泌尿系統微創治療的實證醫療：全人口回溯性世代研究與網絡統合分析

Evidence-Based Approach in Minimally Invasive Urologic Therapy: Population-Based Retrospective Cohort Study and Network Meta-Analysis

黃士維(Shi-wei Huang)

指導教授 ： 簡國龍

共同指導教授 ： 杜裕康

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/博士(2019年)

https://doi.org/10.6342/NTU201903354

摘要

背景與目標
泌尿系統微創治療(minimally-invasive urologic therapy, MIUT)相較於傳統的開腹手術有較低的手術併發症，且手術後復原也相對快速，在某些疾病的治療如泌尿道結石、攝護腺肥大等已取代多數的傳統開刀手術，成為病人與醫師的治療首選。然而MIUT在某些層面仍有待解決之問題，因此創新或改良的微創治療手段仍持續進展。待解問題如：泌尿道結石的病患已知有較高的高血壓、糖尿病風險，而體外震波碎石是否會增加病患在此兩病症的風險？眾多新的良性攝護腺乏大手術治療如雷射和雙極電刀已在本世紀初問世，而相對於”黃金治療術式”的經尿道單極電刀攝護腺括除手術，這些新穎手術是否有超前的療效及安全性？此論文的主題為使用最實際與合適的流行病學方法，探究這些MIUT待解的問題。

方法
高血壓、糖尿病與震波碎石治療已被報導有非常長期的關聯性、又存在著來自於病患本身預患因子的干擾，因此我們採用台灣全民健保資料庫之世代追蹤研究資料(nationwide retrospective cohort data)，並選取接受過體外震波碎石與輸尿管鏡碎石術的兩組病人，利用Cox比例風險模式及時間相依共變數分析方法比較兩組病人的長期罹患高血壓和糖尿病風險。另一方面，由於已問世的新型良性攝護肥大MIUT多樣，我們依術式原理與組織清除機制選取了九種攝護腺手術方法，運用系統性文獻回顧(meta-analysis)篩選針對這九種手術比較的文章、以Cochrane risk of bias table 來評量文獻品質及metafunnel探尋發表誤差；之後採用網路統合分析、隨機效應泛線性混合模型（random effect generalized linear mixed model）探討這九種手術的功效和副作用.

結果
在中位期追蹤74.9和82.6個月後，震波碎石組和輸尿管鏡碎石組分別有2028位及688位病患得到高血壓。接受體外震波碎石病患比起接受輸尿管鏡碎石手術的病患，有較高風險得到高血壓（風險比值：1.20, 95％信賴區間1.10-1.31）。而且這個風險隨著體外震波碎石的次數增加而增加；接受一次，兩次，三次，四次及大於五次後的風險比值分別是1.10 (95% 信賴區間 1.00-1.20), 1.30 (95% 信賴區間 1.15-1.48), 1.55 (95% 信賴區間 1.31-1.85), 1.70 (95% 信賴區間 1.32-2.19,), 及 2.00 (95% 信賴區間1.63-2.45)。相對的，糖尿病的風險和震波碎石則沒有相關。在網路統合分析法研究中，我們分析了105個試驗，一共有13176位病患。我們發現剜除手術，在術後6個月及12個月的最大尿流速和國際攝護腺症狀分數都比括除和汽化手術好。而且這個差異持續到手術後24和36個月。在術後12個月最大尿流速中，前3名分別為極光雷射攝護腺剜除手術，雙極電刀攝護腺剜除手術和鈥雷射攝護腺剜除手術，最差的是極光雷射攝護腺汽化術；和單極電刀攝護腺刮除手術的平均差異分別是3.15 ml/sec (95%信賴區間0.63 to 5.67)，2.80 ml/sec (95%信賴區間1.43 to 4.16)，1.13 ml/sec (95%信賴區間0.13 to 2.13)和 -1.90 ml/sec (95%信賴區間 -5.04 to 1.24)。八種新的治療方式都比傳統單極電刀攝護腺括除手術有較少的出血問題，因此縮短了導尿管放置時間，減少術後血紅素下降，膀胱血塊塞住事件和輸血比例。但短期尿失禁仍然是剜除手術關切的問題。

結論
　研究結果顯示：震波碎石會增加長期高血壓的發險，但是不會增加糖尿病風險；剜除手術在功效方面表現最好，新手術方式都比傳統單極電刀刮除術安全。

關鍵字

體外震波碎石 ； 高血壓 ； 攝護腺肥大 ； 雷射 ； 經尿道前列腺括除術 ； 回溯性世代研究 ； 網路統合分析

並列摘要

Background and Objectives
Minimally invasive urologic therapy (MIUT) has reduced surgery-associated complications and facilitates faster recovery compared to conventional open surgeries. In medical conditions such as urolithiasis and benign prostate hyperplasia (BPH), MIUT has gained preference over conventional treatments. Nevertheless, MIUTs are continuously modified and refined for improvement, and new approaches are being introduced for better surgical outcomes. Although extracorporeal shockwave lithotripsy (SWL) is a favored treatment for urolithiasis, much debate has surrounded its association with long-term risk of hypertension and diabetes. On the other hand, despite monopolar transurethral resection of prostate (TURP) being the gold standard surgical treatment for BPH since the 1970’s, numerous methods including the use of different lasers and bipolar probes have been developed and made available since the start of the century. In the current thesis, we adopted the most appropriate and practical approaches of evidence-based medicine (EBM) to: 1) Study whether SWL will increase the subsequent risk of hypertension and diabetes later in life; and 2) Compare the efficacy and complications of new surgical methods with monopolar TURP.

Methods
To evaluate the reported long-term risk of new-onset hypertension and diabetes, associated with SWL in patients with urolithiasis, we sought to adopt the Taiwanese National Health Insurance Research Database, and a retrospective data collection of cohorts who either received SWL or ureteroscopic lithotripsy (URSL). A Cox proportional model and Time-varying Cox models were applied to evaluate the association between SWL and the incidence of hypertension or diabetes. Meanwhile, a meta-analysis of publications reporting on any of the nine BPH MIUTs, selected based on the instrumental and resection method, was performed. The Cochrane risk of bias table was applied to appraise the quality of studies, metafunnel to identify publication bias, followed by random effects generalized linear mixed model to compare the efficacy and safety of these different surgical methods for BPH.

Results
After a median follow-up of 74.9 and 82.6 months, 2,028 and 688 patients developed hypertension in the SWL and URSL groups, respectively. Patients who underwent SWL had a higher probability of developing hypertension than patients who underwent URSL, with a hazard ratio (HR) of 1.20 (95% confidence interval 1.10-1.31) after adjusting for covariates. The risk increased as the number of SWL sessions increased, with a HR of 1.10 (95% CI 1.00-1.20, p=0.05), 1.30 (95% CI 1.15-1.48, p<0.001), 1.55 (95% CI 1.31-1.85, p<0.001), 1.70 (95% CI 1.32-2.19, p<0.001), and 2.00 (95% CI 1.63-2.45, p<0.001) in one, two, three, four and more than five SWL sessions, respectively. However, the risk of diabetes was similar between the two cohorts. In network meta-analysis, we identified 105 trials that enrolled a total of 13,176 participants. Nine surgical treatments were evaluated. Enucleation achieved better maximal flow rate (Qmax) and International Prostate Symptom Score (IPSS) than resection and vaporization, at 6 and 12 months after surgery, and the difference was maintained postoperative up to 24 and 36 months. For 12-month Qmax, the 3 best methods, compared to monopolar TURP, were diode laser enucleation [mean difference (95% Confidence Interval)]: [3.15 (0.63 to 5.67) mL/s], bipolar enucleation [2.80 (1.43 to 4.16) mL/s], and holmium laser enucleation [1.13 (0.13 to 2.13) mL/s]. The worst was diode laser vaporization [-1.90 (-5.04 to 1.24) mL/s]. The eight new methods were all superior in controlling bleeding than monopolar TURP, resulting in shorter catheterization duration, reduced postoperative hemoglobin level declination, fewer blood clot tamponade events, and lower blood transfusion rate. However, short-term transient urinary incontinence was still a concern for enucleation methods. No inconsistency between direct and indirect evidence was detected in either primary or secondary outcomes.

Conclusion
The current thesis found that: SWL increased the long-term risk of new-onset hypertension but not diabetes; new surgical methods for BPH were superior in safety as compared to monopolar TURP: and enucleation methods were the best in primary efficacy. Our thesis demonstrated two best epidemiologic designs to answer contentious issues.

並列關鍵字

shock wave lithotripsy ； hypertension ； benign prostatic hyperplasia ； laser ； transurethral resection of prostate ； retrospective cohort study ； network meta-analysis

參考文獻

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