St. John Providence Health System, Warren, Mich., USA.
Am J Nephrol. 2013;37(6):549-58. doi: 10.1159/000351175. Epub 2013 May 25.
Recombinant erythropoietin has become a routine component of care of patients with chronic kidney disease reducing the need for blood transfusions but raising the risks for cardiovascular events. We undertook this secondary analysis of subjects enrolled in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial to examine the interrelationships between epoetin-alfa maintenance doses utilized and achieved hemoglobin (Hb) irrespective of treatment target and randomized allocation.
We performed a post hoc analysis from the CHOIR trial. Inclusion criteria were Hb <11.0 g/dl and estimated glomerular filtration rates of 15-50 ml/min/1.73 m(2). To be included in the present analysis, subjects needed to be free of the composite event at 4 months, receive epoetin-alfa, and have ≥1 postbaseline Hb measurement. The mean weekly dose of epoetin-alfa received up to the time of first event or censure was the main exposure variable, while the achieved Hb at month 4 was the confounder representing the subject's underlying response to treatment. The primary outcome was the composite of death, heart failure hospitalization, stroke, or myocardial infarction. A Cox proportional hazard regression model was used in time-to-event analysis.
Among 1,244 subjects with complete data, the average weekly dose of epoetin-alfa ranged 143.3-fold from 133 to 19,106 units/week at the time of first event or censure. Cox proportional hazard analysis found that those in the middle tertile of Hb achieved (>11.5 to <12.7 g/dl) and the lowest tertile of epoetin-alfa dose exposure level (<5,164 units/week) had the lowest risk. Irrespective of Hb achieved, the relative risk in the highest tertile (>10,095 units/week) of epoetin-alfa dose exposure level was significantly escalated (hazard ratios ranged from 2.536 to 3.572, p < 0.05, when compared to the group of middle Hb tertile and lowered dose tertile). In a multivariable model that adjusted for achieved Hb, albumin, cholesterol, age, prior heart failure, prior stroke, prior deep venous thrombosis, atrial fibrillation or malignancy, the average weekly dose had a significant (p = 0.005) relative risk of 1.067 per 1,000 units of epoetin-alfa for the primary end point.
In the CHOIR trial, average epoetin-alfa doses >10,095 units/week were associated with increased risks for cardiovascular events irrespective of the Hb achieved within the first 4 months of treatment. These data suggest the weekly epoetin-alfa dose and not the Hb achieved was a principal determinant in the primary outcome observed implicating a cardiovascular toxicity of this erythrocyte-stimulating agent.
重组促红细胞生成素已成为慢性肾脏病患者治疗的常规组成部分，减少了输血的需求，但增加了心血管事件的风险。我们对参加纠正血红蛋白和肾功能不全结局（CHOIR）试验的患者进行了这项二次分析，以检查无论治疗目标和随机分配如何，使用的促红细胞生成素 -α维持剂量与所达到的血红蛋白（Hb）之间的相互关系。
我们对 CHOIR 试验进行了事后分析。纳入标准为 Hb <11.0 g/dl 和估计肾小球滤过率为 15-50 ml/min/1.73 m（2）。为了纳入本分析，受试者需要在 4 个月时无复合事件，接受促红细胞生成素 -α治疗，并且至少有 1 次基线后 Hb 测量值。直至首次事件或删失时接受的每周平均促红细胞生成素 -α剂量是主要暴露变量，而第 4 个月时达到的 Hb 是代表受试者对治疗的基础反应的混杂因素。主要结局是死亡、心力衰竭住院、中风或心肌梗死的复合事件。采用 Cox 比例风险回归模型进行时间事件分析。
在 1244 名有完整数据的受试者中，在首次事件或删失时，促红细胞生成素 -α的每周平均剂量范围为 133 至 19106 单位/周，范围为 143.3 倍。Cox 比例风险分析发现，Hb 处于中三分位（>11.5 至 <12.7 g/dl）和促红细胞生成素 -α剂量暴露水平最低三分位（<5164 单位/周）的患者风险最低。无论达到的 Hb 如何，最高三分位（>10095 单位/周）的促红细胞生成素 -α剂量暴露水平的相对风险显著增加（风险比范围为 2.536 至 3.572，p<0.05，与 Hb 中三分位和较低剂量三分位组相比）。在调整达到的 Hb、白蛋白、胆固醇、年龄、既往心力衰竭、既往中风、既往深部静脉血栓形成、心房颤动或恶性肿瘤的多变量模型中，每周平均剂量与主要终点的相对风险显著相关（p=0.005），每增加 1000 单位促红细胞生成素 -α，风险增加 1.067 倍。
在 CHOIR 试验中，每周促红细胞生成素 -α剂量>10095 单位/周与心血管事件风险增加相关，无论治疗前 4 个月内达到的 Hb 如何。这些数据表明，每周促红细胞生成素 -α剂量而不是达到的 Hb 是主要决定因素，这表明该红细胞生成刺激剂具有心血管毒性。
