缺血性脑卒中的精准抗血小板治疗

(首都医科大学附属北京天坛医院神经内科，北京 100050)

脑卒中防治50年来，由于抗血小板和降压降脂等二级预防治疗，缺血性脑卒中的年复发率降低近50%[1]。其中，抗血小板治疗因可以显著降低缺血性脑卒中的卒中复发率，已被多个国家治疗指南推荐为卒中二级预防的重要组成部分[2-3]。

血小板通过黏附、聚集、释放、收缩等过程形成血栓，抗血小板药物则主要通过抑制血小板而达到抗血栓形成的目的。上世纪80年代，阿司匹林作为抗血小板药物被美国食品和药物管理局批准上市后，陆续有多种抗血小板药物通过批准并被广泛应用于临床。上世纪90年代，作为最先且最广泛被应用于临床的抗血小板药物，阿司匹林被认为是缺血性脑卒中一级、二级预防及急性期治疗不可或缺的药物[4-6]。然而，循证医学证据表明，阿司匹林仅能将卒中患者心血管事件的复发风险降低13%，仍有30%～40%的患者在接受阿司匹林抗血小板治疗期间出现新发脑缺血事件[7]。究其原因，阿司匹林抵抗可能是主要因素[8]。随后，研究者开始寻求新的、更安全有效的抗血小板药物，氯吡格雷便应运而生。经典的CAPRIE(Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events)研究表明，长期服用氯吡格雷75 mg/d与阿司匹林325 mg/d相比，卒中复发风险相对降低8.7%[9]，由此确定了氯吡格雷在全球范围内缺血性卒中预防及治疗的一线用药地位。

为进一步优化抗血小板治疗的方案，降低卒中患者血管事件复发风险，本世纪初，研究者开始尝试将阿司匹林与其他抗血小板药物联合应用于缺血性脑血管病二级预防。早期的三大临床随机对照试验，即MATCH (Management of ATherothrombosis with Clopidogrel in High-risk patients)、PRoFESS(Prevention Regimen For Effectively avoiding Second Strokes)及SPS3(Secondary Prevention of Small Subcortical Strokes)研究表明，阿司匹林联合其他抗血小板药物用于抗血小板治疗可增加出血风险26%～42%，出血抵消获益[10-12]，故临床不推荐使用[2]。而近些年公布的几项具有代表性的大型临床对照试验，如氯吡格雷应用于伴有急性非致残性脑血管事件高危人群的疗效研究(CHANCE)、SAMMPRIS(Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis)、CARESS(Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis)、CLAIR(Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis)、ARCH(Aortic Arch Related Cerebral Ha-zard)等均表明，在某些特定缺血性卒中病因及发病类型的脑卒中患病人群中，双联抗血小板与单一抗血小板治疗相比，能相对降低卒中复发风险24%～40%[13-17]。然而，仍有部分人群不能从双联抗血小板治疗中获益，原因可能与血小板反应多样性有关[18]。血小板反应多样性与分子生物学因素息息相关，包括蛋白组学、代谢组学因素(糖代谢、吸烟、肾功能等影响肝酶或血小板受体表达)和基因组学因素(细胞色素酶P450[CYP]、P2Y12等基因多态性)等[18]。

因此，缺血性脑卒中患者若想从抗血小板治疗中获益更多，则需要明确可获益的特定病因及发病类型的患病人群，在该部分人群中，明确可额外获益的蛋白及代谢组学因素水平，再进一步明确可额外获益的基因组学因素。在此基础上，便实现了缺血性脑卒中抗血小板的精准治疗。下文将从上述3方面对精准抗血小板治疗进行综述。

1 定位可获益的特定病因及发病类型的患病人群

1.1 高危非致残性脑卒中

高危非致残性脑卒中包括轻型卒中(NIHSS≤4)和高危短暂性脑缺血发作(TIA)。研究表明，高危非致残性脑卒中90 d内卒中复发风险为10%～20%，且接近半数发生在48 h内；而中重度卒中(NIHSS>4)的90 d卒中复发风险较低，仅为3%～4%[19]。在我国，基于社区流行病学调查和医院队列研究发现，非致残性脑卒中患者在卒中患者总体中的比例超过50%，且卒中复发风险是致残性脑卒中的4倍[20-21]。因此，高危非致残性脑卒中应该作为我国脑血管病防控的最佳人群。FASTER(Fast Assessment of Stroke and Transient ischaemic attack to prevent Early Recurrence)研究表明，高危非致残性脑卒中患者，发病24 h内给予阿司匹林81 mg/d、氯吡格雷首次负荷剂量300 mg，维持剂量75 mg/d，与单用阿司匹林相比，90 d卒中复发风险绝对降低3.8%[22]。CHANCE研究表明，发病24 h内给予阿司匹林首次负荷剂量150～300 mg，维持剂量75 mg/d，联合用氯吡格雷首次负荷剂量300 mg，维持剂量75 mg/d，21 d后改为单用氯吡格雷75 mg/d，与全程单用阿司匹林75 mg/d相比，患者90 d时的卒中风险相对降低32%，并且未增加出血风险[13]。上述研究结果表明，高危非致残性脑卒中患者可作为急性期短程阿司匹林联合氯吡格雷强化抗血小板治疗的目标获益人群。而对于中度卒中(430)患者，抗血小板药物需慎用。

1.2 多发脑梗死

TOAST病因分型中，大动脉粥样硬化性狭窄是缺血性脑卒中的主要病因[23]，而由动脉粥样硬化引起的动脉-动脉栓塞，是导致多发脑梗死的主要机制[24]。CHANCE影像学亚组研究指出，与无梗死相比较，伴有多发梗死和单发梗死的患者90 d卒中复发风险更高。与单一抗血小板治疗相比，双联抗血小板治疗能够显著降低伴有多发梗死患者90 d的卒中复发风险，而在无梗死患者及伴有单发梗死的患者中，双联抗血小板与单一抗血小板治疗无显著差异。该研究表明，由动脉-动脉栓塞引起的多发脑梗死患者可作为急性期短程阿司匹林联合氯吡格雷强化抗血小板治疗的目标获益人群。而影像学提示单发梗死或无梗死的患者，双联抗血小板与单一抗血小板治疗的90 d获益相当。

1.3 颅内动脉狭窄(ICAS)

ICAS在亚洲人群更为常见[25-26]。CICAS研究也证实，在所入组的缺血性脑卒中和TIA患者中，合并颅内外动脉狭窄或者闭塞病变者比例高达46.6%，其中单纯ICAS者为37.5%；而ICAS狭窄程度与卒中复发风险呈正相关[27]。WASID(Warfarin versus Aspirin for Symptomatic Intracranial Disease)研究指出，ICAS率≥70%的症状性ICAS患者，脑卒中复发风险高于狭窄率50%～70%的患者[28]。SAMMPRIS研究印证了WASID研究结果，认为对于合并重度ICAS(70%～99%)的新发缺血性脑卒中或TIA患者，阿司匹林联合氯吡格雷强化抗血小板治疗与Wingspan支架植入相比，可以显著降低病人1、2和3年卒中的复发风险[29]。CHANCE研究亚组分析也提示，合并ICAS的高危非致残性脑卒中患者，90 d的卒中复发风险显著高于非合并者[30]；在发病急性期给予短程阿司匹林联合氯吡格雷强化抗血小板治疗，与单用阿司匹林相比，卒中复发风险有降低趋势。上述研究表明，合并ICAS的缺血性脑卒中患者应作为抗血小板治疗的目标获益人群，且阿司匹林联合氯吡格雷强化抗血小板治疗可能比单用阿司匹林获益更多。

2 定位可额外获益的蛋白及代谢组学因素

2.1 糖代谢

高糖血症是脑卒中重要的独立危险因素，与缺血性脑卒中的不良预后显著相关。脑卒中伴有糖代谢异常(包括糖尿病、空腹血糖受损、应激性高糖血症、胰岛素抵抗、β细胞功能受损等)的患者，卒中复发风险显著升高[31-35]。研究发现，当糖化白蛋白低于15.5%时，轻型卒中或TIA患者能更多地从阿司匹林联合氯吡格雷抗血小板治疗中获益[36]。关于其机制，可能是由于糖代谢异常导致血小板表面的P2Y12受体表达增加，从而导致血小板活性增加，抑制了与该受体相结合的氯吡格雷的抗血小板作用，使得卒中复发风险增加。至于糖代谢异常是否影响血小板表面其他受体的表达，目前尚无研究报道。因此，根据目前的研究结果，糖代谢正常的缺血性脑卒中患者，包括糖化白蛋白<15.5%、空腹血糖正常、无糖尿病史、无应激性血糖增高、无胰岛素抵抗或β细胞功能受损者，应该作为抗血小板治疗，尤其是联合氯吡格雷的强化抗血小板治疗的目标获益人群。关于通过快速检测患者血小板表面受体的表达水平来指导抗血小板治疗目前尚未有研究报道，可作为未来抗血小板精准治疗的新方向。

2.2 吸烟

多项研究表明，吸烟是脑卒中的独立的危险因素[37]。但多项研究亦显示，吸烟可能会促进氯吡格雷的代谢，从而改善缺血性脑卒中患者的临床预后，此现象被称之为“吸烟悖论”[38-40]。基于CHANCE研究的分析似乎印证了该悖论，该研究发现，在吸烟者中，氯吡格雷联合阿司匹林强化抗血小板治疗与单用阿司匹林相比，能显著降低脑血管事件复发风险；在非吸烟者中，上述差异仍存在但程度减低[41]。其机制有多种假说，有研究认为，吸烟可以诱导肝酶CYP1A2，从而加快氯吡格雷转化为活性形式的速度[42]。也有研究认为，吸烟可以提高人体内P2Y12受体表达水平及其与氯吡格雷的结合能力，从而可以增强氯吡格雷的生物学作用和临床疗效[43]。因此，缺血性脑卒中患者中，吸烟者可能是抗血小板治疗，尤其联合使用氯吡格雷的抗血小板治疗的目标获益人群。但吸烟的数量及持续时间是否会对氯吡格雷抗血小板作用产生影响，有待进一步研究。

2.3 肾功能

慢性肾脏疾病与较高的卒中患病率相关[44]，且估算的肾小球滤过率(eGFR)减低可能是急性缺血性脑卒中卒中复发风险、合并症及死亡率增高的预测因子[45-46]。基于CHANCE研究的分析也印证了上述研究结果，该研究提示肾功能正常(eGFR≥90 mL/min/1.73 m2)以及轻度慢性肾功能损害者(eGFR 60～89 mL/min/1.73m2)，阿司匹林联合氯吡格雷与单用阿司匹林相比，可显著降低卒中的复发风险，该结果并未在重度肾功能损害(eGFR<60 mL/min /1.73 m2)的患者中发现[47]。因此，可以把eGFR ≥60 mL/min/1.73 m2的缺血性脑卒中患者作为阿司匹林联合氯吡格雷抗血小板治疗的目标获益人群。

2.4 其他

也有一些研究提示，某些血清标记物也可以作为定位可额外获益的代谢组学因素。有研究指出，动脉斑块易损的标记物Lp-PLA2-A、sCD40L增高，卒中复发风险相应增高，从阿司匹林联合氯吡格雷双抗治疗中获益也更多[48-49]。另有研究指出，ICAS患者中hsCRP低者可从阿司匹林联合氯吡格雷双抗治疗中显著获益。上述研究提示我们，某些血清标记物如Lp-PLA2-A、sCD40L和hsCRP等增高的缺血性脑卒中患者可作为抗血小板治疗的目标获益人群。

3 基因组学

3.1 CYP2C19基因多态性

CYP2C19是肝脏合成的细胞色素P450系统的多种药物代谢酶之一，在氯吡格雷代谢过程中扮演最重要的角色。多项研究表明，CYP2C19基因多态位点中，CYP2C19*2、CYP2C19*3及CYP2C19*17与氯吡格雷的血小板反应变异性密切相关[50-51]。国际上把CYP2C19*2、CYP2C19*3称为失功能等位基因，把CYP2C19*17称为功能获得等位基因。根据其对氯吡格雷代谢作用强弱对CYP2C19基因进行代谢分型，将仅携带野生型等位基因*1的基因表型(*1/*1)称为正常代谢型，携带一个失功能等位基因的基因表型(*1/*2，*1/*3)称为中间代谢型，同时携带两个失功能等位基因的基因表型(*2/*2、*2/*3，*3/*3)称为慢代谢型；携带*17基因表型称为强代谢型(*1/*17，*17/*17)；而*2/*17、*3/*17组合的基因表型，因其功能尚未能明确，故称之为未知型[52]。

临床上，脑卒中患者CYP2C19基因变异型和氯吡格雷疗效之间的相关性仍缺乏大样本的随机对照研究证据。有小样本研究表明，CYP2C19失功能等位基因与接受氯吡格雷抗血小板治疗的脑卒中患者的不良临床预后相关[53]。也有研究表明，接受氯吡格雷抗血小板治疗的缺血性脑卒中患者中，携带CYP2C19失功能等位基因者，复合血管事件的发生风险显著增加[54-55]。基于CHANCE的基因亚组研究发现，不携带CYP2C19失功能等位基因者，阿司匹林联合氯吡格雷抗血小板治疗与单用阿司匹林相比，卒中复发风险显著降低，相似的结果未在携带CYP2C19失功能等位基因者中发现。该研究真正开启了缺血性脑卒中精准抗血小板治疗的新时代，当年被评为脑血管病领域五项进展之一。该研究提示我们，仅有CYP2C19的基因表型为正常代谢型者，才能从阿司匹林联合氯吡格雷抗血小板治疗中获益，该部分人群应作为阿司匹林联合氯吡格雷抗血小板治疗的目标获益人群。有研究表明，对于中间代谢型基因表型者，氯吡格雷适当加量也可有效降低脑卒中复发风险，但需要权衡出血风险与获益。而对于慢代谢型基因表型者，氯吡格雷即使增加4倍常规剂量也不能增加获益[56]。对于强代谢型基因表型者，因目前研究较少，获益并不明确。

3.2 P2Y12受体基因多态性

氯吡格雷通过肝脏酶的两步氧化代谢，生成活性产物，尔后与血小板表面的P2Y12受体不可逆结合，发挥其抗血小板聚集的作用。故P2Y12受体的基因多态性也可能影响氯吡格雷的抗血小板作用。有研究发现，外周动脉疾病患者携带至少一个34T等位基因者，应用氯吡格雷抗血小板治疗21个月后，神经系统事件的发生率是只携带34C等位基因患者的4.02倍[57]。关于P2Y12受体其他等位基因如C34T、G52T和T744C等，其基因多态性与氯吡格雷抗血小板作用之间的关系目前尚未明确[58-59]。故尚不能根据P2Y12受体的基因表型差异来指导缺血性脑卒中的抗血小板精准治疗。

综上，现阶段对于缺血性脑卒中，我们已实现将个体病变与分子生物学差异相结合的精准抗血小板治疗。随着基因组测序技术的快速进步以及生物信息与大数据科学的交叉应用，相信在不久的将来，缺血性脑卒中的抗血小板治疗会实现进一步精准化，届时将有更多的缺血性脑卒中患者从抗血小板治疗中获益。

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