- 學位論文
降尿酸藥物治療對無症狀高尿酸血症患者腎功能、血壓和安全性的影響：系統性回顧及網絡統合分析
Effect of Urate Lowering Therapy on Renal Function, Blood Pressure and Safety in Patients with Asymptomatic Hyperuricemia: A Systematic Review and Network Meta-analysis
摘要
一、背景 高尿酸血症被認為與心血管疾病及腎臟疾病相關，相關的機轉包括高尿酸血症為引起血管內皮功能異常的其中一個原因，血管內皮細胞維護著血管的健康也維持著血液動力學的穩定，對於血壓的調控以及諸多生理機轉的維持扮演著重要的角色，因此，越來越多的研究嘗試對於高尿酸血症的病人予以降尿酸療法，以期對血壓以或腎臟功能等達到保護效用，也確實獲得了許多研究上的證實，因此對於高尿酸血症的病人，一旦出現症狀，如痛風發作，臨床醫師一般予以治療。 然而，很大比例的病人是處於“無症狀”高尿酸血症的狀態，考量到降尿酸藥物可能引起嚴重的副作用，目前各國的常規做法未有一致共識。高尿酸的藥物主要分成抑制尿酸合成以及促進尿酸排出兩類，前者如Allopurinol, Febuxostat；後者如Benzbromarone, Sulfinpyrazone等，令人擔心的副作用如嚴重致命之皮膚過敏症、較高之心血管原因死亡率、肝功能異常等，因此對於無症狀高尿酸血症患者是否給予治療，目前未有定論，其帶來之心血管、腎功能等保護效果是否真的如此明確，又或者不同的藥物有不同的機轉，是否因此具有不同的保護效果，仍屬未知。 本研究旨在做一個系統性回顧以及網絡統合分析來探討對於無症狀高尿酸血症患者，不同之降尿酸藥物，對於血液尿酸值、腎功能、以及血壓是否有不同影響，也針對藥物安全性做分析討論。 二、研究方法 利用醫學資料庫，以關鍵字搜尋相關隨機對照試驗，蒐尋截止日至08/10/2020，將本篇主要探討之血液尿酸值、腎功能、以及血壓分成短期 ( <= 6 個月)以及長期 ( >6個月)做統計分析，尿酸之單位為mg/dL，腎功能以估計腎絲球過濾率做分析，單位為mL / min / 1.73m2，血壓分成收縮壓以及舒張壓，單位為mmHg；次要結果即安全性之分析，包括肝功能異常事件、腸胃道事件、心血管事件、皮膚異常反應、以及肌肉骨骼事件，我們也利用考科藍誤差風險評估工具來評讀收錄之研究。對於連續型變項之結果，我們使用平均數之差異來分析，對於二元資料，我們以勝算比來分析；我們利用統計軟體R作為分析的工具。 三、結果與討論 總共收錄13篇研究，共納入2838位病人，介入包括Allopurinol, Febuxostat, 以及Benzbromarone，對照組包括常規治療或使用安慰劑。降尿酸的效果，比起對照組，短程內以Benzbromarone效果最為顯著 (MD= -3.05 mg/dL, 95% CI -5.19~ -0.91)，長程以Allopurinol效果最佳 (MD= -3.17 mg/dL, 95% CI -5.19~ -1.15)；無論短程長程，相較於對照組，Allopurinol組具有顯著較高之腎絲球過濾率 (MD= 3.07 mL / min / 1.73m2, 95% CI 0.18~5.95, MD= 4.10 mL / min / 1.73m2, 95% CI 2.66~5.54)；至於血壓，無論短程長程，Allopurinol以及Febuxostat對於收縮壓並無顯著影響，而舒張壓的分析裡，長期使用Febuxostat，比起對照組，有顯著較低的舒張壓 (MD= -1.55 mmHg, 95% CI -2.99~-0.04)。次要的安全性分析結果顯示，降尿酸藥物比起對照組，並無顯著較高之肝功能異常事件、腸胃道事件、心血管事件、皮膚異常反應、以及肌肉骨骼事件。 過去的研究多是針對有症狀的高尿酸血症患者，因此劑量普遍較我們收錄到的研究為高，不過本研究對於藥物降尿酸的效果，仍與過去的研究相似，Benzbromarone確實有優良的降尿酸效果。腎功能的分析中，患者使用Allopurinol比起Febuxostat組以及對照組皆有較好之腎功能，雖然數值不大但達到統計顯著，且在腎功能退化的病人中，些微的腎功能差異也具重要意義，且此些微的差距數值與過去的研究相近。我們收錄到的研究其報告的血壓，降尿酸藥物並無顯著造成血壓的影響，考量到使用於無症狀患者之藥物劑量可能較低，可能無法突顯藥物之於血壓的效果，相關性還待進一步研究。 四、結論 對於無症狀高尿酸血症的患者，比起對照組，在短期及長期的分析中，Benzbromarone以及Allopurinol分別有顯著最佳之降尿酸效果；使用Allopurinol，有顯著較優之腎功能；使用Febuxostat顯著降低病人的舒張壓。此外，降尿酸藥物並無顯著增加肝功能異常事件、腸胃道事件、心血管事件、皮膚異常反應、以及肌肉骨骼事件之發生。
並列摘要
Background Patients with hyperuricemia have a higher risk of cardiovascular diseases and renal failure. However, many individuals with hyperuricemia remain asymptomatic. Since patients experience no immediate discomfort and there are possible side effects of urate lowering drugs, starting treatments for asymptomatic hyperuricemia is still controversial. we aimed to perform a network meta-analysis to investigate the effects of different urate lowering therapies on serum uric acid level, renal function, and blood pressure in patients with asymptomatic hyperuricemia. We also looked into the safety of those treatments to attain a balanced consideration for patients with asymptomatic hyperuricemia. Methods We searched PubMed and Embase for studies published until October 8, 2020. We included human clinical trials in which patients were randomly allocated to different treatment groups or placebo/usual care group. The primary outcomes were changes in serum uric acid level, renal function assessed by estimated glomerular filtration rate (eGFR) and blood pressure. For the primary outcomes, we evaluated the short-term and long-term treatment effect by dividing the duration of treatment into short-term (<= 6 months) and long-term follow-ups (> 6 months). The secondary outcome was safety, including the risks of impaired liver function, gastrointestinal events, cardiovascular events, skin reaction and musculoskeletal events in patients within the trials identified by our search strategy. For the continuous outcomes, such as serum uric acid level, eGFR, and blood pressure, we estimated the differences in mean changes between treatment and control group. For the dichotomous outcomes, such as safety outcomes, we used Peto odds ratio model, because the event numbers were small or even zero in some studies. We undertook a random-effects network meta-analysis under the frequentist framework by R (version 4.0.3). Results Thirteen eligible trials were identified, including 2838 patients. Urate lowering therapies included allopurinol, febuxostat, and benzbromarone. Compared with placebo, benzbromarone showed a greater urate lowering effect within short-term follow-up (MD= -3.05 mg/dL, 95% CI -5.19~ -0.91). Allopurinol significantly lowered serum uric acid level than placebo in the long-term follow-up (MD= -3.17 mg/dL, 95% CI -5.19~ -1.15). As for renal function, patients using allopurinol had significantly higher eGFR than those using placebo in both short-term and long-term follow-up (MD= 3.07 mL/min/1.73m2, 95% CI 0.18~5.95, MD= 4.10 mL/min/1.73m2, 95% CI 2.66~5.54). No difference in systolic blood pressure and diastolic blood pressure was found between allopurinol/febuxostat and placebo groups, except for diastolic blood pressure in febuxostat group after long-term period of treatment (MD= -1.55 mmHg, 95% CI -2.91~-0.04). Network meta-analysis showed no significantly increased odds of impaired liver function, gastrointestinal event, cardiovascular event, musculoskeletal event, and skin reaction in patients under urate lowering therapies. Conclusions Our result showed that in patients with asymptomatic hyperuricemia, benzbromarone has the best urate lowering effect in the short-term follow-up and allopurinol has the best effect in the long-term follow-up. In addition, allopurinol has shown renoprotective effect. Febuxostat has significant effect on lowering diastolic blood pressure in long-term follow-up. Urate lowering therapy does not result in higher risks of impaired liver function, gastrointestinal events, cardiovascular events, skin reaction and musculoskeletal events.