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负荷剂量氯吡格雷联合阿司匹林治疗急性脑梗死疗效观察

作者 / Author:张继中 郑远征 李 珂 刘 崇

摘要 / Abstract:

目的 观察不同剂量氯吡格雷联合阿司匹林或单用阿司匹林治疗急性脑梗死的临床效果。方法 选取338例脑梗死患者,随机分为联合负荷剂量组(104例)、联合常规剂量组(116例)和阿司匹林负荷剂量组(118例),比较各组总有效率及美国国立卫生研究院卒中量表(NIHSS)评分改善情况。结果 联合负荷剂量组总有效率88.5%,高于联合常规剂量组的72.4%和阿司匹林负荷剂量组的67.7%,差异有统计学意义(P<0.05)。出院时再次应用NIHSS进行评估,3组NIHSS评分均低于治疗前,且联合负荷剂量组与联合常规剂量组、阿司匹林负荷剂量组比较差异有统计学意义(P<0.05),3组不良反应差异无统计学意义(P>0.05)。结论 负荷剂量阿司匹林联合氯吡格雷治疗脑梗死临床效果满意,可提高患者预后质量。

关键词 / KeyWords:

脑梗死,负荷剂量,氯吡格雷,阿司匹林,抗血小板聚集剂
负荷剂量氯吡格雷联合阿司匹林治疗急性脑梗死疗效观察
张继中 郑远征 李 珂 刘 崇
南阳市第一人民医院神经内科,河南南阳 473000
作者简介:张继中,Email:13938976671@163.com
通信作者:郑远征,Email:1471909104@qq.com
 
摘要 目的 观察不同剂量氯吡格雷联合阿司匹林或单用阿司匹林治疗急性脑梗死的临床效果。方法 选取338例脑梗死患者,随机分为联合负荷剂量组(104例)、联合常规剂量组(116例)和阿司匹林负荷剂量组(118例),比较各组总有效率及美国国立卫生研究院卒中量表(NIHSS)评分改善情况。结果 联合负荷剂量组总有效率88.5%,高于联合常规剂量组的72.4%和阿司匹林负荷剂量组的67.7%,差异有统计学意义(P<0.05)。出院时再次应用NIHSS进行评估,3组NIHSS评分均低于治疗前,且联合负荷剂量组与联合常规剂量组、阿司匹林负荷剂量组比较差异有统计学意义(P<0.05),3组不良反应差异无统计学意义(P>0.05)。结论 负荷剂量阿司匹林联合氯吡格雷治疗脑梗死临床效果满意,可提高患者预后质量。
关键词】 脑梗死;负荷剂量;氯吡格雷;阿司匹林;抗血小板聚集剂
中图分类号】  R743.33    【文献标识码】  A    【文章编号】  1673-5110(2019)03-0281-07  DOI:10.12083/SYSJ.2019.03.053
 
Clinical observation of loading dose clopidogrel combined with aspirin on cerebral infarction
ZHANG JizhongZENG YuanzhengLI KeLIU Chong
Department of Neurologythe First Hospital of NanyangNanyang 473000,China
Abstract  Objective  To integrative clinical efficacy of load-dose clopidogrel combined with aspirin in treatment of patients with cerebral infarction.Methods  338 patients with cerebral infarction were randomly divided into three groups:the group with loading dose clopidogrel and aspirin (104 cases),the group with common dose clopidogrel and aspirin (116 cases) and the group with loading dose aspirin (118 cases).The NHISS score,clinical efficacy and adverse drug reactions between groups were compared.Results  After the treatment,the NHISS score of three groups were significantly decreased,and the NHISS score of loading dose clopidogrel and aspirin group was significantly lower than the other groups(P<0.05).The total effective rate of loading dose clopidogrel and aspirin group was significantly higher than the other groups(P<0.05),while adverse drug reactions rate of three groups was no significantly difference.Conclusion  The treatment of load-dose clopidogrel combined with aspirin for cerebral infarction has a curative effect,and it is worth for clinical promotion.
Key words】  Cerebral infarction;Loading dose;Clopidogrel;Aspirin;Antiplatelet aggregation agent
 
        脑梗死是由于脑内血液循环异常导致的脑细胞缺血性功能障碍[1-5]。脑梗死急性期的治疗尤为重要,如何能够早期干预、阻止病情加重及脑梗死的进展目前研究的重点[6-10]。本次研究观察2014-01—2016-04采用首剂负荷剂量氯吡格雷与阿司匹林二联双抗治疗急性脑梗死的有效性及安全性。
 
1  资料与方法
1.1  研究对象 选自南阳市第一人民医院住院的急性脑梗死患者。入院标准:符合2004年全国脑血管病防治指南中相关诊断标准,年龄29~78岁,起病时间2~36 h,无明确心源性脑栓塞依据;达不到溶栓标准、错过溶栓治疗时间窗或家属拒绝溶栓;入院后15~30 min内行头颅CT检查排除脑出血及大面积脑梗死,入院2~4 d后行1.5T磁共振MRI+MRA检查,其DWI序列显示高信号影且为责任病灶;病人或家属知情同意并签字;血压<180/100 mmHg(未达标者先降压处理至达标)。排除标准:短暂脑缺血发作者;存在意识障碍者;既往有血液系统疾病、肿瘤,严重肝肾疾病、严重消瘦、恶病质者;活动性消化道溃疡,近期有内脏出血史;有明确栓塞病因或高度怀疑为栓塞的患者。退出标准:入院后头颅MRI检查为大面积脑梗死;入院后检查考虑为血管炎等患者;治疗期间出现严重上消化道大出血、皮肤黏膜大面积出血点或大片状瘀斑,血小板低于正常低值,出凝血四项两项以上指标严重异常者;对氯吡格雷及阿司匹林过敏者;治疗不足12 d或自动出院患者。退出病例不纳入疗效分析,因并发症退出纳入安全性分析。
1.2  治疗方法 自设立方案起,科内6位值班医生轮流值班,2位医生一组,分为阿司匹林负荷量组、二联负荷量组及二联常规量组,各组收治符合标准病人纳入各自治疗组;阿司匹林负荷剂量组首次口服负荷剂量阿司匹林300 mg(拜耳公司,规格100 mg/片);二联负荷量组首次口服氯吡格雷(商品名波立维,规格75 mg/片)300 mg,拜阿司匹林(拜耳公司,规格100 mg/片)300 mg;二联常规量组首次口服氯吡格雷75 mg,拜阿司匹林100 mg。入院后第2天3组均口服常规氯吡格雷75 mg,拜阿司匹林100 mg,治疗12~14 d。其他扩容、抗氧化、抗自由基、改善循环、降脂、稳定斑块及保护胃黏膜等基础治疗均相同,期间不使用肝素及其他抗凝血药。
1.3  病例情况 本次研究中366例急性脑梗死患者,退出28例,参与并完成研究338例,分为3组,其中阿司匹林负荷量组118例,男62例,女56例,年龄29~78(52.9±8.6)岁;二联常规量组116例,男59例,女57例,年龄32~79(51.1±9.3)岁;二联负荷量组104例,男54例,女50例,年龄29~78(52.9±8.6)岁。3组合并糖尿病及高血压病等情况差异无统计学意义(P>0.05)。
1.4  观察指标  (1)1周内进展脑梗死患者:进展性脑梗死进展定为NIHSS评分较入院时增加2分以上,以未进展为有效;吞咽功能评估依据吞咽障碍评价标准[1]:评分较入院时下降2分以上;(2)治疗前后神经功能缺损评分:入院时及治疗后12~14 d即进行神经功能缺损评分;(3)不良反应。急查血常规、出凝血四项,入院第2天抽血常规检查肝肾功能、出凝血四项;出院前12~14 d再次进行神经功能缺损评分,再次复查血常规、肝肾功能及出凝血四项。观察入院前1周病情加重病例。入院24 h内、入院第2天和第3天连续测评血常规、出凝血四项。
1.5  统计学方法 使用SPSS 12.0统计软件进行数据分析,计量资料用均数±标准差(x±s)表示,采用t检验,定性资料比较采用χ2检验,P<0.05为差异有统计学意义。
 
2  结果
2.1  疗效分析  治疗2周后3组有效率比较见表1。
2.2  治疗前后3组神经功能缺损评分比较 治疗前3组评分差异无统计学意义(P>0.05),治疗后差异有统计学意义(P<0.05)。见表2。
表1  3组有效率比较  (n)
Table 1  Comparison of patients with progressive cerebral infarction in 3 groups  (n)
组别 n 进展病例 未进展病例 有效率/%
阿司匹林负荷量组 118 38 80 67.7
二联常规量组 116 32 84 72.4
二联负荷量组 104 12 92 88.5★△
合计 338 82 256 75.7
 注:3组比较,χ2=13.93,P<0.05;与阿司匹林负荷量组比较,χ2=0.59,P>0.017;与阿司匹林负荷量组比较,χ2=13.53,P<0.01;与二联常规量组比较,χ2=8.83,P<0.01
 
表2  3组治疗前后神经功能缺损评分比较  (x±s)
Table 2  Comparison of neurological deficit scores before and after treatment in 3 groups  (x±s)
组别 n 治疗前 治疗后2
阿司匹林负荷量组 118 11.23±2.28 8.23±1.78
二联常规量组 116 10.78 ±2.39 7.96±1.83
二联负荷量组 104 11.37 ±2.21 5.72±1.71*
              注:与阿司匹林负荷量组比较,P>0.05;与阿司匹林负荷量组及二联常规量组比较,*P<0.05
 
2.3  不良反应  3组治疗期间均3次检查出凝血四项,血常规,3组均未发现明显异常;阿司匹林负荷量组9例出现异常,其中2例皮肤瘀斑及皮下出血点,1例鼻出血,1例牙龈出血,胃部不适4例,1例消化道出血;二联常规量组8例出现异常,其中3例皮肤瘀斑及皮下出血点,1例牙龈出血,胃部不适3例,1例脑出血;二联负荷量组8例出现异常,其中3例皮肤瘀斑及皮下出血点,3例鼻出血,1例牙龈出血,胃部不适3例,1例消化道出血,脑出血1例。3组均未出现死亡。3组不良反应比较差异无统计学意义(P>0.05)。
 
3  讨论
        急性脑梗死早期治疗是减小梗死面积,挽救脑细胞、减轻残废程度的关键环节,是治疗的黄金时间段。目前公认早期溶栓[11-16]、早期开通闭塞的血管[17-22]、恢复缺血区血液供应[23-30]是最为理想的治疗手段。早期溶栓治疗受溶栓标准、溶栓时间窗、医院设备等多种因素制约,导致能够进行溶栓的病例较少,大部分病人到达科室时已丧失溶栓时机。
        研究发现,血管内皮细胞损伤、血流状态改变、血液凝固性增多是血栓形成三个条件[31-39],其中血小板在血栓的发生、形成过程最为重要,是血栓性疾病研究的重点[40-49]。研究发现,抑制血小板激活环节很多,在血小板凝集过程中,许多针对不同环节、不同靶点的抗血小板聚集、黏附功能的药物,如血小板ADP受体体拮抗剂、血小板GPⅠb受体拮抗剂、血小板GPⅡb/GPⅢ受体拮抗剂等[50-57],显示出较强大的抗血小板聚集功能。然而,临床中许多患者即便服用阿司匹林,仍然发生新的梗死,不少脑梗死患者常规服用阿司匹林,脑梗死仍然复发,且较多症状缓慢不断进展加重[58]。尤其在脑梗死急性期,可能由于某种应激因素或致栓因子激活的影响,也可能阿司匹林抵抗,服用阿司匹林达不到抑制血栓继续形成的效果,即便联用常规剂量的氯吡格雷(75 mg),虽然显示一定的临床疗效,可能短时间内由于达不到有效血药浓度,达不到扼制病情进展加重的目的[59-61]。研究[62]显示,在急性冠脉综合征患者冠状动脉支架术前给予600 mg高负荷剂量氯吡格雷,继以75 mg/d维持剂量,显示出良好的临床疗效。再次显示出抗血小板凝集治疗在血栓性疾病治疗中的重要地位。研究证实,顿服氯吡格雷(300 mg)2 h即能达到有效血药浓度[63],3 h内达到全面抑制血小板聚集作用,抑制达80%以上,6 h达到稳态血药浓度;而连续口服氯吡格雷75 mg/d,5 d才能可达到有效血药指标。本次研究中,使用首剂负荷量的治疗组进展性脑梗死较阿司匹林负荷量组及二联常规量组明显减少(P<0.05),3组临床神经功能评分比较也存在显著性差异,提示首剂负荷剂量二联抗血小板凝集可能改善急性脑梗死预后,提高患者生存质量。
        血液流变学骤然变化、血脂突发异常均可能导致脑梗死,可采用早期扩容、强化降脂、抗氧化、抗自由基等进行干预[64-66]。本次研究中常规治疗组使用以上措施,依然出现较多加重病例,负荷量治疗组明显优于常规治疗组。脑细胞对缺血缺氧尤为敏感,一旦出现梗死症状,治疗刻不容缓[67-68]。在不能溶栓或血管内治疗的情况下,早期抗血小板治疗能快速达到有效抑制血小板凝集、抑制血栓形成的目的。氯吡格雷的抗血小板作用为浓度依赖性,负荷剂量可能会获得更快、更强的抗血小板作用,减少氯吡格雷抵抗的发生率,改善临床预后[69]。值得关注的是,使用负荷剂量的氯吡格雷可明显增加出血风险,脑出血一旦发生,将导致病情急剧恶化,预后不佳。因此,在临床实际工作中,部分医务人员更倾向于选择较为保守的治疗方案。但多项关于经皮冠状动脉介入治疗急性心肌梗死的临床研究表明,常规使用负荷剂量的氯吡格雷并未导致严重的并发症[63,70-71]。尽管与心肌细胞相比,脑组织在结构和功能上均有明显差异,但这仍可为神经内科医师如何使用氯吡格雷提供有力参考。本研究表明,急性脑梗死患者早期使用负荷剂量二联抗血小板凝集治疗是安全的。
        急性脑梗死患者早期使用负荷剂量二联抗血小板凝集治疗是较为积极的干预措施,临床使用快捷、简单,安全。
 
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(收稿2018-04-18)
本文责编:夏保军
本文引用信息:张继中,郑远征,李珂,刘崇.负荷剂量氯吡格雷联合阿司匹林治疗急性脑梗死疗效观察[J].中国实用神经疾病杂志,2019,22(3):281-287.DOI:10.12083/SYSJ.2019.03.053

Reference informationZHANG JizhongZENG YuanzhengLI KeLIU Chong.Clinical observation of loading dose clopidogrel combined with aspirin on cerebral infarction[J]Chinese Journal of Practical Nervous Diseases201922(3)281-287.DOI10.12083/SYSJ.2019.03.053

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