Francesco Franchi, Fabiana Rollini, Latonya Been, Naji Maaliki, Patrick Abou Jaoude, Andrea Rivas, Xuan Zhou, Sida Jia, Maryuri Briceno, Chang Hoon Lee, Andres M Pineda, Siva Suryadevara, Daniel Soffer, Martin M Zenni, Theodore A Bass, Dominick J Angiolillo
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How CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor maintenance dose regimens in patients with DM is unknown.</p><p><strong>Methods and results: </strong>In this randomized, crossover study, patients with DM on treatment with dual antiplatelet therapy (aspirin and clopidogrel) were stratified according to CKD status and randomized to ticagrelor 90 or 60 mg bid. PK/PD assessments were performed at baseline, after 7-10 days of ticagrelor (peak and trough), and after 7-10 days of alternative ticagrelor regimen (peak and trough). PK assessments included plasma concentrations of ticagrelor and its major metabolite. PD assessments included vasodilator-stimulated phosphoprotein (VASP)-platelet reactivity index (PRI), VerifyNow P2Y12, and light transmittance aggregometry (LTA). A total of 92 patients with DM (CKD, n = 44; non-CKD, n = 48) were randomized. Levels of platelet reactivity were lower with the 90 mg compared with the 60 mg ticagrelor dose, which was statistically significant in non-CKD but not in CKD patients for most PD measures. There were no significant differences in the primary endpoint (trough levels of VASP-PRI following ticagrelor 90 mg dosing) between cohorts (31 ± 20 vs. 25 ± 14; P = 0.105). VerifyNow and LTA provided similar findings. PK assessments tracked PD profiles showing increased plasma concentrations of ticagrelor and its major metabolite in CKD compared to non-CKD patients.</p><p><strong>Conclusion: </strong>In patients with DM, although ticagrelor maintenance dose regimens (60 and 90 mg) yield potent P2Y12 inhibition, levels of platelet reactivity tended to be higher and subject to broader variability in non-CKD compared with CKD patients.</p><p><strong>Clinical trial registration: </strong>http://www.clinicaltrials.gov Unique Identifier: NCT02539160.</p>","PeriodicalId":11995,"journal":{"name":"European Heart Journal — Cardiovascular Pharmacotherapy","volume":" ","pages":"452-461"},"PeriodicalIF":0.0000,"publicationDate":"2022-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":"{\"title\":\"Impact of chronic kidney disease on the pharmacodynamic and pharmacokinetic effects of ticagrelor in patients with diabetes mellitus and coronary artery disease.\",\"authors\":\"Francesco Franchi, Fabiana Rollini, Latonya Been, Naji Maaliki, Patrick Abou Jaoude, Andrea Rivas, Xuan Zhou, Sida Jia, Maryuri Briceno, Chang Hoon Lee, Andres M Pineda, Siva Suryadevara, Daniel Soffer, Martin M Zenni, Theodore A Bass, Dominick J Angiolillo\",\"doi\":\"10.1093/ehjcvp/pvab042\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aims: </strong>Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk of atherothrombotic events. Ticagrelor reduces ischaemic events compared to clopidogrel, with the greatest risk reduction in patients with both DM and CKD. How CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor maintenance dose regimens in patients with DM is unknown.</p><p><strong>Methods and results: </strong>In this randomized, crossover study, patients with DM on treatment with dual antiplatelet therapy (aspirin and clopidogrel) were stratified according to CKD status and randomized to ticagrelor 90 or 60 mg bid. PK/PD assessments were performed at baseline, after 7-10 days of ticagrelor (peak and trough), and after 7-10 days of alternative ticagrelor regimen (peak and trough). PK assessments included plasma concentrations of ticagrelor and its major metabolite. PD assessments included vasodilator-stimulated phosphoprotein (VASP)-platelet reactivity index (PRI), VerifyNow P2Y12, and light transmittance aggregometry (LTA). A total of 92 patients with DM (CKD, n = 44; non-CKD, n = 48) were randomized. Levels of platelet reactivity were lower with the 90 mg compared with the 60 mg ticagrelor dose, which was statistically significant in non-CKD but not in CKD patients for most PD measures. There were no significant differences in the primary endpoint (trough levels of VASP-PRI following ticagrelor 90 mg dosing) between cohorts (31 ± 20 vs. 25 ± 14; P = 0.105). VerifyNow and LTA provided similar findings. 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引用次数: 2
摘要
目的:糖尿病(DM)和慢性肾脏疾病(CKD)患者发生动脉粥样硬化血栓事件的风险增加。与氯吡格雷相比，替格瑞洛减少了缺血性事件，在DM和CKD患者中风险降低最大。CKD状态如何影响不同替格瑞洛维持剂量方案对DM患者的药效学(PD)和药代动力学(PK)谱尚不清楚。方法和结果:在这项随机交叉研究中，DM患者接受双重抗血小板治疗(阿司匹林和氯吡格雷)，根据CKD状态分层，随机选择替格瑞洛90或60 mg bid。在基线、替格瑞洛治疗7-10天后(高峰和低谷)和替格瑞洛替代治疗7-10天后(高峰和低谷)进行PK/PD评估。PK评估包括替格瑞洛及其主要代谢物的血浆浓度。PD评估包括血管扩张剂刺激磷酸化蛋白(VASP)-血小板反应性指数(PRI)， VerifyNow P2Y12和透光性聚集(LTA)。共92例DM患者(CKD, n = 44;非ckd, n = 48)随机分组。与60 mg替格瑞洛剂量相比，90 mg替格瑞洛的血小板反应性水平较低，这在非CKD患者中具有统计学意义，但在大多数PD测量中，CKD患者没有统计学意义。主要终点(替格瑞洛90mg给药后VASP-PRI谷底水平)在队列间无显著差异(31±20 vs 25±14;p = 0.105)。VerifyNow和LTA提供了类似的发现。PK评估跟踪PD资料显示，与非CKD患者相比，CKD患者的替格瑞洛及其主要代谢物的血浆浓度增加。结论:在DM患者中，尽管替格瑞洛维持剂量方案(60和90mg)产生有效的P2Y12抑制作用，但与CKD患者相比，非CKD患者的血小板反应性水平往往更高，且具有更广泛的变异性。临床试验注册:http://www.clinicaltrials.gov唯一标识符:NCT02539160。
Impact of chronic kidney disease on the pharmacodynamic and pharmacokinetic effects of ticagrelor in patients with diabetes mellitus and coronary artery disease.
Aims: Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk of atherothrombotic events. Ticagrelor reduces ischaemic events compared to clopidogrel, with the greatest risk reduction in patients with both DM and CKD. How CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor maintenance dose regimens in patients with DM is unknown.
Methods and results: In this randomized, crossover study, patients with DM on treatment with dual antiplatelet therapy (aspirin and clopidogrel) were stratified according to CKD status and randomized to ticagrelor 90 or 60 mg bid. PK/PD assessments were performed at baseline, after 7-10 days of ticagrelor (peak and trough), and after 7-10 days of alternative ticagrelor regimen (peak and trough). PK assessments included plasma concentrations of ticagrelor and its major metabolite. PD assessments included vasodilator-stimulated phosphoprotein (VASP)-platelet reactivity index (PRI), VerifyNow P2Y12, and light transmittance aggregometry (LTA). A total of 92 patients with DM (CKD, n = 44; non-CKD, n = 48) were randomized. Levels of platelet reactivity were lower with the 90 mg compared with the 60 mg ticagrelor dose, which was statistically significant in non-CKD but not in CKD patients for most PD measures. There were no significant differences in the primary endpoint (trough levels of VASP-PRI following ticagrelor 90 mg dosing) between cohorts (31 ± 20 vs. 25 ± 14; P = 0.105). VerifyNow and LTA provided similar findings. PK assessments tracked PD profiles showing increased plasma concentrations of ticagrelor and its major metabolite in CKD compared to non-CKD patients.
Conclusion: In patients with DM, although ticagrelor maintenance dose regimens (60 and 90 mg) yield potent P2Y12 inhibition, levels of platelet reactivity tended to be higher and subject to broader variability in non-CKD compared with CKD patients.
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