我国是糖尿病大国,根据2017年国际糖尿病联盟(IDF)发布的最新糖尿病地图:中国糖尿病人群达1.14亿,居世界首位。既往研究显示,糖尿病患者中有三分之一发生急性冠状动脉综合征(ACS),与非糖尿病患者相比,发生ACS的糖尿病患者主要复发性不良心脏事件发生率增加2倍以上。与非糖尿病患者相比,糖尿病患者多为高龄、合并症复杂的患者。因此,考虑到合并糖尿病患者的复杂情况,我们更需选择有充分临床使用经验的抗血小板药物。而几十年内,阿司匹林与氯吡格雷积累了最丰富的临床应用证据,可以说是目前兼具疗效和安全性的最理想选择。下面就让我们一起盘点阿司匹林与氯吡格雷的那些研究。
ACS合并糖尿病患者的抗血小板治疗盘点
1、氯吡格雷与阿司匹林
阿司匹林是抗血小板治疗的重要基础,可用于动脉粥样硬化血栓性疾病患者复发性缺血事件的二级预防,包括糖尿病患者。在有缺血事件风险的患者中(包括MI,近期卒中或外周动脉疾病),CAPRIE研究比较了氯吡格雷(每日75 mg)与高剂量阿司匹林(每日325 mg)在二级预防中的临床获益,研究包括约20%的糖尿病患者(n= 3,866)。结果显示氯吡格雷组复合终点(血管性死亡,心肌梗死或缺血性卒中)的风险显著降低(P=0.043)。且氯吡格雷治疗的获益在糖尿病亚组中更高(15.6%vs. 17.7%,P=0.042)。因此,在ACS合并糖尿病患者的抗血小板单药二级预防中,氯吡格雷是更优的选择。
2、氯吡格雷+阿司匹林
ACS或接受经皮冠状动脉介入治疗(PCI)的冠心病患者血栓形成风险高,对阿司匹林的反应性低,尤其是糖尿病患者;因此,联合非TXA2途径不同抗血小板药物共同作用可起到更好作用。多项安慰剂随机对照研究(RCT)证实了氯吡格雷联合阿司匹林治疗的临床获益(见下表)。CURE研究将约12 000例不稳定性心绞痛或NSTEMI的患者随机分为阿司匹林(75~325 mg/天)联合氯吡格雷(75 mg /天)和单用阿司匹林两组,氯吡格雷双联抗血小板(DAPT)组结果显示血管性死亡,心肌梗死或卒中的复合终点相对风险降低(RRR)20%(分别为9.3%和11.4%,P<0.001),而糖尿病患者主要复合终点事件相对风险降低(RRR)17%。而在CURE研究和其PCI亚组,包括随后发表的CREDO研究,PCI-CLARITY研究我们都可看到阿司匹林联合氯吡格雷在伴糖尿病患者中的获益。这些研究充分证明,氯吡格雷+阿司匹林在ACS合并糖尿病患者中的有效性和安全性。
抗血小板治疗ACS合并糖尿病或PCI临床疗效的随机临床研究主要结果
氯吡格雷+阿司匹林为基础的抗血小板治疗探索
尽管DAPT与COX-1抑制剂阿司匹林和强效P2Y12受体抑制剂如普拉格雷和替卡格雷的临床疗效有所提高,但在相当大比例的ACS中观察到复发性缺血事件(~10%/年)和出血风险增加。表明当前DAPT在减轻缺血事件中的上限效应,而研究者开始对具有不同机制的药物用作DAPT的辅助治疗的方案进行探索。
西洛他唑是PDE3和腺苷再摄取的双重抑制剂。在行PCI治疗的患者中观察到氯吡格雷+阿司匹林联用西洛他唑这种三联疗法的主要获益,包括靶病变血运重建率降低甚至支架内血栓形成。而且,在最近的一项荟萃分析中,加用西洛他唑降低血管造影再狭窄的风险,并且降低支架内血栓形成风险43%,且无大出血增加。中国DECLARE-DIABETES研究比较三联抗血小板治疗(阿司匹林+氯吡格雷+西洛他唑)与DAPT(阿司匹林+氯吡格雷)对接受药物洗脱支架(DES)的糖尿病患者的疗效,结果显示,三联抗血小板治疗组6个月内再狭窄率、9个月内靶血管重建率及主要心血管不良事件发生率均低于DAPT组(P=0.033;P=0.034;P=0.066)。且未发现TIMI大小血风险差异。值得注意,虽然糖尿病亚组在三联疗法中显示更明显获益。但西洛他唑的使用受限于高频率的不良反应(例如,头痛,心悸和胃肠道紊乱)和增加的戒断风险,因此,对于加用西洛他唑的三联治疗需充分评估患者的耐受程度。
综上,ACS合并糖尿病患者的抗血小板单药二级预防中,氯吡格雷是更优的选择。而以阿司匹林联合氯吡格雷为基础的方案仍是目前冠心病合并糖尿病患者抗血小板治疗的基石,多年来积累了丰富的临床应用数据,是有最充分临床使用基础和询证依据的理想选择。
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