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作者：Laurie Barclay, MD  
出處：WebMD醫學新聞

　　December 24, 2009 — 有關腎臟疾病患者的貧血治療，在12月24日線上發表於美國腎臟醫學會期刊的主編評論中詳細討論。
　　
　　根據TREAT（the Trial to Reduce Cardiovascular Events with Aranesp[darbepoeitin]Therapy）研究的結果以及其他最近的研究，麻州波士頓布萊根婦女醫院及哈佛醫學院的Ajay K. Singh醫師表示，在某些病例，補充鐵質或是輸血應該取代紅血球生成刺激藥物（ESA）。
　　
　　Singh醫師寫到，最近發表的標竿研究[TREAT]已經顛覆貧血處理的領域。罹患慢性腎臟疾病（CKD）且貧血的病患，無法安穩地起床，且因保險公司將不讓他們再碰到這些藥物（ESA）而感到絕望，TREAT研究提供確切的證據來做出強硬的給付決定：限制有症狀或是那些等待腎臟移植的病患使用ESAs。
　　
　　大部分CKD患者在疾病進程中的某個時間點發生貧血。Darbepoetin（Aranesp，Amgen藥廠）與其他刺激紅血球產生的ESAs被處方來降低輸血需求與減少疲勞。
　　
　　然而，Singh醫師提醒以TREAT研究的發現顯示，隨機分派接受darbepoetin，相較於那些接受安慰劑的病患，中風發生率高出兩倍，即使心肌梗塞或是其他心血管疾病事件或死亡發生率在兩組間並無差異。
　　
　　除此之外，darbepoetin治療只與生活品質些微改善有關，但是發生癌症的風險有未達統計顯著水準的趨勢。
　　
　　TREAT是一項安慰劑控制、雙盲、隨機分派研究，收納4,038位病患。除了中風風險增加之外，接受darbepoetin治療病患發生血栓栓塞與深部靜脈栓塞的比例比接受安慰劑病患高。
　　
　　另外兩項在這篇綜論討論的研究是Correction of Hemoglobin and Outcomes in Renal Insufficiency（CHOIR）與Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin-beta（CREATE）研究。TREAT研究的是darbepoetin，CHOIR檢驗epoetin-alfa，而CREATE檢驗epoetin-beta。
　　
　　Singh醫師寫到，在這些研究中，並未發現好處或死亡率、心血管併發症風險上升。在CREATE研究中，偏向傷害的風險點估計值為22%（95% CI為0.53-1.14），在CHOIR是34%（95% CI為1.03-1.74），在TREAT是5%（95% CI為0.94-1.17）。換句話說，使用ESAs設定較高的血紅素目標值確實不會有好處，且可能增加風險。
　　
　　根據Singh醫師表示，嚴重貧血的CKD患者需要頻繁地輸血，或者是等待腎臟移植患者，由於無法輸血仍應考慮接受ESA治療。
　　
　　他建議輕中度貧血患者應該補充鐵質，特別是沒有症狀或是僅有輕度疲倦及其他症狀的患者。如果症狀產生或是貧血惡化，可能需要輸血或短期使用ESA治療。大部分罹患癌症的CKD患者應該接受輸血而非ESAs類藥物。
　　
　　患有CKD但尚未透析患者，在處理貧血時應該避免使用ESAs，這樣的做法目前聽起來是根據TREAT研究顯著的觀察結果。TREAT研究中中風與血栓栓塞事件機率較高，甚至是癌症風險較高，且僅有非常微小的生活品質好處，使得對大部分非透析CKD患者來說是偏好不使用ESA治療。
　　
　　然而，他建議更多的臨床研究應該評估ESAs類藥物是否有毒性劑量範圍，投予這些藥物的頻率改變是否影響療效與安全性，以及TREAT研究中觀察到ESA的風險是否也會發生在透析的CKD患者。
　　
　　費城賓州大學醫學院高血壓與腎臟電解質腎臟研究員訓練計畫主持人暨主任Jeffrey S. Berns醫師在一篇新聞稿中表示，Singh醫師的主編評論適當地解釋CKD患者們要謹慎使用靜脈注射鐵劑與ESAs。
　　
　　他所談論到的所有重要研究都是針對糖尿病高盛行率與心血管及其他疾病高負擔病患所進行的。決定TREAT研究真正的應用性將端看針對較為年輕且健康、沒有其他並存疾病的患者進行檢驗。
　　
　　除此之外，Berns醫師表示，TREAT與其他研究維持病患的血紅素值高於10 g/dl，且維持CKD患者的血紅素值低於10 g/dl的風險及好處仍然未知。
　　
　　Singh醫師與TREAT研究主要研究者在同一家機構擔任資深腎臟科醫師，他是CHOIR研究的主要研究者，且是TREAT研究的執行為委員會成員。他接受來自Amgen、Johnson and Johnson與Watson公司的諮詢收入與經費贊助，同時他也接受Fibrogen公司的諮詢費用。Berns醫師擔任顧問或是執行委員會成員，且接受Amgen、Affymax、GSK與Wyeth公司的諮詢費用。


Treatment of Anemia in Patients With Renal Disease Reviewed

By Laurie Barclay, MD
Medscape Medical News

December 24, 2009 — The treatment of anemia in patients with renal disease is reviewed in an editorial published online December 24 in the Journal of the American Society of Nephrology.

On the basis of the results of the Trial to Reduce Cardiovascular Events with Aranesp [darbepoeitin] Therapy (TREAT) and other recent studies, Ajay K. Singh, MD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, suggests that iron or blood transfusions should replace erythropoiesis-stimulating agents (ESAs) in some cases.

"The recently published landmark study [TREAT] has turned the world of anemia management upside down," Dr. Singh writes. "Patients who have chronic kidney disease (CKD) and anemia and literally could not get up in the morning will despair that insurance companies will put [ESAs] beyond their reach.... TREAT provides definitive evidence to justify making tough reimbursement decisions: Restricting the use of ESAs to symptomatic patients or those who are awaiting kidney transplantation."

Anemia develops in most patients with CKD at some point during the course of the illness. Darbepoetin (Aranesp, Amgen) and other ESAs that stimulate red cell production are prescribed to lower blood transfusions requirements and reduce fatigue.

However, Dr. Singh urges caution in light of TREAT findings that stroke incidence was doubled in patients randomly assigned to receive darbepoetin compared with those assigned to receive placebo, even though incidence of myocardial infarction or other cardiovascular event or death were similar in both groups.

In addition, darbepoetin treatment was associated with only modest improvements in quality of life, but there was a nonsignificant trend toward increased risk of developing cancer.

TREAT was a placebo-controlled, double-blind, randomized trial enrolling 4038 patients. In addition to increased stroke risk, darbepoetin-treated patients had a higher rate of thromboembolism and deep venous thrombosis compared with patients receiving placebo.

The other 2 trials reviewed in this editorial are Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) and Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin-beta (CREATE). Whereas TREAT studied darbepoeitin-alfa, CHOIR tested epoetin-alfa, and CREATE tested epoetin-beta.

"In each, there was either no benefit or increased risk for mortality or cardiovascular complications," Dr. Singh writes. "In CREATE, the point estimate of risk in the direction of harm was 22% (95% CI 0.53 to 1.14), in CHOIR 34% (95% CI 1.03 to 1.74), and in TREAT 5% (95% CI 0.94 to 1.17), respectively. In other words, targeting a higher Hb concentration with ESAs was certainly not associated with benefit but perhaps increased risk."

According to Dr. Singh, CKD patients with severe anemia requiring frequent blood transfusions, or who are candidates for a kidney transplant and therefore cannot receive blood transfusions, should still be considered for ESA therapy.

He recommends iron therapy for patients with mild to moderate anemia, particularly if they are asymptomatic or have only low-level fatigue and other symptoms. If symptoms develop or anemia worsens, a blood transfusion or a short course of ESA therapy may be indicated. Most CKD patients with cancer should be treated with blood transfusions rather than ESAs.

"Avoiding use of ESAs in managing anemia in nondialysis patients with CKD is now the soundest approach given the remarkable observations from the TREAT study," Dr. Singh writes. "The higher rate of stroke and thromboembolic events and possibly a higher risk for cancer in TREAT with only very modest benefits to quality of life tip the scale in favor of no ESA treatment of anemia in most nondialysis patients with CKD."

However, he recommends more clinical trials to evaluate whether there is a toxic dosage range of ESAs, whether the frequency of administration of ESAs changes efficacy and safety, and whether the risks of ESA observed in TREAT also occur in dialysis patients with CKD.

"Dr. Singh's editorial appropriately pleads for cautious use of intravenous iron and ESAs in patients with CKD," Jeffrey S. Berns, MD, chief and director of the Nephrology Fellowship Training Program of the Renal-Electrolyte and Hypertension at the University of Pennsylvania School of Medicine in Philadelphia, says in a news release.

"All of the major trials he discusses were conducted in patients with a high prevalence of diabetes and heavy burden of cardiovascular and other comorbid conditions. Determining the true generalizability of TREAT would depend on testing younger and healthier patients without comorbid conditions."

In addition, Dr. Berns notes that TREAT and other trials maintained patient hemoglobin levels at or above 10 g/dL and that the risks and benefits of maintaining hemoglobin levels in CKD patients significantly below 10 g/dL is still unknown.

Dr. Singh is a senior nephrologist at the same institution as the primary investigator of the TREAT study, was principal investigator of CHOIR, and is a member of the executive committee for TREAT. He has received consulting income and grant support from Amgen, Johnson and Johnson, and Watson, and consulting income from Fibrogen. Dr. Berns has served on advisory or executive committees for and received consulting income from Amgen, Affymax, GSK, and Wyeth.

J Am Soc Nephrol. Published online December 24, 2009.