摘要
阿司匹林(Aspirin,ASA)通过不可逆乙酰化环氧化酶—1(COX—1),抑制血栓素A2的合成而发挥抗血小板作用。每日小剂量阿司匹林(75—150mg)即可显著降低心血管不良事件,因而广泛用于动脉粥样硬化血栓栓塞性疾病。但部分病人由于存在阿司匹林抵抗(Aspirin Resistance,AR),正规口服阿司匹林仍然不能预防心脑血管事件的发生。本研究旨在了解阿司匹林抵抗的发生率、流行病学特征及其危险因素,观察复方丹参滴丸对阿司匹林抵抗病人的干预效果,并探讨有无改善阿司匹林抵抗的作用。
方法入选年龄35～80(平均57.03±13.40)岁,连续口服阿司匹林100mg/晚,至少一周以上的住院病人106例(男44例,女62例),以比浊法测定血小板聚集率,筛选出阿司匹林抵抗及半敏感(Aspirin semiresponders,ASR)者30人。随机分为三组:阿司匹林+复方丹参滴丸组;单服复方丹参滴丸组;对照组(单服阿司匹林)。干预2周后抽血复查血小板聚集率。
结果共检出阿司匹林抵抗者6例,发生率为5.7%;阿司匹林抵抗与半敏感者共30例,发生率为28.3%。阿司匹林抵抗的发生率、阿司匹林抵抗与半敏感的总发生率男女无显著差异。阿司匹林抵抗者血糖显著高于阿司匹林敏感者(7.85±6.246 vs 5.59±1.250 mmol/L,P=0.007),血谷草转氨酶水平也高于阿司匹林敏感者(49.0±59.49vs 27.8±23.66 U/L,P=0.037)。阿司匹林抵抗和半敏感者糖尿病(P=0.030)和血脂紊乱(P=0.020)所占比例高于阿司匹林敏感者。Logistic回归分析显示,糖尿病者发生AR和ASR的危险是非糖尿病者的3.236倍(95%CI 0.988～10.596,P=0.052),血脂紊乱者发生AR和ASR的危险是非血脂紊乱者的3.985倍(95%CI 0.973～16.330,P=0.055),AR和ASR发生的危险都有升高的趋势,但未达到统计学意义。二磷酸腺苷(ADP)诱导的血小板聚集率阿司匹林+复方丹参滴丸组和单用复方丹参滴丸组干预后(60.29%,66.33%)较干预前(70.65%,71.72%)分别下降了10.36%(P=0.010)、5.39%(P=0.042);对照组干预前后无统计学意义。花生四烯酸(AA)诱导的血小板聚集率阿司匹林+复方丹参滴丸组和单用复方丹参滴丸组干预后(12.27%,17.67%)较干预前(24.01%,24.37%)分别下降了11.74%(P=0.000),6.70%(P=0.045)。对照组干预前后无统计学意义。组间比较显示,干预前各组间血小板聚集率无显著差异。而干预后阿司匹林+复方丹参滴丸组ADP诱导的血小板聚集率显著低于对照组,亦低于复方丹参滴丸组;复方丹参滴丸组低于对照组。干预后阿司匹林+复方丹参滴丸组AA诱导的血小板聚集率低于对照组。
结论阿司匹林抵抗的发生率为5.7%;阿司匹林抵抗与半敏感者的总发生率为28.3%,男、女性的发生率无显著差异。阿司匹林抵抗可能与糖尿病、血脂紊乱相关,而与年龄、性别、吸烟、冠心病、心力衰竭、高血压、缺血性脑血管病、平均动脉压升高等无显著相关性。复方丹参滴丸可以增加阿司匹林抵抗病人对阿司匹林的敏感性。复方丹参滴丸可能通过多部位、多层面和多靶点抑制血小板活化及聚集功能,可能通过抑制不依赖于环氧化酶—1的血小板旁路活化途径,与阿司匹林发挥协同抗血小板作用。复方丹参滴丸可能成为阿司匹林抵抗的有效干预药物,改善患者的临床预后。
Aspirin (acetylsalicylic acid, ASA) reduces the activation and aggregation of platelets by irreversibly acetylating cyclooxygenase-1 (COX-1), and thereby reduces thromboxane A2 produced by platelets. Widespread use of low dose aspirin(75—150mg per day) has reduced adverse cardiovascular events significantly. However, because the existence of aspirin resistance(AR), a number of patients don't get much benefit from aspirin. Our objective is to find out the prevalence, epidemiologic feature and risk factors of aspirin resistance, and to investigate the effect of Cardiotonic Pill in aspirin resistance.
Methods 106 hospitalized patients(age 35-80, average 57.03±13.40), who intake aspirin 100 mg per day for at least 1 week were enrolled into our trial. 30 patients with Aspirin Resistance and Aspirin Semiresponders (ASR) were selected according to platelet aggregation, and they were randomized to three groups: Aspirin plus Cardiotonic Pill, Cardiotonic Pill only, Aspirin only. Platelet aggregation was reevaluated in two weeks.
Results AR was found in 6 patients (5.7%), AR and ASR were found in 30 patients(28.3%), The prevalence of AR, AR and ASR were similar in male and female. The level of blood glucose (7.85±6.246 vs 5.59±1.250 mmol/L, P = 0.007) and AST(49.0±59.49 vs 27.8±23.66 U/L, P=0.037) was higher in AR, compared with Aspirin sensitive patients. There were more diabetes mellitus(P=0.030) and lipid disorder(P=0.020) patients in AR and ASR, compared with Aspirin sensitive patients. Logistic regression revealed that the risk of AR and ASR was 3.236 times (95%CI 0.988～10.596, P = 0.052) in diabetes mellitus compared with non- diabetes mellitus, and 3.985 times (95%CI 0.973～16.330, P = 0.055) in lipid disorders compared with non-lipid disorders, but both did not have statistic significance. Adenosine diphosphate (ADP)-induced platelet aggregation of group aspirin plus Cardiotonic Pill, Cardiotonic Pill decreased 10.36%(P=0.010), 5.39%(P = 0.042)respectively after interference, there was no significant change in group aspirin. Arachidonic acid (AA) -induced platelet aggregation of group aspirin plus Cardiotonic Pill, Cardiotonic Pill decreased 11.74% (P =0.000) , 6.70% (P = 0.045) respectively, there was no significant change in group aspirin. Group comparison revealed that platelet aggregation has no significant difference in all groups before interference, but ADP-induced platelet aggregation in group aspirin plus Cardiotonic Pill was lower than group Aspirin significantly. ADP-induced platelet aggregation in group Cardiotonic Pill, AA-induced platelet aggregation in group aspirin plus Cardiotonic Pill was lower than group aspirin after interference.
Conclusion The prevalence of AR is 5.7%, total prevalence of AR and ASR is 28.3%. The prevalence of AR, AR and ASR were similar in male and female. Diabetes mellitus and lipid disorder might be risk factors for AR and ASR. Cardiotonic Pill can improve platelet sensitivity to Aspirin, and has synergistic anti-platelet effect, could be administered to interfere aspirin resistance effectively.
引文
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