臺灣博碩士論文加值系統

背景與目的：Tiotropium (Spiriva®) 為一吸入型長效抗膽鹼藥物 (long acting muscarinic antagonist, LAMA)，依2015年GOLD指引 (The Global Initiative for Chronic Obstructive Lung Disease Guideline) 列為慢性阻塞性肺病之長期維持治療藥品。已有諸多研究證明Tiotropium能有效緩解疾病症狀、急性惡化與住院率，然而其心血管安全性仍具爭議。抗膽鹼藥品會對副交感神經產生抑制作用，可能導致心搏過速、心肌缺血、中風以及死亡的風險增加。部份統合分析與觀察性研究指出Tiotropium會增加病人罹患心血管疾病的可能，但亦有大型隨機分派試驗結果顯示Tiotropium可能具心血管保護效果。為了探討Tiotropium在亞洲族群的心血管安全性，本研究使用以族群為基礎的回溯性世代研究來釐清Tiotropium與心血管疾病之間的相關性。
方法：本研究使用健保資料庫2000年百萬歸人檔進行分析，從中定義在研究期間2004年1月1日至2010年11月30日內，年滿40歲且同時有慢性阻塞性肺病診斷與相關用藥紀錄的病人。每位使用Tiotropium的病人將會配對4位未使用Tiotropium的病人，配對條件包含年齡、性別、指標年份及病人罹患慢性阻塞性肺病持續時間。所有的病人會被持續追蹤直至發生心房顫動、心衰竭、心肌梗塞、中風、退保、死亡或研究結束 (2011年12月31日)。 並以Kaplan-Meier法觀察心血管疾病事件發生情形，再以Cox比例風險模型 (Cox proportional hazard model) 計算風險比值與95%信賴區間。控制變項如病人基本特質、慢性阻塞性肺病嚴重度、共用藥品與共病症均會放入模型校正。
結果：本研究世代共5,994人，其中Tiotropium使用者共1,264人，而未使用Tiotropium者共4,680人。相較於未使用者，使用Tiotropium的病人，在校正各控制變項後發生心血管疾病的風險為0.72 (95%CI: 0.55-0.95，p= 0.0181)，具顯著差異；其中次族群包括心房顫動、心衰竭、心肌梗塞與中風等事件風險雖有降低，但未達顯著差異。進一步分析Tiotropium累積用藥天數，結果顯示使用達一年以上者之全部心血管疾病風險為0.41 (95%CI: 0.26-0.66，p= 0.0002)，心肌梗塞風險為0.19 (95%CI: 0.04-0.83，p= 0.0277)，而中風風險為0.40 (95%CI: 0.21-0.79，p= 0.0077)，皆顯著降低；但使用小於一年者，則不具降低心血管疾病之事件風險。
結論：慢性阻塞性肺病病人使用Tiotropium能有效降低罹患心血管疾病事件風險，且使用一年以上更能彰顯其心血管保護效果。

Background: Tiotropium (Spiriva®) is an inhaled, long-acting muscarinic antagonist (LAMA). The 2015 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline included Tiotropium in long-term maintenance therapy for chronic obstructive pulmonary disease (COPD). Tiotropium has been proved to reduce exacerbations, related hospitalizations and symptoms of COPD; however, its cardio-safety is still in debate. Anticholinergic effects of Tiotropium could suppress parasympathetic control, which may lead to tachycardia, cardiac ischemia, stroke and increased risk of cardiovascular related death. Meta-analysis and observational studies have suggested that Tiotropium increased the risk of cardiovascular diseases, whereas large randomized controlled trials reported a reduced risk. In order to elucidate the cardio-safety of Tiotropium in Asian population, we conducted a population-based retrospective cohort study to examine the risk of cardiovascular diseases with Tiotropium.
Method: Using the Longitudinal Health Insurance Database (LHID) 2000, we identified patients ≥40 years of age who had a COPD diagnosis and received COPD medications from January 1, 2004 to November 30, 2010. Each Tiotropium user was matched to 4 randomly selected Tiotropium non-users with similar age (±5 year), gender, index year and COPD duration. All participants were followed up to a diagnosis of atrial fibrillation, heart failure, myocardial fibrillation, stroke, termination of health insurance coverage, death or end of the study period (December 2011), which came first. Kaplan-Meier analysis was used to estimate the probability of cardiovascular diseases in the study period, and cox proportional hazard model was used for computing hazard ratios (HR) and 95% confidence intervals (CI). Control variables such as patient characteristics, COPD severity, comedication and comorbidity were adjusted.
Results: A total of 5,994 COPD patients were included in the study cohort. Among them, 1,264 patients received Tiotropium and 4,680 received other COPD medications. Among those Tiotropium users compared to non-users, the adjusted HRs for total cardiovascular diseases was 0.72 (95%CI: 0.55-0.95, p =0.0181). Subgroup analysis for atrial fibrillation, heart failure, myocardial infraction and stroke, the adjusted HR were non-significant. In addition, the adjusted HRs showed significantly reduced risks for total cardiovascular diseases (HR 0.41, 95%CI: 0.26-0.66, p =0.0002), myocardial infarction (HR 0.19, 95%CI: 0.04-0.83, p =0.0277) and stroke (HR 0.40, 95%CI: 0.21-0.79, p =0.0077) among patients using Tiotropium more than 1 year. However, there was no cardio-protective effect for patients used Tiotropium less than 1 year.
Conclusion: Tiotropium was associated with a reduction in the risk of cardiovascular diseases. The cardio-protective effect would be more significant among patients using Tiotropium more than 1 year.

中文摘要 I
英文摘要 III
目錄 V
圖表索引 VII
縮寫表 VIII
第一章 緒論
第一節 研究背景與動機 1
第二節 研究目的 17
第二章 文獻探討 18
第三章 研究方法與設計
第一節 研究項目與研究假設 29
第二節 研究設計與研究工具 30
第三節 統計方法 46
第四章 研究結果
第一節 研究族群基本資料 48
第二節 Tiotropium與心血管疾病相關性 54
第三節 Tiotropium累積使用天數與心血管疾病相關性 60
第五章 討論
第一節 Tiotropium與心血管疾病相關性 76
第二節 Tiotropium累積使用天數與心血管疾病相關性 80
第三節 研究限制 83
第六章 結論與建議 85
參考文獻 86


圖1-1-1 COPD症狀與風險評估模式 9
圖3-2-1 研究架構 30
圖3-2-2 Tiotropium使用者與指標日期 34
圖3-2-3 資料處理流程圖 45
圖4-2-1 Tiotropium與心血管疾病Kaplan-Meier曲線 54
圖4-2-2 Tiotropium與心房顫動Kaplan-Meier曲線 55
圖4-2-3 Tiotropium與心衰竭Kaplan-Meier曲線 56
圖4-2-4 Tiotropium與心肌梗塞Kaplan-Meier曲線 57
圖4-2-5 Tiotropium與中風Kaplan-Meier曲線 58
圖4-3-1 Tiotropium累積使用天數與心血管疾病Kaplan-Meier曲線60
圖4-3-2 Tiotropium累積使用天數與心房顫動Kaplan-Meier曲線 61
圖4-3-3 Tiotropium累積使用天數與心衰竭Kaplan-Meier曲線 62
圖4-3-4 Tiotropium累積使用天數與心肌梗塞Kaplan-Meier曲線 63
圖4-3-5 Tiotropium累積使用天數與中風Kaplan-Meier曲線 64
表1-1-1 COPD病人分群簡述　13
表1-1-2 GOLD起始藥物治療 13
表2-1-1 歷年Tiotropium與心血管疾病風險之研究 27
表3-2-1 資料檔案名稱與擷取變項 32
表3-2-2 研究變項之操作型定義 42
表4-1-1 病人基本特質表 52
表4-2-1 Tiotropium與心血管疾病相關性 59
表4-3-1 Tiotropium累積使用天數與心血管疾病相關性 65
表4-3-2 Tiotropium與心血管疾病相關性之各控制變項風險比 66
表4-3-3 Tiotropium與心房顫動相關性之各控制變項風險比 68
表4-3-4 Tiotropium與心衰竭相關性之各控制變項風險比 70
表4-3-5 Tiotropium與心肌梗塞相關性之各控制變項風險比 72
表4-3-6 Tiotropium與中風相關性之各控制變項風險比 74

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