Beyond efficacy: pharmacokinetic differences between clopidogrel, prasugrel and ticagrelor

INTRODUCTION: Clinical nonresponse to clopidogrel has been associated with variability in response. This has led to the development of other P2Y12 receptor inhibitors, such as prasugrel and ticagrelor, with different pharmacokinetic characteristics that influence their pharmacodynamics. AREAS COVERED: Clopidogrel response variability is attributable to its complex pharmacokinetics and is vulnerable to genetic polymorphisms in genes involved in absorption, metabolism and drug-drug interactions (i.e., proton pump inhibitors). Prasugrel which has a simpler metabolism, leading to greater bioavailability, seems to be less affected by genetic or drug-drug interactions and achieves a greater antiplatelet effect. Ticagrelor is the most novel compound approved with a simpler metabolism. Both prasugrel and ticagrelor reached their antiplatelet effect faster and to a much greater extent than clopidogrel. All these differences observed in kinetics explain, to some degree, the efficacy and safety profile observed in clinical trials for these molecules associated with other antiplatelet agents (aspirin, gpIIb/IIIa inhibitors) and anticoagulants. EXPERT OPINION: Clopidogrel is still the best standard of care. However, the pharmacokinetic advantages of both prasugrel and ticagrelor allow clinicians to center patient management by selecting the best drug for the appropriate subject.     

新药替卡格雷与普拉格雷及其克服氯吡格雷抵抗的研究进展

目的对新型抗血小板凝集药普拉格雷和替卡格雷及它们与原有抗血小板聚集药氯吡格雷的异同及克服氯吡格雷抵抗作用进行综述。方法参阅最新国内外公开发表的相关文献,阐述新药普拉格雷和替卡格雷的研发思路及作用特点,比较它们与原有抗血小板聚集药氯吡格雷的异同,论述其克服氯吡格雷抵抗的作用机制所在。结果相对于氯吡格雷,新型抗血小板聚集药普拉格雷和替卡格雷更加强力有效,并可明显降低甚至避免氯吡格雷抵抗事件的发生。结论国际知名制药公司对普拉格雷和替卡格雷的研发理念可带给我们新启示,这些新型抗血小板聚集药为临床医师提供了新的用药选择。     

Differential inhibitory effects of proton pump inhibitors on the metabolism and antiplatelet activities of clopidogrel and prasugrel

The interaction between proton pump inhibitors (PPIs) and clopidogrel/prasugrel was investigated. The IC50 values of omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole on the metabolic ratios of 2-oxo-clopidogrel/clopidogrel, H4 (the active metabolite of clopidogrel)/2-oxo-clopidogrel and R-138727 (the active metabolite of prasugrel)/prasugrel thiolactone in human liver microsomes were determined. The antiplatelet activities of clopidogrel and prasugrel were measured with or without PPIs. As a result, most PPIs (except for pantoprazole) inhibited the formation of 2-oxo-clopidogrel with IC50 values of 20-32 μm and inhibited the formation of H4 with IC50 values of 6-20 μm. PPIs inhibited the formation of R-138727 with IC50 values of 9-25 μm. Among the tested PPIs, omeprazole exhibited the highest inhibitory potency on the formation of H4. Omeprazole, esomeprazole and rabeprazole exhibited the highest inhibitory potencies on the formation of R-138727. For platelet aggregation, omeprazole and lansoprazole show higher inhibitory effects on the antiplatelet activity of clopidogrel. On the other hand, omeprazole, esomeprazole and rabeprazole significantly decreased the antiplatelet activity of prasugrel thiolactone. These data indicate that PPIs differ in their effects of inhibiting the metabolism and antiplatelet activities of clopidogrel and prasugrel.     

国内使用氯吡格雷与替格瑞洛治疗急性冠脉综合征的疗效及安全性分析

目的：分析比较氯吡格雷与替格瑞洛治疗急性冠脉综合征（ACS）的临床有效性以及安全性差别,为ACS抗血小板药物的选择提供合理参考。方法：计算机检索中国知网,万方以及维普三个中文数据库,获得国内公开发表的相关文献,统计分析各篇文献的有效性评测指标、疗效差别、不良反应以及不良事件发生情况等数据,比较氯吡格雷与替格瑞洛治疗ACS的有效性与安全性。结果：共纳入52篇有效文献,涉及病例7 839例。有效性方面,更多的证据提示替格瑞洛临床疗效优于氯吡格雷。主要不良心血管事件（MACE）方面,替格瑞洛组比氯吡格雷组MACE发生更少。2组出血事件发生率无统计学差异,在导致轻度呼吸困难方面替格瑞洛表现不及氯吡格雷。结论：在常规治疗基础上,替格瑞洛比氯吡格雷治疗ACS效果更为明显。除轻度呼吸困难外,安全性不劣势于氯吡格雷,临床可以考虑推广使用。     

Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants

AIMS

This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel.

METHODS

Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug''s active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)].

RESULTS

Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001).

CONCLUSIONS

Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel.     

Prevalence of CYP2C19 alleles,pharmacokinetic and pharmacodynamic variation of clopidogrel and prasugrel in Bangladeshi population

The extent to which cytochrome P450 (CYP) 2C19 genotype influences the effectiveness of clopidogrel remains uncertain due to considerable heterogeneity between studies. We used the polymerase chain reaction restriction fragment length polymorphism (PCR‐RFLP) method for genotyping loss of function (LOF) allele, CYP2C19*2 and gain of function (GOF) allele, CYP2C19*17 in 163 patients undergoing PCI and 165 healthy volunteers from an ethnically distinctive Bangladeshi population. Thirty‐eight patients took prasugrel and 125 patients took clopidogrel among whom 30 patients had their clopidogrel active metabolites (CAM) determined by LC‐MS/MS 1–1.5 h after clopidogrel intake. All patients who underwent PCI had their P2Y12 per cent inhibition (PRI) measured by VerifyNow System. The impact of different genotypes on CAM and PRI were also determined. We did not find significant variation of CYP2C19*2 (P > 0.05) and CYP2C9*17 (P > 0.05) alleles among healthy volunteers and patients. CAM concentration as well as PRI by clopidogrel varied significantly (P < 0.05) based on genotypic variation of CYP2C19*2 and CYP2C19*17 individually. Such influence was not observed in case of prasugrel. Genotypic variation did not impact PRI but as a whole PRI by prasugrel was better than that of clopidogrel (P < 0.05). Due to presence of both of alleles the effect on PRI by clopidogrel could not be predicted, effectively indicating possible involvement of other factors. Genotype guided clopidogrel dose adjustment would be beneficial and therefore we propose mandatory genotyping before clopidogrel dosing. Prasugrel proved to be less affected by genotypic variability, but due to lack of sufficient long‐term toxicity data, caution would be adopted before substituting clopidogrel.     

Projected inhibition of platelet aggregation with ticagrelor twice daily vs. clopidogrel once daily based on patient adherence data (the TWICE project)

AIM

Twice daily dosing is often perceived as inferior to once daily dosing due to a higher likelihood of missing a dose. However, more important is the extent to which drug action is maintained when doses are delayed or missed. We compared the estimated inhibition of platelet aggregation (eIPA) for ticagrelor twice daily and clopidogrel once daily, based on their pharmacokinetic/pharmacodynamic relationships and patient dosing history data.

METHODS

Drug dosing histories of 5014 patients prescribed cardiovascular medications (primarily antihypertensive medicines) were extracted from an electronically compiled dosing history database. eIPA levels were simulated for 677 twice daily and 677 once daily dosing histories over a 30 day period, based on published onset/offset models for ticagrelor and clopidogrel IPA characteristics.

RESULTS

While many patients treated twice daily missed at least one dose in 30 days, only 25.7% missed two consecutive doses. By comparison, 46.8% of patients treated once daily missed at least one dose. Simulations based on patient adherence over time showed that the average mean eIPA for ticagrelor twice daily remained significantly higher than for clopidogrel once daily (81.1% vs. 55.0%, P < 0.001). Ticagrelor twice daily patients had an eIPA below 10% for 0.20% of the 30 day period compared with 2.05% for clopidogrel once daily (P A= 0.0001).

CONCLUSIONS

The projected level of platelet inhibition remained higher for ticagrelor twice daily than clopidogrel once daily, mainly due to the higher eIPA level achieved with ticagrelor and the relatively low likelihood of missing two consecutive twice daily doses. This modelling and simulation study suggests a therapeutic benefit of ticagrelor over clopidogrel when taking into account the most common dosing omissions.     

替格瑞洛和氯吡格雷对颈动脉支架术后患者的血小板抑制的临床疗效与安全性

目的用血栓弹力图评价比较替格瑞洛和氯吡格雷对颈动脉支架术(CAS)后患者血小板抑制的临床疗效与安全性。方法将纳入的颈动脉狭窄患者随机分为试验组和对照组,每组各75例。于CAS术前1天,试验组患者口服阿司匹林300 mg和替格瑞洛180 mg;术后予阿司林100 mg qd,替格瑞洛90 mg bid,口服。于CAS术前1天,对照组患者口服阿司匹林300 mg和氯吡格雷300mg;术后给予阿司匹林100 mg qd,氯吡格雷75 mg qd,口服。2组患者术后均服用双联抗血小板药物3个月以上,所有患者均随访至术后3个月。于CAS术后1,30 d,留取患者静脉血液样本,用血栓弹力图仪检测患者的ADP途径血小板抑制率,记录2组缺血性事件及出血性事件发生情况。结果 CAS术后1,30 d的ADP途径血小板抑制率:对照组分别为(65.41±20.75)%,(42.66±26.34)%;试验组分别为(87.37±17.12)%,(81.91±21.18)%,试验组均高于对照组,组间比较差异均有统计学意义(均P<0.05)。术后1 d,试验组和对照组患者CAS的血小板抑制有效率分别为98.7%,92.0%;术后30 d,这2组的血小板抑制有效率分别为94.7%,74.7%,术后1,30 d的组间差异均有统计学意义(均P<0.05)。对照组和试验组患者的缺血性事件发生率分别为37.3%,13.3%,组间比较差异有统计学意义(P<0.05)。对照组和试验组患者的出血性事件发生率分别为6.7%,4.0%,组间比较差异无统计学意义(P>0.05)。结论替格瑞洛对CAS术后患者的血小板抑制效果及临床疗效优于氯吡格雷,且不增加出血风险。     

新型P2Y12受体抑制剂替格瑞洛临床研究进展

抗血小板药物是急性冠脉综合征（Acute Coronary Syndrome,ACS）治疗的基石,对防治心肌缺血和介入并发症是有益的。目前治疗ACS和经皮冠状动脉介入治疗（percutaneous coronary intervention,PCI）指南推荐使用的口服抗血小板药物包括氯吡格雷、替格瑞洛、普拉格雷联合阿司匹林双重抗血小板治疗预防复发性缺血事件。本文对新型P2Y12受体抑制剂替格瑞洛的药代动力学和药效学特点以及在ACS患者中的循证医学证据作一介绍。     

Periprocedural Neuroendovascular Antiplatelet Strategies for Thrombosis Prevention in Clopidogrel-Hyporesponsive Patients

Patients undergoing neuroendovascular procedures such as cerebral aneurysm coiling and intracranial stent deployment are frequently treated with antiplatelet agents to prevent thrombotic complications. The combination of aspirin and a P2Y12 inhibitor such as clopidogrel is often initiated days before elective procedures or as loading doses for emergent procedures; however, some patients may still experience thrombotic complications. Patients identified as clopidogrel hyporesponders are more likely to experience poor outcomes and may require changes to their regimens. Historically, high-dose clopidogrel regimens were used in response to subtherapeutic results of platelet function assays and point-of-care testing despite limited supporting data. Recently, more data have emerged using alternative P2Y12 inhibitors such as prasugrel and ticagrelor. Dosing for neuroendovascular conditions is often extrapolated from the cardiac literature, although outcomes in cardiac patients may not be relevant to neurologic patients, making prophylactic treatment recommendations challenging for these patients. This review summarizes the literature for antiplatelet prophylaxis in patients undergoing neuroendovascular device placement, focusing on alternative regimens for clopidogrel hyporesponders.     

Mean platelet volume and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor

Objective: High on-treatment platelet reactivity (HRPR) is associated with a two- to ninefold increased risk of recurrent ischemic events among patients receiving dual antiplatelet therapy (DAPT) for coronary artery disease. However, its determinants are still poorly understood. The aim of the present study was to assess the impact of mean platelet volume (MPV) on platelet reactivity in patients receiving DAPT after an acute coronary syndrome or PCI.

Methods: Patients treated with DAPT (acetylsalicylic acid [ASA] and clopidogrel or ticagrelor) were scheduled for platelet function assessment at 30 – 90 days post-discharge. By whole blood impedance aggregometry, HRPR was considered for ASPI test > 862 aggregation units (AU)*min (for ASA) and ADP test values ≥ 417 AU*min (for ADP-antagonists).

Results: Our population is represented by a total of 487 patients on DAPT, divided according to MPV tertiles (< 10.4 fl; 10.4 – 11.29 fl; ≥ 11.3 fl). Larger-sized platelets were associated with use of statins (p < 0.001) and beta-blockers (p = 0.03), higher hemoglobin levels (p = 0.002) and lower platelets count (p < 0.001). Higher platelet reactivity was observed at ASPI test in patients with higher MPV (r = 0.12, p = 0.008), but not for ADP-mediated aggregation (r = -0.007, p = 0.88). However, a low prevalence of HRPR was observed with ASA, with no impact of MPV tertiles (1.2 vs 1.1 vs 1.6%, p = 0.70, adjusted OR [95% CI] = 1.05 [0.51 – 1.77], p = 0.87). MPV did not influence the prevalence of HRPR for ADP-antagonists (25.9 vs 1 vs 26.5%, p = 0.89; adjusted OR [95% CI] = 1.1 [0.84 – 1.45], p = 0.50) with similar results among the 259 patients receiving clopidogrel (adjusted OR [95% CI] = 1.15 [0.82 – 1.62], p = 0.43) and the 228 patients on ticagrelor (adjusted OR [95% CI] = 1.46 [0.84 – 2.55], p = 0.18).

Conclusion: In patients receiving DAPT, MPV does not affect the response to major antiplatelet therapies. In fact, MPV elevation does not influence the risk of HRPR with clopidogrel, ticagrelor or ASA.     

Ticagrelor: Positive,negative and misunderstood properties as a new antiplatelet agent

相似文献   

Genetic and non-genetic factors affecting the response to clopidogrel therapy

Introduction: Clopidogrel (CLP) is a second-generation thienopyridine that prevents platelet aggregation by inhibiting the adenosine diphosphate receptor located on the platelet surface. The use of CLP in combination with aspirin has become standard treatment in patients with acute coronary syndromes and stent implantation. Data suggests that a significant percentage of individuals treated with CLP do not receive the expected therapeutic benefit because of a decreased platelet inhibition. The clinical consequences of an inadequate platelet response are cardiovascular complications, which can lead to acute myocardial infarction, stroke and death. The mechanism underlying CLP resistance is multifactorial and includes genetic polymorphisms and non-genetic causes (such as drug–drug interactions, co-morbidities, age).

Areas covered: This article reviews the so-far accumulated evidence on the role of genetic polymorphisms and non-genetic factors, as determinants of the antiplatelet response to CLP. Pharmacodynamic and clinical aspects of the CLP nonresponsiveness are also presented. Relevant papers were identified by an extensive PubMed search using appropriate keywords.

Expert opinion: Impaired platelet inhibition in CLP poor responders is a real problem, as it leads to serious clinical consequences. Therefore, prediction models that include pharmacogenetic knowledge and non-genetic risk factors of low response to the drug are needed in the individualization of antithrombotic therapy. Alternative antiplatelet strategies that should be considered to overcome this problem include dose modification, adjunctive antiplatelet drug usage, and use of newer agents.     

利用GRACE评分评估氯吡格雷与替格瑞洛在PCI患者术后抗栓治疗效果

目的：利用GRACE评分来衡量接受PCI术患者的缺血程度,并评估氯吡格雷或替格瑞洛在PCI患者术后抗栓治疗效果,以便给临床医生治疗方案的选择提供参考。方法：抽取接受PCI术的冠心病患者,记录GRACE计分项数据,计算最终得分。按术后使用不同P2Y12受体抑制剂,把患者分为2组并随访12个月,记录心肌缺血体征并结合用药作出分析。结果：在GRACE风险评分缺血高危组患者术后维持双抗治疗中,替格瑞洛更优于氯吡格雷。在低危组,氯吡格雷组与替格瑞洛组并无明显差异。结论：缺血高风险的患者更推荐选择使用替格瑞洛联合阿司匹林,GRACE评分能区分不同接受PCI术患者缺血风险,在临床抗栓药物使用上具有实际的指导意义。     

Ticagrelor,prasugrel, or clopidogrel in ST-segment elevation myocardial infarction: which one to choose?

Introduction: Clopidogrel, prasugrel, and ticagrelor are the currently available oral P2Y12 inhibitors for the treatment of ST-segment elevation myocardial infarction (STEMI), in association with aspirin. These agents bind the P2Y12 platelet receptor and thus inhibit platelet aggregation. Large randomized clinical trials have provided efficacy and safety data on P2Y12 inhibitors in STEMI patients.

Areas covered: This review focuses on key pharmacologic and clinical aspects of clopidogrel, prasugrel, and ticagrelor, highlighting their differences. Results from the main clinical trials are discussed, as well as the current STEMI guideline recommendations, to help inform agent selection for patients presenting with STEMI.

Expert opinion: Clinical trials studying newer P2Y12 inhibitors with increased potency have shown further reduction of cardiovascular events compared with clopidogrel, therefore suggesting the use of ticagrelor or prasugrel as a first-line agent for STEMI treatment. There are still clinical situations – such as fibrinolysis, high risk of bleeding, use of oral anticoagulant, and financial hurdles – in which clopidogrel maintains a role in the treatment of STEMI.     

A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans

AIMS: This double-blind, placebo-controlled trial was designed to evaluate the pharmacodynamics, pharmacokinetics, safety, and tolerability of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y(12) ADP receptor antagonist compared with clopidogrel, during multiple oral dosing in healthy subjects. METHODS: Thirty subjects received placebo, prasugrel 5 mg, 10 mg, or 20 mg, or clopidogrel 75 mg orally, daily for 10 days. Platelet aggregation, bleeding time, and prasugrel metabolites were measured and adverse events were recorded. RESULTS: Inhibition of ADP-induced platelet aggregation reached steady state by day 3 following prasugrel 10 and 20 mg compared with 5 days for clopidogrel 75 mg or prasugrel 5 mg. Compared with placebo, at 24 h after the last dose of study drug, inhibition of platelet aggregation using (20 microm) ADP was significantly higher in the prasugrel 10 mg group (58.2 +/- 4.9% vs. 9.2 +/- 4.0%, P < 0.001) with no difference in the clopidogrel group (15.7 +/- 6.8% vs. 9.2 +/- 4.0%, P = 0.78). With 5 microm ADP, inhibition of platelet aggregation with prasugrel 10 mg and clopidogrel 75 mg was significantly higher than with placebo (prasugrel 10 mg, 70.5 +/- 4.7%; clopidogrel 75 mg, 36.5 +/- 9.0%; vs. placebo, 11.3 +/- 5.1%; P < 0.0001 and P = 0.02). On day 10 at 4 h postdose, bleeding time was prolonged with prasugrel 10 mg (prasugrel 10 mg, 706 +/- 252 s vs. placebo, 221 +/- 38 s, P = 0.05) but not with clopidogrel (283 +/- 56 s, P = 0.98). There were no clinically significant bleeding events, serious adverse events, or discontinuations of the study drug. CONCLUSIONS: Compared with clopidogrel 75 mg, prasugrel 10 mg and 20 mg daily for 10 days resulted in more rapid, more consistent, and higher levels of platelet inhibition.     

Population pharmacokinetic analysis of clopidogrel in healthy Jordanian subjects with emphasis optimal sampling strategy

Aim: Clopidogrel is metabolized primarily into an inactive carboxyl metabolite (clopidogrel‐IM) or to a lesser extent an active thiol metabolite. A population pharmacokinetic (PK) model was developed using NONMEM® to describe the time course of clopidogrel‐IM in plasma and to design a sparse‐sampling strategy to predict clopidogrel‐IM exposures for use in characterizing anti‐platelet activity.Methods: Serial blood samples from 76 healthy Jordanian subjects administered a single 75 mg oral dose of clopidogrel were collected and assayed for clopidogrel‐IM using reverse phase high performance liquid chromatography. A two‐compartment (2‐CMT) PK model with first‐order absorption and elimination plus an absorption lag‐time was evaluated, as well as a variation of this model designed to mimic enterohepatic recycling (EHC). Optimal PK sampling strategies (OSS) were determined using WinPOPT based upon collection of 3–12 post‐dose samples.Results: A two‐compartment model with EHC provided the best fit and reduced bias in C_max (median prediction error (PE%) of 9.58% versus 12.2%) relative to the basic two‐compartment model, AUC_0‐24 was similar for both models (median PE% = 1.39%). The OSS for fitting the two‐compartment model with EHC required the collection of seven samples (0.25, 1, 2, 4, 5, 6 and 12 h). Reasonably unbiased and precise exposures were obtained when re‐fitting this model to a reduced dataset considering only these sampling times.Conclusions: A two‐compartment model considering EHC best characterized the time course of clopidogrel‐IM in plasma. Use of the suggested OSS will allow for the collection of fewer PK samples when assessing clopidogrel‐IM exposures. Copyright © 2013 John Wiley & Sons, Ltd.     

CYP2C19基因中间代谢型ACS患者双倍剂量氯吡格雷和标准剂量替格瑞洛疗效与安全性评价

目的：探讨CYP2C19中间代谢型急性冠脉综合征（ACS）患者双倍剂量氯吡格雷和标准剂量替格瑞洛的疗效与安全性。方法：就诊的ACS患者,排除未行PCI手术、重度肝功能不全患者,对568例患者进行CYP2C19基因检测,其中CYP2C19中间代谢型患者252例（占比44.37%）,22例因各种原因（包括经济因素等）未接受PCI治疗,最终将230例CYP2C19中间代谢型患者（占比40.49%）随机分配至双倍剂量氯吡格雷组和标准剂量替格瑞洛组,并对2组患者进行长达12个月的随访,统计分析2组患者主要终点事件、出血事件和呼吸困难事件发生率差异。结果：随访1,6,12个月时2组患者主要终点事件发生率方面无显著差异（P＞0.05）。出血事件发生率替格瑞洛组稍高于氯吡格雷组,但无显著性差异（P＞0.05）。替格瑞洛组有2例发生致命颅内出血事件,可能原因是患者为出血高风险人群。呼吸困难发生率标准剂量替格瑞洛组显著高于双倍剂量氯吡格雷组（P<0.05）。替格瑞洛组6例患者发生显著的呼吸困难,导致患者无法耐受均转换成氯吡格雷。结论：CYP2C19基因中间代谢型ACS患者双倍剂量氯吡格雷和标准剂量替格瑞洛疗效无显著性差异。安全性方面,2组患者出血事件无显著性差异,但替格瑞洛组严重出血事件高于氯吡格雷组;呼吸困难发生率标准剂量替格瑞洛组显著高于双倍剂量氯吡格雷组。基于本研究结果,谨慎建议对于CYP2C19基因中间代谢型患者,无出血风险高危因素时,双倍剂量氯吡格雷和标准剂量替格瑞瑞洛均可选择;出血高风险人群,建议选择氯吡格雷。对于使用替格瑞洛过程中发生呼吸困难,建议及时更换为双倍剂量氯吡格雷。     

The genetic basis of antiplatelet and anticoagulant therapy: A pharmacogenetic review of newer antiplatelets (clopidogrel,prasugrel and ticagrelor) and anticoagulants (dabigatran,rivaroxaban, apixaban and edoxaban)

Introduction: The study of pharmacogenomics presents the possibility of individualised optimisation of drug therapy tailored to each patients’ unique physiological traits. Both antiplatelet and anticoagulant drugs play a key role in the management of cardiovascular disease. Despite their importance, there is a substantial volume of literature to suggest marked person-to-person variability in their effect.

Areas covered: This article reviews the data available for the genetic cause for this inter-patient variability of antiplatelet and anticoagulant drugs. The genetic basis for traditional antiplatelets (i.e. aspirin) is compared with the newly available antiplatelet medicines (clopidogrel, prasugrel and ticagrelor). Similarly, the pharmacogenetics of warfarin is compared with the newer direct oral anticoagulants (DOACs) in detail.

Expert Opinion: We identify strengths and weaknesses in the research thus far; including shortcomings in trial design and a review of newer analytical techniques. The direction of this research and its real-world implications are discussed.