探討心血管疾病病人對抗血栓藥劑Aspirin及Clopidogrel抗阻性之研究

A Study of Aspirin and Clopidogrel Resistance in the Patients with Cardiovascular Disease

楊馥鴻(Fu-Hung Yang)

指導教授 ： 賴文德 ； 吳明蒼

高雄醫學大學/醫學院/醫學研究所/碩士(2005年)

摘要

中文摘要

在臨床醫學上,給予Aspirin(阿斯匹靈)或Clopidogrel(保栓通錠) 一直是作為心血管疾病病人治療及預防動脈粥狀硬化、中風、心肌梗塞等的方法(Alberts et al., 2004; Rohatgi et al., 2004)。然而有許多相關研究卻指出在服用後有些人並沒有完全達到所預期的良好效用;如文獻(Zimmermann et al., 2003; Gum et al., 2003; Mason et al., 2004)中指出大約有5~45%的人對Aspirin(阿斯匹靈)有抗阻性,因此本研究想要探討所可能發生抗阻性的原因以及比較這兩種抗血栓藥物Aspirin(阿斯匹靈)和Clopidogrel(保栓通錠)的效用。
2004年11月至2005年2月以高雄醫學大學附設中和紀念醫院心臟內科門診病人(大都同時具有高血壓or 高膽固醇血酯症 or 心絞痛 or 栓塞性腦出血 or CAB or old MI or Cath or Restenosis or repeat PTCA等症候)及健康人為研究對象, 配合問卷資料篩選,共收集了120位研究對象(分為四組:第一組為只服用Aspirin(阿斯匹靈)者共有76位;第二組為只服用Clopidogrel(保栓通錠)共有15位;第三組為兩者服用的有15位;第四組為都沒有服用的有12位及2位健康人來當做對照組)的血液及尿液。在血液方面則利用ADP、collagen等試劑來做血小板凝集測試反應;而尿液方面則進行ELISA來分析11-dTXB2濃度,所有數據均以平均值±SD來表示;並利用SPSS 統計軟體來進行檢測結果是否有統計上的差異(p<0.05)。
結果發現在ADP 10μM及20μM下的最大凝集力:服用Clopidogrel(保栓通錠)組與服用兩種藥物組顯著低於只服用Aspirin(阿斯匹靈)組;而服用Aspirin(阿斯匹靈)組又顯著低於對照組(Table 2)。且以凝集力³70%當作服用藥物效果欠佳,服用Aspirin(阿斯匹靈)組凝集力³70%有40位(52.6%),顯著高於服用Clopidogrel(保栓通錠)組(只有1位(6.7%))。此外在只服用Aspirin(阿斯匹靈)組，我們隨機選取三位病人凝集力大於80%給予美製Aspirin(阿斯匹靈)服用兩個星期再抽血重複實驗,發現凝集力三者均有明顯下降,且尿中11-dTXB2濃度也較為低；隨後將台製與美製Aspirin(阿斯匹靈)做藥物分析,發現Aspirin(阿斯匹靈)量並無顯著差異。於是將三位病人再換回台製Aspirin(阿斯匹靈)且服用大約超過一個月後再抽血重複實驗,雖然只有兩位回診,但結果發現和服用美製時結果差異並不大。
經由這一連串的問題分析及探討後,我們推測是病人對服用藥物的〝順從性〞所造成這樣的結果,而關於病人是否按時服用藥物的問題,在本研究中是藉由病人回答問卷來得知,因此我們無法判斷其準確性與否,這也是本研究的實驗限制,因此在考慮抗血栓藥物之抗阻性時，需先排除病人順從性之問題；而Clopidogrel(保栓通錠)比Aspirin(阿斯匹靈)之抗凝集力佳的問題，仍需做進一步探討。

關鍵字

抗阻性 ； 心血管疾病病人 ； 阿斯匹靈 ； 保栓通錠

並列摘要

Abstract

Aspirin and Clopidogrel have been used in the antiplatelet therapy for patients with cardiovascular disease; however, the evidence of medical resistance in 5-45% population was reported (e.g. Mason et al., 2004). Two goals of this study are to understand what is the key season for the medical resistance and to compare with Aspirin and Clopidogrel for patients with cardiovascular disease.
One hundred and twenty persons were collected by the questionnaire in Division of Cardiology of Chung-Ho Memorial Hospital, KMU and were divided to four groups (Group Aspirin(n=76)、Group Clopidogrel(n=15)、Group Both(n=15) and Controls(n=14)). Three reagents (ADP 10μM、ADP 20μM 、collagen 1μg/ml) were used for the platelet aggregation test. 11-dTXB2 content in urine was measured by ELISA. All data were reported as the mean value ± SD. Significance was accepted at P<0.05. The statistical package used was SPSS for Windows.
The trend of the maximal percentage (MX %) of platelet aggregation among groups is: Group Both < Group Clopidogrel << Group Aspirin << Group Controls. Platelet aggregation for Group Both and Group Clopidogrel is much lower than that in Group Aspirin. MX % for 40 persons (52.6%) in Group Aspirin and 1 person (6.7%) in Group Clopidogrel were over 70%, which was defined as the resistance by Gum et al. 2001; 2003).
For 3 patients in Group Aspirin with high MX% (≧80%), their MX% of platelet aggregation and the concentration of 11-dTXB2 were lower than the previous values after taking another Aspirin made by Bayer, USA for two weeks. There is no significant difference between two kinds (永信; Bayer) of Aspirin by the measurement of HPLC. The patients was re-treated with the Aspirin by 永信, Taiwan over one month after finished taking Aspirin (Bayer, USA). There is no significant difference between the 2nd and 3rd results.
Accordingly, patients’ compliance is the major problem for the medical resistance. Patients should completely follow doctor’s instruction to take medicine can not be guaranteed. We believe to build up patients’ compliance is a key to this therapy. It is noted that the relation between Aspirin and Clopidogrel should be further investigated.

並列關鍵字

ADP ； Collagen ； Resistance ； Clopidogrel ； cardiovascular disease ； Aspirin

參考文獻

參考文獻

Alan D. Michelson, MD (2004). "Platelet Function Testing in Cardiovascular Disease." Circulation 110: e489-e493.

Adnan Kastrati, MD, Nicolas von Beckerath, MD; Alexander Joost; Gisela Pogatsa-Murray, MD; Olga Gorchakova, MD; Albert Schomig, MD (2004). "Loading With 600 mg Clopidogrel in Patients With Coronary Artery Disease With and Without Chronic Clopidogrel Therapy." Circulation 110: 1916-1919.

Askiel Bruno, MD, Joseph P. McConnell, PhD, Stanley N. Cohen, MD, Gretchen E. Tietjen, MD, Roi Ann Wallis, MD, Philip B. Gorelick, MD, MPH, Nils U. Bang, MD (2004). "Serial Urinary 11-Dehydrothromboxane B2, Aspirin Dose, and Vascular Events in Blacks After Recent Cerebral Infarction." Stroke 35: 727-730.

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