作者：Norra MacReady
出處：WebMD醫學新聞
【24drs.com】November 3, 2009 (聖地牙哥) — 一篇設計嚴謹且妥善進行的試驗顯示，對糖尿病、貧血與慢性腎病(chronic kidney disease，CKD)患者而言，使用darbepoetin alfa (商品名Aranesp)治療貧血，在降低死亡率、心衰竭、心臟病發作或透析需求來說，並未優於安慰劑。
在美國腎臟協會(ASN)2009年會腎臟週全體會員大會發表前述資料的Marc A. Pfeffer博士表示，要說有什麼區別的話，darbepoetin alfa與較高的中風風險和癌症相關死亡率有關。Pfeffer博士是麻州布萊根婦女醫院心血管內科的資深醫師。
他預言，這些發現將使醫師對於使用darbepoetin重新考量。他們最可能問自己的問題是：既然我知道有此風險，我現在試著要達到什麼目標？Pfeffer博士解釋，許多研究指出，糖尿病、CKD、貧血是「三重打擊」，大幅增加了各種原因引起的死亡率。貧血被視為風險標記，因為血色素低是腎臟和心血管事件的獨立風險因素，特別是糖尿病患。
「Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT)」試驗始於2004年，目標在確認以darbepoetin增加糖尿病、貧血和不需透析之CKD病患的血色素，是否可降低死亡、心血管發病率、死於末期腎病等風險。該試驗在24國的623個中心進行；Pfeffer博士是主要研究員。
總共有4,038名病患被隨機分派接受darbepoetin alfa (n= 2,012人)或安慰劑(n= 2,026人)。開始時，兩組的年紀、性別、種族、糖尿病期間、心血管病史等都相仿，除了安慰劑組有較高的心衰竭史之外。目標的血色素值為13 g/dL，不論何時，只要病患的血色素值低於9 g/dL，立即進行救援治療。藉由電腦維持雙盲，確認誰需要救援治療、並指示醫師使用預先裝好藥劑的針筒。
TREAT試驗的初級終點有兩個面向：一個是心血管面向，包括死亡、心肌缺血、鬱血性心衰竭與中風；一個是腎臟面向，包括死亡與末期腎病。研究對象有第2型糖尿病、CKD(定義為估計腎絲球過濾速率為20-60 mL/min/1.73 m2)、貧血(定義為血清血色素值小於等於11 g/dL)、運鐵蛋白飽和度大於等於15%。研究對象被追蹤48個月。
Darbepoetin alfa對於血色素值有明顯效果。開始時的整體平均血色素值為10.4 g/dL。進入研究後3個月，darbepoetin組的平均血色素值為12.5 g/dL，安慰劑組的平均血色素值為10.6 g/dL(P< .001)。這些數值持續到試驗結束。
不過，矯正貧血狀況對於結果沒有影響。從研究開始時，兩組顯示發生心血管或腎臟事件的病患的曲線幾乎完全重疊。整體而言，darbepoetin組有632名病患(31.4%)發生某種心血管事件，安慰劑組則有602人(29.7%)發生(P= .41)。腎臟面向方面，darbepoetin組有652名病患(32.4%)發生腎臟事件，安慰劑組則有618人(30.5%)(P= .29)。Pfeffer博士表示，在有心血管事件或死亡風險的糖尿病患中，darbepoetin對於結果並沒有產生改變。
更令人困擾的發現是，darbepoetin 的中風風險達兩倍。在整個試驗中，darbepoetin組有101名病患(5%)發生致命或非致命的中風，安慰劑組則有53人(2.6%；P< .001)。
【TREAT試驗之各面向的事件發生率】
終點 | Darbepoetin Alfa (%) | 安慰劑(%) | P |
末期腎病或死亡 | 32.4 | 30.5 | 0.29 |
心血管事件或死亡 | 31.4 | 29.7 | 0.41 |
各種原因之死亡 | 20.5 | 19.5 | 0.48 |
心肌梗塞 | 6.2 | 6.4 | 0.73 |
心衰竭 | 10.2 | 11.3 | 0.24 |
中風 | 5.0 | 2.6 | <.001 |
該試驗排除正處於惡性病的病患，但是有348名研究對象有惡性病史。這些病患中，有些人在研究期間發展成為癌症。服用darbepoetin組的惡性病死亡率高於安慰劑組(P= .002)。
Darbepoetin的確可以緩解疲勞。Darbepoetin組的病患報告指出，「癌症治療引起之疲累程度對生活功能的影響(Functional Assessment of Cancer Therapy-Fatigue，FACT-F)」分數平均增加4.2分，安慰劑組平均增加2.8分(P= .002)。Pfeffer博士表示，改變3分以上可以視為有臨床顯著意義。不過，這兩組的體能和生理功能沒有差異。
未參與本研究的ASN理事長Thomas M. Coffman醫師表示，TREAT試驗的發現對臨床實務會有影響。這是一個設計良好的研究，人們可根據這個新資訊決定治療決策。Darbepoetin無法全面顯示對心血管幫助的證據，這可能會減少紅血球刺激劑的使用。
Pfeffer博士結論表示，對許多病患而言，這些發現代表darbepoetin的風險大於好處。
美國腎臟協會(ASN)腎臟週：摘要7010。發表於2009年10月30日。
Treating Anemia Does Not Reduce the Risk for Cardiovascular or Renal Events in Diabetics With Renal Disease
By Norra MacReady
Medscape Medical News
November 3, 2009 (San Diego, California) — A rigorously designed and conducted trial has shown that anemia treatment with darbepoetin alfa (Aranesp) is no better than placebo at reducing mortality, heart failure, heart attacks, or the need for dialysis in patients with diabetes, anemia, and chronic kidney disease (CKD).
If anything, darbepoetin alfa was associated with a higher risk for stroke and cancer-related mortality, said Marc A. Pfeffer, MD, PhD, who presented the data in a plenary session here at Renal Week 2009: American Society of Nephrology (ASN) 2009 Annual Meeting. Dr. Pfeffer is a senior physician in cardiovascular medicine at Brigham and Women's Hospital in Boston, Massachusetts.
He predicted that these findings would prompt clinicians to reconsider their use of darbepoetin. "One would have to ask themselves: What am I trying to achieve now that I know there's a risk?"
Several studies have shown that the "triple whammy" of diabetes, CKD, and anemia greatly increases the risk for all-cause mortality, Dr. Pfeffer explained. Anemia was considered a marker of risk because low hemoglobin is an independent risk factor for renal and cardiovascular events, especially among people with diabetes.
The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) was launched in 2004 to determine whether raising hemoglobin with darbepoetin in patients with diabetes, anemia, and CKD not requiring dialysis would lower the risk for death, cardiovascular morbidity, or death from end-stage renal disease. The trial was conducted at 623 centers in 24 countries; Dr. Pfeffer was the principle investigator.
A total of 4038 patients were randomized to receive darbepoetin alfa (n?= 2012) or placebo (n?= 2026). At baseline, the groups were comparable in age, sex, race, ethnicity, duration of diabetes, and history of cardiovascular disease, except for a significantly higher history of heart failure in the placebo group. The target hemoglobin level was 13?g/dL, and rescue therapy was instituted any time a patient's hemoglobin dropped below 9?g/dL. Double-blinding was maintained by having a computer determine who needed rescue therapy and directing clinicians to use prefilled syringes.
TREAT had 2 composite primary end points: a cardiovascular composite, consisting of death, myocardial ischemia, congestive heart failure, and stroke; and a renal composite, consisting of death and end-stage renal disease. Participants had type?2 diabetes, CKD, defined as an estimated glomerular filtration rate of 20 to 60?mL/min per 1.73?m2, anemia, defined as serum hemoglobin of 11?g/dL or less, and transferring saturation of 15% or more. Subjects were followed for 48 months.
Darbepoetin alfa had a marked effect on hemoglobin level. The overall median hemoglobin level at baseline was 10.4?g/dL. Three months into the study, median hemoglobin was 12.5?g/dL in the darbepoetin group and 10.6?g/dL in the placebo group (P?< .001). These levels persisted to the end of the trial.
However, correcting anemia had no effect on outcome. From the beginning of the study, the curves from the 2 groups showing the percent of patients experiencing cardiovascular or renal events overlapped nearly perfectly. In all, 632 patients in the darbepoetin group (31.4%) experienced some type of cardiovascular event, compared with 602 patients in the placebo group (29.7%; P?= .41). For the renal composite, 652 of the darbepoetin patients (32.4%) experienced an event, compared with 618 (30.5%) of the people in the placebo group (P?= .29). Among diabetic patients at risk for a cardiovascular event or mortality, darbepoetin "did not alter their journey" toward that outcome, Dr. Pfeffer said.
A particularly troubling finding was a doubling in the risk for stroke associated with darbepoetin. Over the course of the trial, 101 patients in the darbepoetin group (5%) experienced a fatal or nonfatal stroke, compared with 53 patients in the placebo group (2.6%; P?< .001).
Composite and Component Event Rates in TREAT | End Point | Darbepoetin Alfa (%) | Placebo (%) | P |
| End-stage renal disease or death | 32.4 | 30.5 | 0.29 |
| Cardiovascular events or death | 31.4 | 29.7 | 0.41 |
| All-cause death | 20.5 | 19.5 | 0.48 |
| MI | 6.2 | 6.4 | 0.73 |
| Heart failure | 10.2 | 11.3 | 0.24 |
| Stroke | 5.0 | 2.6 | <.001 |
The trial excluded patients with active malignancy, but 348 participants had a history of malignancy. Of those patients, some developed cancer during the study. Deaths attributable to malignancy in that group was higher among people taking darbepoetin than among those taking placebo (
P?= .002).
Darbepoetin did relieve fatigue. Patients in the darbepoetin group reported a mean increase of 4.2 points on the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) score, compared with a mean of 2.8 points reported by the placebo group (
P?= .002). Changes of 3 points or more are considered to be clinically significant, said Dr. Pfeffer. However, there were no differences in energy level or physical function in the 2 groups.
The TREAT findings could have an impact on clinical practice, said president of the ASN, Thomas M. Coffman, MD, from Durham, North Carolina, who was not involved in this research. "This was a very well-designed study, and people will have to make therapeutic decisions based on this new information. Darbepoetin failed to show evidence of cardiovascular benefit across the board. It will likely lead to a reduction in the use of erythropoietin-stimulating agents."
Dr. Pfeffer concluded that "these findings mean that, for many patients, the risks of darbepoetin outweigh the modest benefits."
American Society of Nephrology (ASN) Renal Week: Abstract 7010. Presented October 30, 2009.
