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研究生:王怡雯
研究生(外文):Yi-Wen Wang
論文名稱:阿茲海默症患者使用乙醯膽鹼酶抑制劑和心血管疾病之關係
論文名稱(外文):The relationship of acetylcholinesterase inhibitors and cardiovascular disease in subjects with Alzheimer’s disease
指導教授:白其卉白其卉引用關係
指導教授(外文):Chyi-Huey Bai
口試委員:徐榮隆謝芳宜
口試委員(外文):Jung-Lung HsuFang-I Hsieh
口試日期:2017-01-10
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:公共衛生學系暨研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:169
中文關鍵詞:阿茲海默症乙醯膽鹼酶抑制劑腦血管疾病冠狀動脈心臟病
外文關鍵詞:Alzheimer’s diseaseacetylcholinesterase inhibitorscerebrovascular diseasescoronary heart diseases
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研究背景:
乙醯膽鹼酶抑制劑是治療阿茲海默症的首選藥物,先前研究發現這類藥物能降低促發炎細胞激素、增加抗發炎細胞激素分泌,並降低內皮細胞受損之標記物,而這些激素與內皮細胞受損標記物皆與動脈粥狀硬化發展及心血管疾病發生有關。目前僅有少數研究說明乙醯膽鹼酶抑制劑可能降低冠狀動脈心臟病與中風之風險,但探討全面性心血管疾病之研究則相對不足。本研究目的為探討阿茲海默症患者使用乙醯膽鹼酶抑制劑與後續發生腦血管疾病、冠狀動脈心臟病、心腦血管疾病之風險,並進一步了解在調整其他心血管疾病風險因子,包括高血壓、糖尿病、高血脂症、憂鬱症、周邊動脈疾病、慢性阻塞性肺部疾病、酒精性相關疾病,及Memantine之使用後,乙醯膽鹼酶抑制劑是否降低發生腦血管疾病、冠狀動脈心臟病、心腦血管疾病的風險。

材料與方法:
本研究為世代研究,資料來源為國家衛生研究院所釋出之全民健康保險研究資料庫之2005年承保抽樣歸人檔(Longitudinal Study Insurance Database,LHID2005)。選取1998年至2008年門診申報資料中30歲以上新發阿茲海默症患者(ICD-9 code=290,331.0)。定義乙醯膽鹼酶抑制劑治療84天以上者為暴露組,經性別、年齡、指標日期(Index date) 1:3配對非暴露組(不曾用藥者),並排除先前已有腦血管疾病史或冠狀動脈心臟病史之對數,共納入258名暴露個案及774名非暴露個案。本研究以暴露組及非暴露組之指標日期(Index date)作為研究起點,暴露組之指標日期為第一次開始使用任何一種乙醯膽鹼酶抑制劑之就醫日期,非暴露組之指標日期為門診或住院看診紀錄中與暴露組指標日期相同之就醫日期。而研究終點為腦血管疾病(ICD-9 code=430-438)、冠狀動脈心臟病(ICD-9 code=410-414)、心腦血管疾病風險(ICD-9 code=430-438, 410-414)。研究結束時間點為發生終點或至2009年12月31日。利用Cox regression分析暴露組與非暴露組發生腦血管疾病、冠狀動脈心臟病、心腦血管疾病之風險比(Hazard ratio, HR)及95%信賴區間(Confidence interval, CI)。

結果:
在校正干擾後,乙醯膽鹼酶抑制劑治療對冠狀動脈心臟病及心腦血管疾病風險具有顯著保護性,其HR分別為0.37(95%CI=0.15-0.89, P=0.0259)、0.65(95%CI=0.43-0.96, P=0.0301),而在用藥3年以上之患者可分別於腦血管疾病風險、心腦血管疾病風險看到更明顯且顯著的保護性,其HR分別為0.47(95%CI=0.22-0.99, P=0.0493)、0.47(95%CI=0.25-0.89, P=0.0213)。

結論與討論:
乙醯膽鹼酶抑制劑治療能降低冠狀動脈心臟病及心腦血管疾病的風險。在用藥3年以上之患者可於腦血管疾病風險、心腦血管疾病風險看到更明顯且顯著的保護性。
Background:
Acetylcholinesterase inhibitors(AChEIs) including donepezil, rivastigmine, and galantamine are currently used to be the primary treatment in patients with Alzheimer''s disease (AD). These drugs could reduced the levels of pro-inflammatory cytokines, and increased secretion of anti-inflammatory cytokine. The pro-inflammatory cytokines, anti-inflammatory cytokines, and the markers of endothelial dysfunction are associated with atherosclerosis and cardiovascular diseases. Currently, few studies have indicated that acetylcholine inhibitors may reduced the risk of coronary heart disease and stroke. But no study focused on a comprehensive cardiovascular disease. The objective of this study is to explore that the AChEIs reduced the risk of cerebrovascular diseases, coronary heart diseases, and cardio- & cerebro- vascular diseases among the AD patients after adjustment for other cardiovascular disease risk factors(including hypertension, diabetes mellitus, hyperlipidemia, depression, peripheral artery disease, chronic obstructive pulmonary disease, alcohol-related illness, and memantine usage).

Materials and Methods:
This study is a cohort study. All subjects were extracted from the 2005 longitudinal national health insurance research database (LHID2005), a subset of the National Health Insurance Research Database(NHIRD). Included patients were those with more than thirty years old and with new diagnosis of AD (ICD-9 code=290,331.0) between 1998 and 2008. According to the usage of AChEIs, we defined those patients using AChEIs for more than eighty-four days wholelife as exposure group. Non-exposed group were defined those never using AChEIs. The ratio of 1:3 for two groups was used to match by age, sex and index date of responder, and further excluded the pairs of those subjects with cerebrovascular diseases history or coronary heart diseases history. A total of 258 persons in exposed group and 774 persons in non-exposure group were included. The index date was used to be the starting point. Index date in exposure group is the first date of prescribing AChEI, and in non-exposed group, is the visit date of hospital which matched with index date of exposure group. The subjects were tracked still the disease onset or Dec 31 2009. The disease outcome included cerebrovascular diseases(ICD-9 code=430-438), coronary heart diseases(ICD-9 code=410-414), and cardio- & cerebro- vascular diseases(ICD-9 code=430-438, 410-414). Cox proportional hazard regression was performed to examine AChEIs to the risk of cerebrovascular diseases, coronary heart diseases, or cardio- & cerebro- vascular diseases, and presented hazard ratio(HR) and the 95% confidence interval(CI).

Results:
After adjusting the confounders, AD patients with usage of AChEIs was significantly lower risk in coronary heart diseases and cardio- & cerebro- vascular diseases,which in comparsion with non-exposure group(HR=0.37, 95%CI=0.15-0.89, P=0.0259; HR=0.65, 95%CI=0.43-0.96, P=0.0301), respectively. For those patients treated by AChEIs for more than three years, their risk of cerebrovascular diseases and cardio- & cerebro- vascular diseases lowered significantly(HR=0.47, 95%CI=0.22-0.99, P=0.0493; HR=0.47, 95%CI=0.25-0.89, P=0.0213), respectively.

Conclusions:
AChEIs usage in AD patients could reduced the following risk of coronary heart diseases and cardio- & cerebro- vascular diseases. While usage for more than 3 years, AD patients had the significant protection in cerebrovascular diseases and cardio- & cerebro- vascular diseases.
致謝 i
摘要 ii
Abstract iv
目錄 vi
圖目錄 viii
表目錄 ix
第一章、緒論 1
第一節、研究背景與研究動機 1
第二節、研究目的 2
第二章、文獻探討 3
第一節、失智症流行病學 3
第二節、阿茲海默症 7
第三節、乙醯膽鹼酶抑制劑 17
第四節、乙醯膽鹼酶抑制劑與心血管疾病風險 21
第五節、文獻探討小結 35
第三章、研究方法與材料 36
第一節、研究設計與研究架構 36
第二節、資料來源 37
第三節、研究對象 41
第四節、暴露組與非暴露組分組定義 42
第五節、研究起點與終點、追蹤人年計算 53
第六節、其它研究變項與操作型定義 55
第七節、統計分析方法 64
第四章、結果 65
第一節、乙醯膽鹼酶抑制劑治療與心、腦血管疾病風險之分析 65
第二節、乙醯膽鹼酶抑制劑治療時間長度與劑量分組之心、腦血管疾病風險
73
第三節、乙醯膽鹼酶抑制劑治療與心、腦血管疾病風險之分層分析 89
第四節、沒有三高之乙醯膽鹼酶抑制劑與心、腦血管疾病風險 97
第五章、討論 99
第一節、研究設計 99
第二節、乙醯膽鹼酶抑制劑對心、腦血管疾病機制討論 104
第三節、乙醯膽鹼酶抑制劑治療與心、腦血管疾病風險 105
第四節、乙醯膽鹼酶抑制劑治療時間、劑量分組與心、腦血管疾病風險 109
第五節、乙醯膽鹼酶抑制劑治療與心、腦血管疾病風險分層分析 113
第六節、沒有三高之乙醯膽鹼酶抑制劑治療與心、腦血管疾病風險 116
第七節、研究限制 123
第六章、結論與展望 126
第一節、結論 126
第二節、貢獻及展望 126
第七章、附錄 127
第八章、參考文獻 133
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中文部份
台灣失智症協會(2012)。認識失智症。取自http://www.tada2002.org.tw/tada_know_02.html
李依甄(2008)。小中風 淺談暫時性腦缺血。取自https://app.tzuchi.com.tw/file/tcmed/200811-59/70-71.pdf
李碩粲、許勝雄(2002)。急性心肌梗塞。取自http://www.kmuh.org.tw/www/kmcj/data/9102/4886.htm
李謙益、廖以誠、王文甫、黃斯聖、黃靜宜、邱南英(2006)。阿茲海默病之病患使用Donepezil與Rivastigmine的治療持續度探討[The Drug Persistency of Donepezil and Rivastigmine in Patients with Alzheimer''s Disease]。台灣老年醫學雜誌,2(1),頁12-20。
周中興等人(譯)(2004)。梅約心臟小百科:心臟保健完整指南(原作者:Mayo Clinic)。台北市:天下生活。
邱銘章、湯麗玉(2009)。失智症照護指南。台北市:原水文化。
梁家欣、程蘊菁、陳人豪(2014)。失智症之重點回顧[Dementia: A Focused Review]。內科學誌,25(3),頁151-157。
連賢明(2008)。如何使用健保資料進行經濟研究[How to Use National Health Insurance Data to Conduct Health Economics Research]。經濟論文叢刊,36(1),頁115-143。doi: 10.6277/ter.2008.361.4
陳志堯等人(譯)(2002)。最新圖解藥理學(原作者:Mary J. Mycek, Richard A. Harvey, Pamela C. Champe)。台北市:合記。
陳偉熹、吳紹琛(2008)。阿茲海默氏症治療藥品在我國全民健康保險藥品給付規定之探討[An Investigation of the Payment of Anti-Alzheimer Drugs by National Health Insurance in Taiwan]。東港安泰醫護雜誌,14(1),頁1-15。
楊雅婷(譯)(2003)。阿茲海默症(原作者:Mayo, Clinic)。台北市:天下生活。
葉淑惠、陳幼梅(2007)。失智症。於葉淑惠、張文芸、陳幼梅、林愛貞、陳美妃、林淑媛等著,老人照護指引:長期照護醫療健康小組適用(178頁)。台北:華都文化。
劉秉彥、陳志鴻(2002)。冠狀動脈疾病。取自http://ejournal.stpi.narl.org.tw/NSC_INDEX/Journal/EJ0001/9104/9104-08.pdf
衛生福利部中央健康保險署(2009)。藥品給付規定第一節神經系統藥物:阿茲海默氏症治療藥品(98年以前給付規定)。取自http://www.nhi.gov.tw/webdata/webdata.aspx?menu=21&menu_id=713&WD_ID=849&webdata_id=3306
衛生福利部中央健康保險署(2009)。藥品給付規定第一節神經系統藥物:阿茲海默氏症治療藥品(98年以前給付規定)。取自http://www.nhi.gov.tw/webdata/webdata.aspx?menu=21&menu_id=713&WD_ID=849&webdata_id=3306
衛生福利部統計處(2015)。104年度死因統計年報。取自http://www.mohw.gov.tw/CHT/DOS/Statistic.aspx?f_list_no=312&fod_list_no=6201
蕭雲菁(譯)(2012)。全彩圖解失智症保健事典:預防、診治、照護新知(原作者:井藤英喜、粟田主一)。台北市:原水文化。
賴志泓(2015)。秋冬常見的心血管疾病:不穩定心絞痛。取自 http://www.vghtc.gov.tw/GipOpenWeb/wSite/public/file/portal/periodical/med211/06-07.pdf
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