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系統識別號 U0026-2301201516362700
論文名稱(中文) 靜脈血栓溶解治療於台灣缺血性腦中風病人合併腎臟功能不良之安全性與療效
論文名稱(英文) Safety and Effectiveness of Intravenous Thrombolytic Therapy for Acute Ischemic Stroke Patients with Renal Dysfunction in Taiwan
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 103
學期 1
出版年 104
研究生(中文) 謝鎮陽
研究生(英文) Cheng-Yang Hsieh
電子信箱 chengyanghsieh@gmail.com
學號 TB8981015
學位類別 博士
語文別 英文
論文頁數 81頁
口試委員 指導教授-高雅慧
召集委員-李中一
口試委員-賴明亮
口試委員-林瑞泰
口試委員-曾美君
中文關鍵字 腦中風  靜脈血栓溶解治療  安全性與療效  腎臟功能不良  症狀性腦出血 
英文關鍵字 stroke  intravenous thrombolytic therapy  safety and effectiveness  renal dysfunction  symptomatic intracerebral hemorrhage 
學科別分類
中文摘要 研究背景:
腦中風是國人十大死因第三位與成人殘障原因第一位,而缺血性腦中風是最常見的腦中風類別。靜脈使用組織胞漿素酶原活化劑 (rtPA)是目前對於缺血腦中風唯一核准之有效治療。由於擔憂治療後可能出現的嚴重症狀性腦出血,rtPA在台灣的缺血性腦中風病人之使用率偏低,但是實際的全國性藥物處方型態還未知。此外,腎臟功能不良是腦中風病人常見的共病症,而且可能跟rtPA治療後症狀性腦出血有關聯性,但是這樣的關聯性目前尚有爭議,徒增臨床上治療決策的困難。

研究目的:
我們欲探討2003-2010年我國缺血性腦中風病人使用rtPA的比率,並將探討rtPA在合併腎臟功能不良之台灣缺血性腦中風病人的安全性與療效。

研究方法:
首先,我們使用全民健康保險研究資料庫來分析2003-2010台灣缺血性腦中風病人的rtPA使用現況,以及預測rtPA使用與否的相關因子;之後,我們使用多中心腦中風登錄資料庫分析腎臟功能不良與缺血性腦中風病人經rtPA治療後產生症狀性腦出血的關聯性,以及腎臟功能不良與rtPA對於所有在發作4.5小時內到院的缺血性腦中風病人的預後(三個月後modified Rankin Scale 3-6)之影響有無交互作用。

結果:
首先,在2003-2010年全國394,9881筆缺血性腦中風住院資料中,僅有0.60%使用rtPA治療,其使用率從2003年的0.03%微幅增加至2010年的1.51%。腦中風病人的共病症越多,接受到rtPA治療的機率越低 (相較於Charlson comorbidity index [CCI] = 0者, CCI = 1的病人接受rtPA的勝算比: 0.45; 95% 信賴區間: 0.40-0.50; CCI ≥ 2者的勝算比: 0.30; 95% 信賴區間: 0.26-0.34)。
經過多變量分析657位經rtPA治療的缺血性腦中風病人資料,腎臟功能不良與症狀性腦出血並不相關 (勝算比: 1.03; 95%信賴區間: 0.55-1.92)。在另一個針對929位4.5小時內到院之缺血性腦中風病人的分析,rtPA與腎臟功能不良對於預後不佳的勝算比分別為0.70 (95%信賴區間: 0.51-0.96)與0.97 (95%信賴區間: 0.71-1.33),而兩者無顯著的交互作用 (p = 0.218)。

結論:
靜脈血栓治療在我國缺血性腦中風病人之使用率偏低,而低使用率可部分歸因於醫師擔心某些共病症會增加出血的風險。而從我們的臨床資料發現,腎臟功能不良既不會增加症狀性腦出血的風險,亦不會改變rtPA的治療效益。腎臟功能不良本身不應該是缺血性腦中風病人接受rtPA的禁忌症。
英文摘要 Background:
Stroke is the third leading cause of death and first leading cause of adult disability, while acute ischemic stroke (AIS) is the most common type of stroke in Taiwan. Intravenous thrombolytic therapy with recombinant tissue-type plasminogen activator (rtPA) is currently the only approved effective treatment for AIS worldwide. Partly due to concern of the devastating symptomatic intracranial hemorrhage (SICH), rtPA is underutilized in Taiwanese AIS patients. However, the exact utilization pattern has not been determined. Furthermore, renal dysfunction, a common comorbidity of stroke patients, might be associated with SICH after treatment with rtPA in AIS patients. However, such association is controversial and increases the uncertainty when deciding rtPA treatment.

Objective:
We aimed to determine the real utilization rate, and factors predicting utilization of rtPA in all Taiwanese AIS patients from 2003 through 2010. Then we aimed to determine the safety and effectiveness of rtPA in our AIS patients with renal dysfunction.

Method:
Firstly, the nationwide survey of intravenous rtPA for AIS patients was done using the National Health Insurance Research Database from 2003 through 2010. Then we used a multicenter stroke registry database to determine the association of renal dysfunction and SICH in AIS patients treated with intravenous rtPA, and the effect of renal dysfunction and rtPA, as well as their interaction on poor outcome (modified Rankin Scale 3-6 at 3 months) for all AIS patients admitted within 4.5 hours of onset.

Results:
Firstly, of the 394,988 AIS admission from 2003 through 2010, only 0.60% received rtPA. The utilization rate increased from 0.03% in 2003 to 1.51% in 2010. Patients with more comorbidities were less likely to receive rtPA (adjusted odds ratio [OR] for Charlson comorbidity index [CCI] = 1: 0.45; 95% CI: 0.40-0.50; OR for CCI ≥ 2: 0.30; 95% CI: 0.26-0.34, compared to those with CCI = 0).
After multivariable analysis of 657 AIS patients treated with rtPA, renal dysfunction was not associated with SICH (OR: 1.03; 95% confidence interval [CI]: 0.55-1.92). In another analysis for 929 AIS patients within 4.5 hours of onset, the OR for rtPA and renal dysfunction on poor outcomes were 0.70 (95% CI: 0.51-0.96) and 0.97 (95% CI: 0.71-1.33), respectively, without significant interaction (p = 0.218).

Conclusion:
Intravenous thrombolytic therapy was underutilized in our AIS patients, partly due to concern of increased bleeding risk under certain comorbidity. From our practice-based data, renal dysfunction neither increased the risk of SICH after rtPA nor modified the effectiveness of rtPA for AIS. Renal dysfunction alone should not be a reason for withholding treatment from otherwise-eligible AIS patients.
論文目次 Part I. Introduction 1
1. Stroke and Renal Dysfunction 1
1.1 Disease Burdens 2
1.2 Cerebrorenal Interaction 3
2. Intravenous Thrombolytic Therapy for Stroke with Renal Dysfunction 5
2.1 Intravenous Thrombolytic Therapy for Acute Ischemic Stroke 5
2.2 Effect of Renal Dysfunction on Intravenous Thrombolytic Therapy 9
2.3 Statement of the Research Questions 11
3. Specific Aims 11
4. Significance 12
Part II. National Survey of Thrombolytic Therapy for Acute Ischemic Stroke in Taiwan 13
1. Introduction 13
2. Methods 13
2.1 Data Source and Study Design 14
2.2 Definition of Acute Ischemic Stroke Admission and Thrombolytic Therapy 14
2.3 Dissemination of Thrombolytic Therapy across Taiwan over Time 15
2.4 Covariates and Outcomes 15
2.5 Statistical Analysis 16
3. Results 16
3.1 Dissemination of Thrombolytic Therapy through the Hospitals and Counties 17
3.2 Factors Predicting Thrombolytic Therapy 17
3.3 Factors Predicting Complications after Thrombolytic Therapy 18
4. Discussion 18
5. Strength and limitations 21
6. Conclusion 22
Part III. Is Renal Dysfunction Associated with Adverse Stroke Outcome after Thrombolytic Therapy? 33
1. Introduction 33
2. Methods 33
2.1 Data Source 34
2.2 Study design and population 34
2.3 Outcome and covariates 35
2.4 Statistical analysis 35
3. Results 36
3.1 Baseline characteristics of patients 36
3.2 Adjusted effect of renal dysfunction on outcome 37
4. Discussion 37
5. Limitations 39
6. Conclusion and Implications for Future Studies 39
Part IV. Does Renal Dysfunction Modify the Effect of Intravenous Thrombolysis for Acute Ischemic Stroke within 4.5 Hours of Onset? 44
1. Introduction 44
2. Methods 44
2.1 Study Population 45
2.2 Outcomes Measures 46
2.3 Statistical Analysis 46
3. Results 47
3.1 Baseline Characteristics of Patients 47
3.2 Effect of Thrombolytic Therapy and Renal Dysfunction on Outcomes 48
4. Discussion 48
5. Limitations 50
6. Conclusion 51
Part V. Summary and Implications for Future Study 60
Part VI. References 61
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