Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.
Gurbel PA Bliden KP ， Butler K Tantry US ， Gesheff T Wei C Teng R Antonino MJ ，Patil SB Karunakaran A Kereiakes DJ Parris C Purdy D Wilson V Ledley GS Storey RF
Sinai Center for Thrombosis Research， Cardiac Catheterization Laboratory， 2401 W Belvedere Ave.， Baltimore， MD 21215， USA
Abstract
BACKGROUND: Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel.
METHODS AND RESULTS: In a multicenter， randomized， double-blind study， 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load， 90-mg BID maintenance dose [n=57])， clopidogrel (600-mg load， 75-mg/d maintenance dose [n=54])， or placebo (n=12) for 6 weeks. Greater IPA (20 micromol/L ADP， final extent) occurred with ticagrelor than with clopidogrel at 0.5， 1， 2， 4， 8， and 24 hours after loading and at 6 weeks (P<0.0001 for all); by 2 hours after loading， a greater proportion of patients achieved >50% IPA (98% versus 31%， P<0.0001) and >70% IPA (90% versus 16%， P<0.0001) in the ticagrelor group than in the clopidogrel group， respectively. A faster offset occurred with ticagrelor than with clopidogrel (4-to-72-hour slope [% IPA/h] -1.04 versus -0.48， P<0.0001). At 24 hours after the last dose， mean IPA was 58% for ticagrelor versus 52% for clopidogrel (P=NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo (P=NS).
CONCLUSIONS: Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation.
背景 Ticagrelor是第一种可逆的结合P2Y12受体拮抗剂。研究比较用PLATO（PLATelet抑制剂和病人预后）采用的ticagrelor负荷剂量180mg的血小板抑制作用（IPA）的起、止，与波立维的大负荷剂量比较。
方法与结果 这是一项多中心、随机化、双盲的研究，123例服阿司匹林（75～100mg/d）的稳定性冠心病病人，接受ticagrelor（180mg负荷剂量，维持量90mg BID，n=57）。波立维-(负荷量600mg，维持量75mg/天，n=54)或安慰剂（n=12）共6周。负荷后0.8、1、2、4、8、24小时和6周时ticagrelor IPA（20μmol/L ADP，最后范围）优于波立维（均P＜0.0001）。负荷后2小时，ticagrelor组＞50 IPA（分别为98%及31%，P＜0.0001），IPA＞70%（分别为90%及16%，P＜0.0001）优于波立维组；ticagrelor组生效较快（4～72小时坡度 % IPA/n-1.04及-0.48，P＜0.0001）。最后剂量24小时后，ticagrelor组平均IPA为58%，波立维52%（P=N），ticagrelor最后剂量后3天时的IPA与波立维5天时相同，前者7天时与IPA与后者5天时相同，与安慰剂无差异。
结论 ticagrelor的血小板抑制快于、强于大负荷剂量的波立维，在维持阶段持续。停药后，作用消退较快