冠心病患者抗血小板药物治疗中血小板功能检测的角色

目的:分析冠心病患者抗血小板药物治疗中血小板功能检测的角色。方法:通过对比国外最新有关冠心病患者抗血小板药物治疗中进行血小板功能检测的临床研究,从抗血小板药物的应用限制、血小板功能检测方法、临床试验结果等方面进行分析讨论。结果与结论:从国外最新的几个临床研究来看,未发现血小板功能检测结果与冠心病缺血事件有显著的相关性。抗血小板药物治疗中推荐常规检测血小板功能仍需要等待前瞻性、大规模的临床试验结果。     

急性冠脉综合征抗血小板治疗的现状和展望

抗血小板治疗是急性冠脉综合征经皮冠状动脉介入治疗前后极其重要和关键的步骤。随着新型抗血小板药物及相关血小板功能检测方法的出现,心血管介入治疗领域的抗血小板治疗也在发生着巨大的变化。本文从口服抗血小板药物历史发展、氯吡格雷抵抗相关研究、血小板功能检测方法以及临床针对药物抵抗相应策略等多个方面,阐述急性冠脉综合征抗血小板治疗的现状及未来发展方向。     

浅谈抗血小板药物治疗监测方法

目前,抗血小板药物监测已经越来越受到临床的重视,对治疗效果的监测往往体现在对血小板功能的监测上,本文总结了临床常用的监测血小板功能的试验,介绍了一些新的监测抗血小板药物手段。     

抗血小板药物的研究进展

抗血小板药可抑制血小板聚集,进而抑制动脉中血栓形成,是防治动脉血栓性疾病的重要治疗药物。随着心脑血管疾病发病率逐年增加,临床对抗血小板药物的应用、疗效和不良反应的研究越来越多。为获得更好的抗血小板效果,目前临床急需一种抗血小板药物或药物组合,能达到提高抗血小板效果,同时降低药物副作用、减少药物抵抗发生概率、降低术后出血再栓塞风险的目的,以适合更广泛的人群。按药物作用机制,抗血小板药分为如下几类：①环氧酶抑制剂：代表药物阿司匹林,具有强烈的抗血小板聚集作用;②二磷酸腺苷受体拮抗药（ADPR - A）：代表药物噻氯匹定、氯吡格雷、普拉格雷;③血小板膜糖蛋白（GP）Ⅱb／Ⅲa 受体抑制剂：代表药物阿昔单抗、依替非巴肽、替罗非班;④磷酸二酯酶抑制剂：代表药物双嘧达莫、西洛他唑,通过激活血小板腺苷环化酶（cAMP）或抑制磷酸二酯酶对 cAMP 的降解作用,使血小板内 cAMP 浓度增高而产生抗血小板作用;⑤5-羟色胺受体拮抗剂：代表药物沙格雷酯,可以特异性地与5- HT2受体结合,抑制血小板的聚集。本文对近年较有潜力的或已上市的几类抗血小板药物的临床研究进展进行综述。     

抗血小板药物临床个体化给药中存在的问题及其研究进展

目的:了解抗血小板药物临床个体化给药中存在的问题及其研究进展。方法:查阅近年来国内外相关文献,从药物相互作用、基因多态性和血小板功能监测方面对抗血小板药物在临床个体化给药中存在的问题进行归纳和总结。结果:药物相互作用和基因多态性均导致抗血小板药物疗效差异,且血小板功能监测对临床的获益尚不能证实。结论:掌握影响抗血小板药物疗效的因素,有助于抗血小板药物的个体化给药,以最大程度地减少抗血小板效应不足导致的血栓性事件或抗血小板效应过度导致的出血性事件。     

三种药物对血小板聚集功能影响的比较

三种药物对血小板聚集功能影响的比较３００１２２天津市民族医院内科李军，徐显章天津市民族医院血液流变室李春娟抗血小板功能药物作为一种防治血栓栓塞性疾病的新途径已为众人所接受．目前用于临床的抗血小板功能药物为数不少，为了比较不同药物对血小板聚集功能的影响...     

抗血小板聚集药物研究进展

目的总结抗血小板聚集药物的研究进展,为抗血小板聚集药物开发研究提供参考。方法查阅国内外文献资料进行整理和归纳。结果中西药中均有抗血小板聚集作用的药物,在治疗人类心脑血管疾病方面发挥了重要作用。结论对药物的抗血小板聚集作用机制进行深入研究,此类药物有更大的发展空间。     

奥扎格雷抗血小板聚集作用的临床观察

目的比较奥扎格雷与阿司匹林对血小板聚集作用的影响,分析二者抵抗概率。方法脑梗死患者120例,随机分为奥扎格雷组与阿司匹林组(各60例),分别用二磷酸腺苷(ADP)、花生四烯酸(AA)诱导,进行血小板聚集试验,检测最大血小板聚集率(MAR)。各组患者均于入院当天、治疗第14天检测血小板聚集率。结果奥扎格雷组与阿司匹林组血小板聚集功能在同一诱导剂作用下,差异无统计学意义,都存在抵抗、半抵抗现象。结论奥扎格雷、阿司匹林对血小板聚集率影响的差异无统计学意义,均可作为抗血小板聚集药物,但也存在抵抗现象。奥扎格雷抗血小板聚集的长期临床效果、与其他抗血小板聚集药物联合应用能否解决抵抗问题,还需进一步的大规模临床实验研究。     

抗血小板药物防治冠心病的研究

抗血小板药物防治冠心病的研究魏文利黄守坚１（中山医科大学卫生部辅助循环重点实验室；１药理教研室，广州５１００８９）中国图书分类号Ｒ９７２；Ｒ５４１．４冠心病的发生发展与血小板功能异常密切相关，高血脂、糖尿病、吸烟及精神压力等因素触发或加重冠心病急性心...     

抗血小板聚集药的安全应用

抗血小板聚集药又称血小板功能抑制剂，60年代已在临床应用，当时将该类药归属于抗凝疗法范畴。随着对血栓性疾病发生机理的认识，抗血小板治疗在临床中的地位愈来愈重要，新的血小板功能抑制剂不断涌现，抗血小板聚集药物已成为单独的一类药物，在血栓性疾病中得到广泛的应用。本文对我院目前所使用的抗血小板聚集药的安全应用做一简要概述。     

血小板反应指数在监测阿司匹林抵抗中的临床评价

目的建立一种规范化、标准化的抗血小板药物实验监测方法。血小板反应指数（PRI）并与光学法血小板聚集试验（PAGT）进行对比，比较二者在监测抗血小板药物疗效方面的相关性，进一步证实PRI实验的可靠性和准确性。方法体检健康者350例，长期服用阿司匹林的心血管患者224例，抽取静脉血进行PAGT和PRI检测，前者血小板聚集率I〉70％为阿司匹林抵抗，后者PRI≥1．25为阿司匹林抵抗。结果健康人PRI参考范围为0．95±0．11；224例患者中，用PRI方法检测，检出阿司匹林抵抗患者30例（13．39％），用PAGT方法检出16例（7．14％）。PRI检出率明显高于血小板聚集率（P〈0．05）。结论PRI可作为监测抗血小板药物抵抗的临床常规检测技术之一，具有实用、快速、成本低、易操作、不受干扰、准确度和可靠性高的优越性。     

Prasugrel hydrochloride for the treatment of acute coronary syndromes

Introduction: P2Y12 receptor antagonists, by inhibiting platelet activation and subsequent aggregation, are critical to prevent ischemic event recurrence after an acute coronary syndrome (ACS). Prasugrel is a third-generation thienopyridine whose metabolites target the P2Y12 receptor. Compared with clopidogrel, prasugrel has a more potent, faster in onset, and more consistent P2Y12 receptor inhibition.

Areas covered: This review describes prasugrel chemistry, pharmacokinetics, pharmacodynamics and clinical studies. In a Phase III randomized clopidogrel-controlled trial, prasugrel improved cardiovascular outcome (risk reduction of cardiovascular death, non-fatal heart attack and non-fatal stroke) at the cost of increased major and fatal bleeding complications. Prasugrel, in combination with aspirin, has been approved by European and American regulatory agencies for the prevention of atherothrombotic events in patients with ACS who undergo percutaneous coronary intervention (PCI).

Expert opinion: Prasugrel is effective for managing ACS patients with planned PCI and it offers an alternative with potential benefits over clopidogrel. Prasugrel is currently challenged by ticagrelor, a P2Y12 receptor antagonist with different pharmacokinetic/pharmacodynamic properties. The superiority of one drug to the other cannot be reliably estimated from the current trials. Ongoing randomized and observational studies may help to provide valuable information on the safety and efficacy of these two drugs and their respective places with ACS patients.     

Antiplatelet drugs and platelet reactivity: is it time to halt clinical research on tailored strategies?

Personalized medicine of antiplatelet drugs in cardiovascular patients has led to a significant enthusiasm. Indeed, numerous longitudinal studies showed an association between high platelet reactivity and the recurrence of ischemic events. The first small randomized trials of P2Y₁₂ blockers tailored to each patient’s platelet reactivity yielded encouraging reductions of coronary stent thrombosis in high-risk populations. The discovery of genetic variants contributing to the pharmacodynamic effect of clopidogrel has then paved the way toward a personalized antiplatelet therapy based on reliable and stable genetic tests. This enthusiasm was soon tempered by large interventional trials demonstrating that a platelet function testing-based strategy did not improve clinical outcome and that genetic variants discovered up to now only explained a small part of the pharmacodynamic effect of clopidogrel, thus limiting its clinical use. Looking back to the most recent trials, their target populations and the type of clinical setting, it seems that the one-size-fits all policy regarding antiplatelet drugs may be well acceptable for low-risk patients. On the contrary, integration of the clinical setting as well as other risk factors may help to identify subgroups of patients who could derive a benefit from a truly personalized management of antiplatelet therapy.     

Interaction analysis between genetic polymorphisms and pharmacodynamic effect in patients treated with adjunctive cilostazol to dual antiplatelet therapy: results of the ACCEL-TRIPLE (Accelerated Platelet Inhibition by Triple Antiplatelet Therapy According to Gene Polymorphism) study

AIMS

Although adjunctive cilostazol to dual antiplatelet therapy can reduce the risks of clinical events after percutaneous coronary intervention (PCI), whether genetic polymorphism can influence the pharmacodynamics of this regimen has not been evaluated.

METHODS

One hundred and twenty-seven patients treated with PCI and taking triple antiplatelet therapy (≥1 month) were enrolled. Platelet reactivity was assessed by conventional aggregometry and the VerifyNow P2Y12 assay. High on-treatment platelet reactivity (HPR) was defined as 5 µm ADP-induced maximal platelet reactivity (Agg_max) >46%. CYP3A5*3, CYP2C19*2/*3 and ABCB1 3435C > T were genotyped.

RESULTS

CYP3A5*3 and ABCB1 3435C > T variants did not affect the antiplatelet effect of triple antiplatelet therapy. For non-carriers, one and two carriers of the CYP2C19 loss-of-function (LOF) allele, Agg_max consecutively increased after the addition of 5 µm[mean (95% confidence intervals): 24.6% (20.8 to 28.5%) vs. 28.7% (25.4 to 32.0%) vs. 32.3% (25.8 to 38.7%), P = 0.062, respectively] and 20 µm ADP [34.2% (29.3 to 39.0%) vs. 41.7% (37.8 to 45.6%) vs. 44.9% (37.9 to 51.9%), P = 0.007, respectively]. Likewise, late platelet reactivity and P2Y12 reaction units proportionally changed according to the number of CYP2C19 LOF alleles. HPRs were observed in 9.2% of subjects: 6.3%, 7.4% and 20.0% with 0, 1 and 2 carriers of CYP2C19 LOF allele(s) (P = 0.099). In multivariate analysis, carriage of two CYP2C19 LOF alleles was a significant predictor for the prevalence of HPR (odds ratio 5.78, 95% CI 1.21, 27.78, P = 0.028).

CONCLUSION

Among PCI-treated patients, the effect of triple antiplatelet therapy is influenced by the CYP2C19 LOF allele. Its clinical benefit needs to be validated according to the CYP2C19 metabolic phenotype in future clinical trials. [Adjunctive Cilostazol Versus High Maintenance dose ClopidogrEL in Acute Myocardial Infarction Patients According to CYP2C19 Polymorphism (ACCEL-AMI-2C19), NCT00915733 and Adjunctive Cilostazol Versus High Maintenance-dose Clopidogrel According to Cytochrome 2C19 Polymorphism (ACCEL-2C19), NCT01012193].     

3种方法检测经皮冠状动脉介入治疗术后患者氯吡格雷的药效学

目的比较光学比浊法(LTA)、血栓弹力图法(TEG)和Verify Now检测系统对患者血小板反应性的能力及影响因素。方法入选174例经皮冠状动脉介入治疗(PCI)术后且口服阿司匹林和氯吡格雷双联抗血小板治疗的患者为研究对象。用LTA法、TEG法和Verify Now法检测血小板聚集功能。结果 LTA组、TEG组和Verify Now组的高血小板反应性(HPR)检出率分别为56.64%(64例/113例),60.38%(32例/52例)和17.24%(15例/87例),LTA法和TEG法的HPR检出率比较,差异无统计学意义(P>0.05),Verify Now法的HPR检出率与LTA和TEG法比较,差异均有统计学意义(均P<0.001)。结论 Verify Now法相比于LTA法和TEG法可能存在高估氯吡格雷抗血小板疗效的问题,3种方法对于临床结局的预测价值有待随访结果验证。     

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.     

Predicting ischaemic events using platelet reactivity in patients receiving clopidogrel: Indirect meta‐comparison among VerifyNow,light transmission aggregometry and thromboelastography

The present study compared performances of the three major methods used for assessing platelet reactivity (PR)—VerifyNow, light transmission aggregometry (LTA) and thromboelastography (TEG)—to predict ischaemic events in patients receiving clopidogrel. PubMed, EMBASE and the Cochrane Library were searched from their inception to April 2019 for prospective studies that examined PR using VerifyNow, LTA or TEG and the incidence of ischaemic events. The investigated diagnostic indices include sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio and area under the receiver operating characteristic curves (AUC) of VerifyNow, LTA and TEG, respectively. A total of 26 prospective studies involving 22 185 patients were included in the analysis. The pooled AUC was 0.71 (95% CI: 0.67‐0.75) for VerifyNow, 0.60 (95% CI: 0.55‐0.64) for LTA and 0.81 (95% CI: 0.77‐0.84) for TEG. Results of indirect comparisons indicated the AUC of VerifyNow was higher than that of LTA (1.18, 95% CI: 1.08‐1.30) and lower than that of TEG (0.88, 95% CI: 0.82‐0.94). TEG outperformed the other two methods for assessing PR in all predictive measures, including sensitivity, specificity, PLR and NLR. Despite a lack of studies that directly compared the three methods, our findings suggest that TEG should be recommended.     

Resistance to antiplatelet drugs: what progress has been made?

Introduction: Despite well-documented efficacy, recurrent thrombotic event occurrences, particularly stent thrombosis, have been repeatedly demonstrated in stented patients treated with aspirin and clopidogrel. The latter observation stimulated the close scrutiny of the pharmacodynamic effects of clopidogrel and revealed the ‘wide variability’ and the phenomenon of ‘antiplatelet resistance’. High on-treatment platelet reactivity to ADP (HPR) during clopidogrel therapy is an independent risk factor for ischemic event occurrences in post-percutaneous coronary intervention (post-PCI) patients. Recent observational studies demonstrated a link between low on-treatment platelet reactivity to bleeding. The concept of a ‘therapeutic window’ of P2Y₁₂ receptor reactivity associated with both ischemic event occurrence (upper threshold) and bleeding risk (lower threshold) has been proposed.

Areas covered: An update on and a brief review of the current knowledge on antiplatelet resistance were presented. Evidence available from studies evaluating aspirin resistance and high and low on-treatment platelet reactivity to ADP during P2Y₁₂ receptor blocker therapy was collected from a selective literature search.

Expert opinion: The available evidence indicates that HPR is an independent risk factor for post-PCI ischemic event occurrences. The therapeutic window concept for the P2Y₁₂ receptor blocker therapy may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome.     

Esomeprazole and rabeprazole did not reduce antiplatelet effects of aspirin/clopidogrel dual therapy in patients undergoing percutaneous coronary intervention: a prospective,randomized, case–control study

Objectives: Controversy has been prompted based on drug interaction between proton pump inhibitors (PPIs) and aspirin/clopidogrel leading to weakened effects. However, whether such interaction was drug-specific or class effect remains controversial. This study predicted the impact of esomeprazole and rabeprazole on efficacy of dual antiplatelet therapy (DAPT).

Methods: This study, involving 150 patients, evaluated the efficacy of DAPT upon concomitant use of esomeprazole (40 mg/d) or rabeprazole (20 mg/d). Platelet reactivity was assessed by value of ADP-induced light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) at day 1, day 3 and day 30 end points after initiation of DAPT.

Results: No significance were observed by post-hoc analysis of treatment-by-period interaction in LTA value and VASP-PRI value when compared with non-PPI users, which suggests no carryover effect in both PPIs over the 30-day treatment period. Moreover, no statistical differences was in LTA or VASP-PRI value in esomeprazole group while rabeprazole group showed decreased in antiplatelet function of DAPT at the day 3 and day 30 end points.

Conclusion: Although antiplatelet effect of DAPT were not affected upon concomitant use of both PPIs over the 30-day treatment period, esomeprazole exerts much more stable impact on antiplatelet effect than rabeprazole among respective end points.     

ROLE OF PLATELET CYTOSOLIC CALCIUM IN THE RESPONSE TO SALT INTAKE IN NORMOTENSIVE SUBJECTS

1. To investigate the role of cytosolic calcium in salt-induced hypertension, a high salt diet was given to young normotensive subjects with or without a family history of hypertension. 2. A high salt diet raised blood pressure significantly in normotensive subjects with a family history compared with the age and gender matched subjects without a predisposition to hypertension. 3. Platelet cytosolic calcium was increased in predisposed subjects in a control period before salt intake. 4. A positive correlation was observed between the changes in mean blood pressure and cytosolic calcium before high salt intake, although salt loading did not induce any significant change in cytosolic calcium. 5. These results suggest that cytosolic calcium plays a role in elevation of blood pressure induced by salt loading in subjects with a family history of hypertension.