陳秀熙臺灣大學：預防醫學研究所黃柏堅Huang, Po-ChienPo-ChienHuang2007-11-282018-06-292007-11-282018-06-292007http://ntur.lib.ntu.edu.tw//handle/246246/59189一、研究背景及目的 針對輸尿管結石在急性期及慢性期的處理，目前已發展出多樣性的治療方式，亦有標準化的臨床指引，其決策皆以臨床經驗上的治療成功率及醫療專家意見為依據，往往忽略了患者本身的主體性、對治療的接受程度及需付出之機會成本。在面對不同預防及治療選擇時，如何在多種治療組合中求得合理且符合成本效益的臨床策略，乃目前極欲解決的問題。此外，在醫療資源有限的情況下，以社會的角度評估輸尿管結石治療及介入預防的成本效用分析，亦為目前重要的課題。 本研究以實證的資料，結合病人的偏好，以社會的角度，針對輸尿管結石患者，分別評估在急性期及慢性期間最具成本效用的治療及預防結石復發之模式，以作為臨床決策之參考。本研究有以下三個主要研究目的： （一） 針對輸尿管結石治療及預防策略，做一連串系統性文獻回顧，進行輸尿管鏡碎石術及體外震波碎石術在結石清除率上的整合性分析(meta-analysis)。 （二） 利用標準博奕法測量患者對治療的偏好程度 (patient preference)，以作為患者在輸尿管結石治療及預防模式中各階段之效用值，並比較不同狀態的效用值大小，並探討解釋效用值變異的因素。 （三） 利用文獻回顧結果及實證資料，建立多階段之疾病處理模型，並針對不同的治療策略及預防模式，進行決定性模式(deterministic analysis)及機率性模式(probabilistic analysis)之成本效用分析，以找出不同情境下最符合成本效益的臨床決策。 二、研究方法 進行文獻回顧，依研究類型分為隨機對照組研究及比較性研究，將結石依部位及大小進行分層，分別進行輸尿管鏡碎石術及體外震波碎石術的結石清除的整合性分析，並估計這二種治療方式之結石清除率及相對效能的估算。 同時，以面訪的方式進行患者偏好度的測量，依據標準博奕法之精神，利用參考狀態的測量，以改良式的標準博奕法測量方式，求得各狀態之相對效用值，再以轉換公式求得絕對效用值，以分辨不同狀態下微小的偏好度差異。進一步利用數值轉換及線性回歸分析，分析影響效用值之相關因子。 接著，由上述整合性分析結果、德菲法求得之專家意見及文獻回顧所得參數的估計，建立結石之急性連續治療模型及慢性結石復發之疾病進展模式。 最後，利用馬可夫模式，建立輸尿管結石急性期及慢性期的成本效用決策樹模型，以蒙地卡羅模擬(Monte Carlo simulation)技術，考慮因機會產生的第一級不確定性及並考慮參數本身所造成的第二級不確定性，進行500個樣本大小為5000人之樣本模擬。由模擬出來的成本及效用參數，分別進行決定性模式分析及機率模式分析的成本效用分析。除了針對不同狀況的輸尿管結石治療策略，逐一比對以選擇最佳的治療方式外，亦針對結石預防的方法進行比較分析，以評估是否需進行特殊性結石預防或定期追蹤治療。 三、主要研究結果 （一） 利用整合性分析結果求得以體外震波碎石術作治療時，依近端結石大小由大至小排列時，其治療成功率為分別為0.303，0.409及0.440。遠端結石而言，由大至小排列時，其治療成功率為分別0.726，0.777及0.831。以輸尿管鏡碎石術作治療時，依近端結石大小由大至小排列，其治療成功率為0.550，0.649及0.649。對於遠端結石而言，依大到小之治療成功率為0.864，0.893，及0.931。 （二） 效用值測量以改良式標準博奕法，針對樣本醫院泌尿科門診共267名結石患者，以隨機抽樣進行問卷訪談，共完成89份有效問卷。分析參考測量的血液透析狀態效用值為0.399±0.343。急性治療中狀況效用值，包括期待性藥物治療(0.935±0.096)，體外震波碎石術(0.930±0.098)，輸尿管鏡碎石術的效用值(0.914±0.106)，及手術治療的效用值(0.846±0.165)。慢性期之狀況包括，無特殊預防(0.959±0.090)，生活飲食型態改變(0.974±0.076)，定期追蹤(0.971±0.079)，及藥物預防(0.955±0.088)。解釋效用值變異的因子包括性別、教育程度及歷經輸尿管鏡碎石手術的經驗。 （三） 對於大型結石而言，若結石處於近端或遠端輸尿管時，均建議以輸尿管鏡碎石為首選治療，合併以輸尿管鏡碎石為挽救治療。對於中型結石而言，若結石位於近端或遠端，均建議使用期待性治療，結石未排出者輔以輸尿管鏡處理結石，為最佳選擇。對於小型結石而言，不論結石位於近端或遠端輸尿管，應選擇以期待性治療為主，若結石未排出時，再採取輸尿管鏡碎石術處理之模式。 （四） 就結石復發預防而言，以結石復發次數為治療結果，分析發現生活飲食調整、藥物預防或接受定期檢查並進行預防性體外震波碎石術，均是符合成本效益的決策，而以生活飲食調整預防為最佳的預防策略。當採用生活品質校正存活時間為結果變項分析成本效用時，發現所有的策略中，僅有生活飲食調整為唯一符合成本效用的預防策略。 四、結論 本研究發展出一種創新的標準博奕法以測量各種與輸尿管結石有關的健康狀態之效用值，其中使用到的整合性分析方法在成本效益分析中的重要性在於可增加資料的強度，並降低重要參數所造成的第二級不確定性。而在考慮個人特質及其主觀意識之臨床個人決策模式時，應採用機率性成本效益分析模式。總結而言，本研究利用正式的成本效用分析，以實證醫學為基礎的觀點提供依輸尿管結石不同部位及大小之下所對應的最佳臨床指引。Introduction While treatment guidelines for ureteral stone are well established, the decision is often based on the expert opinion and clinical tacit knowledge. Very few studies take the patients’ preference into account and the clinical decision making can make better choice. The aims of this study were to perform meta-analysis of the stone clearance rate of ureteroscopic lithotripsy (URSL) and extracorporeal shock wave lithotripsy (ESWL) by using systemic review, to apply standard gamble method to evaluate the patient preference by utility measurement on every treatment and prevention strategy in ureteral stone management, and finally to use a multi-state disease progressive model to evaluate the cost-effectiveness of every treatment and prevention strategies by deterministic and probabilistic methods. Materials and Methods In the literature review, the published studies were divided into randomized control trials and comparative studies according to the study design. The stone clearance rate and relative effectiveness between URSL and ESWL were estimated by the stratification of stone site and size. The utility values of clinical treatment and prevention conditions were measured by modified standard gamble method. The novel method different from conventional standard gamble method includes setting reference state and ranking the target states. After defining the relative utility values, the absolute utility values (with anchor states of complete health and death) were calculated by chaining transformation method. The modified method may even detect difference between minor clinical conditions. For evaluating the associating factors, the value transformation and linear regression analysis were conducted in this study. Incorporating the results of literature review and expert opinion retrieved by Delphi method, the disease progressive models for acute and chronic phases were established. The cost-utility analysis with the constructed Markov chain model was performed by using Monte Carlo simulation in TreeAge®. Two levels of uncertainty were taken into account in the current probabilistic approach, the first-order uncertainty for chance variability and the second-order uncertainty for parameter uncertainty. The available treatment and prevention strategies were evaluated to define the most cost-effective decision. Main Results 1. The meta-analysis revealed the stone clearance rate of ESWL for large, medium, and small stones were 0.303, 0.409, and 0.440 for proximal stones and 0.726, 0.777, and 0.831 for distal ones. The results of URSL for large, medium, and small stones were 0.550, 0.649, and 0.649 for proximal stones and 0.864, 0.893, and 0.931 for distal ones. 2. In a total of 267 cases from urological clinic, 89 were sampled to complete the utility measurement. The utility value of hemodialysis state, as the reference state, was 0.399±0.343. In acute phase condition, the utility values of expected medical treatment (0.935±0.096), ESWL (0.930±0.098), URSL (0.914±0.106), and invasive surgical treatments (0.846±0.165) were measured. The utility value of chronic conditions were also reported: no prevention (0.959±0.090), life style modification (0.974±0.076), regular surveillance (0.971±0.079), and long term medical prophylaxis (0.955±0.088). The associating factors were gender, education level and experience of URSL. 3. For large ureteral stone, the best treatment strategy was the combination of URSL as primary and salvage therapy. For medium stone, the best method was expectant management with URSL as following treatment choice. For small stone, the best strategy was expectant management with applying URSL for residual stones. 4. By the outcome of recursive events, the life style modification, medical prophylaxis and regular surveillance were cost-effective. In considering the willingness to pay as one quarter GNP (NTD 132000), the best choice is life style modification only. However, taking quality-adjusted life time as the outcome parameter, only life style modification was cost-effective. Conclusion In this study, a novel modified standard gamble method was develop to evaluate the patient preference to treatment and prevention conditions in ureteral stone management. The result was constructed into the cost-utility analysis. By considering individual utility, we adopted the probabilistic approach in cost-utility analysis to establish the clinical guideline for ureteral stone treatment and prevention.口試委員會審定書.................................... i 中文摘要............................................ iii 英文摘要............................................vii Manuscript I: Modified Standard Gamble Method for Utility Measurement for Ureteral Stone Management............0-1 Manuscript II: Cost-utility Analysis of Acute Ureteral Stone Management.....................................0-11 Manuscript III: Cost-effectiveness Analysis of Prevention of Ureteral Stone: Comparison of Prophylactic Medication, Surveillance, and Life Style Modification............0-33 第一章 緒論..........................................1-1 第一節 前言......................................1-1 第二節 研究動機..................................1-2 第三節 研究目的..................................1-3 第二章 文獻探討......................................2-1 第一節 尿路結石特性..............................2-1 第二節 輸尿管結石之治療決策......................2-4 第三節 輸尿管結石之預防決策......................2-11 第四節 輸尿管結石的病患偏好研究..................2-15 第三章 材料與方法....................................3-1 第一節 研究流程..................................3-1 第二節 文獻資料整合分析..........................3-3 第三節 病患偏好測量..............................3-8 第四節 疾病進展模型..............................3-15 第五節 成本效用分析..............................3-34 第四章 研究結果......................................4-1 第一節 體外震波碎石術及輸尿管鏡碎石術於結石清除率之整 合性分析結果..............................4-1 第二節 效用值測量結果............................4-3 第三節 基本參數推估結果..........................4-5 第四節 急性結石處理決策的成本效用分析............4-19 第五節 慢性結石預防決策的成本效用分析............4-48 第五章 討論..........................................5-1 第一節 本研究的重要發現..........................5-1 第二節 決策模型的臨床應用........................5-3 第三節 效用值測量方法............................5-5 第四節 資料可靠度................................5-6 第五節 本研究之方法學特色........................5-8 第六節 研究限制..................................5-10 第六章 結論..........................................6-1 參考文獻.............................................7-1 附錄.................................................8-11292403 bytesapplication/pdfen-US輸尿管結石整合性分析醫療決策分析成本效用分析馬可夫模式病患偏好效用Ureteral stoneMeta-analysisMedical decision makingCost-utility analysisMarkov modelPatient preferenceUtility.thesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/59189/1/ntu-96-R94846015-1.pdf