探討紅血球生成素對慢性腎臟疾病患者之腎性貧血療效與不良事件之相關性

Insight into relationship among therapeutic effectiveness and adverse events to the anemic patients with chronic kidney disease treated with erythropoietin

王藝穎(Yi-Ying Wang)

指導教授 ： 黃耀斌

共同指導教授 ： 黃尚志(Shang-Jyh Hwang)

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2013年)

摘要

背景:紅血球生成素的上市，使得慢性腎臟疾病患者的貧血問題顯著改善，並降低原本輸血治療之風險。然而，慢性腎臟疾病患者的貧血治療目標至今仍是備受討論的議題。已有臨床試驗顯示，使用紅血球生成素積極治療貧血可能帶來不良事件產生之風險。台灣是慢性腎臟疾病盛行的國家，目前仍缺乏紅血球生成素治療貧血目標與不良事件發生之相關性探討。
目的:本研究旨在評估台灣紅血球生成素用於慢性腎臟疾病符合台灣健保規範之程度及臨床不良事件發生情形、回顧目前文獻有關紅血球生成素用於慢性腎臟疾病之安全性問題，並探討不同慢性腎臟疾病族群是否為不良反應發生之危險因子。
方法:本研究分成兩部分:(1)系統性文獻回顧及統合分析:以結構性文獻搜索策略，搜尋不同紅血球生成素治療目標與不良事件發生之相關性。(2)病歷回顧:根據台灣南部某醫學中心之病歷資料，以回溯性世代研究的方式，追蹤2007年間首次使用紅血球生成素的住院及門診病人，搜集病人基本資料、用藥紀錄、檢驗數據和診斷紀錄，以評估紅血球生成素使用後的安全性問題及符合健保規範的情形。
結果與討論:(1)系統性文獻回顧及統合分析:系統性文獻回顧分為隨機對照試驗及世代研究兩個部分。隨機對照試驗統合分析的結果顯示，高的血紅素治療目標相較低的血紅素治療目標有較高的中風、高血壓及血液透析血管通路栓塞風險。而高低兩組血紅素治療目標之全因素死亡、嚴重心血管事件、腎功能惡化、住院與其他紅血球生成素相關之不良事件發生風險，並無統計上顯著差異。世代研究呈現之結果與隨機對照試驗一致，高的血紅素治療目標不會增加發生全因素死亡及惡化腎功能之風險。(2)病歷回顧: 病歷回顧分為安全性評估及藥品使用評估兩個部分。安全性評估結果顯示，貧血控制程度佳與貧血控制程度不佳兩個組別間發生死亡、中風、高血壓及血液透析血管通路栓塞風險無統計上顯著差異，不同慢性腎臟疾病族群發上以上不良事件之風險亦無統計上顯著差異。藥品使用評估結果顯示，五成以上患者使用紅血球生成素前未進行鐵質檢測，且多數患者未達成貧血治療目標。
結論:雖然紅血球生成素能夠有效治療慢性腎臟疾病引起的貧血，但血紅素治療目標過高帶來額外的風險也成為另一個隱憂。因此，針對不同年齡及不同既有疾病族群，制定適當的貧血治療目標是有其必要性。

關鍵字

紅血球生成素 ； 慢性腎臟疾病 ； 貧血 ； 系統性文獻回顧 ； 統合分析

並列摘要

Background: Since the launch of erythropoietin, the anemia problem of chronic kidney disease (CKD) has significant improved and the risks of blood transfusion has reduced. Nevertheless, therapeutic target of anemia has been a topic of much debate for several years. Clinical trials have demonstrated aggressive therapy for anemia may increase risk of adverse events. Taiwan is a country with high prevalence of chronic kidney disease, but there is short of investigation of relationship among therapeutic targets and adverse events.
Aim and objectives: This study aimed to explore extent of drug usage fit in with drug subsidy established by Bureau of National Health Insurance, and to explore clinical response of adverse events. Additionally, this study aim to review the issue of safety of erythropoietin and investigate whether CKD population is a risk factor for developing adverse events.
Methods: (1) Systematic review and meta-analysis: A structured search strategy was used to search evidence-based medicine database for studies reported the association among different therapeutic target reached by erythropoietin and risks of adverse events. (2) Chart review: A retrospective cohort study was conducted at a medical center in south Taiwan. Patients who first received erythropoietin in 2007 are followed, and their basic information, medicine record, lab data and diagnosis record are collected for assessing safety of erythropoietin treatment and fitness for the drug subsidy.
Results and discussion: (1) Systematic review and meta-analysis: the systematic review is divided into two parts, randomized controlled trials (RCT) and cohort studies. Results of RCT showed a higher hemoglobin target was associated with increased risks for stroke, hypertension and vascular access thrombosis compared with lower hemoglobin target. There were no statistically difference in risk for mortality, serious cardiovascular events, progression of kidney disease, hospitalization and other ESA-related adverse events. Systematic review of cohort studies corresponded with outcomes of RCTs, suggested higher hemoglobin target does not increase risks of mortality and progression of kidney disease. (2) Chart review: the chart review is divided into two parts, assessment of drug safety and assessment of drug usage. Results of safety assessment showed good anemia-control group did not increased risks for stroke, hypertension and vascular access thrombosis compared with poor anemia-control group significantly. Outcomes of assessment of drug usage showed less than half of patients conducted iron test before use of erythropoietin, and most of patients did not reach recommended therapeutic target.
Conclusion: Although erythropoietin is effective for treating anemia of CKD, excessive therapy may bring additional risks that is a great worry. Hence it is essential to set up therapeutic targets of anemia for different age and patients with assorted comorbidities.

並列關鍵字

erythropoietin ； chronic kidney disease ； anemia ； systematic review ； meta-analysis

參考文獻

1. 李文欽, 張舜智, 黃忠餘, 吳明儒. 慢性腎臟病與貧血. 腎臟與透析 2007;19:81-8.

2. Levin A, Thompson CR, Ethier J, Carlisle EJ, Tobe S, Mendelssohn D, Burgess E, Jindal K, Barrett B, Singer J, Djurdjev O. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis 1999;34:125-34.

3. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. Canadian Erythropoietin Study Group. BMJ 1990;300:573-8.

4. Bahlmann J, Schoter KH, Scigalla P, Gurland HJ, Hilfenhaus M, Koch KM, Muthny FA, Neumayer HH, Pommer W, Quelhorst E. Morbidity and mortality in hemodialysis patients with and without erythropoietin treatment: a controlled study. Contrib Nephrol1991:90-106.

5. Revicki DA, Brown RE, Feeny DH, Henry D, Teehan BP, Rudnick MR, Benz RL. Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis 1995;25:548-54.