after loading dose was higher in ticagrelor group than that of clopidogrel group in the patients with phlegm obstructing the heart,Qi and yin deficiency,heart and kidney yin deficiency,respectively(83.8±10.5%vs.22.0±28.6%,p<0.001;86.6±23.2%vs.32.2±36.4%,p=0.001;92.3±7.8%vs.12.7±24.9%,p<0.001).(6)The maximum plasma concentration(Cmax)of clopidogrel after loading dose was 8.7(6.6-27.8)ng/mL ng/mL andthe Cmax of clopidogrel thiol metabolite was 8.5(6.9-15.9)ng/mL.The time of maximum plasma concentration(Tmax)for clopidogrel and clopidogrel thiol metabolite were both 2 hours.Cmax of ticagrelor was 355.0(242.5-522.0)ng/mL and Cmax of AR-C 124910XX(ticagrelor metabolite)was 63.2(50.8-85.2)ng/mL.Tmax of ticagrelor and AR-C 124910XX were both 8 hours.(7)There was no statisticallysignificant difference in the incidence of NACE at 30 days after loading dose in clopidogrel group and ticagrelor group(6.7%vs.20.0%,p=0.13)according to intention-to-treat database.Though the incidence of all bleeding in ticagrelor group was higher than that of clopidogrel group,there was no statistical difference(13.3%vs.3.3%,p=0.17).There was no statistical difference in the the incidence of BARC 3-5 type bleeding in clopidogrel group and ticagrelor group(3.3%vs.0,p=0.32).Conclusions:Ticagrelor is superior to clopidogrel in pharmacodynamics for getting better inhibition of platelet in patients of CKD and NSTE-ACS,regardless of CYP2C19 genotype,CKD stage.The metabolism of clopidogrel are affected by renal function.However,ticagrelor is not affected by renal function.Four TCM syndrome types were common which including Qi deficiency and blood stasis,Qi and Yin deficiency,Phlegm obstructing heart,heart and kidney Yin deficiency in the patients with CKD and NSTE-ACS.Among which the ratio of Qi and yin deficiency and Phlegm obstructing heart were relatively high. |
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