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Pharmacodynamic Effects of Switching From Ticagrelor to Clopidogrel in Patients With Coronary Artery Disease
Circulation ( IF 35.5 ) Pub Date : 2018-06-05 , DOI: 10.1161/circulationaha.118.033983
Francesco Franchi 1 , Fabiana Rollini 1 , Jose Rivas Rios 1 , Andrea Rivas 1 , Malhar Agarwal 1 , Megha Kureti 1 , Deepa Nagaraju 1 , Mustafa Wali 1 , Zubair Shaikh 1 , Maryuri Briceno 1 , Ahmed Nawaz 1 , Jae Youn Moon 1 , Latonya Been 1 , Siva Suryadevara 1 , Daniel Soffer 1 , Martin M. Zenni 1 , Theodore A. Bass 1 , Dominick J. Angiolillo 1
Affiliation  

Background: Switching between different classes of P2Y12 inhibitors, including de-escalation from ticagrelor to clopidogrel, commonly occurs in clinical practice. However, the pharmacodynamic profiles of this strategy have been poorly explored.
Methods: This was a prospective, randomized, open-label study conducted in patients on maintenance dosing (MD) of aspirin (81 mg/d) and clopidogrel (75 mg/d). After a 7-day run-in with ticagrelor (180 mg loading dose [LD] followed by 90 mg twice daily MD), patients (n=80) were randomized into 1 of 4 groups: group A, clopidogrel 600 mg LD 24 hours after the last MD of ticagrelor (C-600 mg-24h); group B, clopidogrel 600 mg LD 12 hours after the last MD of ticagrelor (C-600 mg-12h); group C, clopidogrel 75 mg/d MD 24 hours after the last MD of ticagrelor (C-75 mg-24h); and group D, ticagrelor 90 mg twice daily MD (T-90 mg twice daily). MD of the randomized treatment was maintained for 10±3 days. Pharmacodynamic assessments were performed at baseline, after run-in, and at 2, 24, 48, and 72 hours and 10 days with P2Y12 reaction units by VerifyNow; platelet reactivity index was assessed by vasodilator-stimulated phosphoprotein; and maximal platelet aggregation was determined by light transmittance aggregometry.
Results: T-90 mg twice daily led to lower platelet reactivity than any clopidogrel regimen using all assays at all time points. P2Y12 reaction unit levels were similar between the C-600 mg-24h (group A) and the C-75 mg-24h (group C) (P=0.29), including at 48 hours (primary end point; least mean difference, −6.9; 95% confidence interval, −38.1 to 24.3; P=0.66). P2Y12 reaction unit levels were lower with C-600 mg-12h (group B) than with C-75 mg-24h (group C; P=0.024). Maximal platelet aggregation over time was lower with both C-600 mg-24h (group A; P=0.041) and C-600 mg-12h (group B; P=0.028) compared with C-75 mg-24h (group C). Platelet reactivity index profiles paralleled those observed with P2Y12 reaction units. There were no pharmacodynamic differences for all tests between C-600 mg-24h (group A) and C-600 mg-12h (group B). In group C (C-75 mg-24h), platelet reactivity increased compared with baseline as early as 24 hours, reaching statistical significance at 48 and 72 hours and up to 10 days. These pharmacodynamic findings were delayed and blunted in magnitude with the administration of an LD, regardless of the timing of administration.
Conclusions: De-escalation from ticagrelor to clopidogrel therapy is associated with an increase in platelet reactivity. The use of an LD before the initiation of an MD regimen of clopidogrel mitigates these observations, although this is not affected by the timing of its administration after ticagrelor discontinuation.
Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02287909.


中文翻译:

替加格雷洛改用氯吡格雷对冠心病患者的药效学作用

背景:在临床实践中通常会在不同种类的P2Y 12抑制剂之间进行切换,包括从替卡格雷或氯吡格雷降级。但是,该策略的药效学概况尚未得到很好的研究。
方法:这是一项针对阿司匹林(81 mg / d)和氯吡格雷(75 mg / d)维持剂量(MD)的患者进行的前瞻性,随机,开放标签研究。在接受替卡格雷治疗7天(180 mg负荷剂量[LD],然后每天两次90 mg,每日两次MD)后,患者(n = 80)被随机分为4组中的1组:A组,氯吡格雷600 mg LD,24小时替卡格雷的最后一次MD治疗后(C-600 mg-24h);B组,最后一次MD替卡格雷的治疗后12小时(C-600 mg-12h)服用氯吡格雷600 mg LD;C组,最后一次MD替卡格雷的治疗后24小时(C-75 mg-24h),氯吡格雷75 mg / d。和D组,替卡格雷90毫克每天两次,MD(T-90毫克每天两次)。随机治疗的MD保持10±3天。使用P2Y在基线,磨合后以及第2、24、48和72小时10天进行药效学评估由VerifyNow提供的12个反应单元;通过血管扩张剂刺激的磷蛋白评估血小板反应性指数。并通过透光度聚集法测定最大的血小板凝集。
结果:在所有时间点使用所有测定法,每天两次T-90 mg导致的血小板反应性低于任何氯吡格雷治疗方案。在C-600 mg-24h(A组)和C-75 mg-24h(C组)之间,P2Y 12反应单位水平相似(P = 0.29),包括在48小时(主要终点;最小均值差, -6.9; 95%置信区间,-38.1至24.3;P = 0.66)。C-600 mg-12h(B组)的P2Y 12反应单位水平低于C-75 mg-24h(C组;P = 0.024)。C-600 mg-24h(A组;P = 0.041)和C-600 mg-12h(B组;P)随时间推移的最大血小板聚集率均较低= 0.028)与C-75 mg-24h(C组)相比。血小板反应性指数分布与P2Y 12反应单位观察到的相似。在C-600 mg-24h(A组)和C-600 mg-12h(B组)之间,所有测试的药效学差异均没有。在C组(C-75 mg-24h)中,血小板反应性最早于24小时与基线相比增加,在48和72小时以及长达10天时达到统计学显着性。无论何时给药,这些药效学发现均因LD的给药而延迟和减弱。
结论:从替卡格雷或氯吡格雷治疗逐步升级与血小板反应性增加有关。在开始使用氯吡格雷的MD方案之前使用LD可以缓解这些现象,尽管这不受替卡格雷停用后给药时间的影响。
临床试验注册: URL:https://www.clinicaltrials.gov。唯一标识符:NCT02287909。
更新日期:2018-06-05
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