Can CYP2C19 genotyping improve antiplatelet therapy efficacy in real-life practice? Recent advances.

IF 3.7 3区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Kardiologia polska Pub Date : 2024-08-14 DOI:10.33963/v.phj.101890
Udaya S Tantry, Sahib Singh, Lekshmi Narayan Raghavakurup, Kevin P Bliden, Paul A Gurbel
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Abstract

Clopidogrel remains the most widely used P2Y₁₂ receptor inhibitor worldwide and is often used in combination with aspirin for secondary prevention in patients with arterial disease. The drug is associated with a wide response variability with one on three patients exhibiting little or no inhibition of adenosine diphosphate-induced platelet aggregation. It is a prodrug that is mainly metabolized by hepatic cytochrome P450 (CYP) 2C19. Patients who carry a CYP2C19 loss-of-function (LoF) allele have reduced metabolism of clopidogrel that is associated with reduced platelet inhibition compared to non-carriers that is associated with increased risk for thrombotic event occurrences, particularly, stent thrombosis. The United States Food and Drug Administration (US FDA) issued a black box warning in the clopidogrel label highlighting the importance of presence of CYP2C19 LOF allele during the insufficient metabolism of clopidogrel and availability of other potent P2Y₁₂ inhibitor for the treatment in CYP2C19 poor metabolizers. Clinical trials have conclusively demonstrated greater anti-ischemic benefits of prasugrel/ticagrelor in the treatment of patients carrying the CYP2C19 LoF allele. However, uniform use of these more potent P2Y₁₂ inhibitors has been associated with greater bleeding and cost, and lower adherence. The latter information provides a strong rationale for personalizing P2Y₁₂ inhibitor therapy based on the laboratory determination of CYP2C19 genotype. However, cardiologists have been slow to take up pharmacogenetic testing possibly due to lack of provider and patient education, clear cardiology guidelines and, and lack of positive results from adequately sized randomized clinical trials. However, current evidence strongly supports genotyping of patients who are candidates for clopidogrel. Physicians should strongly consider performing genetic tests to identify LoF carriers and treat these patients with more pharmacodynamically predictable P2Y₁₂ inhibitors than clopidogrel.

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CYP2C19 基因分型能否提高抗血小板治疗的实际疗效?最新进展。
氯吡格雷仍是全球使用最广泛的 P2Y₁₂受体抑制剂,通常与阿司匹林联用,用于动脉疾病患者的二级预防。这种药物的反应差异很大,每三名患者中就有一人对二磷酸腺苷诱导的血小板聚集几乎没有抑制作用。它是一种原药,主要通过肝细胞色素 P450 (CYP) 2C19 进行代谢。与非携带者相比,携带 CYP2C19 功能缺失(LoF)等位基因的患者对氯吡格雷的代谢减少,这与血小板抑制作用降低有关,而血小板抑制作用降低与血栓事件发生的风险增加有关,尤其是支架血栓形成。美国食品和药物管理局(US FDA)在氯吡格雷的标签上发布了黑框警告,强调在氯吡格雷代谢不足的过程中存在 CYP2C19 LOF 等位基因的重要性,以及其他强效 P2Y₁₂抑制剂对 CYP2C19 代谢不良者的治疗作用。临床试验最终证明,在治疗携带 CYP2C19 LoF 等位基因的患者时,普拉格雷/替卡格雷具有更强的抗缺血作用。然而,统一使用这些药效更强的 P2Y₁₂抑制剂与出血量和费用增加以及依从性降低有关。后者为根据实验室测定的 CYP2C19 基因型对 P2Y₁₂抑制剂进行个性化治疗提供了强有力的依据。然而,可能由于缺乏对提供者和患者的教育、明确的心脏病学指南以及缺乏规模适当的随机临床试验的积极结果,心脏病学家对药物基因检测的接受度一直很慢。然而,目前的证据强烈支持对氯吡格雷的候选患者进行基因分型。医生应积极考虑进行基因检测以确定 LoF 携带者,并使用比氯吡格雷药效学预测性更高的 P2Y₁₂ 抑制剂治疗这些患者。
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来源期刊
Kardiologia polska
Kardiologia polska 医学-心血管系统
CiteScore
3.00
自引率
24.20%
发文量
431
审稿时长
3-6 weeks
期刊介绍: Kardiologia Polska (Kardiol Pol, Polish Heart Journal) is the official peer-reviewed journal of the Polish Cardiac Society (PTK, Polskie Towarzystwo Kardiologiczne) published monthly since 1957. It aims to provide a platform for sharing knowledge in cardiology, from basic science to translational and clinical research on cardiovascular diseases.
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