缺血性中風或暫時性腦缺血病人預防再中風及死亡的抗血小板用藥之研討

Secondary Prevention of Stroke and Death by Antiplatelet Therapies in Patients with Ischemic Stroke or Transient Ischemic Attack

蕭雅方(Ya-Fang Shiau)

指導教授 ： 胡朝榮

共同指導教授 ： 闕壯卿(Chuang Chin Chiueh)

臺北醫學大學/藥學院/藥學研究所/碩士(2009年)

https://doi.org/10.6831/TMU.2009.00079

摘要

摘要
研究背景
缺血性中風或是暫時性腦缺血病人是再中風的高危險族群。用於預防再中風的第一線抗血小板藥物，包括Aspirin、Aspirin合併extended-release dipyridamole (ASA-ERDP)、以及Clopidogrel。根據過去研究結果顯示，價錢較昂貴的藥物如ASA-ERDP和Clopidogrel比Aspirin能更有效預防再中風。但是，大部分的研究並未針對這三種抗血小板藥物預防再中風或是其他缺血性事件的風險進行head-to-head的直接比較。本研究的目的為探討台灣缺血性中風或是暫時性腦缺血病人最有效預防再中風或死亡的抗血小板治療藥物。

研究方法
本回溯性研究所分析之病人資料取自「台灣腦中風學會多醫院中風登錄計畫」，利用其登錄資料來分析缺血性中風或是暫時性腦缺血病人中風後發生危險事件之風險。研究之病人為服用下列三種抗血小板藥物之一: (1) Aspirin (A組)，(2) Aspirin併用Dipyridamole或是複方劑型Aggrenox® (A加D組)，及 (3) Clopidogrel (C組)。本研究之Primary Outcomes為病人發生缺血性中風或是暫時性腦缺血後一個月內、三個月內及六個月內再中風或是死亡的事件。另外，本研究對缺血性中風五種TOAST (Trial of Org 10172 in Acute Stroke Treatment)各亞型、心房震顫病史及上消化道出血併發症的病人針對Primary Outcomes另做分組分析。本研究使用存活分析之Kaplan-Meier method及Cox proportional hazards regression model進行統計分析。

研究結果
本研究共收集10,792位病人，其中A組、A加D組及C組之病人數分別為7,377人、1,902人、1,513人。C組病人有心臟疾病或是中風病史各佔40%，明顯高於其他組約兩倍。中風後六個月內，共有251人發生再中風，包括2.20% A組病人、2.47% A加D組病人、及2.71% C組病人。校正病人基本特性後，三組病人再中風的風險比並沒有差異(p > 0.05)。中風後六個月內有368位病人死亡，包括2.91% A組病人、2.79% A加D組病人、及6.61% C組病人；其中，C組病人的死亡率相對較高(p < 0.001)。校正病人基本特性後(例如：年齡、心臟病史、過去曾發生中風)，三組病人死亡的風險比並沒有差異(p > 0.05)。此外，缺血性中風五種TOAST各亞型、心房震顫病史的分組分析不論是A加D組或是C組，相較於A組，預防再中風或是死亡的風險並沒有差異(p > 0.05)。然而，上消化道出血併發症病人的分組分析中，顯示C組相較於A組在中風後一個月內死亡的風險較低 (p = 0.039)。而在A加D組和C組之間的再中風或死亡的分組比較，研究結果顯示兩組沒有統計上的差異(p > 0.05)。

研究結論
根據過去臨床報告顯示，病人發生缺血性中風後未使用抗血小板藥物，其半年內再中風的風險為7%。根據本研究結果，Aspirin、Aspirin合併Dipyridamole、以及Clopidogrel在降低台灣缺血性中風及暫時性腦缺血病人再中風或是死亡風險的效果是沒有差異的，約2.5%病人半年內發生再中風。基於本研究結果，建議臨床醫師應開立Aspirin為預防再中風的第一線抗血小板治療用藥，除非病人對Aspirin過敏或是無法耐受其副作用 (例如：上消化道出血)。而Aspirin的低藥價亦可以讓病人有較好的長期服藥習慣。病人如果本身有出血症狀且併用抗血小板藥物，有可能會造成較高的死亡率。因此，有出血症狀的缺血性中風病人應使用Clopidogrel作為預防再中風的首選用藥，避免使用含有Aspirin成分的藥物。

關鍵字

缺血性中風；暫時性腦缺血；再中風；台灣腦中風學會多醫院中風登錄計畫；抗血小板藥物 (Aspirin ； Dipyridamole ； Aggrenox&reg ； Clopidogrel)

並列摘要

Abstract
Background
Patients survived from ischemic stroke or transient ischemic attack (TIA) are high risk population for recurrent stroke. Antiplatelet agents, such as aspirin, the combination of aspirin plus extended-release dipyridamole (ASA-ERDP) and clopidogrel, are the first-line antiplatelet therapies for prevention of recurrent stroke in patients with ischemic stroke or TIA. Based on previous reports, the more expensive agents such as ASA-ERDP and clopidogrel are more effective than aspirin alone for the secondary prevention of stroke. However, most of the previous clinical trials fail to compare head-to-head directly three antiplatelet agents for the risk of recurrent stroke or other ischemic events. The aim of the present study was to investigate which antiplatelet therapy is the most effective in reducing the risk of recurrent stroke or death for patients with ischemic stroke or TIA in Taiwan.

Method
In this retrospective study, the patients’ data were obtained from the databank of Taiwan Stroke Registry, for analyzing subsequent risks in patients suffering from prior ischemic stroke or TIA. Patients in this study were treated with one of the following antiplatelet therapies such as (1) aspirin alone (Group A), (2) either the combination of aspirin plus dipyridamole or Aggrenox® (Group A plus D), and (3) clopidogrel alone (Group C). The primary outcomes were recurrent stroke and death within one month, three months, and six months after the onset of ischemic stroke or TIA. The subgroup analyses were performed for the primary outcomes with the baseline features, including five TOAST (Trial of Org 10172 in Acute Stroke Treatment) subtypes of ischemic stroke, history of atrial fibrillation, and patients with upper gastrointestinal bleeding. The statistical methods of the Kaplan-Meier method and the Cox proportional hazards regression model were used to analyze the results.

Results
A total of 10,792 patients were collected in this study. The final patient numbers for each therapy groups of A, A plus D, and C were 7,377, 1,902, and 1,513 patients, respectively. The patients of group C were associated with history of heart disease (40%) or prior stroke (40%), all of which were greater than other two groups. A total of 251 patients suffered recurrent stroke during six months after prior ischemic stroke or TIA. About 2.20% of group A patients, 2.47% of group A plus D patients, and 2.71% of group C patients developed recurrent stroke within six months after ischemic stroke or TIA. After adjusting baseline characteristics, the hazard ratios for recurrent stroke among three treatment groups did not reach statistical significance
(p > 0.05). During the six-month period of follow-up, 368 patients died for unknown reason. The mortality rate of group A, group A plus D, and group C were 2.91%, 2.79%, and 6.61%, respectively. A significant two fold higher mortality rate was observed in group C (p < 0.001). After adjusting baseline features (e.g., age, heart disease, previous stroke), the hazard ratios for death among three treatment groups were not different significantly (p > 0.05). Subgroup analyses of five TOAST subtypes and the history of atrial fibrillation revealed that neither group A plus D treatment nor group C therapy produced a significant effect on the risk of recurrent stroke or death compared with group A (p > 0.05). However, a confirmatory finding was that patients with upper gastrointestinal bleeding in group C after receiving clopidogrel treatment had less risk of death than those in group A after receiving aspirin alone treatment within the first month after the onset of ischemic stroke or TIA (p = 0.039). Consistent with primary outcomes, subgroup analyses for recurrent stroke or death between group A plus D and group C also indicated that there were no statistically significant differences (p > 0.05).

Conclusion
Based on the previous clinical reports, approximately 7% ischemic stroke patients without antiplatelet therapies developed recurrent stroke within six months. In the present study, aspirin alone, the combination of aspirin plus dipyridamole, and clopidogrel alone were effective in the prevention of recurrent stroke or death in Taiwanese patients with ischemic stroke or TIA; patients who received antiplatelet treatments in this study decreased the risk of recurrent stroke to about 2.5%. With this evidence-based information in mind, aspirin monotherapy is recommended to be prescribed as the first-line antiplatelet therapy for secondary prevention of stroke unless patients are allergy to or intolerant of aspirin (e.g., upper gastrointestinal bleeding). Another important reason to use aspirin as initial therapy is the relative low cost of aspirin, which can lead to better long-term adherence in medication use. Further, for ischemic stroke patients with the complication of hemorrhage at any sites, the choice of drug for secondary prevention of stroke is clopidogrel, instead of aspirin-containing agents.

並列關鍵字

Ischemic stroke ； Transient ischemic attack ； Recurrent stroke ； Taiwan Stroke Registry ； Antiplatelet agents (Aspirin ； Dipyridamole ； Aggrenox&reg ； Clopidogrel)

參考文獻

Adams Jr HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL and Marsh Iii EE (1993) Classification of subtype of acute ischemic stroke: Definitions for use in a multicenter clinical trial. Stroke 24:35-41.

Albers GW (2000) Choice of endpoints in antiplatelet trials. Which outcomes are most relevant to stroke patients? Neurology 54:1022-1028.

Albers GW, Amarenco P, Easton JD, Sacco RL and Teal P (2008) Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 133:630S-669S.

Albers GW, Caplan LR, Easton JD, Fayad PB, Mohr JP, Saver JL and Sherman DG (2002) Transient ischemic attack - Proposal for a new definition. New England Journal of Medicine 347:1713-1716.

Algra A and Van Gijn J (1996) Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. Journal of Neurology Neurosurgery and Psychiatry 60:197-199.