Comparative effects of different antiplatelet strategies in carriers of CYP2C19 loss-of-function alleles: a network meta-analysis.

IF 5.3 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

European Heart Journal - Cardiovascular Pharmacotherapy Pub Date : 2024-10-04 DOI:10.1093/ehjcvp/pvae036

Mattia Galli, Giovanni Occhipinti, Stefano Benenati, Renzo Laborante, Luis Ortega-Paz, Francesco Franchi, Domenico D'Amario, Roberto Nerla, Fausto Castriota, Giacomo Frati, Giuseppe Biondi-Zoccai, Sebastiano Sciarretta, Dominick J Angiolillo

{"title":"Comparative effects of different antiplatelet strategies in carriers of CYP2C19 loss-of-function alleles: a network meta-analysis.","authors":"Mattia Galli, Giovanni Occhipinti, Stefano Benenati, Renzo Laborante, Luis Ortega-Paz, Francesco Franchi, Domenico D'Amario, Roberto Nerla, Fausto Castriota, Giacomo Frati, Giuseppe Biondi-Zoccai, Sebastiano Sciarretta, Dominick J Angiolillo","doi":"10.1093/ehjcvp/pvae036","DOIUrl":null,"url":null,"abstract":"Background: Carriers of cytochrome 2C19 (CYP2C19) loss-of-function (LoF) alleles treated with clopidogrel have impaired drug metabolism, resulting in reduced active metabolite levels, high platelet reactivity (HPR), and an increased risk of thrombotic events. Several alternative antiplatelet therapies have been proposed to overcome HPR in these patients, but their comparative effects remain poorly explored.Methods: Randomized controlled trials (RCTs) comparing different oral antiplatelet therapies in carriers of CYP2C19 LoF alleles undergoing percutaneous coronary interventions (PCI) were included. A frequentist network meta-analysis was conducted to estimate mean difference (MD) or odds ratios and 95% confidence intervals (CI). The primary outcome was platelet reactivity assessed by VerifyNow and reported as P2Y12 reaction unit (PRU). The secondary outcome was the rate of HPR. Standard dose of clopidogrel (75 mg daily) was used as a reference treatment.Results: A total of 12 RCTs testing 6 alternative strategies (i.e. clopidogrel 150 mg, prasugrel 3.75 mg, 5 mg, and 10 mg, ticagrelor 90 mg bid, and adjunctive cilostazol 100 mg bid) were included in the network. Compared with standard-dose clopidogrel, the greatest reduction in PRU was observed with prasugrel 10 mg (MD -127.91; 95% CI -141.04; -114.78) and ticagrelor 90 mg bid (MD -124.91; 95% CI -161.78; -88.04), followed by prasugrel 5 mg (MD -76.33; 95% CI -98.01; -54.65) and prasugrel 3.75 mg (MD -73.00; 95% CI -100.28; -45.72). Among other strategies, adjunctive cilostazol (MD -42.64; 95% CI -64.72; -20.57) and high-dose clopidogrel (MD -32.11; 95% CI -51.33; -12.90) were associated with a modest reduction in PRU compared with standard-dose clopidogrel.Conclusion: Among carriers of CYP2C19 LoF alleles undergoing PCI, standard-dose prasugrel or ticagrelor are most effective in reducing platelet reactivity, while double-dose clopidogrel and additional cilostazol showed modest effects. Reduced-dose of prasugrel may represent a balanced strategy to overcome HPR without a significant increase in bleeding. The clinical implications of these pharmacodynamic findings warrant further investigation.","PeriodicalId":11982,"journal":{"name":"European Heart Journal - Cardiovascular Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Heart Journal - Cardiovascular Pharmacotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/ehjcvp/pvae036","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Carriers of cytochrome 2C19 (CYP2C19) loss-of-function (LoF) alleles treated with clopidogrel have impaired drug metabolism, resulting in reduced active metabolite levels, high platelet reactivity (HPR), and an increased risk of thrombotic events. Several alternative antiplatelet therapies have been proposed to overcome HPR in these patients, but their comparative effects remain poorly explored.

Methods: Randomized controlled trials (RCTs) comparing different oral antiplatelet therapies in carriers of CYP2C19 LoF alleles undergoing percutaneous coronary interventions (PCI) were included. A frequentist network meta-analysis was conducted to estimate mean difference (MD) or odds ratios and 95% confidence intervals (CI). The primary outcome was platelet reactivity assessed by VerifyNow and reported as P2Y12 reaction unit (PRU). The secondary outcome was the rate of HPR. Standard dose of clopidogrel (75 mg daily) was used as a reference treatment.

Results: A total of 12 RCTs testing 6 alternative strategies (i.e. clopidogrel 150 mg, prasugrel 3.75 mg, 5 mg, and 10 mg, ticagrelor 90 mg bid, and adjunctive cilostazol 100 mg bid) were included in the network. Compared with standard-dose clopidogrel, the greatest reduction in PRU was observed with prasugrel 10 mg (MD -127.91; 95% CI -141.04; -114.78) and ticagrelor 90 mg bid (MD -124.91; 95% CI -161.78; -88.04), followed by prasugrel 5 mg (MD -76.33; 95% CI -98.01; -54.65) and prasugrel 3.75 mg (MD -73.00; 95% CI -100.28; -45.72). Among other strategies, adjunctive cilostazol (MD -42.64; 95% CI -64.72; -20.57) and high-dose clopidogrel (MD -32.11; 95% CI -51.33; -12.90) were associated with a modest reduction in PRU compared with standard-dose clopidogrel.

Conclusion: Among carriers of CYP2C19 LoF alleles undergoing PCI, standard-dose prasugrel or ticagrelor are most effective in reducing platelet reactivity, while double-dose clopidogrel and additional cilostazol showed modest effects. Reduced-dose of prasugrel may represent a balanced strategy to overcome HPR without a significant increase in bleeding. The clinical implications of these pharmacodynamic findings warrant further investigation.

查看原文本刊更多论文

不同抗血小板策略对 CYP2C19 功能缺失等位基因携带者的比较效应：一项网络荟萃分析。

背景：细胞色素 2C19（CYP2C19）功能缺失（LoF）等位基因携带者在使用氯吡格雷治疗时，药物代谢会受损，导致活性代谢物水平降低、血小板反应性高（HPR）以及血栓事件风险增加。目前已提出了几种替代抗血小板疗法来克服这些患者的高血小板反应性，但对它们的比较效果仍缺乏深入探讨：方法：纳入了在接受经皮冠状动脉介入治疗（PCI）的 CYP2C19 LoF 等位基因携带者中比较不同口服抗血小板疗法的随机对照试验（RCT）。进行了频数网络荟萃分析，以估计平均差（MD）或几率比（OR）和95%置信区间（CI）。主要结果是由 VerifyNow 评估的血小板反应性，并以 P2Y12 反应单位 (PRU) 报告。次要结果是 HPR 发生率。标准剂量的氯吡格雷（每天 75 毫克）作为参考治疗：该网络共纳入了 12 项 RCT，测试了 6 种替代策略（即氯吡格雷 150 毫克、普拉格雷 3.75 毫克、5 毫克和 10 毫克、替卡格雷 90 毫克 bid 和辅助西洛他唑 100 毫克 bid）。与标准剂量氯吡格雷相比，普拉格雷 10 mg（MD -127.91; 95% CI -141.04; -114.78）和替卡格雷 90 mg bid（MD -124.91；95% CI -161.78；-88.04），其次是普拉格雷 5 毫克（MD -76.33；95% CI -98.01；-54.65）和普拉格雷 3.75 毫克（MD -73.00；95% CI -100.28；-45.72）。在其他策略中，与标准剂量氯吡格雷相比，辅助西洛他唑（MD-42.64；95% CI -64.72；-20.57）和大剂量氯吡格雷（MD -32.11；95% CI -51.33；-12.90）与PRU的适度降低有关：结论：在接受PCI治疗的CYP2C19 LoF等位基因携带者中，标准剂量的普拉格雷或替卡格雷能最有效地降低血小板反应性，而双倍剂量的氯吡格雷和额外的西洛他唑效果一般。减少剂量的普拉格雷可能是克服 HPR 的一种平衡策略，同时不会显著增加出血量。这些药效学发现的临床意义值得进一步研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

European Heart Journal - Cardiovascular Pharmacotherapy Medicine-Cardiology and Cardiovascular Medicine

CiteScore

10.10

自引率

14.10%

发文量

期刊介绍： The European Heart Journal - Cardiovascular Pharmacotherapy (EHJ-CVP) is an international, peer-reviewed journal published in English, specifically dedicated to clinical cardiovascular pharmacology. EHJ-CVP publishes original articles focusing on clinical research involving both new and established drugs and methods, along with meta-analyses and topical reviews. The journal's primary aim is to enhance the pharmacological treatment of patients with cardiovascular disease by interpreting and integrating new scientific developments in this field. While the emphasis is on clinical topics, EHJ-CVP also considers basic research articles from fields such as physiology and molecular biology that contribute to the understanding of cardiovascular drug therapy. These may include articles related to new drug development and evaluation, the physiological and pharmacological basis of drug action, metabolism, drug interactions, and side effects.