- 學位論文
探討Febuxostat及其他降尿酸藥品對於慢性腎臟病人之尿酸控制與腎功能之影響
The effect of febuxostat and other urate-lowering agents on uric acid management and renal outcome in patients with chronic kidney disease
摘要
研究背景及目的： 血中尿酸值的提高被認為與慢性腎臟病惡化與末期腎病發生有關，導致健康照護費用支出增加、提高心血管疾病發生率及其相關致死率。Allopurinol曾是最常使用的降尿酸藥，因顧慮亞裔特有HLA-B*58:01基因型相關的嚴重皮膚藥物過敏反應，同時也因為於2012年時febuxostat納入健保給付，使得降尿酸藥品的使用型態因此有了很大的改變。Febuxostat的降尿酸效果目前已在痛風的病人上被證實優於allopurinol，目前尚無足夠證據顯示慢性腎臟病人使用哪一降尿酸藥可以延緩腎臟功能的惡化。因此，本研究主要目的: (1)評估最近五年內降尿酸藥品使用型態及藥費支出；(2)比較febuxostat與其他降尿酸藥品(allopurinol, benzbromarone及sulfinpyrazone) 對慢性腎臟病人的降尿酸、腎臟功能改變及死亡率的差異。 研究方法： 本研究使用一大型醫療機構電子醫療資料分析2010-2015期間，降尿酸藥使用型態及藥費支出改變的趨勢。並利用傾向分數配對法(Propensity Score Matching, PSM) 的世代研究設計，比較慢性腎臟病人首次使用febuxostat (研究組)，相對於non-febuxostat其他降尿酸藥(對照組)的尿酸(serum uric acid, sUA)及腎絲球過濾率(estimated glomerular filtration rate; eGFR)在治療前後改變之差異。Cochrane-Armitage test 檢定降尿酸藥使用趨勢。Kaplan Meier方法與log-rank test用來比較兩組間總體死亡率和新接受腎臟替代療法(腎臟移植及慢性透析)發生率的差異。Cox hazard regression model決定降尿酸藥差異對總體死亡率的影響。 研究結果： 2010-2015之間，allopurinol每季使用率明顯逐漸下降(由2010年第一季的52.56% 降至2015年第四季的26.85%)。Benzbromarone每季使用率則逐漸上升，2013後成為最常處方的降尿酸藥(38.59%)。Febuxostat的高價增加了總體降尿酸藥費支出，自2013到2015上升151.92%。另外，本世代研究共分析2,348位慢性腎臟病人(平均eGFR為42.84 mL/min/1.73m2)，追蹤2.5年期間的效果。降尿酸方面，研究組相對於對照組有效的在三個月內達到治療目標低於6 mg/dL (52.28% vs 22.47%; P<0.001)。腎臟功能在2.5年追蹤期間，研究組與對照組在eGFR治療前後變化並沒有臨床及統計顯著差異 (-3.70 vs -3.47 mL/min/1.73m2; P=0.866)。相對於對照組，研究組校正後的死亡風險比值 (adjusted hazard ratio) 為0.44 (95% 信賴區間為0.25– 0.77)。 研究結論： Febuxostat引用改變此研究機構內降尿酸藥的使用型態與藥費支出。對於慢性腎臟病人，febuxostat相對於其他降尿酸藥呈現持續且較大幅度的降尿酸效果，及降低56%死亡風險。本研究結果無法證實不同降尿酸藥對腎臟保護效果的差異。
並列摘要
Introduction Elevated serum uric acid (sUA) is associated with including end-stage renal disease (ESRD), which imposes high costs on the society in terms of reduced quality of life and cardiovascular diseases morbidity and mortality. Patterns of urate-lowering agents (ULAs) use have changed in Taiwan due to the allopurinol induced severe cutaneous adverse reactions and a newly introduced non-purine xanthine oxidase inhibitor, febuxostat, covered by Taiwan National Health Insurance program for gout in 2012. Chronic use of febuxostat showed a superior effect on lowering sUA than allopurinol on gout patients. However, the role of ULAs in patients with chronic kidney disease (CKD) remains uncertain. The present study aimed to: (1) examine the utilization of ULAs, including longitudinal trends in patterns of use and ULAs expenditures, (2) compare the effectiveness of febuxostat with non-febuxostat ULAs on the sUA reduction, changes in estimated glomerular filtration rate (eGFR), and all-cause mortality among adult patients with CKD. Methods Patients prescribed with febuxostat, allopurinol, benzbromarone, and sulfinpyrazone during 2010 and 2015 in a large medical center were evaluated using electronic medical records. Trends in prevalence of use, switching pattern, and ULAs expenditure were assessed in a 3-month interval over the study period. Only patients received at least 3 months of ULAs and diagnosed with CKD prior to lowering uric acid therapy initiation were included in comparative effectiveness analyses. Patients newly treated with febuxostat (study group) or non-febuxostat ULAs (control group) were matched with 1:1 ratio on the propensity core. Study outcomes were mean changes in serum uric acid (sUA) from baseline, achieving sUA less than 6mg/dL of treatment goal, mean changes in eGFR from baseline, receiving renal replacement therapy (RRT), and all-cause mortality. The Cochrane-Armitage tests were employed for examining the trends in ULAs uses. The Kaplan Meier method with the log-rank tests were employed to compare differences in cumulative incidence of mortality and RRT between groups. The independent effect of ULAs on survival was examined using Cox proportional hazard regression model, controlling for potential confounders. Results Prevalence of allopurinol use declined over the study period (from 52.56% in 2010 to 26.85% in 2015), while benzbromarone increased (from 24.28% in 2010 to 38.59% in 2015) and became the most common ULAs prescribed after febuxostat available in April 2013. During 2013 and 2015, overall ULAs expenditure increased 151.92% due to the high price of febuxostat. In the propensity matched cohort, mean sUA reduction from baseline at 2.5 years was 2.79 mg/dL in febuxostat group and 1.50 mg/dL in control group(P<0.001). Proportion of patients in the first 3 months of therapy achieving sUA less than 6 mg/dL was 52.28% in febuxostat group and 22.47% in control group (P<0.001). Changes in eGFR at 2.5 years was not clinical or statistical significantly different between two groups (-3.70 vs -3.47 mL/min/1.73m2; P=0.866). The adjusted hazard ratio for mortality was 0.44 (95% CI 0.25– 0.77) in febuxostat group relative to control group. Conclusions Both the utilization and expenditure of ULAs changed after febuxostat introduction. Among patients with CKD, initiation of febuxostat was associated with greater sUA reduction and decreased risk of all-cause mortality compared with those with non-febuxostat ULAs, but no associations with renal disease progression.