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
中文摘要 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。
英文摘要 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.
