Pharmacodynamics and pharmacokinetics of ticagrelor vs. clopidogrel in patients with acute coronary syndromes and chronic kidney disease

BackgroundPivotal clinical trials found that ticagrelor reduced ischaemic complications to a greater extent than clopidogrel, and also that the benefit gradually increased with the reduction in creatinine clearance. However, the underlying mechanisms remains poorly explored. MethodsThis was a single-centre, prospective, randomized clinical trial involving 60 hospitalized Adenosine Diphosphate (ADP) P2Y12 receptor inhibitor-naive patients with chronic kidney disease (CKD) (estimated glomerular filtration rate <60ml min(-1) 1.73m(-2)) and non-ST-elevation acute coronary syndromes (NSTE-ACS). Eligible patients were randomly assigned in a 1:1 ratio to receive ticagrelor (180mg loading dose, then followed by 90mg twice daily) or clopidogrel (600mg loading dose, then followed by 75mg once daily). The primary endpoint was the P2Y12 reactive unit (PRU) value assessed by VerifyNow at 30days. The plasma concentrations of ticagrelor and clopidogrel and their active metabolites were measured in the first 10 patients in each group at baseline, and at 1h, 2h, 4h, 8h, 12h and 24h after the loading dose. ResultsBaseline characteristics were well matched between the two groups. Our results indicated a markedly lower PRU in patients treated with ticagrelor vs. clopidogrel at 30days (32.6 11.29 vs. 203.7 +/- 17.92; P < 0.001) as well as at 2h, 8h and 24h after the loading dose (P < 0.001). Ticagrelor and its active metabolite AR-C124910XX showed a similar time to reach maximum concentration (C-max) of 8h, with the maximum concentration (C-max) of 355 (242.50-522.00) ng ml(-1)and 63.20 (50.80-85.15) ng ml(-1), respectively. Both clopidogrel and its active metabolite approached the C-max at 2h, with a similar C-max of 8.67 (6.64-27.75) ng ml(-1)vs. 8.53 (6.94-15.93) ng ml(-1). ConclusionTicagrelor showed much more potent platelet inhibition in comparison with clopidogrel in patients with CKD and NSTE-ACS.