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- Yaling Han1
Pivotal clinical trials found ticagrelor reduced ischemic complications to a greater extent than clopidogrel and what is more, the benefit gradually increased with the reduction on creatinine clearance. However, the underlying mechanisms remains poorly explored. The current study aimed to compare the pharmacodynamic(PD)/ pharmacokinetic(PK) characters of ticagrelor and clopidogrel in patients with Non–ST-Elevation Acute Coronary Syndromes (NSTE-ACS) and moderate to severe chronic kidney disease(CKD).
This is a single-center, prospective, randomized clinical trial designed to involve 60 P2Y12 inhibitor naïve patients with CKD (eGFR<60ml/min/1.73m2) and NSTE-ACS in General hospital of Shenyang Military Region between October 2015 and December 2016. Eligible patients were randomly assigned in a 1:1 ratio to receive ticagrelor(180 mg loading dose, then 90 mg twice daily followed) or clopidogrel (600 mg loading dose, then 75 mg qd followed) on top of chronic aspirin treatment. The primary endpoint was the P2Y12 reactive unit (PRU) by VerifyNow at 30 days after randomization. Plasma concentration of ticagrelor and clopidogrel and its active metabolite was measured in first 10 patients in each group at presetted time frame of baseline, and 1h,2h,4h,8h,12h and 24h after drug administration.
Baseline characteristics were well matched between the two groups. Our results indicated a markedly lower PRU and higher inhibition of platelet aggregation(IPA) in patients treated with ticagrelor vs. clopidogrel at 30 days (P<0.001), as well as any other time point of 2, 8, 24h after loading does(P<0.001). HPR was found in 58.6% patients with clopidogrel while none with ticagrelor at 30 days(P<0.001). No significant correlation was found between eGFR or CYP2C19 and 30-day IPA in either ticagrelor or clopidogrel group(P>0.05). Ticagrelor and its active metabolite AR-C124910XX showed similar Tmax(h) of 8h, with Cmax(ng/ml) of 355(242.50-522.00) and 63.20(50.80-85.15), respectively. Clopidogrel and CAMD both approached maximal plasma concentration at 2 hours,with close Cmax(ng/ml) of 8.67(6.64-27.75) vs 8.53(6.94-15.93).
Ticagrelor showed much more potent platelet inhibition in comparison of clopidogrel in patients with moderate to severe CKD and NSTE-ACS. Among such population, activation of ticagrelor was uninfluenced while biotransformation of clopidogrel might be inhibited.